Search PubMed⌕ Search

Biomedical subjects

G H Jones

Publications and source records attributed to G H Jones.

At least 109 records · Page 6Linked to original sources
PubMed1987

Behavioural, biochemical and histochemical effects of different neurotoxic amino acids injected into nucleus basalis magnocellularis of rats.

Lesions of the nucleus basalis magnocellularis in rats have been used to investigate functions of the extrinsic cortical cholinergic system which originates from these neurons. These lesions also produce extensive non-specific subcortical damage and associated regulatory and neurological impairments, causing doubt about the specificity of consequent functional impairments. Here, nucleus basalis magnocellularis lesions made with four different neurotoxic amino acids (kainic acid, ibotenic acid, N-methyl-D-aspartate, and quisqualic acid) have been compared. Quisqualic acid produced less subcortical damage and lesser neurological and regulatory impairments than the other toxins at doses that produced comparable cholinergic deafferentation of the neocortex, as assessed both histologically and biochemically. This suggests that these impairments are non-specific rather than specific consequences of cholinergic cell loss. The effects on learning a spatial navigation task were more ambiguous, suggesting the involvement of both cholinergic and non-cholinergic systems. Impairment of a passive shock avoidance task was as great following quisqualic acid as the other neurotoxins, which may suggest a more direct relationship specifically with the decline in cortical cholinergic activity. It is concluded that in the absence of availability of a specific cholinergic neurotoxin, quisqualic acid produces less non-specific neuroanatomical and neurological side effects than the more widely used toxins N-methyl-D-aspartate, kainic acid or ibotenic acid.

Acetylcholinesterase↗
PubMed1987

The effects of excitotoxic lesions of the substantia innominata, ventral and dorsal globus pallidus on the acquisition and retention of a conditional visual discrimination: implications for cholinergic hypotheses of learning and memory.

The effects of ibotenic acid-induced lesions of the ventral pallidum/substantia innominata region, the dorsal pallidum or both on the acquisition and retention of a conditional visual discrimination have been studied in the rat. Lesions of the ventral pallidum and large lesions of the dorsal and ventral pallidum severely impaired both the acquisition and retention of the conditional discrimination. Dorsal pallidal lesions had similar, but less marked effects. The same lesions also impaired the retention of a passive avoidance task, but had no effect on a conditioned taste aversion. Neurobiological investigations revealed that the lesions destroyed cholinergic neurons in the magnocellular nucleus basalis and caused reductions in cortical choline acetyltransferase activity of about 30-40%. Tract-tracing experiments indicated that the lesions destroyed, in particular, cholinergic neurons projecting to the frontal dorsolateral cortex and also those projecting to more posterior cortex, but not the occipital lobes. Contingency analysis of the behavioural, neurochemical and neuroanatomical data indicated that those animals with the largest decreases in choline acetyltransferase activity, or the largest areas of neuronal loss in the ventral and dorsal globus pallidus, were most impaired in the retention of the conditional discrimination. The results do not, therefore, indicate a simple relationship between cholinergic neuronal loss and the retention of response rules essential for performance of the task ("reference memory"). The relevance of the results to cholinergic hypotheses of learning and memory is discussed.

Animals↗
PubMed1987

Inhibitors of cyclic AMP phosphodiesterase. 1. Analogues of cilostamide and anagrelide.

Evaluation of a series of lactam heterocyclic analogues of cilostamide (2) as inhibitors of cyclic AMP phosphodiesterase derived from both human platelets and rat heart in comparison with their corresponding methoxy-substituted heterocycles has revealed that the N-cyclohexyl-N-methyl-4-oxybutyramide side chain of 2 is an important lipophilic and/or steric pharmacophore. Attachment of this side chain to the parent heterocycle of the potent cyclic AMP phosphodiesterase inhibitor anagrelide (3) afforded the hybrid structure RS-82856 (1), shown to be more potent than either of its progenitors as an inhibitor of cyclic AMP phosphodiesterase or of ADP-induced platelet aggregation. The available in vitro data suggest that 1 possesses potentially useful antithrombotic and cardiotonic properties.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Inhibitors of cyclic AMP phosphodiesterase. 2. Structural variations of N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin-7-yl)-oxy]butyramide (RS-82856).

