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Biomedical subjects

A R Jacobson

Publications and source records attributed to A R Jacobson.

9 recordsLinked to original sources
PubMed2003

Bioavailability of pentachlorophenol to acclimatised bacteria under batch and flow-through conditions.

Biodegradation of organic contaminants in multi-phase systems, such as soils and aquifers, is often limited by the extent and the rate of contaminant sorption onto the solid matrix. However, information about biodegradation in complex matrices is largely limited to studies of closed systems under batch conditions in which potential bioavailability is characterised by the aqueous-phase concentration of a contaminant. There is little knowledge regarding the influence of flow-through conditions on the availability of contaminants to microbes (contaminant bioavailability). Thus, the aim of this study was to assess and compare contaminant bioavailability, in the presence of a sorptive medium, under both batch and flow-through conditions. Accordingly, experiments were designed in which pentachlorophenol (PCP) was introduced into a mixture of inoculated silica sand and a PCP-retaining resin, under either batch or flow-through (columns) conditions. The results indicated that an increase in the amount of resin (0.1-0.2 g) clearly lowered PCP availability to microbes after 170 h under batch conditions (30 and 45% respectively); whereas, the initial decrease in bioavailability observed under flow-through conditions (45 and 70% respectively) was reversed and no longer observable after 170 h. This increase in PCP availability was linked to an improvement in the contaminant biodegradation capacity from 0.03 to 0.13 mg x l(-1) x h(-1) over 200 h.

Adsorption↗
PubMed1991

Structure and dynamics of alpha-chymotrypsin-N-trifluoroacetyl-4-fluorophenylalanine complexes.

Fluorine NMR lineshape, relaxation and Overhauser effect data collected at 282 and 470 MHz have been used to obtain information about the nature of complexes formed between N-trifluoroacetyl-4-fluorophenylalanine and the enzyme chymotrypsin. Systems involving both enantiomers have been examined as well as derivatives of these in which the aromatic ring hydrogens have been replaced by deuterium. The enzyme-induced fluorine chemical shift effects and the dynamics of molecular motions of the fluorophenyl ring at the respective binding sites appear to be similar in both complexes and, where comparable, the results are in agreement with data obtained at lower frequencies that have been reported by other workers. The dynamics of the fluoroaromatic ring in these complexes are significantly different from those observed in a closely related acylated enzyme.

Animals↗
PubMed1991

Modification of the enkephalin "message" with an artificial polycationic C-terminus.

The C-terminal "address" sequences of prodynorphin-derived opioid peptides contain an unusually high proportion of basic residues, which are known to be crucial for conferring high activity and selectivity for kappa-opioid receptors. In an effort to investigate the possibility that the polycationic "tails" may be involved in a coulombic interaction with a complementary polyanionic receptor domain, we attached a series of achiral peptide-like cationic fragments to the C-terminus of the opioid peptide "message", Tyr-Gly-Gly-Phe. Binding of the various compounds to opioid receptor types in guinea pig brain membranes was weak, and the pharmacologic activities in the guinea pig ileum were marginal. These results indicate either that the chosen ligand design does not satisfy the structural requirements of the hypothesized coulombic interaction or that the latter is a minor criterion governing receptor recognition.

Amino Acid Sequence↗
PubMed1989

Minimum-structure enkephalin analogues incorporating L-tyrosine, D(or L)-phenylalanine, and a diamine spacer.

