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Biomedical subjects

A Erdmann

Publications and source records attributed to A Erdmann.

At least 19 recordsLinked to original sources
PubMed1998

26S proteasome structure revealed by three-dimensional electron microscopy.

In 26S proteasomes, "19S cap complexes" associate with either one or both ends of the barrel-shaped 20S core complex. These regulatory complexes which comprise about 20 different subunits, including 6 ATPases of the AAA family, are thought to recognize ubiquitinated substrate proteins, to dissociate and unfold them before threading them into the 20S core where they are degraded. Here, we examine the structure of 26S proteasomes from Drosophila embryos and Xenopus oocytes by electron microscopy. Image analysis reveals a rather flexible linkage between the 19S caps and the 20S core, with a peculiar wagging-type movement of the caps relative to the core. At this stage of the analysis, it is not clear whether this movement is relevant in terms of function. Three-dimensional reconstructions, taking this into account, provide first insights into the remarkably complex structure of the 19S caps and allows us to put forward a composite model of the entire 26S complex.

Animals↗
PubMed1997

Superantigen and endotoxin synergize in the induction of lethal shock.

Endotoxin (lipopolysaccharide; LPS) and superantigens (exotoxins) have been identified as potent inducers of lethal shock. While endotoxin primarily interacts with CD14 receptors on macrophages, superantigens like the staphylococcal enterotoxin B (SEB) preferentially activate T cells. Both cell types are triggered to release pro-inflammatory cytokines that in turn induce lethal shock. We analyzed whether endotoxin and superantigen interact during the induction phase of lethal shock. We report that LPS and SEB operate synergistically. Lethal doses of both inducers were reduced 100-fold when given in combination. The induced serum levels of tumor necrosis factor, interleukin-6, and interferon-gamma (IFN-gamma) were elevated and remained high for a prolonged period. Moreover, synergistic action of LPS and SEB induced lethal toxic shock even without presensitization of mice with D-galactosamine (D-GalN). Opposed to D-GalN-pretreated mice, mice injected with LPS and SEB showed less liver damage, but rather apoptosis of epithelial cells in the bowel. Cyclosporin A and treatment with anti-IFN-gamma monoclonal antibody blocked the synergistic action of LPS and SEB, indicating that T cell-derived IFN-gamma is the mediator of the observed synergism. Concomitant injection of LPS and SEB had no influence on SEB-induced T cell deletion and anergy induction. Since Gram-positive and Gram-negative bacteria can be recovered from septic blood samples, the synergistic action of endotoxin and superantigens might be relevant during lethal septicemia.

Animals↗
PubMed1997

Macrophages sense pathogens via DNA motifs: induction of tumor necrosis factor-alpha-mediated shock.

Cell surface components of pathogens, such as lipopolysaccharide (LPS), are an important signal for receptor-mediated activation of immune cells. Here we demonstrate that DNA of gram-positive and gram-negative bacteria or certain synthetic oligonucleotides displaying unmethylated CpG-motifs can trigger macrophages in vitro to induce nuclear translocation of nuclear factor-kappa B, accumulate tumor necrosis factor (TNF)-alpha mRNA and release large amounts of TNF-alpha. In vivo these events culminate in acute cytokine-release syndrome which includes systemic but transient accumulation of TNF-alpha. D-Galactosamine (DGalN)-sensitized mice succumb to lethal toxic shock due to macrophage-derived TNF-alpha resulting in fulminant apoptosis of liver cells. LPS and a specific oligonucleotide synergized in vivo as measured by TNF-alpha-release, suggesting that macrophages integrate the respective signals. The ability of macrophages to discriminate and to respond to bacterial DNA with acute release of pro-inflammatory cytokines may point out an important and as yet unappreciated sensing mechanism for foreign DNA.

Animals↗
PubMed1997

Regulation of transforming growth factor beta 1 messenger ribonucleic acid expression in porcine thyroid follicles in vitro by growth factors, iodine, or delta-iodolactone.

