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P Wright

Publications and source records attributed to P Wright.

At least 91 records · Page 5Linked to original sources
PubMed1997

Evidence that bilayer bending rigidity affects membrane protein folding.

The regeneration kinetics of the integral membrane protein bacteriorhodopsin have been investigated in a lipid-based refolding system. Previous studies on bacteriorhodopsin regeneration have involved detergent-based systems, and in particular mixed dimyristoylphosphatidylcholine (DMPC)/CHAPS micelles. Here, we show that the short chain lipid dihexanoylphosphatidylcholine (DHPC) can be substituted for the detergent CHAPS and that bacteriorhodopsin can be regenerated to high yield in mixed DMPC/DHPC micelles. Bacteriorhodopsin refolding kinetics are measured in the mixed DMPC/DHPC micelles. Rapid, stopped flow mixing is employed to initiate refolding of denatured bacterioopsin in SDS micelles with mixed DMPC/DHPC micelles and time-resolved fluorescence spectroscopy to follow changes in protein fluorescence during folding. Essentially identical refolding kinetics are observed for mixed DMPC/CHAPS and mixed DMPC/DHPC micelles. Only one second-order retinal/apoprotein reaction is identified, in which retinal binds to a partially folded apoprotein intermediate, and the free energy of this retinal binding reaction is found to be the same in both types of mixed micelles. Formation of the partially folded apoprotein intermediate is a rate-limiting step in protein folding and appears to be biexponential. Both apparent rate constants are found to be dependent on the relative proportion of DMPC present in the mixed DMPC/DHPC micelles as well as on the pH of the aqueous phase. Increasing the DMPC concentration should increase the bending rigidity of the amphiphilic bilayer, and this is found to slow the rate of formation of the partially folded apoprotein intermediate. Increasing the mole fraction of DMPC from 0.3 to 0.6 slows the two apparent rate constants associated with formation of this intermediate from 0.29 and 0.031 to 0.11 and 0.013 s-1, respectively. Formation of the intermediate also slows with increasing pH, from 0.11 and 0.013 s-1 at pH 6 to 0.033 and 0.0053 s-1 at pH 8. Since this pH change has no known effect on the phase behavior of lecithins, this is more likely to represent a direct effect on the protein itself. Thus, it appears to be possible to control the rate-limiting process in bacterioopsin folding through both bilayer bending rigidity and pH.

Bacteriorhodopsins↗
PubMed1997

Growth factor-induced transcription of GluR1 increases functional AMPA receptor density in glial progenitor cells.

We analyzed the effects of two growth factors that regulate oligodendrocyte progenitor (O-2A) development on the expression of glutamate receptor (GluR) subunits in cortical O-2A cells. In the absence of growth factors, GluR1 was the AMPA subunit mRNA expressed at the lowest relative level. Basic fibroblast growth factor (bFGF) caused an increase in GluR1 and GluR3 steady-state mRNA levels. Platelet-derived growth factor (PDGF) did not modify the mRNA levels for any of the AMPA subunits but selectively potentiated the effects of bFGF on GluR1 mRNA (4.5-fold increase). The kainate-preferring subunits GluR7, KA1, and KA2 mRNAs were increased by bFGF, but these effects were not modified by cotreatment with PDGF. Nuclear run-on assays demonstrated that PDGF+bFGF selectively increased the rate of GluR1 gene transcription (2.5-fold over control). Western blot analysis showed that GluR1 protein levels were increased selectively (sixfold over control) by PDGF+bFGF. Functional expression was assessed by rapid application of AMPA to cultured cells. AMPA receptor current densities (pA/pF) were increased nearly fivefold in cells treated with PDGF+bFGF, as compared with untreated cells. Further, AMPA receptor channels in cells treated with PDGF+bFGF were more sensitive to voltage-dependent block by intracellular polyamines, as expected from the robust and selective enhancement of GluR1 expression. Our combined molecular and electrophysiological findings indicate that AMPA receptor function can be regulated by growth factor-induced changes in the rate of gene transcription.

Animals↗
PubMed1997

The cystic fibrosis delta F508 gene mutation and cancer.

