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Sample records for activation augments nmda

  1. ERK activation causes epilepsy by stimulating NMDA receptor activity

    Nateri, Abdolrahman S.; Raivich, Gennadij; Gebhardt, Christine; Da Costa, Clive; Naumann, Heike; Vreugdenhil, Martin; Makwana, Milan; Brandner, Sebastian; Adams, Ralf H.; Jefferys, John G. R.; Kann, Oliver; Behrens, Axel

    2007-01-01

    The ERK MAPK signalling pathway is a highly conserved kinase cascade linking transmembrane receptors to downstream effector mechanisms. To investigate the function of ERK in neurons, a constitutively active form of MEK1 (caMEK1) was conditionally expressed in the murine brain, which resulted in ERK activation and caused spontaneous epileptic seizures. ERK activation stimulated phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and augmented NMDA receptor 2B (NR2B) protein ...

  2. NMDA receptor activation by spontaneous glutamatergic neurotransmission.

    Espinosa, Felipe; Kavalali, Ege T

    2009-05-01

    Under physiological conditions N-methyl-D-aspartate (NMDA) receptor activation requires coincidence of presynaptic glutamate release and postsynaptic depolarization due to the voltage-dependent block of these receptors by extracellular Mg(2+). Therefore spontaneous neurotransmission in the absence of action potential firing is not expected to lead to significant NMDA receptor activation. Here we tested this assumption in layer IV neurons in neocortex at their resting membrane potential (approximately -67 mV). In long-duration stable recordings, we averaged a large number of miniature excitatory postsynaptic currents (mEPSCs, >100) before or after application of dl-2 amino 5-phosphonovaleric acid, a specific blocker of NMDA receptors. The difference between the two mEPSC waveforms showed that the NMDA current component comprises approximately 20% of the charge transfer during an average mEPSC detected at rest. Importantly, the contribution of the NMDA component was markedly enhanced at membrane potentials expected for the depolarized up states (approximately -50 mV) that cortical neurons show during slow oscillations in vivo. In addition, partial block of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor component of the mEPSCs did not cause a significant reduction in the NMDA component, indicating that potential AMPA receptor-driven local depolarizations did not drive NMDA receptor activity at rest. Collectively these results indicate that NMDA receptors significantly contribute to signaling at rest in the absence of dendritic depolarizations or concomitant AMPA receptor activity. PMID:19261712

  3. NMDA Receptor Activation by Spontaneous Glutamatergic Neurotransmission

    Espinosa, Felipe; Kavalali, Ege T.

    2009-01-01

    Under physiological conditions N-methyl-d-aspartate (NMDA) receptor activation requires coincidence of presynaptic glutamate release and postsynaptic depolarization due to the voltage-dependent block of these receptors by extracellular Mg2+. Therefore spontaneous neurotransmission in the absence of action potential firing is not expected to lead to significant NMDA receptor activation. Here we tested this assumption in layer IV neurons in neocortex at their resting membrane potential (approxi...

  4. NMDA receptor activity in neuropsychiatric disorders

    ShaheenELakhan

    2013-06-01

    Full Text Available N-Methyl-D-aspartate (NMDA receptors play a variety of physiologic roles and their proper signaling is essential for cellular homeostasis. Any disruption in this pathway, leading to either enhanced or decreased activity, may result in the manifestation of neuropsychiatric pathologies such as schizophrenia, mood disorders, substance induced psychosis, Huntington's disease, Alzheimer's disease, and neuropsychiatric systemic lupus erythematosus. Here, we explore the notion that the overlap in activity of at least one biochemical pathway, the NMDA receptor pathway, may be the link to understanding the overlap in psychotic symptoms between diseases. This review intends to present a broad overview of those neuropsychiatric disorders for which alternations in NMDA receptor activity is prominent thus suggesting that continued direction of pharmaceutical intervention to this pathway may present a viable option for managing symptoms.

  5. Chronic hyperammonemia induces tonic activation of NMDA receptors in cerebellum.

    ElMlili, Nisrin; Boix, Jordi; Ahabrach, Hanan; Rodrigo, Regina; Errami, Mohammed; Felipo, Vicente

    2010-02-01

    Reduced function of the glutamate--nitric oxide (NO)--cGMP pathway is responsible for some cognitive alterations in rats with hyperammonemia and hepatic encephalopathy. Hyperammonemia impairs the pathway in cerebellum by increasing neuronal nitric oxide synthase (nNOS) phosphorylation in Ser847 by calcium-calmodulin-dependent protein kinase II (CaMKII), reducing nNOS activity, and by reducing nNOS amount in synaptic membranes, which reduces its activation following NMDA receptors activation. The reason for increased CaMKII activity in hyperammonemia remains unknown. We hypothesized that it would be as a result of increased tonic activation of NMDA receptors. The aims of this work were to assess: (i) whether tonic NMDA activation receptors is increased in cerebellum in chronic hyperammonemia in vivo; and (ii) whether this tonic activation is responsible for increased CaMKII activity and reduced activity of nNOS and of the glutamate--NO--cGMP pathway. Blocking NMDA receptors with MK-801 increases cGMP and NO metabolites in cerebellum in vivo and in slices from hyperammonemic rats. This is because of reduced phosphorylation and activity of CaMKII, leading to normalization of nNOS phosphorylation and activity. MK-801 also increases nNOS in synaptic membranes and reduces it in cytosol. This indicates that hyperammonemia increases tonic activation of NMDA receptors leading to reduced activity of nNOS and of the glutamate--NO--cGMP pathway. PMID:20002515

  6. Interplay between non-NMDA and NMDA receptor activation during oscillatory wave propagation: Analyses of caffeine-induced oscillations in the visual cortex of rats.

    Yoshimura, Hiroshi; Sugai, Tokio; Kato, Nobuo; Tominaga, Takashi; Tominaga, Yoko; Hasegawa, Takahiro; Yao, Chenjuan; Akamatsu, Tetsuya

    2016-07-01

    Generation and propagation of oscillatory activities in cortical networks are important features of the brain. However, many issues related to oscillatory phenomena are unclear. We previously reported neocortical oscillation following caffeine treatment of rat brain slices. Input to the primary visual cortex (Oc1) generates N-methyl-d-aspartate (NMDA) receptor-dependent oscillations, and we proposed that the oscillatory signals originate in the secondary visual cortex (Oc2). Because non-NMDA and NMDA receptors cooperate in synaptic transmission, non-NMDA receptors may also play an important role in oscillatory activities. Here we investigated how non-NMDA receptor activities contribute to NMDA receptor-dependent oscillations by using optical recording methods. After induction of stable oscillations with caffeine application, blockade of NMDA receptors abolished the late stable oscillatory phase, but elicited 'hidden' non-NMDA receptor-dependent oscillation during the early depolarizing phase. An interesting finding is that the origin of the non-NMDA receptor-dependent oscillation moved from the Oc1, during the early phase, toward the origin of the NMDA receptor-dependent oscillation that is fixed in the Oc2. In addition, the frequency of the non-NMDA receptor-dependent oscillation was higher than that of the NMDA receptor-dependent oscillation. Thus, in one course of spatiotemporal oscillatory activities, the relative balance in receptor activities between non-NMDA and NMDA receptors gradually changes, and this may be due to the different kinetics of the two receptor types. These results suggest that interplay between the two receptor types in the areas of Oc1 and Oc2 may play an important role in oscillatory signal communication. PMID:27136667

  7. Formation and maintenance of ventilatory long-term facilitation require NMDA but not non-NMDA receptors in awake rats

    McGuire, Michelle; Liu, Chun; Cao, Ying; Ling, Liming

    2008-01-01

    N-methyl-d-aspartate (NMDA) receptor antagonism in the phrenic motonucleus area eliminates phrenic long-term facilitation (pLTF; a persistent augmentation of phrenic nerve activity after episodic hypoxia) in anesthetized rats. However, whether NMDA antagonism can eliminate ventilatory LTF (vLTF) in awake rats is unclear. The role of non-NMDA receptors in LTF is also unknown. Serotonin receptor antagonism before, but not after, episodic hypoxia eliminates pLTF, suggesting that serotonin recept...

  8. A quantitative method to assess extrasynaptic NMDA receptor function in the protective effect of synaptic activity against neurotoxicity

    Bading Hilmar

    2008-01-01

    Full Text Available Abstract Background Extrasynaptic NMDA receptors couple to a CREB shut-off pathway and cause cell death, whereas synaptic NMDA receptors and nuclear calcium signaling promote CREB-mediated transcription and neuronal survival. The distribution of NMDA receptors (synaptic versus extrasynaptic may be an important parameter that determines the susceptibility of neurons to toxic insults. Changes in receptor surface expression towards more extrasynaptic NMDA receptors may lead to neurodegeneration, whereas a reduction of extrasynaptic NMDA receptors may render neurons more resistant to death. A quantitative assessment of extrasynaptic NMDA receptors in individual neurons is needed in order to investigate the role of NMDA receptor distribution in neuronal survival and death. Results Here we refined and verified a protocol previously used to isolate the effects of extrasynaptic NMDA receptors using the NMDA receptor open channel blocker, MK-801. Using this method we investigated the possibility that the known neuroprotective shield built up in hippocampal neurons after a period of action potential bursting and stimulation of synaptic NMDA receptors is due to signal-induced trafficking of extrasynaptic NMDA receptors or a reduction in extrasynaptic NMDA receptor function. We found that extrasynaptic NMDA receptor-mediated calcium responses and whole cell currents recorded under voltage clamp were surprisingly invariable and did not change even after prolonged (16 to 24 hours periods of bursting and synaptic NMDA receptor activation. Averaging a large number of calcium imaging traces yielded a small (6% reduction of extrasynaptic NMDA receptor-mediated responses in hippocampal neurons that were pretreated with prolonged bursting. Conclusion The slight reduction in extrasynaptic NMDA receptor function following action potential bursting and synaptic NMDA receptor stimulation could contribute to but is unlikely to fully account for activity

  9. In vitro neuronal network activity in NMDA receptor encephalitis

    Jantzen Sabine U

    2013-02-01

    Full Text Available Abstract Background Anti-NMDA-encephalitis is caused by antibodies against the N-methyl-D-aspartate receptor (NMDAR and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. It predominantly occurs in young women and is associated in 59% with an ovarian teratoma. Results We describe effects of cerebrospinal fluid (CSF from an anti-N-methyl-D-aspartate receptor (NMDAR encephalitis patient on in vitro neuronal network activity (ivNNA. In vitro NNA of dissociated primary rat cortical populations was recorded by the microelectrode array (MEA system. The 23-year old patient was severely affected but showed an excellent recovery following multimodal immunomodulatory therapy and removal of an ovarian teratoma. Patient CSF (pCSF taken during the initial weeks after disease onset suppressed global spike- and burst rates of ivNNA in contrast to pCSF sampled after clinical recovery and decrease of NMDAR antibody titers. The synchrony of pCSF-affected ivNNA remained unaltered during the course of the disease. Conclusion Patient CSF directly suppresses global activity of neuronal networks recorded by the MEA system. In contrast, pCSF did not regulate the synchrony of ivNNA suggesting that NMDAR antibodies selectively regulate distinct parameters of ivNNA while sparing their functional connectivity. Thus, assessing ivNNA could represent a new technique to evaluate functional consequences of autoimmune encephalitis-related CSF changes.

  10. NMDA modulates oligodendrocyte differentiation of subventricular zone cells through PKC activation

    Fabio eCavaliere

    2013-12-01

    Full Text Available Multipotent cells from the juvenile subventricular zone (SVZ possess the ability to differentiate into new neural cells. Depending on local signals, SVZ can generate new neurons, astrocytes or oligodendrocytes. We previously demonstrated that activation of NMDA receptors in SVZ progenitors increases the rate of oligodendrocyte differentiation. Here we investigated the mechanisms involved in NMDA receptor-dependent differentiation. Using functional studies performed with the reporter gene luciferase we found that activation of NMDA receptor stimulates PKC. In turn, stimulation of PKC precedes the activation of NADPH oxidase (NOX as demonstrated by translocation of the p67phox subunit to the cellular membrane. We propose that NOX2 is involved in the transduction of the signal from NMDA receptors through PKC activation as the inhibitor gp91 reduced their pro-differentiation effect. In addition, our data and that from other groups suggest that signaling through the NMDA receptor/PKC/NOX2 cascade generates ROS that activate the PI3/mTOR pathway and finally leads to the generation of new oligodendrocytes.

  11. Clozapine functions through the prefrontal cortex serotonin 1A receptor to heighten neuronal activity via calmodulin kinase II-NMDA receptor interactions.

    Purkayastha, Sudarshana; Ford, Jason; Kanjilal, Baishali; Diallo, Souleymane; Del Rosario Inigo, Joseph; Neuwirth, Lorenz; El Idrissi, Abdeslem; Ahmed, Zaghloul; Wieraszko, Andrzej; Azmitia, Efrain C; Banerjee, Probal

    2012-02-01

    Aberrant dopamine release in the prefrontal cortex (PFC) is believed to underlie schizophrenia, but the mechanistic pathway through which a widely used antipsychotic, clozapine (Clz), evokes neurotransmitter-releasing electrical stimulation is unclear. We analyzed Clz-evoked regulation of neuronal activity in the PFC by stimulating axons in layers IV and V and recording the electrical effect in the post-synaptic pyramidal cells of layers II and III. We observed a Clz-evoked increase in population spike (PS), which was mediated by serotonin 1A receptor (5-HT(1A)-R), phospholipase Cβ, and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Immunoblotting demonstrated that the Clz-activation of CaMKII was 5-HT(1A)-R-mediated. Intriguingly, the NMDA receptor (NMDA-R) antagonist (±)2-amino-5-phosphonovaleric acid (APV) eliminated the Clz-mediated increase in PS, suggesting that the 5-HT(1A)-R, NMDA-R and CaMKII form a synergistic triad, which boosts excitatory post-synaptic potential (EPSP), thereby enhancing PS. In corroboration, Clz as well as NMDA augmented field EPSP (fEPSP), and WAY100635 (a 5-HT(1A)-R antagonist), APV, and a CaMKII inhibitor eliminated this increase. As previously shown, CaMKII binds to the NMDA-R 2B (NR2B) subunit to become constitutively active, thereby inducing α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor recruitment to the post-synaptic membrane and an increase in fEPSP. Co-immunoprecipitation demonstrated that Clz potentiates interactions among CaMKII, NR2B, and 5-HT(1A)-R, possibly in the membrane rafts of the post-synaptic density (PSD), because pretreatment with methyl-β-cyclodextrin (MCD), an agent that disrupts rafts, inhibited both co-immunoprecipitation as well as fEPSP. In summary, Clz functions in the PFC by orchestrating a synergism among 5-HT(1A)-R, CaMKII, and NMDA-R, which augments excitability in the PFC neurons of layers II/III. PMID:22044428

  12. NMDA-receptor activation but not ion flux is required for amyloid-beta induced synaptic depression.

    Albert Tamburri

    Full Text Available Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ in the etiology of Alzheimer's disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

  13. Activation of N-methyl-D-aspartate (NMDA) receptors in the dorsal vagal complex lowers glucose production.

    Lam, Carol K L; Chari, Madhu; Su, Brenda B; Cheung, Grace W C; Kokorovic, Andrea; Yang, Clair S; Wang, Penny Y T; Lai, Teresa Y Y; Lam, Tony K T

    2010-07-16

    Diabetes is characterized by hyperglycemia due partly to increased hepatic glucose production. The hypothalamus regulates hepatic glucose production in rodents. However, it is currently unknown whether other regions of the brain are sufficient in glucose production regulation. The N-methyl-D-aspartate (NMDA) receptor is composed of NR1 and NR2 subunits, which are activated by co-agonist glycine and glutamate or aspartate, respectively. Here we report that direct administration of either co-agonist glycine or NMDA into the dorsal vagal complex (DVC), targeting the nucleus of the solitary tract, lowered glucose production in vivo. Direct infusion of the NMDA receptor blocker MK-801 into the DVC negated the metabolic effect of glycine. To evaluate whether NR1 subunit of the NMDA receptor mediates the effect of glycine, NR1 in the DVC was inhibited by DVC NR1 antagonist 7-chlorokynurenic acid or DVC shRNA-NR1. Pharmacological and molecular inhibition of DVC NR1 negated the metabolic effect of glycine. To evaluate whether the NMDA receptors mediate the effects of NR2 agonist NMDA, DVC NMDA receptors were inhibited by antagonist D-2-amino-5-phosphonovaleric acid (D-APV). DVC D-APV fully negated the ability of DVC NMDA to lower glucose production. Finally, hepatic vagotomy negated the DVC glycine ability to lower glucose production. These findings demonstrate that activation of NR1 and NR2 subunits of the NMDA receptors in the DVC is sufficient to trigger a brain-liver axis to lower glucose production, and suggest that DVC NMDA receptors serve as a therapeutic target for diabetes and obesity. PMID:20448042

  14. Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors

    Pawlak, Robert; Melchor, Jerry P.; Matys, Tomasz; Skrzypiec, Anna E.; Strickland, Sidney

    2005-01-01

    Chronic ethanol abuse causes up-regulation of NMDA receptors, which underlies seizures and brain damage upon ethanol withdrawal (EW). Here we show that tissue-plasminogen activator (tPA), a protease implicated in neuronal plasticity and seizures, is induced in the limbic system by chronic ethanol consumption, temporally coinciding with up-regulation of NMDA receptors. tPA interacts with NR2B-containing NMDA receptors and is required for up-regulation of the NR2B subunit in response to ethanol...

  15. Progressive brain damage, synaptic reorganization and NMDA activation in a model of epileptogenic cortical dysplasia.

    Francesca Colciaghi

    Full Text Available Whether severe epilepsy could be a progressive disorder remains as yet unresolved. We previously demonstrated in a rat model of acquired focal cortical dysplasia, the methylazoxymethanol/pilocarpine - MAM/pilocarpine - rats, that the occurrence of status epilepticus (SE and subsequent seizures fostered a pathologic process capable of modifying the morphology of cortical pyramidal neurons and NMDA receptor expression/localization. We have here extended our analysis by evaluating neocortical and hippocampal changes in MAM/pilocarpine rats at different epilepsy stages, from few days after onset up to six months of chronic epilepsy. Our findings indicate that the process triggered by SE and subsequent seizures in the malformed brain i is steadily progressive, deeply altering neocortical and hippocampal morphology, with atrophy of neocortex and CA regions and progressive increase of granule cell layer dispersion; ii changes dramatically the fine morphology of neurons in neocortex and hippocampus, by increasing cell size and decreasing both dendrite arborization and spine density; iii induces reorganization of glutamatergic and GABAergic networks in both neocortex and hippocampus, favoring excitatory vs inhibitory input; iv activates NMDA regulatory subunits. Taken together, our data indicate that, at least in experimental models of brain malformations, severe seizure activity, i.e., SE plus recurrent seizures, may lead to a widespread, steadily progressive architectural, neuronal and synaptic reorganization in the brain. They also suggest the mechanistic relevance of glutamate/NMDA hyper-activation in the seizure-related brain pathologic plasticity.

  16. The Effects of NMDA Antagonists on Neuronal Activity in Cat Spinal Cord Evoked by Acute Inflammation in the Knee Joint.

    Schaible, Hans-Georg; Grubb, Blair D.; Neugebauer, Volker; Oppmann, Maria

    1991-01-01

    In alpha-chloralose-anaesthetized, spinalized cats we examined the effects of NMDA antagonists on the discharges of 71 spinal neurons which had afferent input from the knee joint. These neurons were rendered hyperexcitable by acute arthritis in the knee induced by kaolin and carrageenan. They were located in the deep dorsal and ventral horn and some of them had ascending axons. The N-methyl-d-aspartate (NMDA) antagonists ketamine and d-2-amino-5-phosphonovalerate (AP5), were administered ionophoretically, and ketamine was also administered intravenously. In some of the experiments the antagonists were tested against the agonists NMDA and quisqualate. The effects of the NMDA antagonists consisted of a significant reduction in the resting activity of neurons and/or the responses of the same neurons to mechanical stimulation of the inflamed knee. Intravenous ketamine was most effective in suppressing the resting and mechanically evoked activity in 25 of 26 neurons tested. Ionophoretically applied ketamine had a suppressive effect in 11 of 21 neurons, and AP5 decreased activity in 17 of 24 cells. The reduction in the resting and/or the mechanically evoked discharges was achieved with doses of the antagonists which suppressed the responses to NMDA but not those to quisqualate. These results suggest that NMDA receptors are involved in the enhanced responses and basal activity of spinal neurons induced by inflammation in the periphery. PMID:12106256

  17. Ethanol enhances neurosteroidogenesis in hippocampal pyramidal neurons by paradoxical NMDA receptor activation.

    Tokuda, Kazuhiro; Izumi, Yukitoshi; Zorumski, Charles F

    2011-07-01

    Using an antibody against 5α-reduced neurosteroids, predominantly allopregnanolone, we found that immunostaining in the CA1 region of rat hippocampal slices was confined to pyramidal neurons. This neurosteroid staining was increased following 15 min administration of 60 mm but not 20 mm ethanol, and the enhancement was blocked by finasteride and dutasteride, selective inhibitors of 5α-reductase, a key enzyme required for allopregnanolone synthesis. Consistent with a prior report indicating that N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation can promote steroid production, we observed that D-2-amino-5-phosphonovalerate (APV), a competitive NMDAR antagonist, blocked the effects of 60 mm ethanol on staining. We previously reported that 60 mm ethanol inhibits the induction of long-term potentiation (LTP), a cellular model for memory formation, in the CA1 region. In the present study, LTP inhibition by 60 mm ethanol was also overcome by both the 5α-reductase inhibitors and by APV. Furthermore, the effects of ethanol on neurosteroid production and LTP were mimicked by a low concentration of NMDA (1 μm), and the ability of NMDA to inhibit LTP and to enhance neurosteroid staining was reversed by finasteride and dutasteride, as well as by APV. These results indicate that ethanol paradoxically enhances GABAergic neurosteroid production by activation of unblocked NMDARs and that acute LTP inhibition by ethanol represents a form of NMDAR-mediated metaplasticity. PMID:21734282

  18. Voltage-clamp frequency domain analysis of NMDA-activated neurons.

    Moore, L E; Hill, R H; Grillner, S

    1993-02-01

    1. Voltage and current-clamp steps were added to a sum of sine waves to measure the tetrodotoxin-insensitive membrane properties of neurons in the intact lamprey spinal cord. A systems analysis in the frequency domain was carried out on two types of cells that have very different morphologies in order to investigate the structural dependence of their electrophysiological properties. The method explicitly takes into account the geometrical shapes of (i) nearly spherical dorsal cells with one or two processes and (ii) motoneurons and interneurons that have branched dendritic structures. Impedance functions were analysed to obtain the cable properties of these in situ neurons. These measurements show that branched neurons are not isopotential and, therefore, a conventional voltage-clamp analysis is not valid. 2. The electrophysiological data from branched neurons were curve-fitted with a lumped soma-equivalent cylinder model consisting of eight equal compartments coupled to an isopotential cell body to obtain membrane parameters for both passive and active properties. The analysis provides a quantitative description of both the passive electrical properties imposed by the geometrical structure of neurons and the voltage-dependent ionic conductances determined by ion channel kinetics. The model fitting of dorsal cells was dominated by a one-compartment resistance and capacitance in parallel (RC) corresponding to the spherical, non-branched shape of these cells. Branched neurons required a model that contained both an RC compartment and a cable that reflected the structure of the cells. At rest, the electrotonic length of the cable was about two. Uniformly distributed voltage-dependent ionic conductance sites were adequate to describe the data at different membrane potentials. 3. The frequency domain admittance method in conjunction with a step voltage clamp was used to control and measure the oscillatory behavior induced by N-methyl-D-aspartate (NMDA) on lamprey spinal

  19. EFFECT OF ELECTROACUPUNCTURE ON MYOCARDIAL ISCHEMIA INDUCED CHANGES OF CARDIAC SYMPATHETIC ACTIVITY AND INVOLVEMENT OF SPINIAL δ-OPIOID,NMDA-AND NON-NMDA RECEPTORS IN THE RABBIT

    刘俊岭; 高永辉; 陈淑萍

    2003-01-01

    Aim: To observe the effect of electroacupuncture (EA) on acute myocardial ischemia (AMI) induced changes of cardiac sympathetic discharges and the effects of some related receptors in the spinal cord. Methods: A total of 53 rabbits anesthetized with mixture solution of 25% urethane (420 mg/kg) and 1.5% chloralose (50 mg/kg)were used in this study. AMI was induced by occlusion of the ventricular branch of the left coronary artery. Discharges of the left cardiac sympathetic nerve were recorded by using a bipolar platinum electrode. Bilateral "Ximen"(PC 40)and "Kongzhui"(LU 6) were stimulated electrically by using an EA therapeutic apparatus or an electrical stimulator.DPDPE δ-opiate receptor agonist, 20 nmol, 10 μL, n= 8), Naltrindole Hydrochloride (δ-opiate receptor antagonist, 20nmol, 10 μL, n=8), DAP5 (NMDA receptor antagonist, 5 nmol, 10 μL, n=9) and CNQX (non-NMDA receptor antagonist, 5 nmol, 10 μL, n=8) were respectively injected into the thoracic subarachnoid space of the spinal cord in different groups, followed by observing their effects on changes of sympathetic activity evoked by EA of the abovementioned acupoints. Results: ① After AMI, sympathetic discharges increased (200.56± 79.89%) in 10 cases and decreased (- 59.34 ±7.06% ) in other 9 cases in comparison with their individual basal values. After EA of "Ximen" (PC 4)and "Kongzhui" (Lu 6), AMI-induced increase and decrease changes of the sympathetic activity were suppressed significantly, but the effect of EA of LU-6 was weaker than that of EA of PC-4.②Following EA of PC-4 and LU-6, sympathetic discharges increased significantly in 2 and 4 cases, decreased apparently in 7 and 3 cases, and had no striking changes in 1 and 3 cases respectively. The mean reaction threshold of sympathetic activity after EA of PC-4 and LU-6were 2.1 ± 0.65 mA and 3.28± 1.13 mA separately.③ After pre-treatment with DPDPE, the reaction threshold of the cardiac sympathetic activity to EA of PC-4 elevated

  20. Formation and maintenance of ventilatory long-term facilitation require NMDA but not non-NMDA receptors in awake rats.

    McGuire, Michelle; Liu, Chun; Cao, Ying; Ling, Liming

    2008-09-01

    N-methyl-d-aspartate (NMDA) receptor antagonism in the phrenic motonucleus area eliminates phrenic long-term facilitation (pLTF; a persistent augmentation of phrenic nerve activity after episodic hypoxia) in anesthetized rats. However, whether NMDA antagonism can eliminate ventilatory LTF (vLTF) in awake rats is unclear. The role of non-NMDA receptors in LTF is also unknown. Serotonin receptor antagonism before, but not after, episodic hypoxia eliminates pLTF, suggesting that serotonin receptors are required for induction, but not maintenance, of pLTF. However, because NMDA and non-NMDA ionotropic glutamate receptors are directly involved in mediating the inspiratory drive to phrenic, hypoglossal, and intercostal motoneurons, we hypothesized that these receptors are required for both formation and maintenance of vLTF. vLTF, induced by five episodes of 5-min poikilocapnic hypoxia (10% O(2)) with 5-min normoxia intervals, was measured with plethysmography in conscious adult male Sprague-Dawley rats. Either (+/-)-2-amino-5-phosphonovaleric acid (APV; NMDA antagonist, 1.5 mg/kg) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; non-NMDA antagonist, 10 mg/kg) was systemically (ip) injected approximately 30 min before hypoxia. APV was also injected immediately after or 20 min after episodic hypoxia in additional groups. As control, vehicle was similarly injected in each rat 1-2 days before. Regardless of being injected before or after episodic hypoxia, vehicle did not alter vLTF ( approximately 23%), whereas APV eliminated vLTF while having little effect on baseline ventilation or hypoxic ventilatory response. In contrast, CNQX enhanced vLTF ( approximately 34%) while decreasing baseline ventilation. Collectively, these results suggest that activation of NMDA but not non-NMDA receptors is necessary for formation and maintenance of vLTF in awake rats. PMID:18583381

  1. Abelson tyrosine kinase links PDGFbeta receptor activation to cytoskeletal regulation of NMDA receptors in CA1 hippocampal neurons

    Beazely Michael A

    2008-12-01

    Full Text Available Abstract Background We have previously demonstrated that PDGF receptor activation indirectly inhibits N-methyl-D-aspartate (NMDA currents by modifying the cytoskeleton. PDGF receptor ligand is also neuroprotective in hippocampal slices and cultured neurons. PDGF receptors are tyrosine kinases that control a variety of signal transduction pathways including those mediated by PLCγ. In fibroblasts Src and another non-receptor tyrosine kinase, Abelson kinase (Abl, control PDGF receptor regulation of cytoskeletal dynamics. The mechanism whereby PDGF receptor regulates cytoskeletal dynamics in central neurons remains poorly understood. Results Intracellular applications of active Abl, but not heat-inactivated Abl, decreased NMDA-evoked currents in isolated hippocampal neurons. This mimics the effects of PDGF receptor activation in these neurons. The Abl kinase inhibitor, STI571, blocked the inhibition of NMDA currents by Abl. We demonstrate that PDGF receptors can activate Abl kinase in hippocampal neurons via mechanisms similar to those observed previously in fibroblasts. Furthermore, PDGFβ receptor activation alters the subcellular localization of Abl. Abl kinase is linked to actin cytoskeletal dynamics in many systems. We show that the inhibition of NMDA receptor currents by Abl kinase is blocked by the inclusion of the Rho kinase inhibitor, Y-27632, and that activation of Abl correlates with an increase in ROCK tyrosine phosphorylation. Conclusion This study demonstrates that PDGFβ receptors act via an interaction with Abl kinase and Rho kinase to regulated cytoskeletal regulation of NMDA receptor channels in CA1 pyramidal neurons.

  2. Metabotropic glutamate receptor 5, but not 1, modulates NMDA receptor-mediated activation of neuronal nitric oxide synthase.

    Llansola, Marta; Felipo, Vicente

    2010-03-01

    In cerebellar neurons in culture, activation of group I metabotropic glutamate receptors (mGluRs) prevents glutamate and NMDA-induced neuronal death, indicating that it interferes with the excitotoxic mechanisms leading to death. However, it is not known which step of these mechanisms is affected by mGluRs. The aims of this work were to assess: (a) whether activation of group I mGluRs (mGluR1 or mGluR5) impairs NMDA-induced activation of the glutamate-nitric oxide-cGMP pathway; (b) which mGluR (1 or 5) is responsible for this impairment and (c) whether impairment of the pathway occurs at the level of activation of soluble guanylate cyclase by nitric oxide or of activation of neuronal nitric oxide synthase (nNOS) by NMDA. It is shown that activation of mGluR1 enhances the function of the glutamate-nitric oxide-cGMP pathway by increasing activation of soluble guanylate cyclase by nitric oxide. In contrast, mGluR5 activation inhibits the glutamate-nitric oxide-cGMP pathway by reducing NMDA-induced activation of nNOS. This is due to reduced NMDA-induced increase in cAMP, reduced activation of Akt by cAMP and of nNOS by Akt. The impairment of activation of the glutamate-NO-cGMP pathway by activation of mGluR5 would contribute to its neuroprotective effect against excitotoxicity in cerebellar neurons in culture. PMID:20043967

  3. ARLearn: Learning activities and interaction in augmented reality

    Ternier, Stefaan; Tabuenca, Bernardo; Specht, Marcus

    2013-01-01

    Ternier, S., Tabuenca, B., & Specht, M. (2012). ARLearn: Learning activities and interaction in augmented reality. In M. Specht, J. Multisilta, & M. Sharples (Eds.), Proceedings of the Mobile Augmented Reality for Education Workshop (pp. 10-13). October, 16-17, 2012, Helsinki, Finland.

  4. Current and calcium responses to local activation of axonal NMDA receptors in developing cerebellar molecular layer interneurons.

    Bénédicte Rossi

    Full Text Available In developing cerebellar molecular layer interneurons (MLIs, NMDA increases spontaneous GABA release. This effect had been attributed to either direct activation of presynaptic NMDA receptors (preNMDARs or an indirect pathway involving activation of somato-dendritic NMDARs followed by passive spread of somatic depolarization along the axon and activation of axonal voltage dependent Ca(2+ channels (VDCCs. Using Ca(2+ imaging and electrophysiology, we searched for preNMDARs by uncaging NMDAR agonists either broadly throughout the whole field or locally at specific axonal locations. Releasing either NMDA or glutamate in the presence of NBQX using short laser pulses elicited current transients that were highly sensitive to the location of the spot and restricted to a small number of varicosities. The signal was abolished in the presence of high Mg(2+ or by the addition of APV. Similar paradigms yielded restricted Ca(2+ transients in interneurons loaded with a Ca(2+ indicator. We found that the synaptic effects of NMDA were not inhibited by blocking VDCCs but were impaired in the presence of the ryanodine receptor antagonist dantrolene. Furthermore, in voltage clamped cells, bath applied NMDA triggers Ca(2+ elevations and induces neurotransmitter release in the axonal compartment. Our results suggest the existence of preNMDARs in developing MLIs and propose their involvement in the NMDA-evoked increase in GABA release by triggering a Ca(2+-induced Ca(2+ release process mediated by presynaptic Ca(2+ stores. Such a mechanism is likely to exert a crucial role in various forms of Ca(2+-mediated synaptic plasticity.

  5. Frequency-specific response facilitation of supra and infragranular barrel cortical neurons depends on NMDA receptor activation in rats.

    Barros-Zulaica, N; Castejon, C; Nuñez, A

    2014-10-01

    Sensory experience has a profound effect on neocortical neurons. Passive stimulation of whiskers or sensory deprivation from whiskers can induce long-lasting changes in neuronal responses or modify the receptive field in adult animals. We recorded barrel cortical neurons in urethane-anesthetized rats in layers 2/3 or 5/6 to determine if repetitive stimulation would induce long-lasting response facilitation. Air-puff stimulation (20-ms duration, 40 pulses at 0.5-8Hz) was applied to a single whisker. This repetitive stimulation increased tactile responses in layers 2/3 and 5/6 for 60min. Moreover, the functional coupling (coherence) between the sensory stimulus and the neural response also increased after the repetitive stimulation in neurons showing response facilitation. The long-lasting response facilitation was due to activation of N-methyl-d-aspartate (NMDA) receptors because it was reduced by APV ((2R)-amino-5-phosphonovaleric acid, (2R)-amino-5-phosphonopentanoate) and MK801 application. Inactivation of layer 2/3 also blocked response facilitation in layer 5/6, suggesting that layer 2/3 may be fundamental in this synaptic plasticity processes. Moreover, i.p. injection of eserine augmented the number of layer 2/3 neurons expressing long-lasting response facilitation; this effect was blocked by atropine, suggesting that muscarinic receptor activation favors the induction of the response facilitation. Our data indicate that physiologically repetitive stimulation of a single whisker at the frequency at which rats move their whiskers during exploration of the environment induces long-lasting response facilitation improving sensory processing. PMID:25281880

  6. Dynamic changes in cytosolic ATP levels in cultured glutamatergic neurons during NMDA-induced synaptic activity supported by glucose or lactate

    Lange, Sofie Cecilie; Winkler, Ulrike; Andresen, Lars;

    2015-01-01

    biosensor Ateam1.03YEMK. While inducing synaptic activity by subjecting cultured neurons to two 30 s pulses of NMDA (30 µM) with a 4 min interval, changes in relative ATP levels were measured in the presence of lactate (1 mM), glucose (2.5 mM) or the combination of the two. ATP levels reversibly declined...... following NMDA-induced neurotransmission activity, as indicated by a reversible 10-20 % decrease in the response of the biosensor. The responses were absent when the NMDA receptor antagonist memantine was present. In the presence of lactate alone, the ATP response dropped significantly more than in the...

