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T Holton

Publications and source records attributed to T Holton.

9 recordsLinked to original sources
PubMed2000

Determining protein structure from electron-density maps using pattern matching.

TEXTAL is an automated system for building protein structures from electron-density maps. It uses pattern recognition to select regions in a database of previously determined structures that are similar to regions in a map of unknown structure. Rotation-invariant numerical values, called features, of the electron density are extracted from spherical regions in an unknown map and compared with features extracted around regions in maps generated from a database of known structures. Those regions in the database that match best provide the local coordinates of atoms and these are accumulated to form a model of the unknown structure. Similarity between the regions in the database and an uninterpreted region is determined firstly by evaluating the numerical difference in feature values and secondly by calculating the electron-density correlation coefficient for those regions with similar feature values. TEXTAL has been successful at building protein structures for a wide range of test electron-density maps and can automatically model entire protein structures in a few hours on a workstation. Models built by TEXTAL from test electron-density maps of known protein structures were accurate to within 0.6-0.7 A root-mean-square deviation, assuming prior knowledge of C(alpha) positions. The system represents a new approach to protein structure determination and has the potential to greatly reduce the time required to interpret electron-density maps in order to build accurate protein models.

Algorithms↗
PubMed1999

TEXTAL: a pattern recognition system for interpreting electron density maps.

X-ray crystallography is the most widely used method for determining the three-dimensional structures of proteins and other macromolecules. One of the most difficult steps in crystallography is interpreting the electron density map to build the final model. This is often done manually by crystallographers and is very time-consuming and error-prone. In this paper, we introduce a new automated system called TEXTAL for interpreting electron density maps using pattern recognition. Given a map to be modeled, TEXTAL divides the map into small regions and then finds regions with a similar pattern of density in a database of maps for proteins whose structures have already been solved. When a match is found, the coordinates of atoms in the region are inferred by analogy. The key to making the database lookup efficient is to extract numeric features that represent the patterns in each region and to compare feature values using a weighted Euclidean distance metric. It is crucial that the features be rotation-invariant, since regions with similar patterns of density can be oriented in any arbitrary way. This pattern-recognition approach can take advantage of data accumulated in large crystallographic databases to effectively learn the association between electron density and molecular structure by example.

Algorithms↗
PubMed1995

Building an empowered work team.

A work team taps into each member's unique talents, which allows valuable skills to be shared across medical units. As a result, continuous quality improvement efforts were more objective and systematic; leadership skills were gained, both individually and jointly. The obstacles encountered, stakeholders' responses and the team's productivity analysis are described.

Humans↗
PubMed1986

The transduction channel of hair cells from the bull-frog characterized by noise analysis.

Receptor currents in response to mechanical stimuli were recorded from hair cells in the excised epithelium of the bull-frog sacculus by the whole-cell, gigohm-seal voltage-clamp technique. The stimulus-dependent transduction current was separated from the cell's stimulus-independent K+ and Ca2+ currents; the K+ currents were blocked with an internal solution containing Cs+ while the Ca2+ current was reduced by holding the membrane potential below -70 mV. The temperature of the preparation was maintained at about 10 degrees C to slow the kinetics of the cells' transduction channels. Calibrated displacements of hair bundles of individual hair cells were made with a probe coupled by suction to the kinociliary bulb and moved with a piezoelectricbimorph stimulator. The root mean square noise of probe motion was less than 2 nm. The mean, I, and the variance, sigma 2, of the receptor current were measured from the response to saturating (+/- 0.5 micron) displacements of the hair bundle. I was corrected for current offsets and sigma 2 for the transduction-independent background variance. The relation between sigma 2 and I is consistent with the predictions of a two-conductance-state model of the transduction channel, a model having only one non-zero conductance state. The relation between sigma 2 and I was fitted by the equation sigma 2 = Ii-I2/N, where N is the number of transduction channels in the cell and i is the current through a single open channel. The conductance of the transduction channel is approximately ohmic with a reversal potential near 0 mV. The estimated conductance of a single transduction channel, gamma, is 12.7 +/- 2.7 pS (mean +/- S.D.; n = 18) at 10 degrees C. gamma is independent of the maximum transduction conductance of the cell, Gmax. The number of transduction channels, N, is proportional to Gmax. N ranges from 7 to 280 in cells with Gmax ranging from 0.08 to 2.48 nS. The largest values of N correspond to a few, perhaps four, active transduction channels per stereocilium. Control experiments show that transduction by the hair cell of two artifactual sources of hair-bundle stimulation, noisy or discontinuous motion of the probe, do not contribute substantially to the measured variance, sigma 2. Displacement-response curves are generally sigmoidal and symmetrical; they reasonably fit the predictions of a two-kinetic-state model, comprising one open state and one closed state. The estimated displacement-sensitive free energy, Z, is 5.7 +/- 1.1 kcal/mol micron (mean +/- S.D., n = 18).(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1983

A micromechanical contribution to cochlear tuning and tonotopic organization.

The response properties of hair cells and nerve fibers in the alligator lizard cochlea are frequency selective and tonotopically organized with longitudinal position in the organ. The lengths of the hair-cell hair bundles also vary monotonically with longitudinal position. In this study, quantitative measurements were made of the motion of individual hair bundles in an excised preparation of the cochlea stimulated at auditory frequencies. The angular displacement of hair bundles is frequency selective and tonotopically organized, demonstrating the existence of a micromechanical tuning mechanism.

Acoustic Stimulation↗
PubMed1983

Receptor potentials of lizard cochlear hair cells with free-standing stereocilia in response to tones.

