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Biomedical subjects

E M Nicholson

Publications and source records attributed to E M Nicholson.

9 recordsLinked to original sources
PubMed2000

Adverse effect of previous bronchial asthma on disability in chronic airflow obstruction.

The average distance covered when attempting to hurry on the level for 12 min (12 min walking distance) is linearly correlated to forced expiratory volume in 1 s in healthy middle-aged individuals and patients with chronic airflow obstruction. Patients with current or past asthma, with or without chronic bronchitis and emphysema, walk more slowly than those with chronic obstructive pulmonary disease for a similar degree of airflow obstruction. A previous history of asthma may be a factor in the limitation of effort caused by chronic respiratory disease.

Asthma↗
PubMed1999

Increased helix and protein stability through the introduction of a new tertiary hydrogen bond.

In an effort to quantify the importance of hydrogen bonding and alpha-helix formation to protein stability, a capping box motif was introduced into the small phosphocarrier protein HPr. Previous studies had confirmed that Ser46, at the N-cap position of the short helix-B in HPr, serves as an N-cap in solution. Thus, only a single-site mutation was required to produce a canonical S-X-X-E capping box: Lys49 at the N3 position was substituted with a glutamic acid residue. Thermal and chemical denaturation studies on the resulting K49E HPr show that the designed variant is approximately 2 kcal mol-1 more stable than the wild-type protein. However, NMR studies indicate that the side-chain of Glu49 does not participate in the expected capping H-bond interaction, but instead forms a new tertiary H-bond that links helix-B to the four-stranded beta-sheet of HPr. Here, we demonstrate that a strategy in which new non-native H-bonds are introduced can generate proteins with increased stability. We discuss why the original capping box design failed, and compare the energetic consequences of the new tertiary side-chain to main-chain H-bond with a local (helix-capping) side-chain to main-chain H-bond on the protein's global stability.

Amino Acid Substitution↗
PubMed1996

Influence of N-cap mutations on the structure and stability of Escherichia coli HPr.

This paper describes the effect of N-capping substitutions on the structure and stability of histidine-containing protein (HPr). We have used NMR spectroscopy and conformational stability studies to quantify changes in local and global free energy due to mutagenesis at Ser46, the N-cap for helix B in HPr. Previous NMR studies suggested that helix B of Escherichia coli HPr is dynamic as judged by the rate of exchange of amide protons with solvent. Ser46 was chosen because it is the site of regulatory phosphorylation in HPrs from Gram-positive bacteria, and mutation of this residue to an aspartic acid (S46D) in E. coli HPr (Gram-negative) also makes it a poor substrate in the bacterial phosphoenolpyruvate: sugar phosphotransferase system. Therefore, to understand the mechanism of inactivation of E. coli S46D HPr, as well as the effect of mutagenesis on protein stability, we have characterized three mutants of E. coli HPr: Ser46 has been mutated to an Asp, Asn, and Ala in S46D, S46N, and S46A HPrs, respectively. The results indicate that these N-cap replacements have a marked influence on helix B stability. The effect of mutagenesis on local stability is correlated to global unfolding of HPr. The ability of amino acids to stabilize helix B is Asp > Asn > Ser > Ala. In addition, since there are neither large-scale conformational changes nor detectable changes in the active site of S46D HPr, it is proposed that the loss of phosphotransfer activity of S46D HPr is due to unfavorable steric and/or electrostatic interactions of the Asp with enzyme I of the PTS.

Bacterial Proteins↗
PubMed1996

Conformational stability of the Escherichia coli HPr protein: test of the linear extrapolation method and a thermodynamic characterization of cold denaturation.

The conformational stability of the histidine-containing phosphocarrier protein (HPr) from Escherichia coli has been determined using a combination of thermal unfolding and urea denaturation experiments. The analysis of the denaturation data provides a measure of the changes in conformational free energy, enthalpy, entropy, and heat capacity that accompany the equilibrium folding of HPr over a wide range of temperature and urea concentrations. In moderate concentrations of urea, HPr undergoes both high- and low-temperature unfolding, allowing for a reliable determination of the change in heat capacity for the conformational transition. The data are consistent with the linear free energy relationship commonly employed to analyze protein denaturation data, even over a relatively large temperature and urea concentration range. Furthermore, we find that a temperature-independent delta Cp is adequate to describe HPr stability over the accessible temperature range. Finally, our data allow us to evaluate the energetics of the urea-protein interaction. For HPr, the changes in excess enthalpy and entropy of the denaturant-protein interaction(s) make only minor contributions to the observed delta H and delta S terms, presumably due in some part to the small size of the HPr protein.

Bacterial Proteins↗
PubMed1987

Grading of dyspnoea and walking speed in cardiac disease and in chronic airflow obstruction.

A five-point dyspnoea scale (modified MRC questionnaire) and 12-minute walking test were used to compare the relationship between subjective assessment of dyspnoea and objective measurement of disability in patients with chronic airflow limitation, cardiac disease, and normal subjects. There was no overall difference in exercise performance between the cardiac and respiratory groups. There was a significant correlation between vital capacity and exercise performance, and the slope of the regression line was similar in the two groups. There was no correlation between vital capacity and exercise performance in the group of normal subjects. The five-point dyspnoea scale predicts similar levels of performance in the 12-minute walking test whether the dyspnoea is a result of cardiac or respiratory disease.

Adult↗
PubMed1982

Computed tomography in pulmonary emphysema.

Fifty-three patients with chronic obstructive airways disease and 19 age-matched controls were studied using computed tomography (CT). The study shows that CT can detect the presence and distribution of pulmonary emphysema. Pulmonary vascular changes detectable on chest radiography correlate well with lung density as measured by CT. Patients with marked CT changes of emphysema had significantly greater impairment of diffusion capacity and FEV1.0/VC than the patients with less severe changes.

Adult↗