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Biomedical subjects

V Knott

Publications and source records attributed to V Knott.

At least 37 records · Page 2Linked to original sources
PubMed1999

Event-related potentials in schizophrenic patients during a degraded stimulus version of the visual continuous performance task.

Previous studies of the auditory P300 event-related potential (ERP) have reported smaller amplitudes in chronic schizophrenics but similar consistencies have not been observed with visual P300s. This study examined P300s in symptomatically stable, medicated, chronic schizophrenics (n = 14) and normal controls (n = 14) performing a visual continuous performance task utilizing degraded stimuli to burden encoding processes. Performance analysis found slower response times, fewer target detections and more false alarms in patients than in controls. Analysis of ERPs showed P300 amplitudes of schizophrenics to be significantly smaller than those of controls and, unlike controls, schizophrenics failed to exhibit significant target vs. non-target P300 amplitude differences. Discriminant analysis indicated target and non-target midline (Fz, Cz, Pz) P300 amplitudes together correctly classified all patients and controls. Exploratory topographic analysis indicated that P300 amplitudes were not asymmetrical in patients, as has been observed with auditory P300s, and, unlike the performance measures, the P300s did not correlate with the patient's positive or negative symptom ratings. The implications of these findings are described in relation to attentional disturbances and trait versus state issues in schizophrenics.

Adult↗
PubMed1999

Defective calcium binding to fibrillin-1: consequence of an N2144S change for fibrillin-1 structure and function.

Fibrillin-1 is a major structural component of 10-12 nm connective tissue microfibrils and has a modular organisation that includes 43 calcium binding epidermal growth factor-like (cbEGF) domains and seven transforming growth factor beta-binding protein-like (TB) domains. Mutations in the fibrillin-1 (FBN1) gene cause the Marfan syndrome (MFS) and related connective tissue disorders. We have previously investigated an N2144S change, identified in a MFS patient, which removes one of the key calcium binding ligands within cbEGF domain 32. In this study the structural consequences of the N2144S amino acid change for the folding and calcium binding properties of mutant and wild-type TB6-cbEGF32 and cbEGF32-33 domain pairs have been analysed by nuclear magnetic resonance. The presence of an N2144S substitution does not alter the native fold of either the TB6 domain, or cbEGF domains 32 and 33. Comparison of calcium dissociation constants measured for the wild-type and mutant pairs shows that: (i) the affinity of cbEGF32 is weakly enhanced by N-terminal linkage of TB6 relative to cbEGF32 in isolation; (ii) the affinity of cbEGF32 is approximately ninefold decreased by the N2144S substitution in the TB-cbEGF pair; and (iii) reduced affinity of cbEGF32 does not result in lower affinity of cbEGF33 for calcium. Together, these data suggest that the TB6-cbEGF32 linkage is flexible and the structural effect of the mutation is localised to the interdomain linkage. We have also investigated the effect of defective calcium binding to cbEGF32 on fibrillin-1 produced by N2144S MFS fibroblasts. 35S-pulse-chase analysis shows that the N2144S substitution does not detectably affect fibrillin-1 biosynthesis, rate of secretion or processing. Deposition of reducible fibrillin-1 into the extracellular matrix was also unaffected. The implications of these results for the assembly and properties of the microfibril are discussed.

Actin Cytoskeleton↗
PubMed1999

Transdermal nicotine: single dose effects on mood, EEG, performance, and event-related potentials.

A 21-mg dose of nicotine was administered transdermally to 16 overnight smoking-deprived smokers in a double-blind, placebo-controlled design. Mood ratings, electroencephalography (EEG), behavioral performance and event-related potential (ERP: P300) indices of attention and information processing speed were assessed before and 4 h after placebo/nicotine treatment. Although nicotine, relative to placebo, failed to alter mood, it increased absolute and relative power indices of EEG arousal, shortened reaction times, and increased P300 amplitudes. The results are discussed in relation to nicotine's actions on cholinergic transmission and its role in smoking behavior.

Administration, Cutaneous↗
PubMed1999

EEG and the passive P300 in dementia of the Alzheimer type.

Quantitatively analyzed resting electroencephalographic (EEG) activity and P300 event-related potentials elicited with a passive tone sequence paradigm were examined in 30 patients with dementia of the Alzheimer type (DAT) and 15 age matched controls. Background electrical rhythms of DAT patients evidenced slowing as shown by increased absolute and relative amplitudes in slow frequency bands and decreased amplitudes in fast frequency bands (relative to controls). Electrical slowing was more evident in patients with higher clinical ratings of global intellectual deterioration. Passive P300 amplitude and latency did not differentiate patients and controls and were not related to severity of dementia.

