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Biomedical subjects

A T Smith

Publications and source records attributed to A T Smith.

At least 19 recordsLinked to original sources
PubMed2006

Involvement of the jaw bones in systemic mastocytosis.

Systemic mastocytosis is characterised by proliferation of mast cells and infiltration of organs. Severe bony pain may result from release of chemical mediators from mast cells and affected patients are at an increased risk of anaphylaxis. Traditional analgesics such as non-steroidal anti-inflammatory agents and opioids are contraindicated. Diagnosis is based on presentation, biopsy of bone marrow, and magnetic resonance imaging of the affected area. In the head and neck, the disease may present as facial pain, localised osteomyelitis, oral sinus formation, and oral ulceration. Treatment is with histamine antagonists and bisphosphonates to control symptoms. An adrenaline pen is provided for use in case of anaphylaxis.

Adult↗
PubMed2006

Sensitivity to optic flow in human cortical areas MT and MST.

The macaque V5/MT complex comprises several sub-regions but little is known of their human homologues. We examined human V5/MT with fMRI in terms of specificity to optic flow stimuli, a key characteristic of macaque MST. Stimuli were large fields of moving dots, forming coherent global flow patterns. Random motion was used as a control. Retinotopic mapping was also conducted. The previously suggested existence of at least two distinct sub-regions, MT and MST, within the V5/MT complex was confirmed. Human MT is activated about equally by all moving dot patterns, including random motion, suggesting that it has little sensitivity to global flow structure. As previously described, this region shows strong signs of retinotopic organization and is only weakly activated by stimuli confined to the ipsilateral hemifield. In human MST, located immediately anterior to MT and strongly driven by ipsilateral stimuli, activation varies markedly with optic flow structure. The strongest activation is produced by complex flow that contains multiple flow components (expansion, contraction and rotation). Single components produce rather less response, while rigid translation and random motion produce less still. The results suggest that human MST is strongly specialized for encoding global flow properties, while human MT is less so.

Adult↗
PubMed2003

Behavioural, attitudinal and dietary responses to the consumption of wholegrain foods.

Whole grains are important dietary constituents as they provide a plethora of nutrients and protective chemicals that may have synergistic actions in promoting health. Regular consumption of wholegrain foods has been associated with a reduced risk of several chronic diseases such as CHD and certain cancers, although their exact role in disease prevention is not yet fully elucidated. Studies reporting levels of whole grain consumption reveal that those subjects who include higher levels of whole grain foods in their diets also have many other favourable dietary and lifestyle practices. While the actions of these practices and whole grains may not be mutually exclusive, these variables do not appear to explain the reduction in risk of disease observed for high-whole grain consumers. Actual whole grain consumption levels are extremely low and many practical barriers exist to consumer uptake of these foods. Effective communication of the whole grain health message is an important strategy to increase awareness of the importance of whole grains in the diet. Increasing the variety and availability of acceptable wholegrain foods is also important. Whole grain consumption at breakfast can have an important impact on total daily nutrient intakes. This simple dietary modification is potentially relatively easy to achieve and could greatly contribute to increased whole grain intake for many individuals.

Dietary Fiber↗
PubMed2001

Motion detection in human vision: a unifying approach based on energy and features.

Most studies of human motion perception have been based on the implicit assumption that the brain has only one motion-detection system, or at least that only one is operational in any given instance. We show, in the context of direction perception in spatially filtered two-frame random-dot kinematograms, that two quite different mechanisms operate simultaneously in the detection of such patterns. One mechanism causes reversal of the perceived direction (reversed-phi motion) when the image contrast is reversed between frames, and is highly dependent on the spatial-frequency content of the image. These characteristics are both signatures of detection based on motion energy. The other mechanism does not produce reversed-phi motion and is unaffected by spatial filtering. This appears to involve the tracking of unsigned complex spatial features. The perceived direction of a filtered dot pattern typically reflects a mixture of the two types of behaviour in any given instance. Although both types of mechanism have previously been invoked to explain the perception of motion of different types of image, the simultaneous involvement of two mechanisms in the detection of the same simple rigid motion of a pattern suggests that motion perception in general results from a combination of mechanisms working simultaneously on different principles in the same circumstances.

Energy Metabolism↗
PubMed2001

Reactions of dimethylsulfoxide reductase in the presence of dimethyl sulfide and the structure of the dimethyl sulfide-modified enzyme.

