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Biomedical subjects

J Weiland

Publications and source records attributed to J Weiland.

At least 19 recordsLinked to original sources
PubMed2005

Heat pinches in electron-heated Tokamak plasmas: theoretical turbulence models versus experiments.

Two fluid turbulence models, the drift wave based quasilinear 1.5D Weiland model and the electromagnetic global 3D nonlinear model CUTIE, have been used to account for heat pinch evidence in off-axis modulated electron cyclotron heating experiments in the Rijnhuizen Tokamak Project. Both models reproduce the main features indicating inward heat convection in mildly off-axis cases. In far-off-axis cases with hollow electron temperature profiles, the existence of outward convection was reproduced only by CUTIE. Turbulence mechanisms driving heat convection in the two models are discussed.

Journal Article↗
PubMed2005

Anisotropic diffusion across an external magnetic field and large-scale fluctuations in magnetized plasmas.

The problem of random motion of charged particles in an external magnetic field is studied under the assumption that the Langevin sources produce anisotropic diffusion in velocity space and the friction force is dependent on the direction of particle motion. It is shown that in the case under consideration, the kinetic equation describing particle transitions in phase space is reduced to the equation with a Fokker-Planck collision term in the general form (non-isotropic friction coefficient and nonzero off-diagonal elements of the diffusion tensor in the velocity space). The solution of such an equation has been obtained and the explicit form of the transition probability is found. Using the obtained transition probability, the mean-square particle displacements in configuration and velocity space were calculated and compared with the results of numerical simulations, showing good agreement. The obtained results are used to generalize the theory of large-scale fluctuations in plasmas to the case of anisotropic diffusion across an external magnetic field. Such diffusion is expected to be observed in the case of an anisotropic k spectrum of fluctuations generating random particle motion (for example, in the case of drift-wave turbulence).

Journal Article↗
PubMed2001

Light-driven retinal ganglion cell responses in blind rd mice after neural retinal transplantation.

PURPOSE: Light-elicited retinal ganglion cell (RGC) responses after fetal neural retinal transplantation have not been demonstrated in animal or human subjects blind from outer retinal degeneration, despite apparent morphologic success. This study was designed to test the hypothesis that the functional success of retinal transplantation may be enhanced by using a young host retina (13 days old). METHODS: At postnatal day (P)13 C3H/HeJ (rd/rd) retinal degenerate mice received a subretinal transplant, in one eye only, of neural retinal tissue isolated from newborn normal C57/BL6J mice. Between 33 and 35 days after transplantation, local electroretinograms (ERGs) and ganglion cell responses were recorded directly from the retinal surface using a differential bipolar surface electrode. Measurements were performed both with and without light stimulation. Similar recordings were also performed in age-matched eyes subjected to sham transplantation, in control eyes that were not subjected to surgery, and in animals eyes that underwent transplantation at 8 weeks of age. After the recordings, the eyes were processed for light and transmission electron microscopy. RESULTS: Three of 10 mice showed bursts of ganglion cell action potentials (ON response only) as well as recordable intraocular ERGs over the transplant in response to 1-second and 200-msec light stimuli. Light-driven ganglion cell responses could not be recorded in areas outside the transplant in all transplant-recipient eyes, age-matched control eyes, and sham-transplantation eyes. Light responses also could not be recorded in animal eyes that received transplants at an older age (8 weeks). Electron microscopic examination confirmed the presence of photoreceptor outer segments in the areas affected by transplantation. CONCLUSIONS: This study demonstrates the presence of light-driven ganglion cell responses after subretinal transplantation in a retinal degenerate model. This finding may reflect functional integration of the transplant with the host, but a rescue effect on remaining host photoreceptors cannot be ruled out. The findings suggest, however, that modification of host parameters, such as host age, may be important approaches for improving the functional success of retinal transplantation.

Action Potentials↗
PubMed1998

Partial synthetic derivatization of canrenone and characterization of its impact on the inhibitory effect on Na+/K(+)-ATPase activity in human heart muscle.

