Biomedical subjects

D N Wilson

Publications and source records attributed to D N Wilson.

11 recordsLinked to original sources

PubMed2006

The E-site story: the importance of maintaining two tRNAs on the ribosome during protein synthesis.

In the sixties James Watson suggested a twosite model for the ribosome comprising the P site for the peptidyl transfer RNA (tRNA) before peptide-bond formation and the A site, where decoding takes place according to the codon exposed there. In the eighties a third tRNA binding site was detected, the E site, which was specific for deacylated tRNA and turned out to be a universal feature of ribosomes. However, despite having three tRNA binding sites, only two tRNAs occupy the ribosome at a time during protein synthesis: at the A and P sites before translocation (PRE state) and at the P and E sites after translocation (POST state). The importance of having two tRNAs in the POST state has been revealed during the last 25 years, showing that the E site contributes two fundamental features: (i) the fact that incorporation of a wrong amino acid is not harmful for the cell (only 1 in about 400 misincorporations destroys the function of a protein) stems from the presence of an E-tRNA; (ii) maintenance of the reading frame is one of the most remarkable achievements of the ribosome, essential for faithful translation of the genetic information. The presence of the POST state E-tRNA prevents loss of the reading frame.

Amino Acid Substitution↗

PubMed2004

Smoking prevalence and knowledge of associated risks in adult attenders at day centres for people with learning disabilities.

BACKGROUND: Increased longevity among people with learning disabilities is accompanied by an increase in morbidity. A possible explanation is that living in the community and a move to greater independence may bring higher health risks through obesity and smoking. The study aimed to see if rates of smoking have increased from earlier published rates and to ascertain the awareness of the risks of smoking among people with learning disabilities. METHODS: A total of 435 people attending four social services day centres in a large urban area were assisted to complete a questionnaire. RESULTS: Twenty-seven (6.2%) reported that they currently smoked. Those with mild disabilities were much more likely to smoke than those with more severe disabilities and they also reported smoking more heavily. For those with mild levels of learning disability, a higher than expected proportion living in hospital and staffed housing smoked, a lower proportion living with parents smoked but for those living independently the proportion who smoked was no higher than expected. Smokers were more knowledgeable about the risks than non-smokers even if the level of learning disability was controlled for. Only a third of smokers were concerned about the risks. CONCLUSIONS: The study provides no evidence that rates of smoking are increasing among people with learning disabilities nor that those living independently were more likely to smoke. Knowledge of health risks is poor across the group, but higher among the smokers who were unlikely to express concern about the risks. This may indicate that more support may be needed along with health education in this group.

Adult↗

PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗

PubMed2000

The ribosomal binding and peptidyl-tRNA hydrolysis functions of Escherichia coli release factor 2 are linked through residue 246.

Replacing a cassette of 31 residues from Escherichia coli release factor 1 with the equivalent residues in release factor 2 gave a protein active in codon-specific binding to the ribosome but inactive in peptidyl-tRNA hydrolysis. Such a phenotype is also found unexpectedly with release factor 2 when expressed at high concentration in bacteria. Substituting threonine with the release factor 1 equivalent serine at position 246 within the cassette restored the impaired activity of the chimeric protein, and also that of inactive recombinant release factor 2, both in vitro and in vivo. The differences in activity are not due to posttranslational modifications or a lack of it at this residue. Random mutagenesis of codon 246 suggests that this position is pivotal for the function of the release factor, being able to affect differentially both its binding to the ribosome and its peptide release activities. We propose that amino acid 246 is close to a sharp turn (GGQ motif at position 250), and is essential for transmitting the signal from cognate codon recognition by correctly positioning the peptidyl-tRNA hydrolysis domain of the release factor into the peptidyltransferase center.

Amino Acid Sequence↗

PubMed1999

Alcohol problems and intellectual disability.

The present paper discusses some of the difficulties in working with people with an intellectual disability and an alcohol problem, and draws on the sparse literature about alcohol problems in people with intellectual disability. Four individuals drawn from the current clinical case loads of medical practitioners in UK community intellectual disability services are described. Some suggestions for staff training, patient education and health promotion, and therapeutic approaches are made.

Adult↗

PubMed1999

UGA: a dual signal for 'stop' and for recoding in protein synthesis.

UGA remains an enigma as a signal in protein synthesis. Long recognized as a stop signal that is prone to failure when under competition from near cognate events, there was growing belief that there might be functional significance in the production of small amounts of extended proteins. This view has been reinforced with the discovery that UGA is found at some recoding sites where frameshifting occurs as a regulatory mechanism for controlling the gene expression of specific proteins, and it also serves as the code for selenocysteine (Sec), the 21st amino acid. Why does UGA among the stop signals play this role specifically, and how does it escape being used to stop protein synthesis efficiently at recoding sites involving Sec incorporation or shifts to a new translational frame? These issues concerning the UGA stop signals are discussed in this review.