Following the observation that relatives of cystic fibrosis (CF) patients have an increased mortality due to leukaemia, a study was initiated to determine whether leukaemia patients had an increased prevalence of the delta F508 CF mutation. No increase in carriers were found among leukaemias; however the carrier frequency of the delta F508 mutation appeared to be reduced in patients with malignant melanoma analysed as a control group compared to the normal population. This paper extends our previous study and investigates several other common human tumours, including those of the colon, breast, and lymphoma tissue. Fewer than expected carriers remained among the melanoma group from South Wales. There were fewer than expected carriers among patients with colon cancer compared to the normal population. The prevalence of the delta F508 mutation was normal in lymphomas and leukaemias.

Alleles↗
PubMed1997

Automated chemical synthesis: from resins to instruments.

Solid-phase organic synthesis is now a prevalent activity in drug discovery. In keeping with this keen interest is the need to develop reliable automated synthesis instrumentation as well as polymeric supports and linkers suitable for the full range of organic synthesis applications. In this paper, we review our activities in the development of new and enabling tools for automated chemical synthesis, including the following: (i) new solid supports such as ArgoGel (PS-PEG-based) and Argo-X203 (PS-based); and (ii) the Nautilus 2400 system, a fully closed and inert automated chemistry development workstation. Selected chemistry optimization and synthesis examples performed on the Nautilus and new solid supports will be described.

Automation↗
PubMed1997

Socioeconomic status and adolescent injuries.

Injuries are the major cause of morbidity among children and adolescents in developed countries, but there is a lack of consensus on the relationship between socioeconomic status and risk of injuries. A self-complete questionnaire survey, to gather information on non-fatal injuries and sociodemographic details, was administered in schools during April-June 1994 to a national sample of 4710 Scottish adolescents aged 11, 13 and 15 years. Although there was no evidence of a socioeconomic gradient in the total incidence of medically attended injuries among adolescents, based on the Registrar General's classifications of paternal occupation and a composite measure of family affluence, marked socioeconomic variation in the circumstances in which injuries occurred was observed. There were also socioeconomic differences in the extent and type of risk behaviours reported by adolescents, indicating differential rates of risk exposure. The finding that socioeconomic status affects the kinds of injury events adolescents experience and levels of risk behaviour has implications for the design of injury prevention strategies.

Adolescent↗
PubMed1997

Differential vulnerability of the CA1 and CA3 subfields of the hippocampus to superoxide and hydroxyl radicals in vitro.

The relative roles of the superoxide and hydroxyl radicals in oxidative stress-induced neuronal damage were investigated using organotypic hippocampal slice cultures. Cultures exposed to 100 microM duroquinone, a superoxide-generating compound, for 3 h developed CA1-selective lesions over a period of 24 h. The damage accounted for approximately 64% of the CA1 subfield, whereas CA3 showed just 6% damage, a pattern of damage comparable to that observed following hypoxia/ischaemia. Duroquinone-induced damage was attenuated by a spin-trap agent. In contrast, hydroxyl radical-mediated damage, generated by exposure to 30 microM ferrous sulphate for 1 h, resulted in a CA3-dominant lesion. The damage developed over 24 h, similar to that observed with duroquinone, but with approximately 45% damage in CA3 compared with only 7% in CA1. These data demonstrate a selective vulnerability of the CA1 pyramidal neurones to superoxide-induced damage and suggest that of the free radicals generated following hypoxia/ischaemia, superoxide, rather than hydroxyl radical, is instrumental in producing neuronal damage.

Animals↗
PubMed1997

Enumeration of CD34-positive stem cells: evaluation and comparison of three methods.

Accurate enumeration of CD34+ stem cells is important in assessing the need for continued mobilization and subsequent apheresis collections. We compared two new analysis systems, ProCOUNT (Becton Dickinson Immunocytometry Systems) and IMAGN 2000 STELLer (Biometric Imaging, Inc.) with our current (3-Color) flow cytometry-based method. The ProCOUNT system uses an absolute counting tube, which contains reference beads and a specific (multiple) gating strategy to determine an absolute count. The STELLer assay combines microvolume fluorimetry and automated analysis software to determine an absolute count. To evaluate linearity and reproducibility, peripheral blood was spiked with CD34+ cells (KG1a cell line). Three dilution series (measured at approximately equal to 0, 5, 10, 25, 50, and 100 CD34+ cells/microliter) were analyzed by each method. Analysis of predicted versus actual CD34+ concentration showed excellent correlation with all methods (r2 > or = 0.97, slope 0.98-1.04). To further assess precision, two PBSC samples, at approximately 200 and 800 CD34+ cells/microliter, respectively, were analyzed 10 times by each method. Coefficients of variation for the precision analysis of these samples were 5.1%-6.4% and 5.4%-12.3%, respectively. To assess overall performance, 75 patient specimens were analyzed. Excellent correlation (r2 values of 0.89-0.98) was observed among all three methods. We conclude that the three methods provide comparable linearity and reproducibility.

