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Biomedical subjects

L Blanchard

Publications and source records attributed to L Blanchard.

At least 37 records · Page 2Linked to original sources
PubMed1994

Effects of the Tyr64 substitution on the stability of cytochrome c553, a low oxidoreduction-potential cytochrome from Desulfovibrio vulgaris Hildenborough.

Cytochrome c553 from sulfate-reducing bacteria is a low-oxidoreduction-potential cytochrome. The primary and tertiary structures show notable differences when compared to mitochondrial cytochromes. Tyr64 replacement in cytochrome c553 provides evidence that this residue is not directly involved in the potential modulation but is mostly implicated in the hydrogen-bond network around the heme. While the different variants obtained did not induce drastic structural modifications, they did affect the stability of the protein. This decrease of stability in acidic and alkaline environments was observed by variations in the optical spectra and by mass spectrometry. In addition, the mobility of aromatic side-chain was found to be increased in the mutant proteins as monitored by two-dimensional NMR spectroscopy.

Base Sequence↗
PubMed1994

N-Phosphonomethyl dipeptides and their phosphonate prodrugs, a new generation of neutral endopeptidase (NEP, EC 3.4.24.11) inhibitors.

Inhibitors of the zinc protease neutral endopeptidase (NEP, EC 3.4.24.11) offer significant therapeutic interest as antihypertensives due to their ability to potentiate the biological action of the circulating natriuretic hormone ANF (atrial natriuretic factor). N-Phosphonomethyl dipeptides bearing a central (4-phenyl)phenylalanine residue have been designed to exert potent and selective NEP inhibition. In particular, (S)-3-[N-[2- [(phosphonomethyl)amino]-3-(4-biphenylyl)propionyl]amino]propionic acid (10a) (CGS 24592) displayed high inhibitory potency in vitro (IC50 = 1.9 +/- 0.1 nM) and a long plasma half-life in rats but lacked oral bioavailability. This drawback was overcome by using esterase-sensitive (acyloxy)alkyl phosphonates. More remarkable, several diaryl phosphonate derivatives of 10a also performed as effective prodrugs. Specifically, the structurally simple diphenyl phosphonate 18 (CGS 25462) induced potent inhibition of NEP ex vivo for at least 8 h after oral administration to rats (30 mg/kg). Its antihypertensive effect was demonstrated in DOCA-salt rats. At 30 mg/kg orally, 18 caused a significant reduction in mean arterial pressure measuring -35 +/- 7 mmHg at 5-h postdosing. The alpha-aminomethyl phosphonate 18 represents a new generation of selective NEP inhibitors that combine high potency, long duration of action, and oral bioavailability. Therefore, it holds promise as a novel therapeutic agent for the treatment of human hypertension and congestive heart failure.

Animals↗
PubMed1994

The protein moiety modulates the redox potential in cytochromes c.

Cytochrome c is one of the most thoroughly documented oxidoreduction proteins. Its electron transfer activity, which involves an association between the heme group and the polypeptidic chain, is correlated with the redox potential value of the heme group. The redox potential covers a wide range up to 0.8 V, an extreme case being observed in the low-potential cytochromes c from sulfate reducing bacteria. On of the main roles of the polypeptidic moiety consists of modulating the redox potential value of the heme group. In this paper, some structural factors that seem likely to be involved in maintaining the redox potential value are described.

Cytochrome c Group↗
PubMed1993

Overexpression of Desulfovibrio vulgaris Hildenborough cytochrome c553 in Desulfovibrio desulfuricans G200. Evidence of conformational heterogeneity in the oxidized protein by NMR.

Plasmid pRC41, containing the cyf gene encoding cytochrome c533 from Desulfovibrio vulgaris Hildenborough, was transferred by conjugation from Escherichia coli to Desulfovibrio desulfuricans G200. The structural properties of the purified protein were studied by one-dimensional and two-dimensional NMR. A heterogeneity in the folding of the cytochrome isolated from D. vulgaris Hildenborough and from D. desulfuricans G200 was observed for the oxidized from. Temperature, pH and salt-dependence studies indicated that the heterogeneity does not result from an intermediate in the protein unfolding process, but derives from two conformations which are not in dynamic equilibrium.

Amino Acid Sequence↗
PubMed1993

Intramolecular electron transfer in ferredoxin II from Desulfovibrio desulfuricans Norway.

