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Biomedical subjects

A C Wilson

Publications and source records attributed to A C Wilson.

At least 181 records · Page 10Linked to original sources
PubMed1984

Local effects of amino acid substitutions on the active site region of lysozyme: a comparison of physical and immunological results.

Differences in the binding of the substrate analogue chitotriose to lysozymes correlate with amino acid substitutions in the binding site and not with substitutions elsewhere. This is evident from binding studies done with an immunological method as well as a conventional spectroscopic method. The immunological technique, based on the microcomplement fixation assay, required thousands of times less lysozyme than did the conventional technique. For eight bird lysozymes of known amino acid sequence, the immunologically and physically measured association constants were in approximate agreement. Five of the eight lysozymes have about the same affinity for chitotriose and have identical amino acids at the sites of contact between substrate and enzyme. In contrast, the three lysozymes that have altered affinities have amino acid substitutions in the binding site. Some of the lysozymes with similar affinities for chitotriose differ greatly in amino acid sequence outside the binding site. This suggests that evolutionary substitutions do not generally have long-range effects on the active site region of lysozyme.

Animals↗
PubMed1984

The effect of phenobarbitone pre-treatment on vitamin K1 disposition in the rat and rabbit.

The effect of phenobarbitone enzyme induction on the pharmacokinetics of an intravenous pharmacological dose (1 mg/kg) of vitamin K1 was studied in the rabbit. Phenobarbitone pretreatment significantly (P less than 0.01) increased the plasma clearance of vitamin K1 and decreased the terminal (beta) half-life from 2.08 +/- 0.56 to 0.99 +/- 0.30 hr. However, phenobarbitone pretreatment did not alter the pharmacodynamic response to vitamin K1 measured as the increase in prothrombin complex activity, in brodifacoum-anticoagulated rabbits. In the rat, phenobarbitone enzyme induction increased the extent and rate of biliary excretion of polar vitamin K1 metabolites following intravenous administration of the vitamin. Perturbation of vitamin K1 metabolism by phenobarbitone enzyme induction is not dependent on the concentration of the vitamin. The greater hepatic elimination resulted in lower systemic blood concentrations of both vitamin K1 and the 2,3-epoxide. A similar reduction in the concentration of vitamin K1 in the blood of epileptic mothers treated with anticonvulsants such as phenobarbitone may explain the coagulation defect frequently observed in their offspring [K. R. Mountain, J. Hirsh and A.S. Gallus, Lancet ii, 265 (1970)].

Animals↗
PubMed1984

Molecular evolution in Drosophila and the higher Diptera II. A time scale for fly evolution.

In this paper, we examine first the steadiness of the rate of evolutionary change in a larval hemolymph protein, LHP, in numerous Drosophila species. We estimated amino acid sequence divergence from immunological distances measured with the quantitative microcomplement fixation technique. Using tests not depending on knowledge of absolute times of divergence, we estimated the variance of the rate of evolutionary change to be at least 4 times as large as that for a process resembling radioactive decay. Thus, the rate of evolution of this protein is as uniform as that of vertebrate proteins. Our analysis indicates no acceleration of protein evolution in the lineages leading to Hawaiian drosophilines. Second, we give an explicit description of a procedure for calculating the absolute value of the mean rate of evolutionary change in this protein. This procedure is suggested for general use in calculating absolute rates of molecular evolution. The mean rate of evolution of LHP is about 1.2 immunological distance units per million years, which probably corresponds to a unit evolutionary period of 4 million years; LHP thus evolves at a rate comparable to that of mammalian hemoglobins. Finally, we utilize the calibrated rate of LHP evolution to derive a time scale of evolution in the Drosophilidae and higher Diptera.

Animals↗
PubMed1984

Suppression of experimental atherosclerosis in rabbits by interferon-inducing agents.

