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T Meyer

Publications and source records attributed to T Meyer.

At least 145 records · Page 8Linked to original sources
PubMed2000

Electron and hole focusing in CoSi2/Si(111) observed by ballistic electron emission microscopy

In ballistic electron emission microscopy (BEEM) the propagation of hot carriers in thin metal films has long been treated using a free electron model. While the model explains many experimental findings, it cannot account for the lateral resolution observed for both electrons and holes on epitaxial CoSi(2)/Si(111), where interfacial point defects of atomic size appear as small as 1.3 nm, even below a 5.6 nm thick film. We present ab initio calculations explaining this high resolution in terms of conduction (valence) band structure focusing of electrons (holes), according to a recent Green's function approach to the BEEM process.

Journal Article↗
PubMed2000

In vitro and in vivo evidence for orphan nuclear receptor RORalpha function in bone metabolism.

Bone is a major target site for steroid hormone action. Steroid hormones like cortisol, vitamin D, and estradiol are responsible for principal events associated with bone formation and resorption. Over the past decade, new members of the nuclear hormone gene family have been identified that lack known ligands. These orphan receptors can be used to uncover signaling molecules that regulate yet unidentified physiological networks. In the present study the function of retinoic acid receptor-related orphan receptor (ROR) alpha in bone metabolism has been examined. We showed that RORalpha and RORgamma, but not RORbeta, are expressed in mesenchymal stem cells derived from bone marrow. Interestingly, for RORalpha we observed an increased messenger signal expression between control cells and cells undergoing osteogenic differentiation. Furthermore, the direct activation of mouse bone sialoprotein by RORalpha, typically 7-fold, has been shown. In contrast, transient overexpression of RORalpha overrides the activation of the osteocalcin promoter by 1alpha,25-dihydroxyvitamin D(3). In addition, we have investigated bone mass parameters and bone geometry in the mouse mutant staggerer (sg/sg), a mouse strain that carries a deletion within the RORalpha gene. Homozygote mutants have thin long bones compared with the heterozygote animals and wild-type littermates. More interestingly, the bones of the sg/sg animals are osteopenic as indicated by the comparison of bone mineral contents of sg/sg animals to the heterozygote and wild-type animals. We conclude that these in vitro and in vivo results suggest a function for RORalpha in bone biology. RORalpha most likely acts by direct modulation of a bone matrix component.

Absorptiometry, Photon↗
PubMed2000

Novel inhibition of gbetagamma-activated potassium currents induced by M(2) muscarinic receptors via a pertussis toxin-insensitive pathway.

G(i) protein-coupled receptors such as the M(2) muscarinic acetylcholine receptor (mAChR) and A(1) adenosine receptor have been shown to activate G protein-activated inwardly rectifying K(+) channels (GIRKs) via pertussis toxin-sensitive G proteins in atrial myocytes and in many neuronal cells. Here we show that muscarinic M(2) receptors not only activate but also reversibly inhibit these K(+) currents when stimulated with agonist for up to 2 min. The M(2) mAChR-mediated inhibition of the channel was also observed when the channels were first activated by inclusion of guanosine 5'-O-(thiotriphosphate) in the pipette. Under these conditions the M(2) mAChR-induced inhibition was quasi-irreversible, suggesting a role for G proteins in the inhibitory process. In contrast, when GIRK currents were maximally activated by co-expressing exogenous Gbetagamma, the extent of acetylcholine (ACh)-induced inhibition was significantly reduced, suggesting competition between the receptor-mediated inhibition and the large pool of available Gbetagamma subunits. The signaling pathway that led to the ACh-induced inhibition of GIRK channels was unaffected by pertussis toxin pretreatment. Furthermore, the internalization and agonist-induced phosphorylation of M(2) mAChR was not required because a phosphorylation- and internalization-deficient mutant of the M(2) mAChR was as potent as the wild-type counterpart. Pharmacological agents modulating various protein kinases or phosphatidylinositol 3-kinase did not affect the inhibition of GIRK currents. Furthermore, the signaling pathway that mediates GIRK current inhibition was found to be membrane-delimited because bath application of ACh did not inhibit GIRK channel activity in cell-attached patches. Other G protein-coupled receptors including M(4) mAChR and alpha(1A) adrenergic receptors also caused the inhibition, whereas other G protein-coupled receptors including A(1) and A(3) adenosine receptors and alpha(2A) and alpha(2C) adrenergic receptors could not induce the inhibition. The presented results suggest the existence of a novel signaling pathway that can be activated selectively by M(2) and M(4) mAChR but not by adenosine receptors and that involves non-pertussis toxin-sensitive G proteins leading to an inhibition of Gbetagamma-activated GIRK currents in a membrane-delimited fashion.