In order to elucidate the role of the two (4Fe-4S) clusters in ferredoxins and to determine whether an electron-transfer mechanism may occur between the clusters, the in vitro reduction of cytochrome c3 and cytochrome c553 by Desulfovibrio desulfuricans Norway ferredoxin II was studied using spectrophotometric techniques. Ferredoxin II, covalently cross-linked with either cytochrome c3 or c553, is an obligate intermediate in cytochrome reduction by pyruvate dehydrogenase. Both titration of the complex formation under 1H-NMR spectroscopy and cross-linking experiments between ferredoxin II and either cytochrome c3 or cytochrome c553 gave a stoichiometric ratio of 1:1. Modelling the protein yielded differences between the charge distributions around the two (Fe-S) clusters. The fact that Cluster 2 is blocked in the electron-transfer domain facing the cytochrome interacting heme, indicates Cluster 1 receives electron from pyruvate dehydrogenase. Consecutively, cytochrome reduction occurs owing to an intramolecular electron exchange between the two clusters of the ferredoxin. The properties of two (Fe-S) cluster ferredoxins are compared to those of monocluster ferredoxins and discussed in evolutionary terms.

Amino Acid Sequence↗
PubMed1993

Characterization of a lysine-to-glutamic acid mutation in a conservative sequence of farnesyl diphosphate synthase from Saccharomyces cerevisiae.

The mutant gene erg20-2 was isolated from a yeast strain defective in farnesyl diphosphate synthase (FPPS). This strain had the unusual property of excreting prenyl alcohols such as geraniol. The nucleotide (nt) sequence, compared with that of the wild-type gene, showed a single nt change, resulting in a Lys197-->Glu substitution in FPPS which is directly involved in terpenic alcohol formation. In addition, disruption of ERG20 revealed that in yeast no other prenyl transferase is able to synthesize the FPP molecules required for essential non-sterol metabolites.

Acyclic Monoterpenes↗
PubMed1993

{The perception of mental health professionals of barriers to the delivery of mental health services for the aged in New Brunswick}.

The present survey examines the barriers associated with the delivery of mental health services to the elderly as perceived by mental health professionals. The sample consisted of 139 professionals of the New Brunswick Mental Health Commission. The results reveal that the mean percentage of elderly clients in the practice of mental health professionals is low. The percentage of elderly clients in the practice of mental health professionals was positively correlated with training in gerontology. The attitudes of the respondents toward the elderly were either positive or neutral rather than negative. In addition, the results show that the barriers perceived by the professionals to explain the low utilization rates differ in order of importance from those acknowledged by the elderly. The lack of human resources was identified as the major barrier to the development of specific consultation services to the elderly. Finally, the implications of these results for the development of mental health consultation services for the elderly are examined.

Attitude of Health Personnel↗
PubMed1992

Backward visual masking in children and adolescents: sensory transmission, accrual rate and asymptotic performance.

We have applied the Lagged Accrual Model of visual backward masking to a group of children (aged 10) and a group of adolescents (aged 15). The two groups did not differ on sensory transmission time, indicating that the speed of sensory transmission has already attained its maximum by age 10. The older group showed a significantly greater rate of information accrual and a greater amount of information extraction. An application of the model to previously published data revealed that very young children (aged 5) have slower sensory transmission times.

Adolescent↗
PubMed1991

Sterol pathway in yeast. Identification and properties of mutant strains defective in mevalonate diphosphate decarboxylase and farnesyl diphosphate synthetase.

Yeast mutant strains auxotrophic for ergosterol and blocked in mevalonate diphosphate decarboxylase (erg19) and farnesyl diphosphate (FPP) synthetase (erg20) were isolated. The main feature of the mutants blocked in FPP synthetase is their ability to excrete prenyl alcohols, such as geraniol and farnesol. The isolation of the functional ERG20 gene allowed us to show that farnesyl diphosphate synthetase could be a rate limiting enzyme in ergosterol biosynthesis in yeast.

Acyclic Monoterpenes↗
PubMed1991

[Isoprenoide pathway and cell proliferation in the yeast Saccharomyces cerevisiae].

Yeast mutants blocked in farnesyl diphosphate (FPP) synthetase have been isolated. Their specific phenotype is likely linked to a lowering in the FPP pool required for protein prenylation. The structural gene of FPP synthetase has been isolated. Complete inactivation of FPP synthetase by gene disruption is letal for the yeast cells.

Cell Division↗
PubMed1989

4-(Phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids: synthesis, activity at N-methyl-D-aspartic acid receptors, and anticonvulsant activity.