Animals↗

PubMed1995

Prokaryotic ribosomes recode the HIV-1 gag-pol-1 frameshift sequence by an E/P site post-translocation simultaneous slippage mechanism.

The mechanism favoured for -1 frameshifting at typical retroviral sites is a pre-translocation simultaneous slippage model. An alternative post-translocation mechanism would also generate the same protein sequence across the frameshift site and therefore in this study the strategic placement of a stop codon has been used to distinguish between the two mechanisms. A 26 base pair frameshift sequence from the HIV-1 gag-pol overlap has been modified to include a stop codon immediately 3' to the heptanucleotide frameshift signal, where it often occurs naturally in retroviral recoding sites. Stop codons at the 3'-end of the heptanucleotide sequence decreased the frame-shifting efficiency on prokaryote ribosomes and the recording event was further depressed when the levels of the release factors in vivo were increased. In the presence of elevated levels of a defective release factor 2, frameshifting efficiency in vivo was increased in the constructs containing the stop codons recognized specifically by that release factor. These results are consistent with the last six nucleotides of the heptanucleotide slippery sequence occupying the ribosomal E and P sites, rather than the P and A sites, with the next codon occupying the A site and therefore with a post-translocation rather than a pre-translocation -1 slippage model.

Base Sequence↗

PubMed1993

Asperger's syndrome: three cases and a discussion.

The recently revived academic interest in and controversy over the subject of Asperger's syndrome is briefly discussed. Gillberg & Gillberg's operational criteria for its definition are used to isolate three cases of the syndrome presenting over a single year to a mental handicap service. The cases are described in detail. Common themes and associations with the available literature are discussed. In all three cases, the struggle for clarity in the syndrome's nature or specificity in the literature is also reflected in aspects of their clinical management.

Adult↗

PubMed1991

Systemic lupus erythematosus in a woman with mental handicap.

A woman with a mental handicap developed SLE. This magnified the level of her handicap, and because of her difficulties in giving a history, mildly abnormal results of tests in any one system were dismissed over long periods of time. This resulted in very late diagnosis of a potentially treatable disease.

Adult↗

PubMed1990

Health care screening for people with mental handicap living in the community.

OBJECTIVE: To determine what contact people with mental handicap had had with their general practitioner in the previous year; what prescribed drugs they were taking and whether these had been reviewed; when hearing and vision had last been screened; and what medical problems were found on examination. DESIGN: Case series. SETTING-Day centre for adults with mental handicap. SUBJECTS: A balanced sample of 75 of the 150 people attending the day centre. 10 Were excluded because consent was not given. RESULTS: The subjects did not consult their general practitioners more frequently than the general population but were more likely to be taking prescribed drugs, and 57% of these prescriptions had not been reviewed by a doctor. Thirty three people failed vision screening, including 13 who wore glasses. Twenty seven of the 62 who were testable had a hearing impairment. CONCLUSIONS: As only eight out of 65 people examined in the study did not have an appreciable problem brought to light, screening seems to be worth while. Whether such screening needs to be done by a medically qualified person needs further research.

Adult↗

PubMedDate not supplied

Translational termination efficiency in both bacteria and mammals is regulated by the base following the stop codon.

The translational stop signal and polypeptide release factor (RF) complexed with Escherichia coli ribosomes have been shown to be in close physical contact by site-directed photochemical cross-linking experiments. The RF has a protease-sensitive site in a highly conserved exposed loop that is proposed to interact with the peptidyltransferase center of the ribosome. Loss of peptidyl-tRNA hydrolysis activity and enhanced codon-ribosome binding by the cleaved RF is consistent with a model whereby the RF spans the decoding and peptidyltransferase centers of the ribosome with domains of the RF linked by conformational coupling. The cross-link between the stop signal and RF at the ribosomal decoding site is influenced by the base following the termination codon. This base determines the efficiency with which the stop signal is decoded by the RF in both mammalian and bacterial systems in vivo. The wide range of efficiencies correlates with the frequency with which the signals occur at natural termination sites, with rarely used weak signals often found at recoding sites and strong signals found in highly expressed genes. Stop signals are found at some recoding sites in viruses where -1 frame-shifting occurs, but the generally accepted mechanism of simultaneous slippage from the A and P sites does not explain their presence here. The HIV-1 gag-pol-1 frame shifting site has been used to show that stop signals significantly influence frame-shifting efficiency on prokaryotic ribosomes by a RF-mediated mechanism. These data can be explained by an E/P site simultaneous slippage mechanism whereby the stop codon actually enters the ribosomal A site and can influence the event.

Animals↗