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Biomedical subjects

A Vincent

Publications and source records attributed to A Vincent.

At least 235 records · Page 13Linked to original sources
PubMed1995

Autoantibodies, neurotoxins and the nervous system.

Myasthenia gravis, the Lambert-Eaton myasthenic syndrome, and acquired neuromyotonia are three disorders of the neuromuscular junction or motor nerve that are caused by autoantibodies to ion channel proteins: acetylcholine receptors, voltage-gated calcium channels and voltage-gated potassium channels, respectively. The antibody titres can be measured using the relevant 125I-neurotoxins to label the extracted channels. Other disorders of the peripheral motor nerve are associated with antibodies to gangliosides. Sera with raised levels of anti-ganglioside antibodies have direct effects on the function of the distal motor nerve and motor nerve terminal. These conditions can be improved by therapies designed to reduce circulating antibodies. Antibodies that bind to neuronal surface antigens are proving to be of great clinical importance and interest in neurological disorders.

Autoantibodies↗
PubMed1995

Visual processing of the motion of an object in three dimensions for a stationary or a moving observer.

A rate of change of relatively disparity is a sufficient binocular stimulus for the perception of motion in depth. For motion within the meridian that contains the eyes, disparity change associated with approaching motion is processed through four channels, each tuned to a different direction of motion in depth. Directional discrimination is most acute but detection sensitivity falls to a minimum for a trajectory passing approximately midway between the eyes. This can be explained if discrimination depends on the relatively of the four channels. Two binocular retinal-image correlates of the direction of the motion of an object in depth are the ratio between the velocities of the retinal images of the object in the left and right eyes [(d phi/dt)R/(d phi/dt)L], and the ratio between the translational velocity of the binocularly fused images and the rates of change of disparity [(d phi/dt)/(d gamma/dt)]. Directional discrimination is possible by using the second cue alone. An isotropic rate of expansion of the retinal image is a sufficient monocular stimulus for the perception of motion in depth. There is no evidence that expansion is processed through channels tuned to the direction of motion in depth. Two monocular correlates of the direction of the motion of an object in depth are the ratio between the translational velocity and the rate of expansion of the retinal image of the object [(d phi/dt)/(d theta/dt)], and the ratio between the velocities of opposite edges of the retinal image [(d alpha 1/dt)/(d alpha 2/dt)]. Subjects are able monocularly to discriminate the direction of motion in depth with high acuity (better than 0.1 deg threshold) in the vertical, horizontal, or oblique meridians, even when the direction and the speed of translational motion are removed as cues. Visual discrimination of time to contact with an approaching object can be disconfounded from discrimination of its rate of expansion and vice versa with a threshold separation ratio of as much as 100:1.

Cues↗
PubMed1995

Parallel independent encoding of orientation, spatial frequency, and contrast.

Subjects were presented with a set of 216 test gratings in random order. Each had a different combination of orientation, spatial frequency, and contrast. For each test grating, subjects were instructed to judge whether or not orientation was clockwise of the mean of the stimulus set, whether or not spatial frequency was higher than the mean of the stimulus set, and whether or not contrast was higher than the mean of the stimulus set. Each of the three sets of button presses was analyzed with respect to each of the three parameters, giving nine psychometric functions from one response set. It is concluded that, for gratings of high visibility, changes of orientation, spatial frequency, and contrast are encoded independently and in parallel, at least for small changes in these three visual parameters. In another experiment only one of the three parameters was varied at a time. Neither orientation-discrimination threshold, nor spatial-frequency-discrimination threshold, nor contrast-discrimination threshold was appreciably, if at all, lower than when all three parameters were varied simultaneously. It is concluded that interactions between the processing of small changes in orientation, spatial frequency, and contrast are negligible when all three are processed simultaneously. It is proposed that trial-to-trial variations of orientation, spatial frequency, and contrast are unconfounded by opponent processing within a population of neurons, each of which confounds the three variables.

Adult↗
PubMed1995

An improved diagnostic assay for Lambert-Eaton myasthenic syndrome.

A new immunoprecipitation assay has been established for detecting antibodies to voltage-gated calcium channels (VGCCs) in Lambert-Eaton myasthenic syndrome (LEMS), using 125I-omega-conotoxin MVIIC, which binds to P-type VGCCs, to label extracts of human cerebellum. Fifty six of 66 serum samples (85%) from patients with clinically and electrophysiologically definite LEMS were positive for the presence of VGCC antibodies, defined as a titre > 3 SD above the mean for the healthy controls (n = 10). All disease controls (n = 40) were negative. This sensitive immunoassay should prove valuable in the diagnosis of LEMS.

Aged↗
PubMed1994

Direct control of transcription of the Drosophila morphogen bicoid by the serendipity delta zinc finger protein, as revealed by in vivo analysis of a finger swap.

