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Biomedical subjects

R J Williams

Publications and source records attributed to R J Williams.

At least 19 recordsLinked to original sources
PubMed1992

Squalestatin 1, a potent inhibitor of squalene synthase, which lowers serum cholesterol in vivo.

Squalestatin 1 is a member of a novel family of fermentation products isolated from a previously unknown Phoma species (Coelomycetes). Squalestatin 1 is a potent, selective inhibitor of squalene synthase, a key enzyme in cholesterol biosynthesis; in vitro, 50% inhibition of enzyme activity is observed at a concentration of 12 +/- 5 nM (range of 4-22 nM). Squalestatin 1 inhibits cholesterol biosynthesis from [14C]acetate by isolated rat hepatocytes (50% inhibition at 39 nM) and by rat liver in vivo. In marmosets, a species with a lipoprotein profile similar to that of man, squalestatin 1 lowers serum cholesterol by up to 75%. This compound will allow further investigation of the control of the sterol biosynthesis pathway and could also lead to the development of new therapies for elevated serum cholesterol.

Animals↗
PubMed1992

The binding of polyamines and magnesium to DNA.

1. The binding of spermine and Mg2+ to DNA has been investigated using the dye arsenazo III to measure unbound cations. 2. The apparent dissociation constant, Kd, of DNA for spermine has been found to be 7.4 +/- 3.9 x 10(-8) M and that for Mg2+, 6.5 +/- 3.3 x 10(-7) M. 3. Binding of spermine in the presence of 1 mM Mg2+ has been shown to have a Kd of about 4 x 10(-6) M. 4. Magnesium ion (2 mM) halves the concentration of spermine needed to cause DNA aggregation. 5. Spermidine binds to DNA with a similar affinity to spermine but 3,3'-iminobispropylamine and 1,5,9,13-tetra-azatridecane bind with a lower affinity. The naturally occurring polyamines thus have a higher affinity for DNA than the related polyamines which do not occur naturally. 6. Binding of spermine or spermidine to DNA alters the spectrophotometric absorbance of DNA at 260 nm.

Animals↗
PubMed1992

An investigation of large inhibitors binding to phosphoglycerate kinase and their effect on anion activation.

This study extends, to a series of larger anions, our earlier investigation of the interaction of the trypanocidal drug suramin and other small negatively charged molecules with yeast phosphoglycerate kinase. 1H-NMR structural studies of phosphoglycerate kinase in the presence of varying concentrations of these large molecules (designed to mimic, at one end, the anionic charge distribution in the substrate 3-phosphoglycerate, while possibly being able to interact across the cleft of the enzyme) including inositol 1,4,5-triphosphate, 4-amino-6-trichloroethenyl-1,3- benzenedisulphonamide, gallic acid and sulphasalazine are described. The anion activation and/or inhibition of the enzyme by these molecules are also reported. Evidence that binding to the general anion site in the 'basic patch' region of the protein may be responsible for either the activating or inhibiting effects, while binding at the hydrophobic (catalytic) site leads to inhibition only is presented. A reaction scheme which explains these observations is given.

Anions↗
PubMed1992

Investigating interdomain region mutants Phe194----Leu and Phe194----Trp of yeast phosphoglycerate kinase by 1H-NMR spectroscopy.

Site-directed mutagenesis has been used to produce two mutant forms of yeast phosphoglycerate kinase in which the interdomain residue Phe194 has been replaced by a leucine or tryptophan residue. Using 1H-NMR spectroscopy, it was found that the mutations at position 194 induce both local and long-range conformational changes in the protein. It was also found that 3-phosphoglycerate binding to the mutant proteins induces somewhat different conformational effects to those observed for wild-type phosphoglycerate kinase. The affinity of mutant Phe194----Trp for 3-phosphoglycerate was found by NMR studies to be unaffected, while the affinity of Phe194----Leu mutant is reduced by about threefold relative to the wild-type enzyme. The binding of ATP at the electrostatic site of the mutant proteins is also seen to be about three times weaker for the Phe194----Leu mutant when compared to wild-type or Phe194----Leu mutant. These results are discussed in the light of the kinetic studies on the mutants which show that for Phe194----Leu mutant the Km values for both 3-phosphoglycerate and ATP, as well as the Vmax, are decreased relative to the wild-type enzyme, while for mutant Phe194----Trp, the Km values for 3-phosphoglycerate and ATP are unaffected and the Vmax is decreased when compared to wild-type enzyme. Kinetic studies in the presence of sulphate reveal that the anion activation is greater for mutant Phe194----Trp and less for mutant Phe194----Leu, relative to that observed for wild-type phosphoglycerate kinase. The NMR data, taken together with the kinetic data, are consistent with the on and off rates of 3-phosphoglycerate being affected by the mutations at position 194. It is suggested that Phe194 is important for the mobility of the interdomain region and the relative movement of the 3-phosphoglycerate binding site which allows the optimum conformation for catalysis to be attained. Apparently Trp194 reduces the mobility of the interdomain region of the protein, while Leu194 increases it.

Adenosine Triphosphate↗
PubMed1992

Three-dimensional structure of acylphosphatase. Refinement and structure analysis.

