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Showing papers by "Hungarian Academy of Sciences published in 2000"


Journal Article
TL;DR: The activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages.
Abstract: The brain and the immune system are the two major adaptive systems of the body During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome

2,030 citations


Book
01 Jan 2000
TL;DR: In this paper, four prominent psychoanalysts combine the perspectives of developmental psychology, attachment theory and psychoanalysis technique, and the result of this marriage of disciplines is a bold, energetic and ultimately encouraging vision for the psychotherapy treatment.
Abstract: In a brilliant examination of the frontiers of human emotion and cognition, four prominent psychoanalysts combine the perspectives of developmental psychology, attachment theory and psychoanalytic technique. The result of this marriage of disciplines is a bold, energetic and ultimately encouraging vision for the psychoanalytic treatment.

1,360 citations


Journal ArticleDOI
TL;DR: The finding that VR1 is expressed not only in primary sensory neurons but also in several brain nuclei is of great importance in that it places VRs in a much broader perspective than pain perception.
Abstract: The cloned vanilloid receptor VR1 has attracted recent attention as a molecular integrator of painful stimuli on primary sensory neurons. The existence of vanilloid-sensitive neurons in the brain is, however, controversial. In this study, we have used an antibody and a complementary RNA probe to explore the distribution of neurons that express VR1 in rat and in certain areas of human brain. In the rat, we observed VR1-expressing neurons throughout the whole neuroaxis, including all cortical areas (in layers 3 and 5), several members of the limbic system (e.g., hippocampus, central amygdala, and both medial and lateral habenula), striatum, hypothalamus, centromedian and paraventricular thalamic nuclei, substantia nigra, reticular formation, locus coeruleus, cerebellum, and inferior olive. VR1-immunopositive cells also were found in the third and fifth layers of human parietal cortex. Reverse transcription–PCR performed with rat VR1-specific primers verified the expression of VR1 mRNA in cortex, hippocampus, and hypothalamus. In the central nervous system, neonatal capsaicin treatment depleted VR1 mRNA from the spinal nucleus of the trigeminal nerve, but not from other areas such as the inferior olive. The finding that VR1 is expressed not only in primary sensory neurons but also in several brain nuclei is of great importance in that it places VRs in a much broader perspective than pain perception. VRs in the brain (and putative endogenous vanilloids) may be involved in the control of emotions, learning, and satiety, just to name a few exciting possibilities.

811 citations


Journal ArticleDOI
20 Apr 2000-Nature
TL;DR: Time-lapse two-photon microscopy of pyramidal neurons in layer 2/3 of developing rat barrel cortex is used to image the structural dynamics of dendritic spines and filopodia, which may underlie the reorganization of neural circuits.
Abstract: Do changes in neuronal structure underlie cortical plasticity? Here we used time-lapse two-photon microscopy of pyramidal neurons in layer 2/3 of developing rat barrel cortex to image the structural dynamics of dendritic spines and filopodia. We found that these protrusions were highly motile: spines and filopodia appeared, disappeared or changed shape over tens of minutes. To test whether sensory experience drives this motility we trimmed whiskers one to three days before imaging. Sensory deprivation markedly (approximately 40%) reduced protrusive motility in deprived regions of the barrel cortex during a critical period around postnatal days (P)11-13, but had no effect in younger (P8-10) or older (P14-16) animals. Unexpectedly, whisker trimming did not change the density, length or shape of spines and filopodia. However, sensory deprivation during the critical period degraded the tuning of layer 2/3 receptive fields. Thus sensory experience drives structural plasticity in dendrites, which may underlie the reorganization of neural circuits.

806 citations


Journal ArticleDOI
TL;DR: The general evolutionary strategy for changing the heat stability of proteins, comprising all high-quality structures of thermophilic proteins and their mesophilic homologues from the Protein Data Bank, is revealed.