The effects of two chemically different interferon inducers on the suppression of atherosclerosis were studied in rabbits fed an atherogenic chow diet. One group (10 rabbits per group) was fed normal rabbit chow, and three groups were fed an atherogenic chow. One of the latter groups received the atherogenic feeding alone; the other two were treated with either polyinosinic-polycytidylic acid (poly I:C) or 2-amino-5-bromo-6-phenyl-4-pyrimidinone (ABPP). Neither of the drugs reduced significantly the hypercholesterolemia induced by the feeding. However, both poly I:C and ABPP treatment significantly reduced the percent area of the aortic intimal surface lesions, stained for lipid with Sudan IV, compared with that in untreated rabbits fed atherogenic chow. Microscopic sections of typical aortic plaques showed that both drug treatments significantly reduced the size and number of intimal lipid deposits compared with those observed in the aortas of untreated animals. Chemical analysis for cholesterol and collagen content revealed that interferon-inducing agents significantly reduced cholesterol deposits in the aorta, with little effect on fibrous protein deposition. The results indicate that two unrelated interferon-inducing drugs suppressed atherogenesis without reducing serum cholesterol and low density lipoprotein levels. Whether the protection against atherosclerosis is exerted by endogenous interferon production remains to be determined.

Animals↗
PubMed1984

Polymorphic sites and the mechanism of evolution in human mitochondrial DNA.

Twelve restriction enzymes were used to screen for the presence or absence of cleavage sites at 441 locations in the mitochondrial DNA of 112 humans from four continents. Cleavage maps were constructed by comparison of DNA fragment sizes with those expected from the published sequence for one human mtDNA. One hundred and sixty-three of the sites were polymorphic, i.e., present in some individuals but absent from others, 278 sites being invariant. These polymorphisms probably result from single base substitutions and occur in all functional regions of the genome.--In 77 cases, it was possible to specify the exact nature and location (within a restriction site) of the mutation responsible for the absence of a restriction site in a known human mtDNA sequence and its presence in another human mtDNA. Fifty-two of these 77 gain mutations occur in genes coding for proteins, 34 being silent and 18 causing amino acid replacements; moreover, nine of the replacements are radical.--Notable also is the anomalous ratio of transitions to transversions required to account for these 77 restriction site differences between the known human mtDNA sequences and other human mtDNAs. This ratio is lower for most groups of restriction sites than has been reported from sequence comparisons of limited parts of the mtDNA genome in closely related mammals, perhaps indicating a special functional role or sensitivity to mutagenesis for palindromic regions containing high levels of guanine and cytosine.--From the genomic distribution of the 163 polymorphic sites, it is inferred that the level of point mutational variability in tRNA and rRNA genes is nearly as high as in protein-coding genes but lower than in noncoding mtDNA. Thus, the functional constraints operating on components of the protein-synthetic apparatus may be lower for mitochondria than for other systems. Furthermore, the mitochondrial genes for tRNAs that recognize four codons are more variable than those recognizing only two codons.--Among the more variable of the human mitochondrial genes coding for proteins is that for subunit 2 of cytochrome oxidase; this polypeptide appears to have been evolving about five times faster in primates than in other mammals. Cytochrome c, a nuclearly encoded protein that interacts directly with the oxidase 2 subunit in electron transport, has also evolved faster in primates than in rodents or ungulates. This example, along with that for the mitochondrial rRNA genes and the nuclear genes coding for mitochondrial ribosomal proteins, provides evidence for coevolution between specific nuclear and mitochondrial genes.

Base Sequence↗
PubMed1984

Plasma disposition of vitamin K1 in relation to anticoagulant poisoning.

The disposition of vitamin K1, after intravenous (10 mg) and oral doses (10 mg and 50 mg) was studied in six healthy male subjects. After intravenous administration, the plasma concentration-time profile was adequately fitted with an average terminal half-life of 1.7 h. After oral administration (10 mg and 50 mg) the availability of vitamin K showed marked inter-individual variation (10-63%). With the higher dose intra-individual variation was also observed. Experiments in brodifacoum-anticoagulated rabbits demonstrate that the duration of action of a pharmacological dose (10 mg/kg) is short (9 h) and that high plasma concentrations (ca 1 microgram/ml) of the vitamin are required to drive clotting factor synthesis during maximum coumarin anticoagulation. Taken collectively, these data indicate that the short duration of action of vitamin K, frequently observed in cases of coumarin poisoning, is a consequence of requirements for high vitamin K concentrations and rapid clearance of the vitamin.

