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Biomedical subjects

D Dupuis

Publications and source records attributed to D Dupuis.

At least 19 recordsLinked to original sources

Investigation of the secondary DNA-binding site of the bacterial recombinase RecA.

The L2 loop is a DNA-binding site of RecA protein, a recombinase from Eschericha coli. Two DNA-binding sites have been functionally defined in this protein. To determine whether the L2 loop of RecA protein is part of the primary or secondary binding site, we have constructed proteins with site-specific mutations in the loop and investigated their biological, biochemical, and DNA binding properties. The mutation E207Q inhibits DNA repair and homologous recombination in vivo and prevents DNA strand exchange in vitro (Larminat, F., Cazaux, C., Germanier, M., and Defais, M. (1992) J. Bacteriol. 174, 6264-6269; Cazaux, C., Larminat, F., Villani, G., Johnson, N. P., Schnarr, M., and Defais, M. (1994) J. Biol. Chem. 269, 8246-8254). We have found that mutant protein RecAE207Q lacked one of the two single stranded DNA-binding sites of wild type RecA. The remaining site was functional, and biochemical activities of the mutant protein were the same as wild type RecA with ssDNA in the primary binding site. The second mutation, E207K, reduced but did not eliminate DNA repair, SOS induction, and homologous recombination in vivo. In the presence of ATP, mutant protein RecAE207K catalyzed DNA strand exchange in vitro at a slower rate than wild type protein, and ssDNA binding at site I was competitively inhibited. These results show that the L2 loop is or is part of the functional secondary DNA-binding site of RecA protein.

Amino Acid Sequence↗

Low density lipoprotein-receptors in primary cultures of rat glial cells.

Newborn rat glial cells in primary culture contain an active cholesterol side chain cleavage cytochrome P450. Cholesterol can be supplied either by biosynthesis or derive from low density lipoproteins (LDL), which bind apolipoprotein Band E (apoB,E) (LDL)-receptors and undergo receptor-mediated endocytosis. Using antibodies to purified human plasma LDL and antibodies to bovine adreno-cortical LDL-receptor, the presence of LDL-receptors was demonstrated on rat glial cells after 3-4 weeks of primary culture, by ligand blotting, immunoblotting, and indirect immunofluorescence staining. The latter approach indicated that oligodendrocytes express higher levels of LDL-receptors than astrocytes present in the same culture. The immunofluorescence staining was observed not only at the cell surface, but also within the cytoplasm, suggesting that the LDL-receptor complexes had been internalized. Western blotting of LDL-receptors extracted from glial cells indicated a band of approximately 130 kDa, the size expected for intact receptors. Their functionality was shown by the conversion of [3H]cholesterol linoleate, incorporated into reconstituted LDL and added to the cell cultures, to [3H]pregnenolone and/or its 20 alpha-hydroxy-metabolite. This is the first characterization of functional LDL-receptors on isolated, well characterized, normal brain cells.

Animals↗

Characterization of plasminogen binding to human capillary and arterial endothelial cells.

Phenotypic diversity of endothelial cells that line the various vascular spaces has been well established. However, it is not known if biochemical differences also exist, particularly in the numbers of receptors for plasma proteins. Equilibrium binding techniques were used to assess potential differences in the binding of 125I-labelled plasminogen to cultured human umbilical arterial endothelial cells and capillary endothelium, as compared with umbilical venous cells. The kinetic behaviour of plasminogen binding to all three types of cells was similar, with optimal binding occurring between 20 and 30 min of incubation. Binding of plasminogen to arterial, capillary, and venous cells was concentration dependent and reversible upon addition to excess unlabelled plasminogen. Scatchard analyses showed that artery, capillary, and venous endothelial cells all possess low affinity sites for plasminogen with Kd values of 0.30 +/- 0.07, 0.40 +/- 0.06, and 0.40 +/- 0.08 microM, respectively. Vein cells also possess an additional higher affinity binding site with a Kd of 0.07 +/- 0.01 microM, exhibiting a 6-fold greater affinity for plasminogen than the lower affinity sites on capillary and arterial endothelial cells. Assuming a stoichiometry of 1:1 for binding, the data indicate that arterial and capillary endothelial cells contain approximately 4.2 (+/- 0.9) x 10(6) and 4.1 (+/- 0.6) x 10(6) plasminogen receptors per cell. Venous cells contain both low and high density binding sites with 6.2 (+/- 0.8) x 10(6) and 12.4 (+/- 2.4) x 10(6) sites per endothelial cell. The presence of a higher affinity site on vein cells, but not on artery or capillary cells, may signal functional differences relating to fibrinolytic activity on the surface of these cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗

New fatty monoesters of erythromycin A.