To improve the weak inhibitory effect of 3-oxo-17 alpha-pregna-4,6-diene-21,17-carbolactone (canrenone, II) on Na+/K(+)-ATPase activity in human heart muscle, we have investigated the impact of hydrogenation, reduction, glycosidation, and the introduction of a 3-sulfonamido residue on the inhibitory potency of canrenone. The greatest increase in potency (> 20 times) was found for 3 beta-(alpha-L-rhamnopyranosyloxy)-5 beta, 17 alpha-pregnane-21, 17-carbolactone (IX). The 3-O-glycosides IX-XI are the first representatives of C/D-trans steroids with effector-receptor complex decay half-times longer than those of therapeutically used cardenolides.

Canrenone↗
PubMed1997

The nitration of canrenone with acetic anhydride/nitric acid.

3-Oxo-17 alpha-pregna-4,6-diene-21,17-carbolactone (canrenone, II) is produced from the potassium salt of 17-hydroxy-3-oxo-17 alpha-pregna-4,6-diene-21-carboxylic acid (I) by acid catalyzed lactonization. II reacts with acetic anhydride/nitric acid to give one main product (III) and some minor products. The structure of III was determined by chemical and spectral analysis to the 4-nitro derivative of canrenone. This result is in contrast to the known reactions of II with most other reagents that were found to add at delta(6), and also in contrast to the reactions of acetic anhydride/nitric acid with alkenes. Electrophilic substitution at the ambident C4 is discussed as the reaction path. The 4-nitro group enhances the inhibitory activity of II against Na+/K(+)-ATPase, the target enzyme of the cardioactive digitalis glycosides, which appears to indicate increased cardioactivity.

Acetic Acid↗
PubMed1996

Modeling of the three-dimensional structure of the digitalis intercalating matrix in Na+/K(+)-ATPase protodimer.

Based on the knowledge that the digitalis receptor site in Na+/K(+)-ATPase is the interface between two interacting alpha-subunits of the protodimer (alpha beta)2, the present review makes an approach towards modeling the three-dimensional structure of the digitalis intercalating matrix by exploiting the information on: the primary structure and predicted membrane topology of the catalytic alpha-subunit; the determinants of the secondary, tertiary and quaternary structure of the membrane-spanning protein domains; the impact of mutational amino acid substitutions on the affinity of digitalis compounds, and the structural characteristics in potent representatives. The designed model proves its validity by allowing quantitative interpretations of the contributions of distinct amino acid side chains to the special bondings of the three structural elements of digitalis compounds.

Binding Sites↗
PubMed1995

Location and properties of the digitalis receptor site in Na+/K(+)-ATPase.

Since 1985, several research groups have shown that a number of amino acids in the catalytic alpha-subunit of Na+/K(+)-ATPase more or less strongly modulate the affinity of a digitalis compound like ouabain to the enzyme. However, scrutiny of these findings by means of chimeric Na+/K(+)-ATPase constructs and monoclonal antibodies has recently revealed that the modulatory effect of most of these amino acids does not at all result from direct interaction with ouabain, but rather originates from long-range effects on the properties of the digitalis binding matrix. Starting from this knowledge, the present review brings together the various pieces of evidence pointing to the conclusion that the interface between two interacting alpha-subunits in the Na+/K(+)-ATPase protodimer (alpha beta)2 provides the cleft for inhibitory digitalis intercalation.

Sodium-Potassium-Exchanging ATPase↗
PubMed1995

Differentiation between isoforms of Na+/K+-transporting atpase from human and guinea-pig muscle through use of digitalis derivatives as analytical probes.

The aims of the study included: to explore the protein structure basis for the differences in digitalis sensitivity between isoforms of Na/K-ATPase from human and guinea-pig cardiac muscle; to determine the relative significance of the constituents of tripartite digitalis compounds in their inhibitory action on these Na/K-ATPase isoforms; to evaluate the potential significance of the receptor kinetics for pharmacological characteristics. The analytical method has been the recording of the inhibitory interaction of various digitalis derivatives with the Na/K-ATPase isoforms. The protein structure basis for the isoform differences in digitalis susceptibility has been explored by analysing in free-energy plots the kinetics of their inhibitory interaction with 53 digitalis derivatives of grossly different structure. The slope of the regression line and the parameters of the regression equation proved to be similar for the two isoforms in spite of the great difference in their digitalis susceptibilities. This surprising uniformity indicates that a uniform "macroscopic" mechanism underlies the inhibitory effect of the various derivatives on the two isoforms. On the other hand, the differences in the positions of delta G*on and delta G*off values for particular inhibitors relative to the regression line reveal differences in the "microscopic" interaction energy surfaces of the two isoforms. In conclusion, the origin of the isoform distinctions in their susceptibility towards inhibition by various digitalis derivatives is essentially confined to differences in the chemotopology of the digitalis recognition matrix and binding cleft. Specific observations allowed to disentangle the impact of various steroid derivatizations at carbon atoms 3, 17, and diverse other positions on the kinetics of their interaction with the enzyme isoforms. The steroid nucleus of the cardiac glycosides, 5 beta, 14 beta-androstane, proves to be the basal structural element for discrimination of Na/K-ATPase isoforms. This discrimination becomes much enlarged by steroid glycosidation at C3 beta-OH and/or by steroid substitution of C17 beta-H by a lactone ring. The higher inhibitory sensitivity of the human isoform is based either on an increased association rate or a decreased dissociation rate, depending on the nature of derivatization.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Potential suitability of Na+/K(+)-transporting ATPase in pre-screens for anti-cancer agents.