  7. Activation of N-Methyl-d-aspartate (NMDA) Receptors in the Dorsal Vagal Complex Lowers Glucose Production*

    Lam, Carol K. L.; Chari, Madhu; Su, Brenda B.; Cheung, Grace W.C.; Kokorovic, Andrea; Yang, Clair S.; Wang, Penny Y. T.; Lai, Teresa Y.Y.; Lam, Tony K.T.

    2010-01-01

    Diabetes is characterized by hyperglycemia due partly to increased hepatic glucose production. The hypothalamus regulates hepatic glucose production in rodents. However, it is currently unknown whether other regions of the brain are sufficient in glucose production regulation. The N-methyl-d-aspartate (NMDA) receptor is composed of NR1 and NR2 subunits, which are activated by co-agonist glycine and glutamate or aspartate, respectively. Here we report that direct administration of either co-ag...

  8. Tumor necrosis factor alpha stimulates NMDA receptor activity in mouse cortical neurons resulting in ERK-dependent death

    Jara, Javier H.; Singh, Brij B.; Floden, Angela M.; Combs, Colin K.

    2007-01-01

    Multiple cytokines are secreted in the brain during pro-inflammatory conditions and likely affect neuron survival. Previously, we demonstrated that glutamate and tumor necrosis factor alpha (TNFα) kill neurons via activation of the N-methyl-d-aspartate (NMDA) and TNFα receptors, respectively. This report continues characterizing the signaling cross-talk pathway initiated during this inflammation-related mechanism of death. Stimulation of mouse cortical neuron cultures with TNFα results in a t...

  9. Synthesis of pregnane 3-carboxylic acids via Pd-catalyzed alkoxycarbonylation and their effect on NMDA receptor activity

    Šťastná, Eva; Chodounská, Hana; Pouzar, Vladimír; Borovská, Jiřina; Vyklický ml., Ladislav

    2011-01-01

    Roč. 76, č. 9 (2011), s. 1141-1161. ISSN 0010-0765 R&D Projects: GA ČR(CZ) GA203/08/1498; GA ČR(CZ) GA309/07/0271 Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50110509 Keywords : neurosteroids * carboxylic acid * alkoxycarbonylation * steroids * NMDA receptor activity Subject RIV: CC - Organic Chemistry Impact factor: 1.283, year: 2011

  10. Interaction of neurosteroids with NMDA receptors: Current Insight into Structure-Activity Relationships and Their Neuroprotective Effect

    Kudová, Eva; Chodounská, Hana; Slavíková, Barbora; Kapras, Vojtěch; Valeš, Karel; Rambousek, Lukáš; Borovská, Jiřina; Vyklický, Vojtěch; Krausová, Barbora; Vyklický ml., Ladislav

    Torino : -, 2013. [International Meeting Steroids and Nervous System /7./. 16.02.2013-20.02.2013, Toronto] R&D Projects: GA TA ČR(CZ) TE01020028; GA ČR(CZ) GAP303/12/1464 Institutional support: RVO:61388963 ; RVO:67985823 Keywords : neurosteroid * NMDA-receptor * structure-activity relationship * pregnanolone Subject RIV: CC - Organic Chemistry; ED - Physiology (FGU-C)

  11. NMDA receptor subunit expression and PAR2 receptor activation in colospinal afferent neurons (CANs during inflammation induced visceral hypersensitivity

    Caudle Robert M

    2009-09-01

    Full Text Available Abstract Background Visceral hypersensitivity is a clinical observation made when diagnosing patients with functional bowel disorders. The cause of visceral hypersensitivity is unknown but is thought to be attributed to inflammation. Previously we demonstrated that a unique set of enteric neurons, colospinal afferent neurons (CANs, co-localize with the NR1 and NR2D subunits of the NMDA receptor as well as with the PAR2 receptor. The aim of this study was to determine if NMDA and PAR2 receptors expressed on CANs contribute to visceral hypersensitivity following inflammation. Recently, work has suggested that dorsal root ganglion (DRG neurons expressing the transient receptor potential vanilloid-1 (TRPV1 receptor mediate inflammation induced visceral hypersensitivity. Therefore, in order to study CAN involvement in visceral hypersensitivity, DRG neurons expressing the TRPV1 receptor were lesioned with resiniferatoxin (RTX prior to inflammation and behavioural testing. Results CANs do not express the TRPV1 receptor; therefore, they survive following RTX injection. RTX treatment resulted in a significant decrease in TRPV1 expressing neurons in the colon and immunohistochemical analysis revealed no change in peptide or receptor expression in CANs following RTX lesioning as compared to control data. Behavioral studies determined that both inflamed non-RTX and RTX animals showed a decrease in balloon pressure threshold as compared to controls. Immunohistochemical analysis demonstrated that the NR1 cassettes, N1 and C1, of the NMDA receptor on CANs were up-regulated following inflammation. Furthermore, inflammation resulted in the activation of the PAR2 receptors expressed on CANs. Conclusion Our data show that inflammation causes an up-regulation of the NMDA receptor and the activation of the PAR2 receptor expressed on CANs. These changes are associated with a decrease in balloon pressure in response to colorectal distension in non-RTX and RTX lesioned

  12. Augmenting Learning Activities with Contextual Information Scent

    Li, Nan

    2015-01-01

    Students often have information needs while carrying out a multitude of learning activities at universities. When information is needed for investigating a problem, the student may interrupt the work and switch to an information seeking task. As Internet connectivity becomes ubiquitous, searching information has been routinized and integrated in the learning experience. However, information needs are not always fully recognized, or they can not be well articulated. A MOOC student may perceive...

  13. Differential Involvement of Amygdala and Cortical NMDA Receptors Activation upon Encoding in Odor Fear Memory

    Hegoburu, Chloé; Parrot, Sandrine; Ferreira, Guilaume; Mouly, Anne-Marie

    2014-01-01

    Although the basolateral amygdala (BLA) plays a crucial role for the acquisition of fear memories, sensory cortices are involved in their long-term storage in rats. However, the time course of their respective involvement has received little investigation. Here we assessed the role of the glutamatergic N-methyl-D-aspartate (NMDA) receptors in the…

  14. Pregnanolone 3alpha-Hemiesters - Novel Anionic Steroid Inhibitors of Activated NMDA Receptors

    Slavíková, Barbora; Chodounská, Hana; Vyklický, Vojtěch; Borovská, Jiřina; Krausová, Barbora; Vyklický ml., Ladislav; Kudová, Eva

    Kanazawa : -, 2012. [International Congress on Hormonal Steroids and Hormones and Cancer /15./. 15.11.2012-17.11.2012, Kanazawa] R&D Projects: GA ČR(CZ) GAP303/12/1464; GA TA ČR(CZ) TE01020028 Institutional support: RVO:61388963 ; RVO:67985823 Keywords : NMDA receptors * neurosteroids Subject RIV: CC - Organic Chemistry

  15. MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA-Dependent Mechanism

    Bernard, Laura P.; Zhang, Huaye

    2015-01-01

    The Par1 kinases, also known as microtubule affinity-regulating kinases (MARKs), are important for the establishment of cell polarity from worms to mammals. Dysregulation of these kinases has been implicated in autism, Alzheimer’s disease and cancer. Despite their important function in health and disease, it has been unclear how the activity of MARK/Par1 is regulated by signals from cell surface receptors. Here we show that MARK/Par1 is activated downstream of NMDA receptors in primary hippoc...

  16. Structure-activity relationships of N-substituted 4-(trifluoromethoxy)benzamidines with affinity for GluN2B-containing NMDA receptors.

    Beinat, Corinne; Banister, Samuel D; Hoban, Jane; Tsanaktsidis, John; Metaxas, Athanasios; Windhorst, Albert D; Kassiou, Michael

    2014-02-01

    GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptomatic treatment of multiple CNS pathologies. A series of N-benzyl substituted benzamidines were synthesised and the benzyl ring was further replaced with various polycyclic moieties. Compounds were evaluated for activity at GluN2B containing NMDA receptors where analogues 9, 12, 16 and 18 were the most potent of the series, replacement of the benzyl ring with polycycles resulted in a complete loss of activity. PMID:24412068

  17. MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA-Dependent Mechanism.

    Laura P Bernard

    Full Text Available The Par1 kinases, also known as microtubule affinity-regulating kinases (MARKs, are important for the establishment of cell polarity from worms to mammals. Dysregulation of these kinases has been implicated in autism, Alzheimer's disease and cancer. Despite their important function in health and disease, it has been unclear how the activity of MARK/Par1 is regulated by signals from cell surface receptors. Here we show that MARK/Par1 is activated downstream of NMDA receptors in primary hippocampal neurons. Further, we show that this activation is dependent on protein kinase A (PKA, through the phosphorylation of Ser431 of Par4/LKB1, the major upstream kinase of MARK/Par1. Together, our data reveal a novel mechanism by which MARK/Par1 is activated at the neuronal synapse.

  18. Preferential Inhibition of Tonically over Phasically Activated NMDA Receptors by Pregnane Derivatives

    Vyklický, Vojtěch; Smejkalová, Tereza; Krausová, Barbora; Balík, Aleš; Kořínek, Miloslav; Borovská, Jiřina; Horák, Martin; Chvojková, Markéta; Kletečková, Lenka; Valeš, Karel; Černý, Jiří; Nekardová, Michaela; Chodounská, Hana; Kudová, Eva; Vyklický ml., Ladislav

    2016-01-01

    Roč. 36, č. 7 (2016), s. 2161-2175. ISSN 0270-6474 R&D Projects: GA ČR(CZ) GAP303/12/1464; GA ČR(CZ) GBP304/12/G069; GA TA ČR(CZ) TE01020028; GA ČR(CZ) GBP208/12/G016; GA MŠk(CZ) EE2.3.30.0025; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 ; RVO:61388963 Keywords : memantine * neuroprotection * neurosteroid * NMDA receptor * pregnanolone sulfate * synaptic transmission Subject RIV: ED - Physiology Impact factor: 6.344, year: 2014

  19. Augmented reality to enhance an active telepresence system

    Wheeler, Alison; Pretlove, John R. G.; Parker, Graham A.

    1996-12-01

    Tasks carried out remotely via a telerobotic system are typically complex, occur in hazardous environments and require fine control of the robot's movements. Telepresence systems provide the teleoperator with a feeling of being physically present at the remote site. Stereoscopic video has been successfully applied to telepresence vision systems to increase the operator's perception of depth in the remote scene and this sense of presence can be further enhanced using computer generated stereo graphics to augment the visual information presented to the operator. The Mechatronic Systems and Robotics Research Group have over seven years developed a number of high performance active stereo vision systems culminating in the latest, a four degree-of-freedom stereohead. This carries two miniature color cameras and is controlled in real time by the motion of the operator's head, who views the stereoscopic video images on an immersive head mounted display or stereo monitor. The stereohead is mounted on a mobile robot, the movement of which is controlled by a joystick interface. This paper describes the active telepresence system and the development of a prototype augmented reality (AR) application to enhance the operator's sense of presence at the remote site. The initial enhancements are a virtual map and compass to aid navigation in degraded visual conditions and a virtual cursor that provides a means for the operator to interact with the remote environment. The results of preliminary experiments using the initial enhancements are presented.

  20. Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus

    Harvey, Brian H; Oosthuizen, Frasia; Brand, Linda;

    2004-01-01

    RATIONALE: Stress-related glucocorticoid and glutamate release have been implicated in hippocampal atrophy evident in patients with post-traumatic stress disorder (PTSD). Glutamatergic mechanisms activate nitric oxide synthase (NOS), while gamma-amino-butyric acid (GABA) may inhibit both...... glutamatergic and nitrergic transmission. Animal studies support a role for NOS in stress. OBJECTIVES: We have studied the role of NOS and glucocorticoids, as well as inhibitory and excitatory transmitters, in a putative animal model of PTSD that emphasizes repeated trauma. METHODS: Hippocampal NOS activity, N......-methyl-D-aspartate (NMDA) receptor binding characteristics and GABA levels were studied in Sprague-Dawley rats 21 days after exposure to a stress-restress paradigm, using radiometric analysis, radioligand studies and high-performance liquid chromatography (HPLC) analysis with electrochemical detection, respectively...

  1. Abdomen and spinal cord segmentation with augmented active shape models.

    Xu, Zhoubing; Conrad, Benjamin N; Baucom, Rebeccah B; Smith, Seth A; Poulose, Benjamin K; Landman, Bennett A

    2016-07-01

    Active shape models (ASMs) have been widely used for extracting human anatomies in medical images given their capability for shape regularization of topology preservation. However, sensitivity to model initialization and local correspondence search often undermines their performances, especially around highly variable contexts in computed-tomography (CT) and magnetic resonance (MR) images. In this study, we propose an augmented ASM (AASM) by integrating the multiatlas label fusion (MALF) and level set (LS) techniques into the traditional ASM framework. Using AASM, landmark updates are optimized globally via a region-based LS evolution applied on the probability map generated from MALF. This augmentation effectively extends the searching range of correspondent landmarks while reducing sensitivity to the image contexts and improves the segmentation robustness. We propose the AASM framework as a two-dimensional segmentation technique targeting structures with one axis of regularity. We apply AASM approach to abdomen CT and spinal cord (SC) MR segmentation challenges. On 20 CT scans, the AASM segmentation of the whole abdominal wall enables the subcutaneous/visceral fat measurement, with high correlation to the measurement derived from manual segmentation. On 28 3T MR scans, AASM yields better performances than other state-of-the-art approaches in segmenting white/gray matter in SC. PMID:27610400

  2. Activation of NMDA receptors leads to phosphorylation of TRPV1 S800 by protein kinase C and A-Kinase anchoring protein 150 in rat trigeminal ganglia

    Lee, Jongseok; Chung, Man-Kyo; Ro, Jin Y.

    2012-01-01

    A-Kinase anchoring protein 150 (AKAP150) is required for the phosphorylation of transient receptor potential cation channel subfamily V member 1 (TRPV1) by PKA or PKC in sensory neurons and, hence, affects TRPV1-dependent hyperalgesia under pathological conditions. Recently, we showed that the activation of N-methyl-d-aspartate (NMDA) receptors sensitizes TRPV1 by enhancing serine phosphorylation through PKC in trigeminal nociceptors. In this study, we extended this observation by investigati...

  3. Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons.

    Oswald, Manfred J; Schulz, Jan M; Kelsch, Wolfgang; Oorschot, Dorothy E; Reynolds, John N J

    2015-01-01

    Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg(2+)-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg(2+)-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission. PMID:25914618

  4. Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating.

    Carlson, G C; Lin, R E; Chen, Y; Brookshire, B R; White, R S; Lucki, I; Siegel, S J; Kim, S F

    2016-05-13

    Dexras1 is a novel GTPase that acts at a confluence of signaling mechanisms associated with psychiatric and neurological disease including NMDA receptors, NOS1AP and nNOS. Recent work has shown that Dexras1 mediates iron trafficking and NMDA-dependent neurodegeneration but a role for Dexras1 in normal brain function or psychiatric disease has not been studied. To test for such a role, mice with germline knockout (KO) of Dexras1 were assayed for behavioral abnormalities as well as changes in NMDA receptor subunit protein expression. Because Dexras1 is up-regulated during stress or by dexamethasone treatment, we included measures associated with emotion including anxiety and depression. Baseline anxiety-like measures (open field and zero maze) were not altered, nor were depression-like behavior (tail suspension). Measures of memory function yielded mixed results, with no changes in episodic memory (novel object recognition) but a significant decrement on working memory (T-maze). Alternatively, there was an increase in pre-pulse inhibition (PPI), without concomitant changes in either startle amplitude or locomotor activity. PPI data are consistent with the direction of change seen following exposure to dopamine D2 antagonists. An examination of NMDA subunit expression levels revealed an increased expression of the NR2A subunit, contrary to previous studies demonstrating down-regulation of the receptor following antipsychotic exposure (Schmitt et al., 2003) and up-regulation after exposure to isolation rearing (Turnock-Jones et al., 2009). These findings suggest a potential role for Dexras1 in modulating a selective subset of psychiatric symptoms, possibly via its interaction with NMDARs and/or other disease-related binding-partners. Furthermore, data suggest that modulating Dexras1 activity has contrasting effects on emotional, sensory and cognitive domains. PMID:26946266

  5. Differences in rat dorsal striatal NMDA and AMPA receptors following acute and repeated cocaine-induced locomotor activation.

    Dorothy J Yamamoto

    Full Text Available Sprague-Dawley rats can be classified as low or high cocaine responders (LCRs or HCRs, respectively based on their locomotor activity induced by an acute low dose of cocaine. Upon repeated cocaine exposure, LCRs display greater locomotor sensitization, reward, and reinforcement than HCRs. Altered glutamate receptor expression in the brain reward pathway has been linked to locomotor sensitization and addiction. To determine if such changes contribute to the differential development of locomotor sensitization, we examined protein levels of total, phosphorylated, and cell surface glutamate N-methyl D-aspartate (NMDA and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA receptors (Rs following acute or repeated cocaine (10 mg/kg, i.p. in LCRs, HCRs and saline controls. Three areas involved in the development and expression of locomotor sensitization were investigated: the ventral tegmental area (VTA, nucleus accumbens (NAc and dorsal striatum (dSTR. Our results revealed differences only in the dSTR, where we found that after acute cocaine, GluN2B(Tyr-1472 phosphorylation was significantly greater in LCRs, compared to HCRs and controls. Additionally in dSTR, after repeated cocaine, we observed significant increases in total GluA1, phosphorylated GluA1(Ser-845, and cell surface GluA1 in all cocaine-treated animals vs. controls. The acute cocaine-induced increases in NMDARs in dSTR of LCRs may help to explain the more ready development of locomotor sensitization and susceptibility to addiction-like behaviors in rats that initially exhibit little or no cocaine-induced activation, whereas the AMPAR increases after repeated cocaine may relate to recruitment of more dorsal striatal circuits and maintenance of the marked cocaine-induced locomotor activation observed in all of the rats.

  6. NMDA receptors in hyperammonemia and hepatic encephalopathy.

    Llansola, Marta; Rodrigo, Regina; Monfort, Pilar; Montoliu, Carmina; Kosenko, Elena; Cauli, Omar; Piedrafita, Blanca; El Mlili, Nisrin; Felipo, Vicente

    2007-12-01

    The NMDA type of glutamate receptors modulates learning and memory. Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia and liver failure alter the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors. The function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic liver failure or hyperammonemia and in homogenates from brains of patients died in hepatic encephalopathy. The impairment of this pathway leads to reduced cGMP and contributes to impaired cognitive function in hepatic encephalopathy. Learning ability is reduced in animal models of chronic liver failure and hyperammonemia and is restored by pharmacological manipulation of brain cGMP by administering phosphodiesterase inhibitors (zaprinast or sildenafil) or cGMP itself. NMDA receptors are therefore involved both in death induced by acute ammonia toxicity (and likely by acute liver failure) and in cognitive impairment in hepatic encephalopathy. PMID:17701332

  7. Essential role of presynaptic NMDA receptors in activity-dependent BDNF secretion and corticostriatal LTP.

    Park, Hyungju; Popescu, Andrei; Poo, Mu-ming

    2014-12-01

    Activation of N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) in postsynaptic dendrites is required for long-term potentiation (LTP) of many excitatory synapses, but the role of presynaptic axonal NMDARs in synaptic plasticity remains to be clarified. Here we report that axonal NMDARs play an essential role in LTP induction at mouse corticostriatal synapses by triggering activity-induced presynaptic secretion of brain-derived neurotrophic factor (BDNF). Genetic depletion of either BDNF or the NMDAR subunit GluN1 specifically in cortical axons abolished corticostriatal LTP in response to theta burst stimulation (TBS). Furthermore, functional axonal NMDARs were required for TBS-triggered prolonged axonal Ca(2+) elevation and BDNF secretion, supporting the notion that activation of axonal NMDARs induces BDNF secretion via enhancing Ca(2+) signals in the presynaptic nerve terminals. These results demonstrate that presynaptic NMDARs are equally important as postsynaptic NMDARs in LTP induction of corticostriatal synapses due to their role in mediating activity-induced presynaptic BDNF secretion. PMID:25467984

  8. Novel anionic steroid inhibitors of phasically and tonically activated NMDA receptors

    Kudová, Eva; Chodounská, Hana; Slavíková, Barbora; Vyklický, Vojtěch; Borovská, Jiřina; Krausová, Barbora; Vyklický ml., Ladislav

    2012-01-01

    Roč. 106, - (2012), s778-s778. ISSN 0009-2770. [EuCheMS Chemistry Congress /4./. 26.08.2012-30.08.2012, Prague] Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50110509 Keywords : steroids * receptors * lipophilicity * structure-activity relationships Subject RIV: CC - Organic Chemistry

  9. Antidepressant activity of fluoxetine in the zinc deficiency model in rats involves the NMDA receptor complex.

    Doboszewska, Urszula; Szewczyk, Bernadeta; Sowa-Kućma, Magdalena; Młyniec, Katarzyna; Rafało, Anna; Ostachowicz, Beata; Lankosz, Marek; Nowak, Gabriel

    2015-01-01

    The zinc deficiency animal model of depression has been proposed; however, it has not been validated in a detailed manner. We have recently shown that depression-like behavior induced by dietary zinc restriction is associated with up-regulation of hippocampal N-methyl-d-aspartate receptor (NMDAR). Here we examined the effects of chronic administration of a selective serotonin reuptake inhibitor, fluoxetine (FLX), on behavioral and biochemical alterations (within NMDAR signaling pathway) induced by zinc deficiency. Male Sprague Dawley rats were fed a zinc adequate diet (ZnA, 50mg Zn/kg) or a zinc deficient diet (ZnD, 3mg Zn/kg) for 4 weeks. Then, FLX treatment (10mg/kg, i.p.) begun. Following 2 weeks of FLX administration the behavior of the rats was examined in the forced swim test (FST) and the spontaneous locomotor activity test. Twenty four hours later tissue was harvested. The proteins of NMDAR (GluN1, GluN2A and GluN2B) or AMPAR (GluA1) subunits, p-CREB and BDNF in the hippocampus (Western blot) and serum zinc level (TXRF) were examined. Depression-like behavior induced by ZnD in the FST was sensitive to chronic treatment with FLX. ZnD increased levels of GluN1, GluN2A, GluN2B and decreased pS485-GluA1, p-CREB and BDNF proteins. Administration of FLX counteracted the zinc restriction-induced changes in serum zinc level and hippocampal GluN1, GluN2A, GluN2B and p-CREB but not BDNF or pS845-GluA1 protein levels. This finding adds new evidence to the predictive validity of the proposed zinc deficiency model of depression. Antidepressant-like activity of FLX in the zinc deficiency model is associated with NMDAR complex. PMID:25845739

  10. Nitric oxide-induced activation of NF-κB-mediated NMDA-induced CTP:phosphocholine cytidylyltransferase alpha expression inhibition in A549 cells.

    Li, Lian; Shen, Li; She, Hua; Yue, Shaojie; Feng, Dandan; Luo, Ziqiang

    2011-02-01

    Pulmonary surfactant is a lipoprotein complex on the alveolar surface. It reduces the surface tension at the air-water interface and stabilizes the alveoli during expiration. Surfactant deficiency or dysfunction is associated with occurrence and development of many pulmonary diseases. Family members of CTP:phosphocholine cytidylyltransferase are rate-limiting enzymes for surfactant phospholipid synthesis. We had reported recently that the expression of CTP:phosphocholine cytidylyltransferase alpha (CCT-α) was inhibited during N-methyl-D: -aspartic acid (NMDA)-induced lung injury. But the molecular mechanism underlining remains elusive. In this work, we reported that NMDA induced nitric oxide synthase (NOS) activation and nuclear factor-kB (NF-κB) subunit p65 nuclear translocation in A549 cells, which were responsible for decreased (CCT-α) expression. Furthermore, NOS activation and elevated NO production are upstream regulators for p65 nuclear translocation and (CCT-α) expression inhibition. Our results provided important clues for further elucidating the mechanisms underlying glutamate-induced lung injury. PMID:20661636

  11. Acquisition of specific response-outcome associations requires NMDA receptor activation in the basolateral amygdala but not in the insular cortex.

    Parkes, Shauna L; Ferreira, Guillaume; Coutureau, Etienne

    2016-02-01

    The basolateral amygdala (BLA) and the gustatory region of the insular cortex (IC) are required for the encoding and retrieval of outcome value. Here, we examined if these regions are also necessary to learn associations between actions and their outcomes. Hungry rats were first trained to press two levers for a common outcome. Next, specific response-outcome (R-O) associations were introduced such that each response now earned a distinct food outcome. Prior to each specific R-O training session, rats received a bilateral infusion of the N-methyl-d-aspartate (NMDA) receptor antagonist, DL-APV, into either the BLA or the IC. One of the two outcomes was then devalued immediately prior to a choice test. Inhibition of NMDA receptor activity in the BLA, but not the IC, during the acquisition of specific R-O associations abolished selective devaluation. These results indicate that the BLA is critical for learning the association between actions and their specific consequences. PMID:26740161

  12. Frontopolar activity and connectivity support dynamic conscious augmentation of creative state.

    Green, Adam E; Cohen, Michael S; Raab, Hillary A; Yedibalian, Christopher G; Gray, Jeremy R

    2015-03-01

    No ability is more valued in the modern innovation-fueled economy than thinking creatively on demand, and the "thinking cap" capacity to augment state creativity (i.e., to try and succeed at thinking more creatively) is of broad importance for education and a rich mental life. Although brain-based creativity research has focused on static individual differences in trait creativity, less is known about changes in creative state within an individual. How does the brain augment state creativity when creative thinking is required? Can augmented creative state be consciously engaged and disengaged dynamically across time? Using a novel "thin slice" creativity paradigm in 55 fMRI participants performing verb-generation, we successfully cued large, conscious, short-duration increases in state creativity, indexed quantitatively by a measure of semantic distance derived via latent semantic analysis. A region of left frontopolar cortex, previously associated with creative integration of semantic information, exhibited increased activity and functional connectivity to anterior cingulate gyrus and right frontopolar cortex during cued augmentation of state creativity. Individual differences in the extent of increased activity in this region predicted individual differences in the extent to which participants were able to successfully augment state creative performance after accounting for trait creativity and intelligence. PMID:25394198

  13. NMDA receptors mediate synaptic competition in culture.

    Kevin She

    Full Text Available BACKGROUND: Activity through NMDA type glutamate receptors sculpts connectivity in the developing nervous system. This topic is typically studied in the visual system in vivo, where activity of inputs can be differentially regulated, but in which individual synapses are difficult to visualize and mechanisms governing synaptic competition can be difficult to ascertain. Here, we develop a model of NMDA-receptor dependent synaptic competition in dissociated cultured hippocampal neurons. METHODOLOGY/PRINCIPAL FINDINGS: GluN1 -/- (KO mouse hippocampal neurons lacking the essential NMDA receptor subunit were cultured alone or cultured in defined ratios with wild type (WT neurons. The absence of functional NMDA receptors did not alter neuron survival. Synapse development was assessed by immunofluorescence for postsynaptic PSD-95 family scaffold and apposed presynaptic vesicular glutamate transporter VGlut1. Synapse density was specifically enhanced onto minority wild type neurons co-cultured with a majority of GluN1 -/- neighbour neurons, both relative to the GluN1 -/- neighbours and relative to sister pure wild type cultures. This form of synaptic competition was dependent on NMDA receptor activity and not conferred by the mere physical presence of GluN1. In contrast to these results in 10% WT and 90% KO co-cultures, synapse density did not differ by genotype in 50% WT and 50% KO co-cultures or in 90% WT and 10% KO co-cultures. CONCLUSIONS/SIGNIFICANCE: The enhanced synaptic density onto NMDA receptor-competent neurons in minority coculture with GluN1 -/- neurons represents a cell culture paradigm for studying synaptic competition. Mechanisms involved may include a retrograde 'reward' signal generated by WT neurons, although in this paradigm there was no 'punishment' signal against GluN1 -/- neurons. Cell culture assays involving such defined circuits may help uncover the rules and mechanisms of activity-dependent synaptic competition in the

  14. Optimal placement of active elements in control augmented structural synthesis

    Sepulveda, A. E.; Jin, I. M.; Schmit, L. A., Jr.

    1992-01-01

    A methodology for structural/control synthesis is presented in which the optimal location of active members is treated in terms of (0,1) variables. Structural member sizes, control gains and (0,1) placement variables are treated simultaneously as design variables. Optimization is carried out by generating and solving a sequence of explicit approximate problems using a branch and bound strategy. Intermediate design variable and intermediate response quantity concepts are used to enhance the quality of the approximate design problems. Numerical results for example problems are presented to illustrate the efficacy of the design procedure set forth.

  15. Osmotic Edema Rapidly Increases Neuronal Excitability Through Activation of NMDA Receptor-Dependent Slow Inward Currents in Juvenile and Adult Hippocampus.

    Lauderdale, Kelli; Murphy, Thomas; Tung, Tina; Davila, David; Binder, Devin K; Fiacco, Todd A

    2015-01-01

    Cellular edema (cell swelling) is a principal component of numerous brain disorders including ischemia, cortical spreading depression, hyponatremia, and epilepsy. Cellular edema increases seizure-like activity in vitro and in vivo, largely through nonsynaptic mechanisms attributable to reduction of the extracellular space. However, the types of excitability changes occurring in individual neurons during the acute phase of cell volume increase remain unclear. Using whole-cell patch clamp techniques, we report that one of the first effects of osmotic edema on excitability of CA1 pyramidal cells is the generation of slow inward currents (SICs), which initiate after approximately 1 min. Frequency of SICs increased as osmolarity decreased in a dose-dependent manner. Imaging of real-time volume changes in astrocytes revealed that neuronal SICs occurred while astrocytes were still in the process of swelling. SICs evoked by cell swelling were mainly nonsynaptic in origin and NMDA receptor-dependent. To better understand the relationship between SICs and changes in neuronal excitability, recordings were performed in increasingly physiological conditions. In the absence of any added pharmacological reagents or imposed voltage clamp, osmotic edema induced excitatory postsynaptic potentials and burst firing over the same timecourse as SICs. Like SICs, action potentials were blocked by NMDAR antagonists. Effects were more pronounced in adult (8-20 weeks old) compared with juvenile (P15-P21) mice. Together, our results indicate that cell swelling triggered by reduced osmolarity rapidly increases neuronal excitability through activation of NMDA receptors. Our findings have important implications for understanding nonsynaptic mechanisms of epilepsy in relation to cell swelling and reduction of the extracellular space. PMID:26489684

  16. Augmented active surface model for the recovery of small structures in CT.

    Bradshaw, Andrew Philip; Taubman, David S; Todd, Michael J; Magnussen, John S; Halmagyi, G Michael

    2013-11-01

    This paper devises an augmented active surface model for the recovery of small structures in a low resolution and high noise setting, where the role of regularization is especially important. The emphasis here is on evaluating performance using real clinical computed tomography (CT) data with comparisons made to an objective ground truth acquired using micro-CT. In this paper, we show that the application of conventional active contour methods to small objects leads to non-optimal results because of the inherent properties of the energy terms and their interactions with one another. We show that the blind use of a gradient magnitude based energy performs poorly at these object scales and that the point spread function (PSF) is a critical factor that needs to be accounted for. We propose a new model that augments the external energy with prior knowledge by incorporating the PSF and the assumption of reasonably constant underlying CT numbers. PMID:24048014

  17. Imaging the PCP site of the NMDA ion channel

    Waterhouse, Rikki N. E-mail: rnw7@columbia.edu

    2003-11-01

    The N-methyl-D-aspartate (NMDA) ion channel plays a role in neuroprotection, neurodegeneration, long-term potentiation, memory, and cognition. It is implicated in the pathophysiology of several neurological and neuropsychiatric disorders including Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. The development of effective radiotracers for the study of NMDA receptors is critical for our understanding of their function, and their modulation by endogenousr substances or therapeutic drugs. Since the NMDA/PCP receptor lies within the channel, it is a unique target and is theoretically accessible only when the channel is in the active and 'open' state, but not when it is in the inactive or 'closed' state. The physical location of the NMDA/PCP receptor not only makes it an important imaging target but also complicates the development of suitable PET and SPECT radiotracers for this site. An intimate understanding of the biochemical, pharmacological, physiological and behavioral processes associated with the NMDA ion channel is essential to develop improved imaging agents. This review outlines progress made towards the development of radiolabeled agents for PCP sites of the NMDA ion channel. In addition, the animal and pharmacological models used for in vitro and in vivo assessment of NMDA receptor targeted agents are discussed.

  18. Imaging the PCP site of the NMDA ion channel

    The N-methyl-D-aspartate (NMDA) ion channel plays a role in neuroprotection, neurodegeneration, long-term potentiation, memory, and cognition. It is implicated in the pathophysiology of several neurological and neuropsychiatric disorders including Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. The development of effective radiotracers for the study of NMDA receptors is critical for our understanding of their function, and their modulation by endogenousr substances or therapeutic drugs. Since the NMDA/PCP receptor lies within the channel, it is a unique target and is theoretically accessible only when the channel is in the active and 'open' state, but not when it is in the inactive or 'closed' state. The physical location of the NMDA/PCP receptor not only makes it an important imaging target but also complicates the development of suitable PET and SPECT radiotracers for this site. An intimate understanding of the biochemical, pharmacological, physiological and behavioral processes associated with the NMDA ion channel is essential to develop improved imaging agents. This review outlines progress made towards the development of radiolabeled agents for PCP sites of the NMDA ion channel. In addition, the animal and pharmacological models used for in vitro and in vivo assessment of NMDA receptor targeted agents are discussed

  19. Proteolytically modified human beta 2-microglobulin augments the specific cytotoxic activity in murine mixed lymphocyte culture

    Nissen, Mogens Holst; Claësson, M H

    1987-01-01

    (M-beta 2-m) bind to murine lymphocytes expressing H-2 class I antigens; M-beta 2-m, when added at day 0 and 1 of culture in nanomolar concentrations to a one-way murine allogeneic mixed lymphocyte culture (MLC) augments the generation of specific cytotoxic T lymphocytes; M-beta 2-m increases the...... endogenous production of interleukin 2 in the MLC culture; monoclonal antibody which reacts with both the native beta 2-m and M-beta 2-m molecule blocks the augmentation of cytotoxic T lymphocyte production induced by M-beta 2-m; murine as well as human MLC responder cells can proteolytically modify native...... human beta 2-m; and the modifying activity of murine MLC responder cells was blocked in an intermediary step by an alloantibody, which reacts specifically with murine major histocompatibility complex, class I-associated beta 2-m. These findings suggest that the modification process is preceded by an...

  20. Concept of an immersive assistance system with augmented reality for the support of manual activities in radioactive production environments

    The thesis on an immersive assistance system concept with augmented reality for the support of manual activities in radioactive production environments covers the following topics: analysis of the situation: production and use of radioactive materials, problem analysis of the work in the production facilities, necessity of manual activities, automation, prediction in hot cells; status of research and development; assistance system concept, immersive camera system; augmented reality support in hot cells; economic evaluation and generalization.