Antigens, CD34↗
PubMed1997

Information from time-varying vibrotactile stimuli.

Experiments have been carried out to investigate the information transfer available via a single vibrator on the fingertip. In a first experiment, for stimuli with durations 80 to 320 ms, discrimination of a one-octave step change in frequency at the halfway point was investigated. Results were similar for three stimulus types--sinewave, monophasic pulse and tetraphasic pulse--suggesting temporal cues are more important than spectral cues in this task. In a second experiment, subjects were required to perceive changes in a sequence of stimulus elements. A presentation rate of 6.25 elements s-1 was found to give better results than a rate of 12.5 elements s-1. In the former case, the potential information transfer per element was estimated to be approximately 1.0 bits, corresponding to an information transfer rate of around 6 bits s-1. Implications for the design of a tactile aid to lipreading are discussed.

Adult↗
PubMed1997

Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individual patient data.

OBJECTIVE: An excess of obstetric complications in the histories of schizophrenic patients is a well-replicated finding, but less consistent results have been found concerning the relationships between obstetric complications and family history of schizophrenia, age at onset of schizophrenia, and gender. Small sample size limited the power of previous studies that attempted to assess such relationships. The aim of this study was to use data on individual patients from all available studies to examine the links between a history of obstetric complications and family history of schizophrenia, age at onset, and gender. METHOD: Raw data from 854 schizophrenic patients concerning history of obstetric complications rated according to the Lewis and Murray scale were obtained from 11 different research groups. Weighted average estimates were calculated with the use of regression techniques. RESULTS: A significant association was found between age at onset of schizophrenia and obstetric complications: the earlier the age at onset, the more likely the history of obstetric complications. Subjects with onset of schizophrenia before age 22 were 2.7 times more likely than those with onset at a later age to have had a history of abnormal presentation at birth and 10 times more likely to have had a history of complicated Cesarean birth. No association was found between obstetric complications and family history of schizophrenia or gender. CONCLUSIONS: The association between obstetric complications and early age at onset of schizophrenia indicates that the pathophysiology of early-onset schizophrenia involves neurodevelopmental impairment.

Adolescent↗
PubMed1996

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Journal Article↗
PubMed1996

Autoimmune diseases in the pedigrees of schizophrenic and control subjects.

Autoimmune diseases aggregate in individuals and within pedigrees, and it has been postulated that autoimmune mechanisms may account for a proportion of schizophrenia. Structured questionnaires were used to interview the mothers of 121 DSM-III-R schizophrenic patients and the mothers of 116 controls in order to determine the prevalence of schizophrenia and of autoimmune diseases in their pedigrees. Patients with a schizophrenic first degree relative were significantly more likely to also have a parent or sibling with an autoimmune disease (60% vs. 20%, OR = 6.1, 95% CI = 2.3-6.5, p = 0.0003). A significant excess of insulin dependent diabetes mellitus (IDDM) was present in the parents and siblings of schizophrenic patients (OR = 9.65, 95% CI = 1.3-429.2, p = 0.009). These findings suggest that autoimmune mechanisms may play a role in the aetiology of schizophrenia, particularly familial schizophrenia. Associations have been established between autoimmune diseases and the HLA encoding genes of the major histocompatibility complex on chromosome six, and it may be that some of the genetic liability to schizophrenia involves these genes.

Adult↗
PubMed1996

Oligodendrocyte progenitor cell proliferation and lineage progression are regulated by glutamate receptor-mediated K+ channel block.

