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Sample records for agonist d-cycloserine dcs

  1. D-Cycloserine Does Not Facilitate Fear Extinction by Reducing Conditioned Stimulus Processing or Promoting Conditioned Inhibition to Contextual Cues

    ERIC Educational Resources Information Center

    Baker, Kathryn D.; McNally, Gavan P.; Richardson, Rick

    2012-01-01

    The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions…

  2. D-Cycloserine for Treatment Nonresponders with Obsessive-Compulsive Disorder: A Case Report

    ERIC Educational Resources Information Center

    Norberg, Melissa M.; Gilliam, Christina M.; Villavicencio, Anna; Pearlson, Godfrey D.; Tolin, David F.

    2012-01-01

    Despite being the most effective treatment available, as many as one third of patients who receive exposure and response prevention (ERP) for obsessive-compulsive disorder (OCD) do not initially respond to treatment. Recent research suggests that the n-methyl d-aspartate (NMDA) receptor partial agonist D-Cycloserine (DCS) may speed up the course…

  3. D-Cycloserine Enhances Memory Consolidation of Hippocampus-Dependent Latent Extinction

    ERIC Educational Resources Information Center

    Gabriele, Amanda; Packard, Mark G.

    2007-01-01

    Adult male Long-Evans rats were trained to run in a straight-alley maze for food reward and subsequently received hippocampus-dependent latent extinction training. Immediately following latent extinction, rats received peripheral injections of the NMDA receptor partial agonist D-cycloserine (DCS, 15 mg/kg), or saline. Twenty-four hours later, rats…

  4. The Therapeutic Role of d-Cycloserine in Schizophrenia.

    PubMed

    Goff, D

    2016-01-01

    The ketamine model for schizophrenia has led to several therapeutic strategies for enhancing N-methyl d-aspartate (NMDA) receptor activity, including agonists directed at the glycine receptor site and inhibitors of glycine reuptake. Because ketamine may primarily block NMDA receptors on inhibitory interneurons, drugs that reduce glutamate release have also been investigated as a means of countering a deficit in inhibitory input. These approaches have met with some success for the treatment of negative and positive symptoms, but results have not been consistent. An emerging approach with the NMDA partial agonist, d-cycloserine (DCS), aims to enhance plasticity by intermittent treatment. Early trials have demonstrated benefit with intermittent DCS dosing for negative symptoms and memory. When combined with cognitive remediation, intermittent DCS treatment enhanced learning on a practiced auditory discrimination task and when added to cognitive behavioral therapy, DCS improved delusional severity in subjects who received DCS with the first CBT session. These studies require replication, but point toward a promising strategy for the treatment of schizophrenia and other disorders of plasticity. PMID:27288073

  5. D-Cycloserine in Neuropsychiatric Diseases: A Systematic Review.

    PubMed

    Schade, Sebastian; Paulus, Walter

    2016-04-01

    D-Cycloserine, known from tuberculosis therapy, has been widely introduced to neuropsychiatric studies, since its central active mechanism as a partial NMDA-agonist has been found. In this review, we evaluate its therapeutic potential in neuropsychological disorders and discuss its pitfalls in terms of dosing and application frequency as well as its safety in low-dose therapy. Therefore, we identified 91 clinical trials by performing a Medline search. We demonstrate in part preliminary but increasing evidence that D-cycloserine may be effective in various psychiatric diseases, including schizophrenia, anxiety disorders, addiction, eating disorders, major depression, and autism as well as in neurological diseases, including dementia, Alzheimer's disease, and spinocerebellar degeneration. D-Cycloserine in low-dose therapy is safe, but there is still a need for new drugs with higher specificity to the different N-methyl-D-aspartate-receptor subunits. PMID:26364274

  6. D-Cycloserine in Neuropsychiatric Diseases: A Systematic Review

    PubMed Central

    Paulus, Walter

    2016-01-01

    D-Cycloserine, known from tuberculosis therapy, has been widely introduced to neuropsychiatric studies, since its central active mechanism as a partial NMDA-agonist has been found. In this review, we evaluate its therapeutic potential in neuropsychological disorders and discuss its pitfalls in terms of dosing and application frequency as well as its safety in low-dose therapy. Therefore, we identified 91 clinical trials by performing a Medline search. We demonstrate in part preliminary but increasing evidence that D-cycloserine may be effective in various psychiatric diseases, including schizophrenia, anxiety disorders, addiction, eating disorders, major depression, and autism as well as in neurological diseases, including dementia, Alzheimer’s disease, and spinocerebellar degeneration. D-Cycloserine in low-dose therapy is safe, but there is still a need for new drugs with higher specificity to the different N-methyl-D-aspartate-receptor subunits. PMID:26364274

  7. The Effect of D-Cycloserine on Immediate vs. Delayed Extinction of Learned Fear

    ERIC Educational Resources Information Center

    Langton, Julia M.; Richardson, Rick

    2010-01-01

    We compared the effect of D-cycloserine (DCS) on immediate (10 min after conditioning) and delayed (24 h after conditioning) extinction of learned fear in rats. DCS facilitated both immediate and delayed extinction when the drug was administered after extinction training. However, DCS did not facilitate immediate extinction when administered prior…

  8. D-cycloserine injected into the dorsolateral periaqueductal gray induces anxiolytic-like effects in rats.

    PubMed

    Gomes, Felipe V; Kakihata, Alessandra M; Semedo, Ana Carolina G; Hott, Sara C; Uliana, Daniela L; Guimarães, Francisco S; Resstel, Leonardo B M

    2014-09-01

    D-cycloserine (DCS) is a partial agonist of the glycine site coupled to the NMDA receptor (NMDAR). As a consequence, depending on the doses used it can function as an agonist or antagonist at this site. In rodents, anxiolytic-like effects have been observed after the systemic administration of high doses of DCS. The brain sites of these effects have not been investigated. Direct brain injection of glycine site antagonists or agonists into the dorsolateral periaqueductal gray (dlPAG), a brain structure involved in the modulation of defensive-related behaviors, produces anxiolytic- or anxiogenic-like effects, respectively. The present study investigated if the dlPAG could be a brain site of the anxiolytic effects observed after DCS systemic administration. Male Wistar rats received intra-dlPAG injections of DCS (25, 50, 100 or 200 nmol) and were exposed to the elevated plus-maze (EPM) or to the light-dark box. DCS, at the dose of 200 nmol, increased open arm exploration and the time spent in the light compartment, respectively. Based on this result we tested the effects of intra-dlPAG DCS (200 nmol) administration in animals submitted to the Vogel conflict tests. Anxiolytic-like effect was also observed in this test indicated by the increase of punished responses. The drug did not change locomotor activity, discarding potential confounding factors. These results indicated that administration of DCS, a partial agonist of the NMDAR-associated glycine site, into the dlPAG induces anxiolytic-like effects in different models, pointing to a possible site of action of this compound. PMID:24931794

  9. D-cycloserine Deters Reacquisition of Cocaine Self-Administration by Augmenting Extinction Learning

    PubMed Central

    Nic Dhonnchadha, Bríd Á; Szalay, Jonathan J; Achat-Mendes, Cindy; Platt, Donna M; Otto, Michael W; Spealman, Roger D; Kantak, Kathleen M

    2010-01-01

    Augmentation of cue exposure (extinction) therapy with cognitive-enhancing pharmacotherapy may offer an effective strategy to combat cocaine relapse. To investigate this possibility at the preclinical level, rats and squirrel monkeys were trained to self-administer cocaine paired with a brief visual cue. Lever pressing was subsequently extinguished by withholding cocaine injections while maintaining response-contingent presentations of the cue. The glycine partial agonist D-cycloserine (DCS; 15 and 30 mg/kg in rats, 3 and 10 mg/kg in monkeys) was evaluated for its effects on the rate of extinction and subsequent reacquisition of cocaine self-administration. Compared with vehicle, pretreatment with 30 mg/kg DCS 0.5 h before extinction training reduced the number of responses and latency to reach the extinction criterion in rats, but neither dose of DCS altered these measures in monkeys. In both species, pretreatment with the higher dose of DCS before extinction training significantly attenuated reacquisition of cocaine self-administration compared with either extinction training in the absence of DCS or DCS in the absence of explicit extinction. Furthermore, treatment with 30 mg/kg DCS accompanied by brief handling (a stress induction) immediately after but not 6 h after extinction training attenuated reacquisition of cocaine self-administration in rats. No adverse effects of 10 mg/kg DCS were evident in quantitative observational studies in monkeys. The results suggest that DCS augmented consolidation of extinction learning to deter reacquisition of cocaine self-administration in rats and monkeys. The results suggest that DCS combined with exposure therapy may constitute a rational strategy for the clinical management of cocaine relapse. PMID:19741593

  10. Enhancement of Psychosocial Treatment With D-Cycloserine: Models, Moderators, and Future Directions.

    PubMed

    Otto, Michael W; Kredlow, M Alexandra; Smits, Jasper A J; Hofmann, Stefan G; Tolin, David F; de Kleine, Rianne A; van Minnen, Agnes; Evins, A Eden; Pollack, Mark H

    2016-08-15

    Advances in the understanding of the neurobiology of fear extinction have resulted in the development of d-cycloserine (DCS), a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure treatment. We review a decade of research that has focused on the efficacy of DCS for augmenting the mechanisms (e.g., fear extinction) and outcome of exposure treatment across the anxiety disorders. Following a series of small-scale studies offering strong support for this clinical application, more recent larger-scale studies have yielded mixed results, with some showing weak or no effects. We discuss possible explanations for the mixed findings, pointing to both patient and session (i.e., learning experiences) characteristics as possible moderators of efficacy, and offer directions for future research in this area. We also review recent studies that have aimed to extend the work on DCS augmentation of exposure therapy for the anxiety disorders to DCS enhancement of learning-based interventions for addiction, anorexia nervosa, schizophrenia, and depression. Here, we attend to both DCS effects on facilitating therapeutic outcomes and additional therapeutic mechanisms beyond fear extinction (e.g., appetitive extinction, hippocampal-dependent learning). PMID:26520240

  11. D-cycloserine enhances short-delay, but not long-delay, conditioned taste aversion learning in rats

    PubMed Central

    Davenport, Rachel A.; Houpt, Thomas A.

    2009-01-01

    NMDA receptors have been implicated in conditioned taste aversion (CTA), a form of associative learning with the unique temporal characteristic of associating taste and toxic stimuli across very long delays. D-cycloserine (DCS), an NMDA receptor agonist, has been shown to enhance short-delay CTA learning. Here we examined the interaction of DCS with varying temporal parameters of CTA. DCS (15 mg/kg) administered prior to the pairing of 0.125% saccharin and LiCl (38 mM, 12 ml/kg) enhanced CTA when there was a short delay between the taste-toxin pairing (10 min), but not when there was a long delay (45 min). DCS activity remained at effective levels over the long delay, because DCS administered 60 min prior to a short-delay pairing enhanced CTA. The interaction of DCS with the delay between taste stimulus onset and LiCl injection was investigated by administering DCS and then 5 min access to saccharin 45 min prior to a short-delay pairing of saccharin and LiCl. DCS failed to enhance CTA in rats pre-exposed to saccharin, even with a short-delay between the second saccharin exposure and LiCl injection. These results suggest that DCS enhancement of CTA is dependent on mechanisms underlying gustatory processing during long-delay taste-toxin associations. PMID:18930757

  12. Posttrial d-cycloserine enhances the emotional memory of an incentive downshift event.

    PubMed

    Norris, Jacob N; Ortega, Leonardo A; Papini, Mauricio R

    2011-10-01

    The present research was designed to determine whether an incentive downshift event induces an emotional memory that can be modulated by d-cycloserine (DCS), a partial agonist at the glycine site of N-methyl-d-aspartate receptor (NMDAR). DCS has been reported to have memory-enhancing properties in other training situations. Experiments 1 and 2 involved a consummatory successive negative contrast (cSNC) situation in which animals are exposed to an incentive downshift involving sucrose solutions of different concentrations. DCS administration (30 mg/kg, ip) immediately after the first 32-to-4% sucrose downshift trial (Experiment 1) retarded recovery of consummatory behavior, but immediately after the first 32-to-6% sucrose downshift trial (Experiment 2) did not affect recovery. There was no evidence that DCS affected consummatory behavior in the absence of an incentive downshift in a manner analogous to a conditioned taste aversion (Experiment 3). These results suggest that activation of NMDARs via the glycine modulatory site enhances the emotional memory triggered by exposure to an incentive downshift event. PMID:21596065

  13. Effects of D-cycloserine on extinction: translation from preclinical to clinical work.

    PubMed

    Davis, Michael; Ressler, Kerry; Rothbaum, Barbara O; Richardson, Rick

    2006-08-15

    Administration of benzodiazepines or serotonin reuptake inhibitors in combination with behavior therapy for the treatment of many anxiety disorders has generally lead to only modest gains. In this article we suggest that pharmacotherapy aimed not at treating the symptoms of anxiety but instead aimed at improving the learning that takes place in exposure therapy might actually improve the effectiveness of exposure therapy. This idea was based on animal work showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitated extinction of fear when given either before or shortly after exposure to fearful cues, reduced return of fear that is normally seen when extinction training is followed by stress, and led to generalized extinction, where DCS given in combination with exposure to one fearful cue led to extinction to another cue previously paired with the same aversive event. These finding suggested that DCS might facilitate exposure-based psychotherapy, which was verified in a small clinical study showing that DCS facilitated exposure therapy for fear of heights in a well-controlled virtual reality environment. PMID:16919524

  14. Opposing effects of d-cycloserine on fear despite a common extinction duration: Interactions between brain regions and behavior

    PubMed Central

    Bolkan, Scott S.; Lattal, K. Matthew

    2014-01-01

    A number of studies have reported that D-cycloserine (DCS), a partial agonist of the N-methyl-D-aspartate glutamate receptor, can facilitate the loss of conditioned fear if it is administered during an extinction trial. Here we examine the effects of DCS injected into the hippocampus or amygdala on extinction of context-evoked freezing after contextual fear conditioning in C57BL/6 mice. We find that DCS administered prior to an extinction session decreased freezing from the outset of the session regardless of which brain region was targeted. Retention tests revealed opposite effects on fear expression despite identical behavioral treatments: intra-hippocampal DCS inhibited fear expression while intra-amygdala DCS potentiated fear expression. Following post-extinction session injections of DCS, we found a similar though less pronounced effect. Closer inspection of the data revealed that the effects of DCS interacted with the behavior of the subjects during extinction. Intra-hippocampal injections of DCS enhanced extinction in those mice that showed the greatest amount of within-session extinction, but had less pronounced effects on mice that showed the least within-session extinction. Intra-amygdala injections of DCS impaired extinction in those mice that showed the least within-session, but there was some evidence that the effect in the amygdala did not depend on behavior during extinction. These findings demonstrate that even with identical extinction preparations and trial durations, the effects of DCS administered into the hippocampus and amygdala can heavily depend on the organism’s behavior during the extinction session. The broader implication of these findings is that the effects of pharmacological treatments designed to enhance extinction by targeting hippocampal or amygdalar processes may depend greatly on the responsivity of the subject to the behavioral treatment. PMID:24374132

  15. D-Cycloserine Augmentation of Cognitive-Behavioral Therapy: Directions for Pilot Research in Pediatric Obsessive-Compulsive Disorder

    ERIC Educational Resources Information Center

    Storch, Eric A.; McKay, Dean; Reid, Jeannette M.; Geller, Daniel A.; Goodman, Wayne K.; Lewin, Adam B.; Murphy, Tanya K.

    2010-01-01

    This paper discusses a recent translational success in combining behavioral psychotherapy with a novel medication, d-cycloserine (DCS), to augment cognitive-behavioral therapy (CBT) for anxiety disorders. The literature on behavioral theory of exposure-based therapies is provided, followed by a discussion of the role of DCS in enhancing extinction…

  16. Establishment of an In Vitro d-Cycloserine-Synthesizing System by Using O-Ureido-l-Serine Synthase and d-Cycloserine Synthetase Found in the Biosynthetic Pathway

    PubMed Central

    Uda, Narutoshi; Matoba, Yasuyuki; Kumagai, Takanori; Oda, Kosuke; Noda, Masafumi

    2013-01-01

    We have recently cloned a DNA fragment containing a gene cluster that is responsible for the biosynthesis of an antituberculosis antibiotic, d-cycloserine. The gene cluster is composed of 10 open reading frames, designated dcsA to dcsJ. Judging from the sequence similarity between each putative gene product and known proteins, DcsC, which displays high homology to diaminopimelate epimerase, may catalyze the racemization of O-ureidoserine. DcsD is similar to O-acetylserine sulfhydrylase, which generates l-cysteine using O-acetyl-l-serine with sulfide, and therefore, DcsD may be a synthase to generate O-ureido-l-serine using O-acetyl-l-serine and hydroxyurea. DcsG, which exhibits similarity to a family of enzymes with an ATP-grasp fold, may be an ATP-dependent synthetase converting O-ureido-d-serine into d-cycloserine. In the present study, to characterize the enzymatic functions of DcsC, DcsD, and DcsG, each protein was overexpressed in Escherichia coli and purified to near homogeneity. The biochemical function of each of the reactions catalyzed by these three proteins was verified by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and, in some cases, mass spectrometry. The results from this study demonstrate that by using a mixture of the three purified enzymes and the two commercially available substrates O-acetyl-l-serine and hydroxyurea, synthesis of d-cycloserine was successfully attained. These in vitro studies yield the conclusion that DcsD and DcsG are necessary for the syntheses of O-ureido-l-serine and d-cycloserine, respectively. DcsD was also able to catalyze the synthesis of l-cysteine when sulfide was added instead of hydroxyurea. Furthermore, the present study shows that DcsG can also form other cyclic d-amino acid analogs, such as d-homocysteine thiolactone. PMID:23529730

  17. D-cycloserine in Prelimbic Cortex Reverses Scopolamine-Induced Deficits in Olfactory Memory in Rats

    PubMed Central

    Portero-Tresserra, Marta; Cristóbal-Narváez, Paula; Martí-Nicolovius, Margarita; Guillazo-Blanch, Gemma; Vale-Martínez, Anna

    2013-01-01

    A significant interaction between N-methyl-D-aspartate (NMDA) and muscarinic receptors has been suggested in the modulation of learning and memory processes. The present study further investigates this issue and explores whether d-cycloserine (DCS), a partial agonist at the glycine binding site of the NMDA receptors that has been regarded as a cognitive enhancer, would reverse scopolamine (SCOP)-induced amnesia in two olfactory learning tasks when administered into the prelimbic cortex (PLC). Thus, in experiment 1, DCS (10 µg/site) was infused prior to acquisition of odor discrimination (ODT) and social transmission of food preference (STFP), which have been previously characterized as paradigms sensitive to PLC muscarinic blockade. Immediately after learning such tasks, SCOP was injected (20 µg/site) and the effects of both drugs (alone and combined) were tested in 24-h retention tests. To assess whether DCS effects may depend on the difficulty of the task, in the STFP the rats expressed their food preference either in a standard two-choice test (experiment 1) or a more challenging three-choice test (experiment 2). The results showed that bilateral intra-PLC infusions of SCOP markedly disrupted the ODT and STFP memory tests. Additionally, infusions of DCS alone into the PLC enhanced ODT but not STFP retention. However, the DCS treatment reversed SCOP-induced memory deficits in both tasks, and this effect seemed more apparent in ODT and 3-choice STFP. Such results support the interaction between the glutamatergic and the cholinergic systems in the PLC in such a way that positive modulation of the NMDA receptor/channel, through activation of the glycine binding site, may compensate dysfunction of muscarinic neurotransmission involved in stimulus-reward and relational learning tasks. PMID:23936452

  18. D-Cycloserine improves functional outcome after traumatic brain injury with wide therapeutic window

    SciTech Connect

    Adeleye, A.; Biegon, A.; Adeleye, A.; Shohami, E.; Nachman, D.; Alexandrovich, A.; Trembovler, V.; Yaka, R.; Shoshan, Y.; Dhawan, J.; Biegon, A.

    2009-12-01

    It has been long thought that hyperactivation of N-methyl-D-aspartate (NMDA) receptors underlies neurological decline after traumatic brain injury. However, all clinical trials with NMDA receptor antagonists failed. Since NMDA receptors are down-regulated from 4 h to 2 weeks after brain injury, activation at 24 h, rather than inhibition, of these receptors, was previously shown to be beneficial in mice. Here, we tested the therapeutic window, dose regimen and mechanism of action of the NMDA receptor partial agonist d-cycloserine (DCS) in traumatic brain injury. Male mice were subjected to trauma using a weight-drop model, and administered 10 mg/kg (i.p.) DCS or vehicle once (8, 16, 24, or 72 h) twice (24 and 48 h) or three times (24, 48 and 72 h). Functional recovery was assessed for up to 60 days, using a Neurological Severity Score that measures neurobehavioral parameters. In all groups in which treatment was begun at 24 or 72 h neurobehavioral function was significantly better than in the vehicle-treated groups. Additional doses, on days 2 and 3 did not further improve recovery. Mice treated at 8 h or 16 h post injury did not differ from the vehicle-treated controls. Co-administration of the NMDA receptor antagonist MK-801 completely blocked the protective effect of DCS given at 24 h. Infarct volume measured by 2,3,5-triphenyltetrazolium chloride staining at 48 h or by cresyl violet at 28 days was not affected by DCS treatment. Since DCS is used clinically for other indications, the present study offers a novel approach for treating human traumatic brain injury with a therapeutic window of at least 24 h.

  19. D-Cycloserine as an augmentation strategy for cognitive behavioral therapy of anxiety disorders.

    PubMed

    Hofmann, Stefan G; Wu, Jade Q; Boettcher, Hannah

    2013-01-01

    The goal of this review is to examine the clinical studies on d-cycloserine, a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure procedures during cognitive behavioral therapy for anxiety disorders. Although cognitive behavioral therapy and anxiolytic medications are more effective than placebo for treating anxiety disorders, there is still considerable room for further improvement. Traditional combination strategies typically yield disappointing results. However, recent studies based on translational research have shown promise to augment the neural circuitry underlying fear extinction with pharmacological means. We discuss the current state of the literature, including inconsistencies of findings and issues concerning the drug mechanism, dosing, and dose timing. D-cycloserine is a promising combination strategy for cognitive behavioral therapy of anxiety disorders by augmenting extinction learning. However, there is also evidence to suggest that d-cycloserine can facilitate reconsolidation of fear memory when exposure procedures are unsuccessful. PMID:23768232

  20. D-Cycloserine as an augmentation strategy for cognitive behavioral therapy of anxiety disorders

    PubMed Central

    2013-01-01

    The goal of this review is to examine the clinical studies on d-cycloserine, a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure procedures during cognitive behavioral therapy for anxiety disorders. Although cognitive behavioral therapy and anxiolytic medications are more effective than placebo for treating anxiety disorders, there is still considerable room for further improvement. Traditional combination strategies typically yield disappointing results. However, recent studies based on translational research have shown promise to augment the neural circuitry underlying fear extinction with pharmacological means. We discuss the current state of the literature, including inconsistencies of findings and issues concerning the drug mechanism, dosing, and dose timing. D-cycloserine is a promising combination strategy for cognitive behavioral therapy of anxiety disorders by augmenting extinction learning. However, there is also evidence to suggest that d-cycloserine can facilitate reconsolidation of fear memory when exposure procedures are unsuccessful. PMID:23768232

  1. D-cycloserine facilitates extinction of naloxone-induced conditioned place aversion in morphine-dependent rats

    PubMed Central

    Myers, Karyn M.; Carlezon, William A.

    2016-01-01

    BACKGROUND Cues paired with drug administration trigger relapse to drug-seeking by inducing conditioned drug craving and withdrawal. Because drug cues hinder abstinence in addicts, therapies that reduce responsiveness to drug cues might facilitate rehabilitation. Extinction is a means of reducing conditioned responses and involves exposure to the conditioned stimulus (CS) in the absence of the unconditioned stimulus (US) with which it was paired previously. We examined conditioned withdrawal extinction using naloxone-induced conditioned place aversion (CPA) in morphine-dependent rats. METHOD Morphine-dependent rats were trained to associate an environment with naloxone-precipitated withdrawal. Subsequently they received extinction training in which they were confined in the previously naloxone-paired environment in the absence of acute withdrawal. In some rats, the NMDA receptor partial agonist D-cycloserine (DCS) was administered prior to extinction training. RESULTS Morphine withdrawal-induced CPA persists in the absence of extinction training. Administration of DCS prior to extinction training facilitates extinction. CONCLUSIONS DCS facilitates extinction of morphine withdrawal-associated place aversion. This effect is qualitatively similar to the effect of DCS on extinction of conditioned fear, raising the possibility of common neural mechanisms. This work extends our understanding of drug cue responsivity and provides a rationale for the development of extinction-based treatments for addiction. PMID:19782965

  2. D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury.

    PubMed

    Yaka, Rami; Biegon, Anat; Grigoriadis, Nikolaos; Simeonidou, Constantina; Grigoriadis, Savvas; Alexandrovich, Alexander G; Matzner, Henri; Schumann, Johanna; Trembovler, Victoria; Tsenter, Jeanna; Shohami, Esther

    2007-07-01

    Traumatic brain injury triggers a massive glutamate efflux, activation of NMDA receptor channels, and cell death. Recently, we reported that NMDA receptors in mice are down-regulated from hours to days following closed head injury (CHI), and treatment with NMDA improved recovery of motor and cognitive functions up to 14 d post-injury. Here we show that a single injection of a low dose of D-cycloserine (DCS), a partial NMDA receptor agonist, in CHI mice 24 h post-injury, resulted in a faster and greater recovery of motor and memory functions as assessed by neurological severity score and object recognition tests, respectively. Moreover, DCS treatment of CHI mice led to a significant improvement of hippocampal long-term potentiation (LTP) in the CA1 region that was completely blunted in CHI control mice. However, DCS did not improve CHI-induced impairment in synaptic glutamate release measured by paired pulse facilitation (PPF) ratio in hippocampal CA1 region. Finally, CHI-induced reduction of brain-derived neurotrophic factor (BDNF) was fully restored following DCS treatment. Since DCS is in clinical use for other indications, the present study offers a novel approach to treat human brain injury. PMID:17351125

  3. D-cycloserine facilitates extinction the first time but not the second time: an examination of the role of NMDA across the course of repeated extinction sessions.

    PubMed

    Langton, Julia M; Richardson, Rick

    2008-12-01

    Extinction of learned fear is facilitated by the partial NMDA agonist D-cycloserine (DCS). However, some studies suggest that the involvement of NMDA in learning differs depending on whether learning is for the first or second time. The current study aimed to extend these findings by examining the role of NMDA in extinction for the first and the second time. Specifically, the present series of experiments used Pavlovian fear conditioning and extinction paradigms to compare the effect of DCS on extinction of fear to a light CS the first and second time around. As found previously, DCS facilitated extinction of learned fear (Experiment 1). A novel finding, however, was that DCS did not facilitate the re-extinction of fear to this same CS following retraining (Experiments 2A and 2B). Finally, it was demonstrated that the transition from NMDA-dependent to NMDA-independent extinction was stimulus specific (Experiment 3). That is, rats were first trained to fear a CS (light); this fear was then extinguished. Following this, rats were then retrained to fear the same CS (light) or a new CS (white noise). When given a second extinction session, DCS was found to facilitate extinction of the new CS but not the original CS. The results of this series of experiments suggest that the role of NMDA in extinction depends on whether extinction is new learning (first extinction) or retrieval of a previous extinction memory (re-extinction). PMID:18354389

  4. d-Cycloserine Facilitation of Exposure Therapy Improves Weight Regain in Patients With Anorexia Nervosa: A Pilot Randomized Controlled Trial

    PubMed Central

    Levinson, Cheri A.; Rodebaugh, Thomas L.; Fewell, Laura; Kass, Andrea E.; Riley, Elizabeth N.; Stark, Lynn; McCallum, Kimberly; Lenze, Eric J.

    2016-01-01

    Objective Exposure therapy in anorexia nervosa has preliminarily been shown to be effective for increasing food intake. d-Cycloserine is a glutamatergic N-methyl-d-aspartate receptor agonist that has been shown to facilitate the benefits of exposure therapy for anxiety disorders by enhancing the emotional learning in the exposures; therefore, we examined d-cycloserine–facilitation of exposure therapy to increase body mass index (BMI) in patients with anorexia nervosa. Method Participants (N = 36) with anorexia nervosa (diagnosed via DSM-IV) were recruited from a partial hospitalization eating disorder clinic between February 2013 and November 2013. Participants were randomly assigned to receive exposure therapy plus d-cycloserine (n = 20) or placebo (n = 16). Participants completed psychoeducation and 4 sessions of exposure therapy, with medication (d-cycloserine vs placebo) given prior to the first 3 exposure sessions. They also completed a 1-month follow-up. Results As hypothesized, participants in the d-cycloserine group showed a significantly greater increase in BMI than those in the placebo group (Wilk Λ = 0.86, F3,32 = 2.20, P = .043, ηp2 = 0.12). d-Cycloserine participants gained 3 pounds relative to 0.5 pounds in the placebo group. Both groups experienced significantly decreased anxiety over the course of therapy (Wilk Λ = 0.80, F3,32 = 3.32, P = .023, ηp2 = 0.20). Conclusions This study preliminarily demonstrates that d-cycloserine facilitates exposure therapy for anorexia nervosa, leading to increased weight gain. A potential mechanism is that participants who receive d-cycloserine may generalize learning from within-session exposures to food intake during other similar meals, resulting in sustained increases in BMI. Further research is needed to confirm these findings and test the putative mechanism that generalized learning from exposure therapy can increase BMI and stabilize a healthy weight. Trial Registration ClinicalTrials.gov identifier: NCT

  5. D-cycloserine administered directly to infralimbic medial prefrontal cortex enhances extinction memory in sucrose-seeking animals.

    PubMed

    Peters, J; De Vries, T J

    2013-01-29

    d-Cycloserine (DCS), a co-agonist at the N-methyl-D-aspartate (NMDA) receptor, has proven to be an effective adjunct to cognitive behavioral therapies that utilize extinction. This pharmacological-based enhancement of extinction memory has been primarily demonstrated in neuropsychiatric disorders characterized by pathological fear (e.g. posttraumatic stress disorder and various phobias). More recently, there has been an interest in applying such a strategy in the disorders of appetitive learning (e.g. substance abuse and other addictions), but these studies have generated mixed results. Here we first examined whether extinction memory encoding in a sucrose self-administration model is dependent on NMDA receptors. The NMDA antagonist (±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (5mg/kg, i.p.) administered 2h prior to the first extinction training session effectively inhibited extinction memory recall 24h later, without affecting the expression of the conditioned sucrose-seeking response while the drug was on board. This profile of effects suggests a specific effect on extinction memory consolidation. Next, we sought to enhance extinction memory using the co-agonist DCS (10 μg/side) by infusion directly into infralimbic medial prefrontal cortex, a brain site implicated in extinction memory recall in conditioned fear models. Indeed, infusion of DCS immediately after the first extinction training session effectively enhanced extinction memory recall 24h later. Collectively, these data suggest that the neurobiological mechanisms and the neurocircuitry mediating extinction memory are similar regardless of the valence (aversive or appetitive) of the conditioned behavior, and that similar pharmacological strategies for treatment may be applied to neuropsychiatric disorders characterized by a failure to inhibit pathological emotional memories. PMID:23159319

  6. The Effect of Midazolam and Propranolol on Fear Memory Reconsolidation in Ethanol-Withdrawn Rats: Influence of D-Cycloserine

    PubMed Central

    Ortiz, Vanesa; Giachero, Marcelo; Espejo, Pablo Javier; Molina, Víctor Alejandro

    2015-01-01

    Background: Withdrawal from chronic ethanol facilitates the formation of contextual fear memory and delays the onset to extinction, with its retrieval promoting an increase in ethanol consumption. Consequently, manipulations aimed to reduce these aversive memories, may be beneficial in the treatment of alcohol discontinuation symptoms. Related to this, pharmacological memory reconsolidation blockade has received greater attention due to its therapeutic potential. Methods: Here, we examined the effect of post-reactivation amnestic treatments such as Midazolam (MDZ, 3 mg/kg i.p) and Propranolol (PROP, 5 mg/kg i.p) on contextual fear memory reconsolidation in ethanol- withdrawn (ETOH) rats. Next, we examined whether the activation of N-methyl-D-aspartate (NMDA) receptors induced by d-cycloserine (DCS, 5 mg/kg i.p., a NMDA partial agonist) before memory reactivation can facilitate the disruptive effect of PROP and MDZ on fear memory in ETOH rats. Results: We observed a resistance to the disruptive effect of both MDZ and PROP following memory reactivation. Although intra-basolateral amygdala (BLA; 1.25 ug/side) and systemic PROP administration attenuated fear memory in DCS pre-treated ETOH rats, DCS/MDZ treatment did not affect memory in these animals. Finally, a decrease of both total and surface protein expression of the α1 GABAA receptor (GABAA-R) subunit in BLA was found in the ETOH rats. Conclusions: Ethanol withdrawal facilitated the formation of fear memory resistant to labilization post-reactivation. DCS administration promoted the disruptive effect of PROP on memory reconsolidation in ETOH rats. The resistance to MDZ’s disruptive effect on fear memory reconsolidation may be, at least in part, associated with changes in the GABAA-R composition induced by chronic ethanol administration/withdrawal. PMID:25617327

  7. D-cycloserine 24 and 48 hours after asphyxial cardiac arrest has no effect on hippocampal CA1 neuropathology

    PubMed Central

    Combs, Vélvá M; Crispell, Heather D; Drew, Kelly L

    2014-01-01

    Stimulation of N-methyl-D-aspartate receptors (NMDAR) contributes to regenerative neuroplasticity following the initial excitotoxic insult during cerebral ischemia. Stimulation of NMDAR with the partial NMDAR agonist D-cycloserine (DCS) improves outcome and restores hippocampal synaptic plasticity in models of closed head injury. We thus hypothesized that DCS would improve outcome following restoration of spontaneous circulation (ROSC) from cardiac arrest (CA). DCS (10 mg/kg, IP) was administered to Sprague-Dawley rats (male, 250–330 g; 63–84 days old) 24 and 48 hours after 6 or 8 minutes of asphyxial CA. Heart rate and blood pressure declined similarly in all groups. Animals showed neurological deficits after 6 and 8 minutes CA (P<0.05, Tukey) and these deficits recovered more quickly after 6 minutes than after 8 minutes of CA. CA decreased the number of healthy neurons within CA1 with no difference between 6 and 8 minutes duration of CA (180.8±27.6 (naïve, n=5) versus 46.3±33.8 (all CA groups, n=27) neurons per mm CA1). DCS had no effect on neurological deficits or CA1 hippocampal cell counts (P>0.05, Tukey). PMID:25099755

  8. Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq.

    PubMed

    Malan-Müller, Stefanie; Fairbairn, Lorren; Daniels, Willie M U; Dashti, Mahjoubeh Jalali Sefid; Oakeley, Edward J; Altorfer, Marc; Kidd, Martin; Seedat, Soraya; Gamieldien, Junaid; Hemmings, Sîan Megan Joanna

    2016-02-01

    D-cycloserine (DCS) has been shown to be effective in facilitating fear extinction in animal and human studies, however the precise mechanisms whereby the co-administration of DCS and behavioural fear extinction reduce fear are still unclear. This study investigated the molecular mechanisms of intrahippocampally administered D-cycloserine in facilitating fear extinction in a contextual fear conditioning animal model. Male Sprague Dawley rats (n = 120) were grouped into four experimental groups (n = 30) based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark avoidance test was used to differentiate maladapted (MA) (anxious) from well-adapted (WA) (not anxious) subgroups. RNA extracted from the left dorsal hippocampus was used for RNA sequencing and gene expression data was compared between six fear-conditioned + saline MA (FEAR + SALINE MA) and six fear-conditioned + DCS WA (FEAR + DCS WA) animals. Of the 424 significantly downregulated and 25 significantly upregulated genes identified in the FEAR + DCS WA group compared to the FEAR + SALINE MA group, 121 downregulated and nine upregulated genes were predicted to be relevant to fear conditioning and anxiety and stress-related disorders. The majority of downregulated genes transcribed immune, proinflammatory and oxidative stress systems molecules. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, and genes associated with anxiety, stress-related disorders and co-occurring diseases (e.g., cardiovascular diseases, digestive system diseases and nervous system diseases). Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction. PMID:26400817

  9. Augmentation of fear extinction by D-cycloserine is blocked by proteasome inhibitors.

    PubMed

    Mao, Sheng-Chun; Lin, Hui-Ching; Gean, Po-Wu

    2008-12-01

    D-Cycloserine (DCS) has been shown to facilitate extinction of conditioned fear in rats and to improve fear reduction of social phobia and fear of heights in human studies. Here, we investigate the mechanism of DCS effect by measuring internalized GluR1 and GluR2 using cell-surface biotinylation techniques. DCS selectively increased NMDA receptor-mediated synaptic response without affecting AMPA receptor-mediated synaptic response. Low-frequency stimulation (LFS) when applied in the presence of DCS induced GluR1 and GluR2 internalization in the amygdala slices. Proteasome inhibitors block DCS facilitation of LFS-induced depotentiation and a reduction in surface levels of GluR1 and GluR2. Furthermore, DCS in combination with LFS reduced cellular levels of PSD-95 and synapse-associated protein 97 (SAP97), which were also blocked by proteasome inhibitors. In the in vivo experiments, DCS-induced reduction of fear-potentiated startle and reversal of conditioning-induced increase in surface expression of GluR1 were blocked by proteasome inhibitors. DCS-treated rats fail to exhibit reinstatement after US-alone presentations. These results suggest that DCS facilitates receptor internalization in the presence of extinction training, resulting in augmented reduction of startle potentiation. PMID:18368037

  10. Characterization of Escherichia coli d-Cycloserine Transport and Resistant Mutants

    PubMed Central

    Baisa, Gary; Stabo, Nicholas J.