621 citations


Journal ArticleDOI
TL;DR: The mechanism of regenerating the native disulfide bonds suggests an analogous scenario for conformational folding, and engineered covalent cross-links may be used to assay for the association of protein segments in the folding transition state, as illustrated with RNase A.
Abstract: The applications of disulfide-bond chemistry to studies of protein folding, structure, and stability are reviewed and illustrated with bovine pancreatic ribonuclease A (RNase A). After surveying the general properties and advantages of disulfide-bond studies, we illustrate the mechanism of reductive unfolding with RNase A, and discuss its application to probing structural fluctuations in folded proteins. The oxidative folding of RNase A is then described, focusing on the role of structure formation in the regeneration of the native disulfide bonds. The development of structure and conformational order in the disulfide intermediates during oxidative folding is characterized. Partially folded disulfide species are not observed, indicating that disulfide-coupled folding is highly cooperative. Contrary to the predictions of “rugged funnel” models of protein folding, misfolded disulfide species are also not observed despite the potentially stabilizing effect of many nonnative disulfide bonds. The mechanism of ...

541 citations


Journal ArticleDOI
TL;DR: It is concluded that activation of presynaptic CB1 receptors decreases Ca2+‐dependent GABA release, and thereby reduces the power of hippocampal network oscillations.
Abstract: Using a new antibody developed against the C-terminus of the cannabinoid receptor (CB1), the immunostaining in the hippocampus revealed additional axon terminals relative to the pattern reported previously with an N-terminus antibody. Due to a greater sensitivity of this antibody, a large proportion of boutons in the dendritic layers displaying symmetrical (GABAergic) synapses were also strongly immunoreactive for CB1 receptors, as were axon terminals of perisomatic inhibitory cells containing cholecystokinin. Asymmetrical (glutamatergic) synapses, however, were always negative for CB1. To investigate the effect of presynaptic CB1 receptor activation on hippocampal inhibition, we recorded inhibitory postsynaptic currents (IPSCs) from principal cells. Bath application of CB1 receptor agonists (WIN55,212-2 and CP55,940) suppressed IPSCs evoked by local electrical stimulation, which could be prevented or reversed by the CB1 receptor antagonist SR141716A. Action potential-driven IPSCs, evoked by pharmacological stimulation of a subset of interneurons, were also decreased by CB1 receptor activation. We also examined the effects of CB1 receptor agonists on Ca2+-independent miniature IPSCs (mIPSC). Both agonists were without significant effect on the frequency or amplitude of mIPSCs. Synchronous gamma oscillations induced by kainic acid in the CA3 region of hippocampal slices were reversibly reduced in amplitude by the CB1 receptor agonist CP 55,940, which is consistent with an action on IPSCs. We used CB1-/- knock-out mice to confirm the specificity of the antibody and of the agonist (WIN55,212-2) action. We conclude that activation of presynaptic CB1 receptors decreases Ca2+-dependent GABA release, and thereby reduces the power of hippocampal network oscillations.

537 citations


Journal ArticleDOI
TL;DR: The Sleeping Beauty transposase can efficiently insert transposon DNA into the mouse genome in approximately 5–6% of transfected mouse liver cells, establishing DNA-mediated transposition as a new genetic tool for mammals and providing new strategies to improve existing non-viral and viral vectors for human gene therapy applications.
Abstract: The development of non-viral gene-transfer technologies that can support stable chromosomal integration and persistent gene expression in vivo is desirable. Here we describe the successful use of transposon technology for the nonhomologous insertion of foreign genes into the genomes of adult mammals using naked DNA. We show that the Sleeping Beauty transposase can efficiently insert transposon DNA into the mouse genome in approximately 5-6% of transfected mouse liver cells. Chromosomal transposition resulted in long-term expression (>5 months) of human blood coagulation factor IX at levels that were therapeutic in a mouse model of haemophilia B. Our results establish DNA-mediated transposition as a new genetic tool for mammals, and provide new strategies to improve existing non-viral and viral vectors for human gene therapy applications.

514 citations


Journal ArticleDOI
TL;DR: Results indicate that WSC might be a useful marker for selecting genotypes that are more drought or salt tolerant, and the type of sugar comprising the increase in WSC appears to be a less reliable marker.
Abstract: The effect of drought and salt stresses on the water soluble carbohydrate content in wheat (Triticum aestivum L.) seedlings was examined to characterize the involvement of major sugar components in the adaptive processes. Hydroponically grown seedlings of four wheat varieties differing in drought and salt tolerance were exposed to consecutive water (polyethylene glycol, PEG) and salinity (NaCI) stresses. Total water-soluble carbohydrate (WSC), glucose, fructose, sucrose, and fructan content of stems (non-photosynthetic tissue) were determined. Tolerant genotypes accumulated more soluble carbohydrate than did sensitive ones. Both ionic and non-ionic stresses increased the concentration of reducing sugars, sucrose, and fructans. Drought tolerant varieties accumulated sucrose to a significantly greater level than did sensitive ones under non-ionic stress condition. Changes in fructan content of plants after transfer from PEG to NaCI containing solutions were genotype dependent, increasing in salt tolerant and decreasing in salt sensitive cultivars. These results indicate that WSC might be a useful marker for selecting genotypes that are more drought or salt tolerant. The type of sugar comprising the increase in WSC appears to be a less reliable marker since the initial response was an increase in monosaccharides and the delayed response was an increase in fructan.