A series of analogues of the cyclic AMP phosphodiesterase (PDE) inhibitor N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin-7-yl)oxy]butyramide (RS-82856, 1) was prepared by systematic variation of the side-chain substituent, length, position, connecting atom, and the parent heterocycle itself. The compounds were evaluated as inhibitors of cyclic AMP phosphodiesterase from both human platelets and rat or dog heart tissue and as inhibitors of ADP-induced platelet aggregation. Structure-activity correlations for the analogue series revealed significant limitations on the steric bulk of substituents on the 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one heterocycle and the position and length of the side chain. As inhibitors of cyclic AMP phosphodiesterase (PDE), potency steadily increased with increasingly lipophilic side chains. In platelet aggregation inhibition studies, however, a maximum in activity was reached with 1, while more lipophilic compounds were significantly less active. Major changes in the heterocycle itself, represented by isomeric and other carbonyl variations, also decreased activity. The molecular features defined by this series of analogues of 1 correlate to a high degree with current understanding of the chemical and topographical requirements of the active site of the FIII (type IV) form of cyclic AMP PDE. Selective inhibition of this enzyme has been proposed as the principal component of the positive inotropic action of a number of cardiotonic agents.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

The agarase gene (dag A) of Streptomyces coelicolor A3(2): affinity purification and characterization of the cloned gene product.

The coding and regulatory sequences of the agarase gene of Streptomyces coelicolor A3(2) were cloned in Streptomyces lividans 66 on the plasmid vector pIJ61, resulting in a several hundred-fold increase in the production of the secreted protein. Subcloning experiments localized the sequences required for agarase production and for the mediation of carbon catabolite repression to a segment of about 1.2 kb. A simple protein purification procedure that uses affinity binding of agarase to agarose beads was developed. Preliminary characterization of the enzyme, together with the results of in vitro transcription-translation studies, suggest that the intracellular form of agarase (about 34 kDa) possesses a signal sequence that is cleaved upon secretion across the cell membrane to produce an extracellular protein of about 29 kDa.

Chromatography, Affinity↗
PubMed1987

Actinomycin synthesis in Streptomyces antibioticus: enzymatic conversion of 3-hydroxyanthranilic acid to 4-methyl-3-hydroxyanthranilic acid.

A methyltransferase which utilizes 3-hydroxyanthranilic acid (HAA) as a substrate was identified in detergent-treated extracts of the bacterium Streptomyces antibioticus. The enzyme catalyzes the transfer of methyl groups from [14C]S-adenosylmethionine to HAA, but does not catalyze the methylation of 3-hydroxy-DL-kynurenine. Enzyme, substrate, time, and pH dependencies for the methyl transfer reaction were examined. Reaction products obtained from scaled-up reaction mixtures were fractionated by chromatography on Dowex 1, and the Dowex 1 fractions were examined by paper and thin-layer chromatography. One Dowex fraction was shown to contain a radioactive product with the chromatographic properties of 4-methyl-3-hydroxyanthranilic acid (MHA), a known intermediate in the biosynthesis of actinomycin. Available evidence indicates that the conversion of HAA to MHA is an early step in the biosynthesis of actinomycin by S. antibioticus and other actinomycin-producing streptomycetes.

3-Hydroxyanthranilic Acid↗
PubMed1987

Delayed psychiatric sequelae among Falklands war veterans.

The only published account to date of psychiatric complications among Falklands war veterans suggests that acute reactions are rare. Reported here are three cases of severe delayed reactions in Falklands veterans from South Wales. All three cases demonstrate a common pattern similar to that shown by Vietnam war veterans. Possible aetiological factors and prevention are discussed. It seems likely that relatives of combatants will also be affected and general practitioners are in a unique position to recognize and treat these problems.