    2013-01-01

    d-Cycloserine (DCS) is a broad-spectrum antibiotic that inhibits d-alanine ligase and alanine racemase activity. When Escherichia coli K-12 or CFT073 is grown in minimal glucose or glycerol medium, CycA transports DCS into the cell. E. coli K-12 cycA and CFT073 cycA mutant strains display increased DCS resistance when grown in minimal medium. However, the cycA mutants exhibit no change in DCS sensitivity compared to their parental strains when grown in LB (CFT073 and K-12) or human urine (CFT073 only). These data suggest that cycA does not participate in DCS sensitivity when strains are grown in a non-minimal medium. The small RNA GvcB acts as a negative regulator of E. coli K-12 cycA expression when grown in LB. Three E. coli K-12 gcvB mutant strains failed to demonstrate a change in DCS sensitivity when grown in LB. This further suggests a limited role for cycA in DCS sensitivity. To aid in the identification of E. coli genes involved in DCS sensitivity when grown on complex media, the Keio K-12 mutant collection was screened for DCS-resistant strains. dadA, pnp, ubiE, ubiF, ubiG, ubiH, and ubiX mutant strains showed elevated DCS resistance. The phenotypes associated with these mutants were used to further define three previously characterized E. coli DCS-resistant strains (χ316, χ444, and χ453) isolated by Curtiss and colleagues (R. Curtiss, III, L. J. Charamella, C. M. Berg, and P. E. Harris, J. Bacteriol. 90:1238–1250, 1965). A dadA mutation was identified in both χ444 and χ453. In addition, results are presented that indicate for the first time that DCS can antagonize d-amino acid dehydrogenase (DadA) activity. PMID:23316042

  11. D-cycloserine, sarcosine and D-serine diminish the expression of cocaine-induced conditioned place preference.

    PubMed

    Yang, Fu-Yung; Lee, Yung-Shuan; Cherng, Chianfang G; Cheng, Ling-Yi; Chang, Wan-Ting; Chuang, Jia-Ying; Kao, Gour-Shenq; Yu, Lung

    2013-06-01

    Reactivation of cocaine-associated memories plays a critical role in reinstating the cocaine-seeking behavior and causing relapse. Cocaine-induced conditioned place preference (CPP) was used as a behavioral paradigm indicative of cocaine-associated memory and repeated cocaine-free preference tests served as a behavioral procedure to retrieve such a memory in this study. Since D-cycloserine was reported to eradicate drug-associated memories, two other N-methyl-D-aspartate (NMDA) receptor agonists were assessed for their efficacy on facilitating the extinction of cocaine-induced CPP. Although D-cycloserine (30 mg/kg) abolished cocaine (10 mg/kg)-induced CPP, sarcosine (300 and 600 mg/kg) and D-serine (600 mg/kg) diminished the expression of such a cocaine memory. Sarcosine (600 mg/kg) and D-serine (600 mg/kg) did not affect the storage of this cocaine memory. It was of interest to note that D-cycloserine facilitated the extinction of cocaine-induced CPP in a fast and early-onset manner, while sarcosine and D-serine decreased cocaine-induced CPP expression in a delay-onset manner. D-cycloserine (30 mg/kg), D-serine (600 mg/kg) and sarcosine (600 mg/kg) did not affect the consolidation of cocaine (5 mg/kg)-induced CPP. Finally, sarcosine (at 600 mg/kg/day for 3 consecutive days) and D-serine (at 600 mg/kg/day for 3 consecutive days) did not produce observable aversive effect associated with their administration in a conditioned place aversion paradigm. Likewise, a similar dosing regimen of sarcosine or D-serine did not cause evident activity-impairing effect. In addition to D-cycloserine treatment, our results indicate that long-term treatment with D-serine and sarcosine may afford a therapeutic advance in suppressing the expression of cocaine-associated memory. PMID:21106609

  12. A trial of d-cycloserine to treat the social deficit in older adolescents and young adults with autism spectrum disorders.

    PubMed

    Urbano, Maria; Okwara, Leonore; Manser, Paul; Hartmann, Kathrin; Deutsch, Stephen I

    2015-01-01

    Autism spectrum disorders are difficult for older adolescents and young adults as impaired social communication affects the transition to adult life. d-Cycloserine, a partial glycine agonist at the N-methyl-d-aspartic acid receptor, was tested in a double-blind randomized trial in 20 older adolescents and young adults with autism spectrum disorders using two dosing strategies (50 mg daily versus 50 mg weekly) for 8 weeks with a 2-week follow-up after discontinuation. d-Cycloserine caused statistically and clinically significant improvement with no differentiation between dosing strategies on the Social Responsiveness Scale and the Aberrant Behavior Checklist before and after d-cycloserine administration. PMID:25923852

  13. D-cycloserine to enhance extinction of cue-elicited craving for alcohol: a translational approach

    PubMed Central

    MacKillop, J; Few, L R; Stojek, M K; Murphy, C M; Malutinok, S F; Johnson, F T; Hofmann, S G; McGeary, J E; Swift, R M; Monti, P M

    2015-01-01

    Cue-elicited craving for alcohol is well established but extinction-based treatment to extinguish this response has generated only modest positive outcomes in clinical trials. Basic and clinical research suggests that D-cycloserine (DCS) enhances extinction to fear cues under certain conditions. However, it remains unclear whether DCS would also accelerate extinction of cue-elicited craving for alcohol. The goal of the current study was to examine whether, compared with placebo (PBO), DCS enhanced extinction of cue-elicited craving among treatment-seeking individuals with alcohol use disorders (AUDs). Participants were administered DCS (50 mg) or PBO 1 h before an alcohol extinction paradigm in a simulated bar environment on two occasions. The extinction procedures occurred 1 week apart and were fully integrated into outpatient treatment. Subjective craving for alcohol was the primary variable of interest. Follow-up cue reactivity sessions were conducted 1 week and 3 weeks later to ascertain persisting DCS effects. Drinking outcomes and tolerability were also examined. DCS was associated with augmented reductions in alcohol craving to alcohol cues during the first extinction session and these effects persisted through all subsequent sessions, suggesting facilitation of extinction. Participants in the DCS condition reported significant short-term reductions in drinking, although these did not persist to follow-up, and found the medication highly tolerable. These findings provide evidence that DCS enhances extinction of cue-elicited craving for alcohol in individuals with AUDs in the context of outpatient treatment. The potential clinical utility of DCS is discussed, including methodological considerations and context-dependent learning. PMID:25849983

  14. Dose timing of D-cycloserine to augment cognitive behavioral therapy for social anxiety: Study design and rationale.

    PubMed

    Hofmann, Stefan G; Carpenter, Joseph K; Otto, Michael W; Rosenfield, David; Smits, Jasper A J; Pollack, Mark H

    2015-07-01

    The use of D-cycloserine (DCS) as a cognitive enhancer to augment exposure-based cognitive-behavioral therapy (CBT) represents a promising new translational research direction with the goal to accelerate and optimize treatment response for anxiety disorders. Some studies suggest that DCS may not only augment extinction learning but could also facilitate fear memory reconsolidation. Therefore, the effect of DCS may depend on fear levels reported at the end of exposure sessions. This paper presents the rationale and design for a randomized controlled trial examining the relative efficacy of tailoring DCS administration based on exposure success (i.e. end fear levels) during a 5-session group CBT protocol for social anxiety disorder (n = 156). Specifically, tailored post-session DCS administration will be compared against untailored post-session DCS, untailored pre-session DCS, and pill placebo in terms of reduction in social anxiety symptoms and responder status. In addition, a subset of participants (n = 96) will undergo a fear extinction retention experiment prior to the clinical trial in which they will be randomly assigned to receive either DCS or placebo prior to extinguishing a conditioned fear. The results from this experimental paradigm will clarify the mechanism of the effects of DCS on exposure procedures. This study aims to serve as the first step toward developing an algorithm for the personalized use of DCS during CBT for social anxiety disorder, with the ultimate goal of optimizing treatment outcome for anxiety disorders. PMID:26111923

  15. Dose Timing of D-cycloserine to Augment Cognitive Behavioral Therapy for Social Anxiety: Study Design and Rationale

    PubMed Central

    Carpenter, Joseph K.; Otto, Michael W.; Rosenfield, David; Smits, Jasper A. J.; Pollack, Mark H.

    2015-01-01

    The use of d-cycloserine (DCS) as a cognitive enhancer to augment exposure-based cognitive-behavioral therapy (CBT) represents a promising new translational research direction with the goal to accelerate and optimize treatment response for anxiety disorders. Some studies suggest that DCS may not only augment extinction learning but could also facilitate fear memory reconsolidation. Therefore, the effect of DCS may depend on fear levels reported at the end of exposure sessions. This paper presents the rationale and design for an ongoing randomized controlled trial examining the relative efficacy of tailoring DCS administration based on exposure success (i.e. end fear levels) during a 5-session group CBT protocol for social anxiety disorder (n = 156). Specifically, tailored post-session DCS administration will be compared against untailored post-session DCS, untailored pre-session DCS, and pill placebo in terms of reduction in social anxiety symptoms and responder status. In addition, a subset of participants (n = 96) will undergo a fear extinction retention experiment prior to the clinical trial in which they will be randomly assigned to receive either DCS or placebo prior to extinguishing a conditioned fear. The results from this experimental paradigm will clarify the mechanism of the effects of DCS on exposure procedures. This study aims to serve as the first step toward developing an algorithm for the personalized use of DCS during CBT for social anxiety disorder, with the ultimate goal of optimizing treatment outcome for anxiety disorders. ClinicalTrials.gov identifier: NCT02066792 PMID:26111923

  16. Examining the efficacy of d-cycloserine to augment therapeutic learning in depression.

    PubMed

    Otto, Michael W; Lee, Josephine; Hofmann, Stefan G; Hearon, Bridget A; Smits, Jasper A J; Rosenfield, David; Fava, Maurizio; Wright, Jesse H

    2016-05-01

    Despite advances in individual and combined treatments for major depression, issues with non-response and partial-response remain relatively common, motivating the search for new treatment strategies. This study aims to develop one such novel treatment. In this proof-of-concept study, we are investigating whether the treatment enhancing effects of d-cycloserine (DCS) administration can be extended outside the extinction-learning paradigms where they have been primarily examined. Using uniform delivery of cognitive behavioral therapy (CBT) content via computer-administered interventions for depression, we are assessing the value of pre-session administrations of DCS for retention of therapeutic learning. Recall of this information is evaluated in conjunction with performance on standardized tests of memory recall with both emotional and non-emotional stimuli. Specifically, in a randomized, double-blind trial we will compare the benefits of two pre-session administrations of DCS augmentation to those achieved by similar administrations of modafinil or placebo. Because modafinil is associated with a number of discriminable effects in addition to cognitive enhancement (e.g., feelings of vigor, alertness, positive mood); whereas these effects would not be expected with DCS, we will assess drug context effects in relation to memory augmentation effects. PMID:27094721

  17. Does D-cycloserine enhance exposure therapy for anxiety disorders in humans? A meta-analysis.

    PubMed

    Rodrigues, Helga; Figueira, Ivan; Lopes, Alessandra; Gonçalves, Raquel; Mendlowicz, Mauro Vitor; Coutinho, Evandro Silva Freire; Ventura, Paula

    2014-01-01

    The treatment of anxiety is on the edge of a new era of combinations of pharmacologic and psychosocial interventions. A new wave of translational research has focused on the use of pharmacological agents as psychotherapy adjuvants using neurobiological insights into the mechanism of the action of certain psychological treatments such as exposure therapy. Recently, d-cycloserine (DCS) an antibiotic used to treat tuberculosis has been applied to enhance exposure-based treatment for anxiety and has proved to be a promising, but as yet unproven intervention. The present study aimed to evaluate the efficacy of DCS in the enhancement of exposure therapy in anxiety disorders. A systematic review/meta-analysis was conducted. Electronic searches were conducted in the databases ISI-Web of Science, Pubmed and PsycINFO. We included only randomized, double-blind, placebo-controlled trials with humans, focusing on the role of DCS in enhancing the action of exposure therapy for anxiety disorders. We identified 328 references, 13 studies were included in our final sample: 4 on obsessive-compulsive disorder, 2 on panic disorder, 2 on social anxiety disorder, 2 on posttraumatic stress disorder, one on acrophobia, and 2 on snake phobia. The results of the present meta-analysis show that DCS enhances exposure therapy in the treatment of anxiety disorders (Cohen d =  -0.34; CI: -0.54 to -0.14), facilitating the specific process of extinction of fear. DCS seems to be effective when administered at a time close to the exposure therapy, at low doses and a limited number of times. DCS emerges as a potential new therapeutic approach for patients with refractory anxiety disorders that are unresponsive to the conventional treatments available. When administered correctly, DCS is a promising strategy for augmentation of CBT and could reduce health care costs, drop-out rates and bring faster relief to patients. PMID:24991926

  18. Does D-Cycloserine Enhance Exposure Therapy for Anxiety Disorders in Humans? A Meta-Analysis

    PubMed Central

    Rodrigues, Helga; Figueira, Ivan; Lopes, Alessandra; Gonçalves, Raquel; Mendlowicz, Mauro Vitor; Coutinho, Evandro Silva Freire; Ventura, Paula

    2014-01-01

    The treatment of anxiety is on the edge of a new era of combinations of pharmacologic and psychosocial interventions. A new wave of translational research has focused on the use of pharmacological agents as psychotherapy adjuvants using neurobiological insights into the mechanism of the action of certain psychological treatments such as exposure therapy. Recently, d-cycloserine (DCS) an antibiotic used to treat tuberculosis has been applied to enhance exposure-based treatment for anxiety and has proved to be a promising, but as yet unproven intervention. The present study aimed to evaluate the efficacy of DCS in the enhancement of exposure therapy in anxiety disorders. A systematic review/meta-analysis was conducted. Electronic searches were conducted in the databases ISI-Web of Science, Pubmed and PsycINFO. We included only randomized, double-blind, placebo-controlled trials with humans, focusing on the role of DCS in enhancing the action of exposure therapy for anxiety disorders. We identified 328 references, 13 studies were included in our final sample: 4 on obsessive-compulsive disorder, 2 on panic disorder, 2 on social anxiety disorder, 2 on posttraumatic stress disorder, one on acrophobia, and 2 on snake phobia. The results of the present meta-analysis show that DCS enhances exposure therapy in the treatment of anxiety disorders (Cohen d =  −0.34; CI: −0.54 to −0.14), facilitating the specific process of extinction of fear. DCS seems to be effective when administered at a time close to the exposure therapy, at low doses and a limited number of times. DCS emerges as a potential new therapeutic approach for patients with refractory anxiety disorders that are unresponsive to the conventional treatments available. When administered correctly, DCS is a promising strategy for augmentation of CBT and could reduce health care costs, drop-out rates and bring faster relief to patients. PMID:24991926

  19. Enhancing panic and smoking reduction treatment with d-cycloserine: Study protocol for a randomized controlled trial.

    PubMed

    Smits, Jasper A J; Kauffman, Brooke Y; Lee-Furman, Eunjung; Zvolensky, Michael J; Otto, Michael W; Piper, Megan E; Powers, Mark B; Rosenfield, David

    2016-05-01

    There has been relatively little attention focused on treatment strategies for smokers with panic attacks despite their increased risk of relapse. Panic and Smoking Reduction Treatment (PSRT) integrates standard smoking cessation treatment with an exposure-based intervention targeting the mechanisms underlying panic-smoking relations. Building upon emerging evidence supporting the efficacy of d-cycloserine (DCS) for augmenting exposure-based therapy, we are conducting an initial test of the efficacy of DCS for enhancing PSRT outcomes. Utilizing a randomized, double-blind trial comparing PSRT+DCS to PSRT+placebo, we will obtain initial effect sizes for short-term and long-term smoking cessation outcomes and perform an initial test of putative mechanisms. PMID:27015966

  20. Metabolomics Analysis Identifies D-Alanine-D-alanine Ligase as the Primary Lethal Target of D-cycloserine in Mycobacteria

    PubMed Central

    Halouska, Steven; Fenton, Robert J.; Zinniel, Denise K.; Marshall, Darrell D.; Barletta, Raúl G.; Powers, Robert

    2014-01-01

    D-cycloserine is an effective second line antibiotic used as a last resort to treat multi (MDR)- and extensively (XDR)- drug resistant strains of Mycobacterium tuberculosis. D-cycloserine interferes with the formation of peptidoglycan biosynthesis by competitive inhibition of Alanine racemase (Alr) and D-Alanine-D-alanine ligase (Ddl). Although, the two enzymes are known to be inhibited, the in vivo lethal target is still unknown. Our NMR metabolomics work has revealed that Ddl is the primary target of DCS, as cell growth is inhibited when the production of D-alanyl-D-alanine is halted. It is shown that inhibition of Alr may contribute indirectly by lowering the levels of D-alanine thus allowing DCS to outcompete D-alanine for Ddl binding. The NMR data also supports the possibility of a transamination reaction to produce D-alanine from pyruvate and glutamate, thereby bypassing Alr inhibition. Furthermore, the inhibition of peptidoglycan synthesis results in a cascading effect on cellular metabolism as there is a shift toward the catabolic routes to compensate for accumulation of peptidoglycan precursors. PMID:24303782

  1. Unraveling Comparative Anti-Amyloidogenic Behavior of Pyrazinamide and D-Cycloserine: A Mechanistic Biophysical Insight

    PubMed Central

    Chaturvedi, Sumit Kumar; Zaidi, Nida; Alam, Parvez; Khan, Javed Masood; Qadeer, Atiyatul; Siddique, Ibrar Ahmad; Asmat, Shamoon; Zaidi, Yusra; Khan, Rizwan Hasan

    2015-01-01

    Amyloid fibril formation by proteins leads to variety of degenerative disorders called amyloidosis. While these disorders are topic of extensive research, effective treatments are still unavailable. Thus in present study, two anti-tuberculosis drugs, i.e., pyrazinamide (PYZ) and D-cycloserine (DCS), also known for treatment for Alzheimer’s dementia, were checked for the anti-aggregation and anti-amyloidogenic ability on Aβ-42 peptide and hen egg white lysozyme. Results demonstrated that both drugs inhibit the heat induced aggregation; however, PYZ was more potent and decelerated the nucleation phase as observed from various spectroscopic and microscopic techniques. Furthermore, pre-formed amyloid fibrils incubated with these drugs also increased the PC12/SH-SY5Y cell viability as compare to the amyloid fibrils alone; however, the increase was more pronounced for PYZ as confirmed by MTT assay. Additionally, molecular docking study suggested that the greater inhibitory potential of PYZ as compare to DCS may be due to strong binding affinity and more occupancy of hydrophobic patches of HEWL, which is known to form the core of the protein fibrils. PMID:26312749

  2. D-Cycloserine Augmentation of Cognitive Behavioral Group Therapy of Social Anxiety Disorder: Prognostic and Prescriptive Variables

    PubMed Central

    Smits, Jasper A. J.; Hofmann, Stefan G.; Rosenfield, David; DeBoer, Lindsey B.; Costa, Paul T.; Simon, Naomi M.; O'Cleirigh, Conall; Meuret, Alicia E.; Marques, Luana; Otto, Michael W.; Pollack, Mark H.

    2014-01-01

    Objective The aim of the current study was to identify individual characteristics that (1) predict symptom improvement with group cognitive behavioral therapy (CBT) for social anxiety disorder (SAD; i.e., prognostic variables) or (2) moderate the effects of d-cycloserine vs. placebo augmentation of CBT for SAD (i.e., prescriptive variables). Method Adults with SAD (N=169) provided Liebowitz Social Anxiety Scale (LSAS) scores in a trial evaluating DCS augmentation of group CBT. Rate of symptom improvement during therapy and posttreatment symptom severity were evaluated using multilevel modeling. As predictors of these two parameters, we selected the range of variables assessed at baseline (demographic characteristics, clinical characteristics, personality traits). Using step-wise analyses, we first identified prognostic and prescriptive variables within each of these domains and then entered these significant predictors simultaneously in one final model. Results African American ethnicity and cohabitation status were associated with greater overall rates of improvement during therapy and lower posttreatment severity. Higher initial severity was associated with a greater improvement during therapy, but also higher posttreatment severity (the greater improvement was not enough to overcome the initial higher severity). D-cycloserine augmentation was evident only among individuals low in conscientiousness and high in agreeableness. Conclusions African American ethnicity, cohabitation status, and initial severity are prognostic of favorable CBT outcomes in SAD. D-cycloserine augmentation appears particularly useful for patients low in conscientiousness and high in agreeableness. These findings can guide clinicians in making decisions about treatment strategies and can help direct research on the mechanisms of these treatments. PMID:23937345

  3. Molecular Cloning and Heterologous Expression of a Biosynthetic Gene Cluster for the Antitubercular Agent d-Cycloserine Produced by Streptomyces lavendulae▿

    PubMed Central

    Kumagai, Takanori; Koyama, Yusuke; Oda, Kosuke; Noda, Masafumi; Matoba, Yasuyuki; Sugiyama, Masanori

    2010-01-01

    In the present study, we successfully cloned a 21-kb DNA fragment containing a d-cycloserine (DCS) biosynthetic gene cluster from a DCS-producing Streptomyces lavendulae strain, ATCC 11924. The putative gene cluster consists of 10 open reading frames (ORFs), designated dcsA to dcsJ. This cluster includes two ORFs encoding d-alanyl-d-alanine ligase (dcsI) and a putative membrane protein (dcsJ) as the self-resistance determinants of the producer organism, indicated by our previous work. When the 10 ORFs were introduced into DCS-nonproducing Streptomyces lividans 66 as a heterologous host cell, the transformant acquired DCS productivity. This reveals that the introduced genes are responsible for the biosynthesis of DCS. As anticipated, the disruption of dcsG, seen in the DCS biosynthetic gene cluster, made it possible for the strain ATCC 11924 to lose its DCS production. We here propose the DCS biosynthetic pathway. First, l-serine is O acetylated by a dcsE-encoded enzyme homologous to homoserine O-acetyltransferase. Second, O-acetyl-l-serine accepts hydroxyurea via an O-acetylserine sulfhydrylase homolog (dcsD product) and forms O-ureido-l-serine. The hydroxyurea must be supplied by the catalysis of a dcsB-encoded arginase homolog using the l-arginine derivative, NG-hydroxy-l-arginine. The resulting O-ureido-l-serine is then racemized to O-ureido-d-serine by a homolog of diaminopimelate epimerase. Finally, O-ureido-d-serine is cyclized to form DCS with the release of ammonia and carbon dioxide. The cyclization must be done by the dcsG or dcsH product, which belongs to the ATP-grasp fold family of protein. PMID:20086163

  4. Does d-Cycloserine Augmentation of CBT Improve Therapeutic Homework Compliance for Pediatric Obsessive-Compulsive Disorder?

    PubMed

    Park, Jennifer M; Small, Brent J; Geller, Daniel A; Murphy, Tanya K; Lewin, Adam B; Storch, Eric A

    2014-07-01

    Clinical studies in adults and children with obsessive-compulsive disorder (OCD) have shown that d-cycloserine (DCS) can improve treatment response by enhancing fear extinction learning during exposure-based psychotherapy. Some have hypothesized that improved treatment response is a function of increased compliance and engagement in therapeutic homework tasks, a core component of behavioral treatment. The present study examined the relationship between DCS augmented cognitive-behavioral therapy (CBT) and homework compliance in a double-blind, placebo controlled trial with 30 youth with OCD. All children received 10 CBT sessions, the last seven of which included exposure and response prevention paired with DCS or placebo dosed 1 h before the session started. Results suggested that DCS augmented CBT did not predict improved homework compliance over the course of treatment, relative to the placebo augmented CBT group. However, when groups were collapsed, homework compliance was directly associated with treatment outcome. These findings suggest that while DCS may not increase homework compliance over time, more generally, homework compliance is an integral part of pediatric OCD treatment outcome. PMID:24999301

  5. Effect of a positive reinforcing stimulus on fear memory reconsolidation in ethanol withdrawn rats: Influence of d-cycloserine.

    PubMed

    Ortiz, Vanesa; Molina, Víctor Alejandro; Martijena, Irene Delia

    2016-12-15

    The pharmacological blockade of memory reconsolidation has been suggested as a potential treatment to the attenuation of maladaptive memories associated to psychiatric disorders and drug addiction. To interfere with the process of fear memory reconsolidation using a manipulation safer than pharmacological interventions, here we examined whether a positive reinforcing stimulus (non-alcoholic beer, NB) post-memory retrieval can decrease the fear response in ethanol withdrawn (ETOH) animals. We first evaluated the potential interfering effect of NB on memory reconsolidation in non-ethanol dependent (control, CON) rats. Non-alcoholic beer intake shortly after memory retrieval attenuated the fear response in CON rats. A resistance to destabilization/reconsolidation process was previously observed in ETOH rats, which was reversed by the activation of NMDA receptor induced by pre-retrieval d-cycloserine (DCS) administration. Therefore, the influence of DCS (5mg/kg; i.p.) to facilitate the disruptive effect of NB on fear memory was examined in ETOH animals. As expected, NB was ineffective to attenuate the fear response in ETOH rats, with DCS being necessary to promote the disruptive effect of NB on the reconsolidation in these animals. Hence, DCS/reinforcing stimulus in combination with memory reactivation can be considered as an alternative approach for disrupting resistant fear memories. PMID:27522017

  6. D-Cycloserine Augmentation of Exposure Therapy for Post-Traumatic Stress Disorder: A Pilot Randomized Clinical Trial

    PubMed Central

    Difede, JoAnn; Cukor, Judith; Wyka, Katarzyna; Olden, Megan; Hoffman, Hunter; Lee, Francis S; Altemus, Margaret

    2014-01-01

    Viewing post-traumatic stress disorder (PTSD) as a disorder of emotional learning, this study used a cognitive enhancer synergistically with virtual reality exposure (VRE) therapy for the treatment of PTSD. The main objective was to determine if a novel pharmacotherapy, D-cycloserine (DCS), enhanced the efficacy of the psychotherapy. Pre-clinical studies suggest that when fear extinction occurs during DCS administration, neuroplasticity may be enhanced. VRE therapy is a particularly promising format to test the hypothesis that DCS enhances extinction learning, as sensory fear cues are standardized across patients. In a pilot randomized, double-blind, placebo-controlled trial, 100 mg of DCS or placebo was administered 90 min before each weekly VRE session, to ensure peak plasma concentrations during the sessions in 25 patients with chronic PTSD. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS). Secondary outcome measures included the Beck Depression Inventory-II and the State-Trait Anger Expression Inventory-2. Assessments occurred at pre-treatment, following sessions 3, 6, 10, post-treatment, and at 6 months. The difference in CAPS between the VRE-DCS (n=13) and VRE-placebo (n=12) groups increased over time beginning at 6 weeks, with medium to large between-group effect sizes immediately post-treatment and 6 months later (d=0.68 and d=1.13, respectively). A similar pattern was observed for depression, anger expression, and sleep. PTSD remission rates were significantly greater for the VRE-DCS group (46% vs 8% at post-treatment; 69% vs 17% at 6 months). Patients in the VRE-DCS group showed earlier and greater improvement in PTSD symptoms compared with the VRE-placebo group. These results suggest a promising new treatment for PTSD. PMID:24217129

  7. Randomized, Placebo-Controlled, Double-Blind Pilot Study of D-Cycloserine in Chronic Stroke.

    PubMed

    Butler, Andrew J; Kallos, Justiss; Housley, Stephen N; LaPlaca, Michelle C; Traynelis, Stephen F; Wolf, Steven L

    2015-01-01

    Stroke is a leading cause of death and disability in the USA. Up to 60% of patients do not fully recover despite intensive physical therapy treatment. N-Methyl-D-aspartate receptors (NMDA-R) have been shown to play a role in synaptic plasticity when activated. D-Cycloserine promotes NMDA receptor function by binding to receptors with unoccupied glycine sites. These receptors are involved in learning and memory. We hypothesized that D-cycloserine, when combined with robotic-assisted physiotherapy (RAP), would result in greater gains compared with placebo + RAP in stroke survivors. Participants (n = 14) were randomized to D-cycloserine plus RAP or placebo plus RAP. Functional, cognitive, and quality-of-life measures were used to assess recovery. There was significant improvement in grip strength of the affected hand within both groups from baseline to 3 weeks (95% confidence interval for mean change, 3.95 ± 2.96 to 4.90 ± 3.56 N for D-cycloserine and 5.72 ± 3.98 to 8.44 ± 4.90 N for control). SIS mood domain showed improvement for both groups (95% confidence interval for mean change, 72.6 ± 16.3 to 82.9 ± 10.9 for D-cycloserine and 82.9 ± 13.5 to 90.3 ± 9.9 for control). This preliminary study does not provide evidence that D-cycloserine can provide greater gains in learning compared with placebo for stroke survivors. PMID:26587287

  8. Randomized, Placebo-Controlled, Double-Blind Pilot Study of D-Cycloserine in Chronic Stroke

    PubMed Central

    Butler, Andrew J.; Kallos, Justiss; Housley, Stephen N.; LaPlaca, Michelle C.; Traynelis, Stephen F.; Wolf, Steven L.

    2015-01-01

    Stroke is a leading cause of death and disability in the USA. Up to 60% of patients do not fully recover despite intensive physical therapy treatment. N-Methyl-D-aspartate receptors (NMDA-R) have been shown to play a role in synaptic plasticity when activated. D-Cycloserine promotes NMDA receptor function by binding to receptors with unoccupied glycine sites. These receptors are involved in learning and memory. We hypothesized that D-cycloserine, when combined with robotic-assisted physiotherapy (RAP), would result in greater gains compared with placebo + RAP in stroke survivors. Participants (n = 14) were randomized to D-cycloserine plus RAP or placebo plus RAP. Functional, cognitive, and quality-of-life measures were used to assess recovery. There was significant improvement in grip strength of the affected hand within both groups from baseline to 3 weeks (95% confidence interval for mean change, 3.95 ± 2.96 to 4.90 ± 3.56 N for D-cycloserine and 5.72 ± 3.98 to 8.44 ± 4.90 N for control). SIS mood domain showed improvement for both groups (95% confidence interval for mean change, 72.6 ± 16.3 to 82.9 ± 10.9 for D-cycloserine and 82.9 ± 13.5 to 90.3 ± 9.9 for control). This preliminary study does not provide evidence that D-cycloserine can provide greater gains in learning compared with placebo for stroke survivors. PMID:26587287

  9. Structure of the Mycobacterium tuberculosis D-Alanine:D-Alanine Ligase, a Target of the Antituberculosis Drug D-Cycloserine

    SciTech Connect

    Bruning, John B.; Murillo, Ana C.; Chacon, Ofelia; Barletta, Raúl G.; Sacchettini, James C.

    2011-09-28

    D-Alanine:D-alanine ligase (EC 6.3.2.4; Ddl) catalyzes the ATP-driven ligation of two D-alanine (D-Ala) molecules to form the D-alanyl:D-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis, making Ddl an attractive target for drug development. D-Cycloserine (DCS), an analog of D-Ala and a prototype Ddl inhibitor, has shown promise for the treatment of tuberculosis. Here, we report the crystal structure of Mycobacterium tuberculosis Ddl at a resolution of 2.1 {angstrom}. This structure indicates that Ddl is a dimer and consists of three discrete domains; the ligand binding cavity is at the intersection of all three domains and conjoined by several loop regions. The M. tuberculosis apo Ddl structure shows a novel conformation that has not yet been observed in Ddl enzymes from other species. The nucleotide and D-alanine binding pockets are flexible, requiring significant structural rearrangement of the bordering regions for entry and binding of both ATP and D-Ala molecules. Solution affinity and kinetic studies showed that DCS interacts with Ddl in a manner similar to that observed for D-Ala. Each ligand binds to two binding sites that have significant differences in affinity, with the first binding site exhibiting high affinity. DCS inhibits the enzyme, with a 50% inhibitory concentration (IC{sub 50}) of 0.37 mM under standard assay conditions, implicating a preferential and weak inhibition at the second, lower-affinity binding site. Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more-effective Ddl inhibitors.

  10. D-cycloserine potentiates the reconsolidation of cocaine-associated memories

    PubMed Central

    Lee, Jonathan L.C.; Gardner, Richard J.; Butler, Victoria J.; Everitt, Barry J.

    2009-01-01

    Conditioned cue-induced relapse to drug seeking is a major challenge to the treatment of drug addiction. It has been proposed that D-cycloserine might be useful in the prevention of relapse by reducing the conditioned reinforcing properties of drug-associated stimuli through facilitation of extinction. Here we show that intrabasolateral amygdala infusions of D-cycloserine in fact potentiate the reconsolidation of stimulus–cocaine memories to increase cue-induced relapse to drug seeking in rats with an extensive drug self-administration history. This elevation of cocaine seeking was correlated with an increase in the expression of the reconsolidation-associated gene zif268. PMID:19144966

  11. D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats.

    PubMed

    Seif, Taban; Simms, Jeffrey A; Lei, Kelly; Wegner, Scott; Bonci, Antonello; Messing, Robert O; Hopf, F Woodward

    2015-09-01

    There is considerable interest in NMDAR modulators to enhance memory and treat neuropsychiatric disorders such as addiction, depression, and schizophrenia. D-serine and D-cycloserine, the NMDAR activators at the glycine site, are of particular interest because they have been used in humans without serious adverse effects. Interestingly, D-serine also inhibits some NMDARs active at hyperpolarized potentials (HA-NMDARs), and we previously found that HA-NMDARs within the nucleus accumbens core (NAcore) are critical for promoting compulsion-like alcohol drinking, where rats consume alcohol despite pairing with an aversive stimulus such as quinine, a paradigm considered to model compulsive aspects of human alcohol use disorders (AUDs). Here, we examined the impact of D-serine and D-cycloserine on this aversion-resistant alcohol intake (that persists despite adulteration with quinine) and consumption of quinine-free alcohol. Systemic D-serine reduced aversion-resistant alcohol drinking, without altering consumption of quinine-free alcohol or saccharin with or without quinine. Importantly, D-serine within the NAcore but not the dorsolateral striatum also selectively reduced aversion-resistant alcohol drinking. In addition, D-serine inhibited EPSCs evoked at -70 mV in vitro by optogenetic stimulation of mPFC-NAcore terminals in alcohol-drinking rats, similar to reported effects of the NMDAR blocker AP5. Further, D-serine preexposure occluded AP5 inhibition of mPFC-evoked EPSCs, suggesting that D-serine reduced EPSCs by inhibiting HA-NMDARs. Systemic D-cycloserine also selectively reduced intake of quinine-adulterated alcohol, and D-cycloserine inhibited NAcore HA-NMDARs in vitro. Our results indicate that HA-NMDAR modulators can reduce aversion-resistant alcohol drinking, and support testing of D-serine and D-cycloserine as immediately accessible, FDA-approved drugs to treat AUDs. PMID:25801502

  12. Effect of D-cycloserine in conjunction with fear extinction training on extracellular signal-regulated kinase activation in the medial prefrontal cortex and amygdala in rat.

    PubMed

    Gupta, Subhash C; Hillman, Brandon G; Prakash, Anand; Ugale, Rajesh R; Stairs, Dustin J; Dravid, Shashank M

    2013-06-01

    D-cycloserine (DCS) is currently under clinical trials for a number of neuropsychiatric conditions and has been found to augment fear extinction in rodents and exposure therapy in humans. However, the molecular mechanism of DCS action in these multiple modalities remains unclear. Here, we describe the effect of DCS administration, alone or in conjunction with extinction training, on neuronal activity (c-fos) and neuronal plasticity [phospho-extracellular signal-regulated kinase (pERK)] markers using immunohistochemistry. We found that intraperitoneal administration of DCS in untrained young rats (24-28 days old) increased c-fos- and pERK-stained neurons in both the prelimbic and infralimbic division of the medial prefrontal cortex (mPFC) and reduced pERK levels in the lateral nucleus of the central amygdala. Moreover, DCS administration significantly increased GluA1, GluN1, GluN2A, and GluN2B expression in the mPFC. In a separate set of animals, we found that DCS facilitated fear extinction and increased pERK levels in the infralimbic prefrontal cortex, prelimbic prefrontal cortex intercalated cells and lateral nucleus of the central amygdala, compared with saline control. In the synaptoneurosomal preparation, we found that extinction training increased iGluR protein expression in the mPFC, compared with context animals. No significant difference in protein expression was observed between extinction-saline and extinction-DCS groups in the mPFC. In contrast, in the amygdala DCS, the conjunction with extinction training led to an increase in iGluR subunit expression, compared with the extinction-saline group. Our data suggest that the efficacy of DCS in neuropsychiatric disorders may be partly due to its ability to affect neuronal activity and signaling in the mPFC and amygdala subnuclei. PMID:23551217

  13. D-cycloserine transport in human intestinal epithelial (Caco-2) cells: mediation by a H(+)-coupled amino acid transporter.

    PubMed Central

    Thwaites, D. T.; Armstrong, G.; Hirst, B. H.; Simmons, N. L.

    1995-01-01

    1. The ability of D-cycloserine to act as a substrate for H+/amino acid symport has been tested in epithelial layers of Caco-2 human intestinal cells. 2. In Na(+)-free media with the apical bathing media held at pH 6.0, D-cycloserine (20 mM) is an effective inhibitor of net transepithelial transport (Jnet) of L-alanine (100 microM) and its accumulation (across the apical membrane) in a similar manner to amino acid substrates (L-alanine, beta-alanine, L-proline and glycine). In contrast L-valine was ineffective as an inhibitor for H+/amino acid symport. Both inhibition of L-alanine Jnet and its accumulation by D-cycloserine were dose-dependent, maximal inhibition being achieved by 5-10 mM. 3. Both D-cycloserine and known substrates for H+/amino acid symport stimulated an inward short circuit current (Isc) when voltage-clamped monolayers of Caco-2 epithelia, mounted in Ussing chambers, were exposed to apical substrate in Na(+)-free media, with apical pH held at 6.0. The D-cycloserine dependent increase in Isc was dose-dependent with an apparent Km = 15.8 +/- 2.0 (mean +/- s.e. mean) mM, and Vmax = 373 +/- 21 nmol cm-2h-1. 4. D-Cycloserine (20 mM) induced a prompt acidification of Caco-2 cell cytosol when superfused at the apical surface in both Na+ and Na(+)-free conditions. Cytosolic acidification in response to D-cycloserine was dependent upon superfusate pH, being attenuated at pH 8 and enhanced in acidic media. 5. The increment in Isc with 20 mM D-cycloserine was non-additive with other amino acid substrates for H+/amino acid symport. PMID:8548174

  14. Effects of single prolonged stress and D-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD.

    PubMed

    Yamamoto, Shigeto; Morinobu, Shigeru; Fuchikami, Manabu; Kurata, Akiko; Kozuru, Toshiro; Yamawaki, Shigeto

    2008-08-01

    Although the impaired extinction of traumatic memory is one of the hallmark symptoms of posttraumatic stress disorder (PTSD), the underlying mechanisms of impaired extinction are unclear and effective pharmacological interventions have not yet been developed. Single prolonged stress (SPS) has been proposed as an animal model of PTSD, since rats subjected to SPS (SPS rats) show enhanced negative feedback of the HPA axis and increased contextual fear, which are characteristics similar to those observed in patients with PTSD. In this study, using SPS rats, we examined (a) the ability of SPS to impair fear extinction, (b) whether D-cycloserine (DCS) can alleviate impaired fear extinction in SPS rats, and (c) the effect of SPS and/or DCS on the levels of N-methyl-D-aspartate (NMDA) receptor subunit mRNAs in the rat hippocampus during extinction training. SPS rats exhibited impaired fear extinction in the contextual fear test, which was alleviated by the repeated administration of DCS. The effect of enhanced extinction, induced by the administration of DCS to SPS rats, was maintained for one week following extinction training. SPS induced significant upregulation of the levels of NMDA receptor subunit mRNAs before and during the period of extinction training, while repeated administration of DCS eliminated the enhanced mRNA levels of NMDARs. Behavioral analyses indicated that SPS is an appropriate animal model of PTSD and that DCS may be effective in the treatment of PTSD. These findings suggest that DCS, irrespective of its mechanistic involvement in the enhancement of fear extinction, may help to reverse hippocampal plasticity, and thus reverse the NMDA compensatory alterations. PMID:17957211

  15. D-Cycloserine acts via increasing the GluN1 protein expressions in the frontal cortex and decreases the avoidance and risk assessment behaviors in a rat traumatic stress model.