463 citations


Journal ArticleDOI
TL;DR: A review of the literature on the metal ion complexes of carbohydrate type ligands with the emphasis on the past 20 years, discussing the equilibria and structure in aqueous solution together with the structures determined for the solid state complexes are collected for comparison as discussed by the authors.

390 citations


Journal ArticleDOI
TL;DR: The right rectangular parallelepiped (prism) has an important role mostly in local gravity field modelling studies when the so-called flat-Earth approximation is sufficient as mentioned in this paper.
Abstract: As a simple building block, the right rectangular parallelepiped (prism) has an important role mostly in local gravity field modelling studies when the so called flat-Earth approximation is sufficient. Its primary (methodological) advantage follows from the simplicity of the rigorous and consistent analytical forms describing the different gravitation-related quantities. The analytical forms provide numerical values for these quantities which satisfy the functional connections existing between these quantities at the level of numerical precision applied. Closed expressions for the gravitational potential of the prism and its derivatives (up to the third order) are listed for easy reference.

Journal ArticleDOI
TL;DR: A recently developed general theory for basis construction will be presented, that is a generalization of the classical Laguerre theory, particularly exploiting the property that basis function models are linearly parametrized.


Journal ArticleDOI
TL;DR: It is suggested that spiders tend to remain in diversified patches and that extending the diversification throughout the whole crop (as in interspersed diversification) offers the best prospects for improving pest control.
Abstract: A review of the literature showed that spider abundance was increased by diversification in 63% of studies. A comparison of diversification modes showed that spider abundance in the crop was increased in 33% of studies by ‘aggregated diversification’ (e.g. intercropping and non-crop strips) and in 80% of studies by ‘interspersed diversification’ (e.g., undersowing, partial weediness, mulching and reduced tillage). It is suggested that spiders tend to remain in diversified patches and that extending the diversification throughout the whole crop (as in interspersed diversification) offers the best prospects for improving pest control. There is little evidence that spiders walk in significant numbers into fields from uncultivated field edges, but diversification at the landscape level serves to foster large multi-species regional populations of spiders which are valuable as a source of aerial immigrants into newly planted crops. There are very few manipulative field studies where the impact of spiders on pests has been measured in diversified crops compared with undiversified controls. It is encouraging, however, that in those few studies an increased spider density resulted in improved pest control. Future work needs are identified.

Journal ArticleDOI
TL;DR: This work finds that activation of this innate immune response in Drosophila is preceded by rapid proteolytic cleavage of Relish into two parts, different from previously described mechanisms for Rel factor activation.
Abstract: The Rel/NF-κB transcription factor Relish plays a key role in the humoral immune response in Drosophila. We now find that activation of this innate immune response is preceded by rapid proteolytic cleavage of Relish into two parts. An N-terminal fragment, containing the DNA-binding Rel homology domain, translocates to the nucleus where it binds to the promoter of the Cecropin A1 gene and probably to the promoters of other antimicrobial peptide genes. The C-terminal IκB-like fragment remains in the cytoplasm. This endoproteolytic cleavage does not involve the proteasome, requires the DREDD caspase, and is different from previously described mechanisms for Rel factor activation.