A series of 4-(phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids were synthesized, and their biological activity was assessed as competitive ligands for the NMDA receptor, both in vitro by using a receptor binding assay ([3H]CGS 19755 binding) and in vivo by using an NMDA seizure model in mice. The analogues were also evaluated in [3H]AMPA and [3H]kainate binding to assess their affinity for non-NMDA excitatory amino acid receptor subtypes. A number of these analogues show potent and selective NMDA antagonistic activity both in vitro and in vivo. Most notable are 4-(phosphonomethyl)-2-piperidinecarboxylic acid (1a) (CGS 19755) and the phosphonopropenyl analogue 1i, both of which show anticonvulsant activity in the 1-2 mg/kg ip range. With the aid of computer-assisted modeling, a putative bioactive conformation for AP-5 is hypothesized from the SAR data presented and a preliminary model for the antagonist-preferring state of the NMDA receptor is presented.

Animals↗
PubMed1986

Ontogeny of receptors for thyrotropin-releasing hormone in the rat brain.

Developmental changes in the thyrotropin-releasing hormone (TRH) receptor concentrations of hypothalamic and certain extrahypothalamic structures in the rat were evaluated from 2 days after birth until sexual maturity. The maturational pattern of TRH receptors in hypothalamus, striatum and amygdala follow that of the pituitary and all show the same kinetic properties. The developmental pattern also coincides with that of other components of the hypothalamic-pituitary-thyroid axis. In all tissues, the concentration of receptors increased in early life to reach a maximum between 10 and 30 days of age and then decreased gradually to adult values. Development of TRH receptors reflected changes in the number of receptor sites but not in binding affinity, which remained constant and suggests that the TRH receptor is identical in all 4 tissues studied. These results indicate the parallel development of pituitary and central nervous system TRH receptors.

Aging↗
PubMed1983

Modulation of rat pancreatic amylase secretion and muscarinic receptor populations by chronic bethanechol treatment.

F8P6effect of a chronic bethanechol treatment (12 mg X kg-1 X day-1 i.p., for 14 days) was investigated on pancreatic amylase secretion and muscarinic cholinergic receptors in the rat. Dispersed pancreatic acini were used to evaluate enzyme secretion and binding of [3H]N-methylscopolamine, [( 3H]NMS). The bethanechol treatment caused a 4 fold decrease in sensitivity of the pancreas for amylase release in the presence of carbamylcholine, the EC50 being shifted from 0.69 microM to 2.9 microM. Receptor concentration was reduced by 42%, from 3360 to 1930 fmol/mg DNA. The equilibrium dissociation constant (KD) of the receptors for the ligand remained unchanged at 0.17 nM. Binding analysis of carbachol on the muscarinic receptors in terms of two classes of binding sites indicated that the shift in the dose-response curve of amylase secretion was accompanied by modifications to the high and low affinity forms. The maximal number of high affinity sites remained the same while their affinity was greatly decreased from 0.24 to 6.1 microM. The low affinity form showed a moderate decrease in affinity from 34 to 150 microM but a large drop in their numbers from 2620 to 890 fmol/mg DNA. These results suggest that the shift in the amylase dose-response curve to carbamylcholine, noted following bethanechol treatment in vivo, could be coupled with the observed change in affinity of the two agonist forms of muscarinic receptor in the pancreas. However, gradual occupancy or formation of the high affinity form of muscarinic receptors by cholinergic agonist corresponds well with the gradual stimulation of amylase release.

Amylases↗
PubMed1981

Linear eccrine nevus with comedones.

We report herein a case of a linear nevus comedonicus associated with tumors of sweat gland origin. We propose the term "linear eccrine nevus with comedones" as a suitable title for this disorder. Several similar cases in the literature are reviewed.

Adult↗
PubMed1979

Microscopically controlled surgery for extramammary Paget's disease.

In five cases of extramammary Paget's disease (EMPD), the neoplasms were removed under complete microscopical control by means of fixed-tissue chemosurgical technique in one case and fresh-tissue technique in four cases. In each lesion there were histologically involved areas extending several centimeters into clinically normal-appearing skin. All patients have been free of the disease for periods from four months to nine years. Other authors using conventional surgery have reported a recurrence rate of 44%. Microscopically controlled surgery offers the most reliable method of removing all of the neoplastic tissue EMPD and preserves as much normal tissue as possible.

Aged↗