The bis-molybdopterin enzyme dimethylsulfoxide reductase (DMSOR) from Rhodobacter capsulatus catalyzes the conversion of dimethyl sulfoxide (DMSO) to dimethyl sulfide (DMS), reversibly, in the presence of suitable e(-)-donors or e(-)-acceptors. The catalytically significant intermediate formed by reaction of DMSOR with DMS ('the DMS species') and a damaged enzyme form derived by reaction of the latter with O(2) (DMS-modified enzyme, DMSOR(mod)D) have been investigated. Evidence is presented that Mo in the DMS species is not, as widely assumed, Mo(IV). Formation of the DMS species is reversed on removing DMS or by addition of an excess of DMSO. Equilibrium constants for the competing reactions of DMS and DMSO with the oxidized enzyme (K(d) = 0.07 +/- 0.01 and 21 +/- 5 mM, respectively) that control these processes indicate formation of the DMS species occurs at a redox potential that is 80 mV higher than that required, according to the literature, for reduction of Mo(VI) to Mo(IV) in the free enzyme. Specificity studies show that with dimethyl selenide, DMSOR yields a species analogous to the DMS species but with the 550 nm peak blue-shifted by 27 nm. It is concluded from published redox potential data that this band is due to metal-to-ligand charge transfer from Mo(V) to the chalcogenide. Since the DMS species gives no EPR signal in the normal or parallel mode, a free radical is presumed to be in close proximity to the metal, most likely on the S. The species is thus formulated as Mo(V)-O-S(*)Me(2). Existing X-ray crystallographic and Raman data are consistent with this structure. Furthermore, 1e(-) oxidation of the DMS species with phenazine ethosulfate yields a Mo(V) form without an -OH ligand, since its EPR signal shows no proton splittings. This form presumably arises via dissociation of DMSO. The structure of DMSOR(mod)D has been determined by X-ray crystallography. All four thiolate ligands and Ogamma of serine-147 remain coordinated to Mo, but there are no terminal oxygen ligands and Mo is Mo(VI). Thus, it is a dead-end species, neither oxo group acceptance nor e(-)-donation being possible. O(2)-dependent formation of DMSOR(mod)D represents noncatalytic breakdown of the DMS species by a pathway alternative to that in turnover, with oxidation to Mo(VI) presumably preceding product release. Steps in the forward and backward catalytic cycles are discussed in relation to earlier stopped-flow data. The finding that in the back-assay the Mo(IV) state may at least in part be by-passed via two successive 1e(-) reactions of the DMS species with the e(-)-acceptor, may have implications in relation to the existence of separate molybdopterin enzymes catalyzing DMSO reduction and DMS oxidation, respectively.

Electron Spin Resonance Spectroscopy↗
PubMed2001

Crystal structures of pristine and oxidatively processed lignin peroxidase expressed in Escherichia coli and of the W171F variant that eliminates the redox active tryptophan 171. Implications for the reaction mechanism.

The heme enzyme lignin peroxidase (LiP) from the white rot fungus Phanerochaete chrysosporium contains a solvent exposed redox active tryptophan residue (Trp171) that carries a unique hydroxy group stereo-specifically attached to its C(beta) atom. A Trp171Phe mutant has no activity at all towards the substrate veratryl alcohol. The mechanism of veratryl alcohol oxidation involving beta-hydroxy-Trp171 is largely unknown. Here, we present the first crystal structures of LiP isozyme H8 at high resolution in its pristine non-hydroxylated form, of the C(beta)-hydroxylated form, and of the Trp171Phe mutant using recombinantly expressed and refolded protein produced from Escherichia coli. As a consequence, all structures are unglycosylated. Structural changes in response to the mutation are marginal and allow us to attribute the complete lack of activity exclusively to the absence of the redox active indole side-chain. The origin of the stereospecificity of the Trp171 hydroxylation can be explained on structural grounds. A reaction mechanism involving Trp171 is proposed and the possible function of the modification is discussed. Another important result regarding the ongoing debate on the co-ordination state of the heme iron in the resting state is that the iron is six co-ordinate in all cases the data being collected at room temperature. The mean distance from the iron to the distal water ligand is 2.18(+/-0.08) A. The radical scavenger orcinol was found to decrease radiation damage to the crystals, during data collection at room temperature.

Amino Acid Substitution↗
PubMed2001

Haem-linked interactions in horseradish peroxidase revealed by spectroscopic analysis of the Phe-221-->Met mutant.