Twenty-five compounds [digitalis (generic name for cardenolides, bufadienolides and their glycosides) representatives and derivatives, various steroids as well as some customary carcinostatics] have been compared in terms of their potency to suppress the proliferation of Ehrlich mouse ascites carcinoma (EMAC) cells and to inhibit the activity of Na/K-ATPase from EMAC cells and from human cardiac muscle. The inhibitor susceptibilities of the Na/K-ATPase isoforms of EMAC and cardiac muscle are very different, in favour of the cardiac muscle with the digitalis-like acting steroids, whereas they are quite similar with the digitalis-unlike acting compounds. Whereas the K0.5 values for the inhibition of EMAC Na/K-ATPase display the expected dependence on steroid structure, the IC50 values for the suppression of EMAC cell proliferation all lie within a narrow concentration range. With ouabain, the IC50 value for the suppression of proliferation of oestrogen receptor-negative, human mammary carcinoma (MCA) cells is four orders of magnitude higher than the K0.5 value for inhibition of the activity of human cardiac muscle Na/K-ATPase. In contrast to this effectivity order, some synthetic derivatives of digitalis steroids develop primarily antiproliferative potency.

Animals↗
PubMed1991

Interaction of progesterone derivatives with the digitalis target enzyme: impact of glycosidation on inhibitory potency.

As a function of the structural modification of the steroid nucleus, the inhibitory interaction of 11 progesterone derivatives with human Na/K-ATPase (Na+/K(+)-transporting ATPase, EC 3.6.1.37), through C3-O-rhamnosylation, is either much decreased or weakly up to strongly increased, so that the rhamnosyl residue contributes to the complementary Gibbs energy of interaction, at the most, the same Gibbs energy increment as realized in ouabain. After C3 beta-O-rhamnosylation, the activity of some progesterone derivatives considerably surpasses that of 3 beta-O-rhamnosyl-chlormadinolacetate, which has been known to elicit positive inotropy in cats. The progesterone derivatives (aglycons and glycosides), that have been analysed more closely, produce their effects by the same molecular mechanism of interaction with Na/K-ATPase as characteristic for digitalis aglycons and glycosides. The results promise to pave the way for the identification of the chemical nature of endogenous digitalis and for the design of novel inotropic drugs.

Biotransformation↗
PubMed1991

Chemical models for the chemical nature of endogenous digitalis.

The inability or the capacity to promote the phosphorylation of Na+/K(+)-transporting ATPase (Na/K-ATPase) from [32P]Pi is shown to differentiate between mechanistically digitalis-unlike and digitalis-like inhibitors of this enzyme known to be the receptor for all digitalis actions. A negative or positive response in the phosphorylation promotion assay introduced here appears thus to be suitable to diagnose the chemical species in the isolates of animal origin related to the putative endogenous digitalis. Various digitalis-congeneric C/D-cis steroids, progesterone-congeneric C/D-trans steroids and the Erythrophleum alkaloid cassaine promote the enzyme phosphorylation and show a similar pattern of discrimination between three Na/K-ATPase variants. Thus, their cyclopentanoperhydrophenanthrene or perhydrophenanthrene nuclei appear to serve as the minimal pharmacophoric lead structures for bimolecular recognition and to represent chemical models for the chemical nature of endogenous digitalis. Specifically, the hormonal C/D-trans steroids could provide the basic skeleton in endogenous digitalis biosynthesis.

Animals↗