  1. 洛伐他汀通过抑制Calpain和CDK5的过度激活减轻NMDA的毒性损害%Lovastatin attenuates Calpain and CDK5 over-activation induced by NMDA

    马涛; 许著一; 姚晴宇; 孔岳南

    2012-01-01

    Objective To observe the effect of lovastatin on the excitotoxicity induced by NMDA in cortical neurons in rats and to investigate the underlying mechanism. Methods Cortical neurons prepared from E17 rats were assigned into 4 groups:NMDA group (addition of 100 μmol/L of NMDA for 15 minutes),LOV group (pretreatment of the neurons for 3 days with 500 nmol/L of LOV),LOV+NMDA group (pretreatment of the neurons for 3 days with 500 nmol/L of LOV and addition of 100 μmol/L of NMDA for 15 minutes) and untreated group (addition of isodose solvent).Cell viability was evaluated with the trypan blue dye exclusion test,the morphology and number of neurons were assessed with MAP-2 immunofluorescence staining,and the level of protein was measured with Western blotting assay. Results Trypan blue staining demonstrated that the pretreatment with 500 nmol/L of lovastatin for 3 days significantly protected the neurons against the excitotoxicity induced by NMDA (P<0.05 vs NMDA).Immunofluorescence staining demonstrated the number of MAP-2 positive neurons decreased and the surviving neurons showed a loss of MAP-2 positive dendrites after NMDA treatment (P<0.05 vs untreated),which were not observed after lovastatin pretreatment (P<0.05 vs NMDA).Excitotoxicity was mediated in part by the Calpain over-activation and the subsequent protein truncation events on Calpain substrate, CDK5 co-activator P35 to P25 cleavage. Lovastatin pretreatment remarkably suppressed Calpain over-activation and the conversion from P35 to P25 in response to NMDA exposure as detected by Western blotting analysis (P<0.05 vs NMDA). Conclusions Lovastatin significantly attenuates the excitotoxicity induced by NMDA. The neuroprotection of lovastatin may be mediated by blocking the Calpain and CDK5 over-activation.%目的 探讨洛伐他汀(LOV)对N-甲基-D-天门冬氨酸(NMDA)诱导的大鼠皮质神经元兴奋性毒性损害的神经保护作用及可能机制. 方法 原代培养的大鼠皮质神经

  2. Characterisation of the Redox Sensitive NMDA Receptor

    Alzahrani, Ohood

    2016-05-01

    Glucose entry into the brain and its subsequent metabolism to L-lactate, regulated by astrocytes, plays a major role in synaptic plasticity and memory formation. A recent study has shown that L-lactate produced by the brain upon stimulation of glycolysis, and glycogen-derived L-lactate from astrocytes and its transport into neurons, is crucial for memory formation. A recent study revealed the molecular mechanisms that underlie the role of L-lactate in neuronal plasticity and long-term memory formation. L-lactate was shown to induce a cascade of molecular events via modulation of redox-sensitive N-Methyl-D-aspartate (NMDA) receptor activity that was mimicked by nicotinamide adenine dinucleotide hydride (NADH) co-enzyme. This indicated that changes in cellular redox state, following L-lactate transport inside the cells and its subsequent metabolism, production of NADH, and favouring a reduced state are the key effects of L-lactate. Therefore, we are investigating the role of L-lactate in modulating NMDA receptor function via redox modulatory sites. Accordingly, crucial redox-sensitive cysteine residues, Cys320 and Cys87, of the NR2A NMDA receptor subunit are mutated using site-directed mutation, transfected, and expressed in HEK293 cells. This cellular system will then be used to characterise and monitor its activity upon Llactate stimulation, compared to the wild type. This will be achieved by calcium imaging, using fluorescent microscopy. Our data shows that L-lactate potentiated NMDA receptor activity and increased intracellular calcium influx in NR1/NR2A wild type compared to the control condition (WT NR1/NR2A perfused with (1μM) glutamate and (1μM) glycine agonist only), showing faster response initiation and slower decay rate of the calcium signal to the baseline. Additionally, stimulating with L-lactate associated with greater numbers of cells having high fluorescent intensity (peak amplitude) compared to the control. Furthermore, L-lactate rescued the

  3. Augmentation and Maximization of Per-Capita Call Active Space Through Chorusing in Anuran Amphibians

    Fox, James Henderson

    It is poorly understood why anuran males form choruses. Although various reasons have been proposed, empirical support is lacking. This study proposed, developed, and evaluated the chorus active space (CAS) augmentation theory, which states that anuran choruses are formed and organized so as to augment and maximize per-capita CAS beyond that which could be achieved by an isolated male. This study involved three phases. First, computer models of hypothetical choruses indicated that CAS, as defined, is necessarily augmented for chorusing males. These models provided the necessary information from which optimal interindividual distances (IIDs), corresponding to maximal CASs, could be estimated differentially for linear and planar chorus configurations. The second phase examined Acris crepitans and Hyla cinerea choruses for optimal intermale spacing. A. crepitans, which utilizes mixed chorus geometries (either linear or planar, depending on available resources), cannot optimize IID within any observed pond-type breeding site; however, observed spacing would be optimal along a stream bank, where chorusing often occurs, for a chorus population of 61, approximately the minimum value at which CAS characteristics are stabile. H. cinerea males, which form only planar choruses, space orders of magnitude closer than optimal. Suboptimal spacing in this species is understandable, considering the would-be size of an optimally spaced chorus. In the final phase of this study, a database of CAS-related data was compiled mostly from published sources and was examined for variable relationships predicted on the basis of CAS augmentation theory. The findings suggest that very few planar geometry species may maximize CAS; whereas, a much larger number of mixed geometry species, perhaps as well as linear geometry species, may maximize CAS. These findings loosely agree with the field study findings and suggest that CAS augmentation theory applies to at least a subset of anuran species and

  4. Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons.

    Khodr, Christina E; Chen, Lihua; Dave, Sonya; Al-Harthi, Lena; Hu, Xiu-Ti

    2016-10-01

    Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca(2+) channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca(2+) potentials (Ca(2+) influx) in mPFC pyramidal neurons. Neurons from HIV-1 Tg rats displayed reduced rheobase, spike amplitude and inwardly-rectifying K(+) influx, increased numbers of action potentials, and a trend of aberrant firing compared to those from non-Tg control rats. Neuronal hyper-excitation was associated with abnormally-enhanced Ca(2+) influx (independent of NMDAR), which was eliminated by acute L-channel blockade. Combined chronic blockade of over-active L-channels and NMDARs with open-channel blockers abolished HIV effects on spiking, aberrant firing and Ca(2+) potential half-amplitude duration, though not the reduced inward rectification. In contrast, individual chronic blockade of over-active L-channels or NMDARs did not alleviate HIV-induced mPFC hyper-excitability. These studies demonstrate that HIV alters mPFC neuronal activity by dysregulating membrane excitability and Ca(2+) influx through the L-channels. This renders these neurons more susceptible and vulnerable to excitatory stimuli, and could contribute to HIV-associated neuropathogenesis. Combined targeting of over-active L-channels/NMDARs alleviates HIV-induced dysfunction of mPFC pyramidal neurons, emphasizing a potential novel therapeutic strategy that may effectively decrease HIV-induced Ca(2+) dysregulation in the mPFC. PMID:27326669

  5. N-Methyl-D-aspartic Acid (NMDA in the nervous system of the amphioxus Branchiostoma lanceolatum

    Garcia-Fernàndez Jordi

    2007-12-01

    Full Text Available Abstract Background NMDA (N-methyl-D-aspartic acid is a widely known agonist for a class of glutamate receptors, the NMDA type. Synthetic NMDA elicits very strong activity for the induction of hypothalamic factors and hypophyseal hormones in mammals. Moreover, endogenous NMDA has been found in rat, where it has a role in the induction of GnRH (Gonadotropin Releasing Hormone in the hypothalamus, and of LH (Luteinizing Hormone and PRL (Prolactin in the pituitary gland. Results In this study we show evidence for the occurrence of endogenous NMDA in the amphioxus Branchiostoma lanceolatum. A relatively high concentration of NMDA occurs in the nervous system of this species (3.08 ± 0.37 nmol/g tissue in the nerve cord and 10.52 ± 1.41 nmol/g tissue in the cephalic vesicle. As in rat, in amphioxus NMDA is also biosynthesized from D-aspartic acid (D-Asp by a NMDA synthase (also called D-aspartate methyl transferase. Conclusion Given the simplicity of the amphioxus nervous and endocrine systems compared to mammalian, the discovery of NMDA in this protochordate is important to gain insights into the role of endogenous NMDA in the nervous and endocrine systems of metazoans and particularly in the chordate lineage.

  6. How does the Augmented Reality Manual enhance cognitive activity while doing complex maintenance tasks?: Augmented Tutorial Overlaid Manual (ATOM)

    It has been more than a decade since the concept of Augmented Reality (AR) was introduced. Many related technologies, such as tracking and display, to animate this concept have improved to certain levels. AR is well suited for interaction with the cognitive vision system. In contrast to the virtual reality, AR applications enrich the perceived reality with additional visual information which ranges from text annotation and object highlighting to complex 3D objects. AR has been tested its potentiality in various forms of applications. For example, visitors wear Head Mount Display (HMD) to see virtual guides explaining artifacts in a museum or soldiers are informed geographical features about unfamiliar operation sites. Recently, researchers tried to use AR as a means of teaching or training apparatus; however, there are still some technical obstacles to put this fascinating technology into practice. In this study, we will use Cognitive Load Theory (CLT) to design a manual of pump maintenance and convert it to AR technology to propose a proto type of an on-line AR maintenance manual to prove its possibility as an interactive learning tool

  7. How does the Augmented Reality Manual enhance cognitive activity while doing complex maintenance tasks?: Augmented Tutorial Overlaid Manual (ATOM)

    Yim, Ho Bin; Seong, Poong Hyun [Korea Advanced Institute of Technology and Science, Daejeon (Korea, Republic of)

    2008-10-15

    It has been more than a decade since the concept of Augmented Reality (AR) was introduced. Many related technologies, such as tracking and display, to animate this concept have improved to certain levels. AR is well suited for interaction with the cognitive vision system. In contrast to the virtual reality, AR applications enrich the perceived reality with additional visual information which ranges from text annotation and object highlighting to complex 3D objects. AR has been tested its potentiality in various forms of applications. For example, visitors wear Head Mount Display (HMD) to see virtual guides explaining artifacts in a museum or soldiers are informed geographical features about unfamiliar operation sites. Recently, researchers tried to use AR as a means of teaching or training apparatus; however, there are still some technical obstacles to put this fascinating technology into practice. In this study, we will use Cognitive Load Theory (CLT) to design a manual of pump maintenance and convert it to AR technology to propose a proto type of an on-line AR maintenance manual to prove its possibility as an interactive learning tool.

  8. Requirement of JIP scaffold proteins for NMDA-mediated signal transduction

    Kennedy, Norman J.; Martin, Gilles; Ehrhardt, Anka G.; Cavanagh-Kyros, Julie; Kuan, Chia-Yi; Rakic, Pasko; Richard A Flavell; Treistman, Steven N.; Davis, Roger J

    2007-01-01

    JIP scaffold proteins are implicated in the regulation of protein kinase signal transduction pathways. To test the physiological role of these scaffold proteins, we examined the phenotype of compound mutant mice that lack expression of JIP proteins. These mice were found to exhibit severe defects in N-methyl-D-aspartic acid (NMDA) receptor function, including decreased NMDA-evoked current amplitude, cytoplasmic Ca++, and gene expression. The decreased NMDA receptor activity in JIP-deficient n...

  9. Open Augmented Reality Standards: Current Activities in Standards- Development Organizations%Open Augmented Reality Standards: Current Activities in Standards- Development Organizations

    Christine Perey

    2012-01-01

    Augmented reality (AR) has emerged from research laboratories and is now being accepted in other domains as an attractive way of visualizing information. Before AR can be used in the mass market, there are a number of obstacles that need to be overcome. Several of these can be overcome by adopting open standards. A global grassroots community seeking open, interoperable AR content and experiences began to take shape in early 2010. This community is working collaboratively to reduce the barriers to the flow of data from content provider to AR end user. Standards development organizations and industry groups that provide open interfaces for AR meet regularly to provide updates, identify complementary work, and seek harmonization. The community also identifies deployer and implementer needs, communicates requirements, and discusses emerging challenges that could be resolved with standards. In this article, we describe current activities in international standards-development organizations. We summarize the AR standards gap analysis and shed light on special considerations for using standards in mobile AR.

  10. M-CSF potently augments RANKL-induced resorption activation in mature human osteoclasts.

    Jason M Hodge

    Full Text Available Macrophage-CSF (M-CSF is critical for osteoclast (OC differentiation and is reported to enhance mature OC survival and motility. However, its role in the regulation of bone resorption, the main function of OCs, has not been well characterised. To address this we analysed short-term cultures of fully differentiated OCs derived from human colony forming unit-granulocyte macrophages (CFU-GM. When cultured on dentine, OC survival was enhanced by M-CSF but more effectively by receptor activator of NFκB ligand (RANKL. Resorption was entirely dependent on the presence of RANKL. Co-treatment with M-CSF augmented RANKL-induced resorption in a concentration-dependent manner with a (200-300% stimulation at 25 ng/mL, an effect observed within 4-6 h. M-CSF co-treatment also increased number of resorption pits and F-actin sealing zones, but not the number of OCs or pit size, indicating stimulation of the proportion of OCs activated. M-CSF facilitated RANKL-induced activation of c-fos and extracellular signal-regulated kinase (ERK 1/2 phosphorylation, but not NFκB nor nuclear factor of activated T-cells, cytoplasmic-1 (NFATc1. The mitogen-activated protein kinase kinase (MEK 1 inhibitor PD98059 partially blocked augmentation of resorption by M-CSF. Our results reveal a previously unidentified role of M-CSF as a potent stimulator of mature OC resorbing activity, possibly mediated via ERK upstream of c-fos.

  11. Active Learning based on the use of Augmented Reality Outline of Possible Applications: Serious Games, Scientific Experiments, Confronting Studies with Creation, Training for Carrying out Technical Skills

    Cieutat, Jean-Marc; Hugues, Olivier; Ghouaiel, Nehla

    2012-01-01

    This paper looks at augmented reality as a support for active learning. Fourth areas of application are studied: serious games, scientific experiments, confronting study results with creation and training for carrying out technical skills. After introducing a new proposed augmented reality definition, we illustrate each area with original examples like an augmented reality serious game to understand electromagnetic phenomena and their applications in electrical engineering or still an augment...

  12. Perlecan domain 1 recombinant proteoglycan augments BMP-2 activity and osteogenesis

    DeCarlo Arthur A

    2012-09-01

    Full Text Available Abstract Background Many growth factors, such as bone morphogenetic protein (BMP-2, have been shown to interact with polymers of sulfated disacharrides known as heparan sulfate (HS glycosaminoglycans (GAGs, which are found on matrix and cell-surface proteoglycans throughout the body. HS GAGs, and some more highly sulfated forms of chondroitin sulfate (CS, regulate cell function by serving as co-factors, or co-receptors, in GF interactions with their receptors, and HS or CS GAGs have been shown to be necessary for inducing signaling and GF activity, even in the osteogenic lineage. Unlike recombinant proteins, however, HS and CS GAGs are quite heterogenous due, in large part, to post-translational addition, then removal, of sulfate groups to various positions along the GAG polymer. We have, therefore, investigated whether it would be feasible to deliver a DNA pro-drug to generate a soluble HS/CS proteoglycan in situ that would augment the activity of growth-factors, including BMP-2, in vivo. Results Utilizing a purified recombinant human perlecan domain 1 (rhPln.D1 expressed from HEK 293 cells with HS and CS GAGs, tight binding and dose-enhancement of rhBMP-2 activity was demonstrated in vitro. In vitro, the expressed rhPln.D1 was characterized by modification with sulfated HS and CS GAGs. Dose-enhancement of rhBMP-2 by a pln.D1 expression plasmid delivered together as a lyophilized single-phase on a particulate tricalcium phosphate scaffold for 6 or more weeks generated up to 9 fold more bone volume de novo on the maxillary ridge in a rat model than in control sites without the pln.D1 plasmid. Using a significantly lower BMP-2 dose, this combination provided more than 5 times as much maxillary ridge augmentation and greater density than rhBMP-2 delivered on a collagen sponge (InFuse™. Conclusions A recombinant HS/CS PG interacted strongly and functionally with BMP-2 in binding and cell-based assays, and, in vivo, the pln.247 expression plasmid

  13. Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca(2+)-activated K+ channel to genetic predisposition to anorexia nervosa.

    Koronyo-Hamaoui, Maya; Frisch, Amos; Stein, Daniel; Denziger, Yardena; Leor, Shani; Michaelovsky, Elena; Laufer, Neil; Carel, Cynthia; Fennig, Silvana; Mimouni, Mark; Ram, Anca; Zubery, Eynat; Jeczmien, Pablo; Apter, Alan; Weizman, Abraham; Gak, Eva

    2007-01-01

    Since identification of the genetic component in anorexia nervosa (AN), genes that partake in serotonergic and dopaminergic systems and in hormonal and weight regulation have been suggested as potential candidates for AN susceptibility. We propose another set of candidate genes. Those are genes that are involved in the signaling pathway using NMDA-R and SK channels and have been suggested as possible effectors of NMDA-R driven signaling. The role of NMDA-R in the etiology of schizophrenia has already been substantiated on various levels. Several studies based on population and family groups have implicated SK3 in schizophrenia and more recently in AN as well. Our study group consisted of 90 AN family trios. We examined the transmission of two potentially functional polymorphisms, 5073T>G polymorphism in the gene encoding the NR2B subunit of NMDA-R and CAG repeats in the coding region of SK3 channel gene. Using HHRR and TDT approaches, we found that both polymorphisms were preferentially transmitted to AN offspring (TDT yielded chi(2)=5.01, p=0.025 for NR2B 5073G alleles and chi(2)=11.75, p19 repeats). Distribution analysis of the combined NR2B/SK3 genotypes suggests that the contribution of both polymorphisms to AN risk is independent and cumulative (OR=2.44 for NR2B GG genotype and OR=3.01 for SK3 SL and LL genotypes, and OR=6.8 for the combined NR2B/SK3 genotypes including high-risk alleles). These findings point to the contribution of genes associated with the NMDA-R signaling pathway to predisposition and development of AN. PMID:16157352

  14. Aspirin augments carotid-cardiac baroreflex sensitivity during muscle mechanoreflex and metaboreflex activation in humans.

    Drew, Rachel C; Muller, Matthew D; Blaha, Cheryl A; Mast, Jessica L; Herr, Michael D; Stocker, Sean D; Sinoway, Lawrence I

    2013-10-15

    Muscle mechanoreflex activation decreases the sensitivity of carotid baroreflex (CBR)-heart rate (HR) control during local metabolite accumulation in humans. However, the contribution of thromboxane A2 (TXA2) toward this response is unknown. Therefore, the effect of inhibiting TXA2 production via low-dose aspirin on CBR-HR sensitivity during muscle mechanoreflex and metaboreflex activation in humans was examined. Twelve young subjects performed two trials during two visits, preceded by 7 days' low-dose aspirin (81 mg) or placebo. One trial involved 3-min passive calf stretch (mechanoreflex) during 7.5-min limb circulatory occlusion (CO). In another trial, CO was preceded by 1.5 min of 70% maximal voluntary contraction isometric calf exercise to accumulate metabolites during CO and stretch (mechanoreflex and metaboreflex). HR (ECG) and mean arterial pressure (Finometer) were recorded. CBR function was assessed using rapid neck pressures ranging from +40 to -80 mmHg. Aspirin significantly decreased baseline thromboxane B2 production by 84 ± 4% (P aspirin, stretch with metabolite accumulation significantly augmented maximal gain (GMAX) and operating point gain (GOP) of CBR-HR (GMAX; -0.71 ± 0.14 vs. -0.37 ± 0.08 and GOP; -0.69 ± 0.13 vs. -0.35 ± 0.12 beats·min(-1)·mmHg(-1) for aspirin and placebo, respectively; P aspirin and placebo during stretch with metabolite accumulation. In conclusion, these findings suggest that low-dose aspirin augments CBR-HR sensitivity during concurrent muscle mechanoreflex and metaboreflex activation in humans. This increased sensitivity appears linked to reduced TXA2 production, which likely plays a role in metabolite sensitization of muscle mechanoreceptors. PMID:23970529

  15. In vitro augmentation of natural killer cell activity by manganese chloride

    The in vitro cultivation of murine spleen cells with MnCl2 resulted in the enhancement of natural killer (NK) cell activity as measured in a 4-h 51Cr-release assay. Optimal enhancement of NK activity was observed at concentrations of 10-20 μg MnCl2/culture (72-144 μM Mn2+). Enhancement of NK activity by MnCl2 was not associated with any changes in the number or viability of cells following culture. The addition of antiasialo GM1 antibody and complement to spleen cell cultures completely abrogated the enhancement of NK activity by MnCl2. The enhancement of NK activity by MnCl2 in vitro was accompanied by interferon induction. The addition of rabbit antimouse interferon to spleen cells cultured with MnCl2 reduced NK activity. NK activity in cultures treated with MnCl2 was also reduced upon removal of plastic adherent cells. However, restoration of enhanced NK activity by addition of adherent cells to nonadherent cells in the presence of MnCl2 was not observed. Similar effects of NK activity were observed with polyinosinic-polycytidylic acid (Poly I x C), a known interferon inducer and NK enhancer. The results demonstrate that murine splenic NK activity is enhanced in vitro by MnCl2 and that this enhancement may be mediated by interferon induction. The results also suggest that in vitro enhancement of NK activity by MnCl2, as with Poly I x C, may require participation of an adherent cell population for NK augmentation

  16. β-endorphin augments the cytolytic activity and interferon production of natural killer cells

    The in vitro effects of the neurohormone β-endorphin (b-end) on natural killer (NK) activity and interferon (IFN) production mediated by large granular lymphocytes (LGL) were investigated. LGL-enriched fractions from peripheral blood mononuclear cells (PBMC) from normal human volunteers were obtained by fractionation over discontinuous Percoll gradients. LGL were preincubated with or without various concentrations of b-end or the closely related peptides α-endorphin (a-end), γ-endorphin (g-end), or D-ALA2-β-endorphin (D-ALA2-b-end), a synthetic b-end analogue. NK activity was assayed on 51Cr-labeled K562 target cells. Preincubation of LGL effectors (but not K562 targets) for 2 to 18 hr with concentrations of b-end between 10-7 M and 10-10 M produced significant augmentation of NK cytolytic activity (mean percentage increase: 63%). The classic opiate antagonist naloxone blocked the enhancing effect when used at a 100-fold molar excess relative to b-end. These findings demonstrate that b-end enhances NK activity and IFN production of purified LGL, and suggests that b-end might bind to an opioid receptor on LGL that can be blocked by naloxone. These results lend support to the concepts of regulation of the immune response by neurohormones and the functional relationship between the nervous and immune systems

  17. Nicotine-activated descending facilitation on spinal NMDA-dependent reflex potentiation from pontine tegmentum in rats.

    Pan, Shwu-Fen; Peng, Hsien-Yu; Chen, Chi-Chung; Chen, Mei-Jung; Lee, Shin-Da; Cheng, Chen-Li; Shyu, Jyh-Cherng; Liao, Jiuan-Miaw; Chen, Gin-Den; Lin, Tzer-Bin

    2008-05-01

    This study was conducted to investigate the possible neurotransmitter that activates the descending pathways coming from the dorsolateral pontine tegmentum (DPT) to modulate spinal pelvic-urethra reflex potentiation. External urethra sphincter electromyogram (EUSE) activity in response to test stimulation (TS, 1/30 Hz) and repetitive stimulation (RS, 1 Hz) on the pelvic afferent nerve of 63 anesthetized rats were recorded with or without microinjection of nicotinic cholinergic receptor (nAChR) agonists, ACh and nicotine, to the DPT. TS evoked a baseline reflex activity with a single action potential (1.00 +/- 0.00 spikes/stimulation, n = 40), whereas RS produced a long-lasting reflex potentiation (16.14 +/- 0.96 spikes/stimulation, n = 40) that was abolished by d-2-amino-5-phosphonovaleric acid (1.60 +/- 0.89 spikes/stimulation, n = 40) and was attenuated by 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline (7.10 +/- 0.84 spikes/stimulation, n = 40). ACh and nicotine microinjections to DPT both produced facilitation on the RS-induced reflex potentiation (23.57 +/- 2.23 and 28.29 +/- 2.36 spikes/stimulation, P acid-dependent reflex potentiation via descending serotonergic neurotransmission. This descending modulation may have physiological/pathological relevance in the neural controls of urethral closure. PMID:18287401

  18. An Augmented Reality Approach to Integrate Practical Activities in E-Learning Systems

    EL KABTANE Hamada

    2016-02-01

    Full Text Available In the past, the term E-learning was mentioned to any learning method that used electronic machine for the distribution. With the evolution and the apparition of the internet, the term e learning has been evolved and referred to the online courses. There are a lot of platform which serves to distribute and manage the learning content. In some domain learners need to use some equipment and useful product for purpose completing the image built in the theoretical part by the practical activity part. However, most of those platforms suffer from a lack in tools that offer practical activities for learners. Using videos, virtual laboratories or distance control of real equipment as solutions to solve this lack were proposed but still limited. The mixed reality as new technology promised to create a virtual environment where the learner is an actor and can interact with the virtual objects. This article present an approach for developing integrated E-learning systems, helping to carry out the practical work by establishing a virtual laboratory that all tools and products can be manipulated by learners and teachers like in real practical activity, based on an augmented reality system.

  19. Augmented postcard

    Bernik , Aleš

    2012-01-01

    The aim of this thesis is the examination of augmented reality technology, which allows us mixing real and virtual elements. Augmented reality is a relatively new technology which is becoming more widespread, thanks to a fairly reasonable price of smart phones. Here we presents the types of augmented reality, the necessary technology and their advantages and disadvantages, its current use in applications, and software for building augmented reality applications. The thesis is mainly focuse...

  20. Adenoviral augmentation of elafin protects the lung against acute injury mediated by activated neutrophils and bacterial infection.

    Simpson, A J; Wallace, W A; Marsden, M E; Govan, J R; Porteous, D J; Haslett, C; Sallenave, J M

    2001-08-01

    During acute pulmonary infection, tissue injury may be secondary to the effects of bacterial products or to the effects of the host inflammatory response. An attractive strategy for tissue protection in this setting would combine antimicrobial activity with inhibition of human neutrophil elastase (HNE), a key effector of neutrophil-mediated tissue injury. We postulated that genetic augmentation of elafin (an endogenous inhibitor of HNE with intrinsic antimicrobial activity) could protect the lung against acute inflammatory injury without detriment to host defense. A replication-deficient adenovirus encoding elafin cDNA significantly protected A549 cells against the injurious effects of both HNE and whole activated human neutrophils in vitro. Intratracheal replication-deficient adenovirus encoding elafin cDNA significantly protected murine lungs against injury mediated by Pseudomonas aeruginosa in vivo. Genetic augmentation of elafin therefore has the capacity to protect the lung against the injurious effects of both bacterial pathogens resistant to conventional antibiotics and activated neutrophils. PMID:11466403

  1. Design and evaluation of augmented reality for nuclear power plant maintenance based on Cognitive activity analysis

    The goals of maintenance in nuclear power plants (NPPs) are to reduce the number of plant shutdowns, to decrease the shutdown time, to minimize the maintenance costs, and to improve nuclear safety. Furthermore, it is difficult for maintenance personnel to conduct work in NPPs due to the complexity of NPPs, safety issues and time constraints. Human errors should be prevented to achieve maintenance goals in NPPs. Therefore, it is necessary to improve working conditions by introducing support systems. Augmented Reality (AR) has the potential to assist with maintenance tasks and make maintenance personnel concentrate on the tasks, which will then the reduced human error and improve human performance. The working procedure for AR systems was designed based on the characteristics of cognitive activity, and an experiment was conducted to estimate the effectiveness of AR. The results indicated that a well-designed working procedure for AR systems was more effective than a conventional paper-based working procedure. In addition, participants made fewer errors using the designed working procedure. AR systems as maintenance support systems are beneficial technology that can improve maintenance performance by reducing cognitive loads and unnecessary movements. An AR application can be attractive and effective at supporting maintenance task

  2. Inhibition of elongation factor-2 kinase augments the antitumor activity of Temozolomide against glioma.

    Xiao-Yuan Liu

    Full Text Available BACKGROUND: Glioblastoma multiforme (GBM, the most common form of brain cancer with an average survival of less than 12 months, is a highly aggressive and fatal disease characterized by survival of glioma cells following initial treatment, invasion through the brain parenchyma and destruction of normal brain tissues, and ultimately resistance to current treatments. Temozolomide (TMZ is commonly used chemotherapy for treatment of primary and recurrent high-grade gliomas. Nevertheless, the therapeutic outcome of TMZ is often unsatisfactory. In this study, we sought to determine whether eEF-2 kinase affected the sensitivity of glioma cells to treatment with TMZ. METHODOLOGY/PRINCIPAL FINDINGS: Using RNA interference approach, a small molecule inhibitor of eEF-2 kinase, and in vitro and in vivo glioma models, we observed that inhibition of eEF-2 kinase could enhance sensitivity of glioma cells to TMZ, and that this sensitizing effect was associated with blockade of autophagy and augmentation of apoptosis caused by TMZ. CONCLUSIONS/SIGNIFICANCE: These findings demonstrated that targeting eEF-2 kinase can enhance the anti-glioma activity of TMZ, and inhibitors of this kinase may be exploited as chemo-sensitizers for TMZ in treatment of malignant glioma.

  3. Acute liver failure-induced death of rats is delayed or prevented by blocking NMDA receptors in brain.

    Cauli, Omar; Rodrigo, Regina; Boix, Jordi; Piedrafita, Blanca; Agusti, Ana; Felipo, Vicente

    2008-09-01

    Developing procedures to delay the mechanisms of acute liver failure-induced death would increase patients' survival by allowing time for liver regeneration or to receive a liver for transplantation. Hyperammonemia is a main contributor to brain herniation and mortality in acute liver failure (ALF). Acute ammonia intoxication in rats leads to N-methyl-D-aspartate (NMDA) receptor activation in brain. Blocking these receptors prevents ammonia-induced death. Ammonia-induced activation of NMDA receptors could contribute to ALF-induced death. If this were the case, blocking NMDA receptors could prevent or delay ALF-induced death. The aim of this work was to assess 1) whether ALF leads to NMDA receptors activation in brain in vivo and 2) whether blocking NMDA receptors prevents or delays ALF-induced death of rats. It is shown, by in vivo brain microdialysis, that galactosamine-induced ALF leads to NMDA receptors activation in brain. Blocking NMDA receptors by continuous administration of MK-801 or memantine through miniosmotic pumps affords significant protection against ALF-induced death, increasing the survival time approximately twofold. Also, when liver injury is not 100% lethal (1.5 g/kg galactosamine), blocking NMDA receptors increases the survival rate from 23 to 62%. This supports that blocking NMDA receptors could have therapeutic utility to improve survival of patients with ALF. PMID:18599589

  4. Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation through activating the NR2B subunits of NMDA receptors

    Shi, Wen-Zhu [Anesthesia and Operation Center, Hainan Branch of Chinese PLA General Hospital, Hainan 572013 (China); Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China); Miao, Yu-Liang [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Guo, Wen-Zhi [Department of Anesthesiology, Beijing Military General Hospital of Chinese People’s Liberation Army, Beijing 100700 (China); Wu, Wei, E-mail: wwzwgk@163.com [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); Li, Bao-Wei [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); An, Li-Na [Department of Anesthesiology, Armed Police General Hospital, Beijing 100039 (China); Fang, Wei-Wu [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Mi, Wei-Dong, E-mail: elite2005gg@163.com [Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China)

    2014-04-25

    Highlights: • Leptin promotes the proliferation of neural stem cells isolated from embryonic mouse hippocampus. • Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation. • The effects of leptin are partially mediated by upregulating NR2B subunits. - Abstract: Corticosterone inhibits the proliferation of hippocampal neural stem cells (NSCs). The removal of corticosterone-induced inhibition of NSCs proliferation has been reported to contribute to neural regeneration. Leptin has been shown to regulate brain development, improve angiogenesis, and promote neural regeneration; however, its effects on corticosterone-induced inhibition of NSCs proliferation remain unclear. Here we reported that leptin significantly promoted the proliferation of hippocampal NSCs in a concentration-dependent pattern. Also, leptin efficiently reversed the inhibition of NSCs proliferation induced by corticosterone. Interestingly, pre-treatment with non-specific NMDA antagonist MK-801, specific NR2B antagonist Ro 25-6981, or small interfering RNA (siRNA) targeting NR2B, significantly blocked the effect of leptin on corticosterone-induced inhibition of NSCs proliferation. Furthermore, corticosterone significantly reduced the protein expression of NR2B, whereas pre-treatment with leptin greatly reversed the attenuation of NR2B expression caused by corticosterone in cultured hippocampal NSCs. Our findings demonstrate that leptin reverses the corticosterone-induced inhibition of NSCs proliferation. This process is, at least partially mediated by increased expression of NR2B subunits of NMDA receptors.

  5. Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation through activating the NR2B subunits of NMDA receptors

    Highlights: • Leptin promotes the proliferation of neural stem cells isolated from embryonic mouse hippocampus. • Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation. • The effects of leptin are partially mediated by upregulating NR2B subunits. - Abstract: Corticosterone inhibits the proliferation of hippocampal neural stem cells (NSCs). The removal of corticosterone-induced inhibition of NSCs proliferation has been reported to contribute to neural regeneration. Leptin has been shown to regulate brain development, improve angiogenesis, and promote neural regeneration; however, its effects on corticosterone-induced inhibition of NSCs proliferation remain unclear. Here we reported that leptin significantly promoted the proliferation of hippocampal NSCs in a concentration-dependent pattern. Also, leptin efficiently reversed the inhibition of NSCs proliferation induced by corticosterone. Interestingly, pre-treatment with non-specific NMDA antagonist MK-801, specific NR2B antagonist Ro 25-6981, or small interfering RNA (siRNA) targeting NR2B, significantly blocked the effect of leptin on corticosterone-induced inhibition of NSCs proliferation. Furthermore, corticosterone significantly reduced the protein expression of NR2B, whereas pre-treatment with leptin greatly reversed the attenuation of NR2B expression caused by corticosterone in cultured hippocampal NSCs. Our findings demonstrate that leptin reverses the corticosterone-induced inhibition of NSCs proliferation. This process is, at least partially mediated by increased expression of NR2B subunits of NMDA receptors

  6. Purkinje cell NMDA receptors assume a key role in synaptic gain control in the mature cerebellum.

    Piochon, Claire; Levenes, Carole; Ohtsuki, Gen; Hansel, Christian

    2010-11-10

    A classic view in cerebellar physiology holds that Purkinje cells do not express functional NMDA receptors and that, therefore, postsynaptic NMDA receptors are not involved in the induction of long-term depression (LTD) at parallel fiber (PF) to Purkinje cell synapses. Recently, it has been demonstrated that functional NMDA receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in mice, reaching full expression levels at ∼2 months after birth. Here, we show that in the mature mouse cerebellum LTD (induced by paired PF and CF activation), but not long-term potentiation (LTP; PF stimulation alone) at PF to Purkinje cell synapses is blocked by bath application of the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (D-APV). A blockade of LTD, but not LTP, was also observed when the noncompetitive NMDA channel blocker MK-801 was added to the patch-pipette saline, suggesting that postsynaptically expressed NMDA receptors are required for LTD induction. Using confocal calcium imaging, we show that CF-evoked calcium transients in dendritic spines are reduced in the presence of D-APV. This observation confirms that NMDA receptor signaling occurs at CF synapses and suggests that NMDA receptor-mediated calcium transients at the CF input site might contribute to LTD induction. Finally, we performed dendritic patch-clamp recordings from rat Purkinje cells. Dendritically recorded CF responses were reduced when D-APV was bath applied. Together, these data suggest that the late developmental expression of postsynaptic NMDA receptors at CF synapses onto Purkinje cells is associated with a switch toward an NMDA receptor-dependent LTD induction mechanism. PMID:21068337

  7. Combination treatment with doxorubicin and gamitrinib synergistically augments anticancer activity through enhanced activation of Bim

    Park, Hye-Kyung; Lee, Ji-Eun; Lim, Jaehwa; Jo, Da-Eun; Park, Soo-Ah; Suh, Pann-Ghill; Kang, Byoung Heon

    2014-01-01

    Background A common approach to cancer therapy in clinical practice is the combination of several drugs to boost the anticancer activity of available drugs while suppressing their unwanted side effects. In this regard, we examined the efficacy of combination treatment with the widely-used genotoxic drug doxorubicin and the mitochondriotoxic Hsp90 inhibitor gamitrinib to exploit disparate stress signaling pathways for cancer therapy. Methods The cytotoxicity of the drugs as single agents or in...

