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Biomedical subjects

V Dressler

Publications and source records attributed to V Dressler.

9 recordsLinked to original sources
PubMed1999

CombiTool--a new computer program for analyzing combination experiments with biologically active agents.

CombiTool is a new computer program for the analysis of combination effects of biologically active agents. It performs model calculations and an analysis of experimental combination effects for two or three agents according to both the Bliss independence and the Loewe additivity criteria. Zero interaction response surfaces are calculated from single-agent dose-response relations and compared to experimental combination data. The calculation of response surfaces for Loewe additivity is based on a new approach which combines the implicit definition equation in terms of doses alone with single-agent dose-response relations. The simultaneous analysis of experimental data according to both Loewe additivity and Bliss independence within one program can hopefully contribute to a better understanding of the meaning and limits of the two criteria. CombiTool has a built-in graphics facility which allows the direct visualization of the response surfaces or the corresponding contour plots and the experimental data.

Algorithms↗
PubMed1984

Stabilizing factors of phospholipid asymmetry in the erythrocyte membrane.

Transbilayer reorientation (flip) of exogenous lysophospholipids and changes of the transbilayer distribution of endogenous phospholipids were studied in human erythrocytes and membrane vesicles. (1) Exogenous lysophosphatidylserine irreversibly accumulates in the inner membrane layer of resealed ghosts of human erythrocytes. (2) This accumulation even occurs after complete loss of asymmetric distribution of endogenous phosphatidylethanolamine and partial loss of phosphatidylserine asymmetry in diamide-treated cells. (3) Formation of inside-out and right-side-out vesicles from erythrocyte membranes results in a loss of endogenous phospholipid asymmetry as well as of the ability to establish asymmetry of exogenous lysophosphatidylserine. Rates of transbilayer reorientation of lysophospholipids for the vesicles, however, are comparable to those for intact cells. (4) Loss of endogenous asymmetry of phosphatidylserine is also observed in vesicles isolated from erythrocytes after heat denaturation of spectrin. The asymmetry in the residual cells is maintained. (5) In contrast to the loss of asymmetry of phosphatidylethanolamine and of phosphatidylserine, the asymmetry of sphingomyelin is completely maintained in the vesicles. (6) The stability of phospholipid asymmetry in the native cell is discussed in terms of a limitation of access of phospholipids to hypothetical reorientation sites. Such a limitation may either be the result of interaction of phospholipids with the membrane skeleton as in case of phosphatidylserine and phosphatidylethanolamine, or the result of lipid-lipid interactions as in case of sphingomyelin.

Erythrocyte Membrane↗
PubMed1984

Reorientation rates and asymmetry of distribution of lysophospholipids between the inner and outer leaflet of the erythrocyte membrane.

Labelled lysophospholipids were inserted into the outer layer of the erythrocyte membrane and their reorientation (flip) to the inner layer quantified by following the increase of the fraction of lysophospholipids not extractable by albumin. Flip rate constants were calculated from the kinetics of equilibration of the lysophospholipids between two compartments, the outer and the inner leaf of the bilayer, in the early phase of the flip kinetics where correction for non-enzymatic hydrolysis and acylation could be omitted. The distribution of a lysophospholipid finally attained reflects its affinity for the two layers. Whereas lysophosphatidylcholine has a slight preference for the outer layer of the membrane, lysophosphatidylserine spontaneously concentrates in the inner layer up to a ratio of 4:1. This asymmetry mimics the distribution of phosphatidylserine in the native membrane. Flip rates depend on membrane lipid compositions. They are enhanced by cholesterol depletion. Comparison of various mammalian species demonstrates that erythrocytes with a higher phosphatidylcholine/sphingomyelin ratio and high content of polyunsaturated fatty acids (mouse and rat) have a high transbilayer mobility, in contrast to erythrocytes with a low phosphatidylcholine/sphingomyelin ratio and a low content of polyunsaturated fatty acids (ox). Molecular properties of lysophospholipids influence their transbilayer mobility. Flip rates of lysophospholipids are enhanced not only by unsaturation of their fatty acid, but also by a negative net charge on the headgroup. This indicates that the strongly asymmetric distribution of phosphatidylserine in the native erythrocyte membrane, which is maintained for the lifespan of the cell, does not result from a lack of transbilayer mobility.