    PubMed

    Sarıdoğan, Gökçe Elif; Aykaç, Aslı; Cabadak, Hülya; Cerit, Cem; Çalışkan, Mecit; Gören, M Zafer

    2015-10-15

    D-cycloserine (DCS), an FDA approved anti-tuberculosis drug has extensively been studied for its cognitive enhancer effects in psychiatric disorders. DCS may enhance the effects of fear extinction trainings in animals during exposure therapy and hence we investigated the effects of DCS on distinct behavioral parameters in a predator odor stress model and tested the optimal duration for repeated daily administrations of the agent. Cat fur odor blocks were used to produce stress and avoidance and risk assessment behavioral parameters were used where DCS or saline were used as treatments in adjunct to extinction trainings. We observed that DCS facilitated extinction training by providing further extinction of avoidance responses, risk assessment behaviors and increased the contact with the cue in a setting where DCS was administered before extinction trainings for 3 days without producing a significant tolerance. In amygdala and hippocampus, GluN1 protein expressions decreased 72h after the fear conditioning in the traumatic stress group suggesting a possible down-regulation of NMDARs. We observed that extinction learning increased GluN1 proteins both in the amygdaloid complex and the dorsal hippocampus of the rats receiving extinction training or extinction training with DCS. Our findings also indicate that DCS with extinction training increased GluN1 protein levels in the frontal cortex. We may suggest that action of DCS relies on enhancement of the consolidation of fear extinction in the frontal cortex. PMID:26225843

  16. Advances in the treatment of pediatric obsessive–compulsive d-cycloserine with exposure and response prevention

    PubMed Central

    McGuire, Joseph F; Lewin, Adam B; Geller, Daniel A; Brown, Ashley; Ramsey, Kesley; Mutch, Jane; Mittelman, Andrew; Micco, Jamie; Jordan, Cary; Wilhelm, Sabine; Murphy, Tanya K; Small, Brent J; Storch, Eric A

    2012-01-01

    SUMMARY Exposure-based cognitive-behavioral therapy and serotonin reuptake inhibitor medications are efficacious treatment options for the management of pediatric obsessive-compulsive disorder. Despite established efficacy, many youths receiving either therapy remain symptomatic after acute treatment. Regardless of the rationale for persistent symptoms, a clear need emerges for treatment options that restore functioning efficiently to symptomatic youths. One innovative approach builds upon the identified role of NMDA receptors in the fear extinction process. Instead of breaking existing connections during fear extinction, new associations develop that eventually predominate over prior associations. Recent investigations have explored augmenting exposure-based cognitive-behavioral therapy with the NMDA partial agonist d-cycloserine, with preliminary results demonstrating expedited treatment gains and moderately larger effects above exposure and response prevention therapy alone. A large randomized clinical trial is underway to evaluate the efficacy and efficiency of this therapeutic combination in pediatric obsessive–compulsive disorder. Results from this trial may translate into improved management practices. PMID:24174993

  17. REVERSAL OF d-CYCLOSERINE INHIBITION OF BACTERIAL GROWTH BY ALANINE

    PubMed Central

    Zygmunt, Walter A.

    1962-01-01

    Zygmunt, Walter A. (Mead Johnson & Co., Evansville, Ind.). Reversal of d-cycloserine inhibition of bacterial growth by alanine. J. Bacteriol. 84:154–156. 1962.—Reversal of the antibacterial activity of d-4-amino-3-isoxazolidone by alanine in bacterial cultures actively growing on chemically defined media was compared in cultures requiring exogenous alanine and those capable of its synthesis. dl-Alanine was the most effective reversal agent in Pediococcus cerevisiae, an alanine-requiring organism, and d-alanine was effective in Escherichia coli and Staphylococcus aureus, organisms synthesizing alanine. With all three cultures, l-alanine was the least effective reversal agent. PMID:16561951

  18. PROPRANOLOL AND D-CYCLOSERINE AS ADJUNCTIVE MEDICATIONS IN REDUCING DENTAL FEAR IN SEDATION PRACTICE

    PubMed Central

    Heaton, Lisa J.; McNeil, Daniel W.; Milgrom, Peter

    2010-01-01

    Extensive research and clinical experience have demonstrated the usefulness of sedation in helping fearful patients receive dental treatment, particularly when they have urgent treatment needs. In addition, the efficacy of behavioural programmes for managing dental fears is well established. While often these two approaches are seen as oppositional, our work in Seattle, Morgantown and at King’s College London Dental Institute demonstrates the complementarity of the two approaches. Using the example of two compounds, one very familiar, propranolol, and one that has recently become of interest, D-cycloserine, we wish to illustrate the manner in which these medications can be used to enhance behavioural approaches to managing dental anxiety. PMID:20151608

  19. Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches

    PubMed Central

    Maurer, Verena; Murphy, Conor; Schmuckermair, Claudia; Muigg, Patrick; Neumann, Inga D.; Whittle, Nigel

    2016-01-01

    Background: Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear. Methods: The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse. Results: Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice. Conclusions: By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term. PMID:26625894

  20. A Randomized, Double-blind Evaluation of D-cycloserine or Alprazolam Combined with Virtual Reality Exposure Therapy for Posttraumatic Stress Disorder (PTSD) in Iraq and Afghanistan War Veterans

    PubMed Central

    Rothbaum, Barbara Olasov; Price, Matthew; Jovanovic, Tanja; Norrholm, Seth D.; Gerardi, Maryrose; Dunlop, Boadie; Davis, Michael; Bradley, Bekh; Duncan, Erica; Rizzo, Albert “Skip”; Ressler, Kerry J.

    2014-01-01

    Objective To determine the effectiveness of Virtual Reality Exposure (VRE) augmented with D-cycloserine (50mg) or alprazolam (0.25mg), compared to placebo, in reducing PTSD due to military trauma in Iraq and Afghanistan. Method A double-blind, placebo-controlled randomized clinical trial comparing augmentation methods for VRE for subjects (n= 156) with PTSD was conducted. Results PTSD symptoms significantly improved from pre- to post-treatment over the 6-session VRE treatment (p<.001) across all conditions and were maintained at 3, 6, and 12 months follow-up. There were no overall differences between the D-cycloserine group on symptoms at any time-point. The alprazolam and placebo conditions significantly differed on the post-treatment Clinician Administered PTSD scale (p = .006) and the 3-month post-treatment PTSD diagnosis, such that the alprazolam group showed greater rates of PTSD (79.2% alprazolam vs. 47.8% placebo). Between-session extinction learning was a treatment-specific enhancer of outcome for the D-cycloserine group only (p<.005). At post-treatment, the D-cycloserine group was the lowest on cortisol reactivity (p<.05) and startle response during VR scenes (p<.05). Conclusions A small number of VRE sessions were associated with reduced PTSD diagnosis and symptoms in Iraq/Afghanistan veterans, although there was no control condition for the VRE. Overall, there was no advantage of D-cycloserine on PTSD symptoms in primary analyses. In secondary analyses, benzodiazepine use during treatment may impair recovery, and D-cycloserine may enhance VRE in patients who demonstrate within-session learning. D-cycloserine augmentation treatment in PTSD patients may reduce cortisol and startle reactivity compared to the alprazolam and placebo treatment, consistent with the animal literature. PMID:24743802

  1. Impact of DCS-facilitated cue exposure therapy on brain activation to cocaine cues in cocaine dependence

    PubMed Central

    Prisciandaro, James J.; Myrick, Hugh; Henderson, Scott; McRae-Clark, Aimee L.; Ana, Elizabeth J. Santa; Saladin, Michael E.; Brady, Kathleen T.

    2013-01-01

    Background The development of addiction is marked by a pathological associative learning process that imbues incentive salience to stimuli associated with drug use. Recent efforts to treat addiction have targeted this learning process using cue exposure therapy augmented with D-cycloserine (DCS), a glutamatergic agent hypothesized to enhance extinction learning. To better understand the impact of DCS-facilitated extinction on neural reactivity to drug cues, the present study reports fMRI findings from a randomized, double-blind, placebo-controlled trial of DCS-facilitated cue exposure for cocaine dependence. Methods Twenty-five participants completed two MRI sessions (before and after intervention), with a cocaine-cue reactivity fMRI task. The intervention consisted of 50mg of DCS or placebo, combined with two sessions of cocaine cue exposure and skills training. Results Participants demonstrated cocaine cue activation in a variety of brain regions at baseline. From the pre- to post-study scan, participants experienced decreased activation to cues in a number of regions (e.g., accumbens, caudate, frontal poles). Unexpectedly, placebo participants experienced decreases in activation to cues in the left angular and middle temporal gyri and the lateral occipital cortex, while DCS participants did not. Conclusions Three trials of DCS-facilitated cue exposure therapy for cocaine dependence have found that DCS either increases or does not significantly impact response to cocaine cues. The present study adds to this literature by demonstrating that DCS may prevent extinction to cocaine cues in temporal and occipital brain regions. Although consistent with past research, results from the present study should be considered preliminary until replicated in larger samples. PMID:23497788

  2. Kaiser Crater DCS

    NASA Technical Reports Server (NTRS)

    2004-01-01

    [figure removed for brevity, see original site]

    Released July 29, 2004 This image shows two representations of the same infra-red image covering a portion of Kaiser Crater. On the left is a grayscale image showing surface temperature, and on the right is a false-color composite made from 3 individual THEMIS bands. The false-color image is colorized using a technique called decorrelation stretch (DCS), which emphasizes the spectral differences between the bands to highlight compositional variations.

    In this image, the basaltic sand dunes in bottom of Kaiser crater are colored a bright pink/magenta. The spectral features are clean and prominent on these dust-free surfaces and the dark color of the basaltic dunes helps them to absorb sunlight and produces higher surface temperatures, which also contributes to the image colors.

    Image information: IR instrument. Latitude -46.5, Longitude 20.3 East (339.7 West). 100 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin

  3. DCS in Hesperia Planum

    NASA Technical Reports Server (NTRS)

    2004-01-01

    [figure removed for brevity, see original site]

    Released July 30, 2004 This image shows two representations of the same infra-red image in Hesperia Planum, west of Herschel Crater. On the left is a grayscale image showing surface temperature, and on the right is a false-color composite made from 3 individual THEMIS bands. The false-color image is colorized using a technique called decorrelation stretch (DCS), which emphasizes the spectral differences between the bands to highlight compositional variations.

    The two primary compositions that cover most of Mars - dust and basalt (probably in the form of sand) - are well represented in this image. In this image, the dust is green in color and the basalt is pink/magenta. The strongest basaltic signatures appear in the bottoms of craters, which act as topographic traps for the sand. Green dust streaks appear behind many of the smaller craters. The topographic relief of the crater prevents the wind from cleansing the dust from the surface. These features enable the determination of the prevailing wind direction in the region.

    Image information: IR instrument. Latitude -16.6, Longitude 119.3 East (240.7 West). 100 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS

  4. Canyon in DCS Color

    NASA Technical Reports Server (NTRS)

    2004-01-01

    [figure removed for brevity, see original site]

    Released July 26, 2004 This image shows two representations of the same infra-red image covering a portion of Ganges Chasma. On the left is a grayscale image showing surface temperature, and on the right is a false-color composite made from 3 individual THEMIS bands. The false-color image is colorized using a technique called decorrelation stretch (DCS), which emphasizes the spectral differences between the bands to highlight compositional variations.

    The northern canyon at the top of this image is dominated by a bright red/magenta area consisting primarly basaltic materials on the floor of the canyon and atmospheric dust. Within that area, there are patches of purple, on the walls and in the landslides, that may be due to an olivine rich mineral layer. In the middle of the image, the green on the mesa between the two canyons is from a layer of dust. The patchy blue areas in the southern canyon are likely due to water ice clouds.

    Image information: IR instrument. Latitude -6.6, Longitude 316 East (44 West). 100 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics

  5. Evidence Report: Risk of Decompression Sickness (DCS)

    NASA Technical Reports Server (NTRS)

    Conkin, Johnny; Norcross, Jason R.; Wessel, James H., III; Klein, Jill S.; Dervay, Joseph P.; Gernhardt, Michael L.

    2016-01-01

    Given that tissue inert gas partial pressure is often greater than ambient pressure during phases of a mission, primarily during extravehicular activity (EVA), there is a possibility of decompression sickness (DCS).

  6. Service applications for SONET DCS distributed restoration

    NASA Astrophysics Data System (ADS)

    Sosnosky, Joseph

    1994-01-01

    This paper determines the scope of network applications and services that could be offered using a SONET DCS-based self-recovering mesh architecture with distributed control. The study includes an outage impact analysis on network services and determination of how network restoration time objectives will affect the applicability for the distributed controlled DCS network architecture. It is concluded that using SONET DCS distributed control architecture to provide more complete survivability of network would support numerous applications. Future services will demand a fault-tolerant network with complete survivability: this may only be reached through integration of SONET DCS distributed control architectures with other survivable architectures such as cell networks (e.g., supporting SMDA) and self-healing rings.

  7. DCS Color near Mare Cimmerium

    NASA Technical Reports Server (NTRS)

    2004-01-01

    [figure removed for brevity, see original site]

    Released July 28, 2004 This image shows two representations of the same infra-red image covering an area near Mare Cimmerium. On the left is a grayscale image showing surface temperature, and on the right is a false-color composite made from 3 individual THEMIS bands. The false-color image is colorized using a technique called decorrelation stretch (DCS), which emphasizes the spectral differences between the bands to highlight compositional variations.

    This area contains a mixture of basaltic materials (magenta/purple) and dust (green/blue). Faint blue areas may be due to some thin water ice clouds. The different compositional units are sometimes correlated with crater floors and other surface features, but they are often not tied to valleys, lava flows, etc... indicating that the surface materials could be mobile (dust and sand).

    Image information: IR instrument. Latitude -23.7, Longitude 139.3 East (220.7 West). 100 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter

  8. β2-Agonist clenbuterol hinders human monocyte differentiation into dendritic cells.

    PubMed

    Giordani, Luciana; Cuzziol, Noemi; Del Pinto, Tamara; Sanchez, Massimo; Maccari, Sonia; Massimi, Alessia; Pietraforte, Donatella; Viora, Marina

    2015-12-10

    Clenbuterol (CLB) is a beta2-adrenergic agonist commonly used in asthma therapy, but is also a non-steroidal anabolic drug often abused in sport doping practices. Here we evaluated the in vitro impact of CLB on the physiology and function of human monocytes and dendritic cells (DCs), instrumental in the development of immune responses. We demonstrate that CLB inhibits the differentiation of monocytes into DCs and this effect is specific and dependent on β2-adrenergic receptor (AR) activation. We found that CLB treatment reduced the percentage of CD1a(+) immature DCs, while increasing the frequency of monocytes retaining CD14 surface expression. Moreover, CLB inhibited tumor necrosis factor-alpha (TNF-alpha) enhanced IL-(interleukin)-10 and IL-6 production. In contrast, CLB did not modulate the phenotypic and functional properties of monocytes and DCs, such as the surface expression of HLA-DR, CD83, CD80 and CD86 molecules, cytokine production, immunostimulatory activity and phagocytic activity. Moreover, we found that CLB did not modulate the activation of NF-kB in DCs. Moreover, we found that the differentiation of monocytes into DCs was associated with a significant decrease of β2-ARs mRNA expression. These results provide new insights on the effect of CLB on monocyte differentiation into DCs. Considering the frequent illegal use of CLB in doping, our work suggests that this drug is potentially harmful to immune responses decreasing the supply of DCs, thus subverting immune surveillance. PMID:26524508

  9. The Balance between Conventional DCs and Plasmacytoid DCs Is Pivotal for Immunological Tolerance during Pregnancy in the Mouse.

    PubMed

    Fang, Wen-Ning; Shi, Meng; Meng, Chao-Yang; Li, Dan-Dan; Peng, Jing-Pian

    2016-01-01

    Dendritic cells (DCs), which can shape their functions depending on the microenvironment, are crucial for the delicate balance of immunity and tolerance during pregnancy. However, the mechanism underlying the microenvironment-educated plasticity of DC differentiation during pregnancy remains largely unclear. Here, we found that the differentiation of conventional DCs (cDCs) and plasmacytoid DCs (pDCs) is regulated in a tissue-specific manner during pregnancy. The ratio of cDCs and pDCs remained constant in the spleen. However, the ratio changed in the para-aortic lymph nodes (LNs), where cDC percentages were significantly reduced concurrent with an increase in pDCs from E8.5 to E16.5. Moreover, the expansion of pDCs and T regulatory (Treg) cells was correlated in the para-aortic LNs, and pDCs had more potential to induce regulatory T cells (Tregs) compared with cDCs (independent of IDO expression). Notably, the balance between cDCs and pDCs is disrupted in IFN-γ-induced abnormal pregnancy, accompanied by lower Treg percentages in the para-aortic LNs and decidua. To further identify the underlying mechanism, we found that elevated IFN-γ can increase the levels of GM-CSF to alter the differentiation of pDCs into cDCs in vivo. Therefore, we provide a novel regulatory mechanism underlying pregnancy-related immune tolerance that involves the balance of DC subsets, which may offer a new target for the prevention of human spontaneous abortion. PMID:27229324

  10. The Balance between Conventional DCs and Plasmacytoid DCs Is Pivotal for Immunological Tolerance during Pregnancy in the Mouse

    PubMed Central

    Fang, Wen-ning; Shi, Meng; Meng, Chao-yang; Li, Dan-dan; Peng, Jing-pian

    2016-01-01

    Dendritic cells (DCs), which can shape their functions depending on the microenvironment, are crucial for the delicate balance of immunity and tolerance during pregnancy. However, the mechanism underlying the microenvironment-educated plasticity of DC differentiation during pregnancy remains largely unclear. Here, we found that the differentiation of conventional DCs (cDCs) and plasmacytoid DCs (pDCs) is regulated in a tissue-specific manner during pregnancy. The ratio of cDCs and pDCs remained constant in the spleen. However, the ratio changed in the para-aortic lymph nodes (LNs), where cDC percentages were significantly reduced concurrent with an increase in pDCs from E8.5 to E16.5. Moreover, the expansion of pDCs and T regulatory (Treg) cells was correlated in the para-aortic LNs, and pDCs had more potential to induce regulatory T cells (Tregs) compared with cDCs (independent of IDO expression). Notably, the balance between cDCs and pDCs is disrupted in IFN-γ-induced abnormal pregnancy, accompanied by lower Treg percentages in the para-aortic LNs and decidua. To further identify the underlying mechanism, we found that elevated IFN-γ can increase the levels of GM-CSF to alter the differentiation of pDCs into cDCs in vivo. Therefore, we provide a novel regulatory mechanism underlying pregnancy-related immune tolerance that involves the balance of DC subsets, which may offer a new target for the prevention of human spontaneous abortion. PMID:27229324

  11. The role of satellite communications in the future DCS

    NASA Astrophysics Data System (ADS)

    McKee, W. P., Jr.

    The Defense Communications System (DCS) has the function to provide strategic telecommunications for the U.S. Department of Defense (DOD). In addition, the DCS supports also other U.S. Government communications requirements, such as those of the Department of State. The DCS makes use of military and commercial satellite communications, and of terrestrial transmission media. The role of satellite communications (Satcom) in the current DCS is considered. Military and commercial Satcom used by the DCS employ geostationary satellites in synchronous orbit, generally for continuous point-to-point communications. As a result of recent studies, it was recommended that the DCS adopt the 'mix of media' philosophy to increase its survivability. One of the media which will receive continually expanded employment will be satellite communications. Attention is given to requirements for military communications, and the effectiveness of Satcom. It is concluded that Satcom, which is important in the DCS today, will become even more important in the future.

  12. DCS/FTS Commercial Satellite Communications System

    NASA Astrophysics Data System (ADS)

    Shimabukuro, T.; Rosner, R.; Pearsall, C.

    In order to control the rising costs of telephonic services and meeting the increasing demand for wideband video and data services within U.S. Federal Government agencies, the Defense Communications Agency and the General Services Administration have begun the implementation of a leased Commercial Satellite Communications System. Service volume demand, commonality of service requirements, and common geographic communities of interest facilitate economies of scale in the course of meeting DOD and other Federal agencies' objectives. The service, which incorporates the Federal Telecommunications Service and is therefore designated DCS/FTS, is presently studied with respect to military and national objectives.

  13. Evidence Report: Risk of Decompression Sickness (DCS)

    NASA Technical Reports Server (NTRS)

    Conkin, Johnny; Norcross, Jason R.; Wessel, James H. III; Abercromby, Andrew F. J.; Klein, Jill S.; Dervay, Joseph P.; Gernhardt, Michael L.

    2013-01-01

    The Risk of Decompression Sickness (DCS) is identified by the NASA Human Research Program (HRP) as a recognized risk to human health and performance in space, as defined in the HRP Program Requirements Document (PRD). This Evidence Report provides a summary of the evidence that has been used to identify and characterize this risk. Given that tissue inert gas partial pressure is often greater than ambient pressure during phases of a mission, primarily during extravehicular activity (EVA), there is a possibility that decompression sickness may occur.

  14. Distributed Collector Systems (DCS) for the medium temperature range

    NASA Astrophysics Data System (ADS)

    Kalt, A. C.

    1982-11-01

    The basic layout of a distributed collector system (DCS) is described and questions concerning design are discussed. Plant designs and performance data for four DCS systems are presented. Energy storage techniques, the power conversion cycle, and heat transfer subsystems are addressed.

  15. Enhancing exposure-based therapy from a translational research perspective

    PubMed Central

    Hofmann, Stefan G.

    2007-01-01

    Combining an effective psychological treatment with conventional anxiolytic medication is typically not more effective than unimodal therapy for treating anxiety disorders. However, recent advances in the neuroscience of fear reduction have led to novel approaches for combining psychological therapy and pharmacological agents. Exposure-based treatments in humans partly rely on extinction to reduce the fear response in anxiety disorders. Animal studies have shown that d-cycloserine (DCS), a partial agonist at the glycine recognition site of the glutamatergic N-methyl- d-aspartate receptor facilitates extinction learning. Similarly, recent human trials have shown that DCS enhances fear reduction during exposure therapy of some anxiety disorders. This article discusses the biological and psychological mechanisms of extinction learning and the therapeutic value of DCS as an augmentation strategy for exposure therapy. Areas of future research will be identified. PMID:17659253

  16. Augmentation of cognitive behavioral therapy with pharmacotherapy.

    PubMed

    Ganasen, K A; Ipser, J C; Stein, D J

    2010-09-01

    There has long been interest in combining pharmacotherapy with psychotherapy, including cognitive behavioral therapy (CBT). More recently, basic research on fear extinction has led to interest in augmentation of CBT with the N-methyl Daspartate (NMDA) glutamate receptor partial agonist D-cycloserine (DCS) for anxiety disorders. In this article, the literature on clinical trials that have combined pharmacotherapy and CBT is briefly reviewed, focusing particularly on the anxiety disorders. The literature on CBT and DCS is then systematically reviewed. A series of randomized placebo-controlled trials on panic disorder, obsessive-compulsive disorder, social anxiety disorder, and specific phobia suggest that low dose DCS before therapy sessions may be more effective compared with CBT alone in certain anxiety disorders. The strong translational foundation of this work is compelling, and the positive preliminary data gathered so far encourage further work. Issues for future research include delineating optimal dosing, and demonstrating effectiveness in real-world settings. PMID:20599140

  17. Transcranial direct current stimulation (tDCS) and language

    PubMed Central

    Monti, Alessia; Ferrucci, Roberta; Fumagalli, Manuela; Mameli, Francesca; Cogiamanian, Filippo; Ardolino, Gianluca; Priori, Alberto

    2013-01-01

    Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation technique inducing prolonged brain excitability changes and promoting cerebral plasticity, is a promising option for neurorehabilitation. Here, we review progress in research on tDCS and language functions and on the potential role of tDCS in the treatment of post-stroke aphasia. Currently available data suggest that tDCS over language-related brain areas can modulate linguistic abilities in healthy individuals and can improve language performance in patients with aphasia. Whether the results obtained in experimental conditions are functionally important for the quality of life of patients and their caregivers remains unclear. Despite the fact that important variables are yet to be determined, tDCS combined with rehabilitation techniques seems a promising therapeutic option for aphasia. PMID:23138766

  18. Evaluation of novel synthetic TLR7/8 agonists as vaccine adjuvants.

    PubMed

    Smith, Alyson J; Li, Yufeng; Bazin, Hélène G; St-Jean, Julien R; Larocque, Daniel; Evans, Jay T; Baldridge, Jory R

    2016-08-01

    Small-molecule adjuvants that boost and direct adaptive immunity provide a powerful means to increase the effectiveness of vaccines. Through rational design several novel imidazoquinoline and oxoadenine TLR7/8 agonists, each with unique molecular modifications, were synthesized and assessed for their ability to augment adaptive immunity. All agonists bound human TLR7 and TLR8 and induced maturation of both human mDCs and pDCs. All agonists prompted production of type I interferon and/or proinflammatory cytokines, albeit with varying potencies. In most in vitro assays, the oxoadenine class of agonists proved more potent than the imidazoquinolines. Therefore, an optimized oxoadenine TLR7/8 agonist that demonstrated maximal activity in the in vitro assays was further assessed in a vaccine study with the CRM197 antigen in a porcine model. Antigen-specific antibody production was greatly enhanced in a dose dependent manner, with antibody titers increased 800-fold compared to titers from pigs vaccinated with the non-adjuvanted vaccine. Moreover, pigs vaccinated with antigen containing the highest dose of adjuvant promoted a 13-fold increase in the percentage of antigen-specific CD3(+)/CD8(+) T cells over pigs vaccinated with antigen alone. Together this work demonstrates the promise of these novel TLR7/8 agonists as effective human vaccine adjuvants. PMID:27402566

  19. NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs

    PubMed Central

    Schleicher, Ulrike; Liese, Jan; Knippertz, Ilka; Kurzmann, Claudia; Hesse, Andrea; Heit, Antje; Fischer, Jens A.A.; Weiss, Siegfried; Kalinke, Ulrich; Kunz, Stefanie; Bogdan, Christian

    2007-01-01

    Natural killer (NK) cells are sentinel components of the innate response to pathogens, but the cell types, pathogen recognition receptors, and cytokines required for their activation in vivo are poorly defined. Here, we investigated the role of plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs), Toll-like receptors (TLRs), and of NK cell stimulatory cytokines for the induction of an NK cell response to the protozoan parasite Leishmania infantum. In vitro, pDCs did not endocytose Leishmania promastigotes but nevertheless released interferon (IFN)-α/β and interleukin (IL)-12 in a TLR9-dependent manner. mDCs rapidly internalized Leishmania and, in the presence of TLR9, produced IL-12, but not IFN-α/β. Depletion of pDCs did not impair the activation of NK cells in L. infantum–infected mice. In contrast, L. infantum–induced NK cell cytotoxicity and IFN-γ production were abolished in mDC-depleted mice. The same phenotype was observed in TLR9−/− mice, which lacked IL-12 expression by mDCs, and in IL-12−/− mice, whereas IFN-α/β receptor−/− mice showed only a minor reduction of NK cell IFN-γ expression. This study provides the first direct evidence that mDCs are essential for eliciting NK cell cytotoxicity and IFN-γ release in vivo and demonstrates that TLR9, mDCs, and IL-12 are functionally linked to the activation of NK cells in visceral leishmaniasis. PMID:17389237

  20. Dcs Data Viewer, an Application that Accesses ATLAS DCS Historical Data

    NASA Astrophysics Data System (ADS)

    Tsarouchas, C.; Schlenker, S.; Dimitrov, G.; Jahn, G.

    2014-06-01

    The ATLAS experiment at CERN is one of the four Large Hadron Collider experiments. The Detector Control System (DCS) of ATLAS is responsible for the supervision of the detector equipment, the reading of operational parameters, the propagation of the alarms and the archiving of important operational data in a relational database (DB). DCS Data Viewer (DDV) is an application that provides access to the ATLAS DCS historical data through a web interface. Its design is structured using a client-server architecture. The pythonic server connects to the DB and fetches the data by using optimized SQL requests. It communicates with the outside world, by accepting HTTP requests and it can be used stand alone. The client is an AJAX (Asynchronous JavaScript and XML) interactive web application developed under the Google Web Toolkit (GWT) framework. Its web interface is user friendly, platform and browser independent. The selection of metadata is done via a column-tree view or with a powerful search engine. The final visualization of the data is done using java applets or java script applications as plugins. The default output is a value-over-time chart, but other types of outputs like tables, ascii or ROOT files are supported too. Excessive access or malicious use of the database is prevented by a dedicated protection mechanism, allowing the exposure of the tool to hundreds of inexperienced users. The current configuration of the client and of the outputs can be saved in an XML file. Protection against web security attacks is foreseen and authentication constrains have been taken into account, allowing the exposure of the tool to hundreds of users world wide. Due to its flexible interface and its generic and modular approach, DDV could be easily used for other experiment control systems.

  1. TLR7/8 agonists promote NK-DC cross-talk to enhance NK cell anti-tumor effects in hepatocellular carcinoma.

    PubMed

    Zhou, Zhixia; Yu, Xin; Zhang, Jian; Tian, Zhigang; Zhang, Cai

    2015-12-28

    Hepatocellular carcinoma (HCC) is a common cancer worldwide and the third leading cause of cancer death. Immunotherapy is considered a promising treatment with the aim to boost or arouse HCC-specific immune responses. TLR7 and TLR8 agonists are effective immunomodulators and have been applied topically for the treatment of certain skin tumors and viral infections. Here, we explored the role of TLR7 and TLR8 agonists on the activation of dendritic cells (DCs) and natural killer (NK) cells. We demonstrated that these agonists could directly activate NK cells, promoting the maturation of immature DCs. Meanwhile, DCs also assisted in the function of NK cells, resulting in enhanced anti-tumor immune responses to HCC. Importantly, the combination therapy with NK cells stimulated with DCs and TLR7/8 agonist Gardiquimod (GDQ) significantly suppresses the growth of human HepG2 liver carcinoma xenografts. This study provides a new immunotherapeutic approach for human HCC based on DC-NK cross-talk and also suggests that TLR7 and/or TLR8 agonists, particularly GDQ, may serve as potent innate and adaptive immune response immunomodulators in tumor therapy. PMID:26433159

  2. Adjuvant for vaccine immunotherapy of cancer--focusing on Toll-like receptor 2 and 3 agonists for safely enhancing antitumor immunity.

    PubMed

    Seya, Tsukasa; Shime, Hiroaki; Takeda, Yohei; Tatematsu, Megumi; Takashima, Ken; Matsumoto, Misako

    2015-12-01

    Immune-enhancing adjuvants usually targets antigen (Ag)-presenting cells to tune up cellular and humoral immunity. CD141(+) dendritic cells (DC) represent the professional Ag-presenting cells in humans. In response to microbial pattern molecules, these DCs upgrade the maturation stage sufficient to improve cross-presentation of exogenous Ag, and upregulation of MHC and costimulators, allowing CD4/CD8 T cells to proliferate and liberating cytokines/chemokines that support lymphocyte attraction and survival. These DCs also facilitate natural killer-mediated cell damage. Toll-like receptors (TLRs) and their signaling pathways in DCs play a pivotal role in DC maturation. Therefore, providing adjuvants in addition to Ag is indispensable for successful vaccine immunotherapy for cancer, which has been approved in comparison with antimicrobial vaccines. Mouse CD8α(+) DCs express TLR7 and TLR9 in addition to the TLR2 family (TLR1, 2, and 6) and TLR3, whereas human CD141(+) DCs exclusively express the TLR2 family and TLR3. Although human and mouse plasmacytoid DCs commonly express TLR7/9 to respond to their agonists, the results on mouse adjuvant studies using TLR7/9 agonists cannot be simply extrapolated to human adjuvant immunotherapy. In contrast, TLR2 and TLR3 are similarly expressed in both human and mouse Ag-presenting DCs. Bacillus Calmette-Guerin peptidoglycan and polyinosinic-polycytidylic acid are representative agonists for TLR2 and TLR3, respectively, although they additionally stimulate cytoplasmic sensors: their functional specificities may not be limited to the relevant TLRs. These adjuvants have been posted up to a certain achievement in immunotherapy in some cancers. We herein summarize the history and perspectives of TLR2 and TLR3 agonists in vaccine-adjuvant immunotherapy for cancer. PMID:26395101

  3. TLR8 agonists stimulate newly recruited monocyte-derived cells into potent APCs that enhance HBsAg immunogenicity

    PubMed Central

    Du, Jun; Wu, Zhiyuan; Ren, Shurong; Wei, Yong; Gao, Meihua; Randolph, Gwendalyn J.; Qu, Chunfeng

    2011-01-01

    We previously reported that synthetic or natural Toll-like receptor (TLR) 7/8 agonists present within dead cells enhanced cell-associated antigen presentation both in vitro and in vivo. Here, we investigated the immunopotency of different chemically synthesized TLR7/8 agonists, Resiquimod, Gardiquimod, CL075, and CL097, on HBsAg immunogenicity. These agonists stimulated inflammatory monocyte-derived cells to become potent antigen-presenting dendritic cells (DCs), which augmented HBsAg specific T cell proliferation after they were conditioned with HBsAg. The TLR8 agonist CL075 and the TLR7/8 dual agonist CL097 showed more potent effects than the TLR7 agonist. Compared with alum adjuvant, when HBsAg mixed with CL075 was injected intramuscularly into mice, more monocyte-derived DCs carried antigens into draining lymph nodes and spleens. Specific Abs, particularly IgG2a, were significantly increased, and more IL-5 and IFN-γ were produced by splenocytes and intrahepatic immunocytes in mice that received HBsAg mixed with CL075 and CL097. These results suggest that TLR8 agonists are good candidates to enhance recombinant HBsAg immunogenicity to induce specific humoral and cellular immune responses. PMID:20637759

  4. Human pDCs preferentially sense enveloped hepatitis A virions.

    PubMed

    Feng, Zongdi; Li, You; McKnight, Kevin L; Hensley, Lucinda; Lanford, Robert E; Walker, Christopher M; Lemon, Stanley M

    2015-01-01

    Unlike other picornaviruses, hepatitis A virus (HAV) is cloaked in host membranes when released from cells, providing protection from neutralizing antibodies and facilitating spread in the liver. Acute HAV infection is typified by minimal type I IFN responses; therefore, we questioned whether plasmacytoid dendritic cells (pDCs), which produce IFN when activated, are capable of sensing enveloped virions (eHAV). Although concentrated nonenveloped virus failed to activate freshly isolated human pDCs, these cells produced substantial amounts of IFN-α via TLR7 signaling when cocultured with infected cells. pDCs required either close contact with infected cells or exposure to concentrated culture supernatants for IFN-α production. In isopycnic and rate-zonal gradients, pDC-activating material cosedimented with eHAV but not membrane-bound acetylcholinesterase, suggesting that eHAV, and not viral RNA exosomes, is responsible for IFN-α induction. pDC activation did not require virus replication and was associated with efficient eHAV uptake, which was facilitated by phosphatidylserine receptors on pDCs. In chimpanzees, pDCs were transiently recruited to the liver early in infection, during or shortly before maximal intrahepatic IFN-stimulated gene expression, but disappeared prior to inflammation onset. Our data reveal that, while membrane envelopment protects HAV against neutralizing antibody, it also facilitates an early but limited detection of HAV infection by pDCs. PMID:25415438

  5. The uncertain outcome of prefrontal tDCS

    PubMed Central

    Tremblay, Sara; Lepage, Jean-François; Latulipe-Loiselle, Alex; Fregni, Felipe; Pascual-Leone, Alvaro; Théoret, Hugo

    2015-01-01

    Background Transcranial direct current stimulation (tDCS) is increasingly used in research and clinical settings, and the dorsolateral prefrontal cortex (DLPFC) is often chosen as a target for stimulation. While numerous studies report modulation of cognitive abilities following DLPFC stimulation, the wide array of cognitive functions that can be modulated makes it difficult to predict its precise outcome. Objective The present review aims at identifying and characterizing the various cognitive domains affected by tDCS over DLPFC. Methods Articles using tDCS over DLPFC indexed in PubMed and published between 2000 and January 2014 were included in the present review. Results tDCS over DLPFC affects a wide array of cognitive functions, with sometimes apparent conflicting results. Conclusion Prefrontal tDCS has the potential to modulate numerous cognitive functions simultaneously, but to properly interpret the results, a clear a priori hypothesis is necessary, careful technical consideration are mandatory, further insights into the neurobiological impact of tDCS are needed, and consideration should be given to the possibility that some behavioral effects may be partly explained by parallel modulation of related functions. PMID:25456566

  6. Users` demands narrow PLC-DCS gap

    SciTech Connect

    La Fauci, J.

    1997-02-01

    Supervisory control and data acquisition (SCADA) operator interface (OI) software has propelled programmable logic controllers (PLCs) into areas where they can successfully compete with distributed control systems (DCSs) for many control applications. As a result, automation engineers are struggling to develop guidelines to help determine which is best for batch operations and other applications. There is no clear answer to this issue. There are, however, decision tools such as Kepner-Tregoe (K-T) that can be applied by engineers as a structured approach to decision analysis and system selection. Other factors such as business environment, pressure to reduce project cost, validation, and predicting new technology direction all play a critical role for engineers in choosing between a PLC- or DCS-based control system. Higher-level business issues, however, are seldom considered by engineers during control system selection. Engineers should try to better understand their company`s business objectives and mission statement and how company business direction may affect control system selection. For instance, the pharmaceutical industry can be broken up into the following five basic application groups: bulk chemicals, finishing, biotech, pilot plant, and utilities. Each has a unique set of functional and process-control requirements. Understanding needs and differences of these five basic application groups and applying the optimum control system solution will place the company in a more competitive position. A financial analysis should be one of the first steps in the control system evaluation process. This may include early agreement of contractual terms and conditions as well as a nondisclosure agreement. Other financial considerations may include requesting a financial report on the control system manufacturer or systems integrator that will be performing the work to determine its financial stability. 3 figs.

  7. Cerebellar Transcranial Direct Current Stimulation (ctDCS)

    PubMed Central

    Grimaldi, Giuliana; Argyropoulos, Georgios P.; Bastian, Amy; Cortes, Mar; Davis, Nicholas J.; Edwards, Dylan J.; Ferrucci, Roberta; Fregni, Felipe; Galea, Joseph M.; Hamada, Masahi; Manto, Mario; Miall, R. Chris; Morales-Quezada, Leon; Pope, Paul A.; Priori, Alberto; Rothwell, John; Tomlinson, S. Paul; Celnik, Pablo

    2016-01-01

    The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar–motor cortex connectivity, likely via cerebellar–thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions. PMID:25406224

  8. Dendritic cells and NK cells stimulate bystander T cell activation in response to TLR agonists through secretion of IFN-alpha beta and IFN-gamma.