  8. Augmented supraorbital skin sympathetic nerve activity responses to symptom trigger events in rosacea patients.

    Metzler-Wilson, Kristen; Toma, Kumika; Sammons, Dawn L; Mann, Sarah; Jurovcik, Andrew J; Demidova, Olga; Wilson, Thad E

    2015-09-01

    Facial flushing in rosacea is often induced by trigger events. However, trigger causation mechanisms are currently unclear. This study tested the central hypothesis that rosacea causes sympathetic and axon reflex-mediated alterations resulting in trigger-induced symptomatology. Twenty rosacea patients and age/sex-matched controls participated in one or a combination of symptom triggering stressors. In protocol 1, forehead skin sympathetic nerve activity (SSNA; supraorbital microneurography) was measured during sympathoexcitatory mental (2-min serial subtraction of novel numbers) and physical (2-min isometric handgrip) stress. In protocol 2, forehead skin blood flow (laser-Doppler flowmetry) and transepithelial water loss/sweat rate (capacitance hygrometry) were measured during sympathoexcitatory heat stress (whole body heating by perfusing 50°C water through a tube-lined suit). In protocol 3, cheek, forehead, forearm, and palm skin blood flow were measured during nonpainful local heating to induce axon reflex vasodilation. Heart rate (HR) and mean arterial pressure (MAP) were recorded via finger photoplethysmography to calculate cutaneous vascular conductance (CVC; flux·100/MAP). Higher patient transepithelial water loss was observed (rosacea 0.20 ± 0.02 vs. control 0.10 ± 0.01 mg·cm(-2)·min(-1), P MAP changes were not different between groups during sympathoexcitatory stressors or local heating. SSNA during early mental (32 ± 9 and 9 ± 4% increase) and physical (25 ± 4 and 5 ± 1% increase, rosacea and controls, respectively) stress was augmented in rosacea (both P < 0.05). Heat stress induced more rapid sweating and cutaneous vasodilation onset in rosacea compared with controls. No axon reflex vasodilation differences were observed between groups. These data indicate that rosacea affects SSNA and that hyperresponsiveness to trigger events appears to have a sympathetic component. PMID:26133800

  9. Simplified Model for the Activated Sludge System: WWTP Cost Minimization via an Augmented Lagrangian Pattern Search Method

    Espírito Santo, Isabel A. C. P.; Fernandes, Edite M. G. P.

    2010-09-01

    This paper aims to validate a proposed simplified model of the activated sludge system. A comparison between the classical and simplified models is made. The optimization of the operational and investment costs in order to achieve the best design is conducted using an augmented Lagrangian pattern search based algorithm. The results are similar in both models and reinforced that the simplified model is a good approach.

  10. Dual regulation by ethanol of the inhibitory effects of ketamine on spinal NMDA-induced pressor responses in rats

    Keng Nien-Tzu

    2012-02-01

    Full Text Available Abstract Background Acute exposure of ethanol (alcohol inhibits NMDA receptor function. Our previous study showed that acute ethanol inhibited the pressor responses induced by NMDA applied intrathecally; however, prolonged ethanol exposure may increase the levels of phosphorylated NMDA receptor subunits leading to changes in ethanol inhibitory potency on NMDA-induced responses. The present study was carried out to examine whether acute ethanol exposure influences the effects of ketamine, a noncompetitive NMDA receptor antagonist, on spinal NMDA-induced pressor responses. Methods The blood pressure responses induced by intrathecal injection of NMDA were recorded in urethane-anesthetized rats weighing 250-275 g. The levels of several phosphorylated residues on NMDA receptor GluN1 subunits were determined by western blot analysis. Results Intravenous injection of ethanol or ketamine inhibited spinal NMDA-induced pressor responses in a dose-dependent and reversible manner. Ketamine inhibition of NMDA-induced responses was synergistically potentiated by ethanol when ethanol was applied just before ketamine. However, ketamine inhibition was significantly reduced when applied at 10 min after ethanol administration. Western blot analysis showed that intravenous ethanol increased the levels of phosphoserine 897 on GluN1 subunits (pGluN1-serine 897, selectively phosphorylated by protein kinase A (PKA, in the lateral horn regions of spinal cord at 10 min after administration. Intrathecal administration of cAMPS-Sp, a PKA activator, at doses elevating the levels of pGluN1-serine 897, significantly blocked ketamine inhibition of spinal NMDA-induced responses. Conclusions The results suggest that ethanol may differentially regulate ketamine inhibition of spinal NMDA receptor function depending on ethanol exposure time and the resulting changes in the levels of pGluN1-serine 897.

  11. Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists.

    Borza, István; Kolok, Sándor; Galgóczy, Kornél; Gere, Anikó; Horváth, Csilla; Farkas, Sándor; Greiner, István; Domány, György

    2007-01-15

    A novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed. PMID:17074483

  12. Alendronate augments interleukin-1β release from macrophages infected with periodontal pathogenic bacteria through activation of caspase-1

    Nitrogen-containing bisphosphonates (NBPs) are anti-bone-resorptive drugs with inflammatory side effects that include osteomyelitis and osteonecrosis of the jaw. Oral bacteria have been considered to be a trigger for these NBP-associated jaw bone diseases. The present study examined the effects of alendronate (a typical NBP) and clodronate (a non-NBP) on the production of proinflammatory cytokines by macrophages infected with Porphyromonas gingivalis and Tannerella forsythia, which are important pathogens of periodontal diseases. Pretreatment with alendronate augmented IL-1β, but not TNFα, production by macrophages infected with P. gingivalis or T. forsythia. This augmentation of IL-1β production was inhibited by clodronate. Furthermore, caspase-1, a promoter of IL-1β production, was activated by treatment with alendronate, and caspase-1 inhibitor reduced the production of IL-1β induced by alendronate and P. gingivalis. These results suggest that NBPs augment periodontal pathogenic bacteria-induced IL-1β release via caspase-1 activation, and this phenomenon may contribute to the development of NBP-associated inflammatory side effects including jaw osteomyelitis. Co-treatment with clodronate may prevent and/or reduce these inflammatory effects induced by NBPs

  13. BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals.

    Chen, Wenling; Walwyn, Wendy; Ennes, Helena S; Kim, Hyeyoung; McRoberts, James A; Marvizón, Juan Carlos G

    2014-05-01

    NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin-related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75(NTR) ), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75(NTR) inhibitor TAT-Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full-length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr(1472) phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch-clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA-induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and a Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain. PMID:24611998

  14. Ablation of NMDA receptors enhances the excitability of hippocampal CA3 neurons.

    Fumiaki Fukushima

    Full Text Available Synchronized discharges in the hippocampal CA3 recurrent network are supposed to underlie network oscillations, memory formation and seizure generation. In the hippocampal CA3 network, NMDA receptors are abundant at the recurrent synapses but scarce at the mossy fiber synapses. We generated mutant mice in which NMDA receptors were abolished in hippocampal CA3 pyramidal neurons by postnatal day 14. The histological and cytological organizations of the hippocampal CA3 region were indistinguishable between control and mutant mice. We found that mutant mice lacking NMDA receptors selectively in CA3 pyramidal neurons became more susceptible to kainate-induced seizures. Consistently, mutant mice showed characteristic large EEG spikes associated with multiple unit activities (MUA, suggesting enhanced synchronous firing of CA3 neurons. The electrophysiological balance between fast excitatory and inhibitory synaptic transmission was comparable between control and mutant pyramidal neurons in the hippocampal CA3 region, while the NMDA receptor-slow AHP coupling was diminished in the mutant neurons. In the adult brain, inducible ablation of NMDA receptors in the hippocampal CA3 region by the viral expression vector for Cre recombinase also induced similar large EEG spikes. Furthermore, pharmacological blockade of CA3 NMDA receptors enhanced the susceptibility to kainate-induced seizures. These results raise an intriguing possibility that hippocampal CA3 NMDA receptors may suppress the excitability of the recurrent network as a whole in vivo by restricting synchronous firing of CA3 neurons.

  15. PPARα deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPARγ activation in the liver

    Research highlights: → PPARα deficiency augments a ketogenic diet-induced circadian PAI-1 expression. → Hepatic expressions of PPARγ and PCG-1α are induced by a ketogenic diet. → PPARγ antagonist attenuates a ketogenic diet-induced PAI-1 expression. → Ketogenic diet advances the phase of circadian clock in a PPARα-independent manner. -- Abstract: An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor α (PPARα) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPARα-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPARα-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The KD-induced mRNA expression of typical PPARα target genes such as Cyp4A10 and FGF21 was damped in PPARα-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPARα-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPARα activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPARγ and its coactivator PCG-1α were more effectively induced in PPARα-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPARγ antagonist, in both WT and PPARα-null mice. PPARγ activation seems to be involved in KD-induced hypofibrinolysis by augmenting PAI-1 gene expression

  16. A role of periaqueductal grey NR2B-containing NMDA receptor in mediating persistent inflammatory pain

    Yang Qi

    2009-12-01

    Full Text Available Abstract The midbrain periaqueductal grey (PAG is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp, one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.

  17. DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke

    Tu, Weihong; Xu, Xin; Peng, Lisheng; Zhong, Xiaofen; Zhang, Wenfeng; Soundarapandian, Mangala M.; Balel, Cherine; Wang, Manqi; Jia, Nali; Zhang, Wen; Lew, Frank; Chan, Sic Lung; Chen, Yanfang; Lu, Youming

    2010-01-01

    SUMMARY N-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extra-synaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292–1304 (NR2BCT). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2BCT that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca2+ influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at extra-synaptic sites and this interaction acts as a central mediator for stroke damage. PMID:20141836

  18. Lip augmentation.

    Byrne, Patrick J; Hilger, Peter A

    2004-02-01

    Lip augmentation has become increasingly popular in recent years as a reflection of cultural trends emphasizing youth and beauty. Techniques to enhance the appearance of the lips have evolved with advances in biotechnology. An understanding of lip anatomy and aesthetics forms the basis for successful results. We outline the pertinent anatomy and aesthetics of the preoperative evaluation. A summary of various filler materials available is provided. Augmentation options include both injectable and open surgical techniques. The procedures and materials currently favored by the authors are described in greater detail. PMID:15034811

  19. Augmented Reality

    Kjærgaard, Hanne Wacher; Kjeldsen, Lars Peter Bech; Rahn, Annette

    2015-01-01

    This chapter describes the use of iPad-facilitated application of augmented reality in the teaching of highly complex anatomical and physiological subjects in the training of nurses at undergraduate level. The general aim of the project is to investigate the potentials of this application in term...

  20. Frequency-dependent facilitation of synaptic throughput via postsynaptic NMDA receptors in the nucleus of the solitary tract.

    Zhao, Huan; Peters, James H; Zhu, Mingyan; Page, Stephen J; Ritter, Robert C; Appleyard, Suzanne M

    2015-01-01

    Hindbrain NMDA receptors play important roles in reflexive and behavioural responses to vagal activation. NMDA receptors have also been shown to contribute to the synaptic responses of neurons in the nucleus of the solitary tract (NTS), but their exact role remains unclear. In this study we used whole cell patch-clamping techniques in rat horizontal brain slice to investigate the role of NMDA receptors in the fidelity of transmission across solitary tract afferent-NTS neuron synapses. Results show that NMDA receptors contribute up to 70% of the charge transferred across the synapse at high (>5 Hz) firing rates, but have little contribution at lower firing frequencies. Results also show that NMDA receptors critically contribute to the fidelity of transmission across these synapses during high frequency (>5 Hz) afferent discharge rates. This novel role of NMDA receptors may explain in part how primary visceral afferents, including vagal afferents, can maintain fidelity of transmission across a broad range of firing frequencies. Neurons within the nucleus of the solitary tract (NTS) receive vagal afferent innervations that initiate gastrointestinal and cardiovascular reflexes. Glutamate is the fast excitatory neurotransmitter released in the NTS by vagal afferents, which arrive there via the solitary tract (ST). ST stimulation elicits excitatory postsynaptic currents (EPSCs) in NTS neurons mediated by both AMPA- and NMDA-type glutamate receptors (-Rs). Vagal afferents exhibit a high probability of vesicle release and exhibit robust frequency-dependent depression due to presynaptic vesicle depletion. Nonetheless, synaptic throughput is maintained even at high frequencies of afferent activation. Here we test the hypothesis that postsynaptic NMDA-Rs are essential in maintaining throughput across ST-NTS synapses. Using patch clamp electrophysiology in horizontal brainstem slices, we found that NMDA-Rs, including NR2B subtypes, carry up to 70% of the charge transferred

  1. Healthy older humans exhibit augmented carotid-cardiac baroreflex sensitivity with aspirin during muscle mechanoreflex and metaboreflex activation.

    Drew, Rachel C; Blaha, Cheryl A; Herr, Michael D; Stocker, Sean D; Sinoway, Lawrence I

    2015-10-01

    Low-dose aspirin inhibits thromboxane production and augments the sensitivity of carotid baroreflex (CBR) control of heart rate (HR) during concurrent muscle mechanoreflex and metaboreflex activation in healthy young humans. However, it is unknown how aging affects this response. Therefore, the effect of low-dose aspirin on carotid-cardiac baroreflex sensitivity during muscle mechanoreflex with and without metaboreflex activation in healthy older humans was examined. Twelve older subjects (6 men and 6 women, mean age: 62 ± 1 yr) performed two trials during two visits preceded by 7 days of low-dose aspirin (81 mg) or placebo. One trial involved 3 min of passive calf stretch (mechanoreflex) during 7.5 min of limb circulatory occlusion (CO). In another trial, CO was preceded by 1.5 min of 70% maximal voluntary contraction isometric calf exercise (mechanoreflex and metaboreflex). HR (ECG) and mean arterial blood pressure (MAP; Finometer) were recorded. CBR function was assessed using rapid neck pressure application (+40 to -80 mmHg). Aspirin significantly decreased baseline thromboxane B2 production by 83 ± 4% (P aspirin, CBR-HR maximal gain and operating point gain were significantly higher during stretch with metabolite accumulation compared with placebo (maximal gain: -0.23 ± 0.03 vs. -0.14 ± 0.02 and operating point gain: -0.11 ± 0.03 vs. -0.04 ± 0.01 beats·min(-1)·mmHg(-1) for aspirin and placebo, respectively, P aspirin augments CBR-HR sensitivity during concurrent muscle mechanoreflex and metaboreflex activation in healthy older humans. This increased sensitivity appears linked to reduced thromboxane sensitization of muscle mechanoreceptors, which consequently improves CBR-HR control. PMID:26371168

  2. Molecular pharmacology of human NMDA receptors

    Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard;

    2012-01-01

    current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side......-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest that the...... binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human...

  3. Human Neuroepithelial Cells Express NMDA Receptors

    Cappell B

    2003-11-01

    Full Text Available Abstract L-glutamate, an excitatory neurotransmitter, binds to both ionotropic and metabotropic glutamate receptors. In certain parts of the brain the BBB contains two normally impermeable barriers: 1 cerebral endothelial barrier and 2 cerebral epithelial barrier. Human cerebral endothelial cells express NMDA receptors; however, to date, human cerebral epithelial cells (neuroepithelial cells have not been shown to express NMDA receptor message or protein. In this study, human hypothalamic sections were examined for NMDA receptors (NMDAR expression via immunohistochemistry and murine neuroepithelial cell line (V1 were examined for NMDAR via RT-PCR and Western analysis. We found that human cerebral epithelium express protein and cultured mouse neuroepithelial cells express both mRNA and protein for the NMDA receptor. These findings may have important consequences for neuroepithelial responses during excitotoxicity and in disease.

  4. NMDA receptor function, memory, and brain aging

    Newcomer, John W.; Farber, Nuri B.; Olney, John W.

    2000-01-01

    An increasing level of N-methyl-D-aspartate (NMDA) receptor hypofunction within the brain is associated with memory and learning impairments, with psychosis, and ultimately with excitotoxic brain injury. As the brain ages, the NMDA receptor system becomes progressively hypofunctional, contributing to decreases in memory and learning performance. In those individuals destined to develop Alzheimer's disease, other abnormalities (eg, amyloidopathy and oxidative stress) interact to increase the N...

  5. Musical Peddy-Paper: A Collaborative Learning Activity Suported by Augmented Reality

    Gomes, José Duarte Cardoso; Figueiredo, Mauro Jorge Guerreiro; Amante, Lúcia da Graça Cruz Domingues; Gomes, Cristina Maria Cardoso

    2014-01-01

    Gaming activities are an integral part of the human learning process, in particular for children. Game-based learning focuses on motivation and children's engagement towards learning. Educational game-based activities are becoming effective strategies to enhance the learning process. This paper presents an educational activity focusing to merge…

  6. Membrane phospholipid augments cytochrome P4501a enzymatic activity by modulating structural conformation during detoxification of xenobiotics.

    Manik C Ghosh

    Full Text Available Cytochrome P450 is a superfamily of membrane-bound hemoprotein that gets involved with the degradation of xenobiotics and internal metabolites. Accumulated body of evidence indicates that phospholipids play a crucial role in determining the enzymatic activity of cytochrome P450 in the microenvironment by modulating its structure during detoxification; however, the structure-function relationship of cytochrome P4501A, a family of enzymes responsible for degrading lipophilic aromatic hydrocarbons, is still not well defined. Inducibility of cytochrome P4501A in cultured catfish hepatocytes in response to carbofuran, a widely used pesticide around the world, was studied earlier in our laboratory. In this present investigation, we observed that treating catfish with carbofuran augmented total phospholipid in the liver. We examined the role of phospholipid on the of cytochrome P4501A-marker enzyme which is known as ethoxyresorufin-O-deethylase (EROD in the context of structure and function. We purified the carbofuran-induced cytochrome P4501A protein from catfish liver. Subsequently, we examined the enzymatic activity of purified P4501A protein in the presence of phospholipid, and studied how the structure of purified protein was influenced in the phospholipid environment. Membrane phospholipid appeared to accelerate the enzymatic activity of EROD by changing its structural conformation and thus controlling the detoxification of xenobiotics. Our study revealed the missing link of how the cytochrome P450 restores its enzymatic activity by changing its structural conformation in the phospholipid microenvironment.

  7. Andrographolide protects against cigarette smoke-induced oxidative lung injury via augmentation of Nrf2 activity

    Guan, SP; Tee, W; Ng, DSW; Chan, TK; Peh, HY; Ho, WE; Cheng, C; Mak, JC; Wong, WSF

    2013-01-01

    BACKGROUND AND PURPOSE: Cigarette smoke is a major cause for chronic obstructive pulmonary disease (COPD). Andrographolide is an active biomolecule isolated from the plant Andrographis paniculata. Andrographolide has been shown to activate nuclear factor erythroid-2-related factor 2 (Nrf2), a redox-sensitive antioxidant transcription factor. As Nrf2 activity is reduced in COPD, we hypothesize that andrographolide may have therapeutic value for COPD. EXPERIMENTAL APPROACH: Andrographolide was ...

  8. Natural cytolytic activity in mice with natural or induced cellular defects. I. Differential ability of in vitro interleukin-2 addition to augment natural cytolytic function

    The ability of in vitro addition of recombinant interleukin 2 (rIL-2) to differentially enhance natural cytotoxicity was assessed using cells from mice with natural and induced cellular defects. In vivo treatment with most immunosuppressive or cytoreductive agents, anti-asialo-GM1 antibody, or gamma irradiation dramatically reduced in vitro cytotoxicity against natural killer (NK) sensitive targets by direct reduction in either percentage specific lysis or lytic units per spleen. In most cases, in vitro addition of rIL-2 (at concentrations causing augmented NK function in cells from naive Balb/C mice) enhanced cytotoxic activity of cells from treatment groups to a normal value but not within the rIL-2-enhanced range of nontreated animals. Additionally, cytotoxic activity of cells from animals treated with certain drugs or gamma irradiation could be augmented by rIL-2 when measured by percentage lysis but not lytic units per spleen. In vivo treatment with cyclosporin A did not affect natural cytotoxic activity and addition of rIL-2 augmented the NK activity in a similar fashion to the profile of naive cells. In experiments using cells from beige (C57Bl/6-bg) mice which have a natural defect in NK activity against YAC-1 targets, addition of rIL-2 (at concentrations causing augmented natural cytotoxic function in cells from C57Bl/6 mice) could not effectively enhance in vitro natural cytotoxic function

  9. Walky for embodied microblogging: sharing mundane activities through augmented everyday objects

    Nazzi, Elena; Sokoler, Tomas

    2011-01-01

    In this paper we present our ongoing exploration of a theoretical concept: Embodied Microblogging. Looking for a more situated way to communicate mundane activities in local communities, EM informs the design of digital technology to facilitate senior citizens in making their everyday activities ...

  10. Supplemental Immobilization of Hanford Low-Activity Waste: Cast Stone Augmented Formulation Matrix Tests

    Screening Matrix tests. A set of Cast Stone formulations were devised to augment the original screening test matrix and focus on the range of the test conditions. Fly ash and blast furnace slag were limited to either northwest or southeast and the salt solutions were narrowed to the Average and the SST Blend at the 7.8M Na concentration. To fill in the matrix, a mix ratio of 0.5 was added. In addition, two admixtures, Xypex Admix C-500 and Rheomac SF100 (silica fume), were added as an additional dry material binder in select compositions. As in the Screening Matrix, both fresh and cured properties were evaluated for the formulations. In this study, properties that were influenced by the W/DM ratio in the Screening Matrix; flow diameter, plastic viscosity, density, and compressive strength, showed consistent behavior with respect to W/DM. The leach index for highly soluble components, sodium and nitrate, were not influenced by changes in formulation or the admixtures. The leach index for both iodine and Tc-99 show an influence from the addition of the admixture, Xypex Admix C-500. Additional testing should be performed to further evaluate the influence of Xypex Admix C-500 on the leach index over a range of admixture concentrations, Cast Stone formulations, and curing and storage conditions.

  11. Supplemental Immobilization of Hanford Low-Activity Waste: Cast Stone Augmented Formulation Matrix Tests

    Cozzi, A. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Crawford, C. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Fox, K. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Hansen, E. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Roberts, K. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2015-07-20

    Matrix tests. A set of Cast Stone formulations were devised to augment the original screening test matrix and focus on the range of the test conditions. Fly ash and blast furnace slag were limited to either northwest or southeast and the salt solutions were narrowed to the Average and the SST Blend at the 7.8M Na concentration. To fill in the matrix, a mix ratio of 0.5 was added. In addition, two admixtures, Xypex Admix C-500 and Rheomac SF100 (silica fume), were added as an additional dry material binder in select compositions. As in the Screening Matrix, both fresh and cured properties were evaluated for the formulations. In this study, properties that were influenced by the W/DM ratio in the Screening Matrix; flow diameter, plastic viscosity, density, and compressive strength, showed consistent behavior with respect to W/DM. The leach index for highly soluble components, sodium and nitrate, were not influenced by changes in formulation or the admixtures. The leach index for both iodine and Tc-99 show an influence from the addition of the admixture, Xypex Admix C-500. Additional testing should be performed to further evaluate the influence of Xypex Admix C-500 on the leach index over a range of admixture concentrations, Cast Stone formulations, and curing and storage conditions.

  12. Maternal inflammation activated ROS-p38 MAPK predisposes offspring to heart damages caused by isoproterenol via augmenting ROS generation

    Zhang, Qi; Deng, Yafei; Lai, Wenjing; Guan, Xiao; Sun, Xiongshan; Han, Qi; Wang, Fangjie; Pan, Xiaodong; Ji, Yan; Luo, Hongqin; Huang, Pei; Tang, Yuan; Gu, Liangqi; Dan, Guorong; Yu, Jianhua; Namaka, Michael; Zhang, Jianxiang; Deng, Youcai; Li, Xiaohui

    2016-01-01

    Maternal inflammation contributes to the increased incidence of adult cardiovascular disease. The current study investigated the susceptibility of cardiac damage responding to isoproterenol (ISO) in adult offspring that underwent maternal inflammation (modeled by pregnant Sprague-Dawley rats with lipopolysaccharides (LPS) challenge). We found that 2 weeks of ISO treatment in adult offspring of LPS-treated mothers led to augmented heart damage, characterized by left-ventricular systolic dysfunction, cardiac hypertrophy and myocardial fibrosis. Mechanistically, prenatal exposure to LPS led to up-regulated expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, antioxidant enzymes, and p38 MAPK activity in left ventricular of adult offspring at resting state. ISO treatment exaggerated ROS generation, p38 MAPK activation but down-regulated reactive oxygen species (ROS) elimination capacity in the left ventricular of offspring from LPS-treated mothers, while antioxidant N-acetyl-L-cysteine (NAC) reversed these changes together with improved cardiac functions. The p38 inhibitor SB202190 alleviated the heart damage only via inhibiting the expression of NADPH oxidases. Collectively, our data demonstrated that prenatal inflammation programs pre-existed ROS activation in the heart tissue, which switches on the early process of oxidative damages on heart rapidly through a ROS-p38 MAPK-NADPH oxidase-ROS positive feedback loop in response to a myocardial hypertrophic challenge in adulthood. PMID:27443826

  13. Augmenting the Activity of Monoterpenoid Phenols against Fungal Pathogens Using 2-Hydroxy-4-methoxybenzaldehyde that Target Cell Wall Integrity.

    Kim, Jong H; Chan, Kathleen L; Mahoney, Noreen

    2015-01-01

    Disruption of cell wall integrity system should be an effective strategy for control of fungal pathogens. To augment the cell wall disruption efficacy of monoterpenoid phenols (carvacrol, thymol), antimycotic potency of benzaldehyde derivatives that can serve as chemosensitizing agents were evaluated against strains of Saccharomyces cerevisiae wild type (WT), slt2Δ and bck1Δ (mutants of the mitogen-activated protein kinase (MAPK) and MAPK kinase kinase, respectively, in the cell wall integrity pathway). Among fourteen compounds investigated, slt2Δ and bck1Δ showed higher susceptibility to nine benzaldehydes, compared to WT. Differential antimycotic activity of screened compounds indicated "structure-activity relationship" for targeting the cell wall integrity, where 2-hydroxy-4-methoxybenzaldehyde (2H4M) exhibited the highest antimycotic potency. The efficacy of 2H4M as an effective chemosensitizer to monoterpenoid phenols (viz., 2H4M + carvacrol or thymol) was assessed in yeasts or filamentous fungi (Aspergillus, Penicillium) according to European Committee on Antimicrobial Susceptibility Testing or Clinical Laboratory Standards Institute M38-A protocols, respectively. Synergistic chemosensitization greatly lowers minimum inhibitory or fungicidal concentrations of the co-administered compounds. 2H4M also overcame the tolerance of two MAPK mutants (sakAΔ, mpkCΔ) of Aspergillus fumigatus to fludioxonil (phenylpyrrole fungicide). Collectively, 2H4M possesses chemosensitizing capability to magnify the efficacy of monoterpenoid phenols, which improves target-based (viz., cell wall disruption) antifungal intervention. PMID:26569223

  14. Pomegranate Juice Augments Memory and fMRI Activity in Middle-Aged and Older Adults with Mild Memory Complaints

    Susan Y. Bookheimer

    2013-01-01

    Full Text Available Despite increasing emphasis on the potential of dietary antioxidants in preventing memory loss and on diet as a precursor of neurological health, rigorous studies investigating the cognitive effects of foods and their components are rare. Recent animal studies have reported memory and other cognitive benefits of polyphenols, found abundantly in pomegranate juice. We performed a preliminary, placebo-controlled randomized trial of pomegranate juice in older subjects with age-associated memory complaints using memory testing and functional brain activation (fMRI as outcome measures. Thirty-two subjects (28 completers were randomly assigned to drink 8 ounces of either pomegranate juice or a flavor-matched placebo drink for 4 weeks. Subjects received memory testing, fMRI scans during cognitive tasks, and blood draws for peripheral biomarkers before and after the intervention. Investigators and subjects were all blind to group membership. After 4 weeks, only the pomegranate group showed a significant improvement in the Buschke selective reminding test of verbal memory and a significant increase in plasma trolox-equivalent antioxidant capacity (TEAC and urolithin A-glucuronide. Furthermore, compared to the placebo group, the pomegranate group had increased fMRI activity during verbal and visual memory tasks. While preliminary, these results suggest a role for pomegranate juice in augmenting memory function through task-related increases in functional brain activity.

  15. An Augmented Reality-Based Mobile Learning System to Improve Students' Learning Achievements and Motivations in Natural Science Inquiry Activities

    Chiang, Tosti H. C.; Yang, Stephen J. H.; Hwang, Gwo-Jen

    2014-01-01

    In this study, an augmented reality-based mobile learning system is proposed for conducting inquiry-based learning activities. An experiment has been conducted to examine the effectiveness of the proposed approach in terms of learning achievements and motivations. The subjects were 57 fourth graders from two classes taught by the same teacher in…

  16. Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity

    Activation of Notch signaling contributes to glioblastoma multiform (GBM) tumorigenesis. However, the molecular mechanism that promotes the Notch signaling augmentation during GBM genesis remains largely unknown. Identification of new factors that regulate Notch signaling is critical for tumor treatment. The expression levels of RND3 and its clinical implication were analyzed in GBM patients. Identification of RND3 as a novel factor in GBM genesis was demonstrated in vitro by cell experiments and in vivo by a GBM xenograft model. We found that RND3 expression was significantly decreased in human glioblastoma. The levels of RND3 expression were inversely correlated with Notch activity, tumor size, and tumor cell proliferation, and positively correlated with patient survival time. We demonstrated that RND3 functioned as an endogenous repressor of the Notch transcriptional complex. RND3 physically interacted with NICD, CSL, and MAML1, the Notch transcriptional complex factors, promoted NICD ubiquitination, and facilitated the degradation of these cofactor proteins. We further revealed that RND3 facilitated the binding of NICD to FBW7, a ubiquitin ligase, and consequently enhanced NICD protein degradation. Therefore, Notch transcriptional activity was inhibited. Forced expression of RND3 repressed Notch signaling, which led to the inhibition of glioblastoma cell proliferation in vitro and tumor growth in the xenograft mice in vivo. Downregulation of RND3, however, enhanced Notch signaling activity, and subsequently promoted glioma cell proliferation. Inhibition of Notch activity abolished RND3 deficiency-mediated GBM cell proliferation. We conclude that downregulation of RND3 is responsible for the enhancement of Notch activity that promotes glioblastoma genesis

  17. Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

    Nuno A. L. Pereira

    2016-08-01

    Full Text Available Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool, and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl d-Aspartate (NMDA receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i a stereoselective cyclocondensation of (S- or (R-tryptophanol with appropriate racemic δ-oxoesters; (ii a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson’s disease. This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors.

  18. Augmentation mammoplasty

    Seventy-five cases of breast implants have been reviewed. Two categories of abnormalities were identified: those involving the implant itself and those within the breast parenchyma. Complications of the implant itself include leakage, fibrous capsular contraction, traumatic rupture, displacement, and collapse. Concomitant breast parenchymal abnormalities include breast carcinoma, cysts, solid masses, and clusters of microcalcifications. Mammographic technique is critical and often involves manual settings and special views. Mammography and US in conjunction with physical examination play an important role in detecting breast pathology in the augmented breast

  19. Indomethacin augments lymphokine-activated killer cell generation by patients with malignant mesothelioma

    Manning, L.S.; Bowman, R.V.; Davis, M.R.; Musk, A.W.; Robinson, B.W. (Queen Elizabeth II Medical Centre, Nedlands (Australia))

    1989-10-01

    Human malignant mesothelioma (MM) cells are resistant to natural killer (NK) cell lysis but susceptible to lysis by lymphokine-activated killer (LAK) cells from control individuals. The present study was performed to determine the capacity of patients with MM (n = 22) and individuals occupationally exposed to asbestos (the major population at risk of developing this disease, n = 52) to generate LAK cells capable of effectively lysing human mesothelioma cells. Compared to controls (n = 20), both patient groups demonstrated significantly depressed LAK cell activity against mesothelioma tumor cell targets (55 +/- 3% lysis by controls vs 34 +/- 3% lysis by patients with MM, P less than 0.005; and 45 +/- 3% lysis by asbestos-exposed individuals, P less than 0.025). Addition of 10 micrograms/ml indomethacin during LAK cell generation restored normal LAK cell activity for patients with MM (52 +/- 6% lysis of cultured human MM cells, P = NS compared to controls), suggesting that the defective cytolytic cell function observed in some patients with MM is a result of prostaglandin-induced immunosuppression. The ability of indomethacin to restore suppressed LAK cell activity in patients with MM suggests that the concomitant use of this agent in ex vivo LAK cell generation and in patients undergoing interleukin/LAK cell therapy may be beneficial.

  20. NMDA Receptor Modulators in the Treatment of Drug Addiction

    Foster Olive, M.; Natali E. Nemirovsky; Tomek, Seven E.; LaCrosse, Amber L.

    2013-01-01

    Glutamate plays a pivotal role in drug addiction, and the N-methyl-d-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modu...

  1. Dectin-2 Recognizes Mannosylated O-antigens of Human Opportunistic Pathogens and Augments Lipopolysaccharide Activation of Myeloid Cells.

    Wittmann, Alexandra; Lamprinaki, Dimitra; Bowles, Kristian M; Katzenellenbogen, Ewa; Knirel, Yuriy A; Whitfield, Chris; Nishimura, Takashi; Matsumoto, Naoki; Yamamoto, Kazuo; Iwakura, Yoichiro; Saijo, Shinobu; Kawasaki, Norihito

    2016-08-19

    LPS consists of a relatively conserved region of lipid A and core oligosaccharide and a highly variable region of O-antigen polysaccharide. Whereas lipid A is known to bind to the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex, the role of the O-antigen remains unclear. Here we report a novel molecular interaction between dendritic cell-associated C-type lectin-2 (Dectin-2) and mannosylated O-antigen found in a human opportunistic pathogen, Hafnia alvei PCM 1223, which has a repeating unit of [-Man-α1,3-Man-α1,2-Man-α1,2-Man-α1,2-Man-α1,3-]. H. alvei LPS induced higher levels of TNFα and IL-10 from mouse bone marrow-derived dendritic cells (BM-DCs), when compared with Salmonella enterica O66 LPS, which has a repeat of [-Gal-α1,6-Gal-α1,4-[Glc-β1,3]GalNAc-α1,3-GalNAc-β1,3-]. In a cell-based reporter assay, Dectin-2 was shown to recognize H. alvei LPS. This binding was inhibited by mannosidase treatment of H. alvei LPS and by mutations in the carbohydrate-binding domain of Dectin-2, demonstrating that H. alvei LPS is a novel glycan ligand of Dectin-2. The enhanced cytokine production by H. alvei LPS was Dectin-2-dependent, because Dectin-2 knock-out BM-DCs failed to do so. This receptor cross-talk between Dectin-2 and TLR4 involved events including spleen tyrosine kinase (Syk) activation and receptor juxtaposition. Furthermore, another mannosylated LPS from Escherichia coli O9a also bound to Dectin-2 and augmented TLR4 activation of BM-DCs. Taken together, these data indicate that mannosylated O-antigens from several Gram-negative bacteria augment TLR4 responses through interaction with Dectin-2. PMID:27358401

  2. Targeting myeloid-derived suppressor cells augments antitumor activity against lung cancer

    Srivastava MK

    2012-10-01

    Full Text Available Minu K Srivastava,1,2 Li Zhu,1,2 Marni Harris-White,2 Min Huang,1–3 Maie St John,1,3 Jay M Lee,1,3 Ravi Salgia,4 Robert B Cameron,1,3,5 Robert Strieter,6 Steven Dubinett,1–3 Sherven Sharma1–31Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, 2Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 3Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 4Department of Medicine, University of Chicago, Chicago, IL, 5Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 6Department of Medicine, University of Virginia, Charlottesville, VA, USAAbstract: Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs. MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss tumor-MDSC interactions that suppress host antitumor activities and the authors' recent findings regarding MDSC depletion that led to improved therapeutic vaccination responses against lung cancer. Despite the identification of a repertoire of tumor antigens, hurdles persist for immune-based anticancer therapies. It is likely that combined therapies that address the multiple immune deficits in cancer patients will be required for effective therapy. MDSCs play a major role in the suppression of T-cell activation and they sustain tumor growth, proliferation, and metastases. Regulation of MDSC recruitment, differentiation or expansion, and inhibition of the MDSC suppressive function with pharmacologic agents will be useful in the control of cancer growth and progression. Pharmacologic agents that regulate MDSCs may be more effective when combined with

  3. Benzodiazepines: rat pinealocyte binding sites and augmentation of norepinephrine-stimulated N-acetyltransferase activity

    Matthew, E.; Parfitt, A.G.; Sugden, D.; Engelhardt, D.L.; Zimmerman, E.A.; Klein, D.C.