New fatty polyenic (linoleic, linolenic, arachidonic, linoelaidic) mono esters of erythromycin A have been synthesized by using various reagents such as acyl chloride, carboxylic acid anhydride, and mixed carbonic anhydride. These different ways of activating the fatty acid allowed a regioselectivity of esterification at position 2' of the desosamine ring or position 4" of the cladinose ring of erythromycin A. The in vitro antibacterial properties of these new esters against members of the resident flora of the human skin were determined and compared with those of erythromycin A. The number and the stereochemistry of the double bonds seem to play a crucial role in the expression of the in vitro antibacterial activity.

Bacteria↗

Regional variation in percutaneous absorption in man: measurement by the stripping method.

The influence of anatomic site on the relationship between total penetration of a molecule and its quantities present in the stratum corneum (SC) 30 min after application was quantified in an in vivo study. For each site, six male volunteers received two symmetrical applications of 1,000 nmol benzoic acid 14C to an area of 1 cm2 for 30 min. The first application permitted measurement of total absorption of benzoic acid within 4 days (urinary excretion method), while the second enabled determination of the quantity of benzoic acid in the SC at the end of the application time. Total penetration according to site is: back less than arm less than chest less than thigh less than abdomen less than forehead, (with the forehead being three times more permeable than the back). Whatever the sites and the origin of the differences observed, the results show that the single measurement of the amounts of a compound present in the SC at 30 min postapplication appears sufficient to predict its total penetration, these two parameters being linearly correlated (r = 0.97, P less than 0.001).

Adult↗

The measurement of the stratum corneum reservoir: a simple method to predict the influence of vehicles on in vivo percutaneous absorption.

The influence of nine vehicles on in vivo percutaneous absorption of benzoic acid has been studied in the hairless rat. Although the vehicles used were simple in composition, the total amount of benzoic acid which penetrated varied by a factor of 50. A weak relationship was found between penetration of benzoic acid and its maximum solubility in the different vehicles. A linear relationship was demonstrated between the amount of benzoic acid present in the stratum corneum at the end of a 30 min application period and the total amount absorbed over 4 days. We suggest that the influence of a vehicle on the overall absorption of a substance can therefore be predicted by simply measuring the amount present in the stratum corneum at the end of a 30 min application period.

Animals↗

The measurement of the stratum corneum reservoir. A predictive method for in vivo percutaneous absorption studies: influence of application time.

The relation existing in vivo between the reservoir function of the stratum corneum following a 30-min application time and the total percutaneous absorption of molecules applied for a longer time was studied on hairless rats. One thousand nanomoles of 4 radiolabeled molecules (theophylline, nicotinic acid, acetyl salicylic acid, benzoic acid) were applied on 1 cm2 of back skin for 0.5, 2, 4, and 6 h. The total recovery in excreta and the whole animal body were measured 4 days later in order to determine the level of absorption. A direct proportionality (r = 0.99) between the total percutaneous absorption of these compounds and the duration of their application was observed. This suggests that a constant flux of penetration does exist in vivo. The reservoir function of the stratum corneum was measured by successive stripping of the treated area. Following a 30-min application, a strict correlation (r = 0.99) between the total amounts of molecules penetrated in 4 days and the amounts found in the reservoir of the horny layer was demonstrated. All together these findings show that the simple knowledge of the reservoir effect of the stratum corneum for a molecule applied for 30 min allows the predictive assessment of its total penetration resulting from various times of application.

Animals↗

In vivo relationship between horny layer reservoir effect and percutaneous absorption in human and rat.