    PubMed

    Kamath, Arun T; Sheasby, Christopher E; Tough, David F

    2005-01-15

    Recognition of conserved features of infectious agents by innate pathogen receptors plays an important role in initiating the adaptive immune response. We have investigated early changes occurring among T cells after injection of TLR agonists into mice. Widespread, transient phenotypic activation of both naive and memory T cells was observed rapidly after injection of molecules acting through TLR3, -4, -7, and -9, but not TLR2. T cell activation was shown to be mediated by a combination of IFN-alphabeta, secreted by dendritic cells (DCs), and IFN-gamma, secreted by NK cells; notably, IFN-gamma-secreting NK cells expressed CD11c and copurified with DCs. Production of IFN-gamma by NK cells could be stimulated by DCs from TLR agonist-injected mice, and although soluble factors secreted by LPS-stimulated DCs were sufficient to induce IFN-gamma, maximal IFN-gamma production required both direct contact of NK cells with DCs and DC-secreted cytokines. In vitro, IFN-alphabeta, IL-18, and IL-12 all contributed to DC stimulation of NK cell IFN-gamma, whereas IFN-alphabeta was shown to be important for induction of T cell bystander activation and NK cell IFN-gamma production in vivo. The results delineate a pathway involving innate immune mediators through which TLR agonists trigger bystander activation of T cells. PMID:15634897

  9. DCS of Syrtis Major Sand Migration

    NASA Technical Reports Server (NTRS)

    2004-01-01

    [figure removed for brevity, see original site]

    Released August 2, 2004 This image shows two representations of the same infra-red image of craters and lava flow features in Syrtis Major. On the left is a grayscale image showing surface temperature, and on the right is a false-color composite made from 3 individual THEMIS bands. The false-color image is colorized using a technique called decorrelation stretch (DCS), which emphasizes the spectral differences between the bands to highlight compositional variations.

    The prominent rim of the large crater at the top of the image is blocking migrating sand from entering the crater. This produces a very distinct compositional boundary between the pink/magenta basaltic sand and the green dust covering the crater rim and floor. Many of the smaller craters in this region have dust trails behind them, indicating the prevailing wind direction. At the top of the image, the prevailing wind direction is to the northwest, while at the bottom of the image, the prevailing winds have shifted towards the southwest.

    Image information: IR instrument. Latitude 9.2, Longitude 68.4 East (291.6 West). 100 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip

  10. Vanilloid Receptor 1 Agonists, Capsaicin and Resiniferatoxin, Enhance MHC Class I-restricted Viral Antigen Presentation in Virus-infected Dendritic Cells

    PubMed Central

    Lee, Young-Hee; Im, Sun-A; Kim, Ji-Wan

    2016-01-01

    DCs, like the sensory neurons, express vanilloid receptor 1 (VR1). Here we demonstrate that the VR1 agonists, capsaicin (CP) and resiniferatoxin (RTX), enhance antiviral CTL responses by increasing MHC class I-restricted viral antigen presentation in dendritic cells (DCs). Bone marrow-derived DCs (BM-DCs) were infected with a recombinant vaccinia virus (VV) expressing OVA (VV-OVA), and then treated with CP or RTX. Both CP and RTX increased MHC class I-restricted presentation of virus-encoded endogenous OVA in BM-DCs. Oral administration of CP or RTX significantly increased MHC class I-restricted OVA presentation by splenic and lymph node DCs in VV-OVA-infected mice, as assessed by directly measuring OVA peptide SIINFEKL-Kb complexes on the cell surface and by performing functional assays using OVA-specific CD8 T cells. Accordingly, oral administration of CP or RTX elicited potent OVA-specific CTL activity in VV-OVA-infected mice. The results from this study demonstrate that VR1 agonists enhance anti-viral CTL responses, as well as a neuro-immune connection in anti-viral immune responses. PMID:27574502

  11. Vanilloid Receptor 1 Agonists, Capsaicin and Resiniferatoxin, Enhance MHC Class I-restricted Viral Antigen Presentation in Virus-infected Dendritic Cells.

    PubMed

    Lee, Young-Hee; Im, Sun-A; Kim, Ji-Wan; Lee, Chong-Kil

    2016-08-01

    DCs, like the sensory neurons, express vanilloid receptor 1 (VR1). Here we demonstrate that the VR1 agonists, capsaicin (CP) and resiniferatoxin (RTX), enhance antiviral CTL responses by increasing MHC class I-restricted viral antigen presentation in dendritic cells (DCs). Bone marrow-derived DCs (BM-DCs) were infected with a recombinant vaccinia virus (VV) expressing OVA (VV-OVA), and then treated with CP or RTX. Both CP and RTX increased MHC class I-restricted presentation of virus-encoded endogenous OVA in BM-DCs. Oral administration of CP or RTX significantly increased MHC class I-restricted OVA presentation by splenic and lymph node DCs in VV-OVA-infected mice, as assessed by directly measuring OVA peptide SIINFEKL-K(b) complexes on the cell surface and by performing functional assays using OVA-specific CD8 T cells. Accordingly, oral administration of CP or RTX elicited potent OVA-specific CTL activity in VV-OVA-infected mice. The results from this study demonstrate that VR1 agonists enhance anti-viral CTL responses, as well as a neuro-immune connection in anti-viral immune responses. PMID:27574502

  12. The role of DCs in the immunopathogenesis of chronic HBV infection and the methods of inducing DCs maturation.

    PubMed

    Sun, Hai-Hua; Zhou, Dong-Fang; Zhou, Jun-Ying

    2016-01-01

    Chronic hepatitis B virus (HBV) infection is the result of an inadequate immune response towards the virus. Dendritic cells (DCs), as the most efficient professional antigen-presenting cells (APCs), possess the strongest antigen presenting the effect in the body and can stimulate the initial T cell activation and proliferation. DCs of patients with chronic HBV infection are impaired, resulting in more tolerogenic rather than immunogenic responses, which may contribute to viral persistence. Recently, numerous methods have been developed to induce DCs maturation. To date, recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) combined with interleukin-4 (rhIL-4) has been a classic culture combination to DCs. The recently classified type III interferon group interferon-λ (IFN-λ) displays antiviral, antitumor, and immunoregulatory activity. In our laboratory, we demonstrate that IFN-λ1 combined with rhGM-CSF and rhIL-4 can significantly increase the expression of DC surface molecules and the secretion of interleukin-12 (IL-12) and interferon-γ (IFN-γ) in patients with chronic hepatitis B infection. In this review, we emphasize on the role of DCs in the immunopathogenesis of chronic HBV infection. Importantly, we systematic review that the latest update in the current status of knowledge on the methods of inducing DCs maturation in anti-HBV immunity. What's more, we conclude that IFN-λ1 combined with GM-CSF and IL-4 can induce DCs maturation, which could become a possibility to be applied to the autologus dendritic cell vaccine to treat chronic hepatitis B. PMID:26104380

  13. [Pharmacological support of exposure therapy in anxiety disorders. Animal experiment studies].

    PubMed

    Koch, M

    2002-05-01

    The fear-potentiated startle paradigm (i.e., the enhancement of the startle response in the presence of an aversive conditioned stimulus) is a valuable cross-species model for the study of the neuronal mechanisms underlying fear and anxiety as well as of the cognitive control of those aversive states. Walker et al. present data from a study in rats indicating that extinction of fear in the fear-potentiated startle paradigm is enhanced by the partial agonist of the N-methyl-D-aspartate receptor D-cycloserine (DCS). The authors therefore suggest tests of DCS in clinical trials as a potential pharmacotherapeutic adjuvant for exposition therapies in fear and anxiety disorders. PMID:12078031

  14. Beta-Adrenergic Agonists

    PubMed Central

    Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito

    2010-01-01

    Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.

  15. 75 FR 59686 - Proposed Information Collection; Comment Request; NOAA Space-Based Data Collection System (DCS...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-28

    ... National Oceanic and Atmospheric Administration Proposed Information Collection; Comment Request; NOAA Space- Based Data Collection System (DCS) Agreements AGENCY: National Oceanic and Atmospheric... space-based data collection systems (DCS), the Geostationary Operational Environmental Satellite...

  16. Relating Venous Gas Emboli (VGE) Scores to Altitude Decompression Sickness (DCS) Symptoms

    NASA Technical Reports Server (NTRS)

    Pilmanis, A. A.; Kannan, N.; Krause, K. M.; Webb, J. T.

    1999-01-01

    Purpose. It is generally accepted that DCS symptoms are caused by gas bubbles in tissues. However, current technology of bubble detection only permits monitoring of circulating bubbles, primarily intracardiac. Since the majority of DCS symptoms appear to be caused by extravascular bubbles, it has been suggested that current bubble detection techniques target bubbles that are of importance in only a minority of DCS cases. The purpose of this study is to determine the relationships between measured VGE and DCS symptoms in human subjects exposed to altitude. Methods. The AFRL DCS Research Database contains records on 2044 subject-exposures to simulated altitudes in a hypobaric chamber. VGE monitoring was accomplished using Doppler/Echo Imaging techniques. The Spencer Scale was used to score the VGE. Reporting of DCS symptoms by the subject was the primary end-point of the exposures. Results: The Mantel- Haenzel test indicated a strong correlation between DCS and bubble grade (p-value =0.001). Conclusions. A positive correlation between increasing VGE scores and DCS symptoms, does not imply causatinn. If all non-zero VGE grades are considered, 45.9% of the cases had VGE, but no DCS symptoms. Conversely, almost 1 in 5 subject-exposures resulted in DCS with NO VGE detected. VGE scores are not . good predictors of altitude DCS symptoms and field use of bubble detection for DCS prevention is not supported by this study.

  17. Working memory capacity differentially influences responses to tDCS and HD-tDCS in a retro-cue task.

    PubMed

    Gözenman, Filiz; Berryhill, Marian E

    2016-08-26

    There is growing interest in non-invasive brain stimulation techniques. A drawback is that the relationship between stimulation and cognitive outcomes for various tasks are unknown. Transcranial direct current stimulation (tDCS) provides diffuse current spread, whereas high-definition tDCS (HD-tDCS) provides more targeted current. The direction of behavioral effects after tDCS can be difficult to predict in cognitive realms such as attention and working memory (WM). Previously, we showed that in low and high WM capacity groups tDCS modulates performance in nearly equal and opposite directions on a change detection task, with improvement for the high capacity participants alone. Here, we used the retro-cue paradigm to test attentional shifting among items in WM to investigate whether WM capacity (WMC) predicted different behavioral consequences during anodal tDCS or HD-tDCS to posterior parietal cortex (PPC). In two experiments, with 24 participants each, we used different stimulus categories (colored circles, letters) and stimulation sites (right, left PPC). The results showed a significant (Experiment 1) or trending (Experiment 2) WMC x stimulation interaction. Compared to tDCS, after HD-tDCS the retro-cueing benefit was significantly greater for the low WMC group but numerically worse for the high WMC group. These data highlight the importance of considering group differences when using non-invasive neurostimulation techniques. PMID:27369325

  18. Drawing Control System report. [DCS, for Univac 1108

    SciTech Connect

    Shumway, K.J.; Esch, G.L.

    1980-02-01

    The Drawing Control System (DCS) is described which is a computer-based network for releasing, distributing, and accounting for drawings at Sandia Laboratories in Albuquerque. The System utilizes the resources of the Univac 1108 and the attached teleprocessing equipment. The hardware, computer prorams, terminal dialogs, and files are discussed. The project management techniques used to control and carry out this Sandia project are also described. 17 figures, 1 table.

  19. New TLR7 agonists with improved humoral and cellular immune responses.

    PubMed

    Upchurch, Katherine C; Boquín, José R; Yin, Wenjie; Xue, Yaming; Joo, HyeMee; Kane, Robert R; Oh, SangKon

    2015-11-01

    Toll-like receptor 7 (TLR7) agonists are of interest as vaccine adjuvants and cancer therapeutics. Therefore, development of new TLR7 agonists that can efficiently promote host immune responses without evoking side effects is of great importance. Here, we describe two new compounds, J4 and F4, which elicit intracellular signaling exclusively via TLR7. Interestingly, both J4 and F4 induced less cytokine secretion (IL-1β, IL-6, IL-10, IL-12p40, TNFα, and IL-12p70) from myeloid dendritic cells (mDCs) and monocytes than CL075 and R848; however, they all generated similar levels of phenotype maturation of antigen presenting cells (APCs), including plasmacytoid DCs. We further found that J4- and F4-induced APC activation was largely dependent on the activation of NF-κB and p38. Lastly, J4 and F4 could efficiently promote B cell proliferation and plasmablast differentiation as well as antigen-specific CD8(+) T cell responses in human in vitro. Therefore, these new TLR7 agonists could be employed to facilitate the development of new therapeutics and vaccine adjuvants against cancers and microbial infections. PMID:26381186

  20. Automated 3D measurement with the DCS200 digital camera

    NASA Astrophysics Data System (ADS)

    Van den Heuvel, Frank A.

    1994-03-01

    A digital photogrammetric system for automated 3D coordinate measurement in a production environment has been developed. For the image acquisition the Kodak DCS200 digital camera is used. This camera is based on a standard 35-mm camera. The results of the radiometric and geometric calibration of the DCS200 camera show the potential of this camera for photogrammetric applications. The software part of the system performs the detection, identification, and measurement of artificial targets present in digital images. These artificial targets are designed for automatic detection in images of a complex scene. For the identification of the targets a circular bar code is read by the image processing software. The least squares template matching method is implemented for the target image measurement. A precision better than 2% of a pixel was obtained for the target location. The 3D coordinate computation is performed by Geodelta's bundle adjustment package BINAER. It includes extensive statistical testing to assess the accuracy of the results. Tests with the DCS200 camera show a repeatability of 18 micrometer standard deviation on a test field 60 X 50 X 30 centimeter. The achieved precision is in the order of 2 (DOT) 10-5.

  1. DCS-Neural-Network Program for Aircraft Control and Testing

    NASA Technical Reports Server (NTRS)

    Jorgensen, Charles C.

    2006-01-01

    A computer program implements a dynamic-cell-structure (DCS) artificial neural network that can perform such tasks as learning selected aerodynamic characteristics of an airplane from wind-tunnel test data and computing real-time stability and control derivatives of the airplane for use in feedback linearized control. A DCS neural network is one of several types of neural networks that can incorporate additional nodes in order to rapidly learn increasingly complex relationships between inputs and outputs. In the DCS neural network implemented by the present program, the insertion of nodes is based on accumulated error. A competitive Hebbian learning rule (a supervised-learning rule in which connection weights are adjusted to minimize differences between actual and desired outputs for training examples) is used. A Kohonen-style learning rule (derived from a relatively simple training algorithm, implements a Delaunay triangulation layout of neurons) is used to adjust node positions during training. Neighborhood topology determines which nodes are used to estimate new values. The network learns, starting with two nodes, and adds new nodes sequentially in locations chosen to maximize reductions in global error. At any given time during learning, the error becomes homogeneously distributed over all nodes.

  2. Absence of MHC class II on cDCs results in microbial-dependent intestinal inflammation.

    PubMed

    Loschko, Jakob; Schreiber, Heidi A; Rieke, Gereon J; Esterházy, Daria; Meredith, Matthew M; Pedicord, Virginia A; Yao, Kai-Hui; Caballero, Silvia; Pamer, Eric G; Mucida, Daniel; Nussenzweig, Michel C

    2016-04-01

    Conventional dendritic cells (cDCs) play an essential role in host immunity by initiating adaptive T cell responses and by serving as innate immune sensors. Although both innate and adaptive functions of cDCs are well documented, their relative importance in maintaining immune homeostasis is poorly understood. To examine the significance of cDC-initiated adaptive immunity in maintaining homeostasis, independent of their innate activities, we generated a cDC-specific Cre mouse and crossed it to a floxed MHC class II (MHCII) mouse. Absence of MHCII on cDCs resulted in chronic intestinal inflammation that was alleviated by antibiotic treatment and entirely averted under germ-free conditions. Uncoupling innate and adaptive functions of cDCs revealed that innate immune functions of cDCs are insufficient to maintain homeostasis and antigen presentation by cDCs is essential for a mutualistic relationship between the host and intestinal bacteria. PMID:27001748

  3. Cathodal transcutaneous spinal direct current stimulation (tsDCS) improves motor unit recruitment in healthy subjects.

    PubMed

    Bocci, Tommaso; Vannini, Beatrice; Torzini, Antonio; Mazzatenta, Andrea; Vergari, Maurizio; Cogiamanian, Filippo; Priori, Alberto; Sartucci, Ferdinando

    2014-08-22

    Transcutaneous spinal direct current stimulation (tsDCS) is a new promising technique for modulating spinal cord function in humans. However, its effects on corticospinal pathways and lower motorneuron excitability are poorly understood. We studied the effects of tsDCS on motor unit recruitment by evaluating changes in motor unit number (MUNE) and peripheral silent period (PSP) after sham (s-tsDCS), anodal (a-tsDCS) and cathodal (c-tsDCS) tsDCS applied either over the cervical or the lower thoracic spinal cord in healthy subjects. For the calculation of MUNE we used the multipoint incremental technique recording from either the ulnar nerve innervated abductor digiti minimi (ADM) or the median nerve innervated abductor pollicis brevis (APB) muscle. c-tsDCS dramatically increases MUNE values following cervical polarization, while sham and anodal polarization have no significant effect (APB: F(4,99)=26.4, p<0.001, two-way repeated measures ANOVA with "time" and "stimulation" as factors; ADM: F(4,99)=22.1, p<0.0001). At the same time, c-tsDCS dampened PSP respect to sham and anodal conditions (p<0.0001). Interestingly, also thoracic c-tsDCS significantly improved motor unit recruitment compared with both s-tsDCS and a-tsDCS (APB: F(4,99)=20.1, p<0.0001; ADM: F(4,99)=16.6, p<0.0001). Our data in healthy subjects suggest that tsDCS, possibly also through supraspinal effects, could provide a novel therapeutic tool in managing several pathological conditions characterized by reduced motor unit recruitment, such as stroke and spinal cord injuries. PMID:24970753

  4. Modulation of Female Genital Tract-Derived Dendritic Cell Migration and Activation in Response to Inflammatory Cytokines and Toll-Like Receptor Agonists

    PubMed Central

    Shey, Muki S.; Maharaj, Niren; Archary, Derseree; Ngcapu, Sinaye; Garrett, Nigel; Abdool Karim, Salim; Passmore, Jo-Ann S.

    2016-01-01

    HIV transmission across the genital mucosa is a major mode of new HIV infections in women. The probability of infection may be influenced by several factors including recruitment and activation of HIV target cells, such as dendritic cells (DCs) and cytokine production, associated with genital inflammation. We evaluated the role of inflammatory cytokines and TLR signaling in migration and activation of genital tract DCs in the human cervical explant model. Hysterectomy tissues from 10 HIV-negative and 7 HIV-positive donor women were separated into ecto- and endocervical explants, and incubated with inflammatory cytokines (TNF-α, IL-1β, IL-8, MIP-1β) or agonists for TLR4 (LPS), TLR2/1 (PAM3) and TLR7/8 (R848). Migration (frequency) and activation (HLA-DR expression) of myeloid and plasmacytoid DCs and Langerhans cells were measured by flow cytometry. We observed that cytokines, LPS and PAM3 induced activation of migrating myeloid and plasmacytoid DCs. LPS induced a 3.6 fold lower levels of migration of plasmacytoid DCs from HIV-infected women compared with HIV-uninfected women (median activation indices of 2.932 vs 0.833). There was however a 4.5 fold increase in migration of Langerhans cells in HIV-infected compared with HIV-uninfected women in response to cytokines (median activation indices of 3.539 vs 0.77). Only TLR agonists induced migration and activation of DCs from endocervical explants. Hormonal contraception use was associated with an increase in activation of DC subsets in the endo and ectocervical explants. We conclude that inflammatory signals in the female genital tract induced DC migration and activation, with possible important implications for HIV susceptibility of cervical tissues. PMID:27171482

  5. The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2.

    PubMed

    Scott, Charlotte L; Soen, Bieke; Martens, Liesbet; Skrypek, Nicolas; Saelens, Wouter; Taminau, Joachim; Blancke, Gillian; Van Isterdael, Gert; Huylebroeck, Danny; Haigh, Jody; Saeys, Yvan; Guilliams, Martin; Lambrecht, Bart N; Berx, Geert

    2016-05-30

    Plasmacytoid dendritic cells (DCs [pDCs]) develop from pre-pDCs, whereas two lineages of conventional DCs (cDCs; cDC1s and cDC2s) develop from lineage-committed pre-cDCs. Several transcription factors (TFs) have been implicated in regulating the development of pDCs (E2-2 and Id2) and cDC1s (Irf8, Id2, and Batf3); however, those required for the early commitment of pre-cDCs toward the cDC2 lineage are unknown. Here, we identify the TF zinc finger E box-binding homeobox 2 (Zeb2) to play a crucial role in regulating DC development. Zeb2 was expressed from the pre-pDC and pre-cDC stage onward and highly expressed in mature pDCs and cDC2s. Mice conditionally lacking Zeb2 in CD11c(+) cells had a cell-intrinsic reduction in pDCs and cDC2s, coupled with an increase in cDC1s. Conversely, mice in which CD11c(+) cells overexpressed Zeb2 displayed a reduction in cDC1s. This was accompanied by altered expression of Id2, which was up-regulated in cDC2s and pDCs from conditional knockout mice. Zeb2 chromatin immunoprecipitation analysis revealed Id2 to be a direct target of Zeb2. Thus, we conclude that Zeb2 regulates commitment to both the cDC2 and pDC lineages through repression of Id2. PMID:27185854

  6. Anodal tDCS over the Motor Cortex on Prepared and Unprepared Responses in Young Adults

    PubMed Central

    Marquez, Jodie; Parsons, Mark W.; Heathcote, Andrew

    2015-01-01

    Anodal transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has been proposed as a possible therapeutic rehabilitation technique for motor impairment. However, despite extensive investigation into the effects of anodal tDCS on motor output, there is little information on how anodal tDCS affects response processes. In this study, we used a cued go/nogo task with both directional and non-directional cues to assess the effects of anodal tDCS over the dominant (left) primary motor cortex on prepared and unprepared motor responses. Three experiments explored whether the effectiveness of tDCS varied with timing between stimulation and test. Healthy, right-handed young adults participated in a double-blind randomised controlled design with crossover of anodal tDCS and sham stimulation. In Experiment 1, twenty-four healthy young adults received anodal tDCS over dominant M1 at least 40 mins before task performance. In Experiment 2, eight participants received anodal tDCS directly before task performance. In Experiment 3, twenty participants received anodal tDCS during task performance. In all three experiments, participants responded faster to directional compared to non-directional cues and with their right hand. However, anodal tDCS had no effect on go/nogo task performance at any stimulation – test interval. Bayesian analysis confirmed that anodal stimulation had no effect on response speed. We conclude that anodal tDCS over M1 does not improve response speed of prepared or unprepared responses of young adults in a go/nogo task. PMID:25933204

  7. A Novel TLR-9 Agonist C792 Inhibits Plasmacytoid Dendritic Cell-induced Myeloma Cell Growth and Enhance Cytotoxicity of Bortezomib

    PubMed Central

    Ray, Arghya; Tian, Ze; Das, Deepika Sharma; Coffman, Robert L.; Richardson, Paul; Chauhan, Dharminder; Anderson, Kenneth C.

    2014-01-01

    Our prior study in multiple myeloma (MM) patients showed increased numbers of plasmacytoid dendritic cells (pDCs) in the bone marrow (BM) which both contribute to immune dysfunction as well as promote tumor cell growth, survival, and drug resistance. Here we show that a novel Toll-Like Receptor (TLR-9) agonist C792 restores the ability of MM patient-pDCs to stimulate T cell proliferation. Co-culture of pDCs with MM cells induces MM cell growth; and importantly, C792 inhibits pDC-induced MM cell growth and triggers apoptosis. In contrast, treatment of either MM cells or pDCs alone with C792 does not affect the viability of either cell type. In agreement with our in vitro data, C792 inhibits pDC-induced MM cell growth in vivo in a murine xenograft model of human MM. Mechanistic studies show that C792 triggers maturation of pDCs, enhances interferon-α and interferon-λ secretion, and activates TLR-9/MyD88 signaling axis. Finally, C792 enhances the anti-MM activity of bortezomib, lenalidomide, pomalidomide, SAHA, or melphalan. Collectively, our preclinical studies provide the basis for clinical trials of C792, either alone or in combination, to both improve immune function and overcome drug resistance in MM. PMID:24476765

  8. A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib.

    PubMed

    Ray, A; Tian, Z; Das, D S; Coffman, R L; Richardson, P; Chauhan, D; Anderson, K C

    2014-08-01

    Our prior study in multiple myeloma (MM) patients showed increased numbers of plasmacytoid dendritic cells (pDCs) in the bone marrow (BM), which both contribute to immune dysfunction as well as promote tumor cell growth, survival and drug resistance. Here we show that a novel Toll-like receptor (TLR-9) agonist C792 restores the ability of MM patient-pDCs to stimulate T-cell proliferation. Coculture of pDCs with MM cells induces MM cell growth; and importantly, C792 inhibits pDC-induced MM cell growth and triggers apoptosis. In contrast, treatment of either MM cells or pDCs alone with C792 does not affect the viability of either cell type. In agreement with our in vitro data, C792 inhibits pDC-induced MM cell growth in vivo in a murine xenograft model of human MM. Mechanistic studies show that C792 triggers maturation of pDCs, enhances interferon-α and interferon-λ secretion and activates TLR-9/MyD88 signaling axis. Finally, C792 enhances the anti-MM activity of bortezomib, lenalidomide, SAHA or melphalan. Collectively, our preclinical studies provide the basis for clinical trials of C792, either alone or in combination, to both improve immune function and overcome drug resistance in MM. PMID:24476765

  9. Electrifying the motor engram: effects of tDCS on motor learning and control.

    PubMed

    Orban de Xivry, Jean-Jacques; Shadmehr, Reza

    2014-11-01

    Learning to control our movements is accompanied by neuroplasticity of motor areas of the brain. The mechanisms of neuroplasticity are diverse and produce what is referred to as the motor engram, i.e., the neural trace of the motor memory. Transcranial direct current stimulation (tDCS) alters the neural and behavioral correlates of motor learning, but its precise influence on the motor engram is unknown. In this review, we summarize the effects of tDCS on neural activity and suggest a few key principles: (1) Firing rates are increased by anodal polarization and decreased by cathodal polarization, (2) anodal polarization strengthens newly formed associations, and (3) polarization modulates the memory of new/preferred firing patterns. With these principles in mind, we review the effects of tDCS on motor control, motor learning, and clinical applications. The increased spontaneous and evoked firing rates may account for the modulation of dexterity in non-learning tasks by tDCS. The facilitation of new association may account for the effect of tDCS on learning in sequence tasks while the ability of tDCS to strengthen memories of new firing patterns may underlie the effect of tDCS on consolidation of skills. We then describe the mechanisms of neuroplasticity of motor cortical areas and how they might be influenced by tDCS. We end with current challenges for the fields of brain stimulation and motor learning. PMID:25200178

  10. Electrifying the motor engram: effects of tDCS on motor learning and control

    PubMed Central

    de Xivry, Jean-Jacques Orban; Shadmehr, Reza

    2014-01-01

    Learning to control our movements accompanies neuroplasticity of motor areas of the brain. The mechanisms of neuroplasticity are diverse and produce what is referred to as the motor engram, i.e. the neural trace of the motor memory. Transcranial direct current stimulation (tDCS) alters the neural and behavioral correlates of motor learning, but its precise influence on the motor engram is unknown. In this review, we summarize the effects of tDCS on neural activity and suggest a few key principles: 1) firing rates are increased by anodal polarization and decreased by cathodal polarization, 2) anodal polarization strengthens newly formed associations, and 3) polarization modulates the memory of new/preferred firing patterns. With these principles in mind, we review the effects of tDCS on motor control, motor learning, and clinical applications. The increased spontaneous and evoked firing rates may account for the modulation of dexterity in non-learning tasks by tDCS. The facilitation of new association may account for the effect of tDCS on learning in sequence tasks while the ability of tDCS to strengthen memories of new firing patterns may underlie the effect of tDCS on consolidation of skills. We then describe the mechanisms of neuroplasticity of motor cortical areas and how they might be influenced by tDCS. We end with current challenges for the fields of brain stimulation and motor learning. PMID:25200178

  11. Effects of Transcranial Direct Current Stimulation (tDCS) on Behaviour and Electrophysiology of Language Production

    ERIC Educational Resources Information Center

    Wirth, Miranka; Rahman, Rasha Abdel; Kuenecke, Janina; Koenig, Thomas; Horn, Helge; Sommer, Werner; Dierks, Thomas

    2011-01-01

    Excitatory anodal transcranial direct current stimulation (A-tDCS) over the left dorsal prefrontal cortex (DPFC) has been shown to improve language production. The present study examined neurophysiological underpinnings of this effect. In a single-blinded within-subject design, we traced effects of A-tDCS compared to sham stimulation over the left…

  12. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs. PMID:19275609

  13. DCS - A global satellite environmental data collection system.

    NASA Technical Reports Server (NTRS)

    Claire, E. J.

    1973-01-01

    This paper presents a summary of the results of a comparative study of satellite data collection systems which utilize remote ground data collection platforms transmitting data directly to a satellite and down to low-cost direct read-out local user terminals. The general objective of the study was to evaluate cost and technical feasibility of five medium orbiting and six geo-synchronous satellite data collection system (DCS) configurations with varying degrees of spacecraft and local user terminal (LUT) complexity. The goal of trading spacecraft and LUT complexity was to determine practical feasible systems with low-cost terminals, yet with a reasonable overall system cost the would permit the broad worldwide utilization of a highly beneficial data collection system. Results presented include data collection system analyses, satellite and local user terminal designs, and estimated costs. A summary of the types of local users and their requirements is also included.

  14. Human CD141+ DCs induce CD4+ T cells to produce type 2 cytokines1

    PubMed Central

    Yu, Chun I; Becker, Christian; Metang, Patrick; Marches, Florentina; Wang, Yuanyuan; Toshiyuki, Hori; Banchereau, Jacques; Merad, Miriam; Palucka, Karolina

    2014-01-01

    Dendritic cells (DCs) play the central role in the priming of naïve T cells and the differentiation of unique effector T cells. Here, using lung tissues and blood from both humans and humanized mice, we analyzed the response of human CD1c+ and CD141+ DC subsets to live-attenuated influenza virus (LAIV). Specifically, we analyzed the type of CD4+ T cell immunity elicited by LAIV-exposed DCs. Both DC subsets induce proliferation of allogeneic naïve CD4+ T cells with capacity to secrete IFN-γ. However, CD141+ DCs are uniquely able to induce the differentiation of IL-4 and IL-13 producing CD4+ T cells. CD141+ DCs induce IL-4 and IL-13 secreting CD4+ T cells through OX40L. Thus, CD141+ DCs demonstrate remarkable plasticity in guiding adaptive immune responses. PMID:25246496

  15. The application of tDCS in psychiatric disorders: a brain imaging view

    PubMed Central

    Baeken, Chris; Brunelin, Jerome; Duprat, Romain; Vanderhasselt, Marie-Anne

    2016-01-01

    Background Transcranial direct current stimulation (tDCS) is a non-invasive, non-convulsive technique for modulating brain function. In contrast to other non-invasive brain stimulation techniques, where costs, clinical applicability, and availability limit their large-scale use in clinical practices, the low-cost, portable, and easy-to-use tDCS devices may overcome these restrictions. Objective Despite numerous clinical applications in large numbers of patients suffering from psychiatric disorders, it is not quite clear how tDCS influences the mentally affected human brain. In order to decipher potential neural mechanisms of action of tDCS in patients with psychiatric conditions, we focused on the combination of tDCS with neuroimaging techniques. Design We propose a contemporary overview on the currently available neurophysiological and neuroimaging data where tDCS has been used as a research or treatment tool in patients with psychiatric disorders. Results Over a reasonably short period of time, tDCS has been broadly used as a research tool to examine neuronal processes in the healthy brain. tDCS has also commonly been applied as a treatment application in a variety of mental disorders, with to date no straightforward clinical outcome and not always accompanied by brain imaging techniques. Conclusion tDCS, as do other neuromodulation devices, clearly affects the underlying neuronal processes. However, research on these mechanisms in psychiatric patients is rather limited. A better comprehension of how tDCS modulates brain function will help us to define optimal parameters of stimulation in each indication and may result in the detection of biomarkers in favor of clinical response. PMID:26993785

  16. Enhanced locomotor adaptation aftereffect in the “broken escalator” phenomenon using anodal tDCS

    PubMed Central

    Kaski, D.; Quadir, S.; Patel, M.; Yousif, N.

    2012-01-01

    The everyday experience of stepping onto a stationary escalator causes a stumble, despite our full awareness that the escalator is broken. In the laboratory, this “broken escalator” phenomenon is reproduced when subjects step onto an obviously stationary platform (AFTER trials) that was previously experienced as moving (MOVING trials) and attests to a process of motor adaptation. Given the critical role of M1 in upper limb motor adaptation and the potential for transcranial direct current stimulation (tDCS) to increase cortical excitability, we hypothesized that anodal tDCS over leg M1 and premotor cortices would increase the size and duration of the locomotor aftereffect. Thirty healthy volunteers received either sham or real tDCS (anodal bihemispheric tDCS; 2 mA for 15 min at rest) to induce excitatory effects over the primary motor and premotor cortex before walking onto the moving platform. The real tDCS group, compared with sham, displayed larger trunk sway and increased gait velocity in the first AFTER trial and a persistence of the trunk sway aftereffect into the second AFTER trial. We also used transcranial magnetic stimulation to probe changes in cortical leg excitability using different electrode montages and eyeblink conditioning, before and after tDCS, as well as simulating the current flow of tDCS on the human brain using a computational model of these different tDCS montages. Our data show that anodal tDCS induces excitability changes in lower limb motor cortex with resultant enhancement of locomotor adaptation aftereffects. These findings might encourage the use of tDCS over leg motor and premotor regions to improve locomotor control in patients with neurological gait disorders. PMID:22323638

  17. Development and Validation of a Miniature Programmable tDCS Device.

    PubMed

    Kouzani, Abbas Z; Jaberzadeh, Shapour; Zoghi, Maryam; Usma, Clara; Parastarfeizabadi, Mahboubeh

    2016-01-01

    Research is being conducted on the use of transcranial direct current stimulation (tDCS) for therapeutic effects, and also on the mechanisms through which such therapeutic effects are mediated. A bottleneck in the progress of the research has been the large size of the existing tDCS systems which prevents subjects from performing their daily activities. To help research into the principles, mechanisms, and benefits of tDCS, reduction of size and weight, improvement in simplicity and user friendliness, portability, and programmability of tDCS systems are vital. This paper presents a design for a low-cost, light-weight, programmable, and portable tDCS device. The device is head-mountable and can be concealed in a hat and worn on the head by the subject while receiving the stimulation. The strength of the direct current stimulation can be selected through a simple user interface. The device is constructed and its performance evaluated through bench and in vivo tests. The tests validated the operation of the device in inducing neuromodulatory changes in primary motor cortex, M1, through measuring excitability of dominant M1 of resting right first dorsal interosseus muscle by transcranial magnetic stimulation induced motor evoked potentials. It was observed that the tDCS device induced comparable neuromodulatory effects in M1 as the existing bulky tDCS systems. PMID:26285208

  18. Time Course of Corticospinal Excitability and Autonomic Function Interplay during and Following Monopolar tDCS

    PubMed Central

    Santarnecchi, Emiliano; Feurra, Matteo; Barneschi, Federico; Acampa, Maurizio; Bianco, Giovanni; Cioncoloni, David; Rossi, Alessandro; Rossi, Simone

    2014-01-01

    While polarity-specific after-effects of monopolar transcranial direct current stimulation (tDCS) on corticospinal excitability are well-documented, modulation of vital parameters due to current spread through the brainstem is still a matter of debate, raising potential concerns about its use through the general public, as well as for neurorehabilitation purposes. We monitored online and after-effects of monopolar tDCS (primary motor cortex) in 10 healthy subjects by adopting a neuronavigated transcranial magnetic stimulation (TMS)/tDCS combined protocol. Motor evoked potentials (MEPs) together with vital parameters [e.g., blood pressure, heart-rate variability (HRV), and sympathovagal balance] were recorded and monitored before, during, and after anodal, cathodal, or sham tDCS. Ten MEPs, every 2.5-min time windows, were recorded from the right first dorsal interosseous (FDI), while 5-min epochs were used to record vital parameters. The protocol included 15 min of pre-tDCS and of online tDCS (anodal, cathodal, or sham). After-effects were recorded for 30 min. We showed a polarity-independent stabilization of cortical excitability level, a polarity-specific after-effect for cathodal and anodal stimulation, and an absence of persistent excitability changes during online stimulation. No significant effects on vital parameters emerged both during and after tDCS, while a linear increase in systolic/diastolic blood pressure and HRV was observed during each tDCS condition, as a possible unspecific response to experimental demands. Taken together, current findings provide new insights on the safety of monopolar tDCS, promoting its application both in research and clinical settings. PMID:25101009

  19. Kodak DCS200: a camera for high-accuracy measurements?

    NASA Astrophysics Data System (ADS)

    Gruen, Armin; Maas, Hans-Gerd; Keller, Andrea

    1995-09-01

    The digital high-resolution stillvideo camera Kodak DCS200 has reached a high degree of popularity among photogrammetrists within a very short time. Consisting of a mirror reflex camera, a high resolution CCD sensor, A/D conversion, power supply, and data storage capacity for 50 images, it can basically be considered a comfortable, autonomous device for digital image data acquisition, especially for industrial applications and for architectural photogrammetry. First tests of the camera showed a high precision potential: 1/20-1/30 pixel in image space could be achieved in several applications, and with large self-calibrating networks relative precisions of 1:100,000 and better have been reported. To be able to make more detailed statements on the accuracy potential of the camera, a thorough accuracy test was performed at ETH Zurich by taking 150 images of a 186 target 3D testfield. Although the precision estimates of this large block were exceptionally good, strong systematic object deformations were found in comparison with theodolite-measured reference coordinates of the testfield points. The reasons for these deformations are most probably temporal instabilities of some camera parameters, which could make the use of this camera very problematic for high accuracy applications. It is argued that these instabilities are caused by the weak fixture of the CCD-chip to the camera body. In this context it is often overlooked that this camera was not developed for precise measurement applications but rather for professional photographers.

  20. Zero discharge and large-scale DCS are plant highlights

    SciTech Connect

    Solar, R.

    1995-04-01

    This article reports that the Mulberry cogeneration facility has several features that make it notable in the power field. A zero-discharge wastewater system, an inlet-air chilling system, a secondary boiler, and an extensive distributed-control system (DCS) for overall plant operation are examples. Ability to meet the two-stage NO{sub x}-emission limits -- 25 ppm during the first three years and 15 ppm thereafter -- is a unique challenge. The plant design allows the lower limit to be met now, and retrofit with different burners is possible if NO{sub x}-emission limits are tightened later. The facility, near Bartow in Polk County, Fla, is owned by Polk Power Partners LP, whose members include Central and South West Energy Inc (CSW) of Dallas and ARK Energy of Laguna Hills, Calif. The operating company, CSW Operations, is a subsidiary of CSW. Heart of the plant is a single gas-turbine (GT)/HRSG/steam-turbine combined cycle, providing electric power to Tampa Electric Co and Florida Power Corp, with up to 25,000 lb/hr of process steam for an adjacent ethanol plant which was developed by the facility`s partnership. Commercial operation of Mulberry began on Sept 2, 1994.

  1. Tracy Generating Station main plant DCS control upgrade

    SciTech Connect

    Cruz, N.T.; Cowle, E.S.; Salibi, A.; Turcotte, C.; Setrakian, V.