In order to test the theory that high mu-activity of opioid peptides could be elicited by the presence of an amino-terminal L-Tyr residue and a Phe aromatic ring held in the proper relative spatial disposition, a novel series of hybrid retro peptides were prepared in which L-Tyr was linked to N-acyl Phe through a variety of diamine spacers. These compounds were evaluated for opioid agonist and antagonist activity in the guinea pig ileum (GPI) in vitro assay. Analogues containing a 1,2-ethanediamine spacer, which conferred a Tyr-Phe separation distance closest to that found in Phe3 opioid peptides, were more potent agonists than the corresponding analogues containing a 1,3-propanediamine spacer. Agonist activity was observed for both L-Phe and D-Phe analogues, consistent with the known activity for both Phe stereochemistries for certain Phe3 opioid peptide analogues. Concerning the diamine spacer, conformational constraints imposed by 4-aminopiperidine and 4-(aminomethyl)piperidine as well as the presence of a hydroxyl group eliminated activity, but the presence of gem-dimethyl substitution next to the nitrogen attached to Tyr increased activity substantially for the D-Phe derivatives. Removal of the N-acetyl group from Phe did not eliminate activity. Naloxone Ke values determined for six of the most potent analogues are indicative of predominantly mu-agonism, but the D-Phe compounds 3a and 6a (1.4-2.1 nM) appear to be more mu-selective than the L-Phe compounds 2b, 3b, 5b, and 6b (3.3-4.4 nM), even though the latter are more potent agonists. Compounds 3a and 3b, which were found to be 10 and 21 times more potent, respectively, than morphine in the GPI, are two of the most structurally simple yet potent opioid peptide analogues described to date.

Animals↗
PubMed1988

Paramecium calcium channels are blocked by a family of calmodulin antagonists.

Although the voltage-sensitive Ca channel present in Paramecium has been subjected to detailed physiological and genetic analysis, no organic ligands have been described that block this channel with high affinity and that ultimately can be used to identify channel components. Based on a previous observation that the naphthalene sulfonamide calmodulin antagonist W-7 can block Paramecium Ca channels at high concentration, we have synthesized analogs of W-7 that block these channels at concentrations of less than 1 microM. The effectiveness of these compounds was tested both by a sensitive behavioral assay and on Ca channels that had been incorporated into planar lipid bilayers. Despite the fact that these compounds are effective Paramecium calmodulin antagonists, two independent lines of evidence suggest that W-7 and its analogs block the Ca channel by a mechanism that is independent of their action on calmodulin. In addition, the sensitivity to W-7 or dihydropyridines of Ca channels present in a number of eukaryotic phyla has been used to identify similarities in Ca channels from widely diverse organisms. It appears that the pharmacological specificity provides a means to group Ca channels.

Animals↗
PubMedDate not supplied

Metabolism of profluralin in rats. 1. Identification of metabolites.

Fluorine NMR spectroscopy has been used to identify and quantitate metabolites of profluralin appearing in the urine of rats postingestion of the herbicide. The chemical shift of the trifluoromethyl group was shown to be a useful indicator of the chemical type of metabolite, and the shifts for the classes of materials previously identified as metabolites have been determined. By use of chemical shift criteria this work provides evidence for several metabolites that have not been recognized in previous work; some of these remain incompletely characterized. Though the number and types of metabolites detected in the urine were consistent from animal to animal, the time course for appearance of metabolites was found to be animal dependent.

Animals↗
PubMedDate not supplied

beta,beta'-Iminodipropionitrile (IDPN) neurotoxicity: a mechanistic hypothesis for toxic activation.

beta,beta'-Iminodipropionitrile (IDPN) induces neurobehavioral aberrations in experimental animals and massive focal accumulations of neurofilaments in proximal regions of axons. A hypothesis is presented to explain the neurotoxic activity of IDPN in terms of oxidative amine metabolism, wherein a resonance-stabilized cyanoenamine 3-(2-cyanoethylamino)acrylonitrile (dehydro-IDPN, 5) could be generated. Chemical studies were conducted to verify the likelihood of the proposed enzymatic transformations and their consistency with the known excreted metabolites. Dehydro-IDPN gives rise to a slow hydrolytic release of cyanoacetaldehyde at pH 7, which can transform protein-based amino groups to cyanoenamines, though the latter derivatives could be formed directly through a relatively rapid transamination reaction with dehydro-IDPN at pH 7. Kinetic studies were conducted to assess the balance between competing hydrolysis (pseudo-first order) and transamination (second order) of cyanoenamines as a function of pH. Cyanoethenylation of the epsilon-amino groups of critical lysine residues in the "tail-piece" domains of neurofilament (NF) subunit proteins could disrupt the supramolecular coulombic interactions thought to contribute to maintenance of cytoskeletal caliber. This could result in a defect in the slow axonal transport of NF, and subsequently in the formation of proximal axonal enlargements.

Biotransformation↗