On the origin and frequency of the 35delG allele in GJB2-linked deafness in Europe.
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Connexin 26↗
Biomedical subjects
A Polyakov
Publications and source records attributed to A Polyakov.
Sound lateralization and interaural discrimination. Effects of brainstem infarcts and multiple sclerosis lesions.
Subjects with brainstem lesions due to either an infarct or multiple sclerosis (MS) underwent two types of binaural testing (lateralization testing and interaural discrimination) for three types of sounds (clicks and high and low frequency narrow-band noise) with two kinds of interaural differences (level and time). Two major types of abnormalities were revealed in the lateralization performances: perception of all stimuli, regardless of interaural differences (time and/or level) in the center of the head (center-oriented), or lateralization of all stimuli to one side or the other of the head (side-oriented). Similar patterns of abnormal lateralization (center-oriented and side-oriented) occurred for MS and stroke patients. A subject's pattern of abnormal lateralization testing was the same regardless of the type of stimulus or type of interaural disparity. Lateralization testing was a more sensitive test than interaural discrimination testing for both types of subjects. Magnetic resonance image (MRI) scanning in three orthogonal planes of the brainstem was used to detect lesions. A semi-automated algorithm superimposed the auditory pathway onto each MRI section. Whenever a lesion overlapped the auditory pathway, some binaural performance was abnormal and vice versa. Given a lateralization test abnormality, whether the pattern was center-oriented or side-oriented was mainly determined by lesion site. Center-oriented performance was principally associated with caudal pontine lesions and side-oriented performance with lesions rostral to the superior olivary complex. For lesions restricted to the lateral lemniscus and/or inferior colliculus, whether unilateral or bilateral, just noticeable differences (JNDs) were nearly always abnormal, but for caudal pontine lesions JNDs could be normal or abnormal. MS subjects were more sensitive to interaural time delays than interaural level differences particularly for caudal pontine lesions, while stroke patients showed no differential sensitivity to the two kinds of interaural differences. These results suggest that neural processing of binaural stimuli is multilevel and begins with independent interaural time and level analyzers in the caudal pons.
Adult↗
Clinicians and computers: friends or foes?
BACKGROUND: Computer-aided learning is accepted by students as a learning resource, but the views of the teaching community are largely unknown. PURPOSE: To document clinicians' experience with computers and to record their attitudes toward computer usage in clinical practice and student education. METHODS: Questionnaire mailed out to all clinicians, including interns and residents, fellows, and attending physicians in 3 major teaching hospitals in South Australia, with a total of 646 clinical staff. RESULTS: Replies were received from 246 staff. Eighty percent of clinicians had at least 2 years of experience with computers and used computers for at least 2 hr each week. Despite this, there was an obvious lack of conviction among clinicians that computer-aided learning was of use in student education and assessment. This may reflect their lack of experience with this medium as an educational tool. CONCLUSIONS: If computer-aided learning is to make any significant impact on medical student education, it must be carefully and objectively evaluated, and its benefit must be clearly demonstrated to clinical teachers.
Adult↗
Disruption of substrate binding site in E. coli RNA polymerase by lethal alanine substitutions in carboxy terminal domain of the beta subunit.
Alanine substitution of four amino acids in two evolutionarily conserved motifs, PSRM and RFGEMIE, near the carboxy terminus of the beta subunit of E. coli RNA polymerase results in a dramatic loss of the enzyme's affinity to substrates with no apparent effect on the maximal rate of the enzymatic reaction or on binding to promoters. The magnitude and selectivity of the effect suggest that the mutations disrupt the substrate binding site of the active center.
Binding Sites↗
Evoked potentials in sound localization: timing of activity along the auditory pathway.
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Acoustic Stimulation↗
Insights into Escherichia coli RNA polymerase structure from a combination of x-ray and electron crystallography.