We have analyzed the role of glutamate and its receptors (GluRs) in regulating the development of oligodendrocytes. Activation of AMPA-preferring GluRs with selective agonists inhibited proliferation of purified cortical oligodendrocyte progenitor (O-2A) cells cultured with different mitogens, as measured by [3H]thymidine incorporation or bromodeoxyuridine staining. In contrast, activation of GABA or muscarinic receptors did not affect O-2A proliferation. Cell viability and apoptosis assays demonstrated that the inhibition of O-2A proliferation was not attributable to a cytotoxic action of GluR agonists, and was reversible. Activation of GluRs prevented lineage progression from the O-2A (GD3+/nestin+) stage to the prooligodendroblast (O4+) stage, but did not affect O-2A migration. Additional experiments examined the membrane ionic channels mediating these GluR activation effects. We found that proliferating O-2A cells expressed functional delayed rectifier K+ channels, which were absent in pro-oligodendroblasts. GluR agonists and the K+ channel blocker tetraethylammonium (TEA) strongly inhibited delayed rectifier K+ currents in O-2A cells. TEA reproduced the effects of GluR activation on O-2A proliferation and lineage progression in the same concentration range that blocked delayed rectifier K+ currents. These results indicate that glutamate regulates oligodendrogenesis specifically at the O-2A stage by modulating K+ channel activity.

Animals↗
PubMed1996

Breast conservation or mastectomy: treatment choice of women aged 70 years and older.

Fifty women aged 70 years and older with newly diagnosed carcinoma of the breast were prospectively studied after being offered a choice of four treatment options. Thirty-four of 38 patients who chose their own treatment had breast conservation; four opted for mastectomy. At 12-month follow-up only two women were unhappy with their choice of treatment. It is concluded that elderly women should be involved in deciding the treatment of their breast cancer.

Aged↗
PubMed1996

Family history of autoimmune diseases in psychosis.

The mothers of 101 psychotic patients and 116 normal controls were interviewed using a semi-structured questionnaire designed to determine the presence or absence of autoimmune disorders in first degree relatives of the probands. Thyrotoxicosis and insulin-dependent diabetes mellitus were significantly more common in the relatives of the psychotic patients than in the control relatives; in particular thyrotoxicosis was more frequent in the mothers of patients (11%) than the mothers of controls (2.6%). None of the examined characteristics of the patients, including RDC-diagnosis, family history of psychosis, age at onset of psychosis and winter birth, was predictive of thyrotoxicosis and insulin-dependent diabetes mellitus in relatives.

Adolescent↗
PubMed1996

Incidence and distribution of injury among schoolchildren aged 11-15.

OBJECTIVES: To measure the incidence and age and sex distribution of self reported experience of injuries in the preceding 12 month period among a representative national sample of Scottish schoolchildren and to validate the findings against other data sources. DESIGN: Self completed questionnaire administered in schools, April-June 1994. SUBJECTS: 4710 pupils aged 11, 13, and 15 years drawn from a representative sample of 270 classes with returns from 224 classes (83.2% completion rate). OUTCOME MEASURES: Number, type, site, and severity of injuries reported. RESULTS: 41.9% of pupils reported a medically attended injury, with injury incidence significantly higher in boys than in girls. Using the abbreviated injury scale (maximum abbreviated injury score) one third of injuries were either moderate or severe. CONCLUSION: The incidence and distribution of self reported injury is consistent with estimates based on other data sources thus confirming the utility of this method of injury surveillance in this age group.

Accidents↗
PubMed1996

Genetic association of the HLA DRB1 gene locus on chromosome 6p21.3 with schizophrenia.

OBJECTIVE: The authors investigated the human leukocyte antigen (HLA) DRB1*04 gene in schizophrenic patients because it is positively associated with rheumatoid arthritis, an autoimmune disease that exhibits a strong negative association with schizophrenia. The HLA DQB1*0602 allele was also studied because of previous reports of genetic association between it and schizophrenia. Maternal HLA was investigated because of the reported association between prenatal influenza and schizophrenia and the central role of HLA molecules in the immune response to viral infections. METHOD: Polymerase chain reactions and sequence-specific oligonucleotide probes were used to genotype 94 unrelated patients with DSM-III-R schizophrenia, 92 mothers of schizophrenic offspring who were not related either to each other or to the 94 patients, and 177 healthy comparison subjects. RESULTS: The frequency of DRB1*04 alleles was significantly lower in both the schizophrenic patients and the unrelated mothers of schizophrenic offspring than in the healthy comparison subjects. No significant differences were found for DQB1*0602. CONCLUSIONS: DRB1*04 alleles may partially account for the genetic predisposition to schizophrenia. The association reported here may be explained by genetic linkage or by an autoimmune pathophysiology for a proportion of schizophrenia cases. Alternatively, it may be that maternal B lymphocytes that do not express the DR4 antigen encoded by DRB1*04 respond to influenza virus by producing antibodies that perturb neurodevelopment, thus underpinning a proportion of schizophrenia cases.

Chromosomes, Human, Pair 6↗