Aged↗
PubMed1998

Effects of proline cis-trans isomerization on TB domain secondary structure.

The transforming growth factor beta (TGF-beta) binding protein-like (TB) domain is found principally in proteins localized to extracellular matrix fibrils, including human fibrillin-1, the defective protein in the Marfan syndrome. Analysis of the nuclear magnetic resonance (NMR) data for the sixth TB module from human fibrillin-1 has revealed the existence of two stable conformers that differ in the isomerization states of two proline residues. Unusually, the two isoforms do not readily interconvert and are stable on the time scale of milliseconds. We have computed independent structures of the major and minor conformers of TB6 to assess how the domain fold adjusts to incorporate alternatively cis- or trans-prolines. Based on previous observations, it has been suggested that multiple conformers can only be accommodated in flexible regions of protein structure. In contrast, P22, which exists in trans in the major form and cis in the minor form of TB6, is in a rigid region of the domain, which is confirmed by backbone dynamics measurements. Overall, the structures of the major and minor conformers are similar. However, the secondary structure topologies of the two forms differ as a direct consequence of the changes in proline conformation.

Fibrillin-1↗
PubMed1998

Event-related potential correlates of primed and unprimed words in children co-morbid for disruptive behaviour disorders and academic delay.

Children with disruptive behaviour disorders and academic delay (DD-AD) were compared to children with disruptive behaviour disorders only (DD) and normal control children with no psychiatric disturbance or academic delay (NO) with respect to scalp-recorded event-related electrical potentials (ERPs) elicited by semantically primed and unprimed words. Primed words were preceded by spoken words having a related meaning, while unprimed words were preceded by nonassociated spoken words. For normal controls, the unprimed words elicited greater N400 amplitudes at frontal-central recording sites than primed words. Primed vs. unprimed N400 differences were not evident at frontal sites in DD and the DD-AD group failed to exhibit differences in primed vs. unprimed N400 amplitudes at either frontal, central or parietal sites. These findings suggest that DD-AD children may represent a unique neuroelectric subgroup of learning disabilities.

Adolescent↗
PubMed1997

Solution structure of the transforming growth factor beta-binding protein-like module, a domain associated with matrix fibrils.

Here we describe the high resolution nuclear magnetic resonance (NMR) structure of a transforming growth factor beta (TGF-beta)-binding protein-like (TB) domain, which comes from human fibrillin-1, the protein defective in the Marfan syndrome (MFS). This domain is found in fibrillins and latent TGF-beta-binding proteins (LTBPs) which are localized to fibrillar structures in the extracellular matrix. The TB domain manifests a novel fold which is globular and comprises six antiparallel beta-strands and two alpha-helices. An unusual cysteine triplet conserved in the sequences of TB domains is localized to the hydrophobic core, at the C-terminus of an alpha-helix. The structure is stabilized by four disulfide bonds which pair in a 1-3, 2-6, 4-7, 5-8 pattern, two of which are solvent exposed. Analyses of MFS-causing mutations and the fibrillin-1 cell-binding RGD site provide the first clues to the surface specificity of TB domain interactions. Modelling of a homologous TB domain from LTBP-1 (residues 1018-1080) suggests that hydrophobic contacts may play a role in its interaction with the TGF-beta1 latency-associated peptide.

Amino Acid Sequence↗
PubMed1996

Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders.

The nuclear magnetic resonance structure of a covalently linked pair of calcium-binding (cb) epidermal growth factor-like (EGF) domains from human fibrillin-1, the protein defective in the Marfan syndrome, is described. The two domains are in a rigid, rod-like arrangement, stabilized by interdomain calcium binding and hydrophobic interactions. We propose a model for the arrangement of fibrillin monomers in microfibrils that reconciles structural and antibody binding data, and we describe a set of disease-causing mutations that provide the first clues to the specificity of cbEFG interactions. The residues involved in stabilizing the domain linkage are highly conserved in fibrillin, fibulin, thrombomodulin, and the low density lipoprotein receptor. We propose that the relative orientation of tandem cbEGF domains in these proteins is similar, but that in others, including Notch, pairs adopt a completely different conformation.

Calcium-Binding Proteins↗
PubMed1996

Calcium binding properties of an epidermal growth factor-like domain pair from human fibrillin-1.