Cholesterol↗
PubMed1984

Cross-linking of SH-groups in the erythrocyte membrane enhances transbilayer reorientation of phospholipids. Evidence for a limited access of phospholipids to the reorientation sites.

Oxidation of erythrocyte membrane SH-groups and concomitant cross-linking of spectrin, which induce a partial loss of phospholipid asymmetry (Haest, C.W.M., Plasa, G., Kamp, D. and Deuticke, B. (1978) Biochim. Biophys. Acta 509, 21-32) are now shown to result in a remarkable increase of the rates of transbilayer reorientation of exogenously incorporated lysophospholipids. Reorientation of both, neutral lysophosphatidylcholine and of negatively charged lysophosphatidylserine is enhanced. A decrease of the activation energy of the reorientation process as well as quantitative changes of the dependence of reorientation on the lysophosphatidylcholine and cholesterol content of the membrane indicate formation of new reorientation sites or modification of existing sites. A common mechanism may underly the formation of reorientation sites and the occurrence of leaks for small solutes (Deuticke, B., Poser, B., Lütkemeier, P. and Haest, C.W.M. (1983) Biochim. Biophys. Acta 731, 196-210) subsequent to oxidation of membrane SH-groups. Whereas exogenous lysophospholipids completely equilibrate between the two lipid layers regardless of the extent of oxidation of SH-groups, endogenous inner layer phospholipids become available for reorientation in a graded way. Native phospholipid asymmetry is therefore not the result of a low transbilayer mobility of phospholipids, but probably due to a lack of access of inner layer phospholipids to the reorientation sites.

Animals↗
PubMed1983

Dielectric breakdown of the erythrocyte membrane enhances transbilayer mobility of phospholipids.

Dielectric breakdown of erythrocytes is shown to result in a loss of asymmetry of phosphatidylethanolamine and in a markedly enhanced transbilayer mobility of exogenous lysophosphatidylcholine. The effect is much more pronounced in non-resealed cells than in cells resealed after the breakdown. A casual relationship between the structural defects in the lipid phase, indicated by these results, and fusion by dielectric breakdown is discussed.

Electrophysiology↗
PubMed1983

Concomitant changes of membrane leak permeability and phospholipid dynamics in erythrocytes subjected to chemical and physical membrane perturbation.

A mild selective oxidant of erythrocyte membrane SH-groups producing SS-bonds and inducing reversible crosslinking of spectrin, as well as strong less specific oxidants which produce a more extensive modification of membrane proteins and peroxidation of lipids and dielectric breakdown of the membrane induce formation of structural defects acting as aqueous pores and reorientation sites for phospholipids. The coupling of a process requiring hydrophilic structures (leak permeability) and a process also involving hydrophobic constituents (flip of phospholipids) suggests that the membrane lipid domain is involved in the effects.

Carbon Radioisotopes↗
PubMed1983

Transbilayer mobility of phospholipids in the erythrocyte membrane. Influence of the membrane skeleton.

Oxidative treatment of erythrocytes results in a strong enhancement of transbilayer reorientation of exogenous lysophospholipids. Only upon selective oxidation of SH-groups and concomitant crosslinking of spectrin by diamide, however, asymmetry of distribution of inner layer phospholipids, phosphatidylethanolamine and phosphatidylserine in the erythrocyte membrane becomes lost. This indicates that asymmetry is not due to a low transbilayer reorientation of the inner layer phospholipids, but that phosphatidylethanolamine and phosphatidylserine do not have access to the flip sites in the native membrane. A role of membrane skeleton proteins in the suppression of access of inner layer phospholipids to the flip sites is indicated by the loss of asymmetry of both phospholipids in spectrin depleted inside out vesicles and in vesicles produced by heat denaturation of spectrin. This idea is further supported by the observation that inner layer phospholipids analogues lysophosphatidylethanolamine and lysophosphatidylserine spontaneously accumulate in the inner layer of native erythrocytes, whereas lysolecithin does not. Moreover, this asymmetry is abolished in inside out vesicles.

Erythrocyte Membrane↗