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Biomedical subjects

P L Coleman

Publications and source records attributed to P L Coleman.

At least 19 recordsLinked to original sources
PubMed2025

Polygenic Associations between Motor Behaviour, Neuromotor Traits, and Active Music Engagement in Four Cohorts.

Phenotypic investigations have shown that actively engaging with music, i.e., playing a musical instrument or singing may be protective of motor decline in aging. For example, music training associated with enhanced sensorimotor skills accompanied by changes in brain structure and function. Although it is possible that the benefits of active music engagement "transfer" to benefits in the motor domain, it is also possible that the genetic architecture of motor behaviour and the motor system structure may influence active music engagement. This study investigated whether polygenic scores (PGS) for five behavioural motor traits, 12 neuromotor structural brain traits, and seven rates of change in brain structure traits trained from existing discovery genome-wide association studies (GWAS) predict active music engagement outcomes in four independent cohorts of unrelated individuals of European ancestry: the Canadian Longitudinal Study on Aging (CLSA; N=22,198), Wisconsin Longitudinal Study (WLS; N=4,605), Vanderbilt's BioVU Repository (BioVU; N=6,150), and Vanderbilt's Online Musicality study (OM; N=1,559). Results were meta-analyzed for each PGS main effect across outcomes and cohorts, revealing that PGS for a faster walking pace was associated with higher amounts of active music engagement. Within CLSA, a higher PGS for walking pace was associated with greater odds of engaging with music. Findings suggest a shared genetic architecture between motor function and active music engagement. Future intervention-based research should consider the genetic underpinnings of motor behavior when evaluating the effects of music engagement on motor function across the lifespan.

BioVU↗
PubMed1997

Treatment of hypertension in the elderly.

Hypertension is present in over 50% of elderly patients and constitutes a major risk factor for cardiovascular morbidity and mortality. This paper reviews the rationale for treating hypertension in the elderly, discusses the choice of antihypertensive therapy and optimal target blood pressure, and summarizes ongoing clinical trials. The major questions that remain to be answered are the optimal level of blood pressure reduction in the elderly and the long-term efficacy and safety of newer antihypertensive agents compared with diuretics and beta-blockers.

Aged↗
PubMed1996

Immobilization of manganese peroxidase from Lentinula edodes on alkylaminated Emphaze AB 1 polymer for generation of Mn3+ as an oxidizing agent.

Manganese peroxidase (MnP) is secreted by white-rot fungi and participates in the degradation of lignin by these organisms. MnP uses H2O2 as an oxidant to oxidize MnII to MnIII as the manganic ion Mn3+. The Mn3+ stabilized by chelation, is a highly reactive nonspecific oxidant capable of oxidizing a variety of toxic organic compounds. Previous attempts at immobilization of MnP, purified from Lentinula edodes through reactive amino groups, have been hindered by the protein's low lysing content of only 1% and its instability above pH 6.0. As an alternative to amine coupling, the enzyme has now been covalently immobilized through its carboxyl groups, using an azlactone-functional copolymer derivatized with ethylenediamine and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) as a coupling reagent. The immobilization reaction was performed under acidic (pH 5.25) conditions, and 90% coupling efficiency was achieved within 2h. Net immobilization efficiencies, expressed as the product of protein coupling efficiency and enzyme activity, have been measured at > 95% within 4h. The MnP-NH-polymer and the free soluble protein were characterized and compared for their pH, temperature, and storage stabilities, as well as their H2O2 dependence and kinetics. The tethered MnP, employed in an immobilized enzyme bioreactor for generation of chelated Mn3+ may have industrial applications as a nonspecific oxidant of organopollutants.

Agaricales↗
PubMed1986

Characterization of the dexamethasone-induced inhibitor of plasminogen activator in HTC hepatoma cells.

Incubation of HTC rat hepatoma cells with the synthetic glucocorticoid dexamethasone rapidly inhibits plasminogen activator (PA) activity secondary to the induction of a specific acid-stable inhibitor of plasminogen activation (Cwikel, B. J., Barouski-Miller, P.A., Coleman, P.L., and Gelehrter, T.D. (1984) J. Biol. Chem. 259, 6847-6851). We have further characterized this inhibitor with respect to its interaction with both urokinase and tissue plasminogen activator, and its protease specificity. The HTC PA inhibitor rapidly inhibits urokinase and tissue plasminogen activator with an apparent second-order rate constant of 3-5 x 10(7) M-1 X s-1. The inhibitor forms stable covalent complexes with both urokinase and tissue plasminogen activator, with which plasmin, trypsin, and factor Xa apparently do not compete. Complex formation is saturable and requires the active site of the PA. The mass of the inhibitor-PA complex is 50,000 daltons greater than that of PA alone, consistent with an Mr for the PA inhibitor of 50,000 as demonstrated directly by reverse fibrin autography. The HTC PA inhibitor does not inhibit thrombin and differs in its kinetic and biochemical properties from protease nexin.