Determination of the anterior structures of the Drosophila embryo is under control of the maternal gene product Bicoid (bcd), which specifies distinct domains of embryonic gene expression in a concentration-dependent manner. We show here that bcd transcription is controlled by serendipity delta (sry delta), a zygotic-lethal zinc finger protein gene. This sry delta germ-line function was revealed by transgenic expression of a modified Sry delta protein, Sry DB56, carrying a two-finger swap. Although it almost fully rescues sry delta lethality, Sry DB56 does not substitute for the wild-type protein in activating bcd transcription. Two overlapping sites binding the Sry delta protein were identified in the bcd promoter region, a few base pairs upstream of the putative TATA box. Mutating one site impairs bcd transcription in vivo, indicating that Sry delta acts directly upstream of bcd. The specific requirement of sry delta for bcd transcription in the female germ line constitutes an unexpected link between a zygotic gene with pleiotropic functions and the establishment of coordinates of the Drosophila egg. It highlights the fundamental role of ubiquitous transcription factors in bringing about a specific developmental program.

Amino Acid Sequence↗
PubMed1994

Serum factor in Miller-Fisher variant of Guillain-Barré syndrome and neurotransmitter release.

Serum IgG autoantibodies to GQ1b ganglioside are associated with the acute phase of the Miller-Fisher syndrome (MFS). We investigated the effects of three anti-GQ1b-positive MFS sera in the mouse phrenic-nerve/diaphragm preparation. Miniature endplate potential frequencies increased eight-fold within 25 min, declined rapidly, and ceased altogether after 3 h, when nerve stimulation no longer evoked a response. One MFS convalescent serum (anti-GQ1b negative) and sera from healthy controls and from patients with other neurological diseases were without effect. Thus muscle weakness in MFS may be caused by a serum factor, likely to be GQ1b antibody, that leads to failure of acetylcholine release from motor nerve terminals.

Autoantibodies↗
PubMed1994

Mutations in eukaryotic 18S ribosomal RNA affect translational fidelity and resistance to aminoglycoside antibiotics.

Mutations have been created in the Saccharomyces cerevisiae 18S rRNA gene that correspond to those known to be involved in the control of translational fidelity or antibiotic resistance in prokaryotes. Yeast strains, in which essentially all chromosomal rDNA repeats are deleted and all cellular rRNAs are encoded by plasmid, have been constructed that contain only mutant 18S rRNA. In Escherichia coli, a C-->U substitution at position 912 of the small subunit rRNA causes streptomycin resistance. Eukaryotes normally carry U at the corresponding position and are naturally resistant to streptomycin. We show that a U-->C transition (rdn-4) at this position of the yeast 18S rRNA gene decreases resistance to streptomycin. The rdn-4 mutation also increases resistance to paromomycin and G-418, and inhibits nonsense suppression induced by paromomycin. The same phenotypes, as well as a slow growth phenotype, are also associated with rdn-2, whose prokaryotic counterpart, 517 G-->A, manifests itself as a suppressor rather than an antisuppressor. Neither rdn-2- nor rdn-4-related phenotypes could be detected in the presence of the normal level of wild-type rDNA repeats. Our data demonstrate that eukaryotic rRNA is involved in the control of translational fidelity, and indicate that rRNA features important for interactions with aminoglycosides have been conserved throughout evolution.

Base Sequence↗
PubMed1994

Passive transfer of seronegative myasthenia gravis to mice.

Muscle weakness in myasthenia gravis is due to autoantibody-induced loss of functional acetylcholine receptors (AChR). About 15% of myasthenia gravis patients, however, do not have detectable anti-AChR antibodies. To investigate the effect of their plasma immunoglobulins on neuromuscular transmission, mice were injected with plasma (and in some cases purified immunoglobulin G (IgG)) from 7 "seronegative" myasthenia gravis (SMG) patients, and neuromuscular transmission parameters were examined. When injected for 15 days, all patients' plasma caused reductions in miniature endplate potential amplitudes, while endplate potential quantal content was significantly reduced by plasma from 4 of the 7 patients. There were no changes in ACh-induced depolarization or single channel properties, and 125I-alpha-bungarotoxin binding studies showed no effect on AChR number, except in 1 case. Purified IgG injected for 3 days had similar effects to plasma injected for 15 days. Our findings confirm that SMG is autoantibody mediated and that there are pathogenic IgG antibodies. SMG appears to be a heterogeneous disorder and the target(s) for the antibodies may be diverse.

Acetylcholine↗
PubMed1994

Interspecific comparison of Drosophila serendipity delta and beta: multimodular structure of these C2H2 zinc finger proteins.