Journal Article
TL;DR: The role of nonsynaptic receptors and transporters in presynaptic modulation of chemical transmission in the central nervous system is reviewed and it will be suggested for the first time that the receptors andTransporters expressed nonsynaptically and being of high affinity are the target of drugs taken by the patient.
Abstract: Neurochemical and morphological evidence has shown that some neurotransmitters or substances may be released from both synaptic and nonsynaptic sites for diffusion to target cells more distant than those observed in regular synaptic transmission. There are functional interactions between neurons without synaptic contacts, and matches between release sites and localization of receptors sensitive to the chemical signal are exceptions rather than the rule in the central nervous system. This also indicates that besides cabled information signaling (through synapses), there is a "wireless" nonsynaptic interaction between axon terminals. This would be a form of communication transitional between discrete classical neurotransmission (in Sherrington's synapse) and the relatively nonspecific neuroendocrine secretion. Recent findings indicate that in addition to monoamines (norepinephrine, dopamine, serotonin), other transmitters, such as acetylcholine and nitric oxide (NO), may also be involved in these nonsynaptic interactions. It has been shown that NO, an ideal mediator of nonsynaptic communication, can influence the function of uptake carrier systems, which may be an important factor in the regulation of extracellular concentration of different transmitters. This review will focus on the role of nonsynaptic receptors and transporters in presynaptic modulation of chemical transmission in the central nervous system. The nonsynaptic interaction between neurons mediated via receptors and transports of high affinity not localized in synapses has the potential to be an important contributor to the properties and function of neuronal networks. In addition, it will be suggested for the first time that the receptors and transporters expressed nonsynaptically and being of high affinity are the target of drugs taken by the patient.

Journal ArticleDOI
TL;DR: It is suggested that MRP2 may be responsible for the active secretion of pharmacologically relevant organic anions, such as diuretics and antibiotics, and different modulation possibilities for MRP1 or MRP 2 in drug-resistant tumor cells are indicated.
Abstract: The human multidrug resistance protein MRP1 and its homolog, MRP2, are both suggested as being involved in cancer drug resistance and the transport of organic anions. We expressed MRP1 and MRP2 inSpodoptera frugiperda ovarian cells and compared their ATP-dependent transport properties and vanadate-sensitive ATPase activities in isolated membrane vesicles. Both MRP1 and MRP2 actively transported leukotriene C4 andN-ethylmaleimide glutathione (NEM-GS), although the relative affinity of MRP2 for these substrates was found to be significantly lower than that of MRP1. Methotrexate was actively transported by both proteins, although more efficiently by MRP2. ATP-dependent NEM-GS transport by MRP1 and MRP2 was variably modulated by organic anions. Probenecid and furosemide inhibited, whereas under certain conditions sulfinpyrazone, penicillin G, and indomethacin greatly stimulated, MRP2-mediated NEM-GS uptake. Vanadate-sensitive ATPase activity in isolated membranes containing MRP1 or MRP2 was significantly stimulated by NEM-GS and reduced GS, although these compounds acted only at higher concentrations in MRP2. ATP hydrolysis by MRP2 was also effectively stimulated by methotrexate. Probenecid, sulfinpyrazone, indomethacin, furosemide, and penicillin G all significantly increased MRP2-ATPase activity, whereas these compounds acted more as ATPase inhibitors on MRP1. These results indicate that MRP1 is a more efficient transporter of glutathione conjugates and free glutathione than MRP2, whereas several anions are preferred substrates for MRP2. Our data suggest that MRP2 may be responsible for the active secretion of pharmacologically relevant organic anions, such as diuretics and antibiotics, and indicate different modulation possibilities for MRP1 or MRP2 in drug-resistant tumor cells.

Journal ArticleDOI
10 Aug 2000-Nature
TL;DR: The structure of the late M intermediate of wild-type bacteriorhodopsin is determined and shows a water net that allows proton transfer from the proton donor group Asp 96 towards the Schiff base.
Abstract: The transport of protons across membranes is an important process in cellular bioenergetics. The light-driven proton pump bacteriorhodopsin is the best-characterized protein providing this function. Photon energy is absorbed by the chromophore retinal, covalently bound to Lys 216 via a protonated Schiff base. The light-induced all-trans to 13-cis isomerization of the retinal results in deprotonation of the Schiff base followed by alterations in protonatable groups within bacteriorhodopsin. The changed force field induces changes, even in the tertiary structure, which are necessary for proton pumping. The recent report of a high-resolution X-ray crystal structure for the late M intermediate of a mutant bacteriorhopsin (with Asp 96-->Asn) displays the structure of a proton pathway highly disturbed by the mutation. To observe an unperturbed proton pathway, we determined the structure of the late M intermediate of wild-type bacteriorhodopsin (2.25 A resolution). The cytoplasmic side of our M2 structure shows a water net that allows proton transfer from the proton donor group Asp 96 towards the Schiff base. An enlarged cavity system above Asp 96 is observed, which facilitates the de- and reprotonation of this group by fluctuating water molecules in the last part of the cycle.

