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Biomedical subjects

J Rayner

Publications and source records attributed to J Rayner.

At least 19 recordsLinked to original sources
PubMed2003

Functional expression cloning reveals proapoptotic role for protein phosphatase 4.

Functional expression cloning strategies are highly suitable for the analysis of the molecular control of apoptosis. This approach has two critical advantages. Firstly, it eliminates prior assumptions about the properties of the proteins involved, and, secondly, it selectively targets proteins that are causally involved in apoptosis control and which affect the crucial cellular decision between survival and death. The application of this strategy to the isolation of cDNAs conferring resistance to dexamethasone and gamma-irradiation resulted in the isolation of a partial cDNA for the catalytic subunit of protein phosphatase 4 (PP4). Cells transfected with this partial cDNA in an expression vector downregulated PP4 and were resistant to both dexamethasone and UV radiation, as demonstrated by both membrane integrity and colony-forming assays. These observations suggest that PP4 plays an important proapoptotic role in T lymphocytes.

Animals↗
PubMed2003

Modelling the immunogenicity of therapeutic proteins using T cell epitope mapping.

A new approach to designing therapeutic proteins is emerging, due to an improved understanding of T cell modulation of the immune response and new methods for modelling T cell epitopes using bioinformatics. In silico T cell epitope-mapping using the bioinformatics, when combined with other ex silico means of evaluating MHC-peptide and T cell interaction such as tetramers and HLA transgenic mice, enables the evaluation of dysfunctional immune responses to therapeutic proteins. This approach may even permit researchers to develop means of modulating anticipated adverse effects. The pocket profile method for developing T cell epitope prediction tools is reviewed here, and a comparison between the pocket profile method and the extended anchor method for epitopes restricted by the class II allele HLA DR B*0101 is described.

Animals↗
PubMed2001

Biofilm penetration and disinfection efficacy of alkaline hypochlorite and chlorosulfamates.

AIMS: The purpose of this study was to compare the efficacy, in terms of bacterial biofilm penetration and killing, of alkaline hypochlorite (pH 11) and chlorosulfamate (pH 5.5) formulations. METHODS AND RESULTS: Two species biofilms of Pseudomonas aeruginosa and Klebsiella pneumoniae were grown by flowing a dilute medium over inclined stainless steel slides for 6 d. Microelectrode technology was used to measure concentration profiles of active chlorine species within the biofilms in response to treatment at a concentration of 1000 mg total chlorine l(-1). Chlorosulfamate formulations penetrated biofilms faster than did hypochlorite. The mean penetration time into approximately 1 mm-thick biofilms for chlorosulfamate (6 min) was only one-eighth as long as for the same concentration of hypochlorite (48 min). Chloride ion penetrated biofilms rapidly (5 min) with an effective diffusion coefficient in the biofilm that was close to the value for chloride in water. Biofilm bacteria were highly resistant to killing by both antimicrobial agents. Biofilms challenged with 1000 mg l(-1) alkaline hypochlorite or chlorosulfamate for 1 h experienced 0.85 and 1.3 log reductions in viable cell numbers, respectively. Similar treatment reduced viable numbers of planktonic bacteria to non-detectable levels (log reduction greater than 6) within 60 s. Aged planktonic and resuspended laboratory biofilm bacteria were just as susceptible to hypochlorite as fresh planktonic cells. CONCLUSION: Chlorosulfamate transport into biofilm was not retarded whereas hypochlorite transport clearly was retarded. Superior penetration by chlorosulfamate was hypothesized to be due to its lower capacity for reaction with constituents of the biofilm. Poor biofilm killing despite direct measurement of effective physical penetration of the antimicrobial agent into the biofilm demonstrates that bacteria in the biofilm are protected by some mechanism other than simple physical shielding by the biofilm matrix. SIGNIFICANCE AND IMPACT OF THE STUDY: This study lends support to the theory that the penetration of antimicrobial agents into microbial biofilms is controlled by the reactivity of the antimicrobial agent with biofilm components. The finding that chlorine-based biocides can penetrate, but fail to kill, bacteria in biofilms should motivate the search for other mechanisms of protection from killing by antimicrobial agents in biofilms.