Adult↗
PubMed1984

Enzyme induction by phenobarbitone and vitamin K1 disposition in man.

The plasma disposition of an intravenous pharmacological dose of vitamin K1 was determined in seven healthy volunteers before and after chronic administration of phenobarbitone (100 mg nocte). Phenobarbitone produced a significant increase in antipyrine clearance and 6 beta-hydroxycortisol excretion in all volunteers, indicating induction of hepatic microsomal mixed-function oxidase enzymes. However, phenobarbitone administration had no effect on the plasma disposition of vitamin K1. We conclude therefore, that vitamin K1 is not metabolized to any significant extent, by phenobarbitone-inducible mixed-function oxidase enzymes.

Antipyrine↗
PubMed1983

Intergenic DNA sequences flanking the pseudo alpha globin genes of human and chimpanzee.

We have determined the sequence of 2400 base pairs upstream from the human pseudo alpha globin (psi alpha) gene, and for comparison, 1100 base pairs of DNA within and upstream from the chimpanzee psi alpha gene. The region upstream from the promoter of the psi alpha gene shows no significant homology to the intergenic regions of the adult alpha 2 and alpha 1 globin genes. The chimpanzee gene has a coding defect in common with the human psi alpha gene, showing that the product of this gene, if any, was inactivated before the divergence of human and chimpanzee. However the chimpanzee gene contains a normal ATG initiation codon in contrast to the human gene which has GTG as the initiation codon. The psi alpha genes of both human and chimpanzee are flanked by the same Alu family member. The structure and position of this repeat have not been altered since the divergence of human and chimpanzee, and it is at least as well conserved as its immediate flanking sequence. Comparing human and chimpanzee, the 300 bp Alu repeat has accumulated only two base substitutions and one length mutation; the adjacent 300 bp flanking region has accumulated five base substitutions and twelve length mutations.

Animals↗
PubMed1983

Unusual type of mitochondrial DNA in mice lacking a maternally transmitted antigen.

Mice that lack a maternally transmitted antigen (Mta) on the cell surface share a distinctive type of mitochondrial DNA. This is evident from restriction analyses of mitochondrial DNAs from 25 strains of mice whose antigenic state is known. One hundred sixty-eight cleavage sites have been mapped in the mitochondrial DNA of Mta- mice. Detailed maps for the 8 other types of mitochondrial DNA detected in the survey have also been prepared. The Mta- mice are estimated to differ from those expressing the antigen by 108 to 141 base substitutions at widely scattered points in the mitochondrial genome.

Animals↗
PubMed1983

Rise and fall of the delta globin gene.

This paper examines the molecular basis for the origin and subsequent silencing of the delta globin gene during the evolution of higher primates. We cloned and sequenced the delta gene from representatives of the two most distantly related types of Old World monkeys in which the gene is silent. The silent delta genes of these two monkeys (rhesus and colobus) are highly homologous to each other (97.5%) and to the functional human delta gene (94%). The presumed mutation that silenced the delta gene is therefore unlikely to be obscured by later mutations at the same site. This silencing mutation could have affected transcription since we find no delta transcript in rhesus bone marrow. Furthermore, the delta globin genes from colobus and rhesus monkeys are many times less efficient than the human delta gene in a cell-free transcription assay. The two Old World monkeys share only three nucleotide substitutions in the first 100 base-pairs of the DNA sequence 5' to the site for initiation of transcription when compared to human delta. It is likely that the in vitro silencing of the delta gene was brought about by one (or a combination) of these three substitutions. Three analysis shows how the delta sequences are related to those for other beta-like genes, including the colobus beta gene whose sequence we report. One part of the delta gene appears to be derived from a (pseudo?) beta gene that diverged from beta before the divergence of mice and men. The other part is closely related to the beta gene of higher primates. The mosaic nature of the delta gene is apparently due to a partial conversion which took place between the pseudo beta and the functional beta gene before the divergence of the lineages leading to Old World monkeys and hominoids.

Animals↗
PubMed1983

Birds, behavior, and anatomical evolution.