Journal ArticleDOI
TL;DR: An attachment theory approach to severe personality disorder is described and evidence is presented that suggests that representations of attachment relationships and attachment behaviors of patients with this diagnosis are commonly disorganized in character.

Journal ArticleDOI
TL;DR: FMLP-induced degranulation of primary and secondary granules of neutrophils is mediated by p38 MAPK activated via Src family tyrosine kinases, indicating that the specificity of the Genistein inhibitor is questioned.
Abstract: The aim of the present study was to investigate the role of tyrosine phosphorylation pathways in fMLP-induced exocytosis of the different secretory compartments (primary and secondary granules, as well as secretory vesicles) of neutrophils. Genistein, a broad specificity tyrosine kinase inhibitor, blocked the exocytosis of primary and secondary granules, but had only a marginal effect on the release of secretory vesicles. Genistein also inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (MAPK), raising the possibility that inhibition of ERK and/or p38 MAPK might be responsible for the effect of the drug on the degranulation response. Indeed, SB203580, an inhibitor of p38 MAPK, decreased the release of primary and secondary granules, but not that of secretory vesicles. However, blocking the ERK pathway with PD98059 had no effect on any of the exocytic responses tested. PP1, an inhibitor of Src family kinases, also attenuated the release of primary and secondary granules, and neutrophils from mice deficient in the Src family kinases Hck, Fgr, and Lyn were also defective in secondary granule release. Furthermore, activation of p38 MAPK was blocked by both PP1 and the hck-/-fgr-/-lyn-/- mutation. Taken together, our data indicate that fMLP-induced degranulation of primary and secondary granules of neutrophils is mediated by p38 MAPK activated via Src family tyrosine kinases. Although piceatannol, a reportedly selective inhibitor of Syk, also prevented degranulation and activation of p38 MAPK, no fMLP-induced phosphorylation of Syk could be observed, raising doubts about the specificity of the inhibitor.

Journal ArticleDOI
TL;DR: In this article, a method based on household electricity consumption is used to estimate the ratio of the hidden economy to the official GDP in 20 post-socialist countries, and the relationship between the visible private economy, the advancement of reforms, corruption and the size of hidden economy is analyzed.
Abstract: The study investigates the size of the hidden economy and related features, in post-socialist countries. After dealing critically with the approach of Kaufmann and Kaliberda, a method based on household electricity consumption is used to estimate the ratio of the hidden economy to the official GDP in 20 countries. Following a uniform growth in the size of the hidden economy in all the countries at the beginning of their transition, stagnation or further increase was experienced in the CIS countries, while an explicit declining tendency could be seen in the remaining economies. Comparisons show that the ratio of the hidden economy in post-socialist countries is significantly larger than in developed market economies. The paper analyses the relationships between the visible private economy, the advancement of reforms, corruption, and the size of the hidden economy.

Journal ArticleDOI
TL;DR: In this paper, the authors relax the standard Hermiticity requirement and find an innovative construction which leads to unusual, complex potentials, and their energy spectrum is shown to stay real after a weakening of the Schr?dinger equation to its mere invariance under the combined (parity) and (time-reversal) symmetry.
Abstract: Changes of coordinates represent one of the most effective ways of deriving solvable potentials from ordinary differential equations for separate special functions. Here we relax the standard Hermiticity requirement and find an innovative construction which leads to unusual, complex potentials. Their energy spectrum is shown to stay real after a weakening of the Hermiticity of the Schr?dinger equation to its mere invariance under the combined (parity) and (time-reversal) symmetry. This ultimately results in richer bound-state spectra. Some of our new exactly solvable potentials generalize the current textbook models. Details are given for constructions based on the hypergeometric and confluent hypergeometric special functions.