Animals↗
PubMed2000

How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis.

Therapy for transplant rejection, autoimmune disease and allergy must target mature lymphocytes that have escaped censoring during their development. FK506 and cyclosporin are immunosuppressants which block three antigen-receptor signalling pathways (NFAT, NFkappaB and JNK), through inhibition of calcineurin, and inhibit mature lymphocyte proliferation to antigen. Neither drug induces long-lived tolerance in vivo, however, necessitating chronic use with adverse side effects. Physiological mechanisms of peripheral tolerance to self-antigens provide an opportunity to emulate these processes pharmacologically. Here we use gene-expression arrays to provide a molecular explanation for the loss of mitogenic response in peripheral B-cell anergy, one aspect of immunological tolerance. Self-antigen induces a set of genes that includes negative regulators of signalling and transcription but not genes that promote proliferation. FK506 interferes with calcium-dependent components of the tolerance response and blocks an unexpectedly small fraction of the activation response. Many genes that were not previously connected to self-tolerance are revealed, and our findings provide a molecular fingerprint for the development of improved immunosuppressants that prevent lymphocyte activation without blocking peripheral tolerance.

Animals↗
PubMed2000

B-lymphocyte quiescence, tolerance and activation as viewed by global gene expression profiling on microarrays.

Self-tolerance is achieved by deleting or regulating self-reactive lymphocytes at a series of cellular checkpoints placed at many points along the developmental pathways to plasma cells and effector T cells. At each checkpoint, what are the molecular pathways that determine whether a lymphocyte remains quiescent, begins dividing, differentiates or dies? In splenic B cells, the decision between quiescence, tolerance by anergy, and activation provides a tractable setting to explore these issues by global gene expression profiling on DNA microarrays. Here we discuss the application of microarrays to illuminate a set of cell fate decisions that appear to be determined by summation of numerous small changes in expression of stimulatory and inhibitory genes. Many genes with known or predicted inhibitory functions are highly expressed in naive, quiescent B cells, notably the signal inhibitor SLAP and DNA-binding proteins of the Kruppel family (LKLF, BKLF, GKLF), Tsc-22, GILZ, Id-3, and GADD45. Activation of naive B cells, triggered by acute binding of antigen to the B-cell receptor, involves a rapid decrease in expression of these inhibitory genes. Promitotic genes are induced in parallel, including c myc, LSIRF/IRF4, cyclin D2, Egr-1 and Egr-2, as are the anti-apoptotic gene A1 and genes for the T-cell-attracting chemokines MIP-1alpha and beta. B-cell tolerance through the process of anergy, induced by chronic binding of self antigen, maintains expression of the inhibitory genes found in quiescent B cells and induces an additional set of inhibitory genes. The latter include inhibitors of signaling - CD72, neurogranin, pcp4 - and additional inhibitors of gene expression such as SATB1, MEF2C, TGIF and Nab-2. The effects of tolerance, the immunosuppressive drug FK506 and other modulators of calcium or MAPK signaling allow individual gene responses to be linked to different signal transduction pathways. The global molecular profiles obtained illustrate how quiescence and anergy are actively maintained in circulating B cells, how these states are switched to clonal expansion and how they could be better emulated by pro-tolerogenic drugs.

Animals↗
PubMed2000

Effect of catalase on hydrogen peroxide penetration into Pseudomonas aeruginosa biofilms.

The penetration of hydrogen peroxide into biofilms formed by wild-type and catalase-deficient Pseudomonas aeruginosa strains was measured using microelectrodes. A flowing stream of hydrogen peroxide (50 mM, 1 h) was unable to penetrate or kill wild-type biofilms but did penetrate and partially kill biofilms formed by an isogenic strain in which the katA gene was knocked out. Catalase protects aggregated bacteria by preventing full penetration of hydrogen peroxide into the biofilm.