The in vivo relationship between the reservoir effect of the stratum corneum and the percutaneous absorption was established in both human volunteers and hairless rats. Four doses of [ring-14C]benzoic acid, 125, 250, 500, and 1000 nmol, were applied on 1 cm2 either on the external side of the human arm or on the back of the rat, for 30 min. In both human and rat, the data on percutaneous absorption after 4 days is directly related to the dose administered. In rat, the permeability to benzoic acid is twice that of the human skin and the reservoir effect of the stratum corneum, measured at the end of application (30 min), is also doubled for this molecule in rat. Taking into account these findings and the observed histologic differences between the treated areas of these two species, the molecular reservoir of the horny layer may well be situated within the interlayer spaces. For both species, a linear relationship exists between (x), the amount of substance present in the stratum corneum at the end of application (30 min), and (y), the total amount penetrated in 4 days. The relationship, similar to that obtained in an earlier study on rat with 10 molecules, may be written as follows: y = 1.83 x - 0.52 (r = 0.998, p less than 0.001). Thus the amount of substance liable to penetrate through human skin within 4 days can be predicted by measuring the amount present in the stratum corneum 30 min after application of the drug.

Administration, Topical↗

[Thyroid hormones in alcoholic cirrhosis before and after alcohol withdrawal].

In a controlled study, the authors have assayed the serum values of thyroid hormones, TSH, reverse T3 (rT3) and the T4/TBG ratio in patients with alcoholic liver cirrhosis before and after 15 days of total abstinence from alcohol. Before abstinence, they show a significant decrease of T3 and a significant increase of r T3. Only T3 values are correlated to the clinical and biological signs of liver cirrhosis. The T3 and rT3/T3 ratio allow a good evaluation of the severity of the cirrhotic condition. The study, after abstinence from alcohol, shows an improvement of both biological abnormalities and T3, rT3, rT3/T3 values. Pathogenic mechanisms of these disturbances are discussed and therapeutic prospects considered.

Adult↗

In vivo correlation between stratum corneum reservoir function and percutaneous absorption.

A relationship between stratum corneum reservoir function and percutaneous absorption has been established in the hairless rat. Two hundred nanomoles of 10 substances that have a wide range of chemical structures were topically applied for 30 min and the total body distribution was measured after 96 h. The quantity of substance present in the stratum corneum reservoir after 30-min application was measured by liquid scintillation counting after tape-stripping the treated area. A linear relationship exists between the quantity of substance in this reservoir x(nmol X cm-2) and the total amount of radioactivity distributed in the body and excreta y(nmol X cm-2) after 96 h. The relationship is given by: y = 1.644 X x - 0.536 (r = 0.998, p less than 0.001). Apart from the steroids, 80-95% of the compounds were excreted in the urine; and with the exception of thiourea, this elimination was rapid, especially for mannitol and benzoic acid. We confirmed that in terms of penetration there is a factor of 50 between benzoic acid (best) and dexamethasone (worst). Thus the quantity of substance penetrating through intact rat skin can be predicted by measuring the horny layer concentration. The animal data reported here should be verified in humans.

Animals↗

Surface modifications in the platelets of a patient with alpha-N-acetyl-D-galactosamine residues, the Tn-syndrome.