We report here the complete determination of the solution structure of acylphosphatase, a small enzyme that catalyses the hydrolysis of organic acylphosphates, as determined by distance geometry methods based on nuclear magnetic resonance information. A non-standard strategy for the distance geometry calculations was used and is described here some detail. The five best structures were then refined by restrained energy minimization and molecular dynamics in order to explore the conformational space consistent with the experimental data. We address the question of whether the solution structure of acylphosphatase follows the general principles of protein structure, i.e. those learned from analysing crystal structures. Static and dynamic features are discussed in detail. An uncommon beta-alpha-beta motif, so far found only in procarboxypeptidase B and in an RNA-binding protein, is present in acylphosphatase.

Acid Anhydride Hydrolases↗
PubMed1992

Electron-proton coupling in cytochrome c studied using protein variants.

An NMR study of the cytochrome c variant Asn52Ile is used to show how the redox state change in native cytochrome c is coupled to a rearrangement of a proton network which runs through the cytochrome c molecule. The substitution breaks the H-bond network and removes the coupling. The uncovering of this putative proton channel and the connection of changes to it with redox state changes of the iron centre of the protein allows a possible description of the way in which redox energy state changes can be coupled to energization and gating of protons in membranes.

Amino Acid Sequence↗
PubMed1992

Elemental analysis of neurofibrillary tangles in Alzheimer's disease using proton-induced X-ray analysis.

We have investigated the elemental content of hippocampal slices from normal human brain and from brains of Alzheimer's disease patients by X-ray fluorescence using both electron and proton beam microprobes. The sections have been stained with a dye--toluidine blue--which contains sulphur so that the X-ray fluorescence map can be correlated with known intracellular sites as seen under the light microscope. The results show that associated with neurofibrillary tangles and Hirano bodies (the distinctive internal visual features of cells from Alzheimer's disease patients) there is increased calcium. We cannot confirm that there are peculiarities in the distribution of aluminium in cells.

Alzheimer Disease↗
PubMed1992

Imaging the complex impedance of the thorax.

Respiration-related changes in the complex impedance were obtained on the thorax in three volunteers. The real part of the image clearly showed the lungs as regions of increased conductivity on expiration. The imaginary part of the image, reflecting changes in the ratio of permittivity to conductivity, showed a central negative region surrounded by a positive region extending to the periphery of the lungs. These features may be due to movement of the diaphragm and liver within the sensitive volume during respiration.

Adult↗
PubMed1992

Hospital admissions of adolescent patients with diabetes.

This study formed part of a psychological survey of young people aged 10-17 years attending three Bristol diabetes clinics. The aim was to examine the characteristics of those who were admitted to hospital with unstable diabetes during the period between two assessments, and analyse how they differed from the rest. Ten young people were admitted to hospital during the study period. These 10 individuals had greater emotional difficulty with diabetes as measured by diabetes specific psychometric scales (median scale score: 19) compared to the 89 adolescents who were not readmitted (median scale score: 14) (p = 0.01). They did not differ in demographic characteristics or glycaemic control. Overall there was no relationship between psychological response to diabetes and glycaemic control as assessed by mean glycated haemoglobin. Five of those admitted presented with hyperglycaemia; they had greater emotional difficulty (median scale score: 31, p = 0.02) and a more negative attitude (median scale score: 22, p = 0.02) to diabetes than those presenting with hypoglycaemia (median scale scores: 16). Only those with hyperglycaemia differed from those who were not readmitted, having greater emotional difficulty (p = 0.002) and a more negative attitude (p = 0.01). The possibility of psychological difficulties with diabetes should be sought following an admission, particularly for hyperglycaemia.

Adolescent↗
PubMed1992

Preparations for war in a Saudi Arabian host nation hospital.

This paper describes how the King Fahad National Guard Hospital in Riyadh, The Kingdom of Saudi Arabia, integrated United States Army (USA) medical units and prepared the hospital to receive war casualties during Operation Desert Storm. In particular, preparation of the hospital, the staff, and military systems are reviewed. The report will also discuss operations at the hospital during Operation Desert Storm and the major lessons learned. Comment is provided by the host nation hospital regarding the impact of the experience with the USA medical units and their personnel.

Hospitals, Military↗
PubMed1992

Inhibition of interleukin 1 induced chondrocyte protease activity by a corticosteroid and a nonsteroidal antiinflammatory drug.

We report that administration of the corticosteroid, methylprednisolone (PRED) inhibited interleukin 1 (IL-1) induction of chondrocyte caseinolytic activity (25-55%) and collagenolytic activity (15-24%). The nonsteroidal antiinflammatory drug (NSAID), naproxen (NAP) had no effect on either enzyme activity over a therapeutic range (7-30 micrograms/ml) but at 120 micrograms/ml inhibited IL-1 induced caseinolytic and collagenolytic activity by 17 and 19%, respectively. However, PRED (2 micrograms/ml) in combination with NAP (30 micrograms/ml) significantly increased the inhibition of caseinolytic activity (p less than 0.001) compared to that observed with PRED (2 micrograms/ml) alone. The suppression of IL-1 induced collagenolytic activity noted with PRED in combination with NAP did not exceed that observed with PRED alone.

Adrenal Cortex Hormones↗