    1995-09-01

    Hydro Quebec (HQ) and Bechtel teamed together to assess the potential rehabilitation, modification, and upgrade projects necessary to meet Hydro Quebec`s goals for the Tracy Generating Station (TGS), which included extending the operating life of the units by an additional 25 years. Built in the mid 1960s, TGS is a 4 x 150 MW oil-fired conventional power plant, located 45 miles northeast of Montreal and is presently utilized to provide seasonal peak power generation requirements. Over recent years, HQ has experienced difficulties in obtaining replacement parts for the control system hardware. Additionally, there is a concern with the control system with respect to safety and reliability of plant operation since most of the plant control loops are on a manual mode of control. One of the major projects pursued was the main plant control system upgrade. This paper discusses the project team strategy utilized to perform a cost-effective distributed control system (DCS) upgrade to the main plant controls.

  2. Cyber security risk assessment for SCADA and DCS networks.

    PubMed

    Ralston, P A S; Graham, J H; Hieb, J L

    2007-10-01

    The growing dependence of critical infrastructures and industrial automation on interconnected physical and cyber-based control systems has resulted in a growing and previously unforeseen cyber security threat to supervisory control and data acquisition (SCADA) and distributed control systems (DCSs). It is critical that engineers and managers understand these issues and know how to locate the information they need. This paper provides a broad overview of cyber security and risk assessment for SCADA and DCS, introduces the main industry organizations and government groups working in this area, and gives a comprehensive review of the literature to date. Major concepts related to the risk assessment methods are introduced with references cited for more detail. Included are risk assessment methods such as HHM, IIM, and RFRM which have been applied successfully to SCADA systems with many interdependencies and have highlighted the need for quantifiable metrics. Presented in broad terms is probability risk analysis (PRA) which includes methods such as FTA, ETA, and FEMA. The paper concludes with a general discussion of two recent methods (one based on compromise graphs and one on augmented vulnerability trees) that quantitatively determine the probability of an attack, the impact of the attack, and the reduction in risk associated with a particular countermeasure. PMID:17624350

  3. Lactobacillus crispatus strain SJ-3C-US induces human dendritic cells (DCs) maturation and confers an anti-inflammatory phenotype to DCs.

    PubMed

    Eslami, Solat; Hadjati, Jamshid; Motevaseli, Elahe; Mirzaei, Reza; Farashi Bonab, Samad; Ansaripour, Bita; Khoramizadeh, Mohammad Reza

    2016-08-01

    Lactobacillus crispatus is one of the most predominant species in the healthy vagina microbiota. Nevertheless, the interactions between this commensal bacterium and the immune system are largely unknown. Given the importance of the dendritic cells (DCs) in the regulation of the immunity, this study was performed to elucidate the influence of vaginal isolated L. crispatus SJ-3C-US from healthy Iranian women on DCs, either directly by exposure of DCs to ultraviolet-inactivated (UVI) and heat-killed (HK) L. crispatus SJ-3C-US or indirectly to its cell-free supernatant (CFS), and the outcomes of immune response. In this work we showed that L. crispatus SJ-3C-US induced strong dose-dependent activation of dendritic cells and production of high levels of IL-10, whereas IL-12p70 production was induced at low level in an inverse dose-dependent manner. This stimulation skewed T cells polarization toward CD4(+) CD25(+) FOXP3(+) Treg cells and production of IL-10 in a dose-dependent manner in mixed leukocyte reaction (MLR) test. The mode of bacterial inactivation did not affect the DCs activation pattern, upon encounter with L. crispatus SJ-3C-US. Moreover, while DCs stimulated with CFS showed moderate phenotypic maturation and IL-10 production, it failed to skew T cells polarization toward CD4(+) CD25(+) FOXP3(+) regulatory T cells (Treg) and production of IL-10. This study showed that L. crispatus SJ-3C-US confers an anti-inflammatory phenotype to DCs through up-regulation of anti-inflammatory/regulatory IL-10 cytokine production and induction of CD4(+) CD25(+) FOXP3(+) T cells at optimal dosage. Our findings suggest that L. crispatus SJ-3C-US could be a potent candidate as protective probiotic against human immune-mediated pathologies, such as chronic inflammation, vaginitis or pelvic inflammatory disease (PID). PMID:27245496

  4. Transcranial Direct Current Stimulation (tDCS) and Aphasia: The Case of Mr. C

    PubMed Central

    Cherney, Leora R.; Babbitt, Edna M.; Hurwitz, Rosalind; Rogers, Lynn M.; Stinear, James; Wang, Xue; Harvey, Richard L.; Parrish, Todd

    2014-01-01

    Purpose To illustrate the ethical challenges that arose from investigating a novel treatment procedure, transcranial direct current stimulation (tDCS), in a research participant with aphasia. Method First, we reviewed the current evidence supporting the use of tDCS in aphasia research, highlighting methodological gaps in our knowledge of tDCS. Second, we examined the case of Mr. C, a person with chronic aphasia who participated in a research protocol investigating the impact of tDCS on aphasia treatment. Results We describe the procedures that he underwent and the resulting behavioral and neurophysiological outcomes bed. Finally, we share the steps that were taken to balance beneficence and nonmaleficence, and to ensure Mr. C’s autonomy. Conclusion: Researchers must consider not only the scientific integrity of their studies, but also potential ethical issues and consequences to the research participants. PMID:23340067

  5. Automatic artifact suppression in simultaneous tDCS-EEG using adaptive filtering.

    PubMed

    Mancini, Matteo; Pellicciari, Maria Concetta; Brignani, Debora; Mauri, Piercarlo; De Marchis, Cristiano; Miniussi, Carlo; Conforto, Silvia

    2015-08-01

    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation method that can be used in cognitive and clinical protocols in order to modulate neural activity. Although some macro effects are known, the underlying mechanisms are still not clear. tDCS in combination with electroencephalography (EEG) could help to understand these mechanisms from a neural point of view. However, simultaneous tDCS-EEG still remains challenging because of the artifacts that affect the recorded signals. In this paper, an automated artifact cancellation method based on adaptive filtering is proposed. Using independent component analysis (ICA), the artifacts were characterized using data from both a phantom and a group of healthy subjects. The resulting filter can successfully remove tDCS-related artifacts during anodal and cathodal stimulations. PMID:26736856

  6. 78 FR 68816 - Proposed Information Collection; Comment Request; NOAA Space-Based Data Collection System (DCS...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-15

    ... National Oceanic and Atmospheric Administration Proposed Information Collection; Comment Request; NOAA Space- Based Data Collection System (DCS) Agreements AGENCY: National Oceanic and Atmospheric... National Ocean and Atmospheric Administration (NOAA) operates two space-based data collection systems...

  7. Therapeutic effect of intratumoral administration of DCs with conditional expression of combination of different cytokines

    PubMed Central

    Huang, Chun; Ramakrishnan, Rupal; Trkulja, Marko; Ren, Xiubao

    2015-01-01

    In this study, we tested the effect of intratumoral administration of dendritic cells (DCs) with inducible expression of different cytokines, using the novel Rheoswitch Therapeutic System on the experimental models of renal cell cancer (RENCA) and MethA sarcoma. Intratumoral injection of DCs, engineered to express IL-12, IL-21, or IFN-α, showed potent therapeutic effect against established tumor. This effect was associated with the induction of potent tumor antigen-specific CD8+ T-cell responses, as well as the infiltration of tumors with CD4+ and CD8+ T cells but not with the cytotoxic activity of DCs. Combination of i.t. administration of DCs, producing different cytokines, did not enhance the antitumor effect of therapy with single cytokine. These results indicate that RTS can be a potent tool for conditional topical cytokine delivery, in combination with DC administration. However, combination of different cytokines may not necessarily improve the outcome of treatment. PMID:22223258

  8. The effects of tDCS upon sustained visual attention are dependent on cognitive load.

    PubMed

    Roe, James M; Nesheim, Mathias; Mathiesen, Nina C; Moberget, Torgeir; Alnæs, Dag; Sneve, Markus H

    2016-01-01

    Transcranial Direct Current Stimulation (tDCS) modulates the excitability of neuronal responses and consequently can affect performance on a variety of cognitive tasks. However, the interaction between cognitive load and the effects of tDCS is currently not well-understood. We recorded the performance accuracy of participants on a bilateral multiple object tracking task while undergoing bilateral stimulation assumed to enhance (anodal) and decrease (cathodal) neuronal excitability. Stimulation was applied to the posterior parietal cortex (PPC), a region inferred to be at the centre of an attentional tracking network that shows load-dependent activation. 34 participants underwent three separate stimulation conditions across three days. Each subject received (1) left cathodal / right anodal PPC tDCS, (2) left anodal / right cathodal PPC tDCS, and (3) sham tDCS. The number of targets-to-be-tracked was also manipulated, giving a low (one target per visual field), medium (two targets per visual field) or high (three targets per visual field) tracking load condition. It was found that tracking performance at high attentional loads was significantly reduced in both stimulation conditions relative to sham, and this was apparent in both visual fields, regardless of the direction of polarity upon the brain's hemispheres. We interpret this as an interaction between cognitive load and tDCS, and suggest that tDCS may degrade attentional performance when cognitive networks become overtaxed and unable to compensate as a result. Systematically varying cognitive load may therefore be a fruitful direction to elucidate the effects of tDCS upon cognitive functions. PMID:26556389

  9. Differentiation of immature DCs into endothelial-like cells in human esophageal carcinoma tissue homogenates.

    PubMed

    Lu, Jing; Bai, Ruihua; Qin, Zhenzhu; Zhang, Yanyan; Zhang, Xiaoyan; Jiang, Yanan; Yang, Hongyan; Huang, Youtian; Li, Gang; Zhao, Mingyao; Dong, Ziming

    2013-08-01

    We previously reported endothelial-like differentiation (ELD) of immature dendritic cells (iDCs) in the microenvironment derived from EC9706 human esophageal squamous cell carcinoma conditioned medium (CM). However, the CM is far different from the esophageal carcinoma tissue of patients. In addition, the potential role of peri-esophageal carcinoma in the ELD of iDCs is also unknown. In the present study, we showed that the tumor microenvironment derived from esophageal carcinoma homogenate promoted iDCs to differentiate from the DC pathway toward endothelial cells, while the peri-esophageal carcinoma homogenate did not have this function. During the course of ELD, ERK signaling pathway and CREB were activated. Blocking MEK, both the phosphorylation of ERK and CREB, and the ELD of iDCs were inhibited. These data suggest that esophageal carcinoma tissue, not peri-esophageal carcinoma tissue, can drive iDCs to differentiate into endothelial-like cells, instead of differentiation into mature DCs, thereby losing the ability of antigen presentation. PMID:23708958

  10. Delayed plastic responses to anodal tDCS in older adults

    PubMed Central

    Fujiyama, Hakuei; Hyde, Jane; Hinder, Mark R.; Kim, Seok-Jin; McCormack, Graeme H.; Vickers, James C.; Summers, Jeffery J.

    2014-01-01

    Despite the abundance of research reporting the neurophysiological and behavioral effects of transcranial direct current stimulation (tDCS) in healthy young adults and clinical populations, the extent of potential neuroplastic changes induced by tDCS in healthy older adults is not well understood. The present study compared the extent and time course of anodal tDCS-induced plastic changes in primary motor cortex (M1) in young and older adults. Furthermore, as it has been suggested that neuroplasticity and associated learning depends on the brain-derived neurotrophic factor (BDNF) gene polymorphisms, we also assessed the impact of BDNF polymorphism on these effects. Corticospinal excitability was examined using transcranial magnetic stimulation before and following (0, 10, 20, 30 min) anodal tDCS (30 min, 1 mA) or sham in young and older adults. While the overall extent of increases in corticospinal excitability induced by anodal tDCS did not vary reliably between young and older adults, older adults exhibited a delayed response; the largest increase in corticospinal excitability occurred 30 min following stimulation for older adults, but immediately post-stimulation for the young group. BDNF genotype did not result in significant differences in the observed excitability increases for either age group. The present study suggests that tDCS-induced plastic changes are delayed as a result of healthy aging, but that the overall efficacy of the plasticity mechanism remains unaffected. PMID:24936185

  11. Aging Impairs Interferon Regulatory Factor 7 Upregulation in Plasmacytoid DCs during TLR9 Activation

    PubMed Central

    Stout-Delgado, Heather W.; Yang, Xin; Walker, Wendy E.; Tesar, Bethany M.; Goldstein, Daniel R.

    2008-01-01

    Plasmacytoid dendritic cells (pDCs) are innate sensors that produce IFN-α in response to viral infections. Determining how aging alters the cellular and molecular function of these cells may provide an explanation of increased susceptibility of older people to viral infections. Hence, we examined whether aging critically impairs pDC function during infection with herpes simplex virus type 2 (HSV-2), a viral pathogen that activates TLR9. We found that impaired IFN-α production by aged murine pDCs led to impaired viral clearance with aging. Upon TLR9 activation, aged pDCs displayed defective upregulation of interferon regulatory factor 7 (IRF-7), a key adaptor in the type I IFN pathway, as compared to younger counterparts. Aged pDCs had more oxidative stress, and reducing oxidative stress in aged pDCs partly recovered the age-induced IFN-α defect during TLR9 activation. In sum, aging impairs the type I IFN pathway in pDCs, and this alteration may contribute to the increased susceptibility of older people to certain viral infections. PMID:18981092

  12. Modulation of executive control in dual tasks with transcranial direct current stimulation (tDCS).

    PubMed

    Strobach, Tilo; Soutschek, Alexander; Antonenko, Daria; Flöel, Agnes; Schubert, Torsten

    2015-02-01

    Executive processing in dual tasks is primarily associated with activation of the lateral prefrontal cortex (lPFC), which is demonstrated in functional imaging studies (e.g., Szameitat et al., 2006). However, a causal relation between lPFC activity and executive functions in dual tasks has not been demonstrated so far. Here, we used anodal transcranial direct current stimulation (atDCS [1 mA, 20 min] vs. sham stimulation [1 mA, 30s]) over the left inferior frontal junction under conditions of random and fixed task order in dual tasks as well as in single tasks in healthy young individuals (Experiment 1). We found that atDCS, if administered simultaneously to the task, improved performance in random-order dual tasks, but not in fixed-order dual tasks and single tasks. Moreover, dual-task performance under random-order conditions did not improve if atDCS was applied prior to the task performance. The identical procedure in Experiment 2 showed no difference in dual-task performance under random-task order conditions when we compared cathodal tDCS (ctDCS) with sham stimulation. Our findings suggest that dual-task performance is causally related to lPFC activation under conditions that require task-order decisions and high demands on executive functioning. Subsequent studies may now explore if atDCS leads to sustained improvements parallel to the training of dual tasks. PMID:25556813

  13. Cryopreservation of adenovirus-transfected dendritic cells (DCs) for clinical use.

    PubMed

    Gülen, D; Maas, S; Julius, H; Warkentin, P; Britton, H; Younos, I; Senesac, J; Pirruccello, Samuel M; Talmadge, J E

    2012-05-01

    In this study, we examined the effects of cryoprotectant, freezing and thawing, and adenovirus (Adv) transduction on the viability, transgene expression, phenotype, and function of human dendritic cells (DCs). DCs were differentiated from cultured peripheral blood (PB) monocytes following Elutra isolation using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 6 days and then transduced using an Adv vector with an IL-12 transgene. Fresh, cryopreserved, and thawed transduced immature DCs were examined for their: 1) cellular concentration and viability; 2) antigenicity using an allogeneic mixed lymphocyte reaction (MLR); 3) phenotype (HLA-DR and CD11c) and activation (CD83); and 4) transgene expression based on IL-12 secretion. Stability studies revealed that transduced DCs could be held in cryoprotectant for as long as 75 min at 2-8°C prior to freezing with little effect on their viability and cellularity. Further, cryopreservation, storage, and thawing reduced the viability of the transduced DCs by an average of 7.7%; and had no significant impact on DC phenotype and activation. In summary, cryopreservation, storage, and thawing had no significant effect on DC viability, function, and transgene expression by Adv-transduced DCs. PMID:22465385

  14. Bihemispheric-tDCS and Upper Limb Rehabilitation Improves Retention of Motor Function in Chronic Stroke: A Pilot Study

    PubMed Central

    Goodwill, Alicia M.; Teo, Wei-Peng; Morgan, Prue; Daly, Robin M.; Kidgell, Dawson J.

    2016-01-01

    Background: Single sessions of bihemispheric transcranial direct-current stimulation (bihemispheric-tDCS) with concurrent rehabilitation improves motor function in stroke survivors, which outlasts the stimulation period. However few studies have investigated the behavioral and neurophysiological adaptations following a multi-session intervention of bihemispheric-tDCS concurrent with rehabilitation. Objective: This pilot study explored the immediate and lasting effects of 3-weeks of bihemispheric-tDCS and upper limb (UL) rehabilitation on motor function and corticospinal plasticity in chronic stroke survivors. Methods: Fifteen chronic stroke survivors underwent 3-weeks of UL rehabilitation with sham or real bihemispheric-tDCS. UL motor function was assessed via the Motor Assessment Scale (MAS), Tardieu Scale and grip strength. Corticospinal plasticity was indexed by motor evoked potentials (MEPs), cortical silent period (CSP) and short-interval intracortical inhibition (SICI) recorded from the paretic and non-paretic ULs, using transcranial magnetic stimulation (TMS). Measures were taken at baseline, 48 h post and 3-weeks following (follow-up) the intervention. Results: MAS improved following both real-tDCS (62%) and sham-tDCS (43%, P < 0.001), however at 3-weeks follow-up, the real-tDCS condition retained these newly regained motor skills to a greater degree than sham-tDCS (real-tDCS 64%, sham-tDCS 21%, P = 0.002). MEP amplitudes from the paretic UL increased for real-tDCS (46%: P < 0.001) and were maintained at 3-weeks follow-up (38%: P = 0.03), whereas no changes were observed with sham-tDCS. No changes in MEPs from the non-paretic nor SICI from the paretic UL were observed for either group. SICI from the non-paretic UL was greater at follow-up, for real-tDCS (27%: P = 0.04). CSP from the non-paretic UL increased by 33% following the intervention for real-tDCS compared with sham-tDCS (P = 0.04), which was maintained at 3-weeks follow-up (24%: P = 0

  15. Bidirectional interactions between neuronal and hemodynamic responses to transcranial direct current stimulation (tDCS): challenges for brain-state dependent tDCS

    PubMed Central

    Dutta, Anirban

    2015-01-01

    Transcranial direct current stimulation (tDCS) has been shown to modulate cortical neural activity. During neural activity, the electric currents from excitable membranes of brain tissue superimpose in the extracellular medium and generate a potential at scalp, which is referred as the electroencephalogram (EEG). Respective neural activity (energy demand) has been shown to be closely related, spatially and temporally, to cerebral blood flow (CBF) that supplies glucose (energy supply) via neurovascular coupling. The hemodynamic response can be captured by near-infrared spectroscopy (NIRS), which enables continuous monitoring of cerebral oxygenation and blood volume. This neurovascular coupling phenomenon led to the concept of neurovascular unit (NVU) that consists of the endothelium, glia, neurons, pericytes, and the basal lamina. Here, recent works suggest NVU as an integrated system working in concert using feedback mechanisms to enable proper brain homeostasis and function where the challenge remains in capturing these mostly nonlinear spatiotemporal interactions within NVU for brain-state dependent tDCS. In principal accordance, we propose EEG-NIRS-based whole-head monitoring of tDCS-induced neuronal and hemodynamic alterations during tDCS. PMID:26321925

  16. Bidirectional interactions between neuronal and hemodynamic responses to transcranial direct current stimulation (tDCS): challenges for brain-state dependent tDCS.

    PubMed

    Dutta, Anirban

    2015-01-01

    Transcranial direct current stimulation (tDCS) has been shown to modulate cortical neural activity. During neural activity, the electric currents from excitable membranes of brain tissue superimpose in the extracellular medium and generate a potential at scalp, which is referred as the electroencephalogram (EEG). Respective neural activity (energy demand) has been shown to be closely related, spatially and temporally, to cerebral blood flow (CBF) that supplies glucose (energy supply) via neurovascular coupling. The hemodynamic response can be captured by near-infrared spectroscopy (NIRS), which enables continuous monitoring of cerebral oxygenation and blood volume. This neurovascular coupling phenomenon led to the concept of neurovascular unit (NVU) that consists of the endothelium, glia, neurons, pericytes, and the basal lamina. Here, recent works suggest NVU as an integrated system working in concert using feedback mechanisms to enable proper brain homeostasis and function where the challenge remains in capturing these mostly nonlinear spatiotemporal interactions within NVU for brain-state dependent tDCS. In principal accordance, we propose EEG-NIRS-based whole-head monitoring of tDCS-induced neuronal and hemodynamic alterations during tDCS. PMID:26321925

  17. Antitumor immune response of dendritic cells (DCs) expressing tumor-associated antigens derived from induced pluripotent stem cells: in comparison to bone marrow-derived DCs.

    PubMed

    Iwamoto, Hiromitsu; Ojima, Toshiyasu; Hayata, Keiji; Katsuda, Masahiro; Miyazawa, Motoki; Iida, Takeshi; Nakamura, Masaki; Nakamori, Mikihito; Iwahashi, Makoto; Yamaue, Hiroki

    2014-01-15

    It is generally accepted that the difficulty in obtaining a sufficient number of functional dendritic cells (DCs) is a serious problem in DC-based immunotherapy. Therefore, we used the induced pluripotent stem (iPS) cell-derived DCs (iPSDCs). If the therapeutic efficacy of iPSDCs is equivalent to that of bone marrow-derived DCs (BMDCs), then the aforementioned problems may be solved. In our study, we induced iPSDCs from iPS cells and examined the capacity for maturation of iPSDCs compared to that of BMDCs in addition to the capacity for migration of iPSDCs to regional lymph nodes. We adenovirally transduced the hgp100 gene, natural tumor antigens, into DCs and immunized mice once with the genetically modified DCs. The cytotoxic activity of CD8 (+) cytotoxic T lymphocytes (CTLs) was assayed using a (51) Cr-release assay. The therapeutic efficacy of the vaccination was examined in a subcutaneous tumor model. Our results showed that iPSDCs have an equal capacity to BMDCs in terms of maturation and migration. Furthermore, hgp100-specific CTLs were generated in mice immunized with genetically modified iPSDCs. These CTLs exhibited as high a level of cytotoxicity against B16 cells as BMDCs. Moreover, vaccination with the genetically modified iPSDCs achieved as high a level of therapeutic efficacy as vaccination with BMDCs. Our study clarified experimentally that genetically modified iPSDCs have an equal capacity to BMDCs in terms of tumor-associated antigen-specific therapeutic antitumor immunity. This vaccination strategy may therefore be useful for future clinical application as a cancer vaccine. PMID:23824921

  18. Myeloid Dendritic Cells (DCs) of Mice Susceptible to Paracoccidioidomycosis Suppress T Cell Responses whereas Myeloid and Plasmacytoid DCs from Resistant Mice Induce Effector and Regulatory T Cells

    PubMed Central

    Pina, Adriana; Frank de Araujo, Eliseu; Felonato, Maíra; Loures, Flávio V.; Feriotti, Claudia; Bernardino, Simone; Barbuto, José Alexandre M.

    2013-01-01

    The protective adaptive immune response in paracoccidioidomycosis, a mycosis endemic among humans, is mediated by T cell immunity, whereas impaired T cell responses are associated with severe, progressive disease. The early host response to Paracoccidioides brasiliensis infection is not known since the disease is diagnosed at later phases of infection. Our laboratory established a murine model of infection where susceptible mice reproduce the severe disease, while resistant mice develop a mild infection. This work aimed to characterize the influence of dendritic cells in the innate and adaptive immunity of susceptible and resistant mice. We verified that P. brasiliensis infection induced in bone marrow-derived dendritic cells (DCs) of susceptible mice a prevalent proinflammatory myeloid phenotype that secreted high levels of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-β, whereas in resistant mice, a mixed population of myeloid and plasmacytoid DCs secreting proinflammatory cytokines and expressing elevated levels of secreted and membrane-bound transforming growth factor β was observed. In proliferation assays, the proinflammatory DCs from B10.A mice induced anergy of naïve T cells, whereas the mixed DC subsets from resistant mice induced the concomitant proliferation of effector and regulatory T cells (Tregs). Equivalent results were observed during pulmonary infection. The susceptible mice displayed preferential expansion of proinflammatory myeloid DCs, resulting in impaired proliferation of effector T cells. Conversely, the resistant mice developed myeloid and plasmacytoid DCs that efficiently expanded gamma interferon-, IL-4-, and IL-17-positive effector T cells associated with increased development of Tregs. Our work highlights the deleterious effect of excessive innate proinflammatory reactions and provides new evidence for the importance of immunomodulation during pulmonary paracoccidioidomycosis. PMID:23340311

  19. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  20. Phenotypic and functional alterations of pDCs in lupus-prone mice

    PubMed Central

    Zhou, Zhenyuan; Ma, Jianyang; Xiao, Chunyuan; Han, Xiao; Qiu, Rong; Wang, Yan; Zhou, Yingying; Wu, Li; Huang, Xinfang; Shen, Nan

    2016-01-01

    Plasmacytoid dendritic cells (pDCs) were considered to be the major IFNα source in systemic lupus erythematosus (SLE) but their phenotype and function in different disease status have not been well studied. To study the function and phenotype of pDCs in lupus-prone mice we used 7 strains of lupus-prone mice including NZB/W F1, NZB, NZW, NZM2410, B6.NZMSle1/2/3, MRL/lpr and BXSB/Mp mice and C57BL/6 as control mice. Increased spleen pDC numbers were found in most lupus mice compared to C57BL/6 mice. The IFNα-producing ability of BM pDCs was similar between lupus and C57BL/6 mice, whereas pDCs from the spleens of NZB/W F1 and NZB mice produced more IFNα than pDCs from the spleens of C57BL/6 mice. Furthermore, spleen pDCs from MRL-lpr and NZM2410 mice showed increased responses to Tlr7 and Tlr9, respectively. As the disease progressed, IFN signature were evaluated in both BM and spleen pDC from lupus prone mice and the number of BM pDCs and their ability to produce IFNα gradually decreased in lupus-prone mice. In conclusion, pDC are activated alone with disease development and its phenotype and function differ among lupus-prone strains, and these differences may contribute to the development of lupus in these mice. PMID:26879679

  1. Clinical Research with Transcranial Direct Current Stimulation (tDCS): Challenges and Future Directions

    PubMed Central

    Brunoni, Andre Russowsky; Nitsche, Michael A.; Bolognini, Nadia; Bikson, Marom; Wagner, Tim; Merabet, Lotfi; Edwards, Dylan J.; Valero-Cabre, Antoni; Rotenberg, Alexander; Pascual-Leone, Alvaro; Ferrucci, Roberta; Priori, Alberto; Boggio, Paulo; Fregni, Felipe

    2011-01-01

    Background Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past ten years, tDCS physiological mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodological, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. Methods We convened a workgroup of researchers in the field to review, discuss and provide updates and key challenges of neuromodulation use for clinical research. Main Findings/Discussion We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (i) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (ii) methodological aspects related to the clinical research of tDCS as divided according to study phase (i.e., preclinical, phase I, phase II and phase III studies); (iii) ethical and regulatory concerns; (iv) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS. PMID:22037126

  2. Prefrontal tDCS Decreases Pain in Patients with Multiple Sclerosis

    PubMed Central

    Ayache, Samar S.; Palm, Ulrich; Chalah, Moussa A.; Al-Ani, Tarik; Brignol, Arnaud; Abdellaoui, Mohamed; Dimitri, Dalia; Sorel, Marc; Créange, Alain; Lefaucheur, Jean-Pascal

    2016-01-01

    Background: In the last few years, transcranial direct current stimulation (tDCS) has emerged as an appealing therapeutic option to improve brain functions. Promising data support the role of prefrontal tDCS in augmenting cognitive performance and ameliorating several neuropsychiatric symptoms, namely pain, fatigue, mood disturbances, and attentional impairment. Such symptoms are commonly encountered in patients with multiple sclerosis (MS). Objective: The main objective of the current work was to evaluate the tDCS effects over the left dorsolateral prefrontal cortex (DLPFC) on pain in MS patients.Our secondary outcomes were to study its influence on attention, fatigue, and mood. Materials and Methods: Sixteen MS patients with chronic neuropathic pain were enrolled in a randomized, sham-controlled, and cross-over study.Patients randomly received two anodal tDCS blocks (active or sham), each consisting of three consecutive daily tDCS sessions, and held apart by 3 weeks. Evaluations took place before and after each block. To evaluate pain, we used the Brief Pain Inventory (BPI) and the Visual Analog Scale (VAS). Attention was assessed using neurophysiological parameters and the Attention Network Test (ANT). Changes in mood and fatigue were measured using various scales. Results: Compared to sham, active tDCS yielded significant analgesic effects according to VAS and BPI global scales.There were no effects of any block on mood, fatigue, or attention. Conclusion: Based on our results, anodal tDCS over the left DLPFC appears to act in a selective manner and would ameliorate specific symptoms, particularly neuropathic pain. Analgesia might have occurred through the modulation of the emotional pain network. Attention, mood, and fatigue were not improved in this work. This could be partly attributed to the short protocol duration, the small sample size, and the heterogeneity of our MS cohort. Future large-scale studies can benefit from comparing the tDCS effects over

  3. Neuroimaging correlates of pharmacological and psychological treatments for specific phobia.

    PubMed

    Linares, Ila M; Chags, Marcos H N; Machado-de-Sousa, João P; Crippa, José A S; Hallak, Jaime E C

    2014-01-01

    Specific phobia is an anxiety disorder characterized by irrational fear and avoidance of specific things or situations, interfering significantly with the patients' daily life. Treatment for the disorder consists of both pharmacological and psychological approaches, mainly cognitive behavioral therapy (CBT). Neuroimaging techniques have been used in an attempt to improve our understanding of the neurobiology of SP and of the effects of treatment options available. This review describes the design and results of eight articles investigating the neuroimaging correlates of pharmacological and psychological treatments for SP. The studies show that CBT is effective in SP, leading to a reduction of anxiety symptoms that is accompanied by functional alterations in the brain. The results of pharmacological interventions for SP are less uniform, but suggest that the partial agonist of the NMDA (N-methyl D-aspartate) receptor DCS (D-cycloserine) can be used in combination with psychotherapy techniques for the achievement of quicker treatment response and that DCS modulates the function of structures implicated in the neurobiology of SP. Further research should explore the augmentation of CBT treatment with DCS in controlled trials. PMID:24923351

  4. Anodal tDCS targeting the right orbitofrontal cortex enhances facial expression recognition.

    PubMed

    Willis, Megan L; Murphy, Jillian M; Ridley, Nicole J; Vercammen, Ans

    2015-12-01

    The orbitofrontal cortex (OFC) has been implicated in the capacity to accurately recognise facial expressions. The aim of the current study was to determine if anodal transcranial direct current stimulation (tDCS) targeting the right OFC in healthy adults would enhance facial expression recognition, compared with a sham condition. Across two counterbalanced sessions of tDCS (i.e. anodal and sham), 20 undergraduate participants (18 female) completed a facial expression labelling task comprising angry, disgusted, fearful, happy, sad and neutral expressions, and a control (social judgement) task comprising the same expressions. Responses on the labelling task were scored for accuracy, median reaction time and overall efficiency (i.e. combined accuracy and reaction time). Anodal tDCS targeting the right OFC enhanced facial expression recognition, reflected in greater efficiency and speed of recognition across emotions, relative to the sham condition. In contrast, there was no effect of tDCS to responses on the control task. This is the first study to demonstrate that anodal tDCS targeting the right OFC boosts facial expression recognition. This finding provides a solid foundation for future research to examine the efficacy of this technique as a means to treat facial expression recognition deficits, particularly in individuals with OFC damage or dysfunction. PMID:25971602

  5. Improving Interference Control in ADHD Patients with Transcranial Direct Current Stimulation (tDCS)

    PubMed Central

    Breitling, Carolin; Zaehle, Tino; Dannhauer, Moritz; Bonath, Björn; Tegelbeckers, Jana; Flechtner, Hans-Henning; Krauel, Kerstin

    2016-01-01

    The use of transcranial direct current stimulation (tDCS) in patients with attention deficit hyperactivity disorder (ADHD) has been suggested as a promising alternative to psychopharmacological treatment approaches due to its local and network effects on brain activation. In the current study, we investigated the impact of tDCS over the right inferior frontal gyrus (rIFG) on interference control in 21 male adolescents with ADHD and 21 age matched healthy controls aged 13–17 years, who underwent three separate sessions of tDCS (anodal, cathodal, and sham) while completing a Flanker task. Even though anodal stimulation appeared to diminish commission errors in the ADHD group, the overall analysis revealed no significant effect of tDCS. Since participants showed a considerable learning effect from the first to the second session, performance in the first session was separately analyzed. ADHD patients receiving sham stimulation in the first session showed impaired interference control compared to healthy control participants whereas ADHD patients who were exposed to anodal stimulation, showed comparable performance levels (commission errors, reaction time variability) to the control group. These results suggest that anodal tDCS of the right inferior frontal gyrus could improve interference control in patients with ADHD. PMID:27147964

  6. No Significant Effect of Prefrontal tDCS on Working Memory Performance in Older Adults

    PubMed Central

    Nilsson, Jonna; Lebedev, Alexander V.; Lövdén, Martin

    2015-01-01

    Transcranial direct current stimulation (tDCS) has been put forward as a non-pharmacological alternative for alleviating cognitive decline in old age. Although results have shown some promise, little is known about the optimal stimulation parameters for modulation in the cognitive domain. In this study, the effects of tDCS over the dorsolateral prefrontal cortex (dlPFC) on working memory performance were investigated in thirty older adults. An N-back task assessed working memory before, during and after anodal tDCS at a current strength of 1 mA and 2 mA, in addition to sham stimulation. The study used a single-blind, cross-over design. The results revealed no significant effect of tDCS on accuracy or response times during or after stimulation, for any of the current strengths. These results suggest that a single session of tDCS over the dlPFC is unlikely to improve working memory, as assessed by an N-back task, in old age. PMID:26696882

  7. Facilitative effects of bi-hemispheric tDCS in cognitive deficits of Parkinson disease patients.

    PubMed

    Leite, Jorge; Gonçalves, Oscar F; Carvalho, Sandra

    2014-02-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder, primarily characterized by motor symptoms such as tremor, rigidity, bradykinesia, stiffness, slowness and impaired equilibrium. Although the motor symptoms have been the focus in PD, slight cognitive deficits are commonly found in non-demented and non-depressed PD patients, even in early stages of the disease, which have been linked to the subsequent development of pathological dementia. Thus, strongly reducing the quality of life (QoL). Both levodopa therapy and deep brain stimulation (DBS) have yield controversial results concerning the cognitive symptoms amelioration in PD patients. That does not seems to be the case with transcranial direct current stimulation (tDCS), although better stimulation parameters are needed. Therefore we hypothesize that simultaneously delivering cathodal tDCS (or ctDCS), over the right prefrontal cortex delivered with anodal tDCS (or atDCS) to left prefrontal cortex could be potentially beneficial for PD patients, either by mechanisms of homeostatic plasticity and by increases in the extracellular dopamine levels over the striatum. PMID:24332532

  8. Improving Interference Control in ADHD Patients with Transcranial Direct Current Stimulation (tDCS).

    PubMed

    Breitling, Carolin; Zaehle, Tino; Dannhauer, Moritz; Bonath, Björn; Tegelbeckers, Jana; Flechtner, Hans-Henning; Krauel, Kerstin

    2016-01-01

    The use of transcranial direct current stimulation (tDCS) in patients with attention deficit hyperactivity disorder (ADHD) has been suggested as a promising alternative to psychopharmacological treatment approaches due to its local and network effects on brain activation. In the current study, we investigated the impact of tDCS over the right inferior frontal gyrus (rIFG) on interference control in 21 male adolescents with ADHD and 21 age matched healthy controls aged 13-17 years, who underwent three separate sessions of tDCS (anodal, cathodal, and sham) while completing a Flanker task. Even though anodal stimulation appeared to diminish commission errors in the ADHD group, the overall analysis revealed no significant effect of tDCS. Since participants showed a considerable learning effect from the first to the second session, performance in the first session was separately analyzed. ADHD patients receiving sham stimulation in the first session showed impaired interference control compared to healthy control participants whereas ADHD patients who were exposed to anodal stimulation, showed comparable performance levels (commission errors, reaction time variability) to the control group. These results suggest that anodal tDCS of the right inferior frontal gyrus could improve interference control in patients with ADHD. PMID:27147964

  9. A novel ring electrode setup for the recording of somatosensory evoked potentials during transcranial direct current stimulation (tDCS).

    PubMed

    Sehm, Bernhard; Hoff, Maike; Gundlach, Christopher; Taubert, Marco; Conde, Virginia; Villringer, Arno; Ragert, Patrick

    2013-01-30

    Transcranial direct current stimulation (tDCS) modulates cortical excitability thereby influencing behavior and learning. While previous studies focused on tDCS after-effects, limited information about "online" tDCS effects is available. This in turn is an important prerequisite to better characterize and/or optimize tDCS effects. Here, we aimed to explore the feasibility of recording low-artifact somatosensory evoked potentials (SEPs) during tDCS using a novel ring electrode setup. We recorded SEP before, during and after 10 min of anodal or sham tDCS using a full-band direct current (DC) EEG system in a total number of 3 subjects. SEPs were recorded in the bore of the tDCS ring electrode. Using this approach, no tDCS-induced artifacts could be observed after the application of a standard EEG filter. This new setup might help to better characterize how tDCS alters evoked brain responses thus providing novel insight into underlying physiological effects during stimulation. PMID:23103376

  10. Spatial and polarity precision of concentric high-definition transcranial direct current stimulation (HD-tDCS)

    NASA Astrophysics Data System (ADS)

    Alam, Mahtab; Truong, Dennis Q.; Khadka, Niranjan; Bikson, Marom

    2016-06-01

    Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies low amplitude current via electrodes placed on the scalp. Rather than directly eliciting a neuronal response, tDCS is believed to modulate excitability—enhancing or suppressing neuronal activity in regions of the brain depending on the polarity of stimulation. The specificity of tDCS to any therapeutic application derives in part from how electrode configuration determines the brain regions that are stimulated. Conventional tDCS uses two relatively large pads (>25 cm2) whereas high-definition tDCS (HD-tDCS) uses arrays of smaller electrodes to enhance brain targeting. The 4  ×  1 concentric ring HD-tDCS (one center electrode surrounded by four returns) has been explored in application where focal targeting of cortex is desired. Here, we considered optimization of concentric ring HD-tDCS for targeting: the role of electrodes in the ring and the ring’s diameter. Finite element models predicted cortical electric field generated during tDCS. High resolution MRIs were segmented into seven tissue/material masks of varying conductivities. Computer aided design (CAD) model of electrodes, gel, and sponge pads were incorporated into the segmentation. Volume meshes were generated and the Laplace equation (\

  11. Silencing c-Kit expression in human DCs suppresses Th2, Th17 response but enhances Th1 response

    PubMed Central

    Yang, Bin; Yang, Qin; Huang, Qianchuan; Yan, Hongbo; Sun, Ting; Tong, Hui

    2015-01-01

    Dendritic cells (DCs) are integral to the differentiation of T helper cells into T helper type 1 TH1, TH2 and TH17 subsets. RNA interference (RNAi), which causes the degradation of any RNA in a sequence specific manner, is a posttranscriptional gene silencing mechanism. Targeting the c-Kit in DCs has been used as an approach to enhance antitumor immunity. Here, we shwed that transfection of DCs with siRNA specific for c-Kit gene can significantly knock down c-Kit. When exposed to TNF-α, immature DCs transfected with c-Kit siRNA can differentiate into mature DCs without reducing viability or IL-12p70 production. The c-Kit siRNA-treated DCs exhibited an increased allostimulatory capacity in a lymphocyte proliferation assay. Furthermore, c-Kit siRNA-transfected DCs enhanced TH1 responses by increasing IFN-γ and decreasing IL-4 production, and much stronger cytotoxic activity was observed when DCs were co-transfected with c-Kit siRNA and an endogenous tumor antigen in vitro. Our findings indicate that silencing the c-Kit gene in DCs with siRNA may offer a potential approach to enhance antitumor immunotherapy. PMID:26550451

  12. Testing the involvement of the prefrontal cortex in lucid dreaming: a tDCS study.

    PubMed

    Stumbrys, Tadas; Erlacher, Daniel; Schredl, Michael

    2013-12-01

    Recent studies suggest that lucid dreaming (awareness of dreaming while dreaming) might be associated with increased brain activity over frontal regions during rapid eye movement (REM) sleep. By applying transcranial direct current stimulation (tDCS), we aimed to manipulate the activation of the dorsolateral prefrontal cortex (DLPFC) during REM sleep to increase dream lucidity. Nineteen participants spent three consecutive nights in a sleep laboratory. On the second and third nights they randomly received either 1 mA tDCS for 10 min or sham stimulation during each REM period starting with the second one. According to the participants' self-ratings, tDCS over the DLPFC during REM sleep increased lucidity in dreams. The effects, however, were not strong and found only in frequent lucid dreamers. While this indicates some preliminary support for the involvement of the DLPFC in lucid dreaming, further research, controlling for indirect effects of stimulation and including other brain regions, is needed. PMID:24021850

  13. Understanding public (mis)understanding of tDCS for enhancement

    PubMed Central

    Cabrera, Laura Y.; Reiner, Peter B.