A gene encoding a Phe-221-to-Met substitution in the haem enzyme horseradish peroxidase has been constructed and expressed in Escherichia coli. In the wild-type enzyme the side chain of Phe-221 is tightly stacked against the imidazole ring of His-170, which provides the only axial ligand to the haem iron atom. The Phe-221-->Met enzyme is active, and forms characteristic complexes with typical peroxidase ligands (CO, cyanide, fluoride), and with benzhydroxamic acid. Significant differences between the mutant and wild-type enzymes can be detected spectroscopically. These include a change in the Fe(III) resting state of the enzyme to an unusual quantum mechanically mixed-spin haem species, a marked decrease in the pK(a) of the alkaline transition and a reduction in enzyme stability at alkaline pH for both Fe(III) and Fe(II) forms. The perturbation of the haem pocket in the mutant can be attributed to several factors, including the increased steric freedom and solvent accessibility of the His-170 ligand, as indicated by (1)H-NMR data, and the loss of the pi-pi interaction between His-170 and Phe-221.

Arabidopsis↗
PubMed2001

Mutation of residues critical for benzohydroxamic acid binding to horseradish peroxidase isoenzyme C.

Aromatic substrate binding to peroxidases is mediated through hydrophobic and hydrogen bonding interactions between residues on the distal side of the heme and the substrate molecule. The effects of perturbing these interactions are investigated by an electronic absorption and resonance Raman study of benzohydroxamic acid (BHA) binding to a series of mutants of horseradish peroxidase isoenzyme C (HRPC). In particular, the Phe179 --> Ala, His42 --> Glu variants and the double mutant His42 --> Glu:Arg38 --> Leu are studied in their ferric state at pH 7 with and without BHA. A comparison of the data with those previously reported for wild-type HRPC and other distal site mutants reaffirms that in the resting state mutation of His42 leads to an increase of 6-coordinate aquo heme forms at the expense of the 5-coordinate heme state, which is the dominant species in wild-type HRPC. The His42Glu:Arg38Leu double mutant displays an enhanced proportion of the pentacoordinate heme state, similar to the single Arg38Leu mutant. The heme spin states are insensitive to mutation of the Phe179 residue. The BHA complexes of all mutants are found to have a greater amount of unbound form compared to the wild-type HRPC complex. It is apparent from the spectral changes induced on complexation with BHA that, although Phe179 provides an important hydrophobic interaction with BHA, the hydrogen bonds formed between His42 and, in particular, Arg38 and BHA assume a more critical role in the binding of BHA to the resting state.

Amino Acid Substitution↗
PubMed2001

Lignin peroxidase structure and function.

Lignin peroxidase (LiP) plays a central role in the biodegradation of the plant cell wall constituent lignin. LiP is able to oxidize aromatic compounds with redox potentials higher than 1.4 V (NHE) by single electron abstraction, but the exact redox mechanism is still poorly understood. The finding in our laboratory that the Cbeta-atom of Trp171 carries a unique modification led us to initiate experiments to investigate the role of this residue. These experiments, employing crystallography, site-directed mutagenesis, protein chemistry, spin-trapping and spectroscopy, yielded the following results: (i) Trp171 is stereospecifically hydroxylated at its Cbeta-atom as the result of an auto-catalytic process, which occurs under turnover conditions in the presence of hydrogen peroxide. (ii) Evidence for the formation of a Trp171 radical intermediate has been obtained using spin-trapping, in combination with peptide mapping and protein crystallography. (iii) Trp171 is very likely to be involved in electron transfer from natural substrates to the haem cofactor via LRET. (iv) Mutagenetic substitution of Trp171 abolishes completely the oxidation activity for veratryl alcohol, but not for artificial substrates. (v) Structural changes in response to the mutation are marginal. Therefore the lack of activity is due to the absence of the redox active indole side chain.

Fungi↗
PubMed2001

Estimating receptive field size from fMRI data in human striate and extrastriate visual cortex.

Functional magnetic resonance imaging (fMRI) was used to estimate the average receptive field sizes of neurons in each of several striate and extrastriate visual areas of the human cerebral cortex. The boundaries of the visual areas were determined by retinotopic mapping procedures and were visualized on flattened representations of the occipital cortex. Estimates of receptive field size were derived from the temporal duration of the functional activation at each cortical location as a visual stimulus passed through the receptive fields represented at that location. Receptive fields are smallest in the primary visual cortex (V1). They are larger in V2, larger again in V3/VP and largest of all in areas V3A and V4. In all these areas, receptive fields increase in size with increasing stimulus eccentricity. The results are qualitatively in line with those obtained by others in macaque monkeys using neurophysiological methods.