Transforming growth factor beta 1 (TGF beta 1) is an autocrine growth factor for thyrocytes and is supposed to be the mediator of iodine-induced growth inhibition of thyroid epithelial cells, but this is still controversial. We further investigated this hypothesis using intact porcine thyroid follicles ex vivo in a three-dimensional culture system. In this culture system it has been shown previously that both iodide as well as delta-iodolactone, the putative iodocompound mediating thyroid cell proliferation, inhibit growth of these follicles. We measured the amount of TGF beta 1 mRNA expression in these follicles after treatment either with thyrotropin (TSH), epidermal growth factor (EGF), or transforming growth factor alpha (TGF alpha) for growth stimulation or with inorganic iodine or delta-iodolactone in concentrations known to inhibit growth. TGF beta 1-mRNA was detected by Northern blot analysis. The known major transcript of 2.5 kb was detected in a steady state level up to 48 hours in untreated thyroid follicles. EGF and TGF alpha (5 ng/mL each) enhanced TGF beta 1 mRNA about threefold within 4 and 8 hours. This increase of TGF beta 1 mRNA was slightly decreased by simultaneous incubation with delta-iodolactone (1 microM) or iodide (40 microM KI). In contrast, both TSH (1 mU/mL) and forskolin (16 microM) decreased TGF beta 1 mRNA expression to about 70%, and this effect was abolished when follicles were pretreated with iodide (40 microM KI) in a concentration known to inhibit TSH action on cyclic adenosine monophosphate (cAMP) formation and proliferation. Iodide or delta-iodolactone alone had no significant effect on basal TGF beta 1 mRNA expression. We conclude that the growth inhibitory effect of iodide as well as of delta-iodolactone is not mediated through TGF beta 1 in intact porcine thyroid follicles ex vivo. The stimulatory effect of EGF and TGF alpha on TGF beta 1 expression might be related to extracellular matrix modulation during proliferation.

Animals↗
PubMed1995

Triggering Glutamate Excretion in Corynebacterium glutamicum by Modulating the Membrane State with Local Anesthetics and Osmotic Gradients.

Corynebacterium glutamicum can be triggered to excrete glutamate by the addition of local anesthetics, particularly tetracaine. Glutamate efflux is a carrier-mediated process and not due to unspecific membrane permeabilization. The concentration of local anesthetics triggering optimum excretion depended on the type of anesthetic and varied, ranging from 0.1 (chlorpromazine), 1.3 (tetracaine), and 2.6 mM (butacaine) to 15 mM (benzocaine), in close resemblance to the order of efficiency in anesthetic effect. The onset of glutamate excretion was not correlated to a change in the viscosity or fluidity of the membrane, as measured by electron spin resonance spectroscopy, nor was it related to an action of the anesthetic as an uncoupler. Tetracaine-triggered glutamate excretion was sensitive to changes in the transmembrane osmotic gradient, although an osmotic gradient alone could not trigger glutamate excretion. Tetracaine-triggered glutamate efflux was inhibited by an external rise in osmolality and stimulated by a corresponding decrease. The effects of osmotic gradients and the addition of local anesthetics on glutamate excretion were mutually exchangeable, indicating similar modes of action. We suggest that this common principle is a change in the membrane strain. C. glutamicum cells which excrete glutamate without manipulation of the membrane, e.g., biotin-limited cells or glutamate production mutants, were not stimulated by the addition of tetracaine.

Journal Article↗
PubMed1994

K-Cl cotransport, pH, and role of Mg in volume-clamped low-K sheep erythrocytes: three equilibrium states.

Ouabain-resistant K efflux and Rb influx in Cl and NO3 media were studied in volume-clamped low-K (LK) sheep red blood cells (SRBC) with normal and experimentally reduced cytoplasmic Mg (Mgi) levels as function of pH and at 37 degrees C. Sucrose was added to solutions with constant ionic strength and variable pH to maintain normal cell volume. Cl-dependent ouabain-resistant K(Rb) fluxes (K-Cl cotransport) at unity relative cell volume exhibited a maximum at pH approximately 7 in normal-Mgi LK cells consistent with the apparent acid pH activation reported for human erythrocytes. However, in LK SRBC with Mgi lowered by A-23187 and an external Mg chelator, K(Rb)-Cl cotransport was reversibly activated as the pH was raised from 6.5 to 9. The alkaline pH effect on Cl-dependent Rb influx in low-Mgi LK SRBC was due to a 10-fold rise in the maximum velocity values without a major change in the Km values. The pH dependence of the experimental flux reversal point, i.e., the extracellular Rb concentration at which no net K-Cl cotransport occurs, approximately paralleled that of the flux reversal point predicted from the ratio of the ion products, in both control and low-Mgi LK cells, albeit with a small displacement to higher extracellular Rb concentration at all pH values. The kinetic data can be explained by a general minimum three-state equilibrium in which deprotonation recruits transporters from a resting R state into the active A state modified by Mgi to an inactive I state.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗
PubMed1992

Species-dependent differences in the effect of ionic strength on potassium transport of erythrocytes: the role of lipid composition.