Journal ArticleDOI
TL;DR: A plant-wide nomenclature of CDK-related genes is proposed, using a system similar to that of the plant cyclin genes, and five classes of these genes in plants are described here with respect to their phylogenetic, structural and functional properties.
Abstract: Cyclin-dependent kinases (CDK) form a conserved superfamily of eukaryotic serine-threonine protein kinases, which require binding to a cyclin protein for activity. CDK are involved in different aspects of cell biology and notably in cell cycle regulation. The comparison of nearly 50 plant CDK-related cDNAs with a selected set of their animal and yeast counterparts reveals five classes of these genes in plants. These are described here with respect to their phylogenetic, structural and functional properties. A plant-wide nomenclature of CDK-related genes is proposed, using a system similar to that of the plant cyclin genes. The most numerous class, CDKA, includes genes coding for CDK with the PSTAIRE canonical motif. CDKB makes up a class of plant-specific CDK divided into two groups: CDKB1 and CDKB2. CDKC, CDKD and CDKE form less numerous classes. The CDKD class includes the plant orthologues of metazoan CDK7, which correspond to the CDK-activating kinase (CAK). At present, no functional information is available in plants for CDKC and CDKE.

Journal ArticleDOI
TL;DR: In this article, the authors report correlative in vitro and in vivo evidence that an excitotoxic cascade mediates Abeta neurotoxicity in the rat magnocellular nucleus basalis (MBN).
Abstract: Whereas a cardinal role for beta-amyloid protein (Abeta) has been postulated as a major trigger of neuronal injury in Alzheimer's disease, the pathogenic mechanism by which Abeta deranges nerve cells remains largely elusive. Here we report correlative in vitro and in vivo evidence that an excitotoxic cascade mediates Abeta neurotoxicity in the rat magnocellular nucleus basalis (MBN). In vitro application of Abeta to astrocytes elicits rapid depolarization of astroglial membranes with a concomitant inhibition of glutamate uptake. In vivo Abeta infusion by way of microdialysis in the MBN revealed peak extracellular concentrations of excitatory amino acid neurotransmitters within 20-30 min. Abeta-triggered extracellular elevation of excitatory amino acids coincided with a significantly enhanced intracellular accumulation of Ca2+ in the Abeta injection area, as was demonstrated by 45Ca2+ autoradiography. In consequence of these acute processes delayed cell death in the MBN and persistent loss of cholinergic fibre projections to the neocortex appear as early as 3 days following the Abeta-induced toxic insult. Such a sequence of Abeta toxicity was effectively antagonized by the N-methyl-D-aspartate (NMDA) receptor ligand dizocilpine maleate (MK-801). Moreover, Abeta toxicity in the MBN decreases with advancing age that may be associated with the age-related loss of NMDA receptor expression in rats. In summary, the present results indicate that Abeta compromises neurons of the rat MBN via an excitotoxic pathway including astroglial depolarization, extracellular glutamate accumulation, NMDA receptor activation and an intracellular Ca2+ overload leading to cell death.

Journal ArticleDOI
TL;DR: It is found that the majority of LHRH neurons exhibited hybridization signal for the “β” form of ER (ER-β), and the degree of colocalization was similar in topographically distinct populations of L HRH neurons and was not significantly altered by estradiol.
Abstract: Luteinizing hormone-releasing hormone (LHRH) neurons of the forebrain play a pivotal role in the neuroendocrine control of reproduction. Although serum estrogen levels influence many aspects of LHRH neuronal activity in the female, earlier studies were unable to detect estrogen receptors (ERs) within LHRH neurons, thus shaping a consensus view that the effects of estradiol on the LHRH neuronal system are mediated by interneurons and/or the glial matrix. The present studies used dual-label in situ hybridization histochemistry (ISHH) and combined LHRH-immunocytochemistry/125I-estrogen binding to readdress the estrogen-receptivity of LHRH neurons in the female rat. In ISHH experiments we found that the majority of LHRH neurons exhibited hybridization signal for the “β” form of ER (ER-β). The degree of colocalization was similar in topographically distinct populations of LHRH neurons and was not significantly altered by estradiol (67.2±1.8 % in ovariectomized and 73.8±4.2 % in ovariectomized and estradiol-tre...