Biofilms↗
PubMed1996

Measuring leg thrust forces in the common starling

We describe the design of a force-transducing perch which measures the reaction forces of small birds taking off and landing. In common starlings, landing forces are lower than take-off forces, because the bird may decelerate prior to landing by using its wings. Both landing and take-off forces are significantly correlated with body mass; however, the angles of these reaction forces show no significant mass-dependence and are not repeatable within individuals. Diversity in take-off or landing strategy could be advantageous in confusing predators.

Journal Article↗
PubMed1995

p53 represses SV40 transcription by preventing formation of transcription complexes.

There is now much evidence to suggest that the p53 tumour suppressor protein functions to monitor the integrity of the genome. When DNA damage is detected, p53 suppresses cell growth to allow repair or directs the cell into apoptosis. The mechanism of action of p53 is as yet unclear but recent evidence has accumulated to suggest that p53 might act by regulating gene expression. Consistent with this model, p53 can both activate and repress a number of viral and cellular promoters. p53 has also been shown to bind to the CCAAT-binding Factor and TATA-binding protein (TBP), and there is direct evidence that p53 represses in vitro transcription by preventing TBP from binding DNA. We now provide evidence that p53 can repress transcription from the SV40 promoter by disrupting DNA/protein complexes involving transcription factor Sp1.

Animals↗
PubMed1995

The moment of inertia of bird wings and the inertial power requirement for flapping flight

The agility and manoeuvrability of a flying animal and the inertial power required to flap the wings are related to the moment of inertia of the wings. The moments of inertia of the wings of 29 bird species and three bat species were determined using wing strip analysis. We also measured wing length, wing span, wing area, wing mass and body mass. A strong correlation (r2=0.997) was found between the moment of inertia and the product of wing mass and the square of wing length. Using this relationship, it was found that all birds that use their wings for underwater flight had a higher than average moment of inertia. Assuming sinusoidal wing movement, the inertial power requirement was found to be proportional to (body mass)0.799, an exponent close to literature values for both metabolic power output and minimum power required for flight. Ignoring wing retraction, a fairly approximate estimate showed that the inertial power required is 11­15 % of the minimum flight power. If the kinetic energy of the wings is partly converted into aerodynamic (useful) work at stroke reversal, the power loss due to inertial effects may be smaller.

Journal Article↗
PubMed1994

Transcriptional regulation of the PCNA promoter by p53.

We have examined the ability of p53 to affect transcription from the PCNA promoter in a number of cell types. In HeLa cells, p53 activates the PCNA promoter whereas in CV1, CHO, L929, and Saos-2 cells the same promoter is strongly repressed. By using stepwise deletions of the PCNA promoter, we have identified two potential regions of the promoter which are important for the ability of p53 to activate transcription in HeLa cells.

Animals↗
PubMed1994

A mutation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and IL-5 that leads to ligand independence and tumorigenicity.

The cytokines interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor bind with high affinity to a receptor complex that contains a ligand-specific alpha-chain and a common beta-chain, h beta c. We report here the isolation of a mutant form of h beta c, from growth factor-independent cells, that arose spontaneously after infection of a murine factor-dependent hematopoietic cell line (FDC-P1) with a retroviral h beta c expression construct. Analysis of this h beta c mutation shows that a small (37 amino acid) duplication of extracellular sequence that includes two conserved sequence motifs is sufficient to confer ligand-independent growth on these cells and lead to tumourigenicity. Because this is a conserved region in the cytokine receptor superfamily, our results suggest that the large family of cytokine receptors has the capacity to become oncogenically active.

Amino Acid Sequence↗
PubMed1992

Cationic defensins arise from charge-neutralized propeptides: a mechanism for avoiding leukocyte autocytotoxicity?