Our goal is to understand the mechanism of transcription and its regulation. Determining structures of RNA polymerase and transcription complexes is an essential step. Because of their large size and complexity, determination of these structures will require a combination of electron microscopy, biophysical methods, and biochemical methods to identify functionally and structurally relevant subassemblies and domains and x-ray crystallography to determine high-resolution structures of RNA polymerase components and accessory factors. We recently solved the 2.5-A crystal structure of the Escherichia coli RNA polymerase alpha subunit N-terminal domain, which is the first high-resolution structure of a core component required for RNA polymerase assembly and basal transcription. This structure, combined with a new 19-A resolution structure determined by cryo-electron microscopy of helical crystals of E. coli core RNAP embedded in vitreous ice, leads to a model for the organization of the RNAP subunits.
Crystallography, X-Ray↗
Visualization of the binding site for the transcript cleavage factor GreB on Escherichia coli RNA polymerase.
The structure of Escherichia coli core RNA polymerase (RNAP) complexed with the transcript cleavage factor GreB was determined from electron micrographs of negatively stained, flattened helical crystals. A binding assay was developed to establish that GreB was incorporated into the RNA polymerase crystals with high occupancy through interactions between the globular C-terminal domain and the RNA polymerase. Comparison of the core RNAP:GreB structure with the previously determined structure of core RNAP located the GreB binding site on one face of the RNA polymerase, next to but not in the 25 A-diameter channel of RNA polymerase.
Binding Sites↗
Effects of localized pontine lesions on auditory brain-stem evoked potentials and binaural processing in humans.
OBJECTIVES AND METHODS: Four sets of measurements were obtained from 11 patients (44-80 years old) with small, localized pontine lesions due to vascular disease: (1) Monaural auditory brain-stem evoked potentials (ABEPs; peaks I to VI); (2) Binaural ABEPs processed for their binaural interaction components (BICs) in the latency range of peaks IV to VI; (3) magnetic resonance imaging (MRI) of the brain-stem; and (4) psychoacoustics of interaural time disparity measures of binaural localization. ABEPs and BICs were analyzed for peak latencies and interpeak latency differences. Three-channel Lissajous' trajectories (3-CLTs) were derived for ABEPs and BICs and the latencies and orientations of the equivalent dipoles of ABEP and BICs were inferred from them. RESULTS: Intercomponent latency measures of monaurally evoked ABEPs were abnormal in only 3 of the 11 patients. Consistent correlations between sites of lesion and neurophysiological abnormality were obtained in 9 of the 11 patients using 3-CLT measures of BICs. Six of the 11 patients had absence of one or more BIC components. Seven of the 11 had BICs orientation abnormality and 3 had latency abnormalities. Trapezoid body (TB) lesions (6 patients) were associated with an absent (two patients with ventral-caudal lesions) or abnormal (one patient with ventral-rostral lesions) dipole orientation of the first component (at the time of ABEPs IV), and sparing of this component with midline ventral TB lesions (two patients). A deviant orientation of the second BICs component (at the time of ABEPs V) was observed with ventral TB lesions. Psychoacoustic lateralization in these patients was biased toward the center. Rostral lateral lemniscus (LL) lesions (3 patients) were associated with absent (one patient) or abnormal (two patients) orientation of the third BICs component (at the time of ABEPs VI); and a side-biased lateralization with behavioral testing. CONCLUSIONS: These results indicate that: (1) the BICs component occurring at the time of ABEPs peak IV is dependent on ventral-caudal TB integrity; (2) the ventral TB contributes to the BICs component at the time of ABEPs peak V; and (3) the rostral LL is a contributing generator of the BICs component occurring at the time of ABEP peak VI.
Adolescent↗
Evidence for efferent effects on early components of the human auditory brain-stem evoked potentials.