    2015-01-01

    In order to gain insight into the public’s perspective on using the minimally invasive technique transcranial direct current stimulation (tDCS) as an enhancement tool, we analyzed and compared online comments in key popular press articles from two different periods (pre-commercialization and post-commercialization). The main conclusion drawn from this exploratory investigation is that public perception regarding tDCS has shifted from misunderstanding to cautionary realism. This change in attitude can be explained as moving from a focus on an emergent technology to a focus on its applications, benefits, and risks as the technology becomes more grounded within the public domain. Future governance of tDCS should include the concerns and enthusiasms of the public. PMID:25964748

  14. The Integration of DCS I/O to an Existing PLC

    NASA Technical Reports Server (NTRS)

    Sadhukhan, Debashis; Mihevic, John

    2013-01-01

    At the NASA Glenn Research Center (GRC), Existing Programmable Logic Controller (PLC) I/O was replaced with Distributed Control System (DCS) I/O, while keeping the existing PLC sequence Logic. The reason for integration of the PLC logic and DCS I/O, along with the evaluation of the resulting system is the subject of this paper. The pros and cons of the old system and new upgrade are described, including operator workstation screen update times. Detail of the physical layout and the communication between the PLC, the DCS I/O and the operator workstations are illustrated. The complex characteristics of a central process control system and the plan to remove the PLC processors in future upgrades is also discussed.

  15. Inducible targeting of cDCs and their subsets in vivo.

    PubMed

    Loschko, Jakob; Rieke, Gereon J; Schreiber, Heidi A; Meredith, Matthew M; Yao, Kai-Hui; Guermonprez, Pierre; Nussenzweig, Michel C

    2016-07-01

    Conventional dendritic cells (cDCs) are essential immune cells linking the innate and adaptive immune system. cDC depletion in mice is an important method to study the function of these cells in vivo. Here we report an inducible in vivo system for cDC depletion in which excision of a loxP flanked Stop signal enables expression of the human diphtheria toxin receptor (DTR) under the control of Zbtb46 (zDC(lSlDTR)). cDCs can be specifically depleted by combining zDC(lSlDTR) mice with a Csf1r(Cre) driver line. In addition, we show that zDC(Cre) mice can be used to produce cDC specific conditional knockout mice (Irf8, Irf4, Notch2) which lack specific subsets of cDCs. PMID:27073171

  16. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  17. Monitoring cognitive function and need with the automated neuropsychological assessment metrics in Decompression Sickness (DCS) research

    NASA Technical Reports Server (NTRS)

    Nesthus, Thomas E.; Schiflett, Sammuel G.

    1993-01-01

    Hypobaric decompression sickness (DCS) research presents the medical monitor with the difficult task of assessing the onset and progression of DCS largely on the basis of subjective symptoms. Even with the introduction of precordial Doppler ultrasound techniques for the detection of venous gas emboli (VGE), correct prediction of DCS can be made only about 65 percent of the time according to data from the Armstrong Laboratory's (AL's) hypobaric DCS database. An AL research protocol concerned with exercise and its effects on denitrogenation efficiency includes implementation of a performance assessment test battery to evaluate cognitive functioning during a 4-h simulated 30,000 ft (9144 m) exposure. Information gained from such a test battery may assist the medical monitor in identifying early signs of DCS and subtle neurologic dysfunction related to cases of asymptomatic, but advanced, DCS. This presentation concerns the selection and integration of a test battery and the timely graphic display of subject test results for the principal investigator and medical monitor. A subset of the Automated Neuropsychological Assessment Metrics (ANAM) developed through the Office of Military Performance Assessment Technology (OMPAT) was selected. The ANAM software provides a library of simple tests designed for precise measurement of processing efficiency in a variety of cognitive domains. For our application and time constraints, two tests requiring high levels of cognitive processing and memory were chosen along with one test requiring fine psychomotor performance. Accuracy, speed, and processing throughout variables as well as RMS error were collected. An automated mood survey provided 'state' information on six scales including anger, happiness, fear, depression, activity, and fatigue. An integrated and interactive LOTUS 1-2-3 macro was developed to import and display past and present task performance and mood-change information.

  18. Simultaneous tDCS-fMRI Identifies Resting State Networks Correlated with Visual Search Enhancement

    PubMed Central

    Callan, Daniel E.; Falcone, Brian; Wada, Atsushi; Parasuraman, Raja

    2016-01-01

    This study uses simultaneous transcranial direct current stimulation (tDCS) and functional MRI (fMRI) to investigate tDCS modulation of resting state activity and connectivity that underlies enhancement in behavioral performance. The experiment consisted of three sessions within the fMRI scanner in which participants conducted a visual search task: Session 1: Pre-training (no performance feedback), Session 2: Training (performance feedback given), Session 3: Post-training (no performance feedback). Resting state activity was recorded during the last 5 min of each session. During the 2nd session one group of participants underwent 1 mA tDCS stimulation and another underwent sham stimulation over the right posterior parietal cortex. Resting state spontaneous activity, as measured by fractional amplitude of low frequency fluctuations (fALFF), for session 2 showed significant differences between the tDCS stim and sham groups in the precuneus. Resting state functional connectivity from the precuneus to the substantia nigra, a subcortical dopaminergic region, was found to correlate with future improvement in visual search task performance for the stim over the sham group during active stimulation in session 2. The after-effect of stimulation on resting state functional connectivity was measured following a post-training experimental session (session 3). The left cerebellum Lobule VIIa Crus I showed performance related enhancement in resting state functional connectivity for the tDCS stim over the sham group. The ability to determine the relationship that the relative strength of resting state functional connectivity for an individual undergoing tDCS has on future enhancement in behavioral performance has wide ranging implications for neuroergonomic as well as therapeutic, and rehabilitative applications. PMID:27014014

  19. No Effects of Bilateral tDCS over Inferior Frontal Gyrus on Response Inhibition and Aggression.

    PubMed

    Dambacher, Franziska; Schuhmann, Teresa; Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander T

    2015-01-01

    Response inhibition is defined as the capacity to adequately withdraw pre-planned responses. It has been shown that individuals with deficits in inhibiting pre-planned responses tend to display more aggressive behaviour. The prefrontal cortex is involved in both, response inhibition and aggression. While response inhibition is mostly associated with predominantly right prefrontal activity, the neural components underlying aggression seem to be left-lateralized. These differences in hemispheric dominance are conceptualized in cortical asymmetry theories on motivational direction, which assign avoidance motivation (relevant to inhibit responses) to the right and approach motivation (relevant for aggressive actions) to the left prefrontal cortex. The current study aimed to directly address the inverse relationship between response inhibition and aggression by assessing them within one experiment. Sixty-nine healthy participants underwent bilateral transcranial Direct Current Stimulation (tDCS) to the inferior frontal cortex. In one group we induced right-hemispheric fronto-cortical dominance by means of a combined right prefrontal anodal and left prefrontal cathodal tDCS montage. In a second group we induced left-hemispheric fronto-cortical dominance by means of a combined left prefrontal anodal and right prefrontal cathodal tDCS montage. A control group received sham stimulation. Response inhibition was assessed with a go/no-go task (GNGT) and aggression with the Taylor Aggression Paradigm (TAP). We revealed that participants with poorer performance in the GNGT displayed more aggression during the TAP. No effects of bilateral prefrontal tDCS on either response inhibition or aggression were observed. This is at odds with previous brain stimulation studies applying unilateral protocols. Our results failed to provide evidence in support of the prefrontal cortical asymmetry model in the domain of response inhibition and aggression. The absence of tDCS effects might also

  20. Bilateral tDCS on Primary Motor Cortex: Effects on Fast Arm Reaching Tasks

    PubMed Central

    Arias, Pablo; Corral-Bergantiños, Yoanna; Robles-García, Verónica; Madrid, Antonio; Oliviero, Antonio; Cudeiro, Javier

    2016-01-01

    Background The effects produced by transcranial direct current stimulation (tDCS) applied to the motor system have been widely studied in the past, chiefly focused on primary motor cortex (M1) excitability. However, the effects on functional tasks are less well documented. Objective This study aims to evaluate the effect of tDCS-M1 on goal-oriented actions (i.e., arm-reaching movements; ARM), in a reaction-time protocol. Methods 13 healthy subjects executed dominant ARM as fast as possible to one of two targets in front of them while surface EMG was recorded. Participants performed three different sessions. In each session they first executed ARM (Pre), then received tDCS, and finally executed Post, similar to Pre. Subjects received three different types of tDCS, one per session: In one session the anode was on right-M1 (AR), and the cathode on the left-M1 (CL), thus termed AR-CL; AL-CR reversed the montage; and Sham session was applied likewise. Real stimulation was 1mA-10min while subjects at rest. Three different variables and their coefficients of variation (CV) were analyzed: Premotor times (PMT), reaction-times (RT) and movement-times (MT). Results triceps-PMT were significantly increased at Post-Sham, suggesting fatigue. Results obtained with real tDCS were not different depending on the montage used, in both cases PMT were significantly reduced in all recorded muscles. RT and MT did not change for real or sham stimulation. RT-CV and PMT-CV were reduced after all stimulation protocols. Conclusion tDCS reduces premotor time and fatigability during the execution of fast motor tasks. Possible underlying mechanisms are discussed. PMID:27490752

  1. No Effects of Bilateral tDCS over Inferior Frontal Gyrus on Response Inhibition and Aggression

    PubMed Central

    Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander T.

    2015-01-01

    Response inhibition is defined as the capacity to adequately withdraw pre-planned responses. It has been shown that individuals with deficits in inhibiting pre-planned responses tend to display more aggressive behaviour. The prefrontal cortex is involved in both, response inhibition and aggression. While response inhibition is mostly associated with predominantly right prefrontal activity, the neural components underlying aggression seem to be left-lateralized. These differences in hemispheric dominance are conceptualized in cortical asymmetry theories on motivational direction, which assign avoidance motivation (relevant to inhibit responses) to the right and approach motivation (relevant for aggressive actions) to the left prefrontal cortex. The current study aimed to directly address the inverse relationship between response inhibition and aggression by assessing them within one experiment. Sixty-nine healthy participants underwent bilateral transcranial Direct Current Stimulation (tDCS) to the inferior frontal cortex. In one group we induced right-hemispheric fronto-cortical dominance by means of a combined right prefrontal anodal and left prefrontal cathodal tDCS montage. In a second group we induced left-hemispheric fronto-cortical dominance by means of a combined left prefrontal anodal and right prefrontal cathodal tDCS montage. A control group received sham stimulation. Response inhibition was assessed with a go/no-go task (GNGT) and aggression with the Taylor Aggression Paradigm (TAP). We revealed that participants with poorer performance in the GNGT displayed more aggression during the TAP. No effects of bilateral prefrontal tDCS on either response inhibition or aggression were observed. This is at odds with previous brain stimulation studies applying unilateral protocols. Our results failed to provide evidence in support of the prefrontal cortical asymmetry model in the domain of response inhibition and aggression. The absence of tDCS effects might also

  2. Cathodal HD-tDCS on the right V5 improves motion perception in humans

    PubMed Central

    Zito, Giuseppe A.; Senti, Theresa; Cazzoli, Dario; Müri, René M.; Mosimann, Urs P.; Nyffeler, Thomas; Nef, Tobias

    2015-01-01

    Brain lesions in the visual associative cortex are known to impair visual perception, i.e., the capacity to correctly perceive different aspects of the visual world, such as motion, color, or shapes. Visual perception can be influenced by non-invasive brain stimulation such as transcranial direct current stimulation (tDCS). In a recently developed technique called high definition (HD) tDCS, small HD-electrodes are used instead of the sponge electrodes in the conventional approach. This is believed to achieve high focality and precision over the target area. In this paper we tested the effects of cathodal and anodal HD-tDCS over the right V5 on motion and shape perception in a single blind, within-subject, sham controlled, cross-over trial. The purpose of the study was to prove the high focality of the stimulation only over the target area. Twenty one healthy volunteers received 20 min of 2 mA cathodal, anodal and sham stimulation over the right V5 and their performance on a visual test was recorded. The results showed significant improvement in motion perception in the left hemifield after cathodal HD-tDCS, but not in shape perception. Sham and anodal HD-tDCS did not affect performance. The specific effect of influencing performance of visual tasks by modulating the excitability of the neurons in the visual cortex might be explained by the complexity of perceptual information needed for the tasks. This provokes a “noisy” activation state of the encoding neuronal patterns. We speculate that in this case cathodal HD-tDCS may focus the correct perception by decreasing global excitation and thus diminishing the “noise” below threshold. PMID:26441582

  3. Antioxidants, endothelial dysfunction, and DCS: in vitro and in vivo study.

    PubMed

    Wang, Qiong; Mazur, Aleksandra; Guerrero, François; Lambrechts, Kate; Buzzacott, Peter; Belhomme, Marc; Theron, Michaël

    2015-12-15

    Reactive oxygen species (ROS) production is a well-known effect in individuals after an undersea dive. This study aimed to delineate the links between ROS, endothelial dysfunction, and decompression sickness (DCS) through the use of antioxidants in vitro and in vivo. The effect of N-acetylcysteine (NAC) on superoxide and peroxynitrite, nitric oxide (NO) generation, and cell viability during in vitro diving simulation were analyzed. Also analyzed was the effect of vitamin C and NAC on plasma glutathione thiol and thiobarbituric acid reactive substances (TBARS), plasma angiotensin-converting enzyme (ACE) activity, and angiotensin-II and DCS morbidity during in vivo diving simulation. During an in vitro diving simulation, vascular endothelial cells showed overproduction of superoxide and peroxynitrite, obvious attenuation of NO generation, and promotion of cell death, all of which were reversed by NAC treatment. After in vivo diving simulation, plasma ACE activity and angiotensin-II level were not affected. The plasma level of glutathione thiol was downregulated after the dive, which was attenuated partially by NAC treatment. Plasma TBARS level was upregulated; however, either NAC or vitamin C treatment failed to prevent DCS morbidity. During in vitro simulation, endothelial superoxide and peroxynitrite-mediated oxidative stress were involved in the attenuation of NO availability and cell death. This study is the first attempt to link oxidative stress and DCS occurrence, and the link could not be confirmed in vivo. Even in the presence of antioxidants, ROS and bubbles generated during diving and/or decompression might lead to embolic or biochemical stress and DCS. Diving-induced oxidative stress might not be the only trigger of DCS morbidity. PMID:26472863

  4. Batf3-independent langerin- CX3CR1- CD8α+ splenic DCs represent a precursor for classical cross-presenting CD8α+ DCs.

    PubMed

    Petersen, Troels R; Knight, Deborah A; Tang, Ching-Wen; Osmond, Taryn L; Hermans, Ian F

    2014-12-01

    This study tests the hypothesis that CD8α(+) DCs in the spleen of mice contain an immature precursor for functionally mature, "classical" cross-presenting CD8α(+) DCs. The lymphoid tissues contain a network of phenotypically distinct DCs with unique roles in surveillance and immunity. Splenic CD8α(+) DCs have been shown to exhibit a heightened capacity for phagocytosis of cellular material, secretion of IL-12, and cross-priming of CD8(+) T cells. However, this population can be subdivided further on the basis of expression of both langerin/CD207 and CX(3)CR1. We therefore evaluated the functional capacities of these different subsets. The CX(3)CR1(+) CD8α(+) DC subset does not express langerin and does not exhibit the classical features above. The CX(3)CR1(-) CD8α(+) DC can be divided into langerin-positive and negative populations, both of which express DEC205, Clec9A, and high basal levels of CD86. However, the langerin(+) CX(3)CR1(-) CD8α(+) subset has a superior capacity for acquiring cellular material and producing IL-12 and is more susceptible to activation-induced cell death. Significantly, following purification and adoptive transfer into new hosts, the langerin(-) CX(3)CR1(-) CD8α(+) subset survives longer, up-regulates expression of langerin, and becomes more susceptible to activation-induced cell death. Last, in contrast to langerin(+) CX(3)CR1(-) CD8α(+), the langerin(-) CX(3)CR1(-) CD8α(+) are still present in Batf3(-/-) mice. We conclude that the classical attributes of CD8α(+) DC are confined primarily to the langerin(+) CX(3)CR1(-) CD8α(+) DC population and that the langerin(-) CX(3)CR1(-) subset represents a Batf3-independent precursor to this mature population. PMID:25170118

  5. Evaluating Effect of Mesenchymal Stem Cells on Expression of TLR2 and TLR4 in Mouse DCs

    PubMed Central

    Karimi, Mohammad Hossein; Barzkar, Zahra; Babaee, Maryam; Naghdi, Majid

    2016-01-01

    Purpose: Mesenchymal stem cells (MSCs) are multipotent cells and recent findings suggest immunomodulatory effect of them on immune cells including T cells and dendritic cells (DCs). DCs are the most potent antigen presenting cells. It seems because of immunoregulatory properties of MSCs, they can affect the maturation and differentiation of DCs. DCs express a kind of surface receptors called toll-like receptors (TLRs) and play a key role in maturation process and activation of DCs. The aim of this study was to evaluate expression of TLR2 and TLR4 on DCs after exposure to mesenchymal stem cell’s supernatant in culture media containing LPS and devoid of it. Methods: In this experimental study, MSCs and DCs were extracted from adult Balb/c mouse bone marrow and spleen, respectively. MSCs supernatant were collected 24 and 48 h after 5th passage, and in adjusted with DCs culture. Isolated DCs were co-cultured with MSCs supernatant, incubation time were 24 and 48 hours. mRNA levels of TLR2 and TLR4 were evaluated using real time PCR technique. Results: The results demonstrated that although, expressions of these two receptors were up-regulated in culture media lacking LPS in comparison with the control group but the increase was not significant. There were no significant associations between LPS stimulated DCs with and without MSCs supernatants. Conclusion: According to the results presented here, it appears that TLR2 and TLR4 gene expressions on the DCs are not affected by MSCs supernatant. PMID:27478779

  6. Transcranial direct current stimulation (tDCS) of frontal cortex decreases performance on the WAIS-IV intelligence test.

    PubMed

    Sellers, Kristin K; Mellin, Juliann M; Lustenberger, Caroline M; Boyle, Michael R; Lee, Won Hee; Peterchev, Angel V; Fröhlich, Flavio

    2015-09-01

    Transcranial direct current stimulation (tDCS) modulates excitability of motor cortex. However, there is conflicting evidence about the efficacy of this non-invasive brain stimulation modality to modulate performance on cognitive tasks. Previous work has tested the effect of tDCS on specific facets of cognition and executive processing. However, no randomized, double-blind, sham-controlled study has looked at the effects of tDCS on a comprehensive battery of cognitive processes. The objective of this study was to test if tDCS had an effect on performance on a comprehensive assay of cognitive processes, a standardized intelligence quotient (IQ) test. The study consisted of two substudies and followed a double-blind, between-subjects, sham-controlled design. In total, 41 healthy adult participants were included in the final analysis. These participants completed the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) as a baseline measure. At least one week later, participants in substudy 1 received either bilateral tDCS (anodes over both F4 and F3, cathode over Cz, 2 mA at each anode for 20 min) or active sham tDCS (2 mA for 40 s), and participants in substudy 2 received either right or left tDCS (anode over either F4 or F3, cathode over Cz, 2 mA for 20 min). In both studies, the WAIS-IV was immediately administered following stimulation to assess for performance differences induced by bilateral and unilateral tDCS. Compared to sham stimulation, right, left, and bilateral tDCS reduced improvement between sessions on Full Scale IQ and the Perceptual Reasoning Index. This demonstration that frontal tDCS selectively degraded improvement on specific metrics of the WAIS-IV raises important questions about the often proposed role of tDCS in cognitive enhancement. PMID:25934490

  7. The anodal tDCS over the left posterior parietal cortex enhances attention toward a focus word in a sentence.

    PubMed

    Minamoto, Takehiro; Azuma, Miyuki; Yaoi, Ken; Ashizuka, Aoi; Mima, Tastuya; Osaka, Mariko; Fukuyama, Hidenao; Osaka, Naoyuki

    2014-01-01

    The posterior parietal cortex (PPC) has two attentional functions: top-down attentional control and stimulus-driven attentional processing. Using the focused version of the reading span test (RST), in which the target word to be remembered is the critical word for comprehending a sentence (focused word) or a non-focused word, we examined the effect of tDCS on resolution of distractor interference by the focused word in the non-focus condition (top-down attentional control) and on augmented/shrunk attentional capture by the focused word in both the focus and non-focus conditions (stimulus-driven attentional processing). Participants were divided into two groups: anodal tDCS (atDCS) and cathodal tDCS (ctDCS). Online stimulation was given while participants performed the RST. A post-hoc recognition task was also administered in which three kinds of words were presented: target words in the RST, distractor words in the RST, and novel words. atDCS augmented the effect of the focused word by increasing differences in performance between the focus and non-focus conditions. Such an effect was not observed in the ctDCS group. As for the recognition task, atDCS again produced the augmented effect of the focused words in the distractor recognition. On the other hand, ctDCS brought less recognition of non-focused target words in comparison to sham. The results indicate that atDCS promotes stimulus-driven attentional processing, possibly by affecting neural firing in the inferior parietal regions. In contrast, ctDCS appears to prevent retrieval of less important information from episodic memory, which may require top-down attentional processing. PMID:25538609

  8. The anodal tDCS over the left posterior parietal cortex enhances attention toward a focus word in a sentence

    PubMed Central

    Minamoto, Takehiro; Azuma, Miyuki; Yaoi, Ken; Ashizuka, Aoi; Mima, Tastuya; Osaka, Mariko; Fukuyama, Hidenao; Osaka, Naoyuki

    2014-01-01

    The posterior parietal cortex (PPC) has two attentional functions: top-down attentional control and stimulus-driven attentional processing. Using the focused version of the reading span test (RST), in which the target word to be remembered is the critical word for comprehending a sentence (focused word) or a non-focused word, we examined the effect of tDCS on resolution of distractor interference by the focused word in the non-focus condition (top-down attentional control) and on augmented/shrunk attentional capture by the focused word in both the focus and non-focus conditions (stimulus-driven attentional processing). Participants were divided into two groups: anodal tDCS (atDCS) and cathodal tDCS (ctDCS). Online stimulation was given while participants performed the RST. A post-hoc recognition task was also administered in which three kinds of words were presented: target words in the RST, distractor words in the RST, and novel words. atDCS augmented the effect of the focused word by increasing differences in performance between the focus and non-focus conditions. Such an effect was not observed in the ctDCS group. As for the recognition task, atDCS again produced the augmented effect of the focused words in the distractor recognition. On the other hand, ctDCS brought less recognition of non-focused target words in comparison to sham. The results indicate that atDCS promotes stimulus-driven attentional processing, possibly by affecting neural firing in the inferior parietal regions. In contrast, ctDCS appears to prevent retrieval of less important information from episodic memory, which may require top-down attentional processing. PMID:25538609

  9. Skin tumor immunity: Site does matter for antigen presentation by DCs.

    PubMed

    Waithman, Jason; Gebhardt, Thomas; Bedoui, Sammy

    2016-03-01

    The immune system has the ability to specifically identify and eliminate tumors, but the underlying mechanisms responsible for this phenomenon are not fully understood. A study published in this issue of the European Journal of Immunology now provides new insights into this important problem. Joncker et al. [Eur. J. Immunol. 2016. 46: 609-618] show that the timely mobilization of tumor antigen-bearing dendritic cells (DCs) from the periphery to the lymph nodes is critical for effective antitumor T-cell immunity, and that DCs present tumor antigens much more efficiently when encountered in the skin rather than in the subcutaneous tissues. PMID:26842676

  10. Investigating the cortical regions involved in MEP modulation in tDCS

    PubMed Central

    Salvador, Ricardo; Wenger, Cornelia; Miranda, Pedro C.

    2015-01-01

    Transcranial magnetic stimulation (TMS) is used in several studies to evaluate cortical excitability changes induced by transcranial direct current stimulation (tDCS) of the primary motor cortex. Interpretation of these results, however, is hindered by the very different spatial distribution of the electric field (E-field) induced by the two techniques and by the different target neurons that they might act upon. In this study we used the finite element method to calculate the E-field distribution induced by TMS and tDCS in a realistically shaped model of a human head. A model of a commercially available figure-8 coil was placed over a position above the identified hand knob (HK) region. We also modeled two configurations of bipolar tDCS montages with one of the electrodes placed over the HK and a return electrode over the contralateral orbital region. The electrodes over the HK were either rectangular in shape, with an area of 35 cm2 or cylindrical with an area of π cm2 (1 cm radius). To compare the E-field distribution in TMS and the two tDCS models, average values of the E-field's magnitude as well as the polar and azimuthal angle were investigated in the HK region and premotor areas. The results show that both techniques induce fields with different magnitudes and directions in the HK: the field in tDCS is predominantly perpendicular to the cortical surface, contrary to what happens in TMS where the field is mostly parallel to it. In the premotor areas, the magnitude of the E-field induced in TMS was well below the accepted threshold for MEP generation, 100 V/m. In tDCS, the magnitude of the field in these areas was comparable to that induced at the HK with a significant component perpendicular to the cortical surface. These results indicate that tDCS and TMS target preferentially different neuronal structures at the HK. Besides, they show that premotor areas may play a role in the tDCS-induced after effects on motor cortex excitability. PMID:26528134

  11. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  12. Selected commensal-related bacteria and Toll-like receptor 3 agonist combinatorial codes synergistically induce interleukin-12 production by dendritic cells to trigger a T helper type 1 polarizing programme

    PubMed Central

    Baba, Nobuyasu; Samson, Sandrine; Bourdet-Sicard, Raphaëlle; Rubio, Manuel; Sarfati, Marika

    2009-01-01

    Enteric infections remain a major health problem causing millions of deaths in developing countries. The interplay among the host intestinal epithelium, the mucosa-associated immune system and microbiota performs an essential role in gut homeostasis and protection against infectious diseases. Dendritic cells (DCs) play a key role in orchestrating protective immunity and tolerance in the gut. The mechanisms by which DCs adapt their responses and discriminate between virulent microbes and trillions of innocuous bacteria remain ill-defined. Here we investigated the effect of cross-talk between commensal-related bacteria (CB) and Toll-like receptor (TLR) agonists on DC activation and the outcome of the in vitro T helper response. Human monocyte-derived DCs were exposed to eight different Gram-positive or Gram-negative CB strains prior to activation with five different TLR agonists. The key polarizing cytokines interleukin (IL)-12p70, IL-10, IL-1β and IL-6 were quantified and the fate of naïve T-cell differentiation was evaluated. We identified a unique combination of Lactobacillus casei and TLR3 signals that acted in synergy to selectively increase IL-12p70 secretion. Exposure to poly(I:C) converted L. casei-treated DCs into potent promoters of T helper type 1 (Th1) responses. We propose that DCs can integrate harmless and dangerous non-self signals delivered by viral products, to mount robust Th1 responses. Thus, in vivo DC targeting with selective probiotics may improve strategies for the management of enteric diseases. PMID:19740313

  13. DCIR2+ cDC2 DCs and Zbtb32 Restore CD4+ T-Cell Tolerance and Inhibit Diabetes.

    PubMed

    Price, Jeffrey D; Hotta-Iwamura, Chie; Zhao, Yongge; Beauchamp, Nicole M; Tarbell, Kristin V

    2015-10-01

    During autoimmunity, the normal ability of dendritic cells (DCs) to induce T-cell tolerance is disrupted; therefore, autoimmune disease therapies based on cell types and molecular pathways that elicit tolerance in the steady state may not be effective. To determine which DC subsets induce tolerance in the context of chronic autoimmunity, we used chimeric antibodies specific for DC inhibitory receptor 2 (DCIR2) or DEC-205 to target self-antigen to CD11b(+) (cDC2) DCs and CD8(+) (cDC1) DCs, respectively, in autoimmune-prone nonobese diabetic (NOD) mice. Antigen presentation by DCIR2(+) DCs but not DEC-205(+) DCs elicited tolerogenic CD4(+) T-cell responses in NOD mice. β-Cell antigen delivered to DCIR2(+) DCs delayed diabetes induction and induced increased T-cell apoptosis without interferon-γ (IFN-γ) or sustained expansion of autoreactive CD4(+) T cells. These divergent responses were preceded by differential gene expression in T cells early after in vivo stimulation. Zbtb32 was higher in T cells stimulated with DCIR2(+) DCs, and overexpression of Zbtb32 in T cells inhibited diabetes development, T-cell expansion, and IFN-γ production. Therefore, we have identified DCIR2(+) DCs as capable of inducing antigen-specific tolerance in the face of ongoing autoimmunity and have also identified Zbtb32 as a suppressive transcription factor that controls T cell-mediated autoimmunity. PMID:26070317

  14. Impact of tDCS on Performance and Learning of Target Detection: Interaction with Stimulus Characteristics and Experimental Design

    ERIC Educational Resources Information Center

    Coffman, B. A.; Trumbo, M. C.; Flores, R. A.; Garcia, C. M.; van der Merwe, A. J.; Wassermann, E. M.; Weisend, M. P.; Clark, V. P.

    2012-01-01

    We have previously found that transcranial direct current stimulation (tDCS) over right inferior frontal cortex (RIFC) enhances performance during learning of a difficult visual target detection task (Clark et al., 2012). In order to examine the cognitive mechanisms of tDCS that lead to enhanced performance, here we analyzed its differential…

  15. Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue DCs

    PubMed Central

    Kuan, Emma L.; Ivanov, Stoyan; Bridenbaugh, Eric A.; Victora, Gabriel; Wang, Wei; Childs, Ed W.; Platt, Andrew M.; Jakubzick, Claudia V.; Mason, Robert J.; Gashev, Anatoliy A.; Nussenzweig, Michel; Swartz, Melody A.; Dustin, Michael L.; Zawieja, David C.; Randolph, Gwendalyn J.

    2015-01-01

    Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. Here, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived antigens by these cells supported recall T cell responses in the fat and also generated antigen-bearing DCs for emigration into adjacent lymph nodes. Enhanced recruitment of DCs to inflammation-reactive lymph nodes significantly relied on adipose tissue DCs to maintain sufficient numbers of antigen-bearing DCs as the lymph node expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for antigen transport into the adjacent lymph node. PMID:25917096

  16. Transcranial direct current stimulation and power spectral parameters: a tDCS/EEG co-registration study

    PubMed Central

    Mangia, Anna L.; Pirini, Marco; Cappello, Angelo

    2014-01-01

    Transcranial direct current stimulation (tDCS) delivers low electric currents to the brain through the scalp. Constant electric currents induce shifts in neuronal membrane excitability, resulting in secondary changes in cortical activity. Concomitant electroencephalography (EEG) monitoring during tDCS can provide valuable information on the tDCS mechanisms of action. This study examined the effects of anodal tDCS on spontaneous cortical activity in a resting brain to disclose possible modulation of spontaneous oscillatory brain activity. EEG activity was measured in ten healthy subjects during and after a session of anodal stimulation of the postero-parietal cortex to detect the tDCS-induced alterations. Changes in the theta, alpha, beta, and gamma power bands were investigated. Three main findings emerged: (1) an increase in theta band activity during the first minutes of stimulation; (2) an increase in alpha and beta power during and after stimulation; (3) a widespread activation in several brain regions. PMID:25147519

  17. Using cyber vulnerability testing techniques to expose undocumented security vulnerabilities in DCS and SCADA equipment

    SciTech Connect

    Pollet, J.

    2006-07-01

    This session starts by providing an overview of typical DCS (Distributed Control Systems) and SCADA (Supervisory Control and Data Acquisition) architectures, and exposes cyber security vulnerabilities that vendors never admit, but are found through a comprehensive cyber testing process. A complete assessment process involves testing all of the layers and components of a SCADA or DCS environment, from the perimeter firewall all the way down to the end devices controlling the process, including what to look for when conducting a vulnerability assessment of real-time control systems. The following systems are discussed: 1. Perimeter (isolation from corporate IT or other non-critical networks) 2. Remote Access (third Party access into SCADA or DCS networks) 3. Network Architecture (switch, router, firewalls, access controls, network design) 4. Network Traffic Analysis (what is running on the network) 5. Host Operating Systems Hardening 6. Applications (how they communicate with other applications and end devices) 7. End Device Testing (PLCs, RTUs, DCS Controllers, Smart Transmitters) a. System Discovery b. Functional Discovery c. Attack Methodology i. DoS Tests (at what point does the device fail) ii. Malformed Packet Tests (packets that can cause equipment failure) iii. Session Hijacking (do anything that the operator can do) iv. Packet Injection (code and inject your own SCADA commands) v. Protocol Exploitation (Protocol Reverse Engineering / Fuzzing) This paper will provide information compiled from over five years of conducting cyber security testing on control systems hardware, software, and systems. (authors)

  18. Potentials and limits to enhance cognitive functions in healthy and pathological aging by tDCS.

    PubMed

    Prehn, Kristin; Flöel, Agnes

    2015-01-01

    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that is increasingly used in research and clinical settings to enhance the effects of cognitive training. In our present review, we will first summarize studies using tDCS alone and in combination with cognitive training in older adults and patients with Alzheimer's dementia (AD). We will also review one study (Meinzer et al., 2014c) that showed an improvement in cognitive performance during anodal tDCS over the left inferior frontal cortex in patients with mild cognitive impairment (MCI) which is regarded as a prodromal stage of AD. Although promising short-term results have been reported, evidence from randomized controlled trials (RCTs) with sufficient sample sizes is scarce. In addition, stimulation protocols (in terms of intensity, duration, and repetition of stimulation) that lead to sustained improvements in outcome measures relevant for daily life still remain to be established. Following, we will discuss modulating factors such as technical parameters as well as the question whether there are specific cognitive functions (e.g., learning, memory consolidation, executive control) which are more amenable to tDCS enhancement than others. Finally, we will highlight future directions and limitations in this field and emphasize the need to conduct RCTs to establish efficacy of interventions for activities of daily life for a given patient population. PMID:26441526

  19. Effects of tDCS on executive function in Parkinson's disease.

    PubMed

    Doruk, Deniz; Gray, Zachary; Bravo, Gabriela L; Pascual-Leone, Alvaro; Fregni, Felipe

    2014-10-17

    Non-motor symptoms in patients with Parkinson's disease (PD) are often poorly recognized, significantly impair quality of life and cause severe disability. Currently, there is limited evidence to guide treatment of associated psychiatric and cognitive problems. Non-invasive brain stimulation techniques have emerged as non-pharmacological alternatives to target cognitive symptoms without worsening motor function. In this context, we conducted a multicenter, sham controlled, double-blinded study to assess the immediate and long-term effects of ten consecutive sessions of transcranial direct current stimulation (tDCS) over the anode on the right dorsolateral prefrontal cortex (DLPFC) (n=5), left DLPFC (n=6) or sham (n=7). We assessed cognitive functions, depressive symptoms and motor functions in 18 PD patients at baseline, at the end of the 2-week stimulation sessions and at 1-month follow-up. Our results showed that active stimulation of both left and right DLPFC resulted in prolonged improvements in Trail Making Test B, an established test to measure executive function, compared to sham tDCS at the 1-month follow-up. These results suggest the existence of a beneficial long-term effect on executive functions in PD patients following active tDCS over the DLPFC. Thus, our findings encourage further investigation exploring tDCS as an adjuvant therapy for cognitive and behavioral treatment in PD. PMID:25179996

  20. Complement activation in divers after repeated air/heliox dives and its possible relevance to DCS.

    PubMed

    Hjelde, A; Bergh, K; Brubakk, A O; Iversen, O J

    1995-03-01

    Plasma levels of the anaphylatoxin C5a were measured in 19 divers performing repeated air dives. Blood samples were collected immediately before the first dive and 2 h after the first and the second or third dive. Serum obtained at the same times was subjected to complement activation in vitro by air bubbles. Six divers developed symptoms of decompression sickness (DCS). Most intravascular bubbles were observed in divers with the lowest plasma levels of C5a. Postdive plasma levels of C5a did not increase compared with predive levels, nor were postdive levels significantly different after two or three dives compared with the first dive. Repeated dives did not influence the amounts of C5a generated in vitro. Neither plasma levels of C5a nor C5a generated in vitro were significantly different in divers who experienced symptoms of DCS vs. divers without symptoms of DCS. We conclude that plasma level of C5a and measurement of C5a generation in vitro cannot be used to predict DCS. PMID:7775308

  1. Modulation of Total Sleep Time by Transcranial Direct Current Stimulation (tDCS).

    PubMed

    Frase, Lukas; Piosczyk, Hannah; Zittel, Sulamith; Jahn, Friederike; Selhausen, Peter; Krone, Lukas; Feige, Bernd; Mainberger, Florian; Maier, Jonathan G; Kuhn, Marion; Klöppel, Stefan; Normann, Claus; Sterr, Annette; Spiegelhalder, Kai; Riemann, Dieter; Nitsche, Michael A; Nissen, Christoph

    2016-09-01

    Arousal and sleep are fundamental physiological processes, and their modulation is of high clinical significance. This study tested the hypothesis that total sleep time (TST) in humans can be modulated by the non-invasive brain stimulation technique transcranial direct current stimulation (tDCS) targeting a 'top-down' cortico-thalamic pathway of sleep-wake regulation. Nineteen healthy participants underwent a within-subject, repeated-measures protocol across five nights in the sleep laboratory with polysomnographic monitoring (adaptation, baseline, three experimental nights). tDCS was delivered via bi-frontal target electrodes and bi-parietal return electrodes before sleep (anodal 'activation', cathodal 'deactivation', and sham stimulation). Bi-frontal anodal stimulation significantly decreased TST, compared with cathodal and sham stimulation. This effect was location specific. Bi-frontal cathodal stimulation did not significantly increase TST, potentially due to ceiling effects in good sleepers. Exploratory resting-state EEG analyses before and after the tDCS protocols were consistent with the notion of increased cortical arousal after anodal stimulation and decreased cortical arousal after cathodal stimulation. The study provides proof-of-concept that TST can be decreased by non-invasive bi-frontal anodal tDCS in healthy humans. Further elucidating the 'top-down' pathway of sleep-wake regulation is expected to increase knowledge on the fundamentals of sleep-wake regulation and to contribute to the development of novel treatments for clinical conditions of disturbed arousal and sleep. PMID:27143601

  2. Multisession Anodal tDCS Protocol Improves Motor System Function in an Aging Population

    PubMed Central

    Dumel, G.; Bourassa, M.-E.; Desjardins, M.; Voarino, N.; Charlebois-Plante, C.; Doyon, J.; De Beaumont, Louis

    2016-01-01

    Objectives. The primary objective of this study was to investigate the effects of five consecutive, daily 20-minute sessions of M1 a-tDCS on motor learning in healthy, cognitively intact, aging adults. Design. A total of 23 participants (51 to 69 years old) performed five consecutive, daily 20-minute sessions of a serial reaction time task (SRT task) concomitant with either anodal (n = 12) or sham (n = 11) M1 a-tDCS. Results. We found a significant group × training sessions interaction, indicating that whereas aging adults in the sham group exhibited little-to-no sequence-specific learning improvements beyond the first day of training, reproducible improvements in the ability to learn new motor sequences over 5 consecutive sessions were the net result in age-equivalent participants from the M1 a-tDCS group. A significant main effect of group on sequence-specific learning revealed greater motor learning for the M1 a-tDCS group when the five learning sessions were averaged. Conclusion. These findings raise into prominence the utility of multisession anodal TDCS protocols in combination with motor training to help prevent/alleviate age-associated motor function decline. PMID:26881118

  3. Potentials and limits to enhance cognitive functions in healthy and pathological aging by tDCS

    PubMed Central

    Prehn, Kristin; Flöel, Agnes

    2015-01-01

    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that is increasingly used in research and clinical settings to enhance the effects of cognitive training. In our present review, we will first summarize studies using tDCS alone and in combination with cognitive training in older adults and patients with Alzheimer’s dementia (AD). We will also review one study (Meinzer et al., 2014c) that showed an improvement in cognitive performance during anodal tDCS over the left inferior frontal cortex in patients with mild cognitive impairment (MCI) which is regarded as a prodromal stage of AD. Although promising short-term results have been reported, evidence from randomized controlled trials (RCTs) with sufficient sample sizes is scarce. In addition, stimulation protocols (in terms of intensity, duration, and repetition of stimulation) that lead to sustained improvements in outcome measures relevant for daily life still remain to be established. Following, we will discuss modulating factors such as technical parameters as well as the question whether there are specific cognitive functions (e.g., learning, memory consolidation, executive control) which are more amenable to tDCS enhancement than others. Finally, we will highlight future directions and limitations in this field and emphasize the need to conduct RCTs to establish efficacy of interventions for activities of daily life for a given patient population. PMID:26441526

  4. Efficient delivery of antigen to DCs using yeast-derived microparticles.

    PubMed

    Pan, Ying; Li, Xiaopeng; Kang, Tianyi; Meng, Hui; Chen, Zhouli; Yang, Li; Wu, Yang; Wei, Yuquan; Gou, Maling

    2015-01-01

    Some pathogens can be naturally recognized and internalized by antigen presentation cells (APCs) in vivo, providing a platform for efficient vaccine delivery. However, the biosafety concerns discourage the clinical applications of live pathogens. Here, yeast-derived microparticles were prepared for cancer vaccine delivery. By chemical treatment of bread yeast, capsular yeast shell (YS) microparticles were obtained. Ovalbumin (OVA), as a model antigen, was conjugated to the surface of YS. Results indicated that these YS microparticles with a uniform size of ~3.4 μm can be recognized and internalized by dendritic cells (DCs). The YS-mediated antigen delivery can enhance the cellular uptake of antigen by DCs, promote the maturation of DCs, and trigger DCs to release immune co-stimulatory molecules. Immunization with YS-mediated antigen can induce an effective immune response against tumor cells in vivo, with contributions from both humoral and cellular immunity. This work suggests that yeast shell microparticles as efficient vaccine delivery system has promising applications in cancer immunotherapy. PMID:26022399

  5. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  6. The strategy and motivational influences on the beneficial effect of neurostimulation: a tDCS and fNIRS study.