Ca2+ binding epidermal growth factor-like (EGF-like) domains are found in a large number of extracellular proteins with diverse functions, including those involved in blood coagulation, determination of cell fate, cell adhesion and connective tissue architecture. Their importance is emphasised by the identification of mutations in these domains in patients with haemophilia B (defective in coagulation factor IX) and the Marfan syndrome (defective in the connective tissue protein fibrillin-1). The X-ray crystal structure of a single Ca2+ binding EGF-like domain from human coagulation factor IX has recently been solved. It shows that the Ca2+ ligands form a pentagonal bipyramid, where one ligand is provided by an adjacent (N-terminal) EGF-like domain in the crystal. The N and C termini of the neighbouring domains are only approximately 4 angstrum apart, hence the crystal packing has been proposed as a model for the association of contiguous EGF-like domains in proteins. Since the adjacent EGF-like domain in the crystal, although close, is not covalently linked to its neighbour, this model requires verification. In this study we have expressed and purified a Ca2+ binding EGF-like domain pair from human fibrillin-1 and used an in vitro refolding system to obtain protein with the correct EGF fold. The Ca2+ binding properties of the protein have been investigated by two-dimensional NMR. The affinity of the C-terminal domain for Ca2+ is approximately 25-fold higher than that of the N-terminal domain, consistent with the two Ca2+ binding sites having different local environments. In addition, these data provide the first direct experimental evidence that Ca2+ plays a major role in defining the interdomain linkage in multiple repeats of Ca2+ binding EGF-like domains.

Amino Acid Sequence↗
PubMed1995

The structure of a Ca(2+)-binding epidermal growth factor-like domain: its role in protein-protein interactions.

Various diverse extracellular proteins possess Ca(2+)-binding epidermal growth factor (EGF)-like domains, the function of which remains uncertain. We have determined, at high resolution (1.5 A), the crystal structure of such a domain, from human clotting factor IX, as a complex with Ca2+. The Ca2+ ligands form a classic pentagonal bipyramid with six ligands contributed by one polypeptide chain and the seventh supplied by a neighboring EGF-like domain. The crystal structure identifies the role of Ca2+ in maintaining the conformation of the N-terminal region of the domain, but more importantly demonstrates that Ca2+ can directly mediate protein-protein contacts. The observed crystal packing of the domains provides a plausible model for the association of multiple tandemly linked EGF-like domains in proteins such as fibrillin-1, Notch, and protein S. This model is consistent with the known functional data and suggests a general biological role for these domains.

Amino Acid Sequence↗
PubMed1995

Crystallization of a calcium-binding EGF-like domain.

Crystals of a calcium-binding epidermal growth factor (EGF)-like domain of human clotting factor IX suitable for X-ray diffraction analysis have been obtained by vapour diffusion (sitting drop) against 48% PEG 400. The crystals belong to the tetragonal space group P4(3)2(1)2, with unit-cell dimensions a = b = 40.3, c = 98.2 A. The crystals diffract beyond 1.5 A resolution and are relatively stable in the X-ray beam. This is the first reported crystallization of a calcium-binding EGF-like domain.

Journal Article↗
PubMed1995

Cognitive and quantified electroencephalographic correlates of cycloserine treatment in Alzheimer's disease.

Cycloserine acts as a potent and selective modulator of the N-methyl-D- aspartate (NMDA) receptor-associated glycine recognition site, which may be a possible mechanism for this compound's positive effects on memory formation and retrieval processes in animals. Studies in normal human volunteers have shown that cycloserine can have significant positive effects on cognitive processing in the elderly and can ameliorate memory deficits induced by subcutaneously administered scopolamine. Based on this profile, a double-blind, placebo controlled, parallel group (three drug dosages) study was conducted as part of a larger study to assess the efficacy and safety, as well as the cognitive and central nervous system (CNS) impact, of 6 months of cycloserine treatment in patients (N = 40) with probable dementia of the Alzheimer type (DAT). The Cognitive Drug Research Computerize Assessment System (CDR System) served as the primary outcome measure of efficacy. CNS activity was assessed using quantified electroencephalography (QEEG). Safety measures included adverse effects documentation and analysis of blood chemistry/hematology. Cycloserine proved to be a safe agent in this population at the doses given but failed to show any statistically significant effects in the areas of cognition and global clinical ratings and did not indicate significant CNS activity on QEEG. These findings suggest that cycloserine has no measurable therapeutic effect on Alzheimer's disease at the doses given.

Aged↗
PubMed1992

Clinical, cognitive, and neurophysiological effects of alprazolam in children and adolescents with overanxious and avoidant disorders.