    1984-02-01

    Studies of (/sup 3/H)diazepam binding to intact rat pineal cells were carried out in tissue culture preparations. The binding was saturable, reversible and proportional to the number of cells used. Scatchard analysis resulted in a linear plot (Kd . 23 nM, maximum binding sites (Bmax) . 1.56 pmol/mg of protein for cells in monolayer culture; Kd . 7 nM, Bmax . 1.3 pmol/mg of protein for cells in suspension culture). Inhibition constants (Ki) for clonazepam (500 nM), flunitrazepam (38 nM) and Ro-5-4864 (5 nM) indicated that the binding sites were probably of the ''peripheral'' type. In addition, the effects of diazepam on norepinephrine-stimulated N-acetyltransferase (NAT) activity were studied in organ culture and dissociated cell culture. Diazepam (10-50 microM) both prolonged and increased the magnitude of the norepinephrine-induced increase in NAT activity but did not affect the initial rate of rise of enzyme activity. The effect was dose-dependent and was also seen with clonazepam, flunitrazepam and Ro-5-4864, but not with Ro-15-1788. Diazepam, by itself, at these concentrations, had no effect on NAT, but enzyme activity was increased by higher concentrations (0.1-1 mM). Although a relationship between the (/sup 3/H)diazepam binding sites described here and the effect of benzodiazepines on NAT cannot be established from these studies, the data suggest that the benzodiazepines may alter melatonin levels through their action on NAT.

  4. Benzodiazepines: rat pinealocyte binding sites and augmentation of norepinephrine-stimulated N-acetyltransferase activity

    Studies of [3H]diazepam binding to intact rat pineal cells were carried out in tissue culture preparations. The binding was saturable, reversible and proportional to the number of cells used. Scatchard analysis resulted in a linear plot [Kd . 23 nM, maximum binding sites (Bmax) . 1.56 pmol/mg of protein for cells in monolayer culture; Kd . 7 nM, Bmax . 1.3 pmol/mg of protein for cells in suspension culture]. Inhibition constants (Ki) for clonazepam (500 nM), flunitrazepam (38 nM) and Ro-5-4864 (5 nM) indicated that the binding sites were probably of the ''peripheral'' type. In addition, the effects of diazepam on norepinephrine-stimulated N-acetyltransferase (NAT) activity were studied in organ culture and dissociated cell culture. Diazepam (10-50 microM) both prolonged and increased the magnitude of the norepinephrine-induced increase in NAT activity but did not affect the initial rate of rise of enzyme activity. The effect was dose-dependent and was also seen with clonazepam, flunitrazepam and Ro-5-4864, but not with Ro-15-1788. Diazepam, by itself, at these concentrations, had no effect on NAT, but enzyme activity was increased by higher concentrations (0.1-1 mM). Although a relationship between the [3H]diazepam binding sites described here and the effect of benzodiazepines on NAT cannot be established from these studies, the data suggest that the benzodiazepines may alter melatonin levels through their action on NAT

  5. Leptin into the rostral ventral lateral medulla (RVLM) augments renal sympathetic nerve activity and blood pressure

    Barnes, Maria J.; David Harry McDougal

    2014-01-01

    Leptin is a hormone released from adipose tissue. While this hormone normally acts to reduce feeding behavior and increase energy expenditure, in obesity, resistance to these effects occurs even though the hormone is released in large amounts. Although leptin no longer works to suppress feeding in the obese, leptin retains its potent effects on other autonomic functions such as blood pressure regulation. Leptin has been associated with hypertension and increased sympathetic autonomic activ...

  6. Leptin into the rostral ventral lateral medulla (RVLM) augments renal sympathetic nerve activity and blood pressure

    Barnes, Maria J.; McDougal, David H.

    2014-01-01

    Leptin is a hormone released from adipose tissue. While this hormone normally acts to reduce feeding behavior and increase energy expenditure, in obesity, resistance to these effects occurs even though the hormone is released in large amounts. Although leptin no longer works to suppress feeding in the obese, leptin retains its potent effects on other autonomic functions such as blood pressure regulation. Leptin has been associated with hypertension and increased sympathetic autonomic activity...

  7. Aeromechanical stability augmentation using semi-active friction-based lead-lag damper

    Agarwal, Sandeep

    2005-11-01

    Lead-lag dampers are present in most rotors to provide the required level of damping in all flight conditions. These dampers are a critical component of the rotor system, but they also represent a major source of maintenance cost. In present rotor systems, both hydraulic and elastomeric lead-lag dampers have been used. Hydraulic dampers are complex mechanical components that require hydraulic fluids and have high associated maintenance costs. Elastomeric dampers are conceptually simpler and provide a "dry" rotor, but are rather costly. Furthermore, their damping characteristics can degrade with time without showing external signs of failure. Hence, the dampers must be replaced on a regular basis. A semi-active friction based lead-lag damper is proposed as a replacement for hydraulic and elastomeric dampers. Damping is provided by optimized energy dissipation due to frictional forces in semi-active joints. An actuator in the joint modulates the normal force that controls energy dissipation at the frictional interfaces, resulting in large hysteretic loops. Various selective damping strategies are developed and tested for a simple system containing two different frequency modes in its response, one of which needs to be damped out. The system reflects the situation encountered in rotor response where 1P excitation is present along with the potentially unstable regressive lag motion. Simulation of the system response is obtained to compare their effectiveness. Next, a control law governing the actuation in the lag damper is designed to generate the desired level of damping for performing adaptive selective damping of individual blade lag motion. Further, conceptual design of a piezoelectric friction based lag damper for a full-scale rotor is presented and various factors affecting size, design and maintenance cost, damping capacity, and power requirements of the damper are discussed. The selective semi-active damping strategy is then studied in the context of classical

  8. Leptin into the rostral ventral lateral medulla (RVLM augments renal sympathetic nerve activity and blood pressure

    Maria J Barnes

    2014-08-01

    Full Text Available Leptin is a hormone released from adipose tissue. While this hormone normally acts to reduce feeding behavior and increase energy expenditure, in obesity, resistance to these effects occurs even though the hormone is released in large amounts. Although leptin no longer works to suppress feeding in the obese, leptin retains its potent effects on other autonomic functions such as blood pressure regulation. Leptin has been associated with hypertension and increased sympathetic autonomic activity. Therefore, leptin is emerging as a major contributor to the hypertensive state observed in obesity. Sympathetic control of blood pressure is maintained principally by autonomic reflex control circuits in the caudal brainstem. The rostral ventral-lateral medulla (RVLM is the primary regulator of the sympathetic nervous system, sending excitatory fibers to sympathetic preganglionic neurons to regulate sympathetic control over resistance vessels and blood pressure. Previous studies from our laboratory have shown that neurons in the ventral lateral medulla express leptin receptors (ObRb. Our present study using pseudo-rabies multi-synaptic retrograde tract tracing and immunohistochemical methods revealed that neurons within the RVLM that send sympathetic projections to the kidney express leptin receptors. Acute microinjection of leptin (1 and 3µg; 40nL into the RVLM evoked a significant increase in Mean Arterial Pressure (MAP and renal sympathetic nerve activity (RSNA. When the 3µg dose of leptin was preceded with a leptin antagonist, (SLAN-4; 1ng, it attenuated the cardiovascular response of leptin. Taken together, these data suggest that leptin’s actions within the RVLM may influence blood pressure and renal sympathetic nerve activity.

  9. Depression Augments Activity-Related Pain in Women but not in Men with Chronic Musculoskeletal Conditions

    Heather Adams; Pascal Thibault; Nicole Davidson; Maureen Simmonds; Ana Velly; Michael JL Sullivan

    2008-01-01

    OBJECTIVES: The primary objective of the present study was to examine the role of sex as a moderator of the relation between depression and activity-related pain.METHODS: The study sample consisted of 83 participants (42 women, 41 men) with musculoskeletal conditions. Participants were asked to lift a series of 18 canisters that varied in weight (2.9 kg, 3.4 kg and 3.9 kg) and distance from the body. Participants were asked to rate their pain while they lifted each canister and estimate the w...

  10. Effects of Anti-NMDA Antibodies on Functional Recovery and Synaptic Rearrangement Following Hemicerebellectomy.

    Laricchiuta, Daniela; Cavallucci, Virve; Cutuli, Debora; De Bartolo, Paola; Caporali, Paola; Foti, Francesca; Finke, Carsten; D'Amelio, Marcello; Manto, Mario; Petrosini, Laura

    2016-06-01

    The compensation that follows cerebellar lesions is based on synaptic modifications in many cortical and subcortical regions, although its cellular mechanisms are still unclear. Changes in glutamatergic receptor expression may represent the synaptic basis of the compensated state. We analyzed in rats the involvement of glutamatergic system of the cerebello-frontal network in the compensation following a right hemicerebellectomy. We evaluated motor performances, spatial competencies and molecular correlates in compensated hemicerebellectomized rats which in the frontal cortex contralateral to the hemicerebellectomy side received injections of anti-NMDA antibodies from patients affected by anti-NMDA encephalitis. In the compensated hemicerebellectomized rats, the frontal injections of anti-NMDA antibodies elicited a marked decompensation state characterized by slight worsening of the motor symptoms as well as severe impairment of spatial mnesic and procedural performances. Conversely, in the sham-operated group the frontal injections of anti-NMDA antibodies elicited slight motor and spatial impairment. The molecular analyses indicated that cerebellar compensatory processes were related to a relevant rearrangement of glutamatergic synapses (NMDA and AMPA receptors and other glutamatergic components) along the entire cortico-cerebellar network. The long-term maintenance of the rearranged glutamatergic activity plays a crucial role in the maintenance of recovered function. PMID:27027521

  11. New benzoyl urea derivatives as novel NR2B selective NMDA receptor antagonists.

    Borza, I; Greiner, I; Kolok, S; Galgóczy, K; Ignácz-Szendrei, Gy; Horváth, Cs; Farkas, S; Gáti, T; Háda, V; Domány, Gy

    2006-09-01

    A novel series of benzoyl urea derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the substitution of the piperidine ring on the biological activity of the compounds was studied. Compound 9 was active in the formalin test in mice. PMID:17020160

  12. Analysis of Whole-Cell NMDA Receptor Currents

    Vyklický, Vojtěch; Kořínek, Miloslav; Balík, Aleš; Smejkalová, Tereza; Krausová, Barbora; Vyklický ml., Ladislav

    Totowa: Humana Press Inc., 2016, s. 205-219. (Neuromethods. 106). ISBN 978-1-4939-2811-8 R&D Projects: GA ČR(CZ) GAP303/12/1464; GA ČR(CZ) GPP303/11/P391; GA TA ČR(CZ) TE01020028; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : NMDA receptor * whole-cell * kinetic analysis * desensitization * activation * deactivation * probability of channel opening * perfusion Subject RIV: FH - Neurology

  13. Cholinergic muscarinic receptor activation augments murine intestinal epithelial cell proliferation and tumorigenesis

    Previously, we showed that M3 muscarinic receptor (M3R; gene name Chrm3) deficiency attenuates murine intestinal neoplasia, supporting the hypothesis that muscarinic receptors play an important role in intestinal tumorigenesis. To test this hypothesis, in the present study we treated mice with bethanechol, a non-selective muscarinic receptor agonist without nicotinic receptor activity, and examined its effects on azoxymethane (AOM)-induced colon neoplasia. Mice were provided with drinking water containing 400 μg/mL bethanechol chloride or water without additions (control) for a total of 20 weeks, a period that included the initial 6 weeks when mice received intraperitoneal injections of AOM. When euthanized at week 20, control mice had 8.0 ± 1.3 tumors per animal, whereas bethanechol-treated mice had 10.4 ± 1.5 tumors per mouse (mean ± SE; P = 0.023), a 30% increase. Strikingly, tumor volume per animal was increased 52% in bethanechol-treated compared with control mice (179.7 ± 21.0 vs. 111. 8 ± 22.4 mm3; P = 0.047). On histological examination, bethenechol-treated mice also had more adenocarcinomas per animal (8.0 ± 1.0 vs. 4.1 ± 0.6 for control mice, P = 0.0042). Cell proliferation in both normal mucosa and adenocarcinomas was increased in bethanechol-treated compared to control mice. Also, in tumors, bethanechol treatment increased expression of Chrm3, Egfr and post-Egfr signaling molecules Myc and cyclin D1. Bethanechol treatment increased the thickness of normal colonic mucosa and the expression of selected matrix metalloproteinase (Mmp) genes, including Mmp7, Mmp10 and Mmp13. These findings support a prominent role for muscarinic receptors in colon neoplasia, and identify post-receptor signaling molecules as potential therapeutic targets

  14. Subthreshold receptive fields and baseline excitability of "silent" S1 callosal neurons in awake rabbits: contributions of AMPA/kainate and NMDA receptors.

    Swadlow, H A; Hicks, T P

    1997-07-01

    The contribution of NMDA and non-NMDA receptors to excitatory subthreshold receptive fields was examined in callosal efferent neurons (CC neurons) in primary somatosensory cortex of the fully awake rabbit. Only neurons showing no traditional (suprathreshold) receptive fields were examined. Subthreshold responses were examined by monitoring the thresholds of efferent neurons to juxtasomal current pulses (JSCPs) delivered through the recording microelectrode. Changes in threshold following a peripheral conditioning stimulus signify a subthreshold response. Using this method, excitatory postsynaptic potentials and inhibitory postsynaptic potentials are manifested as decreases and increases in JSCP threshold, respectively. NMDA and non-NMDA agonists and antagonists were administered iontophoretically via a multibarrel micropipette assembly attached to the recording/stimulating microelectrode. Receptor-selective doses of both AMPA/kainate and NMDA antagonists decreased the excitability of CC neurons in the absence of any peripheral stimulation. Threshold to JSCPs rose by a mean of 20% for both classes of antagonist. Despite the similar effects of NMDA and non-NMDA antagonists on baseline excitability, these antagonists had dramatically different effects on the subthreshold excitatory response to activation of the receptive field. Whereas receptor-selective doses of AMPA/kainate antagonists either eliminated or severely attenuated the subthreshold excitatory responses to peripheral stimulation, NMDA antagonists had little or no effect on the subthreshold evoked response. PMID:9262195

  15. Quantitative Structure-Activity Relationships of Noncompetitive Antagonists of the NMDA Receptor: A Study of a Series of MK801 Derivative Molecules Using Statistical Methods and Neural Network

    T. Lakhlifi

    2003-04-01

    Full Text Available Abstract: From a series of 50 MK801 derivative molecules, a selected set of 44 compounds was submitted to a principal components analysis (PCA, a multiple regression analysis (MRA, and a neural network (NN. This study shows that the compounds' activity correlates reasonably well with the selected descriptors encoding the chemical structures. The correlation coefficients calculated by MRA and there after by NN, r = 0.986 and r = 0.974 respectively, are fairly good to evaluate a quantitative model, and to predict activity for MK801 derivatives. To test the performance of this model, the activities of the remained set of 6 compounds are deduced from the proposed quantitative model, by NN. This study proved that the predictive power of this model is relevant.

  16. Synergy of AMPA and NMDA Receptor Currents in Dopaminergic Neurons: A Modeling Study.

    Zakharov, Denis; Lapish, Christopher; Gutkin, Boris; Kuznetsov, Alexey

    2016-01-01

    Dopaminergic (DA) neurons display two modes of firing: low-frequency tonic and high-frequency bursts. The high frequency firing within the bursts is attributed to NMDA, but not AMPA receptor activation. In our models of the DA neuron, both biophysical and abstract, the NMDA receptor current can significantly increase their firing frequency, whereas the AMPA receptor current is not able to evoke high-frequency activity and usually suppresses firing. However, both currents are produced by glutamate receptors and, consequently, are often co-activated. Here we consider combined influence of AMPA and NMDA synaptic input in the models of the DA neuron. Different types of neuronal activity (resting state, low frequency, or high frequency firing) are observed depending on the conductance of the AMPAR and NMDAR currents. In two models, biophysical and reduced, we show that the firing frequency increases more effectively if both receptors are co-activated for certain parameter values. In particular, in the more quantitative biophysical model, the maximal frequency is 40% greater than that with NMDAR alone. The dynamical mechanism of such frequency growth is explained in the framework of phase space evolution using the reduced model. In short, both the AMPAR and NMDAR currents flatten the voltage nullcline, providing the frequency increase, whereas only NMDA prevents complete unfolding of the nullcline, providing robust firing. Thus, we confirm a major role of the NMDAR in generating high-frequency firing and conclude that AMPAR activation further significantly increases the frequency. PMID:27252643

  17. Appetitive Cue-Evoked ERK Signaling in the Nucleus Accumbens Requires NMDA and D1 Dopamine Receptor Activation and Regulates CREB Phosphorylation

    Kirschmann, Erin K. Z.; Mauna, Jocelyn C.; Willis, Cory M.; Foster, Rebecca L.; Chipman, Amanda M.; Thiels, Edda

    2014-01-01

    Conditioned stimuli (CS) can modulate reward-seeking behavior. This modulatory effect can be maladaptive and has been implicated in excessive reward seeking and relapse to drug addiction. We previously demonstrated that exposure to an appetitive CS causes an increase in the activation of extracellular signal-regulated kinase (ERK) and cyclic-AMP…

  18. ARLearn: augmented reality meets augmented virtuality

    Ternier, Stefaan; Klemke, Roland; Kalz, Marco; Van Ulzen, Patricia; Specht, Marcus

    2012-01-01

    Ternier, S., Klemke, R., Kalz, M., Van Ulzen, P., & Specht, M. (2012). ARLearn: augmented reality meets augmented virtuality [Special issue]. Journal of Universal Computer Science - Technology for learning across physical and virtual spaces, 18(15), 2143-2164.

  19. Counting NMDA Receptors at the Cell Surface

    Horák, Martin; Suh, Y. H.

    Totowa: Humana Press Inc., 2016, s. 31-44. (Neuromethods. 106). ISBN 978-1-4939-2811-8 R&D Projects: GA ČR(CZ) GA14-02219S Institutional support: RVO:67985823 Keywords : NMDA receptor * ionotropic glutamate receptor * mammalian cell lines * intracellular trafficking * quantitative assay * biotinylation assay * biochemistry Subject RIV: FH - Neurology

  20. Clozapine Functions Through the Prefrontal Cortex Serotonin 1A Receptor to Heighten Neuronal Activity via Calmodulin Kinase II-NMDA Receptor Interactions

    Purkayastha, Sudarshana; Ford, Jason; Kanjilal, Baishali; Diallo, Souleymane; Del Rosario Inigo, Joseph; Neuwirth, Lorenz; El Idrissi, Abdelsem; Ahmed, Zaghloul; Wieraszko, Andrzej; Efrain, C.; Azmitia; Banerjee, Probal

    2011-01-01

    Aberrant dopamine release in the prefrontal cortex (PFC) is believed to underlie schizophrenia, but the mechanistic pathway through which a widely used antipsychotic, clozapine (Clz), evokes neurotransmitter-releasing electrical stimulation is unclear. We analyzed Clz-evoked regulation of neuronal activity in the PFC by stimulating axons in layers IV and V and recording the electrical effect in the postsynaptic pyramidal cells of layers II and III. We observed a Clz-evoked increase in populat...

  1. Osmotic Edema Rapidly Increases Neuronal Excitability Through Activation of NMDA Receptor-Dependent Slow Inward Currents in Juvenile and Adult Hippocampus

    Lauderdale, Kelli; Murphy, Thomas; Tung, Tina; Davila, David; Binder, Devin K.; Fiacco, Todd A.

    2015-01-01

    Cellular edema (cell swelling) is a principal component of numerous brain disorders including ischemia, cortical spreading depression, hyponatremia, and epilepsy. Cellular edema increases seizure-like activity in vitro and in vivo, largely through nonsynaptic mechanisms attributable to reduction of the extracellular space. However, the types of excitability changes occurring in individual neurons during the acute phase of cell volume increase remain unclear. Using whole-cell patch clamp techn...

  2. Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons.

    Toulmond, S; Vige, X; Fage, D; Benavides, J

    1992-09-14

    The potential neuroprotective effects of IL-6 against the excitotoxic neuronal loss induced by N-methyl-D-aspartate (NMDA) have been studied. Infusion into the rat striatum of excitotoxic amounts (250 nmol) of NMDA resulted in a 45% decrease in striatal choline acetyl transferase activity (ChAT; a marker of cholinergic neurons) and glutamate decarboxylase (GAD, a marker of GABAergic neurons) at 2 days post-injection. Co-infusion of 10 U of IL-6 reduced the loss of ChAT activity to 21% but failed to prevent the loss of GAD activity. IL-6 per se, up to the dose of 500 U, failed to affect ChAT or GAD activities. The in vivo effects of IL-6 are not mediated by a direct antagonism of NMDA toxicity, since IL-6 (up to a concentration of 500 and 5000 U/ml, respectively) did not antagonize either the increase in cyclic GMP levels resulting from NMDA receptor activation in cerebellar slices or the glutamate-induced release of lactate dehydrogenase, an index of neurotoxicity, by cultured cortical neurons. These results suggest that the increase in IL-6 levels observed in experimental brain lesions may play a role in the protection and regeneration of cholinergic neurons. PMID:1331914

  3. Stochastic hybrid model of spontaneous dendritic NMDA spikes

    Following recent advances in imaging techniques and methods of dendritic stimulation, active voltage spikes have been observed in thin dendritic branches of excitatory pyramidal neurons, where the majority of synapses occur. The generation of these dendritic spikes involves both Na+ ion channels and M-methyl-D-aspartate receptor (NMDAR) channels. During strong stimulation of a thin dendrite, the resulting high levels of glutamate, the main excitatory neurotransmitter in the central nervous system and an NMDA agonist, modify the current-voltage (I–V) characteristics of an NMDAR so that it behaves like a voltage-gated Na+ channel. Hence, the NMDARs can fire a regenerative dendritic spike, just as Na+ channels support the initiation of an action potential following membrane depolarization. However, the duration of the dendritic spike is of the order 100 ms rather than 1 ms, since it involves slow unbinding of glutamate from NMDARs rather than activation of hyperpolarizing K+ channels. It has been suggested that dendritic NMDA spikes may play an important role in dendritic computations and provide a cellular substrate for short-term memory. In this paper, we consider a stochastic, conductance-based model of dendritic NMDA spikes, in which the noise originates from the stochastic opening and closing of a finite number of Na+ and NMDA receptor ion channels. The resulting model takes the form of a stochastic hybrid system, in which membrane voltage evolves according to a piecewise deterministic dynamics that is coupled to a jump Markov process describing the opening and closing of the ion channels. We formulate the noise-induced initiation and termination of a dendritic spike in terms of a first-passage time problem, under the assumption that glutamate unbinding is negligible, which we then solve using a combination of WKB methods and singular perturbation theory. Using a stochastic phase-plane analysis we then extend our analysis to take proper account of the

  4. Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice.

    Moriguchi, Shigeki; Han, Feng; Shioda, Norifumi; Yamamoto, Yui; Nakajima, Takeharu; Nakagawasai, Osamu; Tadano, Takeshi; Yeh, Jay Z; Narahashi, Toshio; Fukunaga, Kohji

    2009-07-01

    Aberrant behaviors related to learning and memory in olfactory bulbectomized (OBX) mice have been documented in the previous studies. We reported that the impairment of long-term potentiation (LTP) of hippocampal CA1 regions from OBX mice was associated with down-regulation of CaM kinase II (CaMKII) and protein kinase C (PKC) activities. We now demonstrated that the nootropic drug, nefiracetam, significantly improved spatial reference memory-related behaviors as assessed by Y-maze and novel object recognition task in OBX mice. Nefiracetam also restored hippocampal LTP injured in OBX mice. Nefiracetam treatment restored LTP-induced PKCalpha (Ser657) and NR1 (Ser896) phosphorylation as well as increase in their basal phosphorylation in the hippocampal CA1 region of OBX mice. Likewise, nefiracetam improved LTP-induced CaMKIIalpha (Thr286) autophosphorylation and GluR1 (Ser831) phosphorylation and increased their basal phosphorylation. The enhancement of PKCalpha (Ser657) and CaMKIIalpha (Thr286) autophosphorylation by nefiracetam was inhibited by treatment with (+/-)-alpha-Methyl-(4-carboxyphenyl)glycine and DL-2-Amino-5-phosphonovaleric acid, respectively. The enhancement of LTP induced by nefiracetam is inhibited by treatment with 2-methyl-6-(phenylethynyl)-pyridine, but not by treatment with LY367385, suggesting that metabotropic glutamate receptor 5 (mGluR5) but not mGluR1 is involved in the nefiracetam-induced LTP enhancement. Taken together, nefiracetam ameliorates OBX-induced deficits in memory-related behaviors and impairment of LTP in the hippocampal CA1 region through activation of NMDAR and mGluR5, thereby leading to an increase in activities of CaMKIIalpha (Thr286) and PKCalpha (Ser657), respectively. PMID:19457128

  5. Activity-induced synaptic delivery of the GluN2A-containing NMDA receptor is dependent on endoplasmic reticulum chaperone Bip and involved in fear memory.

    Zhang, Xiao-min; Yan, Xun-yi; Zhang, Bin; Yang, Qian; Ye, Mao; Cao, Wei; Qiang, Wen-bin; Zhu, Li-jun; Du, Yong-lan; Xu, Xing-xing; Wang, Jia-sheng; Xu, Fei; Lu, Wei; Qiu, Shuang; Yang, Wei; Luo, Jian-hong

    2015-07-01

    The N-methyl-D-aspartate receptor (NMDAR) in adult forebrain is a heterotetramer mainly composed of two GluN1 subunits and two GluN2A and/or GluN2B subunits. The synaptic expression and relative numbers of GluN2A- and GluN2B-containing NMDARs play critical roles in controlling Ca(2+)-dependent signaling and synaptic plasticity. Previous studies have suggested that the synaptic trafficking of NMDAR subtypes is differentially regulated, but the precise molecular mechanism is not yet clear. In this study, we demonstrated that Bip, an endoplasmic reticulum (ER) chaperone, selectively interacted with GluN2A and mediated the neuronal activity-induced assembly and synaptic incorporation of the GluN2A-containing NMDAR from dendritic ER. Furthermore, the GluN2A-specific synaptic trafficking was effectively disrupted by peptides interrupting the interaction between Bip and GluN2A. Interestingly, fear conditioning in mice was disrupted by intraperitoneal injection of the interfering peptide before training. In summary, we have uncovered a novel mechanism for the activity-dependent supply of synaptic GluN2A-containing NMDARs, and demonstrated its relevance to memory formation. PMID:26088419

  6. Ethanol Extract of Ganoderma lucidum Augments Cellular Anti-oxidant Defense through Activation of Nrf2/HO-1

    Yoo-hwan Lee

    2016-03-01

    augments the cellular anti-oxidant defense capacity through activation of Nrf2/HO-1, thereby protecting C2C12 myoblasts from H2O2-induced oxidative cytotoxicity.

  7. Developments of PET radioligands for NMDA receptors

    Aim: There has been a great demand for developments of the radioligands to visualize the N-methyl-D-aspartate (NMDA) receptors by PET/SPECT. We have recently synthesized two C-11 labeled antagonists for the glycine-binding site on NMDA receptors. The aim of this work is to examine for their in vitro and in vivo binding characteristics, and to evaluate their potentials as PET radioligands for the NMDA receptors. Materials and methods: Two C-11 labeled 4-hydroxy-2-quinolones (1 and 2) were synthesized by conventional methylation of the corresponding phenols with [11C]methyl iodide. In vitro and ex vivo quantitative autoradiographs with imaging plate, as well as animal PET, were employed in order to evaluate their in vitro and in vivo binding to the NMDA receptors. Results: The compound 1 showed the specific binding to rat brain slices with higher localization in the hippocampus and cerebral cortex than in the cerebellum. Both glycine antagonists and agonists (glycine and D-serine) inhibited the in vitro binding of 1. On the other hand, the compound 2 displayed the specific binding to rat brain slices with no regional difference. Very interestingly, glycine agonists gave no significant change in the in vitro binding of 2, while glycine antagonists strongly inhibited the binding. Ex vivo autoradiography and monkey PET studies showed that 1 localizes only in the cerebellum, whereas 2 localizes in the cortex regions than in the cerebellum. Simultaneous injection with non-radioactive 1 or 2 (2 mg/kg) reduced the radioactivity to their non-specific level. Conclusion: The present studies indicated that the structural change of 4-hydroxy-2-quinolones results in the great change in both in vitro and in vivo binding characteristics of the antagonists. We have recently reported that in vivo binding of 1 ([11C]L-703,717) is inhibited by high content of endogenous glycine and D-serine, and that 1 localizes only in the cerebellum having low content of the agonists. The present in

  8. Anti-Diabetic Activities of Jiaotaiwan in db/db Mice by Augmentation of AMPK Protein Activity and Upregulation of GLUT4 Expression

    Na Hu

    2013-01-01

    Full Text Available Jiaotaiwan (JTW, which is composed of Coptis chinensis (CC and cinnamon (CIN, is one of the most well-known traditional Chinese medicines. In this study, we investigated the antidiabetic effects and mechanism of JTW in db/db mice. Results showed that JTW significantly decreased the level of fasting blood glucose and improved glucose and insulin tolerance better than CC or CIN alone. JTW also effectively protected the pancreatic islet shape, augmented the activation of AMP-activated protein kinase (AMPK in the liver, and increased the expression of glucose transporter 4 (GLUT4 protein in skeletal muscle and white fat. AMPK and GLUT4 contributed to glucose metabolism regulation and had an essential function in the development of diabetes mellitus (DM. Therefore, the mechanisms of JTW may be related to suppressing gluconeogenesis by activating AMPK in the liver and affecting glucose uptake in surrounding tissues through the upregulation of GLUT4 protein expression. These findings provided a new insight into the antidiabetic clinical applications of JTW and demonstrated the potential of JTW as a new drug candidate for DM treatment.

  9. Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors.

    Provencio, Jose Javier; Swank, Valerie; Lu, Haiyan; Brunet, Sylvain; Baltan, Selva; Khapre, Rohini V; Seerapu, Himabindu; Kokiko-Cochran, Olga N; Lamb, Bruce T; Ransohoff, Richard M

    2016-05-01

    Cognitive deficits after aneurysmal subarachnoid hemorrhage (SAH) are common and disabling. Patients who experience delayed deterioration associated with vasospasm are likely to have cognitive deficits, particularly problems with executive function, verbal and spatial memory. Here, we report neurophysiological and pathological mechanisms underlying behavioral deficits in a murine model of SAH. On tests of spatial memory, animals with SAH performed worse than sham animals in the first week and one month after SAH suggesting a prolonged injury. Between three and six days after experimental hemorrhage, mice demonstrated loss of late long-term potentiation (L-LTP) due to dysfunction of the NMDA receptor. Suppression of innate immune cell activation prevents delayed vasospasm after murine SAH. We therefore explored the role of neutrophil-mediated innate inflammation on memory deficits after SAH. Depletion of neutrophils three days after SAH mitigates tissue inflammation, reverses cerebral vasoconstriction in the middle cerebral artery, and rescues L-LTP dysfunction at day 6. Spatial memory deficits in both the short and long-term are improved and associated with a shift of NMDA receptor subunit composition toward a memory sparing phenotype. This work supports further investigating suppression of innate immunity after SAH as a target for preventative therapies in SAH. PMID:26872422

  10. Involvement of ERK in NMDA receptor-independent cortical neurotoxicity of hydrogen sulfide

    Kurokawa, Yuko; Sekiguchi, Fumiko; Kubo, Satoko; Yamasaki, Yoshiko; Matsuda, Sachi; Okamoto, Yukari; Sekimoto, Teruki; Fukatsu, Anna; Nishikawa, Hiroyuki [Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan); Kume, Toshiaki [Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501 (Japan); Fukushima, Nobuyuki [Division of Molecular Neurobiology, Department of Life Sciences, Kinki University School of Science and Engineering, 3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan); Akaike, Akinori [Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501 (Japan); Kawabata, Atsufumi, E-mail: kawabata@phar.kindai.ac.jp [Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan)

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer Hydrogen sulfide causes NMDA receptor-independent neurotoxicity in mouse fetal cortical neurons. Black-Right-Pointing-Pointer Activation of ERK mediates the toxicity of hydrogen sulfide. Black-Right-Pointing-Pointer Apoptotic mechanisms are involved in the hydrogen-induced cell death. -- Abstract: Hydrogen sulfide (H{sub 2}S), a gasotransmitter, exerts both neurotoxicity and neuroprotection, and targets multiple molecules including NMDA receptors, T-type calcium channels and NO synthase (NOS) that might affect neuronal viability. Here, we determined and characterized effects of NaHS, an H{sub 2}S donor, on cell viability in the primary cultures of mouse fetal cortical neurons. NaHS caused neuronal death, as assessed by LDH release and trypan blue staining, but did not significantly reduce the glutamate toxicity. The neurotoxicity of NaHS was resistant to inhibitors of NMDA receptors, T-type calcium channels and NOS, and was blocked by inhibitors of MEK, but not JNK, p38 MAP kinase, PKC and Src. NaHS caused prompt phosphorylation of ERK and upregulation of Bad, followed by translocation of Bax to mitochondria and release of mitochondrial cytochrome c, leading to the nuclear condensation/fragmentation. These effects of NaHS were suppressed by the MEK inhibitor. Our data suggest that the NMDA receptor-independent neurotoxicity of H{sub 2}S involves activation of the MEK/ERK pathway and some apoptotic mechanisms.

  11. Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain

    Ivo Bendix

    2014-03-01

    Full Text Available Exposure to N-methyl-d-aspartate (NMDA receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP-2 and brain-derived neurotrophic factor (BDNF after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine and the acetylcholinesterase (AChE inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix.

  12. Involvement of ERK in NMDA receptor-independent cortical neurotoxicity of hydrogen sulfide

    Highlights: ► Hydrogen sulfide causes NMDA receptor-independent neurotoxicity in mouse fetal cortical neurons. ► Activation of ERK mediates the toxicity of hydrogen sulfide. ► Apoptotic mechanisms are involved in the hydrogen-induced cell death. -- Abstract: Hydrogen sulfide (H2S), a gasotransmitter, exerts both neurotoxicity and neuroprotection, and targets multiple molecules including NMDA receptors, T-type calcium channels and NO synthase (NOS) that might affect neuronal viability. Here, we determined and characterized effects of NaHS, an H2S donor, on cell viability in the primary cultures of mouse fetal cortical neurons. NaHS caused neuronal death, as assessed by LDH release and trypan blue staining, but did not significantly reduce the glutamate toxicity. The neurotoxicity of NaHS was resistant to inhibitors of NMDA receptors, T-type calcium channels and NOS, and was blocked by inhibitors of MEK, but not JNK, p38 MAP kinase, PKC and Src. NaHS caused prompt phosphorylation of ERK and upregulation of Bad, followed by translocation of Bax to mitochondria and release of mitochondrial cytochrome c, leading to the nuclear condensation/fragmentation. These effects of NaHS were suppressed by the MEK inhibitor. Our data suggest that the NMDA receptor-independent neurotoxicity of H2S involves activation of the MEK/ERK pathway and some apoptotic mechanisms.

  13. Augmented Reality in Astrophysics

    Vogt, Frédéric P. A.; Shingles, Luke J.

    2013-01-01

    Augmented Reality consists of merging live images with virtual layers of information. The rapid growth in the popularity of smartphones and tablets over recent years has provided a large base of potential users of Augmented Reality technology, and virtual layers of information can now be attached to a wide variety of physical objects. In this article, we explore the potential of Augmented Reality for astrophysical research with two distinct experiments: (1) Augmented Posters and (2) Augmented...