Adult↗
PubMed1986

Effects of dopamine-rich grafts on conditioned rotation in rats with unilateral 6-hydroxydopamine lesions.

To assess the capacity of dopamine-rich grafts to ameliorate conditioned behavioural deficits induced by dopamine depleting lesions, rats with unilateral 6-hydroxydopamine lesions and intrastriatal grafts were compared with rats with lesions alone and with unoperated control rats in learning a conditioned turning response ('conditioned rotation') for water. The lesions impaired conditioned contralateral rotation and the grafts ameliorated the impairment. By contrast, the grafts introduced an ipsilateral impairment which was not apparent in the rats with lesions alone. The results show that some aspects of graft function are adaptive, but that other aspects of function are not well controlled by the host brain, and so may be maladaptive.

Animals↗
PubMed1986

Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives.

On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis bioassay. Of these six (5, 6, 9a, 10, 11a, 11b), the most effective compound was found to be 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene (RS-43179, lonapalene, 11a). An extensive series of 1,2,3,4-tetraoxygenated naphthalenes (16-74) incorporating variations of the ester, ether, and aryl substituents were prepared as analogues of 11a to examine the structural requirements for activity and were screened in vivo as inhibitors of arachidonic acid induced mouse ear edema, a topical bioassay capable of detecting 5-lipoxygenase inhibitors. Net lipophilicity, hydrolytic stability, and ring substitution play significant roles in determining the observed in vivo activity. Lonapalene (11a) is currently in clinical development as a topically applied nonsteroidal antipsoriatic agent.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Uveitis induction in the rabbit by muramyl dipeptides.

Intraocular inflammation (uveitis) was produced in rabbits by intravenous or subcutaneous treatment with N-acetylmuramyl-L-alanyl-D-isoglutamine and several of its synthetic analogs at doses of greater than or equal to 0.2 mg/kg in saline. A dose-dependent increase in permeability of the ocular blood-aqueous barrier as measured by leakage of protein or fluoresceinated dextran from the serum into the eye was observed from 2 to 14 h after glycopeptide treatment. Peak response occurred at approximately 3 h postdose. The lowest dose found to produce maximal vascular leakage for the most active glycopeptide analogs was 1 mg/kg. The adjuvant-inactive L-L stereoisomer of N-acetylmuramyl-L-alanyl-D-isoglutamine was inactive, even at doses as high as 10 mg/kg. Analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine which were homologous in the lactyl side chain were found to cause less uveitis. Chronic biweekly intravenous treatment of rabbits for 1 month with either N-acetyl-L-alpha-aminobutyryl-D-isoglutamine or its lipophilic 6-O-stearoyl derivative at 1 mg/kg, but not with murabutide, resulted in leukocytic inflammatory lesions unique to the uveal tract of the eye. The uveitis was potentially reversible and occurred with decreased severity as long as 2 months after cessation of chronic treatment. Vascular leakage but not cellular infiltrate in the choroid could be modulated by pharmacologic means. Pyrogenicity but not adjuvanticity correlated with ability of glycopeptides to induce vascular leakage. Several adjuvant-active muramyl dipeptide analogs with minimal ability to cause acute vascular leakage or chronic inflammation in the rabbit eye have been identified.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Function of ribosomes and glutamyl-tRNA isoacceptors in protein synthesis in regenerating skeletal muscle.