Study of more than 200 species suggests that the anatomical differences among birds are as big as those among other vertebrates of comparable taxonomic rank. The result is notable because, for more than 100 years, many biologists have believed that birds are more uniform anatomically than other classes of vertebrates. Furthermore, assessment of biochemical and geological evidence suggests that the time scale for bird evolution could be quite short. Hence, birds may share with placental mammals the distinction of having had a high rate of anatomical evolution, compared to that in lower vertebrates. The rate appears to have been very high in songbirds and higher primates and extremely high in the genus Homo. In an attempt to explain such contrasts in rates of anatomical evolution, we advance the hypothesis that in higher vertebrates, behavior, rather than environmental change, is the major driving force for evolution at the organismal level. This hypothesis predicts accelerated anatomical evolution in species composed of numerous mobile individuals with the dual capacity for behavioral innovation and social propagation of new habits. Consistent with this hypothesis, we demonstrate a correlation between relative brain size and rate of anatomical evolution in land vertebrates.

Animals↗
PubMed1983

Flow of mitochondrial DNA across a species boundary.

Restriction analysis shows that wild Scandinavian mice belonging to the species Mus musculus contain the mitochondrial DNA of a neighboring species, M. domesticus. This demonstration results from comparisons of Scandinavian mice with authentic M. domesticus and M. musculus from other parts of Europe. Electrophoretic and immunological analysis of eight diagnostic proteins confirms that mice from north of the hybrid zone in Denmark are M. musculus in regard to their nuclear genes. In contrast, the mice tested from this region and a nearby part of Sweden have exclusively M. domesticus types of mitochondrial DNA. Phylogenetic analysis of the restriction maps suggests that the mitochondrial DNAs found in Scandinavian M. musculus could stem from a single M. domesticus female.

Alleles↗
PubMed1983

Length mutations in human mitochondrial DNA.

By high-resolution, restriction mapping of mitochondrial DNAs purified from 112 human individuals, we have identified 14 length variants caused by small additions and deletions (from about 6 to 14 base pairs in length). Three of the 14 length differences are due to mutations at two locations within the D loop, whereas the remaining 11 occur at seven sites that are probably within other noncoding sequences and at junctions between coding sequences. In five of the nine regions of length polymorphism, there is a sequence of five cytosines in a row, this sequence being comparatively rare in coding DNA. Phylogenetic analysis indicates that, in most of the polymorphic regions, a given length mutation has arisen several times independently in different human lineages. The average rate at which length mutations have been arising and surviving in the human species is estimated to be many times higher for noncoding mtDNA than for noncoding nuclear DNA. The mystery of why vertebrate mtDNA is more prone than nuclear DNA to evolve by point mutation is now compounded by the discovery of a similar bias toward rapid evolution by length mutation.

Chromosome Deletion↗
PubMed1983

Mitochondrial DNA evolution in mice.

This study extends knowledge of mitochondrial DNA (mtDNA) diversity in mice to include 208 animals belonging to eight species in the subgenus Mus. Highly purified mtDNA from each has been subjected to high-resolution restriction mapping with respect to the known sequence of one mouse mtDNA. Variation attributed to base substitutions was encountered at about 200 of the 300 cleavage sites examined, and a length mutation was located in or near the displacement loop. The variability of different functional regions in this genome was as follows, from least to most: ribosomal RNA, transfer RNA, known proteins, displacement loop and unidentified reading frames. --Phylogenetic analysis confirmed the utility of the Sage and Marshall revision of mouse classification, according to which there are at least four species of commensal mice and three species of aboriginal mice in the complex that was formerly considered to be one species. The most thoroughly studied of these species is Mus domesticus, the house mouse of Western Europe and the Mediterranean region, which is the mitochondrial source of all 50 of the laboratory strains examined and of the representatives of wild house mice introduced by Europeans to North and South America during the past few hundred years. --The level of mtDNA variation among wild representatives of M. domesticus is similar to that for the Eastern European house mouse (M. musculus) and several other mammalian species. By contrast, among the many laboratory strains that are known or suspected to stem from the pet mouse trade, there is little interstrain variation, most strains having the "old inbred" type of domesticus mtDNA, whose frequency in the 145 wild mice examined is low, about 0.04. Also notable is the apparent homogeneity of mtDNA in domesticus races that have fixed six or more fused chromosomes and the close relationship of some of these mtDNAs to those of karyotypically normal mice. --In addition, this paper discusses fossil and other evidence for the view that in mice, as in many other mammals, the average rate of point mutational divergence in mtDNA is 2-4% per million years. From this, it is estimated that the commensal association between mice and our ancestors began more than a million years ago, i.e., at an early stage in the evolution of Homo erectus.

