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Biomedical subjects

E Meier

Publications and source records attributed to E Meier.

At least 55 records · Page 3Linked to original sources
PubMed1993

Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists.

The (+)-and (-)-enantiomer of compounds 4 and 5 were synthesized and tested for central dopamine (DA) receptor stimulating activity, using biochemical and behavioral tests in rats. Based on the available data the (-)-enantiomers of 4 and 5 are characterized as centrally acting DA autoreceptor antagonists with oral activity. They display a similar pharmacological profile as the prototype DA autoreceptor antagonists (+)-1 and (+)-2 and show a certain preference for the D3 DA receptor antagonist binding site.

Animals↗
PubMed1993

Two nuclear signalling pathways for vitamin D.

The dihydroxylated form of vitamin D3 (1,25-dihydroxy-D3)mediates a biological response by binding to intracellular receptors which belong to the steroid receptor superfamily. These receptors act as ligand-dependent transcription factors that bind to specific DNA sequences (reviewed in refs 6-9). We have identified two classes of vitamin D response elements that are activated either by the vitamin D receptor (VDR) alone or by heterodimers of VDR and the retinoid-X receptor-alpha (RXR-alpha). The motif GGGTGA arranged as a direct repeat with a spacing of six nucleotides or as a palindrome without spacing, or as an inverted palindrome with a 12-nucleotide spacing, confers vitamin D inducibility mediated by VDR alone. A second class of response elements, composed of directly repeated pairs of motifs (GGTCCA, AGGTCA, or GGGTGA) spaced by three nucleotides, is synergistically activated by RXR and VDR, but only in the presence of both ligands. Thus, the RXR ligand and the nature of the response element determine whether a nuclear receptor is co-regulated by RXR.

Base Sequence↗
PubMed1993

Switch in antiviral specificity of a GTPase upon translocation from the cytoplasm to the nucleus.

The Mx2 protein of rats is a cytoplasmic GTPase that protects cells against vesicular stomatitis virus but not against influenza virus. Since vesicular stomatitis virus replicates in the cytoplasm and influenza virus replicates in the nucleus, it was possible that the antiviral specificity of rat Mx2 protein was determined solely by the protein's subcellular localization. Here, we found that, indeed, rat Mx2 protein lost its anti-vesicular stomatitis virus activity and gained anti-influenza virus activity when it was directed to the nucleus by way of a foreign nuclear-transport signal appended to its amino terminus. These data show that rat Mx2 protein possesses an antiviral activity that is revealed only when the protein is shuttled to the nucleus.

3T3 Cells↗
PubMed1992

Age-related white matter atrophy in the human brain.

Aging of the brain involves not only appreciable shrinkage of the cortex and other gray matter structures but above all loss of white matter. This could be due to a decline in the number of myelinated fibers or to a loss of water. To assess the role played by each of these factors we studied brains from 33 neurologically intact subjects at autopsy representing three different age groups: 15-50, 51-70, and 71-93 years. The precentral gyrus, gyrus rectus, and corpus callosum were selected for investigation, with staining for alkaline phosphatase on native cryostat sections to visualize the capillary network, and staining for myelin on semithin sections for nerve fiber visualization. Atrophy was objectified by measuring the number of capillaries, the intercapillary distance, and capillary length, since the capillary network remains constant throughout normal life. A mean difference of 16-20% was found, representing white matter atrophy, between the oldest and youngest age-groups. The cortex of the corresponding gyri, on the other hand, showed a difference of less than 6%. Morphometric investigation of sections stained for myelin showed that the brains with a mean age of 78.7 +/- 6.6 years had 10-15% fewer myelinated fibers. This was only partly offset by an increase in the volume of extracellular space. Our findings show that the age-related decline in brain volume is much more a question of white matter atrophy than of brain cortex atrophy. White matter atrophy could be an indirect indicator of nerve cell loss, since the volume of a nerve cell is much smaller than its myelinated fiber.

Adolescent↗
PubMed1992

Discriminative stimulus properties of the muscarinic receptor agonists Lu 26-046 and O-Me-THPO in rats: evidence for involvement of different muscarinic receptor subtypes.