  14. NMDA Receptors in Glial Cells: Pending Questions

    Džamba, Dávid; Honsa, Pavel; Anděrová, Miroslava

    2013-01-01

    Roč. 11, č. 3 (2013), s. 250-262. ISSN 1570-159X R&D Projects: GA ČR GA309/08/1381; GA ČR(CZ) GBP304/12/G069 Grant ostatní: GA UK(CZ) 604212 Institutional support: RVO:68378041 Keywords : astrocytes * ischemia * NMDA receptors Subject RIV: FH - Neurology Impact factor: 2.347, year: 2013

  15. Computational study of NMDA conductance and cortical oscillations in schizophrenia

    Kubra Komek Kirli

    2014-10-01

    Full Text Available N-methyl-D-aspartate (NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia. The illness is also characterized by gamma oscillatory disturbances, which can be evaluated with precise frequency specificity employing auditory cortical entrainment paradigms. This computational study investigates how synaptic NMDA hypofunction may give rise to network level oscillatory deficits as indexed by entrainment paradigms. We developed a computational model of a local cortical circuit with pyramidal cells and fast-spiking interneurons (FSI, incorporating NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA, and γ-aminobutyric acid (GABA synaptic kinetics. We evaluated the effects of varying NMDA conductance on FSIs and pyramidal cells, as well as AMPA to NMDA ratio. We also examined the differential effects across a broad range of entrainment frequencies as a function of NMDA conductance. Varying NMDA conductance onto FSIs revealed an inverted-U relation with network gamma whereas NMDA conductance onto the pyramidal cells had a more monotonic relationship. Varying NMDA vs. AMPA conductance onto FSIs demonstrated the necessity of AMPA in the generation of gamma while NMDA receptors had a modulatory role. Finally, reducing NMDA conductance onto FSI and varying the stimulus input frequency reproduced the specific reductions in gamma range (~40 Hz as observed in schizophrenia studies. Our computational study showed that reductions in NMDA conductance onto FSIs can reproduce similar disturbances in entrainment to periodic stimuli within the gamma range as reported in schizophrenia studies. These findings provide a mechanistic account of how specific cellular level disturbances can give rise to circuitry level pathophysiologic disturbance in schizophrenia.

  16. Repeated exposure to methamphetamine, cocaine or morphine induces augmentation of dopamine release in rat mesocorticolimbic slice co-cultures.

    Takayuki Nakagawa

    Full Text Available Repeated intermittent exposure to psychostimulants and morphine leads to progressive augmentation of its locomotor activating effects in rodents. Accumulating evidence suggests the critical involvement of the mesocorticolimbic dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex, in the behavioral sensitization. Here, we examined the acute and chronic effects of psychostimulants and morphine on dopamine release in a reconstructed mesocorticolimbic system comprised of a rat triple organotypic slice co-culture of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex regions. Tyrosine hydroxylase-positive cell bodies were localized in the ventral tegmental area, and their neurites projected to the nucleus accumbens and medial prefrontal cortex regions. Acute treatment with methamphetamine (0.1-1000 µM, cocaine (0.1-300 µM or morphine (0.1-100 µM for 30 min increased extracellular dopamine levels in a concentration-dependent manner, while 3,4-methylenedioxyamphetamine (0.1-1000 µM had little effect. Following repeated exposure to methamphetamine (10 µM for 30 min every day for 6 days, the dopamine release gradually increased during the 30-min treatment. The augmentation of dopamine release was maintained even after the withdrawal of methamphetamine for 7 days. Similar augmentation was observed by repeated exposure to cocaine (1-300 µM or morphine (10 and 100 µM. Furthermore, methamphetamine-induced augmentation of dopamine release was prevented by an NMDA receptor antagonist, MK-801 (10 µM, and was not observed in double slice co-cultures that excluded the medial prefrontal cortex slice. These results suggest that repeated psychostimulant- or morphine-induced augmentation of dopamine release, i.e. dopaminergic sensitization, was reproduced in a rat triple organotypic slice co-cultures. In addition, the slice co-culture system revealed that the NMDA

  17. Antagonistas de los receptores glutamatérgicos NMDA en el tratamiento del dolor crónico NMDA glutamatergic receptor antagonists for the management of chronic pain

    F. Neira

    2004-05-01

    receptores opioides mu, pero además es un antagonista no competitivo de los receptores NMDA. La utilización de la metadona permite mejorar el control del dolor al disminuir el desarrollo de tolerancia a los opioides. La memantina es un antagonista no competitivo de los receptores NMDA. Disminuye la facilitación intracortical y aumenta la inhibición intracortical. Experimentalmente ha demostrado características antinociceptivas en la fase secundaria a la inflamación inducida por la prueba de la formalina. Disminuye la hiperalgesia térmica y mecánica. Los antagonistas de los receptores NMDA, abren un nuevo horizonte en el tratamiento del dolor neuropático. Son fármacos que habitualmente requieren la asociación de otros analgésicos, normalmente actúan como coadyuvantes. Los resultados dispares de los diferentes antagonistas sobre una misma indicación, no hacen sino confirmar la complejidad de su mecanismo de acción, que no se limita a antagonizar los receptores NMDA, sino que va mucho más allá.NMDA receptors are associated to learning and memory processes, development and neural plasticity, as well as acute and chronic pain conditions. They are involved in the outset and maintenance of central sensitization associated to damage or inflammation of peripheral tissues. Glutamate is the main amino acid that stimulates the CNS, can be involved in nociceptive transmission processes at the spine level and is the main responsible for the fast synaptic transmission. The action of glutamate in the pain routes is mostly mediated by ionotropic receptors (AMPA, NMDA and kainic. The activation of NMDA receptors plays a major role in the excitatory neurotransmission and the synaptic plasticity of the CNS. Glutamate and its agonists (NMDA, AMPA or kainic acid are involved in the generation and maintenance of hyperalgesia conditions (exacerbated response to noxious stimulus and alodynia (decrease of pain threshold. The clinical effectiveness of NMDA receptor antagonists

  18. NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII

    Tao-Cheng, Jung-Hwa [EM Facility, NINDS, NIH, Bethesda, MD (United States); Yang, Yijung [Laboratory of Neurobiology, NINDS, NIH, Bethesda, MD (United States); Bayer, K. Ulrich [Department of Pharmacology, University of Colorado Denver, School of Medicine, Aurora, CO (United States); Reese, Thomas S. [Laboratory of Neurobiology, NINDS, NIH, Bethesda, MD (United States); Dosemeci, Ayse, E-mail: dosemeca@ninds.nih.gov [Laboratory of Neurobiology, NINDS, NIH, Bethesda, MD (United States)

    2014-07-18

    Highlights: • NMDA-induces accumulation of Shank at the postsynaptic density. • Shank accumulation is preferential to the distal region of the postsynaptic density. • Shank accumulation is mediated by CaMKII. - Abstract: Shank is a specialized scaffold protein present in high abundance at the postsynaptic density (PSD). Using pre-embedding immunogold electron microscopy on cultured hippocampal neurons, we had previously demonstrated further accumulation of Shank at the PSD under excitatory conditions. Here, using the same experimental protocol, we demonstrate that a cell permeable CaMKII inhibitor, tatCN21, blocks NMDA-induced accumulation of Shank at the PSD. Furthermore we show that NMDA application changes the distribution pattern of Shank at the PSD, promoting a 7–10 nm shift in the median distance of Shank labels away from the postsynaptic membrane. Inhibition of CaMKII with tatCN21 also blocks this shift in the distribution of Shank. Altogether these results imply that upon activation of NMDA receptors, CaMKII mediates accumulation of Shank, preferentially at the distal regions of the PSD complex extending toward the cytoplasm.

  19. Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade

    Elena eNosyreva

    2014-12-01

    Full Text Available Ketamine is a NMDA receptor antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDA receptor activation at rest, which inhibits eukaryotic elongation factor2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from older animals (6-9 weeks old. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDA receptors is sufficient to trigger this effect. These findings suggest that global blockade of NMDA receptors in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.

  20. Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia

    Colin Kehrer

    2008-04-01

    Full Text Available Schizophrenia is a common psychiatric disorder of high incidence, affecting approximately 1% of the world population. The essential neurotransmitter pathology of schizophrenia remains poorly defined, despite huge advances over the past half-century in identifying neurochemical and pathological abnormalities in the disease. The dopamine/serotonin hypothesis has originally provided much of the momentum for neurochemical research in schizophrenia. In recent years, the attention has, however, shifted to the glutamate system, the major excitatory neurotransmitter in the CNS and towards a concept of functional imbalance between excitatory and inhibitory transmission at the network level in various brain regions in schizophrenia. The evidence indicating a central role for the NMDAreceptor subtype in the etiology of schizophrenia has led to the NMDA-hypofunction model of this disease and the use of phencyclidines as a means to induce the NMDA-hypofunction state in animal models. The purpose of this review is to discuss recent findings highlighting the importance of the NMDA-hypofunction model of schizophrenia, both from a clinical perspective, as well as in opening a line of research, which enables electrophysiological studies at the cellular and network level in vitro. In particular, changes in excitation-inhibition (E/I balance in the NMDA-hypofunction model of the disease and the resulting changes in network behaviours, particularly in gamma frequency oscillatory activity, will be discussed.

  1. NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII

    Highlights: • NMDA-induces accumulation of Shank at the postsynaptic density. • Shank accumulation is preferential to the distal region of the postsynaptic density. • Shank accumulation is mediated by CaMKII. - Abstract: Shank is a specialized scaffold protein present in high abundance at the postsynaptic density (PSD). Using pre-embedding immunogold electron microscopy on cultured hippocampal neurons, we had previously demonstrated further accumulation of Shank at the PSD under excitatory conditions. Here, using the same experimental protocol, we demonstrate that a cell permeable CaMKII inhibitor, tatCN21, blocks NMDA-induced accumulation of Shank at the PSD. Furthermore we show that NMDA application changes the distribution pattern of Shank at the PSD, promoting a 7–10 nm shift in the median distance of Shank labels away from the postsynaptic membrane. Inhibition of CaMKII with tatCN21 also blocks this shift in the distribution of Shank. Altogether these results imply that upon activation of NMDA receptors, CaMKII mediates accumulation of Shank, preferentially at the distal regions of the PSD complex extending toward the cytoplasm

  2. Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications.

    Rodrigo, Regina; Cauli, Omar; Boix, Jordi; ElMlili, Nisrin; Agusti, Ana; Felipo, Vicente

    2009-01-01

    Acute liver failure (ALF) may lead to rapid death unless the patients receive a liver for transplantation. However, the number of livers available is not enough and a number of patients die before a suitable liver is available for transplantation. The liver has a high capacity for regeneration which may allow complete recovery even in patients with severe liver failure. It would be therefore very useful to have procedures to prevent or delay the mechanisms by which ALF leads to death. These mechanisms are no well understood. Progression of ALF leads to multi-organ failure, systemic inflammatory response, hepatic encephalopathy, cerebral oedema and increased intracranial pressure, which seem the most important immediate causes of mortality in patients with ALF. A main contributor to these events is hyperammonemia, due to impaired ammonia detoxification in the liver. Acute hyperammonemia per se leads to death, which is mediated by activation of the NMDA type of glutamate receptors in brain and may be prevented by antagonists blocking these receptors. Acute liver failure also leads to hyperammonemia and excessive activation of NMDA receptors in brain which contributes to ALF-induced death. Sustained blocking of NMDA receptors by continuous administration of the antagonists MK-801 or memantine increases about twice the survival time of rats with severe ALF due to injection of 2.5g/kg of galactosamine. In rats with milder ALF due to injection of 1.5g/kg of galactosamine, blocking NMDA receptors increases the percentage of surviving rats from 23% to 62% and increases about twice the survival time of the rats which die. These data strongly support that blocking NMDA receptors would improve survival of patients with ALF, either by allowing more time for liver regeneration or to get a liver suitable for transplantation. PMID:19428814

  3. Investigating the influence of PFC transection and nicotine on dynamics of AMPA and NMDA receptors of VTA dopaminergic neurons

    Chen Ting

    2011-10-01

    Full Text Available Abstract Background All drugs of abuse, including nicotine, activate the mesocorticolimbic system that plays critical roles in nicotine reward and reinforcement development and triggers glutamatergic synaptic plasticity on the dopamine (DA neurons in the ventral tegmental area (VTA. The addictive behavior and firing pattern of the VTA DA neurons are thought to be controlled by the glutamatergic synaptic input from prefrontal cortex (PFC. Interrupted functional input from PFC to VTA was shown to decrease the effects of the drug on the addiction process. Nicotine treatment could enhance the AMPA/NMDA ratio in VTA DA neurons, which is thought as a common addiction mechanism. In this study, we investigate whether or not the lack of glutamate transmission from PFC to VTA could make any change in the effects of nicotine. Methods We used the traditional AMPA/NMDA peak ratio, AMPA/NMDA area ratio, and KL (Kullback-Leibler divergence analysis method for the present study. Results Our results using AMPA/NMDA peak ratio showed insignificant difference between PFC intact and transected and treated with saline. However, using AMPA/NMDA area ratio and KL divergence method, we observed a significant difference when PFC is interrupted with saline treatment. One possible reason for the significant effect that the PFC transection has on the synaptic responses (as indicated by the AMPA/NMDA area ratio and KL divergence may be the loss of glutamatergic inputs. The glutamatergic input is one of the most important factors that contribute to the peak ratio level. Conclusions Our results suggested that even within one hour after a single nicotine injection, the peak ratio of AMPA/NMDA on VTA DA neurons could be enhanced.

  4. NMDA receptors are involved in the antidepressant-like effects of capsaicin following amphetamine withdrawal in male mice.

    Amiri, Shayan; Alijanpour, Sakineh; Tirgar, Fatemeh; Haj-Mirzaian, Arya; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Rastegar, Mojgan; Ghaderi, Marzieh; Ghazi-Khansari, Mahmoud; Zarrindast, Mohammad-Reza

    2016-08-01

    Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a key role in drug relapse and addictive behaviors. There is no efficient treatment for AW-induced depression and underpinning mechanisms were not well determined. Considering both transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and N-Methyl-d-aspartate (NMDA) receptors contribute to pathophysiology of mood and addictive disorders, in this study, we investigated the role of TRPV1 and NMDA receptors in mediating depressive-like behaviors following AW in male mice. Results revealed that administration of capsaicin, TRPV1 agonist, (100μg/mouse, i.c.v.) and MK-801, NMDA receptor antagonist (0.005mg/kg, i.p.) reversed AW-induced depressive-like behaviors in forced swimming test (FST) and splash test with no effect on animals' locomotion. Co-administration of sub-effective doses of MK-801 (0.001mg/kg, i.p.) and capsaicin (10μg/mouse, i.c.v) exerted antidepressant-like effects in behavioral tests. Capsazepine, TRPV1 antagonist, (100μg/mouse, i.c.v) and NMDA, NMDA receptor agonist (7.5mg/kg, i.p.) abolished the effects of capsaicin and MK-801, respectively. None of aforementioned treatments had any effect on behavior of control animals. Collectively, our findings showed that activation of TRPV1 and blockade of NMDA receptors produced antidepressant-like effects in male mice following AW, and these receptors are involved in AW-induced depressive-like behaviors. Further, we found that rapid antidepressant-like effects of capsaicin in FST and splash test are partly mediated by NMDA receptors. PMID:27167081

  5. Neurally augmented sexual function.

    Meloy, S

    2007-01-01

    Neurally Augmented Sexual Function (NASF) is a technique utilizing epidural electrodes to restore and improve sexual function. Orgasmic dysfunction is common in adult women, affecting roughly one quarter of populations studied. Many male patients suffering from erectile dysfunction are not candidates for phosphdiesterase therapy due to concomitant nitrate therapy. Positioning the electrodes at roughly the level of the cauda equina allows for stimulation of somatic efferents and afferents as well as modifying sympathetic and parasympathetic activity. Our series of women treated by NASF is described. Our experience shows that the evaluation of potential candidates for both correctable causes and psychological screening are important considerations. PMID:17691397

  6. PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPAR{gamma} activation in the liver

    Oishi, Katsutaka, E-mail: k-ooishi@aist.go.jp [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Uchida, Daisuke [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki (Japan); Ohkura, Naoki [Department of Clinical Molecular Biology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa (Japan); Horie, Shuichi [Department of Clinical Biochemistry, Kagawa Nutrition University, Sakado, Saitama (Japan)

    2010-10-15

    Research highlights: {yields} PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression. {yields} Hepatic expressions of PPAR{gamma} and PCG-1{alpha} are induced by a ketogenic diet. {yields} PPAR{gamma} antagonist attenuates a ketogenic diet-induced PAI-1 expression. {yields} Ketogenic diet advances the phase of circadian clock in a PPAR{alpha}-independent manner. -- Abstract: An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPAR{alpha}-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPAR{alpha}-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The KD-induced mRNA expression of typical PPAR{alpha} target genes such as Cyp4A10 and FGF21 was damped in PPAR{alpha}-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPAR{alpha}-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPAR{alpha} activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPAR{gamma} and its coactivator PCG-1{alpha} were more effectively induced in PPAR{alpha}-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPAR{gamma} antagonist, in both WT and PPAR

  7. The NMDA receptor changes during reperfusion after local ischemia in the rat brain

    excitatory amino acids increased greatly and remained high for a few hours. NMDA receptor was activated and its ion channel opened accordingly, which produced the ischemia damage. The best time of the therapy window of brain ischemia should be within 4 h

  8. The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation.

    Gollob, J A; Schnipper, C P; Murphy, E A; Ritz, J; Frank, D A

    1999-04-15

    IL-12 and IL-2 can stimulate mitogen- or CD3-activated T cells to proliferate, produce IFN-gamma, and kill tumor cells. The magnitude of these functional responses is greatly augmented when T cells are activated by the combination of IL-12 and IL-2. Although peripheral blood T cells are largely unresponsive to these cytokines without prior activation, a small subset of CD8+ T cells (CD8+CD18bright) is strongly activated by the combination of IL-12 and IL-2. In this report we show that the functional synergy between IL-12 and IL-2 in CD8+CD18bright T cells correlates with the activation of the stress kinases, p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase (SAPK)/Jun N-terminal kinase, but not with the activation of the extracellular signal-regulated kinases. The functional synergy between IL-2 and IL-12 is also associated with a prominent increase in STAT1 and STAT3 serine phosphorylation over that observed with IL-12 or IL-2 alone. By contrast, STAT tyrosine phosphorylation is not augmented over that seen with either cytokine alone. A specific inhibitor of p38 MAP kinase completely inhibits the serine phosphorylation of STAT1 and STAT3 induced by IL-12 and IL-2 and abrogates the functional synergy between IL-12 and IL-2 without affecting STAT tyrosine phosphorylation. This suggests that p38 MAP kinase may play an important role in regulating STAT serine phosphorylation in response to the combination of IL-12 and IL-2. Furthermore, these findings indicate that the optimal activation of T cells by IL-12 and IL-2 may depend on an interaction between the p38 MAP kinase and Janus kinase/STAT signaling pathways. PMID:10201984

  9. N-Methyl D-Aspartic Acid (NMDA Receptors and Depression

    Enver Yusuf Sivrioglu

    2009-06-01

    Full Text Available The monoaminergic hypothesis of depression has provided the basis for extensive research into the pathophysiology of mood disorders and has been of great significance for the development of effective antidepressants. Current antidepressant treatments not only increase serotonin and/or noradrenaline bioavailability but also originate adaptive changes increasing synaptic plasticity. Novel approaches to depression and to antidepressant therapy are now focused on intracellular targets that regulate neuroplasticity and cell survival. Accumulating evidence indicates that there is an anatomical substrate for such a devastating neuropsychiatric disease as major depression. Loss of synaptic plasticity and hippocampal atrophy appear to be prominent features of this highly prevalent disorder. A combination of genetic susceptibility and environmental factors make hippocampal neurons more vulnerable to stress. Abundant experimental evidence indicates that stress causes neuronal damage in brain regions, notably in hippocampal subfields. Stress-induced activation of glutamatergic transmission may induce neuronal cell death through excessive stimulation of N-methyl-D-aspartic acid (NMDA receptors. Recent studies mention that the increase of nitric oxide synthesis and inflammation in major depression may contribute to neurotoxicity through NMDA receptor. Both standard antidepressants and NMDA receptor antagonists are able to prevent stress-induced neuronal damage. NMDA antagonists are effective in widely used animal models of depression and some of them appear to be effective also in the few clinical trials performed to date. We are still far from understanding the complex cellular and molecular events involved in mood disorders. There appears to be an emerging role for glutamate neurotransmission in the search for the pathogenesis of major depression. Attenuation of NMDA receptor function mechanism appears to be a promising target in the search for a more

  10. AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons

    Rathje, Mette; Fang, Huaqiang; Bachman, Julia L;

    2013-01-01

    NMDA receptor activation promotes endocytosis of AMPA receptors, which is an important mechanism underlying long-term synaptic depression. The pH-sensitive GFP variant pHluorin fused to the N terminus of GluA2 (pH-GluA2) has been used to assay NMDA-mediated AMPA receptor endocytosis and recycling...... fluorescence recovery was eliminated in the presence of the NHE1 inhibitor zoniporide. Our results indicate that the pH-GluA2 recycling assay is an unreliable assay for studying AMPA receptor trafficking and also suggest a role for PICK1 in regulating intracellular pH via modulation of NHE activity....

  11. Augmented Reality in Astrophysics

    Vogt, Frédéric P A

    2013-01-01

    Augmented Reality consists of merging live images with virtual layers of information. The rapid growth in the popularity of smartphones and tablets over recent years has provided a large base of potential users of Augmented Reality technology, and virtual layers of information can now be attached to a wide variety of physical objects. In this article, we explore the potential of Augmented Reality for astrophysical research with two distinct experiments: (1) Augmented Posters and (2) Augmented Articles. We demonstrate that the emerging technology of Augmented Reality can already be used and implemented without expert knowledge using currently available apps. Our experiments highlight the potential of Augmented Reality to improve the communication of scientific results in the field of astrophysics. We also present feedback gathered from the Australian astrophysics community that reveals evidence of some interest in this technology by astronomers who experimented with Augmented Posters. In addition, we discuss p...

  12. Benzimidazole-2-carboxamides as novel NR2B selective NMDA receptor antagonists.

    Borza, István; Kolok, Sándor; Gere, Anikó; Nagy, József; Fodor, László; Galgóczy, Kornél; Fetter, József; Bertha, Ferenc; Agai, Béla; Horváth, Csilla; Farkas, Sándor; Domány, György

    2006-09-01

    A novel series of benzimidazole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of some structural elements, like H-bond donor groups placed on the benzimidazole skeleton and the substitution pattern of the piperidine ring, on the biological activity was studied. Compound 6a showed excellent analgetic activity in the mouse formalin test following po administration. PMID:16782335

  13. NMDA Receptor Modulators in the Treatment of Drug Addiction

    M. Foster Olive

    2013-02-01

    Full Text Available Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

  14. NMDA Receptor Modulators in the Treatment of Drug Addiction

    Tomek, Seven E.; LaCrosse, Amber L.; Nemirovsky, Natali E.; Olive, M. Foster

    2013-01-01

    Glutamate plays a pivotal role in drug addiction, and the N-methyl-d-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist d-Cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function. PMID:24275950

  15. NMDA Receptor Antagonism in the Lateral/Basolateral but Not Central Nucleus of the Amygdala Prevents the Induction of Facilitated Learning in Response to Stress

    Shors, Tracey J.; Mathew, Pramod R.

    1998-01-01

    Exposure to an acute stressful event facilitates classical eye-blink conditioning in the male rat. The facilitation persists for days after the stressor and its induction is prevented by antagonism of the N-methyl-d-aspartate (NMDA) type of glutamate receptor. To determine whether NMDA receptor antagonists prevent the facilitated conditioning by activity in the amygdala, a competitive antagonist, AP5, was injected bilaterally into the lateral/basolateral versus central nuclei of the amygdala....

  16. The Emergence of NMDA Receptor Metabotropic Function: Insights from Imaging

    Dore, Kim; Aow, Jonathan; Malinow, Roberto

    2016-01-01

    The NMDA receptor (R) participates in many important physiological and pathological processes. For example, its activation is required for both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission, cellular models of learning and memory. Furthermore, it may play a role in the actions of amyloid-beta on synapses as well as in the signaling leading to cell death following stroke. Until recently, these processes were thought to be mediated by ion-flux through the receptor. Using a combination of imaging and electrophysiological approaches, ion-flux independent functions of the NMDAR were recently examined. In this review, we will discuss the role of metabotropic NMDAR function in LTD and synaptic dysfunction. PMID:27516738

  17. On the Role of Glutamate in Presynaptic Development: Possible Contributions of Presynaptic NMDA Receptors

    Karlie N. Fedder

    2015-12-01

    Full Text Available Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is a key question in neuroscience. In this review, we focus on the regulation of excitatory presynaptic terminal development by glutamate, the predominant excitatory neurotransmitter in the brain. We discuss the evidence that NMDA receptor activation mediates these effects of glutamate and present the hypothesis that local activation of presynaptic NMDA receptors (preNMDARs contributes to glutamate-dependent control of presynaptic development. Abnormal glutamate signaling and aberrant synapse development are both thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, epilepsy, anxiety, depression, and schizophrenia. Therefore, understanding how glutamate signaling and synapse development are linked is important for understanding the etiology of these diseases.

  18. On the Role of Glutamate in Presynaptic Development: Possible Contributions of Presynaptic NMDA Receptors.

    Fedder, Karlie N; Sabo, Shasta L

    2015-01-01

    Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is a key question in neuroscience. In this review, we focus on the regulation of excitatory presynaptic terminal development by glutamate, the predominant excitatory neurotransmitter in the brain. We discuss the evidence that NMDA receptor activation mediates these effects of glutamate and present the hypothesis that local activation of presynaptic NMDA receptors (preNMDARs) contributes to glutamate-dependent control of presynaptic development. Abnormal glutamate signaling and aberrant synapse development are both thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, epilepsy, anxiety, depression, and schizophrenia. Therefore, understanding how glutamate signaling and synapse development are linked is important for understanding the etiology of these diseases. PMID:26694480

  19. [Participation of receptors of the NMDA type in regulation by glutamate of alimentary motor program of the freshwater mollusc lymnaea stagnalis].

    D'iakonova, T L; D'iakonova, V E

    2010-01-01

    A possible participation of receptors of the NMDA type in regulation by glutamate of the Lymnaea stagnalis feeding program was studied in electrophysiological experiments. The specific antagonist of receptors of the N-methyl-D-aspartate (NMDA) type MK-801 has been shown to turn off the endogenous generation of the standard three-phase rhythm or the two-phase rhythm. Stimulation of receptors of this type by their specific agonist, NMDA, on the contrary, increased frequency of the alimentary rhythm and transformed it into the two-phase one. All NMDA effects are eliminated by MK-801. Apart from action on generation of central feeding rhythms, ligands of receptors of the NMDA type changes the tonical level of depolarization and activity of the alimentary circuit motoneurons. MK-801 decreased the initial level of the motoneuron B4 activity and inhibited the excitatory effect both of NMDA and of glutamate itself. There are also obtained data in favor of that earlier reported effect of transformation of the inhibitory response of neurons B4 to glutamate into the excitatory one at action of nitric oxide (NO) donors can be mediated by the specific NO effect on the activity of receptors of the NMDA type. The blocker of NMDA receptors MK-801 has been shown to inhibit the effect of transformation of the response to glutamate. The NO donor nitroprusside enhanced essentially the NMDA excitatory action, while the NO acceptor oral PTIO decreased it. The results obtained with use of ODQ, the blocker of NO-sensitive guanylyl cyclase (GC), allow thinking that effect of NO on activity of the NMDA receptors of the pond snail feeding program can be realized through the metabolic pathway GC--cGMP. On the whole, the obtained results show the pond snail receptors of the NMDA type to participate in generation and rearragement of rhythmical alimentary programs in the tonical excitatory effect on the feeding program motoneurons in the NO-dependent transformation of the glutamate response

  20. Neuroprotection, excitotoxicicity and nmda antagonists Neuroproteção, excitotoxicidade e antagonistas do NMDA

    RUBENS JOSÉ GAGLIARDI

    2000-06-01

    Full Text Available PURPOSE: To analyze the main aspects of neuroprotection and excitotoxicity. DISCUSSION: This is a significant theory on the pathophysiology of cerebral ischemia; it is based on the release of excitatory aminoacid (EAA, mainly glutamate. The sequence starts with a decrease of the blood flow and ends in neuronal death. The main stages of this reaction are herein presented and discussed. An in depth study of the effects of the excessive intracellular calcium is undertaken. Neuroprotectors (NP are a group of drugs that reduce the excitotoxicity, opposing the excessive release of EAA and its intracellular effects. Neuroprotectors represent a rational approach to stroke treatment and offer a number of potential advantages. They prevent or limit ischemia-induced damage. CONCLUSION: There are many experimental and clinical NP trials. A minimum of 800 trials are currently under study worldwide. The most important NP subgroups are: N-methyl D-aspartate (NMDA antagonists, gamma-amino butyric acid (GABA agonists, amino-hydroxy-methyl-isoxalone propionic acid (AMPA antagonists, reducers of intracellular Ca++ inhibitors of nitric oxide modulation pathway free radicals scavengers, sodium channel antagonists, glutamate release inhibitor, growth factors, hypothermia and potassium channel activators.PROPÓSITO: Analisar importantes aspectos da neuroproteção e da excitotoxicidade. DISCUSSÃO: Excitotoxicidade é teoria que explica os mecanismos básicos da fisiopatologia da isquemia cerebral; é baseada na liberação excessiva de amino-ácidos excitatórios (AAE, principalmente o glutamato. A sequência se inicia com o decréscimo do fluxo sanguíneo cerebral e termina com a morte neuronal. Os principais aspectos desta cadeia de reações são apresentados e discutidos. Os efeitos do excesso de cálcio intracelular são analisados. Neuroprotetores (NP são um grupo de drogas que reduzem a excitotoxicidade combatendo a excessiva liberação de AAE e os seus

  1. Hyperammonemia alters the modulation by different neurosteroids of the glutamate-nitric oxide-cyclic GMP pathway through NMDA- GABAA - or sigma receptors in cerebellum in vivo.

    González-Usano, Alba; Cauli, Omar; Agustí, Ana; Felipo, Vicente

    2013-04-01

    Several neurosteroids modulate the glutamate-nitric oxide (NO)-cGMP pathway in cerebellum through modulation of NMDA- GABAA - or sigma receptors. Hyperammonemia alters the concentration of several neurosteroids and impairs the glutamate-NO-cGMP pathway, leading to impaired learning ability. This work aimed to assess whether chronic hyperammonemia alters the modulation by different neurosteroids of GABAA, NMDA, and/or sigma receptors and of the glutamate-NO-cGMP pathway in cerebellum. Neurosteroids were administered through microdialysis probes, and extracellular cGMP and citrulline were measured. Then NMDA was administered to assess the effects on the glutamate-NO-cGMP pathway activation. Hyperammonemia completely modifies the effects of pregnanolone and pregnenolone. Pregnanolone acts as a GABAA receptor agonist in controls, but as an NMDA receptor antagonist in hyperammonemic rats. Pregnenolone does not induce any effect in controls, but acts as a sigma receptor agonist in hyperammonemic rats. Hyperammonemia potentiates the actions of tetrahydrodeoxy-corticosterone (THDOC) as a GABAA receptor agonist, allopregnanolone as an NMDA receptor antagonist, and pregnenolone sulfate as an NMDA receptor activation enhancer. Neurosteroids that reduce the pathway (pregnanolone, THDOC, allopregnanolone, DHEAS) may contribute to cognitive impairment in hyperammonemia and hepatic encephalopathy. Pregnenolone would impair cognitive function in hyperammonemia. Neurosteroids that restore the pathway in hyperammonemia (pregnenolone sulfate) could restore cognitive function in hyperammonemia and encephalopathy. PMID:23227932

  2. Gambierol inhibition of voltage-gated potassium channels augments spontaneous Ca2+ oscillations in cerebrocortical neurons.

    Cao, Zhengyu; Cui, Yanjun; Busse, Eric; Mehrotra, Suneet; Rainier, Jon D; Murray, Thomas F

    2014-09-01

    Gambierol is a marine polycyclic ether toxin produced by the marine dinoflagellate Gambierdiscus toxicus and is a member of the ciguatoxin toxin family. Gambierol has been demonstrated to be either a low-efficacy partial agonist/antagonist of voltage-gated sodium channels or a potent blocker of voltage-gated potassium channels (Kvs). Here we examined the influence of gambierol on intact cerebrocortical neurons. We found that gambierol produced both a concentration-dependent augmentation of spontaneous Ca(2+) oscillations, and an inhibition of Kv channel function with similar potencies. In addition, an array of selective as well as universal Kv channel inhibitors mimicked gambierol in augmenting spontaneous Ca(2+) oscillations in cerebrocortical neurons. These data are consistent with a gambierol blockade of Kv channels underlying the observed increase in spontaneous Ca(2+) oscillation frequency. We also found that gambierol produced a robust stimulation of phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2). Gambierol-stimulated ERK1/2 activation was dependent on both inotropic [N-methyl-d-aspartate (NMDA)] and type I metabotropic glutamate receptors (mGluRs) inasmuch as MK-801 [NMDA receptor inhibitor; (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], S-(4)-CGP [S-(4)-carboxyphenylglycine], and MTEP [type I mGluR inhibitors; 3-((2-methyl-4-thiazolyl)ethynyl) pyridine] attenuated the response. In addition, 2-aminoethoxydiphenylborane, an inositol 1,4,5-trisphosphate receptor inhibitor, and U73122 (1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), a phospholipase C inhibitor, both suppressed gambierol-induced ERK1/2 activation, further confirming the role of type I mGluR-mediated signaling in the observed ERK1/2 activation. Finally, we found that gambierol produced a concentration-dependent stimulation of neurite outgrowth that was mimicked by 4-aminopyridine, a universal

  3. Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression

    Corlew, Rebekah; Wang, Yun; Ghermazien, Haben; Erisir, Alev; Philpot, Benjamin D.

    2007-01-01

    NMDA receptor (NMDAR) activation is required for many forms of learning and memory as well as sensory system receptive field plasticity, yet the relative contribution of pre- and postsynaptic NMDARs over cortical development remains unknown. Here we demonstrate a rapid developmental loss of functional presynaptic NMDARs in the neocortex. Presynaptic NMDARs enhance neurotransmitter release at synapses onto visual cortex pyramidal cells in young mice (< postnatal day 20; P20), but they have no ...

  4. Combined stimulation of IL-2 and 4-1BB receptors augments the antitumor activity of E7 DNA vaccines by increasing Ag-specific CTL responses.

    Kim, Ha; Kwon, Byungsuk; Sin, Jeong-Im

    2013-01-01

    Human papillomavirus (HPV) infection is a major cause of cervical cancer. Here, we investigate whether concurrent therapy using HPV E7 DNA vaccines (pE7) plus IL-2 vs. IL-15 cDNA and anti-4-1BB Abs might augment antitumor activity against established tumors. IL-2 cDNA was slightly better than IL-15 cDNA as a pE7 adjuvant. Co-delivery of pE7+IL-2 cDNA increased tumor cure rates from 7% to 27%, whereas co-delivery of pE7+IL-2 cDNA with anti-4-1BB Abs increased tumor cure rates from 27% to 67% and elicited long-term memory responses. This increased activity was concomitant with increased induction of Ag-specific CTL activity and IFN-γ responses, but not with Ag-specific IgG production. Moreover, the combined stimulation of IL-2 and 4-1BB receptors with rIL-2 and anti-4-1BB Abs resulted in enhanced production of IFN-γ from Ag-specific CD8+ T cells. However, this effect was abolished by treatment with anti-IL-2 Abs and 4-1BB-Fc, suggesting that the observed effect was IL-2- and anti-4-1BB Ab-specific. A similar result was also obtained for Ag-specific CTL activity. Thus, these studies demonstrate that combined stimulation through the IL-2 and 4-1BB receptors augments the Ag-specific CD8+ CTL responses induced by pE7, increasing tumor cure rates and long-term antitumor immune memory. These findings may have implications for the design of DNA-based therapeutic vaccines against cancer. PMID:24391824

  5. Combined stimulation of IL-2 and 4-1BB receptors augments the antitumor activity of E7 DNA vaccines by increasing Ag-specific CTL responses.