The Rb+(K+) efflux of erythrocytes from six mammalian species was investigated in solutions of physiological and low ionic strength. A species dependent increase of the Rb+(K+) efflux in low ionic strength solution could be observed. The rate constant of Rb+(K+) efflux of erythrocytes in physiological ionic strength solution correlates with the content of arachidonic acid of the membrane phospholipids. The same relation was observed in solution of low ionic strength with the exception of human erythrocytes. In addition, an age-dependent correlation of the rate constant of Rb+(K+) efflux from calf erythrocytes in low ionic strength solution with the content of arachidonic acid of the membrane phospholipids was found. The Rb+(K+) efflux of human erythrocytes, which is enhanced in low ionic strength solution, decreases with the decreasing temperature. The temperature-dependent ESR order parameter of a fatty acid spin label for human and cow erythrocytes in solution of physiological and low ionic strength media suggested that the effect of low ionic strength on Rb+(K+) efflux is not solely based on a change of membrane fluidity. The results are interpreted as being due to a specific influence of membrane phospholipids on the Rb+(K+) efflux.

Aging↗
PubMed1991

Investigation of monovalent cation influxes of diamide-treated human erythrocytes in solutions of different ionic strength.

Total and residual i.e. (ouabain + bumetanide + EGTA)-insensitive K+ as well as Na+ influxes were investigated in human erythrocytes before and after treatment with diamide (5 mM). In physiological and in low ionic strength solution these influxes were increased after diamide treatment. Diamide-treated cells do not exhibit significant differences between the total and residual influxes for both Na+ and K+. The diamide-induced cation fluxes in low ionic strength solution are significantly higher compared with the fluxes in physiological ionic strength solution. The diamide-induced K+ influx is not chloride-dependent, and replacement of NaCl by sodium methylsulfate does not significantly reduce this flux. A subsequent incubation of diamide-treated erythrocytes with dithioerythritol which restores the cellular glutathione level to its original value only partly decreases the enhanced K+ influx. From these results it can be concluded that electrodiffusion and K/Cl cotransport are not involved in the diamide-induced stimulation of the residual K+ influx of human erythrocytes.

Biological Transport↗
PubMed1991

Low potassium-type but not high potassium-type sheep red blood cells show passive K+ transport induced by low ionic strength.

Low potassium-type (LK) sheep red blood cells show a significant increase of the residual (i.e., ouabain-insensitive) K+ influx when the ionic strength of the solution is decreased. This effect is absent from high potassium-type (HK) sheep red blood cells. The KCl cotransport system is not involved since three different manoeuvres to suppress the KCl cotransport (replacement of Cl- by NO3-, volume-decrease, inhibition by anti-L1 antibodies) have no effect on the low ionic strength-stimulated K+ influx.

Animals↗
PubMed1990

Species-dependent differences in the influence of ionic strength on potassium transport of erythrocytes. The role of membrane fluidity and Ca2+.

The passive Rb+ (K+) efflux from erythrocytes of seven mammalian species was investigated in solutions of physiological and low ionic strength. Furthermore the fluidity of the erythrocyte membrane in the same solutions was estimated by measuring the ESR order parameter. The rate constant of Rb+ (K+) efflux in solution of high ionic strength could be correlated with the order parameter obtained and with the mean number of double bonds to the membrane phospholipid fatty acids. The same relationships could be observed for the low ionic strength solutions if the values for human erythrocytes were excluded. The appearance of Na+, K+, Cl- cotransport to a significant extent, only in human erythrocytes, was supposed to be the reason for this different behaviour of human red blood cells. It was demonstrated that the strong increase of the Rb+ (K+) efflux rate constant for human erythrocytes in low ionic strength solution is not due to Ca2+, as quinine treatment and replacement of all external potassium, both inhibiting the Ca2(+)-induced K+ efflux, did not abolish the increase of (Rb+) K+ efflux in solutions of low ionic strength.

Animals↗
PubMed1987

Factors involved in the increase of K+ efflux of erythrocytes in low chloride media.

The rate constant of the Rb+(K+) efflux in isotonic NaCl solutions containing sucrose is increased when the NaCl concentration is reduced. When NaCl is replaced by Na-gluconate no change of the rate constant can be observed. The ionic strength of the solution is discussed as one factor influencing the Rb+(K+) efflux. The addition of furosemide (0.5 mM) inhibits the rate constant of the Rb+(K+) efflux in solutions of different ionic strength by about 50%. The increase of the rate constant in solutions of low ionic strength containing sucrose is interpreted as a stimulation of the chloride-dependent Na,K cotransport and the K,Cl cotransport.

Biological Transport, Active↗
PubMed1986

[Radioimmunologic determination of the progestagen dienogest in plasma and saliva].