The discriminative cues induced by the muscarinic receptor agonists Lu 26-046 ((-)-7-methyl-3(2-propynyloxy)-4,5,6,7-tetrahydroisothiazolo [4,5-c]pyridine ) and O-Me-THPO (3-methoxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine) were investigated. The results were compared with those obtained for the binding profiles of these agonists at central muscarinic receptors and with results concerning their functional effects at peripheral muscarinic receptors in vitro. Lu 26-046 had preferential affinity for M1 versus M2 receptors (Ki index [3H]quinuclidinyl benzilate ([3H]QNB/[3H]pirenzepine 4.2) and had partial agonistic activity at M1 and M2 receptors in rat superior cervical ganglion and guinea pig left atrim, respectively. A weak antagonistic effect at M3 receptors in guinea pig ileum was observed. O-Me-THPO had non-selective agonistic effects at peripheral M1, M2 and M3 receptors and had a slight preference for central M2 receptors in binding experiments (M2/M1 index 0.31). Lu 26-046 dose dependently substituted for Lu 26-046 and partially substituted for O-Me-THPO in rats trained to discriminate Lu 26-046 and O-Me-THPO from saline, respectively. The (+)-enantiomer of Lu 26-046, Lu 26-047, had weak partial M1 agonistic activity and M2/M3 antagonistic effects at peripheral receptors. Lu 26-047 also had a high M2/M1 index (9.3) in binding experiments. Lu 26-047 substituted for Lu 26-046, but preferentially inhibited the effect of O-Me-THPO. Pilocarpine had a preferential effect in Lu 26-046-trained rats, while oxotremorine and arecoline had preferential effects in O-Me-THPO-trained rats. Large increases in latency times or a disruption of responding was generally observed. These compounds were full agonists at peripheral M1, M2 and M3 receptors. The muscarinic receptor antagonist scopolamine antagonized the effect of O-Me-THPO and partially inhibited the effect of Lu 26-046. Scopolamine partially substituted for Lu 26-046. The quaternary muscarinic receptor agonist N-methyl atropine had no effect, indicating that the cues are mediated by central muscarinic receptors. It is suggested that the discriminative cues of Lu 26-046 and O-Me-THPO are preferentially mediated by central M1 (partial) and M2 receptor stimulation, respectively. The role of central M3 receptors is not known.

Animals↗
PubMed1991

A complex of nuclear pore proteins required for pore function.

A family of proteins bearing novel N-acetylglucosamine residues has previously been found to be required to form functional nuclear pores. To begin to determine which of the proteins in this family are essential for pore function, antisera were raised to each of three members of the family, p62, p58, and p54. With these antisera, it was possible to deplete nuclear reconstitution extracts of the proteins and to test the depleted nuclei for nuclear transport. In the course of the experiments, it was found that the three proteins exist as a complex; antisera to any one, while specific on a protein blot, coimmunoprecipitated all three proteins. This complex of pore proteins is stable to 2 M salt, 2 M urea, and the detergent Mega 10, indicating the presence of specific and tight protein-protein interactions. By gel filtration, the complex has a molecular mass of 550-600 kD. Nuclei containing pores depleted of the complex are found to be defective for nuclear transport; moreover, we observe a strict linear correlation between the amount of complex present in nuclei and the amount of nuclear transport of which those nuclei are capable. Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function.

Animals↗
PubMed1990

Transgenic mice with intracellular immunity to influenza virus.

We have generated transgenic mice that express the intracellular anti-influenza virus protein Mx1 under control of an interferon-responsive regulatory element. Upon infection with influenza virus, mice of a high responder line produce Mx1 protein locally at the sites of initial viral replication, exhibit little viral spread, and survive infection. Mice of a low responder line show more extensive viral spread and survive infection only when virus is given at high doses. To survive low dose infections, these mice require injection of interferon along with virus. The results show that influenza viral pathogenesis is determined by a subtle balance between the dose of the infecting virus and the levels of the antiviral host factor Mx1 and that mice can be rendered resistant to a virulent infection by "intracellular immunization" achieved through germline transformation.

Animals↗
PubMed1990

Senile plaques: staining for acetylcholinesterase and A4 protein: a comparative study in the hippocampus and entorhinal cortex.

In 20 unselected autopsy cases tissue blocks from the hippocampus with adjacent entorhinal cortex and neocortex were stained for acetylcholinesterase (AChE). From five brains shown to have large numbers of senile plaques tissue, adjacent to that taken for AChE tissue blocks, was embedded in paraffin and sections were immunostained for the A4 protein. The morphological aspects were compared. Equivalent types of plaques and plaque-like structures were observed in the A4- and ACHE-stained sections. On selected tissue blocks from patients with many senile plaques two immediately adjacent cryostat sections were stained, one for AChE and one for A4 protein. The same individual plaques could be identified on the two sections. These findings suggest that high AChE activity is intimately associated with the process of A4 protein formation and accumulation in plaques and that this association already occurs at a very early stage of plaque formation.