Animals↗
PubMed1986

The dexamethasone-induced inhibitor of plasminogen activator in hepatoma cells is antigenically-related to an inhibitor produced by bovine aortic endothelial cells.

Glucocorticoids decrease plasminogen activator (PA) activity in HTC rat hepatoma cells by inducing a specific inhibitor of PA activity (PAI). This inhibitor is similar in several biochemical properties to the PAI purified from bovine aortic endothelial cells (BAEs). We have used reverse fibrin autography and antiserum against BAE PAI to establish more fully the biochemical and immunological relationship of these inhibitors. Both inhibitors migrated with an apparent Mr of approximately 50,000, and the activity of both PAIs was stimulated by treatment with SDS suggesting that each of these molecules exists in both an active and a latent form. Antiserum to the BAE PAI immunoprecipitated all of the HTC PAI demonstrable by reverse fibrin autography. Finally, using this antiserum in a functional immunoassay, we have demonstrated that dexamethasone increases both active and latent PAI made by HTC cells. These results indicate that HTC PAI and BAE PAI are antigenically as well as biochemically related molecules.

Animals↗
PubMed1984

Dexamethasone induction of an inhibitor of plasminogen activator in HTC hepatoma cells.

Incubation of HTC rat hepatoma cells with dexamethasone causes a rapid decrease in cellular plasminogen activator (PA) activity. Mixing experiments show the presence of an inhibitor of PA in dexamethasone-treated cells. This study investigates whether the decrease in PA activity is secondary to the induction of an inhibitor by glucocorticoids, to a decrease in the amount of PA, or to a combination of both mechanisms. PA and its inhibitor are dissociated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under non-reducing conditions, and both activities are then recovered and quantitated. HTC cells have two major forms of PA with Mr values of 110,000 and 64,000. Although PA activity in the unfractionated extracts from dexamethasone-treated cells is inhibited by 90% relative to control, there is no decrease in the total activity of sodium dodecyl sulfate-dissociated PA activity, suggesting that dexamethasone causes no decrease in the amount of the enzyme. PA inhibitor activity migrates as a single band of Mr = 50,000. The total activity of inhibitor increases in a time-dependent fashion, reaching a maximum of greater than 10 times control after a 4-6-h incubation with 0.1 microM dexamethasone. The induction of inhibitor requires both RNA and protein synthesis and shows a dependence on dexamethasone concentration identical to that for responses known to be mediated by glucocorticoid receptors. We conclude that dexamethasone inhibits PA activity by inducing the synthesis of an inhibitor rather than by decreasing the amount of PA.

Animals↗
PubMed1983

Hormonal regulation of plasminogen activator in rat hepatoma cells.

Plasminogen activators are membrane-associated, arginine-specific serine proteases which convert the inactive plasma zymogen plasminogen to plasmin, an active, broad-spectrum serine protease. Plasmin, the major fibrinolytic enzyme in blood, also participates in a number of physiologic functions involving protein processing and tissue remodelling, and may play an important role in tumor invasion and metastasis. In HTC rat hepatoma cells in tissue culture, glucocorticoids rapidly decrease plasminogen activator (PA) activity. We have shown that this decrease is mediated by induction of a soluble inhibitor of PA activity rather than modulation of the amount of PA. The hormonally-induced inhibitor is a cellular product which specifically inhibits PA but not plasmin. We have isolated variant lines of HTC cells which are selectively resistant to the glucocorticoid inhibition of PA but retain other glucocorticoid responses. These variants lack the hormonally-induced inhibitor; PA from these variants is fully sensitive to inhibition by inhibitor from steroid-treated wild-type cells. Cyclic nucleotides dramatically stimulate PA activity in HTC cells in a time- and concentration-dependent manner. Paradoxically, glucocorticoids further enhance this stimulation. Thus glucocorticoids exert two separate and opposite effects on PA activity. The availability of glucocorticoid-resistant variant cell lines, together with the unique regulatory interactions of steroids and cyclic nucleotides, make HTC cells a useful experimental system in which to study the multihormonal regulation of plasminogen activator.