OBJECTIVES AND METHODS: Auditory brain-stem evoked potentials (ABEPs) were recorded from 10 normal hearing subjects in response to rarefaction clicks, presented at a rate of 11/s. Stimuli were binaurally symmetrical and isochronic at 75 dB peSPL or with interaural time disparities (ITDs) of +/-0.4 ms, or intensity disparities (IIDs) of +/-10 dB. Potentials were recorded from vertex-neck, as well as from 3 orthonormally positioned differential derivations. The amplified potentials were averaged over 8000 repetitions using a dwell time of 20 micros/address/channel. The effects of contralateral stimulation on neural responses of the peripheral auditory system were obtained by subtracting the binaural response from the algebraic sum of responses to left and right monaural stimuli. From the 3 orthonormal derivations, 3-channel Lissajous' trajectories (3-CLTs) to the various stimulus conditions and difference waveforms were derived. RESULTS: The results corroborated earlier studies on binaural interaction components (BICs), which include 3 major components corresponding in latency to the vertex-mastoid peaks IV-VI of ABEP. In addition, the binaural difference waveforms included 3 earlier, low-amplitude components. Latency correspondence and comparison of difference waveform and ABEP 3-CLTs indicated that the first and third early difference waveform components corresponded to the negative peaks following I and III, respectively, of the vertex-neck ABEP to binaural clicks. CONCLUSIONS: These results indicate that early ABEP peaks, generated peripheral to binaural convergence, may be affected by contralateral stimulation. These contralateral effects were in a pattern compatible with suppression. most probably by efferents of the olivo-cochlear bundle.
Acoustic Stimulation↗
Contralaterally evoked transient otoacoustic emissions.
Contralaterally evoked transient otoacoustic emissions (CETOAEs) were recorded from 10 normal-hearing young adults (20 ears) in response to monaural, 11/s, 65 dB pe SPL clicks to the ear contralateral to the microphone probe. A burst of CETOAEs was observed 12-22 ms (average peak at 18.5 ms) after the contralateral click, and its mean level was -7.3 dB pe SPL, 4 dB above the averaged noise level. The frequency content of CETOAEs included a prominence around 1 kHz. In 40% of the ears examined CETOAEs were 3 dB or more above noise level in both replications of records from the same ear. To explain these results CETOAEs are suggested to reflect mechanical events induced by the crossed efferent system in the cochlea that was contralateral to the stimulated ear. The latency of the contralateral responses suggests that they may be related to the contralateral suppression effect observed with binaural stimulation. The latency of the response, coupled with the anatomical origin of the crossed efferent system at the superior olivary complex, suggest its involvement in the contralateral CETOAEs reported here.
Acoustic Stimulation↗
Binaural masking level difference in human binaural interaction components.
OBJECTIVE: The purpose of this study was to compare the effects of monaural and binaural broadband masking noise on binaural interaction components (BICs) of the human auditory brain stem evoked potentials (ABEPs). DESIGN: The BICs of the human ABEPs were studied by subtracting the potentials to binaural clicks from the algebraic sum of monaurally evoked potentials to clicks alone or to clicks with ipsilateral monaural or binaural broadband masking noise. Alternating polarity, 11/sec clicks were presented at 65 dB nHL, and noise was presented at 45 dB nHL. Analysis included peak-to-prestimulus baseline amplitudes and latencies of BICs' peaks and troughs from the vertex-mastoid (A) and vertex-neck (Z) channels. In addition, 3-channel Lissajous' trajectory (3-CLT) analysis, estimating the single, centrally located dipole equivalent of surface activity, was performed on data recorded from three orthogonally positioned electrode pairs. 3-CLT measures included apex latency, amplitude, and orientation, as well as planar segment duration, size, shape, and orientation. RESULTS: All BICs 3-CLTs included five main components (labeled BdI, BdII, BdIII, BeI, and BeII). In general, apex latencies were longer with masking noise. However, BdII and BeI apex latencies were shorter with binaural than with ipsilateral monaural masking noise. Apex amplitude and planar segment size of component BeI, as well as P1 peak amplitude in BICs of the Z-channel records, were larger with binaural than with monaural noise. No significant difference between the monaural and binaural noise conditions was found in durations, shapes, and orientations of planar segments of BICs 3-CLT, nor in peak latency of BICs in the A- and Z-channel records. CONCLUSIONS: We suggest that these effects on the latency and amplitude of BICs reflect binaural processing in the human brain stem. In particular, the larger amplitudes and shorter latencies of P1 and BeI with binaural than with ipsilateral monaural masking may be associated with the psychophysical effect of binaural masking level difference.