The Drosophila serendipity (sry) beta and delta genes, which resulted from a gene duplication event, provide an interesting model for the evolutionary diversification in structure and function of C2H2 zinc finger proteins. We examined here the divergence of the sry beta and delta proteins over an estimated period of 45 million years by comparing their predicted sequences in D. melanogaster, D. pseudoobscura, and D. subobscura. Between orthologs, i.e., pairs of either sry beta or sry delta, the NH2-proximal region delineated by pairs of C-X2-C motifs and the DNA-binding finger domain are highly conserved. Sequence conservation operates over the entire finger domain, including the links separating adjacent fingers, even though each has a unique sequence different from the widespread TGEKP motif. In contrast, the sequence of the central acidic region has extensively diverged and differs between species in the number of amino acids, probably because of slippage-driven mutations. The NH2-terminal region and fingers 1, 5, and 6 differentiate the sry beta and delta proteins while zinc fingers 2, 3, and 4 are virtually identical in these two paralogs. A nuclear localization signal of the SV40T antigen type, preceded by a potential CKII phosphorylation regulatory site, is conserved in sry delta but not found in sry beta. The interspecific conserved regions correlate well with the positions of zygotic lethal mutations in the D. melanogaster sry delta protein. Furthermore, P-element transformation experiments show that a transgenic copy of the D. pseudoobscura sry delta gene rescues the sry delta mutant phenotype. Convergence of genetic and structural data on the sry proteins supports a multimodular function and mode of evolution of these C2H2 finger proteins.

Amino Acid Sequence↗
PubMed1994

Plasma from patients with seronegative myasthenia gravis inhibit nAChR responses in the TE671/RD cell line.

Myasthenia gravis (MG) is an autoimmune disorder in which anti-acetylcholine receptor (AChR) antibodies cause muscle weakness. In 10-15% of MG patients anti-AChR antibodies are undetectable (seronegative MG, SMG), though clinical and experimental evidence points to causative circulating factors. Using whole-cell patch-clamp techniques, we investigated the effects of heat-inactivated plasma from SMG patients (n = 7) on voltage-gated sodium [INa(V)] and ACh-induced nicotinic AChR (nAChR) currents in the human rhabdomyosarcoma cell line TE671/RD, comparing the results to those obtained with plasma from healthy individuals (HC, n = 6), patients with Guillain-Barré syndrome (GBS, n = 3) or those with other neurological diseases (OND, n = 3). None of the plasma samples inhibited INa(V). nAChR currents were rapidly (< 1 min) and significantly (P < 0.01) reduced by a 1:10 dilution of plasma from SMG patients compared with plasma from healthy controls and were not restored by washing. The inhibition appeared in some cases to be calcium dependent since for one of three plasmas it was prevented by 10 mM EGTA in the patch pipette. Currents were also reduced by two of three plasmas obtained from GBS patients at 1:3 dilution, but not by the three plasmas from patients with ONDs. The rapid action of plasma from SMG patients argues against an antibody-induced reduction in nAChR numbers; its calcium dependence in one case suggests action by a second messenger that might involve nAChR phosphorylation.

Adolescent↗
PubMed1994

Response to human acetylcholine receptor alpha 138-199: determinant spreading initiates autoimmunity to self-antigen in rabbits.

NZW rabbits immunised with a mixture of synthetic peptides representing alpha 138-199 of the human acetylcholine receptor (AChR) alpha-subunit exhibited clinical, biochemical and electrophysiological signs of experimental autoimmune myasthenia gravis (EAMG), with raised levels of anti-rabbit AChR antibodies. Surprisingly, these were partly directed at the main immunogenic region (MIR, thought to be alpha 67-76) and alpha-Bungarotoxin binding sites on rabbit AChR, and reacted less well with human AChR. Moreover, they could be separated from the anti-peptide antibodies by fractionation on immobilised peptide. We conclude that immunisation with these peptides led, by 'determinant spreading', to a response directed at self-AChR. Similar phenomena may have been overlooked in previous studies of responses to synthetic or recombinant AChR sequences. These findings suggest that autoimmunity could be induced by low-affinity, cross-reacting epitopes even when the observed serum response is highly specific for the autoantigen.

Animals↗
PubMed1994

The yeast translational allosuppressor, SAL6: a new member of the PP1-like phosphatase family with a long serine-rich N-terminal extension.

The allosuppressor mutation, sal6-1, enhances the efficiency of all tested translational suppressors, including codon-specific tRNA suppressors as well as codon-nonspecific omnipotent suppressors. The SAL6 gene has now been cloned by complementation of the increased suppression efficiency and cold sensitivity caused by sal6-1 in the presence of the omnipotent suppressor sup45. Physical analysis maps SAL6 to chromosome XVI between TPK2 and spt14. The SAL6 gene encodes a very basic 549-amino acid protein whose C-terminal catalytic region of 265 residues is 63% identical to serine/threonine PP1 phosphatases, and 66% identical to yeast PPZ1 and PPZ2 phosphatases. The unusual 235 residue N-terminal extension found in SAL6, like those in the PPZ proteins, is serine-rich. The sal6-1 mutation is a frameshift at amino acid position 271 which destroys the presumed phosphatase catalytic domain of the protein. Disruptions of the entire SAL6 gene are viable, cause a slight growth defect on glycerol medium, and produce allosuppressor phenotypes in suppressor strain backgrounds. The role of the serine-rich N terminus is unclear, since sal6 phenotypes are fully complemented by a SAL6 allele that contains an in-frame deletion of most of this region. High copy number plasmids containing wild-type SAL6 cause antisuppressor phenotypes in suppressor strains. These results suggest that the accuracy of protein synthesis is affected by the levels of phosphorylation of the target(s) of SAL6.

Amino Acid Sequence↗