    Ha Kim

    Full Text Available Human papillomavirus (HPV infection is a major cause of cervical cancer. Here, we investigate whether concurrent therapy using HPV E7 DNA vaccines (pE7 plus IL-2 vs. IL-15 cDNA and anti-4-1BB Abs might augment antitumor activity against established tumors. IL-2 cDNA was slightly better than IL-15 cDNA as a pE7 adjuvant. Co-delivery of pE7+IL-2 cDNA increased tumor cure rates from 7% to 27%, whereas co-delivery of pE7+IL-2 cDNA with anti-4-1BB Abs increased tumor cure rates from 27% to 67% and elicited long-term memory responses. This increased activity was concomitant with increased induction of Ag-specific CTL activity and IFN-γ responses, but not with Ag-specific IgG production. Moreover, the combined stimulation of IL-2 and 4-1BB receptors with rIL-2 and anti-4-1BB Abs resulted in enhanced production of IFN-γ from Ag-specific CD8+ T cells. However, this effect was abolished by treatment with anti-IL-2 Abs and 4-1BB-Fc, suggesting that the observed effect was IL-2- and anti-4-1BB Ab-specific. A similar result was also obtained for Ag-specific CTL activity. Thus, these studies demonstrate that combined stimulation through the IL-2 and 4-1BB receptors augments the Ag-specific CD8+ CTL responses induced by pE7, increasing tumor cure rates and long-term antitumor immune memory. These findings may have implications for the design of DNA-based therapeutic vaccines against cancer.

  6. Gene-Activated Matrix Comprised of Atelocollagen and Plasmid DNA Encoding BMP4 or Runx2 Promotes Rat Cranial Bone Augmentation.

    Umebayashi, Mayumi; Sumita, Yoshinori; Kawai, Yousuke; Watanabe, Sumiko; Asahina, Izumi

    2015-01-01

    To date, therapeutic method for in vivo gene delivery has not been established on bone engineering though its potential usefulness has been suggested. For clinical applications, an effective condition should be developed to transfer the genes in vivo without any transfection reagents or virus vectors. In this study, to facilitate the clinical setting of this strategy, particularly aimed at atrophic bone repair, we simply investigated whether manufactured gene-activated matrix (GAM) with atelocollagen containing a certain amount of plasmid (p) DNA encoding osteogenic proteins could augment the cranial bone in rat. GAMs were manufactured by mixing 0.02, 0.1, or 1 mg of AcGFP plasmid vectors harboring cDNA of BMP4 (pBMP4) or Runx2 (pRunx2) with 2% bovine atelocollagen and β-tricalcium phosphate granules. Before manufacturing GAMs, to determine the biological activity of generated pDNAs, we confirmed GFP expression and increased level of alkaline phosphatase activities in MC3T3-E1 cells transfected with pBMP4 or pRunx2 during culture. Then, GAMs were lyophilized and transplanted to onlay placement on the cranium. At 2 weeks of transplantation, GFP-expressing cells could be detectable in only GAMs containing 1 mg of AcGFP plasmid vectors. Then, at 4 weeks, significant bone formation was recognized in GAMs containing 1 mg of pDNAs encoding BMP4 or Runx2 but not in 0.02 or 0.1 mg of GAMs. These newly formed bone tissues surrounded by osteocalcin-stained area were augmented markedly until 8 weeks after transplantation. In contrast, minimal bone formation was observed in GAMs without harboring cDNA of osteogenic proteins. Meanwhile, when GAMs were transplanted to the cranial bone defect, bone formation was detectable in specimens containing 1 mg of pBMP4 or pRunx2 at 8 weeks as well. Thus, atelocollagen-based GAM reliably could form the engineered bone even for the vertical augmentation when containing a certain amount of plasmid vectors encoding osteogenic

  7. INFLUENCE OF NMDA AND NON-NMDA ANTAGONISTS ON ACUTE AND INFLAMMATORY PAIN IN THE TRIGEMINAL TERRITORY

    Piovesan, Elcio Juliato; Randunz, Vitor; Utiumi, Marco; Lange, Marcos Cristiano; Kowacs, Pedro André; Mulinari, Rogério Andrade; Oshinsky, Michael; Vital, Maria; Sereniki, Adriana; Fernandes, Artur Furlaneto; Silva, Lucas Leite e; Werneck, Lineu César

    2016-01-01

    NMDA and non-NMDA receptors are involved in spinal transmission of nociceptive information in physiological and pathological conditions. Our objective was to study the influence of NMDA and non-NMDA receptor antagonists on pain control in the trigeminal system using a formalin-induced orofacial pain model. Motor performance was also evaluated. Male Rattus norvegicus were pre-treated with topiramate (T) (n=8), memantine (M) (n=8), divalproex (D) (n=8) or isotonic saline solution (ISS) (n=10) intraperitoneally 30 minutes before the formalin test. Formalin 2.5% was injected into the right upper lip (V2 branch) and induced two phases: phase I (early or neurogenic) (0–3 min) and phase II (late or inflammatory) (12–30 min). For motor behavior performance we used the open-field test and measured latency to movement onset, locomotion and rearing frequencies, and immobility time. Pre-treatment of animals with M and D only attenuated nociceptive formalin behavior for phase II. T increased locomotion and rearing frequencies and reduced immobility time. Treatment with M increased immobility time and with D reduced locomotion frequency. Our results showed that the NMDA antagonist (M) is more potent than the non-NMDA antagonists (D and T) in the control of pain in the inflammatory phase. The non-NMDA topiramate improved motor performance more than did D and M, probably because T has more anxiolytic properties. PMID:19099122

  8. AUGMENTATION-RELATED BRAIN PLASTICITY

    Giovanni eDi Pino

    2014-06-01

    Full Text Available Today, the anthropomorphism of the tools and the development of neural interfaces require reconsidering the concept of human-tools interaction in the framework of human augmentation. This review analyzes the plastic process that the brain undergoes when it comes into contact with augmenting artificial sensors and effectors and, on the other hand, the changes that the use of external augmenting devices produces in the brain.Hitherto, few studies investigated the neural correlates of augmentation, but clues on it can be borrowed from logically-related paradigms: sensorimotor training, cognitive enhancement, cross-modal plasticity, sensorimotor functional substitution, use and embodiment of tools.Augmentation modifies function and structure of a number of areas, i.e. primary sensory cortices shape their receptive fields to become sensitive to novel inputs. Motor areas adapt the neuroprosthesis representation firing-rate to refine kinematics. As for normal motor outputs, the learning process recruits motor and premotor cortices and the acquisition of proficiency decreases attentional recruitment, focuses the activity on sensorimotor areas and increases the basal ganglia drive on the cortex. Augmentation deeply relies on the frontoparietal network. In particular, premotor cortex is involved in learning the control of an external effector and owns the tool motor representation, while the intraparietal sulcus extracts its visual features. In these areas, multisensory integration neurons enlarge their receptive fields to embody supernumerary limbs. For operating an anthropomorphic neuroprosthesis, the mirror system is required to understand the meaning of the action, the cerebellum for the formation of its internal model and the insula for its interoception. In conclusion, anthropomorphic sensorized devices can provide the critical sensory afferences to evolve the exploitation of tools through their embodiment, reshaping the body representation and the

  9. Augmentation-related brain plasticity

    Di Pino, Giovanni; Maravita, Angelo; Zollo, Loredana; Guglielmelli, Eugenio; Di Lazzaro, Vincenzo

    2014-01-01

    Today, the anthropomorphism of the tools and the development of neural interfaces require reconsidering the concept of human-tools interaction in the framework of human augmentation. This review analyses the plastic process that the brain undergoes when it comes into contact with augmenting artificial sensors and effectors and, on the other hand, the changes that the use of external augmenting devices produces in the brain. Hitherto, few studies investigated the neural correlates of augmentation, but clues on it can be borrowed from logically-related paradigms: sensorimotor training, cognitive enhancement, cross-modal plasticity, sensorimotor functional substitution, use and embodiment of tools. Augmentation modifies function and structure of a number of areas, i.e., primary sensory cortices shape their receptive fields to become sensitive to novel inputs. Motor areas adapt the neuroprosthesis representation firing-rate to refine kinematics. As for normal motor outputs, the learning process recruits motor and premotor cortices and the acquisition of proficiency decreases attentional recruitment, focuses the activity on sensorimotor areas and increases the basal ganglia drive on the cortex. Augmentation deeply relies on the frontoparietal network. In particular, premotor cortex is involved in learning the control of an external effector and owns the tool motor representation, while the intraparietal sulcus extracts its visual features. In these areas, multisensory integration neurons enlarge their receptive fields to embody supernumerary limbs. For operating an anthropomorphic neuroprosthesis, the mirror system is required to understand the meaning of the action, the cerebellum for the formation of its internal model and the insula for its interoception. In conclusion, anthropomorphic sensorized devices can provide the critical sensory afferences to evolve the exploitation of tools through their embodiment, reshaping the body representation and the sense of the self

  10. Mobile Augmented Reality Applications

    Prochazka, David; Stencl, Michael; Popelka, Ondrej; Stastny, Jiri

    2011-01-01

    Augmented reality have undergone considerable improvement in past years. Many special techniques and hardware devices were developed, but the crucial breakthrough came with the spread of intelligent mobile phones. This enabled mass spread of augmented reality applications. However mobile devices have limited hardware capabilities, which narrows down the methods usable for scene analysis. In this article we propose an augmented reality application which is using cloud computing to enable using...

  11. Confronting an augmented reality

    Munnerley, Danny; Bacon, Matt; Wilson, Anna,; Steele, James; Hedberg, John; Fitzgerald, Robert

    2012-01-01

    How can educators make use of augmented reality technologies and practices to enhance learning and why would we want to embrace such technologies anyway? How can an augmented reality help a learner confront, interpret and ultimately comprehend reality itself ? In this article, we seek to initiate a discussion that focuses on these questions, and suggest that they be used as drivers for research into effective educational applications of augmented reality. We discuss how multi-modal, sensorial...

  12. Mobile Augmented Reality Applications

    Prochazka, David; Popelka, Ondrej; Stastny, Jiri

    2011-01-01

    Augmented reality have undergone considerable improvement in past years. Many special techniques and hardware devices were developed, but the crucial breakthrough came with the spread of intelligent mobile phones. This enabled mass spread of augmented reality applications. However mobile devices have limited hardware capabilities, which narrows down the methods usable for scene analysis. In this article we propose an augmented reality application which is using cloud computing to enable using of more complex computational methods such as neural networks. Our goal is to create an affordable augmented reality application suitable which will help car designers in by 'virtualizing' car modifications.

  13. Stress-induced changes of hippocampal NMDA receptors: modulation by duloxetine treatment.

    Francesca Calabrese

    Full Text Available It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. On the other hand, it has been demonstrated that NMDA antagonists, like ketamine, exert an antidepressant effect at preclinical and clinical levels. On these bases, the purpose of our study was to investigate whether chronic mild stress is associated with specific alterations of the NMDA receptor complex, in adult rats, and to establish whether concomitant antidepressant treatment could normalize such deficits. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Our data suggest that prolonged stress, a condition that has etiologic relevance for depression, may enhance glutamate activity through post-synaptic mechanisms, by regulating NMDA receptors, and that antidepressants may in part normalize such changes. Our results provide support to the notion that antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.

  14. Osteosynthesis-screw augmentation by ultrasound-activated biopolymer - an ovine in vivo study assessing biocompatibility and bone-to-implant contact

    Neumann, Hanjo; Breer, Stefan; Reimers, Nils; Kasch, Richard; Schulz, Arndt-Peter; Kienast, Benjamin

    2015-01-01

    Objectives Screw fixation and fragment anchoring in osteoporotic bones is often difficult. Problems like the cut out phenomenon and implant migration in osteoporotic bones have been reported. One possibility of improving the anchoring force of screws is augmentation of the screw. Cement-augmented screws in spinal surgery could exhibit a better anchoring in osteoporotic bones. Methods The purpose of this study was to examine the effect of screw augmentation using a resorbable polymer. Ultrasou...

  15. Adaptive Augmented Reality: Plasticity of Augmentations

    Ghouaiel, Nehla; Cieutat, Jean-Marc; Jessel, Jean-Pierre

    2014-01-01

    International audience An augmented reality system is used to complete the real world with virtual objects (computer generated) so they seem to coexist in the same space as the real world. The concept of plasticity [4][5] was first introduced for Human Computer Interaction (HCI). It denotes the ability of an HCI interface to fit the context of use defined by the user, the environment and the platform. We believe that plasticity is a very important notion in the domain of augmented reality....

  16. NMDA receptors in the basolateral amygdala and gustatory neophobia

    Figueroa-Guzmán, Yazmín; Reilly, Steve

    2008-01-01

    The attenuation of gustatory neophobia occurs during repeated exposures to an initially novel taste solution that is increasingly perceived as safe and familiar. The present study examined whether NMDA receptors in the basolateral region of the amygdala (BLA) are involved in this important behavioral phenomenon. The results, which show that the attenuation, but not initial occurrence, of gustatory neophobia is dependent upon NMDA receptors in the BLA, are discussed with reference to a similar...

  17. NMDA receptors and fear extinction: implications for cognitive behavioral therapy

    Davis, Michael

    2011-01-01

    Based primarily on studies that employ Pavlovian fear conditioning, extinction of conditioned fear has been found to be mediated by N-methyl-D-aspartate (NMDA) receptors in the amygdala and medial prefrontal cortex. This led to the discovery that an NMDA partial agonist, D-cycloserine, could facilitate fear extinction when given systemically or locally into the amygdala. Because many forms of cognitive behavioral therapy depend on fear extinction, this led to the successful use of D-cycloseri...

  18. Equating of Augmented Subscores

    Sinharay, Sandip; Haberman, Shelby J.

    2011-01-01

    Recently, there has been an increasing level of interest in subscores for their potential diagnostic value. Haberman (2008b) suggested reporting an augmented subscore that is a linear combination of a subscore and the total score. Sinharay and Haberman (2008) and Sinharay (2010) showed that augmented subscores often lead to more accurate…

  19. Confronting an Augmented Reality

    Munnerley, Danny; Bacon, Matt; Wilson, Anna; Steele, James; Hedberg, John; Fitzgerald, Robert

    2012-01-01

    How can educators make use of augmented reality technologies and practices to enhance learning and why would we want to embrace such technologies anyway? How can an augmented reality help a learner confront, interpret and ultimately comprehend reality itself ? In this article, we seek to initiate a discussion that focuses on these questions, and…

  20. AUGMENTATION OF IMMUNE FUNCTIONS AND AUTOLOGOUS TUMOR-KILLING ACTIVITY BY KAPPA-SELENOCARRAGEENAN IN MICE BEARING SARCOMA 180

    Wei Hulai; Jia Zhengping; Zhao Huishun

    1998-01-01

    Objective: To study the enhancement of the immune functions and autologous tumor-killing (ATK) activity by kappa-selenocarrageenan (KSC) in mice bearing sarcoma 180. Methods: To measure the effects of KSC and/or Cyclophosphamide (Cy) on natural killer (NK) activity,lymphokine-activated killer (LAK) activity, the production of interleukin-2 (IL-2), ATK activity and the growth of sarcoma 180 (S180). Results: KSC promoted NK activity, LAK activity and ATK activity in vivo, increased IL-2 production at 40 mg/kg/d×9d. It also enhanced the antitumor action of Cy (20 mg/kg/d×9d) and offset the inhibition of Cy on immunocopetent cells. The ATK activity in splenocytes of S180-bearing mice could be induced and increased by recombinant interleukin-2 (rIL-2) in vitro. Conclusion: KSC has an up- regulating effect on the immune functions and ATK activity in tumorbearing mice. It can be used as a biological response modifier (BRM) in cancer biotherapy.

  1. Combined stimulation of the glycine and polyamine sites of the NMDA receptor attenuates NMDA blockade-induced learning deficits of rats in a 14-unit T-maze.

    Meyer, R C; Knox, J; Purwin, D A; Spangler, E L; Ingram, D K

    1998-02-01

    The present study examined the effects of multi-site activation of the glycine and polyamine sites of the NMDA receptor on memory formation in rats learning a 14-unit T-maze task. The competitive NMDA receptor antagonist, (+/-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP, 9 mg/kg), was used to impair learning. The objectives were two-fold: (1) to investigate the effects of independent stimulation of the strychnine-insensitive glycine site or the polyamine site; (2) to investigate the effects of simultaneous activation of these two sites. Male, Fischer-344 rats were pretrained to a criterion of 13 out of 15 shock avoidances in a straight runway, and 24 h later were trained in a 14-unit T-maze that also required shock avoidance. Prior to maze training, rats received intraperitoneal (i.p.) injections of saline, saline plus CPP, CPP plus the glycine agonist, D-cycloserine (DCS, 30 or 40 mg/kg), CPP plus the polyamine agonist, spermine (SPM, 2.5 or 5 mg/kg), or CPP plus a combination of DCS (7.5 mg/kg) and SPM (0.625 mg/kg). Individual administration of either DCS or SPM attenuated the CPP-induced maze learning impairment in a dose-dependent manner. However, the combined treatment with both DCS and SPM completely reversed the learning deficit at doses five-fold less than either drug given alone. These findings provide additional evidence that the glycine and polyamine modulatory sites of the NMDA receptor are involved in memory formation. Furthermore, the potent synergistic effect resulting from combined activation of the glycine and polyamine sites would suggest a stronger interaction between these two sites than previously considered, and might provide new therapeutic approaches for enhancing glutamatergic function. PMID:9498733

  2. GluN3A promotes NMDA spiking by enhancing synaptic transmission in Huntington's disease models.

    Mahfooz, Kashif; Marco, Sonia; Martínez-Turrillas, Rebeca; Raja, Mathan K; Pérez-Otaño, Isabel; Wesseling, John F

    2016-09-01

    Age-inappropriate expression of juvenile NMDA receptors (NMDARs) containing GluN3A subunits has been linked to synapse loss and death of spiny projection neurons of the striatum (SPNs) in Huntington's disease (HD). Here we show that suppressing GluN3A expression prevents a multivariate synaptic transmission phenotype that precedes morphological signs at early prodromal stages. We start by confirming that afferent fiber stimulation elicits larger synaptic responses mediated by both AMPA receptors and NMDARs in SPNs in the YAC128 mouse model of HD. We then show that the enhancement mediated by both is fully prevented by suppressing GluN3A expression. Strong fiber-stimulation unexpectedly elicited robust NMDAR-mediated electrogenic events (termed "upstates" or "NMDA spikes"), and the effective threshold for induction was more than 2-fold lower in YAC128 SPNs because of the enhanced synaptic transmission. The threshold could be restored to control levels by suppressing GluN3A expression or by applying the weak NMDAR blocker memantine. However, the threshold was not affected by preventing glutamate spillover from synaptic clefts. Instead, long-lasting NMDAR responses interpreted previously as activation of extrasynaptic receptors by spilled-over glutamate were caused by NMDA spikes occurring in voltage clamp mode as escape potentials. Together, the results implicate GluN3A reactivation in a broad spectrum of early-stage synaptic transmission deficits in YAC128 mice; question the current concept that NMDAR mislocalization is the pathological trigger in HD; and introduce NMDA spikes as a new candidate mechanism for coupling NMDARs to neurodegeneration. PMID:27072890

  3. NMDA antagonists exert distinct effects in experimental organophosphate or carbamate poisoning in mice

    Organophosphate (OP) and carbamate acetylcholinesterase (AChE) inhibitors produce seizures and lethality in mammals. Anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) antagonists encourage the investigation of their effects in AChE inhibitor-induced poisonings. In the present study, the effects of dizocilpine (MK-801, 1 mg/kg) or 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10 mg/kg), alone or combined with muscarinic antagonist atropine (1.8 mg/kg), on convulsant and lethal properties of an OP pesticide dichlorvos or a carbamate drug physostigmine, were studied in mice. Both dichlorvos and physostigmine induced dose-dependent seizure activity and lethality. Atropine did not prevent the occurrence of convulsions but decreased the lethal effects of both dichlorvos and physostigmine. MK-801 or CPP blocked or attenuated, respectively, dichlorvos-induced convulsions. Contrariwise, NMDA antagonists had no effect in physostigmine-induced seizures or lethality produced by dichlorvos or physostigmine. Concurrent pretreatment with atropine and either MK-801 or CPP blocked or alleviated seizures produced by dichlorvos, but not by physostigmine. Both MK-801 and CPP co-administered with atropine enhanced its antilethal effects in both dichlorvos and physostigmine poisoning. In both saline- and AChE inhibitor-treated mice, no interaction of the investigated antidotes with brain cholinesterase was found. The data indicate that both muscarinic ACh and NMDA receptor-mediated mechanisms contribute to the acute toxicity of AChE inhibitors, and NMDA receptors seem critical to OP-induced seizures

  4. Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats

    Roesler R.

    1998-01-01

    Full Text Available The purpose of this research was to evaluate the role of hippocampal N-methyl-D-aspartate (NMDA receptors in acquisition and consolidation of memory during shuttle avoidance conditioning in rats. Adult male Wistar rats were surgically implanted with cannulae aimed at the CA1 area of the dorsal hippocampus. After recovery from surgery, animals were trained and tested in a shuttle avoidance apparatus (30 trials, 0.5-mA footshock, 24-h training-test interval. Immediately before or immediately after training, animals received a bilateral intrahippocampal 0.5-µl infusion containing 5.0 µg of the NMDA competitive receptor antagonist aminophosphonopentanoic acid (AP5 or vehicle (phosphate-buffered saline, pH 7.4. Infusion duration was 2 min per side. Pre-training infusion of AP5 impaired retention test performance (mean ± SEM number of conditioned responses (CRs during retention test session was 16.47 ± 1.78 in the vehicle group and 9.93 ± 1.59 in the AP5 group; P<0.05. Post-training infusion of AP5 did not affect retention (mean ± SEM number of conditioned responses during retention test session was 18.46 ± 1.94 in the vehicle group and 20.42 ± 2.38 in the AP5 group; P>0.10. This impairment could not be attributed to an effect on acquisition, motor activity or footshock sensitivity since AP5 affected neither training session performance measured by the number of CRs nor the number of intertrial crossings during the training session. These data suggest that NMDA receptors in the hippocampus are critical for retention of shuttle avoidance conditioning, in agreement with previous evidence showing a role of NMDA receptors in fear memory.

  5. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

    Yang, Jiangyan

    2014-07-28

    L-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. L-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, L-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of L-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of L-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived L-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of L-lactate as a signaling molecule for neuronal plasticity.

  6. Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.

    Chun-Lei Zhang

    Full Text Available Methylphenidate (MPH, commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD. Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC. To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca(2+ increase, but does not require PKA and extracellular Ca(2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.

  7. Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.

    Zhang, Chun-Lei; Feng, Ze-Jun; Liu, Yue; Ji, Xiao-Hua; Peng, Ji-Yun; Zhang, Xue-Han; Zhen, Xue-Chu; Li, Bao-Ming

    2012-01-01

    Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca(2+) increase, but does not require PKA and extracellular Ca(2+) influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects. PMID:23284812

  8. Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons

    Xanthi Antoniou

    2010-01-01

    Full Text Available The phosphorylation of Amyloid Precursor Protein (APP at Thr668 plays a key role in APP metabolism that is highly relevant to AD. The c-Jun-N-terminal kinase (JNK, glycogen synthase kinase-3β (GSK-3β and cyclin-dependent kinase 5 (Cdk5 can all be responsible for this phosphorylation. These kinases are activated by excitotoxic stimuli fundamental hallmarks of AD. The exposure of cortical neurons to a high dose of NMDA (100 μM for 30’-45’ led to an increase of P-APP Thr668. During NMDA stimulation APP hyperphosphorylation has to be assigned to GSK-3β activity, since addition of L803-mts, a substrate competitive inhibitor of GSK-3β reduced APP phosphorylation induced by NMDA. On the contrary, inhibition of JNK and Cdk5 with D-JNKI1 and Roscovitine respectively did not prevent NMDA-induced P-APP increase. These data show a tight connection, in excitotoxic conditions, between APP metabolism and the GSK-3β signaling pathway.

  9. Retrieval-induced NMDA receptor-dependent Arc expression in two models of cocaine-cue memory.

    Alaghband, Yasaman; O'Dell, Steven J; Azarnia, Siavash; Khalaj, Anna J; Guzowski, John F; Marshall, John F

    2014-12-01

    The association of environmental cues with drugs of abuse results in persistent drug-cue memories. These memories contribute significantly to relapse among addicts. While conditioned place preference (CPP) is a well-established paradigm frequently used to examine the modulation of drug-cue memories, very few studies have used the non-preference-based model conditioned activity (CA) for this purpose. Here, we used both experimental approaches to investigate the neural substrates of cocaine-cue memories. First, we directly compared, in a consistent setting, the involvement of cortical and subcortical brain regions in cocaine-cue memory retrieval by quantifying activity-regulated cytoskeletal-associated (Arc) protein expression in both the CPP and CA models. Second, because NMDA receptor activation is required for Arc expression, we investigated the NMDA receptor dependency of memory persistence using the CA model. In both the CPP and CA models, drug-paired animals showed significant increases in Arc immunoreactivity in regions of the frontal cortex and amygdala compared to unpaired controls. Additionally, administration of a NMDA receptor antagonist (MK-801 or memantine) immediately after cocaine-CA memory reactivation impaired the subsequent conditioned locomotion associated with the cocaine-paired environment. The enhanced Arc expression evident in a subset of corticolimbic regions after retrieval of a cocaine-context memory, observed in both the CPP and CA paradigms, likely signifies that these regions: (i) are activated during retrieval of these memories irrespective of preference-based decisions, and (ii) undergo neuroplasticity in order to update information about cues previously associated with cocaine. This study also establishes the involvement of NMDA receptors in maintaining memories established using the CA model, a characteristic previously demonstrated using CPP. Overall, these results demonstrate the utility of the CA model for studies of cocaine

  10. Comparison of anticonvulsant effect of competitive non-NMDA and noncompetitive NMDA receptor antagonists in adult rats

    Lojková, Denisa; Živanovič, Dragana; Mareš, Pavel

    -, - (2005), s. 160-160. [Conference of the Czech Neuroscience Society /5./, The Annual Meeting of the Network of European Neuroscience Institutes. 19.11.2005-21.11.2005, Prague] R&D Projects: GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : anticonvulsant effect * non-NMDA- receptor antagonist * NMDA receptor antagonist * rats Subject RIV: ED - Physiology

  11. miR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γc cytokines

    Ji, Yun; Wrzesinski, Claudia; Yu, Zhiya; Hu, Jinhui; Gautam, Sanjivan; Hawk, Nga V.; Telford, William G.; Palmer, Douglas C.; Franco, Zulmarie; Sukumar, Madhusudhanan; Roychoudhuri, Rahul; Clever, David; Klebanoff, Christopher A.; Surh, Charles D.; Waldmann, Thomas A.; Restifo, Nicholas P.; Gattinoni, Luca

    2015-01-01

    Lymphodepleting regimens are used before adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic “cytokine sinks.” These conditioning modalities, however, are often associated with severe toxicities. We found that microRNA-155 (miR-155) enabled tumor-specific CD8+ T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T-cell responsiveness to limited amounts of homeostatic γc cytokines, resulting in delayed cellular contraction and sustained cytokine production. miR-155 restrained the expression of the inositol 5-phosphatase Ship1, an inhibitor of the serine-threonine protein kinase Akt, and multiple negative regulators of signal transducer and activator of transcription 5 (Stat5), including suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine phosphatase Ptpn2. Expression of constitutively active Stat5a recapitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be used to increase the effectiveness of adoptive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers. PMID:25548153

  12. Ligation of FcγR Alters Phagosomal Processing of Protein via Augmentation of NADPH Oxidase Activity.

    Balce, Dale R; Rybicka, Joanna M; Greene, Catherine J; Ewanchuk, Benjamin W; Yates, Robin M

    2016-07-01

    Proteolysis and the reduction of disulfides, both major components of protein degradation, are profoundly influenced by phagosomal redox conditions in macrophages. We evaluated the activation of phagocytic receptors that are known to influence activation of the phagocyte NADPH oxidase (NOX2), and its effect on phagosomal protein degradation. Population-based and single phagosome analyses of phagosomal chemistries in murine macrophages revealed that activation of NOX2 via the Fcγ receptor (FcγR) during phagocytosis decreased rates of proteolysis and disulfide reduction. Immunoglobulin G (IgG)-stimulated reactive oxygen species (ROS) production and the inhibition of phagosomal proteolysis and disulfide reduction were dependent on NOX2, FcγR and protein kinase C (PKC)/spleen tyrosine kinase (Syk) signaling. In contrast, low levels of ROS production were observed following the phagocytosis of unopsonized beads, which resulted in higher rates of phagosomal proteolysis and disulfide reduction. Phagosomes displayed autonomy with respect to FcγR-mediated differences in NOX2 activation and proteolysis, as phagosomes containing unopsonized cargo retained low NOX2 activation and high proteolysis even in the presence of phagosomes containing IgG-opsonized cargo in the same macrophage. These results show that opsonization of phagocytic cargo results in vastly different phagosomal processing of proteins through the FcγR-triggered, PKC/Syk-dependent local assembly and activation of NOX2. PMID:27020146

  13. Control Augmented Structural Synthesis

    Lust, Robert V.; Schmit, Lucien A.

    1988-01-01

    A methodology for control augmented structural synthesis is proposed for a class of structures which can be modeled as an assemblage of frame and/or truss elements. It is assumed that both the plant (structure) and the active control system dynamics can be adequately represented with a linear model. The structural sizing variables, active control system feedback gains and nonstructural lumped masses are treated simultaneously as independent design variables. Design constraints are imposed on static and dynamic displacements, static stresses, actuator forces and natural frequencies to ensure acceptable system behavior. Multiple static and dynamic loading conditions are considered. Side constraints imposed on the design variables protect against the generation of unrealizable designs. While the proposed approach is fundamentally more general, here the methodology is developed and demonstrated for the case where: (1) the dynamic loading is harmonic and thus the steady state response is of primary interest; (2) direct output feedback is used for the control system model; and (3) the actuators and sensors are collocated.

  14. Partial involvement of NMDA receptors and glial cells in the nociceptive behaviors induced by intrathecally administered histamine.

    Mizoguchi, Hirokazu; Komatsu, Takaaki; Iwata, Yoko; Watanabe, Chizuko; Watanabe, Hiroyuki; Orito, Tohru; Katsuyama, Soh; Yonezawa, Akihiko; Onodera, Kenji; Sakurada, Tsukasa; Sakurada, Shinobu

    2011-05-16

    The involvement of spinal glial cells in the nociceptive behaviors induced by 800 pmol of histamine was determined in mice. Histamine at 800 pmol injected intrathecally (i.t.) produced nociceptive behaviors, consisting of scratching, biting and licking. The nociceptive behaviors induced by histamine were significantly suppressed by i.t. co-administration with tachykinin NK(1) receptor antagonist CP99,994 or competitive antagonist for N-methyl-d-aspartate (NMDA) receptor d-(-)-2-amino-5-phosphonovaleric acid (d-APV). The i.t. pretreatment with the glial cell inhibitor dl-fluorocitric acid or minocycline failed to affect the nociceptive behaviors induced by histamine. However, in mice pretreated i.t. with dl-fluorocitric acid or minocycline, the nociceptive behaviors induced by histamine were significantly suppressed by i.t. co-administration with CP99,994 but not d-APV. In Western blot analysis using lumbar spinal cords, i.t. treatment with 800 pmol of histamine increased the phosphorylation of the NR1 subunit of NMDA receptors. The increased phosphorylation of the NR1 subunit of NMDA receptors by histamine was abolished by i.t. pretreatment with dl-fluorocitric acid or minocycline. The present results suggest that histamine at 800 pmol elicits nociceptive behaviors through activation of the neuronal NK(1) receptor and the NR1 subunit-containing NMDA receptors on glial cells in the spinal cord. PMID:21352890

  15. Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains.

    Weed, Michael R; Bookbinder, Mark; Polino, Joseph; Keavy, Deborah; Cardinal, Rudolf N; Simmermacher-Mayer, Jean; Cometa, Fu-ni L; King, Dalton; Thangathirupathy, Srinivasan; Macor, John E; Bristow, Linda J

    2016-01-01

    Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains. PMID:26105137

  16. Magnetic resonance analysis of the effects of acute ammonia intoxication on rat brain. Role of NMDA receptors.

    Cauli, Omar; López-Larrubia, Pilar; Rodrigues, Tiago B; Cerdán, Sebastián; Felipo, Vicente

    2007-11-01

    Acute ammonia intoxication leads to rapid death, which is prevented by blocking N-methyl-d-aspartate (NMDA) receptors. The subsequent mechanisms leading to death remain unclear. Brain edema seems an important step. The aim of this work was to study the effects of acute ammonia intoxication on different cerebral parameters in vivo using magnetic resonance and to assess which effects are mediated by NMDA receptors activation. To assess edema induction, we injected rats with ammonium acetate and measured apparent diffusion coefficient (ADC) in 16 brain areas. We also analyzed the effects on T1, T2, and T2* maps and whether these effects are prevented by blocking NMDA receptors. The effects of acute ammonia intoxication are different in different brain areas. T1 relaxation time is reduced in eight areas. T2 relaxation time is reduced only in ventral thalamus and globus pallidus. ADC values increased in hippocampus, caudate-putamen, substantia nigra and cerebellar cortex, reflecting vasogenic edema. ADC decreased in hypothalamus, reflecting cytotoxic edema. Myo-inositol increased in cerebellum and substantia nigra, reflecting vasogenic edema. N-acetyl-aspartate decreased in cerebellum, reflecting neuronal damage. Changes in N-acetyl-aspartate, T1 and T2 are prevented by blocking NMDA receptors with MK-801 while changes in ADC or myo-inositol (induction of edema) are not. PMID:17727627

  17. Augmented reality: a review.

    Berryman, Donna R

    2012-01-01

    Augmented reality is a technology that overlays digital information on objects or places in the real world for the purpose of enhancing the user experience. It is not virtual reality, that is, the technology that creates a totally digital or computer created environment. Augmented reality, with its ability to combine reality and digital information, is being studied and implemented in medicine, marketing, museums, fashion, and numerous other areas. This article presents an overview of augmented reality, discussing what it is, how it works, its current implementations, and its potential impact on libraries. PMID:22559183

  18. Toll-like receptor agonist augments virus-like particle-mediated protection from Ebola virus with transient immune activation.

    Karen A O Martins

    Full Text Available Identifying safe and effective adjuvants is critical for the advanced development of protein-based vaccines. Pattern recognition receptor (PRR agonists are increasingly being explored as potential adjuvants, but there is concern that the efficacy of these molecules may be dependent on potentially dangerous levels of non-specific immune activation. The filovirus virus-like particle (VLP vaccine protects mice, guinea pigs, and nonhuman primates from viral challenge. In this study, we explored the impact of a stabilized dsRNA mimic, polyICLC, on VLP vaccination of C57BL/6 mice and Hartley guinea pigs. We show that at dose levels as low as 100 ng, the adjuvant increased the efficacy of the vaccine in mice. Antigen-specific, polyfunctional CD4 and CD8 T cell responses and antibody responses increased significantly upon inclusion of adjuvant. To determine whether the efficacy of polyICLC correlated with systemic immune activation, we examined serum cytokine levels and cellular activation in the draining lymph node. PolyICLC administration was associated with increases in TNFα, IL6, MCP1, MIP1α, KC, and MIP1β levels in the periphery and with the activation of dendritic cells (DCs, NK cells, and B cells. However, this activation resolved within 24 to 72 hours at efficacious adjuvant dose levels. These studies are the first to examine the polyICLC-induced enhancement of antigen-specific immune responses in the context of non-specific immune activation, and they provide a framework from which to consider adjuvant dose levels.