Adolescent↗
Structural studies of Escherichia coli RNA polymerase.
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Computer Graphics↗
Evidence for separate processing in the human brainstem of interaural intensity and temporal disparities for sound lateralization.
Sound lateralization can be induced by interaural intensity disparities (IIDs) or by interaural temporal disparities (ITDs). The purpose of this study was to indicate whether IIDs and ITDs are processed by the same central units that detect interaural disparity in timing of afferent activity. If sound lateralization to intensity and time cues was determined by the same afferent latency disparity detectors in the brainstem, lateralization would be the same, regardless of whether latency disparity was induced by IIDs or ITDs. Moreover, the disparity detectors, and thus their dipole equivalents, would be the same for equal lateralizations, whether induced by IIDs or ITDs. Auditory brainstem evoked potentials (ABEPs) were recorded in response to monaural and binaural clicks, with a variety of IIDs and ITDs. Peak II (proximal auditory nerve activity), peak III (input to the superior olivary complex), and binaural interaction components (BICs) BeI and BeII (binaurally activated upper pons) were identified and their latencies measured. The psychophysical lateralization of the clicks (in cm from vertex) was also measured in response to the same binaural stimuli. The correlations between interaural afferent latency disparities (difference in corresponding peak latencies originating in each ear) and psychophysical click lateralization were calculated. Similarly, the correlations with click lateralization of the BICs equivalent dipole latency as well as orientation change (relative to symmetrical clicks) were determined. A strong correlation with lateralization was found for peaks II and III latency disparities, with steeper slopes for IIDs than for ITDs. Moreover, binaural activity across the same lateralizations differed between IIDs and ITDs. These results, therefore, indicate that interaural time and intensity cues are processed by separate systems in the brainstem, both at the afferent convergence level and after interaural disparities are determined.
Acoustic Stimulation↗
Effects of interaural intensity and time disparity on transient evoked otoacoustic emissions.
Monaural and binaural 11/s, 65 dB pe SPL clicks with interaural time and intensity disparities known to affect central auditory processing were used to study contralateral suppression of transient evoked otoacoustic emissions (TEOAEs) in 10 subjects (20 ears). Psychophysical assessment of sound lateralization induced by the same stimuli was also conducted. TEOAEs were recorded to monaural (ipsilateral to the OAE recording probe) and to binaural clicks when clicks to the contralateral ear were synchronous and symmetrical in intensity, or, in the binaural intensity disparity conditions, synchronous but 10 dB higher or 10 dB lower in the ear contralateral to the OAE recording probe. When interaural time disparities were studied, the clicks to the contralateral ear were of the same intensity throughout, but 400 micros earlier or 400 micros later than to the ear with the probe. The TEOAE components at 13-15.8 ms showed suppression, relative to monaural responses, under all binaural conditions. This contralateral suppression did not correlate with the psychophysical findings. Suppression effects were more pronounced with binaural disparity than with binaurally symmetrical clicks. Thus, although contralateral click intensity was the same with time disparities, suppression was paradoxically enhanced compared to the binaurally symmetrical stimulation. To explain these results we propose that two factors are involved in TEOAE suppression with binaural clicks: (1) contralateral intensity and (2) interaural disparity (time or intensity). The latency of the suppressions observed, the effect of interaural disparity on these suppressions, coupled with the anatomical origin of the crossed efferent fibers and the disparity sensitivity of the superior olivary complex (SOC), all suggest SOC involvement in these TEOAE suppressions.
Acoustic Stimulation↗
Evidence for spatio-topic organization of binaural processing in the human brainstem.