Ribosomes from 8-day-regenerating rat skeletal muscle have been shown to be more active in poly(U)-directed polyphenylalanine synthesis than ribosomes from control muscle. This difference persists after salt washing of the ribosomes and does not appear to be due to the presence of ribonuclease associated with the control ribosome population. Ribosomes from control muscle were also less active than those from regenerates in the nonenzymatic binding of phenylalanyl-tRNA to ribosomes and in the peptidyltransferase reaction. Three glutamyl-tRNA isoacceptors have been isolated from 8-day-regenerating rat skeletal muscle by preparative RPC-5 chromatography of total tRNA charged with [3H]glutamic acid. The two major isoacceptors observed, tRNAgluI and tRNAgluIII, respond to the glutamic acid codons GAG and GAA, respectively. A third, minor glutamyl isoacceptor, tRNAgluII, also responds to the codon GAA. When the three isoacceptors were tested for function in a polysomal cell-free protein synthesizing system, it was found that their relative levels of utilization were essentially identical to their relative abundances. Thus, the tRNA which increases in relative amount after the induction of regeneration, tRNAgluII, is not preferentially utilized for overall muscle protein synthesis.

Animals↗
PubMed1985

Regulation of phenoxazinone synthase expression in Streptomyces antibioticus.

The cloned gene for the subunit of phenoxazinone synthase (PHS), an enzyme implicated in the biosynthesis of actinomycin in Streptomyces antibioticus, was used as a probe to study the regulation of the enzyme. The direction of transcription of the PHS gene was determined with end-labeled restriction fragments derived from the gene. Low-resolution S1 mapping revealed that transcription was initiated at a position which may lie within the SphI restriction site, which represents the limit of the cloned sequence. Northern blotting allowed the identification of the putative PHS message. This RNA appeared to be significantly larger than the size required to encode the PHS subunit. RNA dot blotting showed that the increase in PHS specific activity observed in cultures grown on antibiotic production medium, with galactose as a carbon source, was due in part to an increased production of PHS mRNA. PHS was also more stable than most cellular proteins and appeared to be protected against degradation under conditions in which most other proteins are broken down. This protective effect also contributed to the increase in PHS specific activity observed in S. antibioticus cultures grown on production medium. The repression of PHS synthesis by glucose was also reflective of a transcriptional control mechanism. At early time points postinoculation, PHS mRNA levels were lower in cultures grown on glucose as a carbon source than in cultures of the same age grown on galactose. mRNA levels presumably begin to increase only after all the glucose in the medium is utilized. The ability of 5-fluorouracil to stimulate PHS production in young cultures was also due to the synthesis of new mRNA for the enzyme.

Base Sequence↗
PubMed1984

Molecular cloning and expression of the phenoxazinone synthase gene from Streptomyces antibioticus.

DNA fragments from the Streptomyces antibioticus genome have been cloned in Streptomyces lividans using the SphI site of the vector, pIJ702. Using a sib selection procedure, transformants were screened for their ability to produce levels of the enzyme, phenoxazinone synthase, which were detectable by enzyme assay. Three clones were obtained by this procedure. The recombinant plasmids from these clones contained inserts of 1.77, 2.45, and 4.28 kilobases in size. The clones and the corresponding recombinant plasmids were, therefore, referred to as PHS 1.8, PHS 2.4 and PHS 4.3. PHS 2.4 produced transformants with significantly higher phenoxazinone synthase specific activities than those observed in comparably grown S. antibioticus. Southern blotting showed that the cloned 2.45-kilobase insert hybridized to a fragment of exactly the same size in an SphI digest of S. antibioticus total DNA. Using a streptomycete-coupled transcription-translation system, PHS 2.4 was shown to code for the synthesis of a protein with the electrophoretic and immunological properties of the phenoxazinone synthase subunit. Thus, the 2.45-kilobase insert represents the structural gene for that subunit. The protein produced by S. lividans transformed with PHS 2.4 was shown to be virtually identical to the S. antibioticus subunit in terms of its electrophoretic mobility, peptide profile, and amino acid composition. It was further observed that cloning of the 2.45-kilobase insert in the orientation opposite to that obtained originally still resulted in high levels of phenoxazinone synthase expression in transformed S. lividans. However, the repression of phenoxazinone synthase synthesis by glucose which has been observed in S. antibioticus was not found when PHS 2.4 was used to transform S. lividans.