The Tn-syndrome is an acquired disorder characterized by the polyagglutination of blood cells and the pathological exposure of alpha-N-acetyl-D-galactosamine residues (Tn-antigen) at the cell surface. We now report studies on the platelet of a patient (Ba.) of which 81% reacted positively with a fluorescein conjugate of Helix pomatia agglutinin (HPA). The surface proteins of Ba. platelets were labeled with 125I by the lactoperoxidase-catalyzed procedure; single and two-dimensional electrophoresis on sodium dodecyl sulfate (SDS)-polyacrylamide gels was followed by autoradiography that revealed normal 125I-labeling of the major membrane glycoproteins (GP) but that GP Ib had a faster than normal migration. the abnormal GP Ib of Ba. platelets was strongly labeled when platelet suspensions were treated sequentially with neuraminidase, galactose oxidase, and sodium [3H]borohydride. Unlike the GP Ib of normal human platelets, it was also strongly labeled when Ba. platelets were treated with galactose oxidase and sodium [3H]borohydride alone. Both the alloantigen, PlA1, and quinidine-dependent antibody receptor activity were normally expressed by Ba. platelets, which also bound a monoclonal antibody (AN51) to GP Ib. Analysis of Ba. platelets by crossed immunoelectrophoresis using a rabbit anti-human platelet antibody preparation revealed the presence of an immunoprecipitate in the GP Ib position that had an abnormal appearance and migration in the second dimension. An altered position of the precipitate given by Factor VIIIR:Ag was also noted. Incorporation of HPA into the agarose gel during the first dimension electrophoresis resulted in the specific precipitation of the abnormal GP Ib of Ba. platelets. Our studies show that circulating Tn-platelets contain GP Ib with a modified oligosaccharide chain structure responsible for the platelet expression of Tn-antigen activity.

Acetylgalactosamine↗

Specific protein and glycoprotein deficiencies in platelets isolated from two patients with the gray platelet syndrome.

The gray platelet syndrome is a rare inherited platelet disorder characterized by the absence of alp ha-granules as observed by electron microscopy. Analysis of the glycoprotein composition of the platelets of 2 such patients by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) revealed decreased or absent staining for carbohydrate of several high molecular weight glycoproteins. The major periodic acid Schiff (PAS) staining membrane glycoproteins were normally detected and were normally labeled with 125I during lactoperoxidase-catalyzed iodination. Analysis of the protein composition of gray platelets by single or two-dimensional SDS-PAGE followed by Coomassie blue staining revealed an apparent absence of GP Ig (thrombospondin), markedly reduced platelet fibrinogen and albumin concentrations, and severely reduced levels of 2 low molecular weight polypeptides exhibiting identical rates of migration on SDS-PAGE as platelet factor 4 and beta-thromboglobulin. SDS-PAGE profiles similar to those of the gray platelets were observed with normal human platelets that had undergone the release reaction induced by thrombin. Analysis of gray platelet proteins by crossed immunoelectrophoresis using a rabbit anti-human platelet antibody preparation and rocket immunoelectrophoresis using monospecific antisera confirmed the above findings and showed additional severe deficiencies of factor VIIIR:Ag and cold-insoluble globulin. In contrast, factor XIII (subunit A), a cytoplasmic protein, was normally detected. Our studies provide further evidence that circulating gray platelets specifically lack, or have markedly decreased concentrations of, the alpha-granule proteins.

Adult↗

Analysis of the glycoprotein and protein composition of Bernard-Soulier platelets by single and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Previous reports have described conflicting results concerning the glycoprotein (GP) and protein composition of Bernard-Soulier platelets. In view of this controversy we have analyzed the platelets of four Bernard-Soulier patients using improved single and two-dimensional sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis procedures. An absence of staining for carbohydrate of membrane GP Ib was characteristic for the platelets of each patient. Major periodate-Schiff staining bands corresponding to membrane GP IIb, IIIa, and IIIb were clearly detected and their presence was confirmed by two-dimensional SDS-polyacrylamide gel electrophoresis. The protein content of the Bernard-Soulier platelets was increased two- to fourfold. However, analysis of their protein composition using 7-12% acrylamide gradient gels showed normal polypeptide profiles. Lactoperoxidase-catalyzed 125I-labeling of the Bernard-Soulier platelet surface proteins was followed by SDS-polyacrylamide gel electrophoresis and autoradiography. No labeling in the Ib position was detected whereas the other major membrane GP, including Ia and IIa, were normally located. In contrast, GP Ib was clearly detected by periodate-Schiff staining and autoradiography when normal human platelets that had been exhaustively treated with neuraminidase before the lactoperoxidase-catalyzed iodination were analysed. No abnormalities were detected in the GP patterns of membranes isolated from the patients' erythrocytes. Only a severe molecular abnormality or possible deletion of GP Ib could account for this major platelet lesion in the Bernard-Soulier syndrome.

Blood Platelet Disorders↗