Animals↗
PubMed1983

Optimization of enzyme-based assays in coagulation testing.

Optimized assays for antithrombin III and plasminogen have been developed based on a study of the kinetic parameters Km and Kcat for four commercially available substrates: the p-nitroanilide derivatives of D-Phe-pipecolyl-Arg (S-2238), and toluenesulfonyl-Gly-Pro-Arg (Chromozym TH), which are thrombin substrates; D-Val-Leu-Lys (S-2251), a plasminogen/streptokinase substrate; and alpha-N-carbobenzoxy-L-lysine thiobenzyl ester, a substrate for both enzymes. We used a centrifugal analyzer system for rapid data acquisition and interactive analysis. Optimized conditions for assay of a particular enzyme are not constant for different substrates in the same buffering agent. For example, in 1,4-piperazine diethanesulfonic acid buffer at 37 degrees C, thrombin-catalyzed hydrolysis of Chromozym TH is optimal at 125 mmol/L buffer, 100 mmol/L NaCl, and pH 8.2, whereas substitution of S-2238, also a tripeptide p-nitroanilide, yields optimal hydrolysis at 85 mmol/L buffer, 300 mmol/L NaCl, and pH 7.2. We conclude that optimized assay conditions are best obtained by an extensive survey of available buffers and a detailed investigation of the effects of variation in pH and in the concentrations of the buffer and auxiliary reagents through use of both one-factor-at-a-time and multivariate response surface experimentation.

Blood Coagulation Tests↗
PubMed1983

Development and analytical performance of automated tests for antithrombin III and plasminogen on the Du Pont aca analyzer.

We describe assays for functional antithrombin III (AT III) and plasminogen in plasma with the Du Pont aca discrete clinical analyzer. Both are two-stage kinetic assays, based on synthetic substrate methodologies, and require 20-microL sample volumes. In the AT III assay the sample is incubated with excess thrombin and heparin to form the functionally inactive AT III-thrombin complex. Residual thrombin is measured through its rate of hydrolysis of a lysine thioester and is inversely related to analyte concentration. In the plasminogen assay excess streptokinase is reacted with the sample to form an enzymatically active complex. The substrate hydrolysis rate of this complex is measured, which is linearly related to the concentration of plasminogen in the sample. Reaction conditions for both assays were optimized by univariate and response surface techniques. The assay for AT III has a range of 0 to 150% of the value for normal human plasma (% NHP) with a CV of 3% at 80% NHP. The plasminogen assay is linear from 25 to 200% NHP with a CV of less than 2% at 80% NHP. No significant interferences with either method by common blood components or drugs were found.

Antithrombin III↗
PubMed1982

The dexamethasone-induced inhibitor of fibrinolytic activity in hepatoma cells. A cellular product which specifically inhibits plasminogen activation.

Dexamethasone induces an inhibitor of plasminogen-dependent fibrinolysis in rat hepatoma (HTC) cells. The specificity of the inhibitor for urokinase and plasmin was investigated using both fibrinolytic and esterolytic assays. Urokinase, but not plasmin, was inhibited by serum-free conditioned medium from cells incubated with 0.1 microM dexamethasone. The specificity of the inhibitor for plasminogen activator was demonstrated directly by the inhibition of the urokinase-catalyzed activation of 125I-plasminogen to 125I-plasmin. The inhibitory activity was stable to pH 3 for 2 h at 37 degrees C, a condition which inactivated fibrinolytic inhibitors in serum, suggesting a cellular origin for the inhibitor. Further evidence for the cellular origin was the constant daily production of inhibitor throughout a 4-day incubation with dexamethasone in serum-free medium. SF HTC-H1 cells, selected for their ability to grow in serum-free medium (Thompson, E. B., Anderson, C. U., and Lippman, M. E. (1975) J. Cell Physiol. 86, 403-412), were grown for 76 days (at least 30 generations) in the presence or absence of serum; dexamethasone induced equivalent amounts of inhibitory activity in cells which had been grown under both conditions. We conclude that the dexamethasone-induced inhibitor from HTC cells is a cellular product which is specific for the inhibition of plasminogen activation and which differs from other reported fibrinolytic inhibitors.

Animals↗