Adult↗
PubMed2001

First-order and second-order signals combine to improve perceptual accuracy.

The question of whether first-order (luminance-defined) and second-order (contrast-defined) stimuli can be combined in order to improve perceptual accuracy was examined in the context of two suprathreshold discrimination experiments, one spatial and the other temporal. The stimuli were either gratings of one type of image alone or else the sum of two gratings of the same orientation, spatial frequency, temporal frequency, and phase, but of different types. For both spatial frequency discrimination (static gratings) and speed discrimination (1-c/deg drifting gratings), performance was markedly better for a combined grating stimulus than predicted on the basis of independent processing of the two types of stimulus. But this was true only for stimuli of low contrast. Facilitation of discrimination performance occurred only in the contrast range where discrimination performance is contrast dependent. At higher contrasts, where performance has reached an asymptote for each type of pattern alone, there was no facilitation. The results suggest that first- and second-order stimuli, although believed by most researchers to be detected separately, can subsequently be combined in order to improve perceptual accuracy in conditions of low visibility.

Contrast Sensitivity↗
PubMed2000

Reversible dissociation of thiolate ligands from molybdenum in an enzyme of the dimethyl sulfoxide reductase family.

Much is unknown concerning the role of thiolate ligands of molybdenum in molybdopterin enzymes. It has been suggested that thiolate dissociation from molybdenum is part of the catalytic mechanism of bis-molybdopterin enzymes of the dimethyl sulfoxide reductase (DMSOR) family. For DMSOR from Rhodobacter capsulatus, thiolate dissociation has therefore been investigated crystallographically, by UV/visible spectroscopy, and by enzyme assays. When crystallized from sodium citrate, all four thiolates of DMSOR are within bonding distance of Mo, but after extended exposure to Na(+)-Hepes, a pair of thiolates dissociates, a mixture of structures being indicated after shorter exposures to this buffer. DMSOR is stable in sodium citrate and other buffers but unstable aerobically although not anaerobically in Na(+)-Hepes. Aerobically in Na(+)-Hepes, a first-order reaction (k = 0.032 hr(-)(1) at 37 degrees C) leads to loss of activity in the backward but not the forward (dimethyl sulfoxide reduction) assay and loss of absorption at lambda > approximately 450 nm. This reaction can be reversed by a cycle of reduction and reoxidation ("redox-cycling"). Slower irreversible loss of activity in the forward assay and cofactor dissociation follow. Spectral analogy with a mono-molybdopterin enzyme supports the conclusion that in the Hepes-modified DMSOR form, only two cofactor dithiolene sulfur atoms are coordinated to molybdenum. Loss of activity provides the first clear evidence that sulfur ligand dissociation is an artifact, not part of the catalytic cycle. Clearly, structural data on DMSOR samples extensively exposed to Hepes is not directly relevant to the native enzyme. The nature of the oxygen ligands detected crystallographically is discussed, as is the specificity of Hepes and the mechanism whereby its effects are achieved. DMSOR forms complexes with Na(+)-Hepes and other buffer ions. For DMSOR crystallized from Hepes, electron density in the substrate binding channel suggests that buffers bind in this site. Like the as-prepared enzyme, the modified form (DMSOR(mod)D), known to arise on extended aerobic exposure to dimethyl sulfide, is susceptible to a further degradative reaction, although this is not buffer-dependent. It involves loss of absorption at lambda > approximately 450 nm and, presumably, dissociation of thiolate ligands. Evidence is presented that, as a result of O(2) damage, DMSOR samples not submitted to redox-cycling may be contaminated with DMSOR(mod)D and with material absorbing in the region of 400 nm, analogous to the Hepes-modified enzyme. Since the latter lacks absorption at lambda > approximately 450 nm, its presence may escape detection.

Buffers↗
PubMed2000

Attentional suppression of activity in the human visual cortex.

We have used fMRI to examine the nature of the changes that occur in the human visual cortex when an observer attends to a particular location in the visual image. Previous studies have shown that the magnitude of the response to a visual stimulus is increased when the observer attends to the stimulus. We show that, in addition, attention to a particular location results in a widespread suppression of activity levels at all other locations. This suggests that a key mechanism of attentional modulation may be that spontaneous (baseline) levels of neural activity are adjusted in a position-dependent manner across the entire visual field.