Amino Acids↗
PubMed1984

Activation of phenoxazinone synthase expression in Streptomyces lividans by cloned DNA sequences from Streptomyces antibioticus.

Recombinant plasmids carrying Streptomyces antibioticus DNA (phenoxazinone synthase plasmids 1.8 and 4.3) have been used as templates in a streptomycete-coupled transcription-translation system. Analysis of the synthetic products from these experiments shows that PHS 1.8 and 4.3 appear to code for polypeptides which are not structurally related, as judged by immunoprecipitability, to the phenoxazinone synthase subunit. 35S-labeled cell extracts of Streptomyces lividans and S. lividans transformed with the phenoxazinone synthase plasmids each contain a protein which is precipitable with antiserum to S. antibioticus phenoxazinone synthase. These proteins have exactly the same electrophoretic mobility as the S. antibioticus phenoxazinone synthase subunit on one-and two-dimensional gels and the peptide maps of the proteins from the S. lividans clones are essentially indistinguishable from the map of the S. antibioticus phenoxazinone synthase subunit. Glycerol-gradient centrifugation of extracts of cells transformed with PHS 1.8 and 4.3 showed that both the large and small phenoxazinone synthase enzyme forms were present. Southern hybridization experiments demonstrated that pIJ2505, a pBR322 derivative containing the phenoxazinone synthase structural gene, hybridized to S. lividans DNA digested with BclI, SphI, SstI, and XhoI. The results obtained are discussed in terms of the hypothesis that the expression of phenoxazinone synthase activity in cells transformed with the PHS 1.8 and 4.3 plasmids results from the activation of an endogenous phenoxazinone synthase gene in S. lividans (and perhaps in other streptomycetes in the case of PHS 4.3) which is normally "silent" or expressed at very low levels.

Centrifugation, Density Gradient↗
PubMed1984

Time course of changes in protein synthesis in marcaine-induced skeletal muscle regeneration.

The time course of the regeneration of rat skeletal muscle has been examined after injection of the myotoxic drug, Marcaine, to induce regeneration. Muscle wet weight decreases during the initial phase of the regeneration process while the ability of the regenerating muscle to incorporate [35S]methionine into protein, the yield and activity of muscle polysomes and the yield of total and poly(A) + RNA all increase initially. Following the initial changes, these parameters return to near control values by 30 days after Marcaine injection. Theoretical calculations suggest that the changes in polysome yield and activity are sufficient to account for the changes in the ability of muscle fragments to synthesize protein during the regeneration process. The specific activity of total muscle RNA in the wheat germ cell-free system decreases initially during the early stages of the regeneration process. This decrease may reflect the fact that while the yields of both total and poly(A) + RNA increase during the early stages of regeneration, the percentage of the total RNA which is poly(A) + decreases initially.

Animals↗
PubMed1984

Synaptonemal complex-associated centromeres and recombination nodules in plant meiocytes prepared by an improved surface-spreading technique.

An improved method of preparing two-dimensional surface spreads of plant synaptonemal complexes (SCs) is described. This technique produces clear preparations of SCs and, in addition, consistently reveals both centromeres and recombination nodules (RNs) in PTA-stained preparations viewed by electron microscopy. A preliminary study of RN number and distribution in Allium fistulosum indicates that they faithfully reflect the positions of cross-over exchange events as revealed by chiasmata.

Cell Nucleus↗
PubMed1984

A method for preparing two-dimensional surface-spreads of synaptonemal complexes from plant meiocytes for light and electron microscopy.

A method has been developed for preparing two-dimensional surface spreads of synaptonemal complexes (SCs) from plant meiocytes for examination by light and/or electron microscopy. Clear, well-spread preparations of SCs and unpaired axial cores have been obtained from a range of meiotic prophase I stages (leptotene to pachytene) from Allium and Secale meiocytes.

Botany↗