Animals↗
PubMed2000

Overexpressed A(1) adenosine receptors reduce activation of acetylcholine-sensitive K(+) current by native muscarinic M(2) receptors in rat atrial myocytes.

In adult rat atrial myocytes, muscarinic acetylcholine (ACh)-sensitive K(+) current activated by a saturating concentration of adenosine (I(K(ACh),(Ado))) via A(1) receptors (A(1)Rs) amounts to only 30% of the current activated by a saturating concentration of ACh (I(K(ACh),(ACh))) via muscarinic M(2) receptors. The half-time of activation of I(K(ACh),(Ado)) on a rapid exposure to agonist was approximately 4-fold longer than that of I(K(ACh),(ACh)). Furthermore, I(K(ACh),(Ado)) never showed fast desensitization. To study the importance of receptor density for A(1)R-I(K(ACh),(Ado)) signaling, adult atrial myocytes in vitro were transfected with cDNA encoding for rat brain A(1)R and enhanced green fluorescent protein (EGFP) as a reporter. Whole-cell current was measured on days 3 and 4 after transfection. Time-matched cells transfected with only the EGFP vector served as controls. In approximately 30% of EGFP-positive cells (group I), the density of I(K(ACh),(Ado)) was increased by 72%, and its half-time of activation was reduced. Density and kinetic properties of I(K(ACh),(ACh)) were not affected in this fraction. In approximately 70% of transfection-positive myocytes (group II), the density of I(K(ACh),(ACh)) was significantly reduced, its activation was slowed, and the fast desensitizing component was lost. Adenosine-induced currents were larger in group II than in group I, their activation rate was further increased, and a fast desensitizing component developed. These data indicate that in native myocytes the amplitude and activation kinetics of I(K(ACh),(Ado)) are limited by the expression of A(1)R. Overexpression of A(1)R negatively interferes with signal transduction via the muscarinic M(2) receptor-linked pathway, which might reflect a competition of receptors with a common pool of G proteins. Negative interference of an overexpressed receptor with physiological regulation of a target protein by a different receptor should be considered in attempts to use receptor overexpression for gene therapy.

Acetylcholine↗
PubMed2000

Differential codes for free Ca(2+)-calmodulin signals in nucleus and cytosol.

BACKGROUND: Many targets of calcium signaling pathways are activated or inhibited by binding the Ca(2+)-liganded form of calmodulin (Ca(2+)-CaM). Here, we test the hypothesis that local Ca(2+)-CaM-regulated signaling processes can be selectively activated by local intracellular differences in free Ca(2+)-CaM concentration. RESULTS: Energy-transfer confocal microscopy of a fluorescent biosensor was used to measure the difference in the concentration of free Ca(2+)-CaM between nucleus and cytoplasm. Strikingly, short receptor-induced calcium spikes produced transient increases in free Ca(2+)-CaM concentration that were of markedly higher amplitude in the cytosol than in the nucleus. In contrast, prolonged increases in calcium led to equalization of the nuclear and cytosolic free Ca(2+)-CaM concentrations over a period of minutes. Photobleaching recovery and translocation measurements with fluorescently labeled CaM showed that equalization is likely to be the result of a diffusion-mediated net translocation of CaM into the nucleus. The driving force for equalization is a higher Ca(2+)-CaM-buffering capacity in the nucleus compared with the cytosol, as the direction of the free Ca(2+)-CaM concentration gradient and of CaM translocation could be reversed by expressing a Ca(2+)-CaM-binding protein at high concentration in the cytosol. CONCLUSIONS: Subcellular differences in the distribution of Ca(2+)-CaM-binding proteins can produce gradients of free Ca(2+)-CaM concentration that result in a net translocation of CaM. This provides a mechanism for dynamically regulating local free Ca(2+)-CaM concentrations, and thus the local activity of Ca(2+)-CaM targets. Free Ca(2+)-CaM signals in the nucleus remain low during brief or low-frequency calcium spikes, whereas high-frequency spikes or persistent increases in calcium cause translocation of CaM from the cytoplasm to the nucleus, resulting in similar concentrations of nuclear and cytosolic free Ca(2+)-CaM.

Animals↗
PubMed2000

Phosphatidylinositol 4,5-bisphosphate functions as a second messenger that regulates cytoskeleton-plasma membrane adhesion.