Attention↗
PubMed2000

Spatiotemporal frequency and direction sensitivities of human visual areas measured using fMRI.

Using functional magnetic resonance imaging (fMRI) we have studied the variation in response magnitude, in each visual area (V1-V5), as a function of spatial frequency (SF), temporal frequency (TF) and unidirectional motion versus counterphase flicker. Each visual area was identified in each subject using a combination of retinotopic mapping fMRI and cortical flattening techniques. A drifting (or counterphasing) sinusoidal grating was used as the stimulus in a study in which we parametrically varied SF between 0.4 and 7 cycles/degree and TF between 0 and 18 Hz. For each experiment we constructed fMRI amplitude tuning curves, averaged across subjects, for each visual area. The tuning curves that resulted are consistent with the known physiological properties of cells in the corresponding macaque visual areas, previous functional imaging studies, and in the case of V1, the psychophysically determined contrast sensitivity functions for spatial and temporal frequency. In the case of V3A, the SF tuning functions obtained were more similar to those found in single cell studies of macaque V3 rather than macaque V3A. All areas showed at least a moderate preference for directed versus counterphasing motion with V5 showing the largest preference. Visual areas V1, V2, V3, and V3A showed more direction sensitivity at low spatial frequencies, while VP, V4, and V5 had the highest drifting versus counterphasing ratios for higher spatial frequencies.

Adult↗
PubMed2000

Interactions between first- and second-order motion revealed by optokinetic nystagmus.

A previous study has suggested that second-order motion is ineffective at driving optokinetic nystagmus (OKN) when presented alone. First- and second-order motion cues interact in creating the perception of motion. Is there an interaction between first- and second-order cues in the control of eye movements? We presented combinations of first- and second-order cues moving in the same or opposite directions and measured the eye movements evoked, to look for a modification of the oculomotor response to first-order motion by simultaneously presented second-order cues. Dynamic random noise was used as a carrier for first- and second-order drifting gratings (13.4 degrees/s; 0.25 cycles/degree; 64 x 48 degrees screen viewed at 28.5 cm). Second-order gratings were defined by spatial modulation of the luminance flicker frequency of noise pixels of constant contrast (50%). A first-order, luminance-defined grating (13.4 degrees/s; 0.25 cycles/degree; variable contrast from 4-50%) was moved in either the same or the opposite direction. Eye movements were recorded by video-oculography from six subjects as they looked straight ahead. The gain (eye velocity/stimulus velocity) of first-order-evoked OKN increased with contrast. The presence of flicker-defined second-order motion in the opposite direction attenuated this OKN below a first-order contrast of 15%, although it had little effect at higher contrasts. When first- and second-order motion were in the same direction, there was an enhancement of the OKN response. We conclude that second-order motion can modify the optokinetic response to simultaneously presented first-order motion.

Contrast Sensitivity↗
PubMed2000

Continuity-based and discontinuity-based segmentation in transparent and spatially segregated global motion.

The mechanisms underlying the parsing of a spatial distribution of velocity vectors into two adjacent (spatially segregated) or overlapping (transparent) motion surfaces were examined using random dot kinematograms. Parsing might occur using either of two principles. Surfaces might be defined on the basis of similarity of motion vectors and then sharp perceptual boundaries drawn between different surfaces (continuity-based segmentation). Alternatively, detection of a high gradient of direction or speed separating the motion surfaces might drive the process (discontinuity-based segmentation). To establish which method is used, we examined the effect of blurring the motion direction gradient. In the case of a sharp direction gradient, each dot had one of two directions differing by 135 degrees. With a shallow gradient, most dots had one of two directions but the directions of the remainder spanned the range between one motion-defined surface and the other. In the spatial segregation case the gradient defined a central boundary separating two regions. In the transparent version the dots were randomly positioned. In both cases all dots moved with the same speed and existed for only two frames before being randomly replaced. The ability of observers to parse the motion distribution was measured in terms of their ability to discriminate the direction of one of the two surfaces. Performance was hardly affected by spreading the gradient over at least 25% of the dots (corresponding to a 1 degrees strip in the segregation case). We conclude that detection of sharp velocity gradients is not necessary for distinguishing different motion surfaces.

Discrimination, Psychological↗