Journal ArticleDOI
TL;DR: The most powerful, consistent, and earliest attention effects were those found to occur in area V4, during the 100-300 ms poststimulus interval, and attention effects grew over the time course of the neuronal response.
Abstract: This study quantified the magnitude and timing of selective attention effects across areas of the macaque visual system, including the lateral geniculate nucleus (LGN), lower cortical areas V1 and V2, and multiple higher visual areas in the dorsal and ventral processing streams. We used one stimulus configuration and behavioral paradigm, with simultaneous recordings from different areas to allow direct comparison of the distribution and timing of attention effects across the system. Streams of interdigitated auditory and visual stimuli were presented at a high rate with an irregular interstimulus interval (mean of 4/s). Attention to visual stimuli was manipulated by requiring subjects to make discriminative behavioral responses to stimuli in one sensory modality, ignoring all stimuli in the other. The attended modality was alternated across trial blocks, and difficulty of discrimination was equated across modalities. Stimulus presentation was gated, so that no stimuli were presented unless the subject gazed at the center of the visual stimulus display. Visual stimuli were diffuse light flashes differing in intensity or color and subtending 12 degrees centered at the point of gaze. Laminar event-related potential (ERP) and current source density (CSD) response profiles were sampled during multiple paired penetrations in multiple visual areas with linear array multicontact electrodes. Attention effects were assessed by comparing responses to specific visual stimuli when attended versus when visual stimuli were looked at the same way, but ignored. Effects were quantified by computing a modulation index (MI), a ratio of the differential CSD response produced by attention to the sum responses to attended and ignored visual stimuli. The average MI increased up levels of the lower visual pathways from none in the LGN to 0.0278 in V1 to 0.101 in V2 to 0.170 in V4. Above the V2 level, attention effects were larger in ventral stream areas (MI = 0. 152) than in dorsal stream areas (MI = 0.052). Although onset latencies were shortest in dorsal stream areas, attentional modulation of the early response was small relative to the stimulus-evoked response. Higher ventral stream areas showed substantial attention effects at the earliest poststimulus time points, followed by the lower visual areas V2 and V1. In all areas, attentional modulation lagged the onset of the stimulus-evoked response, and attention effects grew over the time course of the neuronal response. The most powerful, consistent, and earliest attention effects were those found to occur in area V4, during the 100-300 ms poststimulus interval. Smaller effects occurred in V2 over the same interval, and the bulk of attention effects in V1 were later. In the accompanying paper, we describe the physiology of attention effects in V1, V2 and V4.

Journal ArticleDOI
TL;DR: The conduction electron density of states nearby single magnetic impurities, as measured recently by scanning tunneling microscopy (STM), is calculated, taking into account tunneling into conduction electrons states only.
Abstract: The conduction electron density of states nearby single magnetic impurities, as measured recently by scanning tunneling microscopy (STM), is calculated, taking into account tunneling into conduction electron states only. The Kondo effect induces a narrow Fano resonance in the conduction electron density of states. The line shape varies with the distance between STM tip and impurity, in qualitative agreement with experiments, but is very sensitive to details of the band structure. For a Co impurity the experimentally observed width and shift of the Kondo resonance are in accordance with those obtained from a combination of band structure and strongly correlated calculations.

Journal ArticleDOI
TL;DR: A stress-activated alfalfa gene encoding a novel plant NADPH-dependent aldose/aldehyde reductase that also exhibited characteristics of the homologous human enzyme is identified, revealing a new and efficient detoxification pathway in plants.
Abstract: Rapid accumulation of toxic products from reactions of reactive oxygen species (ROS) with lipids and proteins significantly contributes to the damage of crop plants under biotic and abiotic stresses. Here we have identified a stress-activated alfalfa gene encoding a novel plant NADPH-dependent aldose/aldehyde reductase that also exhibited characteristics of the homologous human enzyme. The recombinant alfalfa enzyme is active on 4-hydroxynon-2-enal, a known cytotoxic lipid peroxide degradation product. Ectopic synthesis of this enzyme in transgenic tobacco plants provided considerable tolerance against oxidative damage caused by paraquat and heavy metal treatment. These transformants could also resist a long period of water deficiency and exhibited improved recovery after rehydration. We found a reduced production of lipid peroxidation-derived reactive aldehydes in these transformed plants under different stresses. These studies reveal a new and efficient detoxification pathway in plants.

Journal ArticleDOI
TL;DR: A unique expression pattern and the presynaptic modulation of GABA release suggests a conserved role for CB1 receptors in controlling inhibitory networks of the hippocampus that are responsible for the generation and maintenance of fast and slow oscillatory patterns.

Journal ArticleDOI
TL;DR: In this article, an increased directional transport of several MDR1 P-glycoprotein substrates, such as digoxin, paclitaxel, and vinblastine, through polarized monolayers of MDR3-transfected cells was reported.