  19. Combination immunotherapy and active-specific tumor cell vaccination augments anti-cancer immunity in a mouse model of gastric cancer

    van den Engel Natasja K

    2011-08-01

    Full Text Available Abstract Background Active-specific immunotherapy used as an adjuvant therapeutic strategy is rather unexplored for cancers with poorly characterized tumor antigens like gastric cancer. The aim of this study was to augment a therapeutic immune response to a low immunogenic tumor cell line derived from a spontaneous gastric tumor of a CEA424-SV40 large T antigen (CEA424-SV40 TAg transgenic mouse. Methods Mice were treated with a lymphodepleting dose of cyclophosphamide prior to reconstitution with syngeneic spleen cells and vaccination with a whole tumor cell vaccine combined with GM-CSF (a treatment strategy abbreviated as LRAST. Anti-tumor activity to subcutaneous tumor challenge was examined in a prophylactic as well as a therapeutic setting and compared to corresponding controls. Results LRAST enhances tumor-specific T cell responses and efficiently inhibits growth of subsequent transplanted tumor cells. In addition, LRAST tended to slow down growth of established tumors. The improved anti-tumor immune response was accompanied by a transient decrease in the frequency and absolute number of CD4+CD25+FoxP3+ T cells (Tregs. Conclusions Our data support the concept that whole tumor cell vaccination in a lymphodepleted and reconstituted host in combination with GM-CSF induces therapeutic tumor-specific T cells. However, the long-term efficacy of the treatment may be dampened by the recurrence of Tregs. Strategies to counteract suppressive immune mechanisms are required to further evaluate this therapeutic vaccination protocol.

  20. Ethanol affects NMDA receptor signaling at climbing fiber-Purkinje cell synapses in mice and impairs cerebellar LTD.

    He, Qionger; Titley, Heather; Grasselli, Giorgio; Piochon, Claire; Hansel, Christian

    2013-03-01

    Ethanol profoundly influences cerebellar circuit function and motor control. It has recently been demonstrated that functional N-methyl-(D)-aspartate (NMDA) receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in the adult cerebellum. Using whole cell patch-clamp recordings from mouse cerebellar slices, we examined whether ethanol can affect NMDA receptor signaling in mature Purkinje cells. NMDA receptor-mediated currents were isolated by bath application of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol[f]quinoxaline (NBQX). The remaining (D)-2-amino-5-phosphonovaleric acid ((D)-APV)-sensitive current was reduced by ethanol at concentrations as low as 10 mM. At a concentration of 50 mM ethanol, the blockade of (D)-APV-sensitive CF-excitatory postsynaptic currents was significantly stronger. Ethanol also altered the waveform of CF-evoked complex spikes by reducing the afterdepolarization. This effect was not seen when NMDA receptors were blocked by (D)-APV before ethanol wash-in. In contrast to CF synaptic transmission, parallel fiber (PF) synaptic inputs were not affected by ethanol. Finally, ethanol (10 mM) impaired long-term depression (LTD) at PF to Purkinje cell synapses as induced under control conditions by paired PF and CF activity. However, LTD induced by pairing PF stimulation with depolarizing voltage steps (substituting for CF activation) was not blocked by ethanol. These observations suggest that the sensitivity of cerebellar circuit function and plasticity to low concentrations of ethanol may be caused by an ethanol-mediated impairment of NMDA receptor signaling at CF synapses onto cerebellar Purkinje cells. PMID:23221414

  1. Increased diacylglycerol kinase ζ expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion

    Unraveling the signaling pathways responsible for the establishment of a metastatic phenotype in carcinoma cells is critically important for understanding the pathology of cancer. The acquisition of cell motility is a key property of metastatic tumor cells and is a prerequisite for invasion. Rho GTPases regulate actin cytoskeleton reorganization and the cellular responses required for cell motility and invasion. Diacylglycerol kinase ζ (DGKζ), an enzyme that phosphorylates diacylglycerol to yield phosphatidic acid, regulates the activity of the Rho GTPases Rac1 and RhoA. DGKζ mRNA is highly expressed in several different colon cancer cell lines, as well as in colon cancer tissue relative to normal colonic epithelium, and thus may contribute to the metastatic process. To investigate potential roles of DGKζ in cancer metastasis, a cellular, isogenic model of human colorectal cancer metastatic transition was used. DGKζ protein levels, Rac1 and RhoA activity, and PAK phosphorylation were measured in the non-metastatic SW480 adenocarcinoma cell line and its highly metastatic variant, the SW620 line. The effect of DGKζ silencing on Rho GTPase activity and invasion through Matrigel-coated Transwell inserts was studied in SW620 cells. Invasiveness was also measured in PC-3 prostate cancer and MDA-MB-231 breast cancer cells depleted of DGKζ. DGKζ protein levels were elevated approximately 3-fold in SW620 cells compared to SW480 cells. There was a concomitant increase in active Rac1 in SW620 cells, as well as substantial increases in the expression and phosphorylation of the Rac1 effector PAK1. Similarly, RhoA activity and expression were increased in SW620 cells. Knockdown of DGKζ expression in SW620 cells by shRNA-mediated silencing significantly reduced Rac1 and RhoA activity and attenuated the invasiveness of SW620 cells in vitro. DGKζ silencing in highly metastatic MDA-MB-231 breast cancer cells and PC-3 prostate cancer cells also significantly attenuated

  2. Media-Augmented Exercise Machines

    Krueger, T.

    2002-01-01

    Cardio-vascular exercise has been used to mitigate the muscle and cardiac atrophy associated with adaptation to micro-gravity environments. Several hours per day may be required. In confined spaces and long duration missions this kind of exercise is inevitably repetitive and rapidly becomes uninteresting. At the same time, there are pressures to accomplish as much as possible given the cost- per-hour for humans occupying orbiting or interplanetary. Media augmentation provides a the means to overlap activities in time by supplementing the exercise with social, recreational, training or collaborative activities and thereby reducing time pressures. In addition, the machine functions as an interface to a wide range of digital environments allowing for spatial variety in an otherwise confined environment. We hypothesize that the adoption of media augmented exercise machines will have a positive effect on psycho-social well-being on long duration missions. By organizing and supplementing exercise machines, data acquisition hardware, computers and displays into an interacting system this proposal increases functionality with limited additional mass. This paper reviews preliminary work on a project to augment exercise equipment in a manner that addresses these issues and at the same time opens possibilities for additional benefits. A testbed augmented exercise machine uses a specialty built cycle trainer as both input to a virtual environment and as an output device from it using spatialized sound, and visual displays, vibration transducers and variable resistance. The resulting interactivity increases a sense of engagement in the exercise, provides a rich experience of the digital environments. Activities in the virtual environment and accompanying physiological and psychological indicators may be correlated to track and evaluate the health of the crew.

  3. ANTIDEPRESSANT-LIKE EFFECTS OF LOW KETAMINE DOSE IS ASSOCIATED WITH INCREASED HIPPOCAMPAL AMPA/NMDA RECEPTOR DENSITY RATIO IN FEMALE WISTAR-KYOTO RATS

    Tizabi, Yousef; Bhatti, Babur H; Manaye, Kebreten F; Das, Jharna R; Akinfiresoye, Luli

    2012-01-01

    Preclinical as well as limited clinical studies indicate that ketamine, a non-competitive glutamate NMDA receptor antagonist, may exert a quick and prolonged antidepressant effect. It has been postulated that ketamine action is due to inhibition of NMDA and stimulation of AMPA receptors. Here, we sought to determine whether ketamine would exert antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of depression and whether this effect would be associated with changes in AMPA/NMDA receptor densities in the hippocampus. Adult female WKY rats and their control Wistar rats were subjected to acute and chronic ketamine doses and their locomotor activity (LMA) and immobility in the forced swim test (FST) were evaluated. Hippocampal AMPA and NMDA receptor densities were also measured following a chronic ketamine dose. Ketamine, both acutely (0.5–5.0 mg/kg ip) and chronically (0.5–2.5 mg/kg daily for 10 days) resulted in a dose-dependent and prolonged decrease in immobility in the FST in WKY rats only, suggesting an antidepressant-like effect in this model. Chronic treatment with an effective dose of ketamine also resulted in an increase in AMPA/NMDA receptor density ratio in the hippocampus of WKY rats. LMA was not affected by any ketamine treatment in either strain. These results indicate a rapid and lasting antidepressant-like effect of a low ketamine dose in WKY rat model of depression. Moreover, the increase in AMPA/NMDA receptor density in hippocampus could be a contributory factor to behavioral effects of ketamine. These findings suggest potential therapeutic benefit in simultaneous reduction of central NMDA and elevation of AMPA receptor function in treatment of depression. PMID:22521815

  4. Augmenting the Antifungal Activity of an Oxidizing Agent with Kojic Acid: Control of Penicillium Strains Infecting Crops

    Kim, Jong H.; Chan, Kathleen L.

    2014-01-01

    Oxidative treatment is one of the strategies for preventing Penicillium contamination in crops/foods. The antifungal efficacy of hydrogen peroxide (H2O2; oxidant) was investigated in Penicillium strains by using kojic acid (KA) as a chemosensitizing agent, which can enhance the susceptibility of pathogens to antifungal agents. Co-application of KA with H2O2 (chemosensitization) resulted in the enhancement of antifungal activity of either compound, when compared to the independent application ...

  5. Postreduction Breast Augmentation

    Hidalgo, David A.; Doft, Melissa A.

    2015-01-01

    Background: Most breast reduction patients are highly satisfied after surgery. However, there is a subset of women who seek breast augmentation years later to restore lost volume chiefly associated with weight loss and postpartum changes. Breast shape and overall aesthetics are often revised at the same time. Methods: A retrospective review was performed of 2 surgeons’ experiences with post-reduction breast augmentation. Twenty patients were identified between 2002 and 2014. An in-depth chart...

  6. Transaxillary Endoscopic Breast Augmentation

    Sim, Hyung-Bo

    2014-01-01

    The axillary technique is the most popular approach to breast augmentation among Korean women. Transaxillary breast augmentation is now conducted with sharp electrocautery dissection under direct endoscopic vision throughout the entire process. The aims of this method are clear: both a bloodless pocket and a sharp non-traumatic dissection. Round textured or anatomical cohesive gel implants have been used to make predictable well-defined inframammary creases because textured surface implants d...

  7. Augmented Reality im Techniktraining

    Schack, Thomas; Heinen, Thomas; Hermann, Thomas

    2007-01-01

    In den letzten Jahren wurden in Bereichen wie Robotik, Telemanipulation und Militär neue Technologien entwickelt, die als Augmented Reality (Erweiterte Realität) (Milgram et al., 1994) bezeichnet werden. Durch Augmented Reality wird die Leistungs fähigkeit der beteiligten Menschen nachweisbar unterstützt. Dabei wird die Realität eines Agenten computergestützt mit virtueller Information - auf visueller, akustischer oder taktiler Basis - in Echtzeit überlagert (erweitert). Die wesentliche Eig...

  8. Marketing and Augmented Reality

    Zelený, Martin

    2010-01-01

    The main goal of this diploma thesis is to identify the usage of augmented reality in contemporary marketing practice and the expectations of marketers for the future use. This will be achieved by conducting a quantitative and qualitative research among existing creative and advertising companies. Secondary goal is introducing the concept of augmented reality from the theoretical point of view and also description of potential utilization based on known examples. The tools for the practical p...

  9. Magnetohydrodynamic Augmented Propulsion Experiment

    Litchford, Ron J.; Cole, John; Lineberry, John; Chapman, Jim; Schmidt, Harold; Cook, Stephen (Technical Monitor)

    2002-01-01

    that an MHD accelerator can be an effective augmentation system for increasing engine exhaust velocity. More specifically, the experiment is intended to show that electromagnetic effects are effective at producing flow acceleration whereas electrothermal effects do not cause unacceptable heating of the working fluid. The MHD accelerator was designed as an externally diagonalized segmented Faraday channel, which will be inserted into an existing 2-tesla electromagnet. This allows the external power to be connected through two terminals thereby minimizing the complexity and cost associated with powering each segment independently. The design of the accelerator and other components in the flow path has been completed and fabrication activities are underway. This paper provides a full description of MAPX including performance analysis, design, and test plans, and current status.

  10. Confronting an augmented reality

    John Hedberg

    2012-08-01

    Full Text Available How can educators make use of augmented reality technologies and practices to enhance learning and why would we want to embrace such technologies anyway? How can an augmented reality help a learner confront, interpret and ultimately comprehend reality itself? In this article, we seek to initiate a discussion that focuses on these questions, and suggest that they be used as drivers for research into effective educational applications of augmented reality. We discuss how multi-modal, sensorial augmentation of reality links to existing theories of education and learning, focusing on ideas of cognitive dissonance and the confrontation of new realities implied by exposure to new and varied perspectives. We also discuss connections with broader debates brought on by the social and cultural changes wrought by the increased digitalisation of our lives, especially the concept of the extended mind. Rather than offer a prescription for augmentation, our intention is to throw open debate and to provoke deep thinking about what interacting with and creating an augmented reality might mean for both teacher and learner.

  11. Intraoperative Endoscopic Augmented Reality in Third Ventriculostomy

    Ciucci, Matteo

    2009-01-01

    In neurosurgery, as a result of the brain-shift, the preoperative patient models used as a intraoperative reference change. A meaningful use of the preoperative virtual models during the operation requires for a model update. The NEAR project, Neuroendoscopy towards Augmented Reality, describes a new camera calibration model for high distorted lenses and introduces the concept of active endoscopes endowed with with navigation, camera calibration, augmented reality and triangulation modules.

  12. Copper(II) oxide nanoparticles augment antifilarial activity of Albendazole: In vitro synergistic apoptotic impact against filarial parasite Setaria cervi.

    Zafar, Atif; Ahmad, Irshad; Ahmad, Ajaz; Ahmad, Masood

    2016-03-30

    Mass treatment of lymphatic filariasis with Albendazole (ABZ), a therapeutic benzimidazole, is fraught with serious limitations such as possible drug resistance and poor macrofilaricidal activity. Therefore, we need to develop new ABZ-based formulations to improve its antifilarial effectiveness. CuO nanoparticles were used as an adjuvant with ABZ to form ABZ-CuO nanocomposite, which was characterized by UV-vis spectroscopy, FT-IR, AFM and SEM. Antifilarial activity of nanocomposite was evaluated using relative motility assay and dye exclusion test in dark and under UV light. ROS generation, antioxidant levels, lipid peroxidation and DNA fragmentation in nanocomposite treated parasites were estimated. Biophysical techniques were employed to ascertain the mode of binding of nanocomposite to parasitic DNA. Nanocomposite increases parasite mortality as compared to ABZ in dark, and its antifilarial effect was increased further under UV light. Elevated ROS production and decline of parasitic-GST and GSH levels were observed in nanocomposite treated worms in dark, and these effects were pronounced further under UV light. Nanocomposite leads to higher DNA fragmentation as compared to ABZ alone. Further, we found that nanocomposite binds parasitic DNA in an intercalative manner where it generates ROS to induce DNA damage. Thus, oxidative stress production due to ROS generation and consequent DNA fragmentation leads to apoptosis in worms. This is the first report supporting CuO nanoparticles as a potential adjuvant with ABZ against filariasis along with enhanced antifilarial activity of nanocomposite under UV light. These findings, thus, indicate that development of ABZ-loaded nanoparticle compounds may serve as promising leads for filariasis treatment. PMID:26827921

  13. Competitive (AP7) and non-competitive (MK-801) NMDA receptor antagonists differentially alter glucose utilization in rat cortex

    The effects of D,L-2-amino-7-phosphonoheptanoic acid (AP7), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801, a non-competitive NMDA receptor antagonist, on regional brain metabolism were studied in unanesthetized, freely moving rats by using the quantitative 14C2-deoxyglucose autoradiographic procedure. AP7 (338 or 901 mg/kg) produced a dose-dependent decrease of metabolic activity throughout most of the regions studied including sensory, motor, and limbic cortices. In contrast, MK-801 (0.1 or 1.0 mg/kg) resulted in a dose-dependent decrease of metabolic activity in sensory cortices, and an increase in limbic regions such as the hippocampal stratum lacunosum moleculare and entorhinal cortex. MK-801 also produced a biphasic response in agranular motor cortex, whereby the low dose increased while the high dose decreased labeling. In addition, MK-801 produced heterogeneous effects on regional cerebral metabolism in sensory cortices. Metabolic activity decreased in layer IV relative to layer Va following MK-801 treatment in primary somatosensory (SI) and visual (VI) cortices, suggesting a shift in activity from afferent fibers innervating layer IV to those innervating layer Va. MK-801 administration also decreased metabolic activity in granular SI relative to dysgranular SI, and in VI relative to secondary visual cortex (VII), thus providing a relative sparing of activity in dysgranular SI and VII. Thus, the non-competitive NMDA receptor antagonist suppressed activity from extrinsic neocortical sources, enhancing relative intracortical activity and stimulating limbic regions, while the competitive NMDA antagonist depressed metabolic activity in all cortical regions

  14. Activation of human B cells by the agonist CD40 antibody CP-870,893 and augmentation with simultaneous toll-like receptor 9 stimulation

    Rüter Jens

    2009-11-01

    capacity. Simultaneous TLR9 ligation augments the effect of CP-870,893 alone. These results provide further rationale for combining CD40 and TLR9 activation using available clinical reagents in strategies of novel tumor immunotherapy.

  15. Landfill leachate treatment using powdered activated carbon augmented sequencing batch reactor (SBR) process: Optimization by response surface methodology

    Aziz, Shuokr Qarani [School of Civil Engineering, Universiti Sains Malaysia (USM), 14300 Nibong Tebal, Penang (Malaysia); Aziz, Hamidi Abdul, E-mail: cehamidi@eng.usm.my [School of Civil Engineering, Universiti Sains Malaysia (USM), 14300 Nibong Tebal, Penang (Malaysia); Yusoff, Mohd Suffian; Bashir, Mohammed J.K. [School of Civil Engineering, Universiti Sains Malaysia (USM), 14300 Nibong Tebal, Penang (Malaysia)

    2011-05-15

    In this study, landfill leachate was treated by using the sequencing batch reactor (SBR) process. Two types of the SBR, namely non-powdered activated carbon and powdered activated carbon (PAC-SBR) were used. The influence of aeration rate and contact time on SBR and PAC-SBR performances was investigated. Removal efficiencies of chemical oxygen demand (COD), colour, ammoniacal nitrogen (NH{sub 3}-N), total dissolved salts (TDS), and sludge volume index (SVI) were monitored throughout the experiments. Response surface methodology (RSM) was applied for experimental design, analysis and optimization. Based on the results, the PAC-SBR displayed superior performance in term of removal efficiencies when compared to SBR. At the optimum conditions of aeration rate of 1 L/min and contact time of 5.5 h the PAC-SBR achieved 64.1%, 71.2%, 81.4%, and 1.33% removal of COD, colour, NH{sub 3}-N, and TDS, respectively. The SVI value of PAC-SBR was 122.2 mL/g at optimum conditions.

  16. Landfill leachate treatment using powdered activated carbon augmented sequencing batch reactor (SBR) process: optimization by response surface methodology.

    Aziz, Shuokr Qarani; Aziz, Hamidi Abdul; Yusoff, Mohd Suffian; Bashir, Mohammed J K

    2011-05-15

    In this study, landfill leachate was treated by using the sequencing batch reactor (SBR) process. Two types of the SBR, namely non-powdered activated carbon and powdered activated carbon (PAC-SBR) were used. The influence of aeration rate and contact time on SBR and PAC-SBR performances was investigated. Removal efficiencies of chemical oxygen demand (COD), colour, ammoniacal nitrogen (NH(3)-N), total dissolved salts (TDS), and sludge volume index (SVI) were monitored throughout the experiments. Response surface methodology (RSM) was applied for experimental design, analysis and optimization. Based on the results, the PAC-SBR displayed superior performance in term of removal efficiencies when compared to SBR. At the optimum conditions of aeration rate of 1L/min and contact time of 5.5h the PAC-SBR achieved 64.1%, 71.2%, 81.4%, and 1.33% removal of COD, colour, NH(3)-N, and TDS, respectively. The SVI value of PAC-SBR was 122.2 mL/g at optimum conditions. PMID:21420786

  17. Landfill leachate treatment using powdered activated carbon augmented sequencing batch reactor (SBR) process: Optimization by response surface methodology

    In this study, landfill leachate was treated by using the sequencing batch reactor (SBR) process. Two types of the SBR, namely non-powdered activated carbon and powdered activated carbon (PAC-SBR) were used. The influence of aeration rate and contact time on SBR and PAC-SBR performances was investigated. Removal efficiencies of chemical oxygen demand (COD), colour, ammoniacal nitrogen (NH3-N), total dissolved salts (TDS), and sludge volume index (SVI) were monitored throughout the experiments. Response surface methodology (RSM) was applied for experimental design, analysis and optimization. Based on the results, the PAC-SBR displayed superior performance in term of removal efficiencies when compared to SBR. At the optimum conditions of aeration rate of 1 L/min and contact time of 5.5 h the PAC-SBR achieved 64.1%, 71.2%, 81.4%, and 1.33% removal of COD, colour, NH3-N, and TDS, respectively. The SVI value of PAC-SBR was 122.2 mL/g at optimum conditions.

  18. Oxygen plasma surface modification augments poly(L-lactide-co-glycolide) cytocompatibility toward osteoblasts and minimizes immune activation of macrophages.

    Scislowska-Czarnecka, Anna; Szmigiel, Dariusz; Genet, Michel; Dupont-Gillain, Christine; Pamula, Elzbieta; Kolaczkowska, Elzbieta

    2015-12-01

    Here, we report on modification of one of the model biomedical polymers, poly L-lactide-co-glycolide (PLGA; 85:15), by reactive ion etching (RIE) oxygen plasma treatment. PLGA's major disadvantage is high hydrophobicity which restrains binding of cell-adhesive proteins and host cells. In the current approach, we aimed to answer two questions: (1) will only short (10 s) and moderate (20-200 mTorr, 45-90 W) RIE oxygen plasma treatment, leading to decrease of water contact angle by only up to 10°, sufficiently improve PLGA adherence to cells, and (2) how will this affect osteoblasts and activation of the immune system? All obtained modified PLGAs had improved hydrophilicity but unaltered roughness (as revealed by water contact angle measurements, X-ray photoelectron spectroscopy, and atomic force microscopy) resulting in significantly improved adhesion of osteoblasts (MG-63) and their low activation. Importantly, macrophages (RAW 264.7), one of the key cells initiating inflammation and bone resorption, responded significantly less vigorously to the modified polymers, expressing/releasing lower amounts of nitric oxide, matrix metalloproteinases (MMP-9), and pro-inflammatory cytokines (TNF-α, IL-6, IL-12p70, IFN-γ, IL-10). We conclude that already slight RIE oxygen plasma modification of PLGA is sufficient to improve its surface properties, and enhance cytocompatibility. Most importantly, this type of modification prevents excessive immune response. PMID:26014580

  19. BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals

    Chen, Wenling; Walwyn, Wendy; Ennes, Helena S.; Kim, Hyeyoung; McRoberts, James A.; Marvizón, Juan Carlos G.

    2014-01-01

    NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was medi...

  20. Synthesis of a Series of Novel 3,9-Disubstituted Phenanthrenes as Analogues of Known NMDA Receptor Allosteric Modulators

    Irvine, Mark W.; Fang, Guangyu; Eaves, Richard; Mayo-Martin, Maria B.; Burnell, Erica S.; Costa, Blaise M.; Culley, Georgia R.; Volianskis, Arturas; Collingridge, Graham L; Monaghan, Daniel T.; Jane, David E.

    2015-01-01

    9-Substituted phenanthrene-3-carboxylic acids have been reported to have allosteric modulatory activity at the NMDA receptor. This receptor is activated by the excitatory neurotransmitter L-glutamate and has been implicated in a range of neurological disorders such as schizophrenia, epilepsy and chronic pain and neurodegenerative disorders such as Alzheimer’s disease. Herein, the convenient synthesis of a wide range of novel 3,9-disubstituted phenanthrene derivatives starting from a few commo...

  1. Activated platelet supernatant can augment the angiogenic potential of human peripheral blood stem cells mobilized from bone marrow by G-CSF.

    Kang, Jeehoon; Hur, Jin; Kang, Jin-A; Yun, Ji-Yeon; Choi, Jae-Il; Ko, Seung Bum; Lee, Choon-Soo; Lee, Jaewon; Han, Jung-Kyu; Kim, Hyun Kyung; Kim, Hyo-Soo

    2014-10-01

    Platelets not only play a role in hemostasis, but they also promote angiogenesis and tissue recovery by releasing various cytokines and making an angiogenic milieu. Here, we examined autologous 'activated platelet supernatant (APS)' as a priming agent for stem cells; thereby enhance their pro-angiogenic potential and efficacy of stem cell-based therapy for ischemic diseases. The mobilized peripheral blood stem cells ((mob)PBSCs) were isolated from healthy volunteers after subcutaneous injection of granulocyte-colony stimulating factor. APS was collected separately from the platelet rich plasma after activation by thrombin. (mob)PBSCs were primed for 6h before analysis. Compared to naive platelet supernatants, APS had a higher level of various cytokines, such as IL8, IL17, PDGF and VEGF. APS-priming for 6h induced (mob)PBSCs to express key angiogenic factors, surface markers (i.e. CD34, CD31, and CXCR4) and integrins (integrins α5, β1 and β2). Also (mob)PBSCs were polarized toward CD14(++)/CD16(+) pro-angiogenic monocytes. The priming effect was reproduced by an in vitro reconstruction of APS. Through this phenotype, APS-priming increased cell-cell adhesion and cell-extracellular matrix adhesion. The culture supernatant of APS-primed (mob)PBSCs contained high levels of IL8, IL10, IL17 and TNFα, and augmented proliferation and capillary network formation of human umbilical vein endothelial cells. In vivo transplantation of APS-primed (mob)PBSCs into athymic mice ischemic hindlimbs and Matrigel plugs elicited vessel differentiation and tissue repair. In safety analysis, platelet activity increased after mixing with (mob)PBSCs regardless of priming, which was normalized by aspirin treatment. Collectively, our data identify that APS-priming can enhance the angiogenic potential of (mob)PBSCs, which can be used as an adjunctive strategy to improve the efficacy of cell therapy for ischemic diseases. PMID:25016235

  2. Review of passive heat transfer augmentation techniques

    Dewan, A.; Mahanta, P.; Sumithra Raju, K. [Indian Institute of Technology, Guwahati (India). Dept. of Mechanical Engineering; Suresh Kumar, P. [Indian Institute of technology, Kharagpur (India). Dept. of Oocean Engineering and Naval Architecture

    2004-12-01

    Heat transfer augmentation techniques (passive, active or a combination of passive and active methods) are commonly used in areas such as process industries, heating and cooling in evaporators, thermal power plants, air- conditioning equipment, refrigerators, radiators for space vehicles, automobiles, etc. Passive techniques, where inserts are used in the flow passage to augment the heat transfer rate, are advantageous compared with active techniques, because the insert manufacturing process is simple and these techniques can be easily employed in an existing heat exchanger. In design of compact heat exchangers, passive techniques of heat transfer augmentation can play an important role if a proper passive insert configuration can be selected according to the heat exchanger working condition (both flow and heat transfer conditions). In the past decade, several studies on the passive techniques of heat transfer augmentation have been reported. The present paper is a review on progress with the passive augmentation techniques in the recent past and will be useful to designers implementing passive augmentation techniques in heat exchange. Twisted tapes, wire coils, ribs, fins, dimples, etc., are the most commonly used passive heat transfer augmentation tools. In the present paper, emphasis is given to works dealing with twisted tapes and wire coils because, according to recent studies, these are known to be economic heat transfer augmentation tools. The former insert is found to be suitable in a laminar flow regime and the latter is suitable for turbulent flow. The thermohydraulic behaviour of an insert mainly depends on the flow conditions (laminar or turbulent) apart from the insert configurations. The present review is organized in five different sections: twisted tape in laminar flow; twisted tape in turbulent flow; wire coil in laminar flow; wire coil in turbulent flow; other inserts such as ribs, fins, dimples, etc. (author)

  3. NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse

    Feltenstein, Matthew W.; See, Ronald E.

    2007-01-01

    Previous research from our laboratory has implicated the basolateral amygdala (BLA) complex in the acquisition and consolidation of cue-cocaine associations, as well as extinction learning, which may regulate the long-lasting control of conditioned stimuli (CS) over drug-seeking behavior. Given the well established role of NMDA glutamate receptor activation in other forms of amygdalar-based learning, we predicted that BLA-mediated drug-cue associative learning would be NMDA receptor dependent...

  4. sPLA2-IIA Augments Oxidized LDL-Induced MCP-1 Expression in Vitro Through Activation of Akt

    Yongjun Guo

    2015-10-01

    Full Text Available Background/Aims: Group IIA secretory phospholipase A2 (sPLA2-IIA has an important role in atherosclerosis. In this study, we explored whether sPLA2-IIA overexpression could promote atherosclerosis in normal environment alone or with other inflammatory factors. Methods: Human aortic smooth muscle cells (HASMCs were transduced with Lv-GFP-sPLA2-IIA, a plasmid containing sPLA2-IIA coupled with green fluorescent protein (GFP. Cells were incubated in the presence or absence of oxidized low-density lipoprotein (LDL, sPLA2 inhibitor LY315920 or PI3K/Akt inhibitor LY294002. The mRNA expression and protein secretion of monocyte chemoattractant protein-1 (MCP-1 were assessed by quantitative real-time polymerase chain reaction (QRT-PCR and enzyme-linked immunosorbent assay (ELISA, respectively. Phosphorylation of Akt was examined by western blotting. Results: Lv-GFP-sPLA2-IIA-transduced HASMCs remained fluorescent during 72 h of the study period with infection ratio of around 80%. The mRNA expression and protein secretion of MCP-1was not altered in groups of HASMCs, Lv-GFP transduced and Lv-GFP-sPLA2-IIA-transduced HASMCs (p>0.05, but was significantly increased in the presence of oxidized LDL especially in Lv-GFP-sPLA2-IIA transduction group (ppConclusions: Overexpression of sPLA2-IIA does not alter MCP-1 level at baseline, but could enhance the atherogenic effect of oxidized LDL in HASMCs, at least partly due to activation of Akt. These findings may provide a strategy for treatment of inflammatory cardiovascular diseases.

  5. PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarisation in cortical spreading depression

    Kucharz, Krzysztof; Søndergaard Rasmussen, Ida; Bach, Anders;

    2016-01-01

    Cortical spreading depression is associated with activation of NMDA receptors, which interact with the postsynaptic density protein 95 (PSD-95) that binds to nitric oxide synthase (nNOS). Here, we tested whether inhibition of the nNOS/PSD-95/NMDA receptor complex formation by anti-ischemic compound...... during the first hour after i.v. injection. The Tat-N-dimer suppressed stimulation-evoked synaptic activity by 2-20%, while cortical blood flow and cerebral oxygen metabolic (CMRO2) responses were preserved. During cortical spreading depression, the Tat-N-dimer reduced the average amplitude of the...... negative shift in direct current potential by 33% (4.1 mV). Furthermore, the compound diminished the average depression of spontaneous electrocorticographic activity by 11% during first 40 min of post-cortical spreading depression recovery, but did not mitigate the suppressing effect of cortical spreading...

  6. Time and space profiling of NMDA receptor co-agonist functions.

    Mothet, Jean-Pierre; Le Bail, Matildé; Billard, Jean-Marie

    2015-10-01

    The N-Methyl D-Aspartic acid (NMDA) receptors (NMDAR) are key tetrameric ionotropic glutamate receptors that transduce glutamatergic signals throughout the central nervous system (CNS) and spinal cord. Although NMDARs are diverse in their subunit composition, subcellular localization, and biophysical and pharmacological properties, their activation always requires the binding of a co-agonist that has long been thought to be glycine. However, intense research over the last decade has challenged this classical model by showing that another amino acid, d-serine, is the preferential co-agonist for a subset of synaptic NMDARs in many areas of the adult brain. Nowadays, a totally new picture of glutamatergic synapses at work is emerging where both glycine and d-serine are involved in a complex interplay to regulate NMDAR functions in the CNS following time and space constraints. The purpose of this review was to highlight the particular role of each co-agonist in modulating NMDAR-dependent activities in healthy and diseased brains. We have herein integrated our most advanced knowledge of how glycine and d-serine may orchestrate synapse dynamics and drive neuronal network activity in a time- and synapse-specific manner and how changes in synaptic availability of these amino acids may contribute to cognitive impairments such as those associated with healthy aging, epilepsy, and schizophrenia. The N-Methyl D-Aspartic acid (NMDA) subtype of glutamate receptors are central to many physiological functions and are linked to brain disorders. Their functions require glutamate and a co-agonist d-serine or glycine. After years of intense research and controversy on the identity of the amino acid that serves as the right co-agonist, we are just entering a new era of consensus where glycine and d-serine are teaming up to regulate the function of different subsets of NMDA receptors and at different synapses during different time windows of brain development. PMID:26088787

  7. Augmenting computer networks

    Bokhari, S. H.; Raza, A. D.

    1984-01-01

    Three methods of augmenting computer networks by adding at most one link per processor are discussed: (1) A tree of N nodes may be augmented such that the resulting graph has diameter no greater than 4log sub 2((N+2)/3)-2. Thi O(N(3)) algorithm can be applied to any spanning tree of a connected graph to reduce the diameter of that graph to O(log N); (2) Given a binary tree T and a chain C of N nodes each, C may be augmented to produce C so that T is a subgraph of C. This algorithm is O(N) and may be used to produce augmented chains or rings that have diameter no greater than 2log sub 2((N+2)/3) and are planar; (3) Any rectangular two-dimensional 4 (8) nearest neighbor array of size N = 2(k) may be augmented so that it can emulate a single step shuffle-exchange network of size N/2 in 3(t) time steps.

  8. Prototyping Augmented Reality

    Mullen, Tony

    2011-01-01

    Learn to create augmented reality apps using Processing open-source programming language Augmented reality (AR) is used all over, and you may not even realize it. Smartphones overlay data onto live camera views to show homes for sale, restaurants, or historical sites. American football broadcasts use AR to show the invisible first-down line on the field to TV viewers. Nike and Budweiser, among others, have used AR in ads. Now, you can learn to create AR prototypes using 3D data, Processing open-source programming language, and other languages. This unique book is an easy-to-follow guide on how

  9. Augmented reality som wearable

    Buhl, Mie; Rahn, Annette

    2015-01-01

    Artiklen omhandler design og implementering af Augmented Reality (AR) i form af en wearable i sygeplejerskeuddannelsens anatomiundervisning, mere specifikt undervisning i lungeanatomi og respiration, med fokus på potentialer for visuel læring. Projektet undersøger, hvordan en udviklet AR-applikat......Artiklen omhandler design og implementering af Augmented Reality (AR) i form af en wearable i sygeplejerskeuddannelsens anatomiundervisning, mere specifikt undervisning i lungeanatomi og respiration, med fokus på potentialer for visuel læring. Projektet undersøger, hvordan en udviklet AR...

  10. Estradiol-Induced Enhancement of Object Memory Consolidation Involves NMDA Receptors and Protein Kinase A in the Dorsal Hippocampus of Female C57BL/6 Mice

    Michael C. Lewis; Kerr, Kristin M.; Orr, Patrick T.; Frick, Karyn M.

    2008-01-01

    This study examined the role of dorsal hippocampal NMDA receptors and PKA activation in 17β-estradiol (E2)-induced enhancement of object memory consolidation. Mice explored two identical objects during training, after which they immediately received intraperitoneal injections of 0.2 mg/kg E2, and bilateral dorsal hippocampal infusions of Vehicle, the NMDA receptor antagonist APV (2.5 μg/side), or the cAMP inhibitor Rp-cAMPS (18.0 μg/side). Retention was tested 48 hours later. The enhanced obj...