In a double-blind, placebo-controlled study, the efficacy and safety of alprazolam was investigated in childhood and adolescent anxiety disorders. Thirty patients (mean, 12.6 years) diagnosed with overanxious or avoidant disorders participated in the study. Evaluations included clinical, laboratory, cognitive, and qualitative EEG measurements. On a clinical global rating, there was no statistical difference between alprazolam and placebo. Relative to baseline EEG, acute alprazolam administration increased beta power in the right occipital lead, and chronic administration increased beta power in both leads. Alprazolam was well tolerated, and adverse effects were few, mild, and transient.

Adolescent↗
PubMed1991

Event-related potentials and selective attention in major depressive illness.

Depressive episodes have been frequently characterized by deficits in information processing efficiency which are particularly evident when required to sustain or focus attention. As cerebral event-related potentials (ERPs) have been shown to reflect various aspects of selective attention and attentional dysfunction, this study attempted to examine ERPs in depressed patients performing a selective auditory attention task. Twenty-nine patients with a diagnosis of major depressive disorder (DSM-III) and 15 normal, non-psychiatric controls served as experimental subjects. Auditory potentials were recorded from the vertex of subjects who listened selectively to a series of tone pips in one ear and ignored concurrent tone pips to the other ear. Tone pips were delivered at short (320-500 ms) interstimulus intervals and subjects were required to detect, within the attended ear, rare 'target' tones of a different pitch than the more frequent 'standard' tones. In addition to behavioral indices of 'hits' and 'false alarms', ERP-derived measures included N1 amplitudes to attended and ignored stimuli, 'coefficients of attention' as calculated from N1 amplitude ratios and the latency onset and amplitude of the 'negative difference' (Nd) wave resulting from the subtraction of attended and ignored waveforms. Behavioral measures indicated that depressed patients were as efficient as controls in task performance and in fact they exhibited a significant left ear advantage in the additional task. Although a significant 'N1 effect' was observed with attended tones eliciting larger amplitudes than unattended tones, ERP measures of selective attention did not tend to differentiate the two groups.

Adult↗
PubMed1991

Auditory evoked potentials in panic disorder.

Neuroimaging studies of behavioral-induced anxiety in non-patients and of lactate-induced anxiety in panic disorder patients have indicated that normal and pathological anxiety may share a common pathway involving the temporal poles. As panic-related anxiety may reflect faulty temporopolar evaluative processing of input, the objective of this study was to examine sensory reactivity in panic disorder patients via scalp recordings of the late auditory evoked 'vertex' potential (LAEP) which appears to have a predominantly temporal lobe origin. Twelve patients diagnosed according to DSM-III criteria as panic disorder and ten normal controls served as subjects in this study. EEG was recorded from 16 scalp sites using a monopolar fronto-occipital derivation and LAEPs were separately averaged in response to four acoustic intensities. Analysis focused on group and electrode-site differences in the negative (N1) and positive (P2) component amplitudes of the LAEPs. Panic disorder patients were found to exhibit significantly larger N1 amplitudes across all stimulus intensities and across all recording sites. No significant group differences were observed with P2. Although the results provide indirect support for a temporal focus, other modulating influences must be considered in data interpretation.

Adult↗
PubMed1989

Completion of the detailed restriction map of the E. coli genome by the isolation of overlapping cosmid clones.

Ordered sets of cosmids derived from E. coli K-12 803 overlap the 6 remaining gaps left in the physical map of strain W3110. We present detailed restriction maps of the gaps and surrounding regions, thus providing a comparison of about 30% of the genome of the two E. coli strains. Our analysis shows that there is a high degree of homology between the strains, with only occasional restriction fragment differences. However, the large inversion occurring between rrnD (72.1') and rrnE (90.4') in strain W3110 is absent in strain 803. Instead, a new inversion and adjacent deletion near argF is present in strain 803. The distribution of cosmid clones at, and adjacent to, the gaps shows that all gaps except one were difficult to clone in both lambda and cosmid clones. A low copy number cosmid vector, pOU61cos, developed previously, was essential for cloning 3 of the 8 gaps.

Chromosome Mapping↗
PubMed1988

Randomly picked cosmid clones overlap the pyrB and oriC gap in the physical map of the E. coli chromosome.

Sets of overlapping cosmid clones generated by random sampling and fingerprinting methods complement data at pyrB (96.5') and oriC (84') in the published physical map of E. coli. A new cloning strategy using sheared DNA, and a low copy, inducible cosmid vector were used in order to reduce bias in libraries, in conjunction with micro-methods for preparing cosmid DNA from a large number of clones. Our results are relevant to the design of the best approach to the physical mapping of large genomes.

Chromosome Mapping↗