Binding interactions between the plasma membrane and the cytoskeleton define cell functions such as cell shape, formation of cell processes, cell movement, and endocytosis. Here we use optical tweezers tether force measurements and show that plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) acts as a second messenger that regulates the adhesion energy between the cytoskeleton and the plasma membrane. Receptor stimuli that hydrolyze PIP2 lowered adhesion energy, a process that could be mimicked by expressing PH domains that sequester PIP2 or by targeting a 5'-PIP2-phosphatase to the plasma membrane to selectively lower plasma membrane PIP2 concentration. Our study suggests that plasma membrane PIP2 controls dynamic membrane functions and cell shape by locally increasing and decreasing the adhesion between the actin-based cortical cytoskeleton and the plasma membrane.

3T3 Cells↗
PubMed2000

D(A) steps and 2D islands of double layer height in the SiGe(001) system

The surfaces of step graded, partially relaxed Si(1-x)Ge(x)/Si(001) buffers were studied by scanning tunneling microscopy. The surface slips along <110> forming the crosshatch pattern, consisting of bunches of D(A) steps of double layer height. The D(A) steps are present in regions of large surface gradients close to the slips, as well as in planar regions between the slips. These regions are also characterized by the appearance of 2D islands of double layer height. The observations can be explained by assuming the strain due to the misfit dislocations to be locally anisotropic. Anisotropic misfit strain and efficient strain relaxation by the ( 2x8) Ge reconstruction were identified as the main factors causing the unusual step structure.

Journal Article↗
PubMed2000

Total deposition of therapeutic particles during spontaneous and controlled inhalations.

Treatment of systemic diseases by means of the inhalation route is hampered by uncertainties of the drug dose applied by inhalation. In this study, the hypothesis was tested that by standardization of the breathing maneuver used for inhalation, the interindividual variability of the dose deposited intrathoracically can be reduced. Therefore, breathing pattern during routine inhalations with jet nebulizers was measured in 18 patients with lung disease. Using monodisperse 3 microm particles, total deposition was then assessed for the measured spontaneous and for three controlled, slow breathing patterns. Particle deposition for the three controlled breathing patterns was additionally measured in 14 healthy subjects. The study has shown that within the study population the inhaled air volume and flow rate were quite different. Consequently, total particle deposition varied between 20 and 95%, depending on breathing pattern. For controlled, slow breathing patterns, deposition was on average higher, intersubject variability of deposition was smaller, and differences in deposition between healthy subjects and patients were negligible. Therefore, to perform efficient systemic treatment with aerosolized drugs, controlled, slow breathing patterns should be used.

Administration, Inhalation↗
PubMed2000

Ca2+ entry but not Ca2+ release is necessary for desensitization of ET(A)receptors in airway apithelial cells.

Ca2+ transients evoked by endothelin-1 (ET-1) were measured in single cells of a human tracheal epithelial cell line using the fluorescent Ca2+ indicator fura-2. In line with a previous study, a single exposure to ET-1 (10 nM) for 10-20 s resulted in a long-lasting desensitization to a subsequent challenge by the peptide, without affecting sensitivity to agonists for other Ca2+-mobilizing receptors such as P2y or H1, respectively. In the absence of extracellular Ca2+ ET-1 elicited a Ca2+ signal of comparable amplitude as in the presence of extracellular Ca2+ but of shorter duration. Exposure to ET-1 in the absence of Ca2+ caused significantly less desensitization. Inhibition of the Ca2+ entry component of the Ca2+ transient by means of SK&F 96365, an inhibitor of Ca2+ entry, had effects comparable to Ca2+ removal. The Ca2+ transient was shortened but not significantly reduced in amplitude, and desensitization was reduced in the presence of the compound. These data demonstrate that desensitization of ET(A) receptors (ET(A)R) is promoted by transmembrane Ca2+ entry but not by Ca2+ release.

Calcium↗
PubMed2000

The role of excitotoxicity in ALS--what is the evidence?

It is well accepted that excitotoxic mechanisms contribute to the pathogenesis of acute neuronal death in stroke, epilepsy, or brain trauma. It is less widely acknowledged that excitotoxic mechanisms play a role in the pathogenesis of chronic neurological disorders, in particular neurodegenerative diseases. However, evidence is accumulating that this mechanism is indeed part of the pathogenesis of late-onset neurodegenerative diseases. One of the clinical examples may be amyotrophic lateral sclerosis, a disease in which antiexcitotoxic strategies have neuroprotective effects in both, an established animal model and in man. In addition, there is accumulating neuropathological, pathobiochemical and pathophysiological evidence which indicates that excitotoxic mechanisms are part of the pathogenesis of the human disease and consequently part of the mechanisms explaining selective vulnerability ("pathoclisis") in the human motor system.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Transferability of workload measurements between three different types of ergometer.