Defensins, small cationic polypeptides with antimicrobial and cytotoxic properties, are among the principal constituents of cytoplasmic granules of mammalian neutrophils and certain macrophages. To identify conserved structural features of defensin precursors that may be important for their targeting to cytoplasmic granules or for prevention of autocytotoxicity, we isolated and sequenced three neutrophil-specific rabbit defensin cDNAs that code for preproprotein precursors to the mature defensins NP-3a, NP-4, and NP-5. The preprodefensins NP-3a, NP-4, and NP-5, like the previously characterized preprodefensins, lack consensus sequences for N-linked glycosylation, suggesting that defensins are targeted to lysosome-like granules by a mechanism not dependent on the mannose-6-phosphate receptor. Analysis of all seven known myeloid prodefensins revealed a structure wherein an anionic propiece neutralizes the cationicity of the mature peptide. Because defensins apparently require cationic epitopes for cell membrane permeabilization and cytotoxicity, charge neutralization of mature peptides by their anionic propieces may prevent autocytotoxicity during defensin synthesis and processing.

Amino Acid Sequence↗
PubMed1990

Cancer and other causes of death among a cohort of dry cleaners.

Mortality among 5365 members of a dry cleaning union in St. Louis, Missouri, was less than expected for all causes combined (SMR = 0.9) but slightly raised for cancer (SMR = 1.2). Among the cancers, statistically significant excesses occurred for oesophagus (SMR = 2.1) and cervix (SMR = 1.7) and non-significant excesses for larynx (SMR = 1.6), lung (SMR = 1.3), bladder (SMR = 1.7), thyroid (SMR = 3.3), lymphosarcoma and reticulosarcoma (SMR = 1.7), and Hodgkin's disease (SMR = 2.1). Mortality from emphysema was also significantly raised (SMR = 2.0). Eleven of the 13 deaths from oesophageal cancer occurred among black men. The risk of this cancer showed a significant association with estimated cumulative exposure to dry cleaning solvents (rising to 2.8-fold in the highest category) but not with level or duration of exposure. Mortality from kidney cancer was not excessive as reported in other studies. Excesses for emphysema and cancers of the larynx, lung, oesophagus, bladder, and cervix may be related to socioeconomic status, tobacco, or alcohol use. Although the number of deaths was small, the greatest risk for cancers of the lymphatic and haematopoietic system (fourfold) occurred among workers likely to have held jobs where exposures were the heaviest. Small numbers and limited information on exposure to specific substances complicates interpretation of this association but is unlikely to be due to confounding by tobacco use. It was not possible to identify workers exposed to specific dry cleaning solvents but mortality among those entering the union after 1960, when use of perchloroethylene was predominant, was similar to those entering before 1960.

Cause of Death↗
PubMed1979

Predicting drug-free improvement in schizophrenic psychosis.

In a sample of 22 psychotic schizophrenic patients, eight improved substantially during a 30-day drug-free period. The drug-free improver group differed from the nonimprover group in demonstrating a later age of onset, briefer psychotic episodes, shorter hospitalizations, and better prognostic scores on the Phillips Scale, Strauss-Carpenter Modified Prognostic Scale, and the Vaillant Scale. After drug withdrawal, drug-free improvers frequently demonstrated further improvement when treated with doses of neuroleptic drugs that were substantially lower than the clinically recommended doses. The authors raise the question as to whether the drug-free improvers may represent a subgroup of schizophrenic patients who are being overtreated presently by standard neuroleptic practice.

Adolescent↗
PubMed1976

Evaluating signs and symptoms: comparison of structured interview ans clinical approaches.

Are research interview techniques adequate in assessing signs and symptoms? This question is investigated by obtaining two sets of interview schedule ratings on 49 patients, one by a research psychiatrist applying the interview and one by the patient's psychiatrist using all available information. The latter was considered a clinical standard with which a cross-sectional research interview could be contrasted. These two data sets were subjected to several types of analysis commonly undertaken with research interview ratings. Results indicated that the research interview adequately represents symptom data, but is seriously lacking in the assessment of observed behaviour. The effect of this difference depends on the goals of the study and the nature of the data analysis. If overall group findings are desired, or if analysis relies primarily on symptom data, results with a research interview may be similar to results based on a far more extensive evaluation. On the other hand, if conclusions are to be drawn on individual patients, or if data analysis relies heavily on observed behaviour, then data derived from research interviews are questionable.

Behavior↗