Following oral administration of 2 mg of dienogest (17 alpha-cyanomethyl-17 beta-hydroxy-4,9-estradien-3-one) to female volunteers, the dienogest concentration courses in plasma and saliva were determined by means of a specific radioimmunoassay (RIA). Three different procedures of the plasma sample preparation prior to the RIA were compared. The dienogest RIA was directly applied to saliva. There is a high correlation between the dienogest concentrations in plasma and saliva. The dienogest plasma elimination half life of about 9 hrs is not significantly different from that derived from saliva. The salivary dienogest concentrations indicate a relatively high non-protein bound portion of this steroid drug in plasma. Following repeated oral administration of dienogest (tau = 24 hrs), there is no significant cumulation of plasma dienogest.

Administration, Oral↗
PubMed1983

Studies on pharmacokinetics of STS 557 in animal species and man.

Following oral and i.v. administration of [14 alpha, 15 alpha-3H]-STS 557 to beagle dogs, baboons, rats and female volunteers, plasma level courses of total radioactivity and STS 557, and radioactivity excretion in urine and feces have been investigated. Bioavailability of orally administered STS 557 was found to be 80--90% in man and beagle dog, 70--80% in baboon and rat. Concerning the systemic availability following oral administration of equivalent doses, the following order was established: beagle dog greater than man greater than baboon greater than rat. Equilibrium dialysis indicates species differences in plasma protein binding and a considerable part of STS 557 to be present in plasma unbound. STS 557 is rather rapidly eliminated from the plasma compartment of all species investigated with half lives less than or equal to 10 h. As an additional time parameter of pharmacokinetics the "mean residence time" was used. Urinary excretion of STS 557 metabolites is dominant in all species, including the rat. In contrast to the great part of STS 557 in plasma total radioactivity, only small amounts of unchanged STS 557 are excreted in urine. First results of current studies in rabbits are presented, too.

Animals↗
PubMed1980

[Problems of statistical evaluation of stereological data from single cells].

A definition of morphometrical parameters of single cell populations is given. Methods for estimating these quantities (confidence estimation included) are described. For the comparison of equivalent parameters of 2 cell populations 2 statistical test procedures replacing the common t-test, are discussed. In addition, a homogeneity test is proposed for comparing the distributions of morphometrical data.

Cell Nucleus↗
PubMed1979

Distribution functions of variables characterizing the mycelial morphology of Streptomyces hygroscopicus grown in glucose-limited chemostat cultures.

The distribution of variables characterizing the morphology of the mycelium of Streptomyces hygroscopicus grown in glucose-limited chemostat cultures at different specific growth rates were investigated statistically. The values of the hyphal growth unit (L/N) and the values of the distance from the apex to the first branch (Lp) are normally distributed, but the values of the distance between neighbouring branches are logarithmically normal distributed. The distribution functions are discussed from the biological point of view.

Glucose↗
PubMedDate not supplied

Hematopoietic turnover index in reactive and neoplastic bone marrow lesions: quantification by apoptosis and PCNA labeling.

In order to determine the dynamics of hematopoietic cell turnover, proliferative activity and incidence of apoptosis (programmed cell death) were evaluated in bone marrow trephine biopsies. Selection of patients (20 in each group) included in addition to a control group, idiopathic thrombocytopenia (ITP), reactive thrombocytosis (TH), secondary polycythemia-smokers' polyglobuly (PG), primary (essential-hemorrhagic) thrombocythemia (PTH), polycythemia vera (PV), and finally acute myeloid leukemia (AML). Apoptosis was demonstrated by the in situ end-labeling technique (ISEL) and proliferative activity by applying the monoclonal antibody PC10 raised against proliferating cell nuclear antigen (PCNA). To assess dynamic features of hematopoiesis, an index was calculated consisting of the ratio between PCNA-positive nuclei and the apoptotic cell fraction. This factor was termed the hematopoietic turnover index (HTI). Morphometric analysis revealed that the HTI was significantly increased in AML and PV. According to cell culture studies both disorders are characterized by either a prevalent proliferation of the myeloid or erythroid cell mass. On the other hand, PG, PTH, and TH showed no relevant enhancement of this index in comparison to the control specimen. In vitro experiment results are in keeping with the finding that PG and PTH are not associated with a significant expansion of the erythroid lineage (CFU-E). Similar to ITP and TH, in PTH megakaryocyte proliferation (CFU-MEG) is the predominant feature of cell turnover. Differences between PTH and TH are in line with the reduced in vitro formation of CFU-MEG in the latter disorder. In conclusion, our in situ study on turnover rates of the bone marrow in various neoplastic and reactive lesions extends previous experimental data on hematopoietic cell kinetics.

Acute Disease↗