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Biomedical subjects

D McMurray

Publications and source records attributed to D McMurray.

8 recordsLinked to original sources
PubMed2001

Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction.

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Interruption of the cydB locus in Brucella abortus attenuates intracellular survival and virulence in the mouse model of infection.

Brucellosis is characterized by abortion in ruminants and a protracted undulant fever in humans, which often results in severe pathological manifestations. Scant information exists about the molecular mechanisms employed by Brucella abortus to combat host defenses or to persist and replicate within host cells. Transposon (Tn5) mutagenesis of B. abortus and the subsequent screening of mutants for sensitivity to killing in murine macrophages and in the mouse model led to the identification of mutants which were severely attenuated for intracellular survival. One group of mutants was interrupted in cydB, a gene that is part of the cydAB operon encoding cytochrome bd oxidase, which catalyzes an alternate terminal electron transport step in bacterial respiration. The elevated affinity for molecular oxygen of this enzyme in Escherichia coli has suggested that it is involved in the protection of sensitive enzymatic activities such as those of hydrogenases and nitrogenases from damage. B. abortus cydB::Tn5 strains exhibited heightened sensitivity to the respiratory inhibitors zinc and azide, highly reactive oxygen species such as hydrogen peroxide, low pH, and attenuated virulence in the mouse model of infection. Virulence was restored by an intact copy of cydAB or by B. abortus genes encoding the oxidative radical-scavenging enzyme Cu/Zn superoxide dismutase or catalase. These results suggest a bifunctional role for the products of the cydAB operon, both in preventing the buildup of oxidative free radicals and in detoxifying the intracellular compartment, thus indicating the importance of these products in preventing intracellular destruction. Intracellular conditions that favor expression of the cydAB operon are under investigation and may be linked to the acid sensitivity also observed in this strain.

Animals↗
PubMed1995

Outcome of wheeze in childhood: the influence of atopy.

We have previously demonstrated that the adult outcome of childhood asthma differs from that of wheeze occurring only in the presence of infection. This paper examines the role of atopy in relation to outcome. We investigated the atopic status, current symptoms and bronchial reactivity to methacholine of 235 subjects aged 34-40 yrs, originally classified at age 10-15 yrs as having asthma (asthma group), wheeze only in the presence of infection (wheezy group), or no respiratory symptoms (comparison group). Subjects from the original asthma group were more likely to be atopic as defined by skin test reactivity, total serum immunoglobulin E (IgE) measurement or specific IgE radio allergosorbent test (RAST) measurement than those from the wheezy group. The wheezy group differed significantly from the reference group only in RAST results, when other variables were taken into account. In a logistic regression model, the important independent predictors for adult wheezing symptoms were original group, atopy and current smoking. Methacholine responsiveness was independently associated with original group (the asthma group were more likely to respond positively), atopy and female gender. The results suggest that atopy is an important predictor for wheeze and bronchial hyperreactivity in middle age. However, the difference in outcome for children who had asthma compared to those who had wheeze only in the presence of infection cannot be explained by atopy alone.

Adolescent↗
PubMed1994

Outcome of wheeze in childhood. Symptoms and pulmonary function 25 years later.

The outcome after 25 yr was studied for three groups of children classified in a random community survey in 1964 as having asthma (121 subjects), wheeze in the presence of infection (167 subjects), or no respiratory symptoms (167 comparison subjects). Approximately 80% of the subjects in each group, now aged 34 to 40 yr, were successfully traced. Current symptoms and smoking habit were recorded by questionnaire, and ventilatory function, peak flow variability, and bronchial reactivity to inhaled methacholine were measured. Subjects who had asthma in childhood were more likely to wheeze (odds ratio [OR] 14.4) or produce phlegm (OR 3.3) than comparison subjects. They also had significantly lower FEV1 values and greater bronchial reactivity than comparison subjects. Adult FEV1 correlated with childhood FEV1 (both expressed as % of predicted) (r = 0.44, p < 0.01). The prognosis for those children who were classed as having wheeze in the presence of infection in 1964 was better than for those who had asthma. Although they also were more likely to report wheeze (OR 3.8) or phlegm (OR 4.4) than comparison subjects, the wheezy symptoms were unlikely to interfere with activities and the ventilatory function and bronchial reactivity to methacholine did not differ from those of comparison subjects. Smokers were more likely to report wheeze (OR 2.0), cough (OR 7.2), and phlegm (OR 3.1) than never-smokers, and current smokers with current wheezy symptoms had significantly reduced FEV1 values, although smoking was not associated with increased methacholine reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Asthma↗
PubMed1992

Social effects of wheeze in childhood: a 25 year follow up.

OBJECTIVES: To determine the outcome of childhood wheeze in terms of education, employment, housing, and social class. DESIGN: 25 year follow up study. SETTING: Community study based at the department of thoracic medicine, Aberdeen Royal Infirmary. PARTICIPANTS: Three groups of subjects who had been identified in a random community survey in 1964: those who had had asthma in childhood (n = 97), those who had wheezed only in the presence of upper respiratory tract infections (n = 132), and a comparison group who had had no respiratory symptoms as children (n = 131). Subjects were aged 34 to 40 years at the time of the current study. MAIN OUTCOME MEASURES: Interview and questionnaire data on education, employment, housing and social class, ventilatory function, and peak flow rate. RESULTS: Pulmonary function testing showed that only the "asthmatic" group had airways obstruction; this group showed greater peak flow variation than the "wheezy" group, which did not differ from the comparison group. The asthmatic subjects were more likely to have experienced respiratory problems during their school years and associated with their work. Despite these problems, educational attainment, employment, housing, and eventual social class were similar for all three groups. CONCLUSION: Childhood wheeze did not adversely affect education, employment, housing, or social class in this population.

Asthma↗
PubMed1971

A co-operative evaluation of test systems used to assay tuberculosis vaccines.

The results of research on the immunogenicity of experimental mycobacterial vaccines are characterized by a remarkable lack of agreement about which substances are most immunogenic. The disagreement has usually been attributed to the differences in the methods of preparing the vaccines. An alternative hypothesis is that the conflicting results are a product of the different methods used to assess the potency of the vaccines.To determine if the method by which a vaccine is tested is a major factor contributing to the disagreement, an experiment was conducted in which a series of five different vaccines was distributed to each of nine participating laboratories. Each investigator evaluated the potency of the vaccines in one or more animal models of his own choosing. This in effect held the method of vaccine preparation constant while permitting all other variables to change.The ranking of the five vaccines was random, thus demonstrating that the method by which a vaccine is tested influences the apparent potency of a vaccine. These results cast doubt on the conclusions about the relative potency of tuberculosis vaccines evaluated by different methods.

Animals↗