Intracellular potentials were recorded with micropipettes from hair cells with free-standing stereocilia in the cochleae of anaesthetized alligator lizards. Wave forms of intracellular responses to click stimuli were classified into three types: hair cells, supporting cells, and untuned cells. We studied primarily the responses of hair cells to tonal stimuli. For most frequencies, f, and levels, P, of tone-burst stimuli, the response envelope of the receptor potential increases monotonically at the tone-burst onset, and decreases monotonically at tone-burst offset. Overshoot in the envelope of the response at the onset and offset of tone bursts is observed only for tone bursts of low f, high P, and short (approximately equal to 1 msec) rise/fall time. The steady-state response to tones consists of a positive (depolarizing) d.c. component, V0, plus a.c. components (e.g. a fundamental component, V1, second harmonic, V2, and third harmonic, V3). The magnitudes of a.c. and d.c. components are functions of f and P, and show three characteristics: frequency selectivity, non-linearity, and low-pass filtering. The receptor potential is frequency selective. The frequency selectivity of V0 and V1 components was measured by means of iso-voltage (iso-V0 and iso-V1) contours. Iso-V0 and iso-V1 contours are V-shaped: the maximum sensitivity occurs at a characteristic frequency (c.f.). The shapes of these contours near the c.f. depend on the values of V0 and V1 at which the contours were measured and are sharper for lower values of V0 and V1. The mean slopes of the low- and high-frequency sides of these contours are: -45.0 and +85.1 dB/decade for iso-V0 contours (n = 26), and -33.6 and +103.8 dB/decade for iso-V1 contours (n = 28). The receptor potential has non-linear properties. The magnitudes and phase angles of V0, V1, V2, and V3 receptor-potential components were measured as a function of P for different f. The slopes of level functions (the dependence of log V0 and log magnitude of V1 on log P) were measured at low levels for different f. For values of f differing from c.f. by more than a half-octave, the slope for V0 is between 1 and 2 with a mean of 1.3; the slope for V1 is about 1, i.e. magnitude of V1 increases approximately linearly with P. For frequencies near c.f., the slopes for V0 and V1 are approximately 0.8 and 0.5, respectively, indicating the presence of a compressive non-linearity.(ABSTRACT TRUNCATED AT 400 WORDS)

Acoustic Stimulation↗
PubMed1983

Frequency selectivity of hair cells and nerve fibres in the alligator lizard cochlea.

Receptor potentials of hair cells and spike discharges of cochlear nerve fibres were recorded with micropipettes from the free-standing region of the basilar papilla of anaesthetized alligator lizards in response to tones. In this region the hair-cell stereocilia are free-standing, i.e. they protrude directly into endolymph and are not in contact with a tectorial membrane. The frequency selectivity of hair-cell responses was measured by means of isovoltage contours of the d.c. (V0) and fundamental-a.c. (V1) component of the receptor potential, i.e. iso-V0 and iso-V1 contours. The frequency selectivity of the nerve-fibre discharge was measured by iso-rate (iso-V0) contours. Iso-V0, iso-V1 and iso-V0 contours are basically V-shaped with a characteristic frequency (c.f.) defined as the frequency at which minimum sound pressure (Pmin) is required to evoke the criterion value of the response. Receptor potential iso-V0 contours and neural iso-V0 contours have similar slopes: the mean slopes of the low-frequency sides (dB/decade) are -43.0 and -44.3; the slopes of the high-frequency sides are 85.0 and 80.2. The band widths of iso-V0 and iso-V0 contours away from c.f. are similar (mean values of Q30dB are 0.40 and 0.53, respectively). The band widths of iso-V0 contours near c.f. are narrower than those of iso-V0 contours (mean values of Q10dB are 2.34 and 1.20, respectively). However, the shapes of the contours near c.f. depend on the iso-response criteria, and we have not determined whether or not iso-V0 and iso-V0 contours are similar near c.f. The shapes of iso-V1 contours differ from those of iso-V0 and iso-V0 contours. Nerve fibre c.f.s are tonotopically organized in the nerve, with lowest c.f.s recorded from fibres innervating the border of free-standing and tectorial regions, a region in which hair-cell stereocilia are longest, and the highest c.f.s recorded from fibres innervating the end of the free-standing region in which hair-cell stereocilia are shortest. The c.f. of nerve-fibre response (and by implication hair-cell response) is, therefore, correlated with the height of the stereociliary tuft. The shapes of iso-V0 contours vary systematically with c.f. and, therefore, tonotopically with nerve position.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1980

Relations between frequency selectivity and two-tone rate suppression in lizard cochlear-nerve fibers.

Cochlear-nerve fibers innervating the apicial region of the alligator lizard basilar papilla show sharp frequency selectivity in response to single tones (measured with the frequency threshold contour, or FTC), and the phenomenon of two-tone rate suppression (TTRS) in response to two simultaneously presented tones (measured with the iso-TTRS contour, or ITC). The gross shapes of the FTCs, as characterized by the slopes of the sides and Q10dB, vary systematically with the fiber's characteristic frequency (CF). 'Fine-structural' features are also found: below CF, notches (frequency regions of relatively high threshold) occur in the FTC at frequencies related to CF. Above CF, a break frequency, which varies with CF, divides the FTC into segments of different slope. Features of the ITC also vary with CF. The detailed shapes of the FTCs and ITCs are related: lobes of the ITC interdigitate with notches in the FTC; the side of the FTC with steepest slope is closely associated with the side of the ITC with steepest slope. The close relation that is observed between sharp frequency selectivity and TTRS suggests that both phenomena arise from a common cochlear mechanism.

Acoustic Stimulation↗