Animals↗
PubMed1983

An integrated liquid-frozen blood banking system.

Frozen red cells have been field-tested at the Mobile Fleet Hospital deployed at 29 Palms, Calif., and at Bridgeport, Calif., and at the PACOM Blood Program Office, Okinawa, Japan, to evaluate the feasibility of using these products to support the US Navy and Marines in combat areas. We studied both nonrejuvenated and rejuvenated cryopreserved red cell concentrates. Red cells stored at 4 degrees C in CPD or CPDA-1 for 3-6 days (nonrejuvenated), and red cells stored at 4 degrees C in CPD for 22-26 days or in CPDA-1 for 36-38 days before biochemical modification (rejuvenated), were frozen with 40% w/v glycerol at -80 degrees C. A multiple-bag collection system with a 600 or 800 ml primary bag was used for blood collection, and the primary bag was used for processing from preparation of the red cell concentrate through prewash dilution. The thawed red cells were washed with 1.5 liters of a sodium chloride-glucose-phosphate solution. As part of this feasibility study, frozen red cells were shipped by air in dry ice (-79 degrees C), and previously frozen washed red cells were shipped in wet ice (4 degrees C). In vitro red cell recovery values were at least 90%. After postwash storage at 4 degrees C for as long as 3 days, the red cells had 24-hour posttransfusion survivals of at least 70%, normal or slightly impaired oxygen transport function, and minimal hemolysis.

Blood Banks↗
PubMed1983

Comparison of the effects of the hypolipidaemic agents ICI53072 and clofibrate with those of phenobarbitone on liver size, blood flow and DNA content in the rat.

1 The effects of the hypolipidaemic agents ICI 53072 and clofibrate on cardiac output and its distribution to the hepatosplanchnic bed were determined by the use of radioactive microspheres in the rat. The effects of these agents on hepatic DNA content were compared with those of phenobarbitone. Also the effects of ICI 53072 on hepatic microsomal enzymes and bile flow were determined together with the effects of phenobarbitone. 2 ICI 53072 and clofibrate both increased liver size and liver blood flow. A daily dose of 25 mg kg-1 ICI 53072 for 5 days increased liver weight by 55% and liver blood flow by 43%, the latter by enhancing the proportion of cardiac output passing to the hepatosplanchnic bed. The increased liver blood flow with clofibrate (480 mg kg-1 daily for 5 days) was the result of greater cardiac output but the change (35%) was half the increase in liver weight. 3 Phenobarbitone (80 mg kg-1 daily for 5 days) produced a fall in DNA content per unit mass of liver but no change in hepatic DNA relative to body weight. ICI 53072 (25 mg kg-1 daily) increased hepatic DNA relative to body weight but by a lesser extent than it increased liver weight as a proportion of body weight; hence DNA content per unit mass of liver decreased. Clofibrate at three dose levels increased hepatic DNA relative to body weight but only one dose significantly decreased DNA content as a proportion of liver weight. 4 Phenobarbitone (80 mg kg-1 daily) increased bile flow whereas ICI 53072 (25 mg kg-1 daily) had no effect. Both treatments increased hepatic cytochrome P450 content and cytochrome c reductase activity. 5 It is concluded that phenobarbitone increases liver size by hepatocyte enlargement rather than cellular proliferation but that the hepatomegaly produced by the hypolipidaemic agents, at least at some doses, is due to a mixture of both processes. 6 It is further concluded that there is no simple relationship between the mechanism of hepatic enlargement resulting from drug treatment and changes in liver blood flow.

Animals↗