Three-channel Lissajous' trajectories (3-CLT) of the binaural interaction (BI) in auditory brainstem evoked potentials (ABEP) were derived from 13 normally and symmetrically hearing adults by subtracting the response to binaural clicks from the algebraic sum of monaural responses. ABEPs were recorded from four channels, three of them orthonormal to each other, in response to alternating polarity clicks, presented at a rate of 11/s with interaural time differences (ITD) of 0.2, 0.4 and 1.0 ms and an intensity of 65 dB nHL, or isochronic to both ears with interaural intensity differences (IIDs) of 5, 10 and 15 dB (65 dB nHL +/- 2.5, 5.0 and 7.5 dB, respectively). All 3-CLTs included 6 planar segments (labeled BdI, BdII, BdIII, BeI, BeII and Bf). Amplitudes of 3-CLT BI components were not significantly affected by increasing ITDs and IIDs, but latencies of all components increased significantly. The most remarkable finding was a significant change in apex orientations of BeI and BeII of the BI 3-CLT across stimulus conditions. The changes in BeI and BeII apex orientations, across stimulus conditions, may reflect differences in the anatomical representation of activity evoked by differently lateralized sounds. We suggest that this may indicate spatio-topic organization in the human brainstem.
Acoustic Stimulation↗
Electrophysiological evidence of a sound localizing binaural subsystem in the human auditory brainstem.
The binaural interaction components of auditory brainstem evoked potentials reflect electrical changes which are specific to binaural stimuli. Analysis of these components indicated that different click lateralizations result in spatially distinct distributions of activity in the pons, but not at more peripheral levels. The effects of ipsilateral and binaural masking on evoked activity indicated distinct binaurally- and monaurally-activated neural subsets in the human brainstem. These results on the effects of noise and the distinct distributions of pontine activity to different lateralizations provide the first electrophysiological evidence that the auditory system in the humans pons includes a subset which is specific to binaurally presented sounds and which is anatomically distributed according to the lateralization of the sound. These results suggest auditory spatial mapping, similar to other sensory systems. In contrast to other systems, in which mapping is according to receptor distribution in the periphery, auditory spatial mapping is achieved computationally at central levels of the pathway.
Acoustic Stimulation↗
Three-dimensional structure of E. coli core RNA polymerase: promoter binding and elongation conformations of the enzyme.
The structure of E. coli core RNA polymerase (RNAP) has been determined to approximately 23 A resolution by three-dimensional reconstruction from electron micrographs of flattened helical crystals. The structure reveals extensive conformational changes when compared with the previously determined E. coli RNAP holoenzyme structure, but resembles the yeast RNAPII structure. While each of these structures contains a thumb-like projection surrounding a channel 25 A in diameter, the E. coli RNAP holoenzyme thumb defines a deep but open groove on the molecule, whereas the thumb of E. coli core and yeast RNAPII form part of a ring that surrounds the channel. This may define promoter-binding and elongation conformations of RNAP, as E. coli holoenzyme recognizes promoter sites on double-stranded DNA, while both E. coli core and yeast RNAPII are elongating forms of the polymerase and are incapable of promoter recognition.
Crystallography↗
Crystal structure of the GreA transcript cleavage factor from Escherichia coli.
Transcription elongation factors stimulate the activity of DNA-dependent RNA polymerases by increasing the overall elongation rate and the completion of RNA chains. One group of such factors, which includes Escherichia coli GreA, GreB and eukaryotic SII (TFIIS), acts by inducing hydrolytic cleavage of the transcript within the RNA polymerase, followed by release of the 3'-terminal fragment. Here we report the crystal structure of GreA at 2.2 A resolution. The structure contains an amino-terminal domain consisting of an antiparallel alpha-helical coiled-coil dimer which extends into solution, reminiscent of the coiled coil in seryl-tRNA synthetases. A site near the tip of the coiled-coil 'finger' plays a direct role in the transcript cleavage reaction by contacting the 3'-end of the transcript. The structure exhibits an unusual asymmetric charge distribution which indicates the manner in which GreA interacts with the RNA polymerase elongation complex.
Amino Acid Sequence↗