Acetylcholinesterase↗
PubMed1990

Effects of inhibitors of protein synthesis and intracellular transport on the gamma-aminobutyric acid agonist-induced functional differentiation of cultured cerebellar granule cells.

The effect of inhibitors of protein synthesis (actinomycin D, cycloheximide), proteases (leupeptin), and intracellular transport (colchicine, monensin) on the gamma-aminobutyric acid (GABA) agonist [4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP)]-induced changes in morphological differentiation and GABA receptor expression was investigated in cultured cerebellar granule cells. After 4 days in culture the neurons were exposed to the inhibitors for 6 h in the simultaneous presence of THIP. Subsequently, cultures were either fixed for electron microscopic examination or used for preparation of membranes for [3H]GABA binding assays. In some experiments the functional activity of the newly induced low-affinity GABA receptors was assessed by investigation of the ability of GABA to inhibit neurotransmitter release from the neurons. These experiments were performed to differentiate between an intracellular and a plasma membrane localization of the receptors. In all experiments cultures treated with THIP alone served as controls. The inhibitors of protein synthesis totally abolished the ability of THIP to induce low-affinity GABA receptors. In contrast, the inhibitors of intracellular transport as well as the protease inhibitor did not affect this parameter. However, studies of effects of GABA on transmitter release from monensin-treated cultures showed that transmitter release could not be inhibited by GABA in these cells in spite of the presence of low-affinity GABA receptors in the membrane preparations. This indicates that the low-affinity receptors were not located in the plasma membrane. This is in good agreement with the corresponding morphological findings, that monensin treatment led to an intense vacuolization of the Golgi apparatus, thereby preventing intracellular transport of the newly synthesized GABA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Activity of rat Mx proteins against a rhabdovirus.

Upon stimulation with alpha/beta interferon, rat cells synthesize three Mx proteins. Sequence analysis of corresponding cDNAs reveals that these three proteins are derived from three distinct genes. One of the rat cDNAs is termed Mx1 because it is most closely related to the mouse Mx1 cDNA and because it codes for a nuclear protein that, like the mouse Mx1 protein, inhibits influenza virus growth. However, this protein differs from mouse Mx1 protein, in that it also inhibits vesicular stomatitis virus (VSV), a rhabdovirus. A second rat cDNA is more closely related to the mouse Mx2 cDNA and directs the synthesis of a cytoplasmic protein that inhibits VSV but not influenza virus. The third rat cDNA codes for a cytoplasmic protein that differs from the second one in only eight positions and has no detectable activity against either virus. These results indicate that rat Mx proteins have antiviral specificities not anticipated from the analysis of the murine Mx1 protein.

Amino Acid Sequence↗
PubMed1990

Mx proteins: antiviral proteins by chance or by necessity?

The interferon-inducible Mx1 protein is responsible for inborn resistance of mice to influenza. It is now recognized that this protein is a member of a family of interferon-inducible, putative GTP-binding proteins found in many organisms. Thus, these proteins, called the Mx proteins, are found in species that are naturally infected with influenza virus, and also in species that are not. Some Mx proteins display a broader antiviral profile than the one observed for Mx1 in mice. Others, however, may not be antiviral. Two recently discovered GTP-binding proteins, Vps1p in yeast and dynamin in rat, are also related to Mx1. These proteins are synthesized constitutively and serve basic cellular functions.

Animals↗
PubMed1989

Coding and recall of categorized material in aphasics.

The aim of the present study was to examine whether the often reported impairments of aphasics in different short-term memory tasks could be the result of a failure to use the facilitating strategy of clustering. Aphasics (n = 60), right hemisphere brain-damaged (n = 36) and normal (n = 10) controls were tested with a modification of tasks developed by Petrides and Milner (1982). They were presented with sets of 16 cards with a random arrangement of the same 16 stimuli. On each card subjects had to point to one of the stimuli, trying not to point to the same stimulus in different cards. In some of the tasks pictures were selected to suggest a clustering into four equally sized subsets; in others the stimuli were highly heterogeneous with respect to perceptual and semantic characteristics. Prior to each task with items easy to categorize, half of the subjects were requested to sort the pictures into subsets, while the other half were given the pictures without any specific instruction, having been requested to do the sortings only after the main task. Aphasics (1) showed less clustering, i.e., sequential pointing according to the predefined categories, and (2) made significantly more errors than RH-controls especially in the tasks easy to categorize. While RH-controls benefited from the preceding sorting of the pictures aphasics made more errors when first introduced to the categorization task.

Adolescent↗