    PubMed

    Jones, Kevin T; Gözenman, Filiz; Berryhill, Marian E

    2015-01-15

    Working memory (WM) capacity falls along a spectrum with some people demonstrating higher and others lower WM capacity. Efforts to improve WM include applying transcranial direct current stimulation (tDCS), in which small amounts of current modulate the activity of underlying neurons and enhance cognitive function. However, not everyone benefits equally from a given tDCS protocol. Recent findings revealed tDCS-related WM benefits for individuals with higher working memory (WM) capacity. Here, we test two hypotheses regarding those with low WM capacity to see if they too would benefit under more optimal conditions. We tested whether supplying a WM strategy (Experiment 1) or providing greater extrinsic motivation through incentives (Experiment 2) would restore tDCS benefit to the low WM capacity group. We also employed functional near infrared spectroscopy to monitor tDCS-induced changes in neural activity. Experiment 1 demonstrated that supplying a WM strategy improved the high WM capacity participants' accuracy and the amount of oxygenated blood levels following anodal tDCS, but it did not restore tDCS-linked WM benefits to the low WM capacity group. Experiment 2 demonstrated that financial motivation enhanced performance in both low and high WM capacity groups, especially after anodal tDCS. Here, only the low WM capacity participants showed a generalized increase in oxygenated blood flow across both low and high motivation conditions. These results indicate that ensuring that participants' incentives are high may expand cognitive benefits associated with tDCS. This finding is relevant for translational work using tDCS in clinical populations, in which motivation can be a concern. PMID:25462798

  7. Acute working memory improvement after tDCS in antidepressant-free patients with major depressive disorder.

    PubMed

    Oliveira, Janaina F; Zanão, Tamires A; Valiengo, Leandro; Lotufo, Paulo A; Benseñor, Isabela M; Fregni, Felipe; Brunoni, André R

    2013-03-14

    Based on previous studies showing that transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique that employs weak, direct currents to induce cortical-excitability changes, might be useful for working memory (WM) enhancement in healthy subjects and also in treating depressive symptoms, our aim was to evaluate whether tDCS could acutely enhance WM in depressed patients. Twenty-eight age- and gender-matched, antidepressant-free depressed subjects received a single-session of active/sham tDCS in a randomized, double-blind, parallel design. The anode was positioned over the left and the cathode over the right dorsolateral prefrontal cortex. The n-back task was used for assessing WM and it was performed immediately before and 15min after tDCS onset. We found that active vs. sham tDCS led to an increase in the rate of correct responses. We also used signal detection theory analyses to show that active tDCS increased both discriminability, i.e., the ability to discriminate signal (correct responses) from noise (false alarms), and response criterion, indicating a lower threshold to yield responses. All effect sizes were large. In other words, one session of tDCS acutely enhanced WM in depressed subjects, suggesting that tDCS can improve "cold" (non affective-loaded) working memory processes in MDD. Based on these findings, we discuss the effects of tDCS on WM enhancement in depression. We also suggest that the n-back task could be used as a biomarker in future tDCS studies investigating prefrontal activity in healthy and depressed samples. PMID:23370288

  8. Transcranial direct current stimulation (tDCS) of left parietal cortex facilitates gesture processing in healthy subjects.

    PubMed

    Weiss, Peter H; Achilles, Elisabeth I S; Moos, Katharina; Hesse, Maike D; Sparing, Roland; Fink, Gereon R

    2013-12-01

    Gesture processing deficits constitute a key symptom of apraxia, a disorder of motor cognition frequently observed after left-hemispheric stroke. The clinical relevance of apraxia stands in stark contrast to the paucity of therapeutic options available. Transcranial direct current stimulation (tDCS) is a promising tool for modulating disturbed network function after stroke. Here, we investigate the effect of parietal tDCS on gesture processing in healthy human subjects. Neuropsychological and imaging studies suggest that the imitation and matching of hand gestures involve the left inferior parietal lobe (IPL). Using neuronavigation based on cytoarchitectonically defined anatomical probability maps, tDCS was applied over left IPL-areas PF, PFm, or PG in healthy participants (n = 26). Before and after tDCS, subjects performed a gesture matching task and a person discrimination task for control. Changes in error rates and reaction times were analyzed for the effects of anodal and cathodal tDCS (compared with sham tDCS). Matching of hand gestures was specifically facilitated by anodal tDCS applied over the cytoarchitectonically defined IPL-area PFm, whereas tDCS over IPL-areas PF and PG did not elucidate significant effects. Taking into account tDCS electrode size and the central position of area PFm within IPL, it can be assumed that the observed effect is rather the result of a combined stimulation of the supramarginal and angular gyrus than an isolated PFm stimulation. Our data confirm the pivotal role of the left IPL in gesture processing. Furthermore, anatomically guided tDCS of the left IPL may constitute a promising approach to neurorehabilitation of apraxic patients with gesture processing deficits. PMID:24305816

  9. Remotely-supervised transcranial direct current stimulation (tDCS) for clinical trials: guidelines for technology and protocols.

    PubMed

    Charvet, Leigh E; Kasschau, Margaret; Datta, Abhishek; Knotkova, Helena; Stevens, Michael C; Alonzo, Angelo; Loo, Colleen; Krull, Kevin R; Bikson, Marom

    2015-01-01

    The effect of transcranial direct current stimulation (tDCS) is cumulative. Treatment protocols typically require multiple consecutive sessions spanning weeks or months. However, traveling to clinic for a tDCS session can present an obstacle to subjects and their caregivers. With modified devices and headgear, tDCS treatment can be administered remotely under clinical supervision, potentially enhancing recruitment, throughput, and convenience. Here we propose standards and protocols for clinical trials utilizing remotely-supervised tDCS with the goal of providing safe, reproducible and well-tolerated stimulation therapy outside of the clinic. The recommendations include: (1) training of staff in tDCS treatment and supervision; (2) assessment of the user's capability to participate in tDCS remotely; (3) ongoing training procedures and materials including assessments of the user and/or caregiver; (4) simple and fail-safe electrode preparation techniques and tDCS headgear; (5) strict dose control for each session; (6) ongoing monitoring to quantify compliance (device preparation, electrode saturation/placement, stimulation protocol), with corresponding corrective steps as required; (7) monitoring for treatment-emergent adverse effects; (8) guidelines for discontinuation of a session and/or study participation including emergency failsafe procedures tailored to the treatment population's level of need. These guidelines are intended to provide a minimal level of methodological rigor for clinical trials seeking to apply tDCS outside a specialized treatment center. We outline indication-specific applications (Attention Deficit Hyperactivity Disorder, Depression, Multiple Sclerosis, Palliative Care) following these recommendations that support a standardized framework for evaluating the tolerability and reproducibility of remote-supervised tDCS that, once established, will allow for translation of tDCS clinical trials to a greater size and range of patient populations

  10. The strategy and motivational influences on the beneficial effect of neurostimulation: a tDCS and fNIRS study

    PubMed Central

    Jones, Kevin T.; Gözenman, Filiz; Berryhill, Marian E.

    2014-01-01

    Working memory (WM) capacity falls along a spectrum with some people demonstrating higher and others lower WM capacity. Efforts to improve WM include applying transcranial direct current stimulation (tDCS), in which small amounts of current modulate the activity of underlying neurons and enhance cognitive function. However, not everyone benefits equally from a given tDCS protocol. Recent findings revealed tDCS-related WM benefits for individuals with higher working memory (WM) capacity. Here, we test two hypotheses regarding those with low WM capacity to see if they too would benefit under more optimal conditions. We tested whether supplying a WM strategy (Experiment 1) or providing greater extrinsic motivation through incentives (Experiment 2) would restore tDCS benefit to the low WM capacity group. We also employed functional near infrared spectroscopy to monitor tDCS-induced changes in neural activity. Experiment 1 demonstrated that supplying a WM strategy improved the high WM capacity participants’ accuracy and the amount of oxygenated blood levels following anodal tDCS, but it did not restore tDCS-linked WM benefits to the low WM capacity group. Experiment 2 demonstrated that financial motivation enhanced performance in both low and high WM capacity groups, especially after anodal tDCS. Here, only the low WM capacity participants showed a generalized increase in oxygenated blood flow across both low and high motivation conditions. These results indicate that ensuring that participants’ incentives are high may expand cognitive benefits associated with tDCS. This finding is relevant for translational work using tDCS in clinical populations, in which motivation can be a concern. PMID:25462798

  11. Human CD1c(+) DCs are critical cellular mediators of immune responses induced by immunogenic cell death.

    PubMed

    Di Blasio, Stefania; Wortel, Inge M N; van Bladel, Diede A G; de Vries, Laura E; Duiveman-de Boer, Tjitske; Worah, Kuntal; de Haas, Nienke; Buschow, Sonja I; de Vries, I Jolanda M; Figdor, Carl G; Hato, Stanleyson V

    2016-08-01

    Chemotherapeutics, including the platinum compounds oxaliplatin (OXP) and cisplatin (CDDP), are standard care of treatment for cancer. Although chemotherapy has long been considered immunosuppressive, evidence now suggests that certain cytotoxic agents can efficiently stimulate antitumor responses, through the induction of a form of apoptosis, called immunogenic cell death (ICD). ICD is characterized by exposure of calreticulin and heat shock proteins (HSPs), secretion of ATP and release of high-mobility group box 1 (HMGB1). Proper activation of the immune system relies on the integration of these signals by dendritic cells (DCs). Studies on the crucial role of DCs, in the context of ICD, have been performed using mouse models or human in vitro-generated monocyte-derived DCs (moDCs), which do not fully recapitulate the in vivo situation. Here, we explore the effect of platinum-induced ICD on phenotype and function of human blood circulating DCs. Tumor cells were treated with OXP or CDDP and induction of ICD was investigated. We show that both platinum drugs triggered translocation of calreticulin and HSP70, as well as the release of ATP and HMGB1. Platinum treatment increased phagocytosis of tumor fragments by human blood DCs and enhanced phenotypic maturation of blood myeloid and plasmacytoid DCs. Moreover, upon interaction with platinum-treated tumor cells, CD1c(+) DCs efficiently stimulated allogeneic proliferation of T lymphocytes. Together, our observations indicate that platinum-treated tumor cells may exert an active stimulatory effect on human blood DCs. In particular, these data suggest that CD1c(+) DCs are critical mediators of immune responses induced by ICD. PMID:27622063

  12. Human CD1c+ DCs are critical cellular mediators of immune responses induced by immunogenic cell death

    PubMed Central

    Di Blasio, Stefania; Wortel, Inge M. N.; van Bladel, Diede A. G.; de Vries, Laura E.; Duiveman-de Boer, Tjitske; Worah, Kuntal; de Haas, Nienke; Buschow, Sonja I.; de Vries, I. Jolanda M.; Figdor, Carl G.; Hato, Stanleyson V.

    2016-01-01

    ABSTRACT Chemotherapeutics, including the platinum compounds oxaliplatin (OXP) and cisplatin (CDDP), are standard care of treatment for cancer. Although chemotherapy has long been considered immunosuppressive, evidence now suggests that certain cytotoxic agents can efficiently stimulate antitumor responses, through the induction of a form of apoptosis, called immunogenic cell death (ICD). ICD is characterized by exposure of calreticulin and heat shock proteins (HSPs), secretion of ATP and release of high-mobility group box 1 (HMGB1). Proper activation of the immune system relies on the integration of these signals by dendritic cells (DCs). Studies on the crucial role of DCs, in the context of ICD, have been performed using mouse models or human in vitro-generated monocyte-derived DCs (moDCs), which do not fully recapitulate the in vivo situation. Here, we explore the effect of platinum-induced ICD on phenotype and function of human blood circulating DCs. Tumor cells were treated with OXP or CDDP and induction of ICD was investigated. We show that both platinum drugs triggered translocation of calreticulin and HSP70, as well as the release of ATP and HMGB1. Platinum treatment increased phagocytosis of tumor fragments by human blood DCs and enhanced phenotypic maturation of blood myeloid and plasmacytoid DCs. Moreover, upon interaction with platinum-treated tumor cells, CD1c+ DCs efficiently stimulated allogeneic proliferation of T lymphocytes. Together, our observations indicate that platinum-treated tumor cells may exert an active stimulatory effect on human blood DCs. In particular, these data suggest that CD1c+ DCs are critical mediators of immune responses induced by ICD. PMID:27622063

  13. Remotely-supervised transcranial direct current stimulation (tDCS) for clinical trials: guidelines for technology and protocols

    PubMed Central

    Charvet, Leigh E.; Kasschau, Margaret; Datta, Abhishek; Knotkova, Helena; Stevens, Michael C.; Alonzo, Angelo; Loo, Colleen; Krull, Kevin R.; Bikson, Marom

    2015-01-01

    The effect of transcranial direct current stimulation (tDCS) is cumulative. Treatment protocols typically require multiple consecutive sessions spanning weeks or months. However, traveling to clinic for a tDCS session can present an obstacle to subjects and their caregivers. With modified devices and headgear, tDCS treatment can be administered remotely under clinical supervision, potentially enhancing recruitment, throughput, and convenience. Here we propose standards and protocols for clinical trials utilizing remotely-supervised tDCS with the goal of providing safe, reproducible and well-tolerated stimulation therapy outside of the clinic. The recommendations include: (1) training of staff in tDCS treatment and supervision; (2) assessment of the user’s capability to participate in tDCS remotely; (3) ongoing training procedures and materials including assessments of the user and/or caregiver; (4) simple and fail-safe electrode preparation techniques and tDCS headgear; (5) strict dose control for each session; (6) ongoing monitoring to quantify compliance (device preparation, electrode saturation/placement, stimulation protocol), with corresponding corrective steps as required; (7) monitoring for treatment-emergent adverse effects; (8) guidelines for discontinuation of a session and/or study participation including emergency failsafe procedures tailored to the treatment population’s level of need. These guidelines are intended to provide a minimal level of methodological rigor for clinical trials seeking to apply tDCS outside a specialized treatment center. We outline indication-specific applications (Attention Deficit Hyperactivity Disorder, Depression, Multiple Sclerosis, Palliative Care) following these recommendations that support a standardized framework for evaluating the tolerability and reproducibility of remote-supervised tDCS that, once established, will allow for translation of tDCS clinical trials to a greater size and range of patient populations

  14. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  15. Investigation of tDCS volume conduction effects in a highly realistic head model

    NASA Astrophysics Data System (ADS)

    Wagner, S.; Rampersad, S. M.; Aydin, Ü.; Vorwerk, J.; Oostendorp, T. F.; Neuling, T.; Herrmann, C. S.; Stegeman, D. F.; Wolters, C. H.

    2014-02-01

    Objective. We investigate volume conduction effects in transcranial direct current stimulation (tDCS) and present a guideline for efficient and yet accurate volume conductor modeling in tDCS using our newly-developed finite element (FE) approach. Approach. We developed a new, accurate and fast isoparametric FE approach for high-resolution geometry-adapted hexahedral meshes and tissue anisotropy. To attain a deeper insight into tDCS, we performed computer simulations, starting with a homogenized three-compartment head model and extending this step by step to a six-compartment anisotropic model. Main results. We are able to demonstrate important tDCS effects. First, we find channeling effects of the skin, the skull spongiosa and the cerebrospinal fluid compartments. Second, current vectors tend to be oriented towards the closest higher conducting region. Third, anisotropic WM conductivity causes current flow in directions more parallel to the WM fiber tracts. Fourth, the highest cortical current magnitudes are not only found close to the stimulation sites. Fifth, the median brain current density decreases with increasing distance from the electrodes. Significance. Our results allow us to formulate a guideline for volume conductor modeling in tDCS. We recommend to accurately model the major tissues between the stimulating electrodes and the target areas, while for efficient yet accurate modeling, an exact representation of other tissues is less important. Because for the low-frequency regime in electrophysiology the quasi-static approach is justified, our results should also be valid for at least low-frequency (e.g., below 100 Hz) transcranial alternating current stimulation.

  16. Irreversible loss of pDCs by apoptosis during early HIV infection may be a critical determinant of immune dysfunction.

    PubMed

    Meera, Singh; Madhuri, Thakar; Manisha, Ghate; Ramesh, Paranjape

    2010-06-01

    The dendritic cell subsets myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) play an important role in HIV pathogenesis. While pDCs play a major role in the innate immune response, mDCs are important for induction of the antigen-specific immune response. We studied pDCs and mDCs at different stages of HIV infection, and found that there were decreased percentages of pDCs and mDCs in the advanced stage of the disease (p < 0.0001), and that slow progressors did not show as great a decrease as more healthy individuals. Persons who had acquired infection within the last year showed a normal mDC percentage but a lower pDC percentage (p = 0.0092) than healthy individuals (0.16%). pDC percentages in those with late-stage disease did not revert to normal after successful antiretroviral therapy (ART), whereas mDC percentages reverted to levels comparable to those seen in the healthy population (0.08% pre-ART to 0.18% post-ART; p < 0.0001). The pDC population had high levels of apoptotic markers in those with recent (p = 0.0025) and advanced (p = 0.0012) HIV infection, with no difference in their migratory capacity from controls and slow progressors, indicating that apoptosis is the major mechanism of declining pDC numbers in the circulation. mDCs showed increased levels of apoptotic markers (p = 0.0012), as well as migration (p = 0.03), in those with advanced-stage disease compared to controls, suggesting that both migration and apoptosis contribute to the decline seen in mDCs in the circulation. The irreversible loss of pDCs due to apoptosis seen early in HIV infection may be responsible for an impaired innate anti-HIV immune response. However, the presence of functionally-competent pDCs in slow progressors implies that the loss of pDCs early in infection may be critical to control of HIV infection through innate immune mechanisms, and may influence the progression of disease. PMID:20565289

  17. 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.

    PubMed

    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

  18. Piperidine derivatives as nonprostanoid IP receptor agonists.

    PubMed

    Hayashi, Ryoji; Sakagami, Hideki; Koiwa, Masakazu; Ito, Hiroaki; Miyamoto, Mitsuko; Isogaya, Masafumi

    2016-05-01

    The discovery of a new class of nonprostanoid prostaglandin I2 receptor (IP receptor) agonists is reported. Among them, the unique piperidine derivative 31b (2-((1-(2-(N-(4-tolyl)benzamido)ethyl)piperidin-4-yl)oxy)acetic acid) was a good IP receptor agonist and was 50-fold more selective for the human IP receptor than for other human prostanoid receptors. This compound showed good pharmacokinetic properties in dog. PMID:26996371

  19. Mycobacterium tuberculosis and TLR2 Agonists Inhibit Induction of Type I IFN and Class I MHC Antigen Cross Processing by TLR9

    PubMed Central

    Simmons, Daimon P.; Canaday, David H.; Liu, Yi; Li, Qing; Huang, Alex; Boom, W. Henry; Harding, Clifford V.

    2010-01-01

    Dendritic cells (DCs) cross process exogenous Ags and present them by class I MHC (MHC-I) molecules to CD8+ T cells specific for Ags from viruses and bacteria such as Mycobacterium tuberculosis. Unmethylated CpG DNA signals through TLR9 to induce type I IFN (IFN-α/β), which enhances MHC-I Ag cross processing, but lipoproteins that signal through TLR2 do not induce IFN-α/β. In these studies we observed that M. tuberculosis, which expresses agonists of both TLR9 and TLR2, did not induce production of IFN-α/β or cross processing by murine DCs. Furthermore, M. tuberculosis and TLR2 agonists inhibited induction of IFN-α/β and DC cross processing by CpG DNA. Exogenous IFN-α/β effectively enhanced cross processing of M. bovis bacillus Calmette-Guérin expressing OVA, bypassing the inhibition of induction of endogenous IFN-α/β. In addition, inhibition of TLR9-induced cross processing of M. bovis bacillus Calmette-Guérin expressing OVA could be circumvented by pretreating cells with CpG DNA to induce IFN-α/β and MHC-I cross processing before inhibitory mycobacterial TLR2 agonists were present. Inhibition of the response to one TLR by another may affect the ultimate response to pathogens like M. tuberculosis that express agonists of multiple TLRs, including TLR2 and TLR9. This mechanism may contribute to immune evasion and explain why IFN-α/β provides little contribution to host immunity to M. tuberculosis. However, downregulation of certain TLR responses may benefit the host by preventing detrimental excessive inflammation that may occur in the presence of persistent infection. PMID:20660347

  20. Neonatal Plasmacytoid Dendritic Cells (pDCs) Display Subset Variation but Can Elicit Potent Anti-Viral Innate Responses

    PubMed Central

    Zhang, Xiaoming; Lepelley, Alice; Azria, Elie; Lebon, Pierre; Roguet, Gwenaelle; Schwartz, Olivier; Launay, Odile; Leclerc, Claude; Lo-Man, Richard

    2013-01-01

    Neonates are highly susceptible to infectious diseases and defective antiviral pDC immune responses have been proposed to contribute to this phenomenon. Isolated cord blood pDCs innately responded to a variety of TLR7 and TLR9 dependent viruses, including influenza A virus (IAV), human immunodeficiency virus (HIV) or herpes-simplex virus (HSV) by efficiently producing IFN-α, TNF-α as well as chemokines. Interestingly, following activation by CpGA, but not viruses, cord pDCs tend to survive less efficiently. We found that a hallmark of pDCs in neonates is an extended CD2+pDCs compartment compared to adult pDCs without affecting the antiviral IFN-α response. Within CD2+pDCs, we identified a subpopulation expressing CD5 and responsible for IL-12p40 production, however this population is significantly decreased in cord blood compared to adult blood. Therefore, neonatal pDCs clearly display variation in phenotype and subset composition, but without major consequences for their antiviral responses. PMID:23326320

  1. MIF Promotes Classical Activation and Conversion of Inflammatory Ly6Chigh Monocytes into TipDCs during Murine Toxoplasmosis

    PubMed Central

    Ruiz-Rosado, Juan de Dios; Olguín, Jonadab E.; Juárez-Avelar, Imelda; Saavedra, Rafael; Terrazas, Luis I.; Robledo-Avila, Frank H.; Vazquez-Mendoza, Alicia; Fernández, Jacquelina; Satoskar, Abhay R.; Partida-Sánchez, Santiago; Rodriguez-Sosa, Miriam

    2016-01-01

    Macrophage migration inhibitory factor (MIF) mediates immunity against Toxoplasma gondii infection by inducing inflammatory cytokines required to control the parasite replication. However, the role of this inflammatory mediator in the cell-mediated immune response against this infection is still poorly understood. Here, we used T. gondii-infected WT and Mif−/− mice to analyze the role of MIF in the maturation of CD11b+ and CD8α+ dendritic cells (DCs). We found that MIF promotes maturation of CD11b+ but not CD8α+ DCs, by inducing IL-12p70 production and CD86 expression. Infected Mif−/− mice showed significantly lower numbers of TNF and inducible nitric oxide synthase- (iNOS-) producing DCs (TipDCs) compared to infected WT mice. The adoptive transfer of Ly6Chigh monocytes into infected WT or Mif−/− mice demonstrated that MIF participates in the differentiation of Ly6Chigh monocytes into TipDCs. In addition, infected Mif−/− mice display a lower percentage of IFN-γ-producing natural killer (NK) cells compared to WT mice, which is associated with reducing numbers of TipDCs in Mif−/− mice. Furthermore, administration of recombinant MIF (rMIF) into T. gondii-infected Mif−/− mice restored the numbers of TipDCs and reversed the susceptible phenotype of Mif−/− mice. Collectively, these results demonstrate an important role for MIF inducing cell-mediated immunity to T. gondii infection. PMID:27057101

  2. Maturation and upregulation of functions of murine dendritic cells (DCs) under the influence of purified Aromatic-Turmerone (AR)

    PubMed Central

    Yonggang, Tan; Yiming, Meng; Heying, Zhang; Cheng, Sun; Qiushi, Wang; Xianghong, Yang; Wei, Zheng; Huawei, Zhou; Shan, Fengping

    2012-01-01

    The aim of this work is to evaluate the effects of purified aromatic-turmerone(ar-turmerione, AR) on murine dendritic cells (DCs). These impacts of AR on DCs from bone marrow derived DCs(BMDCs) were assessed with use of conventional scanning electron microscopy (SEM), fluorescence activated cell sorting (FACS), transmission electron microscopy (TEM), cytochemistry assay, FITC-dextran, bio-assay and enzyme linked immunosorbent assay (ELISA). We found that AR induced phenotypic maturation as evidenced by increased expression of CD86, CD40, CD83, CD80 and major histocompatibility complex II (MHC II). The functional tests showed the activity of acidic phosphatase (ACP) inside the DCs were downregulated after treatment with AR (which occurs when phagocytosis of DCs were decreased). Finally, we proved that AR increased the production of IL-12 and tumor necrosis factor α (TNF-α). These data suggested that AR could promote phenotypic and functional maturation of DCs and this adjuvant-like activity may have potential therapeutic value. It is therefore concluded that AR could exert positive modulation on murine DCs. PMID:23095866

  3. Assessment of anodal and cathodal transcranial direct current stimulation (tDCS) on MMN-indexed auditory sensory processing.

    PubMed

    Impey, Danielle; de la Salle, Sara; Knott, Verner

    2016-06-01

    Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation which uses a very weak constant current to temporarily excite (anodal stimulation) or inhibit (cathodal stimulation) activity in the brain area of interest via small electrodes placed on the scalp. Currently, tDCS of the frontal cortex is being used as a tool to investigate cognition in healthy controls and to improve symptoms in neurological and psychiatric patients. tDCS has been found to facilitate cognitive performance on measures of attention, memory, and frontal-executive functions. Recently, a short session of anodal tDCS over the temporal lobe has been shown to increase auditory sensory processing as indexed by the Mismatch Negativity (MMN) event-related potential (ERP). This preliminary pilot study examined the separate and interacting effects of both anodal and cathodal tDCS on MMN-indexed auditory pitch discrimination. In a randomized, double blind design, the MMN was assessed before (baseline) and after tDCS (2mA, 20min) in 2 separate sessions, one involving 'sham' stimulation (the device is turned off), followed by anodal stimulation (to temporarily excite cortical activity locally), and one involving cathodal stimulation (to temporarily decrease cortical activity locally), followed by anodal stimulation. Results demonstrated that anodal tDCS over the temporal cortex increased MMN-indexed auditory detection of pitch deviance, and while cathodal tDCS decreased auditory discrimination in baseline-stratified groups, subsequent anodal stimulation did not significantly alter MMN amplitudes. These findings strengthen the position that tDCS effects on cognition extend to the neural processing of sensory input and raise the possibility that this neuromodulatory technique may be useful for investigating sensory processing deficits in clinical populations. PMID:27054908

  4. The Effects of tDCS Across the Spatial Frequencies and Orientations that Comprise the Contrast Sensitivity Function

    PubMed Central

    Richard, Bruno; Johnson, Aaron P.; Thompson, Benjamin; Hansen, Bruce C.

    2015-01-01

    Transcranial Direct Current Stimulation (tDCS) has recently been employed in traditional psychophysical paradigms in an effort to measure direct manipulations on spatial frequency channel operations in the early visual system. However, the effects of tDCS on contrast sensitivity have only been measured at a single spatial frequency and orientation. Since contrast sensitivity is known to depend on spatial frequency and orientation, we ask how the effects of anodal and cathodal tDCS may vary according to these dimensions. We measured contrast sensitivity with sinusoidal gratings at four different spatial frequencies (0.5, 4, 8, and 12 cycles/°), two orientations (45° Oblique and Horizontal), and for two stimulus size conditions [fixed size (3°) and fixed period (1.5 cycles)]. Only contrast sensitivity measured with a 45° oblique grating with a spatial frequency of 8 cycles/° (period = 1.5 cycles) demonstrated clear polarity specific effects of tDCS, whereby cathodal tDCS increased and anodal tDCS decreased contrast sensitivity. Overall, effects of tDCS were largest for oblique stimuli presented at high spatial frequencies (i.e., 8 and 12 cycles/°), and were small or absent at lower spatial frequencies, other orientations and stimulus size. Thus, the impact of tDCS on contrast sensitivity, and therefore on spatial frequency channel operations, is opposite in direction to other behavioral effects of tDCS, and only measurable in stimuli that generally elicit lower contrast sensitivity (e.g., oblique gratings with period of 1.5 cycles at spatial frequencies above the peak of the contrast sensitivity function). PMID:26640448

  5. Building up analgesia in humans via the endogenous μ-opioid system by combining placebo and active tDCS: a preliminary report.

    PubMed

    DosSantos, Marcos F; Martikainen, Ilkka K; Nascimento, Thiago D; Love, Tiffany M; DeBoer, Misty D; Schambra, Heidi M; Bikson, Marom; Zubieta, Jon-Kar; DaSilva, Alexandre F

    2014-01-01

    Transcranial Direct Current Stimulation (tDCS) is a method of non-invasive brain stimulation that has been frequently used in experimental and clinical pain studies. However, the molecular mechanisms underlying tDCS-mediated pain control, and most important its placebo component, are not completely established. In this pilot study, we investigated in vivo the involvement of the endogenous μ-opioid system in the global tDCS-analgesia experience. Nine healthy volunteers went through positron emission tomography (PET) scans with [11C]carfentanil, a selective μ-opioid receptor (MOR) radiotracer, to measure the central MOR activity during tDCS in vivo (non-displaceable binding potential, BPND)--one of the main analgesic mechanisms in the brain. Placebo and real anodal primary motor cortex (M1/2mA) tDCS were delivered sequentially for 20 minutes each during the PET scan. The initial placebo tDCS phase induced a decrease in MOR BPND in the periaqueductal gray matter (PAG), precuneus, and thalamus, indicating activation of endogenous μ-opioid neurotransmission, even before the active tDCS. The subsequent real tDCS also induced MOR activation in the PAG and precuneus, which were positively correlated to the changes observed with placebo tDCS. Nonetheless, real tDCS had an additional MOR activation in the left prefrontal cortex. Although significant changes in the MOR BPND occurred with both placebo and real tDCS, significant analgesic effects, measured by improvements in the heat and cold pain thresholds, were only observed after real tDCS, not the placebo tDCS. This study gives preliminary evidence that the analgesic effects reported with M1-tDCS, can be in part related to the recruitment of the same endogenous MOR mechanisms induced by placebo, and that such effects can be purposely optimized by real tDCS. PMID:25029273

  6. Spatial and polarity precision of concentric high-definition transcranial direct current stimulation (HD-tDCS).

    PubMed

    Alam, Mahtab; Truong, Dennis Q; Khadka, Niranjan; Bikson, Marom

    2016-06-21

    Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies low amplitude current via electrodes placed on the scalp. Rather than directly eliciting a neuronal response, tDCS is believed to modulate excitability-enhancing or suppressing neuronal activity in regions of the brain depending on the polarity of stimulation. The specificity of tDCS to any therapeutic application derives in part from how electrode configuration determines the brain regions that are stimulated. Conventional tDCS uses two relatively large pads (>25 cm(2)) whereas high-definition tDCS (HD-tDCS) uses arrays of smaller electrodes to enhance brain targeting. The 4  ×  1 concentric ring HD-tDCS (one center electrode surrounded by four returns) has been explored in application where focal targeting of cortex is desired. Here, we considered optimization of concentric ring HD-tDCS for targeting: the role of electrodes in the ring and the ring's diameter. Finite element models predicted cortical electric field generated during tDCS. High resolution MRIs were segmented into seven tissue/material masks of varying conductivities. Computer aided design (CAD) model of electrodes, gel, and sponge pads were incorporated into the segmentation. Volume meshes were generated and the Laplace equation ([Formula: see text] · (σ [Formula: see text] V)  =  0) was solved for cortical electric field, which was interpreted using physiological assumptions to correlate with stimulation and modulation. Cortical field intensity was predicted to increase with increasing ring diameter at the cost of focality while uni-directionality decreased. Additional surrounding ring electrodes increased uni-directionality while lowering cortical field intensity and increasing focality; though, this effect saturated and more than 4 surround electrode would not be justified. Using a range of concentric HD-tDCS montages, we showed that cortical region of influence can be

  7. Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using Toll-like receptor 7 agonist imiquimod as vaccine adjuvant

    PubMed Central

    Adams, Sylvia; O'Neill, David W.; Nonaka, Daisuke; Hardin, Elizabeth; Chiriboga, Luis; Siu, Kimberly; Cruz, Crystal M.; Angiulli, Angelica; Angiulli, Francesca; Ritter, Erika; Holman, Rose Marie; Shapiro, Richard L.; Berman, Russell S.; Berner, Natalie; Shao, Yongzhao; Manches, Olivier; Pan, Linda; Venhaus, Ralph R.; Hoffman, Eric W.; Jungbluth, Achim; Gnjatic, Sacha; Old, Lloyd; Pavlick, Anna C.; Bhardwaj, Nina

    2008-01-01

    T cell-mediated immunity to microbes and to cancer can be enhanced by the activation of dendritic cells (DCs) via Toll-like receptors (TLRs). In this study, we evaluated the safety and feasibility of topical imiquimod, a TLR7 agonist, in a series of vaccinations (26) proteins,(27) and DNA, (28, 29) as well as in vaccines using recombinant Listeria(30) or DCs.(31) In humans, it was shown that topical imiquimod treatment may enhance the immunogenicity of a melanoma peptide vaccine when given with systemic FLT3 ligand. (32) In addition, injection of immature DCs into imiquimod pretreated skin lead to DC activation in situ and enhanced migratory capacity to draining lymph nodes in cancer patients. (33) In this study, we test the safety and feasibility of imiquimod in a vaccine against the cancer/testis antigen NY-ESO-1, and evaluate the immunogenicity of the combination. NY-ESO-1 is detectable in approximately 30% of metastatic melanomas. (34-36) It is against the cancer/testis antigen NY-ESO-1 in patients with malignant melanoma. Recombinant, full-length NY-ESO-1 protein was administered intradermally into imiquimod pre-conditioned sites followed by additional topical applications of imiquimod. The regimen was very well-tolerated with only mild and transient local reactions and constitutional symptoms. Secondarily, we examined the systemic immune response induced by the imiquimod/NY-ESO-1 combination, and show that it elicited both humoral and cellular responses in a significant fraction of patients. Skin biopsies were assessed for imiquimod's in situ immunomodulatory effects. Compared with untreated skin, topical imiquimod induced dermal mononuclear cell infiltrates in all patients composed primarily of T cells, monocytes, macrophages, myeloid DCs and natural killer (NK) cells, and to a lesser extent plasmacytoid DCs. DC activation was evident. This study demonstrates the feasibility and excellent safety profile of a topically applied TLR7 agonist utilized as a

  8. Cyclophosphamide and IL-12-transduced DCs enhance the antitumor activity of tumor antigen-stimulated DCs and reduce Tregs and MDSCs number.