The aim of this study was to test the transferability of workload measurements between three different types of bicycle ergometer. Two common ergometers (Lode Excalibur and Avantronic Cyclus 2) were compared with a powermeter (Schoberer SRM system) that enables the measurement of power output during road cycling. Twelve well-trained subjects participated in this study. Within 12 h, each subject carried out three separate graded incremental exercise tests on each of the ergometric devices, and their oxygen uptake (VO2) and heart rate were determined. The three test protocols were identical: after warm-up, four stages of 4 min each at exercise intensities of 100, 150, 200, and 250 W. Pedalling frequency was controlled and there was no difference between the three ergometers. Tests were administered in a random order. Neither VO2 nor heart rate was affected by the type of ergometer used. For a given intensity, the same values were found in the two laboratory tests and in the field test (VO2: P = 0.425; heart rate: P = 0.845). Thus, the transferability of workload measurements between two different laboratory cycling ergometers and an ambulatory device was proven. Equivalency was determined using VO2 and heart rate as indices of metabolic and cardiovascular strain, respectively.

Adult↗
PubMed2000

Duplex ultrasonography in the diagnosis of incompetent Cockett veins.

OBJECTIVE: Incompetent perforating veins of the medial calf, i.e. those of the Cockett groups, play a major role in the developement of chronic venous insufficiency. The aim of the present study was to test the value of duplex ultrasonography (DUS) in the diagnosis of function and localisation of those veins. METHODS: Eighty-nine legs with incompetent perforating veins of the medial calf selected for subfascial endoscopic perforator surgery (SEPS) were included in a prospective study. Preoperative DUS was used to determine the number and localisation of the perforator veins. Findings were compared with preoperative ascending phlebography and intraoperative endoscopy during SEPS. RESULTS: Nearly equal numbers of insufficient Cockett veins at each level were detected by DUS and ascending phlebography (Cockett III: n, 76 vs. n, 76, P, 1.0; Cockett: II n=84 vs. n=82, P=0.569; Cockett I: n, 36 vs. n, 37, P=1.0; chi(2)-test). Findings were confirmed intraoperatively. CONCLUSION: The accuracy of DUS is comparable to phlebography for the diagnosis of incompetent perforating veins of the lower leg. DUS is non-invasive and avoids the potential risks of radiologic imaging.

Chronic Disease↗
PubMed2000

In and out of the postsynaptic region: signalling proteins on the move.

Reversible translocation of signalling proteins to and from their sites of action has emerged as an important theme in signal transduction. The recent findings of the stimulus-induced translocation of Ca2+-calmodulin-dependent protein kinase II (CaMKII) and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor to and from the postsynaptic region are model cases for understanding how the dynamic localization of signalling proteins is used to regulate signal transduction.

Animals↗
PubMed2000

Structure-based design of potent CDK1 inhibitors derived from olomoucine.

Cyclin-dependent kinase 1 (CDK1), an enzyme participating in the regulation of the cell cycle, constitutes a possible target in the search for new antitumor agents. Starting from the purine derivative olomoucine and following a structure-based approach, potent inhibitors of this enzyme were rapidly identified. The molecular modeling aspects of this work are described.

Amino Acid Sequence↗
PubMed2000

The importance of social comparisons for high levels of subjective quality of life in chronic schizophrenic patients.

In schizophrenic patients, quality of life (QoL) studies often find high levels of general life satisfaction and satisfaction in various life domains despite deprived living conditions. Therefore, the usefulness of QoL as an outcome indicator has been questioned. Since social comparison processes have been postulated to be related to the level of satisfaction, this hypothesis was analysed empirically by the present study in schizophrenic patients. Satisfaction and social comparisons of 148 schizophrenic inpatients and 66 mentally healthy controls were examined with regard to the domains 'health' and 'family' by means of a standardised interview. The schizophrenic patients had a history of either long-term (n = 75) or short-term (n = 73) restricted and deprived living conditions. Long-term patients showed significantly higher satisfaction levels than short-term patients. They compared themselves predominantly laterally or downwards with fellow inpatients. Significant relationships between the direction of social comparisons and satisfaction ratings were found in all three samples. Social comparisons proved to be important for the level of satisfaction in schizophrenic patients. Results indicate that experiences of restricted and deprived living conditions induce accommodation processes and response-shifts that should be taken into account in the interpretation of quality-of-life data.

Aged↗