    PubMed

    Rossowska, Joanna; Pajtasz-Piasecka, Elżbieta; Anger, Natalia; Wojas-Turek, Justyna; Kicielińska, Jagoda; Piasecki, Egbert; Duś, Danuta

    2014-01-01

    A hostile tumor microenvironment, characterized by an abundance of T regulatory cells and myeloid-derived suppressor cells (MDSCs), considerably limits the efficacy of dendritic cell (DC)-based vaccines. The intention of this study was to enhance the antitumor activity of vaccines consisting of bone marrow-derived DCs stimulated with TAg (BMDC/TAg) via single administration of cyclophosphamide and multiple injections of interleukin (IL)-12-transduced DCs (BMDC/IL-12). The combined chemoimmunotherapy was applied in the treatment of mice with subcutaneously (SC) growing, advanced MC38 colon carcinoma. The highest level of tumor growth inhibition, accompanied by high cytotoxic activity of effector cells, and their increased influx into tumor tissue, was observed after application of cyclophosphamide in combination with BMDC/TAg and BMDC/IL-12. The effect was probably associated with the elimination of T regulatory cells from spleens and tumors, but most of all with changes in the number and differentiation stage of MDSCs. After the therapy, the percentage of granulocytic and monocytic MDSCs in spleens was significantly lower than in the control group. Moreover, MDSCs derived from spleens and tumors showed increased expression of MHC class II, which may indicate the higher maturation stage of the myeloid cells as well as their enhanced capacity toward antigen presentation. The obtained data indicate that the optimal composition of antitumor vaccines able to limit the suppressor activity of MDSCs is essential to enhance the elimination of tumor cells and to achieve an optimal therapeutic effect. PMID:25304726

  9. [Treatment of posttraumatic stress disorder and extinction learning of traumatic memory].

    PubMed

    Asukai, Nozomu

    2013-06-01

    Posttraumatic stress disorder (PTSD) is a debilitating psychological condition that develops following exposure to a traumatic event. The characteristic symptoms of PTSD are re-experience, avoidance, psychic numbing and hyper-arousal. The biological PTSD literature has been dramatically growing over the past three decades. PTSD symptoms related to re-experiencing the traumatic event may be conceptualized within a fear conditioning framework. Recent findings suggest that PTSD is associated with a failure of extinction learning of an acquired fear response. A fear-circuit model of PTSD posits that vmPFC fails to inhibit the amygdala, which has a crucial role in fear learning. Exposure therapy currently has the largest number of randomized clinical trials demonstrating its efficacy, and is recommended with substantial clinical confidence in treatment guidelines for PTSD. The efficacy of Prolonged Exposure (PE) was also shown for Japanese PTSD patients in a randomized controlled trial (Asukai et al., 2010). The emotional processing theory that accounts for the treatment mechanism of PE may be consistent with the hypothesis of a neurobiological mechanism in PTSD. D-cycloserine (DCS), an NMDA partial agonist, has been shown to facilitate extinction learning in animals and humans. Clinically, DCS has been shown to be a promising augmentation to PE, particularly for those who need longer treatment. PMID:25069244

  10. Effect of tDCS on task relevant and irrelevant perceptual learning of complex objects.

    PubMed

    Van Meel, Chayenne; Daniels, Nicky; de Beeck, Hans Op; Baeck, Annelies

    2016-01-01

    During perceptual learning the visual representations in the brain are altered, but these changes' causal role has not yet been fully characterized. We used transcranial direct current stimulation (tDCS) to investigate the role of higher visual regions in lateral occipital cortex (LO) in perceptual learning with complex objects. We also investigated whether object learning is dependent on the relevance of the objects for the learning task. Participants were trained in two tasks: object recognition using a backward masking paradigm and an orientation judgment task. During both tasks, an object with a red line on top of it were presented in each trial. The crucial difference between both tasks was the relevance of the object: the object was relevant for the object recognition task, but not for the orientation judgment task. During training, half of the participants received anodal tDCS stimulation targeted at the lateral occipital cortex (LO). Afterwards, participants were tested on how well they recognized the trained objects, the irrelevant objects presented during the orientation judgment task and a set of completely new objects. Participants stimulated with tDCS during training showed larger improvements of performance compared to participants in the sham condition. No learning effect was found for the objects presented during the orientation judgment task. To conclude, this study suggests a causal role of LO in relevant object learning, but given the rather low spatial resolution of tDCS, more research on the specificity of this effect is needed. Further, mere exposure is not sufficient to train object recognition in our paradigm. PMID:27096945

  11. Effects of Transcranial Direct Current Stimulation (tDCS) on Human Memory.

    SciTech Connect

    Matzen, Laura E.; Trumbo, Michael Christopher Stefan

    2014-10-01

    Training a person in a new knowledge base or skill set is extremely time consuming and costly, particularly in highly specialized domains such as the military and the intelligence community. Recent research in cognitive neuroscience has suggested that a technique called transcranial direct current stimulation (tDCS) has the potential to revolutionize training by enabling learners to acquire new skills faster, more efficiently, and more robustly (Bullard et al., 2011). In this project, we tested the effects of tDCS on two types of memory performance that are critical for learning new skills: associative memory and working memory. Associative memory is memory for the relationship between two items or events. It forms the foundation of all episodic memories, so enhancing associative memory could provide substantial benefits to the speed and robustness of learning new information. We tested the effects of tDCS on associative memory, using a real-world associative memory task: remembering the links between faces and names. Working memory refers to the amount of information that can be held in mind and processed at one time, and it forms the basis for all higher-level cognitive processing. We investigated the degree of transfer between various working memory tasks (the N-back task as a measure of verbal working memory, the rotation-span task as a measure of visuospatial working memory, and Raven's progressive matrices as a measure of fluid intelligence) in order to determine if tDCS-induced facilitation of performance is task-specific or general.

  12. Differential influences of unilateral tDCS over the intraparietal cortex on numerical cognition

    PubMed Central

    Artemenko, Christina; Moeller, Korbinian; Huber, Stefan; Klein, Elise

    2015-01-01

    Recent neuro-imaging research identified the bilateral intraparietal sulcus (IPS) to be a key area associated with number processing. However, causal structure-function relationships are hard to evaluate from neuro-imaging techniques such as fMRI. Nevertheless, brain stimulation methods like transcranial direct current stimulation (tDCS) allow for investigating the functional relevance of the IPS for number processing. Following up on a study using bilateral bi-cephalic tDCS over the IPS, the current study aimed at evaluating the differential lateralized functional contributions of the left and right IPS to number processing using unilateral bi-cephalic tDCS over either the left or right IPS. Results indicated a right lateralization for the processing of the place-value structure of the Arabic number system. Importantly, the processing of number magnitude information was not affected by unilateral IPS corroborating the assumption that number magnitude is processed in the bilateral IPS. Taken together, these data suggest that even though number magnitude is represented bilaterally, the left and right IPS seem to contribute differentially to numerical cognition with respect to the processing of specific other aspects of numerical information. PMID:25798099

  13. "Unfocus" on foc.us: commercial tDCS headset impairs working memory.

    PubMed

    Steenbergen, Laura; Sellaro, Roberta; Hommel, Bernhard; Lindenberger, Ulman; Kühn, Simone; Colzato, Lorenza S

    2016-03-01

    In this study, we tested whether the commercial transcranial direct current stimulation (tDCS) headset foc.us improves cognitive performance, as advertised in the media. A single-blind, sham-controlled, within-subject design was used to assess the effect of online and off-line foc.us tDCS-applied over the prefrontal cortex in healthy young volunteers (n = 24) on working memory (WM) updating and monitoring. WM updating and monitoring, as assessed by means of the N-back task, is a cognitive-control process that has been shown to benefit from interventions with CE-certified tDCS devices. For both online and off-line stimulation protocols, results showed that active stimulation with foc.us, compared to sham stimulation, significantly decreased accuracy performance in a well-established task tapping WM updating and monitoring. These results provide evidence for the important role of the scientific community in validating and testing far-reaching claims made by the brain training industry. PMID:26280313

  14. Incidence of DCS and oxygen toxicity in chamber attendants: a 28-year experience.

    PubMed

    Witucki, Pete; Duchnick, Jay; Neuman, Tom; Grover, Ian

    2013-01-01

    Decompression sickness (DCS) and central nervous system oxygen toxicity are inherent risks for "inside" attendants (IAs) of hyperbaric chambers. At the Hyperbaric Medicine Center at the University of California San Diego (UCSD), protocols have been developed for decompressing IAs. Protocol 1: For a total bottom time (TBT) of less than 80 minutes at 2.4 atmospheres absolute (atm abs) or shallower, the U.S. Navy (1955) no-decompression tables were utilized. Protocol 2: For a TBT between 80 and 119 minutes IAs breathed oxygen for 15 minutes prior to initiation of ascent. Protocol 3: For a TBT between 120-139 minutes IAs breathed oxygen for 30 minutes prior to ascent. These protocols have been utilized for approximately 28 years and have produced zero cases of DCS and central nervous system oxygen toxicity. These results, based upon more than 24,000 exposures, have an upper limit of risk of DCS and oxygen toxicity of 0.02806 (95% CI) using UCSD IA decompression Protocol 1, 0.00021 for Protocol 2, and 0.00549 for Protocol 3. We conclude that the utilization of this methodology may be useful at other sea-level multiplace chambers. PMID:23957205

  15. CD1c-Related DCs that Express CD207/Langerin, but Are Distinguishable from Langerhans Cells, Are Consistently Present in Human Tonsils

    PubMed Central

    De Monte, Anne; Olivieri, Charles-Vivien; Vitale, Sébastien; Bailleux, Sonanda; Castillo, Laurent; Giordanengo, Valérie; Maryanski, Janet L.; Segura, Elodie; Doglio, Alain

    2016-01-01

    Several subsets of dendritic cells (DCs) are present in the oropharyngeal tonsillar tissues and are thought to behave as major actors in development and regulation of immunity by acting as a first line of recognition for airborne and alimentary antigens. We previously discovered in human adult tonsils infected with Epstein–Barr virus (EBV), a subset of DCs that expressed langerin/CD207, a lectin usually recognized as a hallmark of epidermal Langerhans cells (LCs). In the present study, we analyzed the content of several child and adult tonsils in order to characterize in more detail the phenotype of these tonsillar CD207-expressing DCs (tCD207 DCs) and to compare it with that of other human DC subsets. We showed that all the human tonsils studied (n = 12) contained significant proportions of tCD207 DCs among tonsillar cells expressing HLA-DR. Moreover, the presence of tCD207 DCs in tonsils from young children free of EBV infection indicated that these cells could be established early in the tonsil independently of EBV infection. We also showed that tCD207 DCs, that were found mainly located within the tonsillar lymphoid stroma, were distinguishable from LCs by the level of expression of CD1a and EpCAM, and also from human inflammatory DCs by the lack of CD1a, CD206, and CD14 expression. Detailed analysis of cell surface DC markers showed that tCD207 DCs were unrelated to CD141+ DCs or macrophages, but defined a subtype of tonsillar DCs closely related to myeloid resident CD1c DCs. Since it was established that blood CD1c myeloid DCs exhibit plasticity and are capable of expressing CD207 notably in the presence of inflammatory cytokines, it is tempting to speculate that CD207+ CD1c+ DCs may play a specific immune role. PMID:27252701

  16. Finite-Element Model Predicts Current Density Distribution for Clinical Applications of tDCS and tACS.

    PubMed

    Neuling, Toralf; Wagner, Sven; Wolters, Carsten H; Zaehle, Tino; Herrmann, Christoph S

    2012-01-01

    Transcranial direct current stimulation (tDCS) has been applied in numerous scientific studies over the past decade. However, the possibility to apply tDCS in therapy of neuropsychiatric disorders is still debated. While transcranial magnetic stimulation (TMS) has been approved for treatment of major depression in the United States by the Food and Drug Administration (FDA), tDCS is not as widely accepted. One of the criticisms against tDCS is the lack of spatial specificity. Focality is limited by the electrode size (35 cm(2) are commonly used) and the bipolar arrangement. However, a current flow through the head directly from anode to cathode is an outdated view. Finite-element (FE) models have recently been used to predict the exact current flow during tDCS. These simulations have demonstrated that the current flow depends on tissue shape and conductivity. To face the challenge to predict the location, magnitude, and direction of the current flow induced by tDCS and transcranial alternating current stimulation (tACS), we used a refined realistic FE modeling approach. With respect to the literature on clinical tDCS and tACS, we analyzed two common setups for the location of the stimulation electrodes which target the frontal lobe and the occipital lobe, respectively. We compared lateral and medial electrode configuration with regard to their usability. We were able to demonstrate that the lateral configurations yielded more focused stimulation areas as well as higher current intensities in the target areas. The high resolution of our simulation allows one to combine the modeled current flow with the knowledge of neuronal orientation to predict the consequences of tDCS and tACS. Our results not only offer a basis for a deeper understanding of the stimulation sites currently in use for clinical applications but also offer a better interpretation of observed effects. PMID:23015792

  17. beta2-Agonists at the Olympic Games.

    PubMed

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  18. Proposal of DCS-OFDM-PON upstream transmission with intensity modulator and collective self-coherent detection

    NASA Astrophysics Data System (ADS)

    Zhang, Jing; Yang, Heming; Zhao, Difu; Qiu, Kun

    2016-07-01

    We introduce digital coherent superposition (DCS) into optical access network and propose a DCS-OFDM-PON upstream transmission scheme using intensity modulator and collective self-coherent detection. The generated OFDM signal is real based on Hermitian symmetry, which can be used to estimate the common phase error (CPE) by complex conjugate subcarrier pairs without any pilots. In simulation, we transmit an aggregated 40 Gb/s optical OFDM signal from two ONUs. The transmission performance with DCS is slightly better after 25 km transmission without relative transmission time delay. The fiber distance for different ONUs to RN are not same in general and there is relative transmission time delay between ONUs, which causes inter-carrier-interference (ICI) power increasing and degrades the transmission performance. The DCS can mitigate the ICI power and the DCS-OFDM-PON upstream transmission outperforms the conventional OFDM-PON. The CPE estimation is by using two pairs of complex conjugate subcarriers without redundancy. The power variation can be 9 dB in DCS-OFDM-PON, which is enough to tolerate several kilometers fiber length difference between the ONUs.

  19. Synergistic production of TNFα and IFNα by human pDCs incubated with IFNλ3 and IL-3.

    PubMed

    Finotti, Giulia; Tamassia, Nicola; Cassatella, Marco A

    2016-10-01

    In this study, we investigated whether IFNλ3 and IL-3 reciprocally influence their capacity to activate various functions of human plasmacytoid dendritic cells (pDCs). In fact, we preliminarily observed that IFNλ3 upregulates the expression of the IL-3Rα (CD123), while IL-3 augments the expression of IFNλR1 in pDCs. As a result, we found that combination of IFNλ3 and IL-3 induces a strong potentiation in the production of TNFα, IFNα, as well as in the expression of Interferon-Stimulated Gene (ISG) mRNAs by pDCs, as compared to either IFNλ3 or IL-3 alone. In such regard, we found that endogenous IFNα autocrinally promotes the expression of ISG mRNAs in IL-3-, but not in IFNλ3 plus IL-3-, treated pDCs. Moreover, we uncovered that the production of IFNα by IFNλ3 plus IL-3-treated pDCs is mostly dependent on endogenously produced TNFα. Altogether, our data demonstrate that IFNλ3 and IL-3 collaborate to promote, at maximal levels, discrete functional responses of human pDCs. PMID:27513213

  20. Introduction of a single isomer beta agonist.

    PubMed

    Rau, J L

    2000-08-01

    The release of levalbuterol offers the first approved single-isomer beta agonist for oral inhalation. Data from in vitro studies support the concept that S albuterol is not inactive and may have properties antagonistic to bronchodilation. There is some variability in the results of clinical studies with the separate isomers of albuterol, which suggests the need for further study. The introduction of levalbuterol into general clinical use in managing asthma and chronic obstructive disease should begin to offer additional information on the effects of a single isomer beta agonist in comparison to previous racemic mixtures. PMID:10963321

  1. HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates

    NASA Astrophysics Data System (ADS)

    Wille-Reece, Ulrike; Flynn, Barbara J.; Loré, Karin; Koup, Richard A.; Kedl, Ross M.; Mattapallil, Joseph J.; Weiss, Walter R.; Roederer, Mario; Seder, Robert A.

    2005-10-01

    Induction and maintenance of antibody and T cell responses will be critical for developing a successful vaccine against HIV. A rational approach for generating such responses is to design vaccines or adjuvants that have the capacity to activate specific antigen-presenting cells. In this regard, dendritic cells (DCs) are the most potent antigen-presenting cells for generating primary T cell responses. Here, we report that Toll-like receptor (TLR) agonists and ligands that activate DCs in vitro influence the magnitude and quality of the cellular immune response in nonhuman primates (NHPs) when administered with HIV Gag protein. NHPs immunized with HIV Gag protein and a TLR7/8 agonist or a TLR9 ligand [CpG oligodeoxynucleotides (CpG ODN)] had significantly increased Gag-specific T helper 1 and antibody responses, compared with animals immunized with HIV Gag protein alone. Importantly, conjugating the HIV Gag protein to the TLR7/8 agonist (Gag-TLR7/8 conjugate) dramatically enhanced the magnitude and altered the quality of the T helper 1 response, compared with animals immunized with HIV Gag protein and the TLR7/8 agonist or CpG ODN. Furthermore, immunization with the Gag-TLR7/8 conjugate vaccine elicited Gag-specific CD8+ T responses. Collectively, our results show that conjugating HIV Gag protein to a TLR7/8 agonist is an effective way to elicit broad-based adaptive immunity in NHPs. This type of vaccine formulation should have utility in preventive or therapeutic vaccines in which humoral and cellular immunity is required. vaccine | dendritic cell | cross-presentation | cellular immunity

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

    PubMed

    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-methyi-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-cycloserine as an adjunct to psychotherapy in patients with so-called simple phobias (fear of heights), social phobia, obsessive-compulsive behavior, and panic disorder. Data in support of these conclusions are reviewed, along with some of the possible limitations of D-cycloserine as an adjunct to psychotherapy. PMID:22275851

  3. Rapid reconstitution of functionally active 6-sulfoLacNAc+ dendritic cells (slanDCs) of donor origin following allogeneic haematopoietic stem cell transplant

    PubMed Central

    Mimiola, E; Marini, O; Perbellini, O; Micheletti, A; Vermi, W; Lonardi, S; Costantini, C; Meneghelli, E; Andreini, A; Bonetto, C; Vassanelli, A; Cantini, M; Zoratti, E; Massi, D; Zamo', A; Leso, A; Quaresmini, G; Benedetti, F; Pizzolo, G; Cassatella, M A; Tecchio, C

    2014-01-01

    The role of dendritic cells (DCs) and macrophages in allogeneic haematopoietic stem cell transplant (HSCT) is critical in determining the extent of graft-versus-host response. The goal of this study was to analyse slanDCs, a subset of human proinflammatory DCs, in haematopoietic stem cell (HSC) sources, as well as to evaluate their 1-year kinetics of reconstitution, origin and functional capacities in peripheral blood (PB) and bone marrow (BM) of patients who have undergone HSCT, and their presence in graft-versus-host disease (GVHD) tissue specimens. slanDCs were also compared to myeloid (m)DCs, plasmacytoid (p)DCs and monocytes in HSC sources and in patients' PB and BM throughout reconstitution. slanDCs accounted for all HSC sources. In patients' PB and BM, slanDCs were identified from day +21, showing median frequencies comparable to healthy donors, donor origin and kinetics of recovery similar to mDCs, pDCs, and monocytes. Under cyclosporin treatment, slanDCs displayed a normal pattern of maturation, and maintained an efficient chemotactic activity and capacity of releasing tumour necrosis factor (TNF)-α upon lipopolysaccharide (LPS) stimulation. None the less, they were almost undetectable in GVHD tissue specimens, being present only in intestinal acute GVHD samples. slanDCs reconstitute early, being donor-derived and functionally competent. The absence of slanDCs from most of the GVHD-targeted tissue specimens seems to rule out the direct participation of these cells in the majority of the local reactions characterizing GVHD. PMID:24853271

  4. Reciprocity of agonistic support in ravens

    PubMed Central

    Fraser, Orlaith N.; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim’s likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  5. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  6. Small molecule TSHR agonists and antagonists.

    PubMed

    Neumann, S; Gershengorn, M C

    2011-04-01

    TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule "drug-like" ligands. Recombinant human TSH (rhTSH, Thyrogen(®)) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential. PMID:21511239

  7. Reciprocity of agonistic support in ravens.

    PubMed

    Fraser, Orlaith N; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  8. Induction of innate immune signatures following polyepitope protein-glycoprotein B-TLR4&9 agonist immunization generates multifunctional CMV-specific cellular and humoral immunity

    PubMed Central

    Dasari, Vijayendra; Smith, Corey; Schuessler, Andrea; Zhong, Jie; Khanna, Rajiv

    2014-01-01

    Recent studies have suggested that a successful subunit human cytomegalovirus (CMV) vaccine requires improved formulation to generate broad-based anti-viral immunity following immunization. Here we report the development of a non-live protein-based vaccine strategy for CMV based on a polyepitope protein and CMV glycoprotein B (gB) adjuvanted with TLR4 and/or TLR9 agonists. The polyepitope protein includes contiguous multiple MHC class I-restricted epitopes with an aim to induce CD8+ T cell immunity, while gB is an important target for CD4+ T cell immunity and neutralizing antibodies. Optimal immunogenicity of this bivalent non-live protein vaccine formulation was dependent upon the co-administration of both the TLR4 and TLR9 agonist, which was associated with the activation of innate immune signatures and the influx of different DC subsets including plasmacytoid DCs and migratory CD8-DEC205+CD103-CD326- langerin-negative dermal DCs into the draining lymph nodes. Furthermore these professional antigen presenting cells also expressed IL-6, IL-12p70, TNFα, and IFNα which play a crucial role in the activation of adaptive immunity. In summary, this study provides a novel platform technology in which broad-based anti-CMV immune responses upon vaccination can be maximized by co-delivery of viral antigens and TLR4 and 9 agonists which induce activation of innate immune signatures and promote potent antigen acquisition and cross-presentation by multiple DC subsets. PMID:24463331

  9. Improved picture naming in aphasia patients treated with cathodal tDCS to inhibit the right Broca's homologue area

    PubMed Central

    Kang, Eun Kyoung; Kim, Yu Kyeong; Sohn, Hae Min; Cohen, Leonardo G.; Paik, Nam-Jong

    2016-01-01

    PURPOSE Previous reports have suggested that noninvasive cortical stimulation could influence speech production in patients with chronic stroke. Here, we evaluated the hypothesis that cathodal transcranial DC stimulation (ctDCS), a technique that decreases excitability of stimulated cortical sites, applied over a healthy right Broca's homologue area could improve picture naming in patients with post-stroke aphasia. METHODS Ten right-handed patients with post-stroke aphasia were enrolled in this double blind, counterbalanced sham-controlled, crossover study. Each patient received an intervention of ctDCS (2 mA for 20 min) and of sham tDCS (2 mA for 1 min) daily for 5 consecutive days in a randomized crossover manner with a minimum interval of one week between interventions, over a healthy right Broca's homologue area using a left supraorbital anode and simultaneous daily sessions of conventional word-retrieval training. The primary endpoint measure of this study was a standardized, validated Korean version of the Boston Naming Test, which is a measure of picture naming skills. RESULTS ctDCS was not found to have any adverse effects. Furthermore, significantly improved picture naming (p=0.02) was observed at 1 hour following the last (5th) ctDCS treatment session, but no changes were observed after sham tDCS. CONCLUSION These results demonstrate that cathodal tDCS over the right healthy Broca's homologue area with a left supraorbital anodal location can improve picture naming task performance in post-stroke aphasia. PMID:21586821

  10. Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease.

    PubMed

    Grimaldi, Giuliana; Argyropoulos, Georgios P; Bastian, Amy; Cortes, Mar; Davis, Nicholas J; Edwards, Dylan J; Ferrucci, Roberta; Fregni, Felipe; Galea, Joseph M; Hamada, Masahi; Manto, Mario; Miall, R Chris; Morales-Quezada, Leon; Pope, Paul A; Priori, Alberto; Rothwell, John; Tomlinson, S Paul; Celnik, Pablo

    2016-02-01

    The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar-motor cortex connectivity, likely via cerebellar-thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions. PMID:25406224

  11. Electric fields of motor and frontal tDCS in a standard brain space: A computer simulation study.

    PubMed

    Laakso, Ilkka; Tanaka, Satoshi; Mikkonen, Marko; Koyama, Soichiro; Sadato, Norihiro; Hirata, Akimasa

    2016-08-15

    The electric field produced in the brain is the main physical agent of transcranial direct current stimulation (tDCS). Inter-subject variations in the electric fields may help to explain the variability in the effects of tDCS. Here, we use multiple-subject analysis to study the strength and variability of the group-level electric fields in the standard brain space. Personalized anatomically-accurate models of 62 subjects were constructed from T1- and T2-weighted MRI. The finite-element method was used to computationally estimate the individual electric fields, which were registered to the standard space using surface based registration. Motor cortical and frontal tDCS were modelled for 16 electrode montages. For each electrode montage, the group-level electric fields had a consistent strength and direction in several brain regions, which could also be located at some distance from the electrodes. In other regions, the electric fields were more variable, and thus more likely to produce variable effects in each individual. Both the anode and cathode locations affected the group-level electric fields, both directly under the electrodes and elsewhere. For motor cortical tDCS, the electric fields could be controlled at the group level by moving the electrodes. However, for frontal tDCS, the group-level electric fields were more variable, and the electrode locations had only minor effects on the group average fields. Our results reveal the electric fields and their variability at the group level in the standard brain space, providing insights into the mechanisms of tDCS for plasticity induction. The data are useful for planning, analysing and interpreting tDCS studies. PMID:27188218

  12. Transcranial direct current stimulation (tDCS) reduces the cost of performing a cognitive task on gait and postural control

    PubMed Central

    Zhou, Junhong; Hao, Ying; Wang, Ye; Jor’dan, Azizah; Pascual-Leone, Alvaro; Zhang, Jue; Fang, Jing; Manor, Brad

    2014-01-01

    This proof-of-concept, double-blind study is designed to determine the effects of transcranial direct current stimulation (tDCS) on the “cost” of performing a secondary cognitive task on gait and postural control in healthy young adults. Twenty adults aged 22±2yrs completed two separate double-blind visits in which gait and postural control were assessed immediately before and after a 20-minute session of either real or sham tDCS (1.5 mA) targeting the left dorsolateral prefrontal cortex. Gait speed and stride duration variability, along with standing postural sway speed and area, were recorded under normal conditions and while simultaneously performing a serial-subtraction cognitive task. Dual task cost was calculated as the percent change in each outcome from normal to dual task conditions. tDCS was well-tolerated by all subjects. Stimulation did not alter gait or postural control under normal conditions. As compared to sham stimulation, real tDCS led to increased gait speed (p=0.006), as well as decreased standing postural sway speed (p=0.01) and area (p=0.01), when performing serial-subtraction task. Real tDCS also diminished (p<0.01) the dual task cost on each of these outcomes. No effects of tDCS were observed for stride duration variability. A single session of tDCS targeting the left dorsolateral prefrontal cortex improved the ability to adapt one’s gait and postural control to a concurrent cognitive task and reduced the cost normally associated with such dual tasking. These results highlight the involvement of cortical brain networks in gait and posture control, and implicate the modulation of prefrontal cortical excitability as a potential therapeutic intervention. PMID:24443958

  13. [Pronostic value of the immunohistochemical expression of cyclin D1 (DCS6) in epidermoid larynx carcinoma].

    PubMed

    García Lozano, M C; Orradre Romero, J L; Sánchez Carrión, S; Caro Garcia, M; Lasso Luis, O; Piris Pinilla, M A

    2006-01-01

    In this paper we carried out an immunohistochemical study of cyclin D1 (DCS6 ) expression in a series of 195 patients with laryngeal carcinoma that were diagnosticated, treated and followed at the Department of Otolaryngology at "Virgen de la Salud" Hospital (Toledo, Spain) for a time of 5 years. In the cases with lymph node metastasis we also studied cyclin D1 expression at this level. Furthermore we have analysed the value of cyclin D1 expression as a prognostic factor (tumor recurrence, deads due to cancer and survival) and we evaluate the relationship between cyclin D1 expression and other clinic and pathologic parameters. PMID:16881553

  14. Immediate effects of tDCS on the μ-opioid system of a chronic pain patient.

    PubMed

    DosSantos, Marcos Fabio; Love, Tiffany M; Martikainen, Ilkka Kristian; Nascimento, Thiago Dias; Fregni, Felipe; Cummiford, Chelsea; Deboer, Misty Dawn; Zubieta, Jon-Kar; Dasilva, Alexandre F M

    2012-01-01

    We developed a unique protocol where transcranial direct current stimulation (tDCS) of the motor cortex is performed during positron emission tomography (PET) scan using a μ-opioid receptor (μOR) selective radiotracer, [(11)C]carfentanil. This is one of the most important central neuromechanisms associated with pain perception and regulation. We measured μOR non-displaceable binding potential (μOR BP(ND)) in a trigeminal neuropathic pain patient (TNP) without creating artifacts, or posing risks to the patient (e.g., monitoring of resistance). The active session directly improved in 36.2% the threshold for experimental cold pain in the trigeminal allodynic area, mandibular branch, but not the TNP patient's clinical pain. Interestingly, the single active tDCS application considerably decreased μORBP(ND) levels in (sub)cortical pain-matrix structures compared to sham tDCS, especially in the posterior thalamus. Suggesting that the μ-opioidergic effects of a single tDCS session are subclinical at immediate level, and repetitive sessions are necessary to revert ingrained neuroplastic changes related to the chronic pain. To our knowledge, we provide data for the first time in vivo that there is possibly an instant increase of endogenous μ-opioid release during acute motor cortex neuromodulation with tDCS. PMID:23130002

  15. Emotional Distraction and Bodily Reaction: Modulation of Autonomous Responses by Anodal tDCS to the Prefrontal Cortex

    PubMed Central

    Schroeder, Philipp A.; Ehlis, Ann-Christine; Wolkenstein, Larissa; Fallgatter, Andreas J.; Plewnia, Christian

    2015-01-01

    Prefrontal electric stimulation has been demonstrated to effectively modulate cognitive processing. Specifically, the amelioration of cognitive control (CC) over emotional distraction by transcranial direct current stimulation (tDCS) points toward targeted therapeutic applications in various psychiatric disorders. In addition to behavioral measures, autonomous nervous system (ANS) responses are fundamental bodily signatures of emotional information processing. However, interactions between the modulation of CC by tDCS and ANS responses have received limited attention. We here report on ANS data gathered in healthy subjects that performed an emotional CC task parallel to the modulation of left prefrontal cortical activity by 1 mA anodal or sham tDCS. Skin conductance responses (SCRs) to negative and neutral pictures of human scenes were reduced by anodal as compared to sham tDCS. Individual SCR amplitude variations were associated with the amount of distraction. Moreover, the stimulation-driven performance- and SCR-modulations were related in form of a quadratic, inverse-U function. Thus, our results indicate that non-invasive brain stimulation (i.e., anodal tDCS) can modulate autonomous responses synchronous to behavioral improvements, but the range of possible concurrent improvements from prefrontal stimulation is limited. Interactions between cognitive, affective, neurophysiological, and vegetative responses to emotional content can shape brain stimulation effectiveness and require theory-driven integration in potential treatment protocols. PMID:26733808

  16. Differential roles of migratory and resident DCs in T cell priming after mucosal or skin HSV-1 infection

    PubMed Central

    Lee, Heung Kyu; Zamora, Melodie; Linehan, Melissa M.; Iijima, Norifumi; Gonzalez, David; Haberman, Ann

    2009-01-01

    Although mucosal surfaces represent the main portal of entry for pathogens, the mechanism of antigen presentation by dendritic cells (DCs) that patrol various mucosal tissues remains unclear. Instead, much effort has focused on the understanding of initiation of immune responses generated against antigens delivered by injection. We examined the contributions of migratory versus lymph node–resident DC populations in antigen presentation to CD4 and CD8 T cells after needle injection, epicutaneous infection, or vaginal mucosal herpes simplex virus (HSV) 1 infection. We show that upon needle injection, HSV-1 became lymph-borne and was rapidly presented by lymph node–resident DCs to CD4 and CD8 T cells. In contrast, after vaginal HSV-1 infection, antigens were largely presented by tissue-derived migrant DCs with delayed kinetics. In addition, migrant DCs made more frequent contact with HSV-specific T cells after vaginal infection compared with epicutaneous infection. Thus, both migrant and resident DCs play an important role in priming CD8 and CD4 T cell responses, and their relative importance depends on the mode of infection in vivo. PMID:19153243

  17. Stimulating somatosensory psychophysics: a double-blind, sham-controlled study of the neurobiological mechanisms of tDCS

    PubMed Central

    Hanley, Claire J.; Tommerdahl, Mark; McGonigle, David J.

    2015-01-01

    The neuromodulation technique transcranial direct current stimulation (tDCS) is thought to produce its effects on behavior by altering cortical excitability. Although the mechanisms underlying the observed effects are thought to rely on the balance of excitatory and inhibitory neurotransmission, the physiological principles of the technique are not completely understood. In this study, we examine the influence of tDCS on vibrotactile adaptation, using a simple amplitude discrimination paradigm that has been shown to exhibit modifications in performance due to changes in inhibitory neurotransmission. Double-blind tDCS (Anodal/Sham) of 1 mA was delivered for 600 s to electrodes positioned in a somatosensory/contralateral orbit montage. Stimulation was applied as part of a pre/post design, between blocks of the behavioral tasks. In accordance with previous work, results obtained before the application of tDCS indicated that amplitude discrimination thresholds were significantly worsened during adaptation trials, compared to those achieved at baseline. However, tDCS failed to modify amplitude discrimination performance. Using a Bayesian approach, this finding was revealed to constitute substantial evidence for the null hypothesis. The failure of DC stimulation to alter vibrotactile adaptation thresholds is discussed in the context of several factors that may have confounded the induction of changes in cortical plasticity. PMID:26500499

  18. A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation (tDCS) in Multiple Sclerosis (MS).

    PubMed

    Kasschau, Margaret; Sherman, Kathleen; Haider, Lamia; Frontario, Ariana; Shaw, Michael; Datta, Abhishek; Bikson, Marom; Charvet, Leigh

    2015-01-01

    Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low amplitude direct currents to alter cortical excitability. With well-established safety and tolerability, tDCS has been found to have the potential to ameliorate symptoms such as depression and pain in a range of conditions as well as to enhance outcomes of cognitive and physical training. However, effects are cumulative, requiring treatments that can span weeks or months and frequent, repeated visits to the clinic. The cost in terms of time and travel is often prohibitive for many participants, and ultimately limits real-world access. Following guidelines for remote tDCS application, we propose a protocol that would allow remote (in-home) participation that uses specially-designed devices for supervised use with materials modified for patient use, and real-time monitoring through a telemedicine video conferencing platform. We have developed structured training procedures and clear, detailed instructional materials to allow for self- or proxy-administration while supervised remotely in real-time. The protocol is designed to have a series of checkpoints, addressing attendance and tolerability of the session, to be met in order to continue to the next step. The feasibility of this protocol was then piloted for clinical use in an open label study of remotely-supervised tDCS in multiple sclerosis (MS). This protocol can be widely used for clinical study of tDCS. PMID:26780383

  19. Immediate Effects of tDCS on the μ-Opioid System of a Chronic Pain Patient

    PubMed Central

    DosSantos, Marcos Fabio; Love, Tiffany M.; Martikainen, Ilkka Kristian; Nascimento, Thiago Dias; Fregni, Felipe; Cummiford, Chelsea; Deboer, Misty Dawn; Zubieta, Jon-Kar; DaSilva, Alexandre F. M.

    2012-01-01

    We developed a unique protocol where transcranial direct current stimulation (tDCS) of the motor cortex is performed during positron emission tomography (PET) scan using a μ-opioid receptor (μOR) selective radiotracer, [11C]carfentanil. This is one of the most important central neuromechanisms associated with pain perception and regulation. We measured μOR non-displaceable binding potential (μOR BPND) in a trigeminal neuropathic pain patient (TNP) without creating artifacts, or posing risks to the patient (e.g., monitoring of resistance). The active session directly improved in 36.2% the threshold for experimental cold pain in the trigeminal allodynic area, mandibular branch, but not the TNP patient’s clinical pain. Interestingly, the single active tDCS application considerably decreased μORBPND levels in (sub)cortical pain-matrix structures compared to sham tDCS, especially in the posterior thalamus. Suggesting that the μ-opioidergic effects of a single tDCS session are subclinical at immediate level, and repetitive sessions are necessary to revert ingrained neuroplastic changes related to the chronic pain. To our knowledge, we provide data for the first time in vivo that there is possibly an instant increase of endogenous μ-opioid release during acute motor cortex neuromodulation with tDCS. PMID:23130002

  20. tDCS and Robotics on Upper Limb Stroke Rehabilitation: Effect Modification by Stroke Duration and Type of Stroke

    PubMed Central

    Straudi, Sofia; Fregni, Felipe; Martinuzzi, Carlotta; Pavarelli, Claudia; Salvioli, Stefano; Basaglia, Nino

    2016-01-01

    Objective. The aim of this exploratory pilot study is to test the effects of bilateral tDCS combined with upper extremity robot-assisted therapy (RAT) on stroke survivors. Methods. We enrolled 23 subjects who were allocated to 2 groups: RAT + real tDCS and RAT + sham-tDCS. Each patient underwent 10 sessions (5 sessions/week) over two weeks. Outcome measures were collected before and after treatment: (i) Fugl-Meyer Assessment-Upper Extremity (FMA-UE), (ii) Box and Block Test (BBT), and (iii) Motor Activity Log (MAL). Results. Both groups reported a significant improvement in FMA-UE score after treatment (p < 0.01). No significant between-groups differences were found in motor function. However, when the analysis was adjusted for stroke type and duration, a significant interaction effect (p < 0.05) was detected, showing that stroke duration (acute versus chronic) and type (cortical versus subcortical) modify the effect of tDCS and robotics on motor function. Patients with chronic and subcortical stroke benefited more from the treatments than patients with acute and cortical stroke, who presented very small changes. Conclusion. The additional use of bilateral tDCS to RAT seems to have a significant beneficial effect depending on the duration and type of stroke. These results should be verified by additional confirmatory studies. PMID:27123448

  1. tDCS and Robotics on Upper Limb Stroke Rehabilitation: Effect Modification by Stroke Duration and Type of Stroke.

    PubMed

    Straudi, Sofia; Fregni, Felipe; Martinuzzi, Carlotta; Pavarelli, Claudia; Salvioli, Stefano; Basaglia, Nino

    2016-01-01

    Objective. The aim of this exploratory pilot study is to test the effects of bilateral tDCS combined with upper extremity robot-assisted therapy (RAT) on stroke survivors. Methods. We enrolled 23 subjects who were allocated to 2 groups: RAT + real tDCS and RAT + sham-tDCS. Each patient underwent 10 sessions (5 sessions/week) over two weeks. Outcome measures were collected before and after treatment: (i) Fugl-Meyer Assessment-Upper Extremity (FMA-UE), (ii) Box and Block Test (BBT), and (iii) Motor Activity Log (MAL). Results. Both groups reported a significant improvement in FMA-UE score after treatment (p < 0.01). No significant between-groups differences were found in motor function. However, when the analysis was adjusted for stroke type and duration, a significant interaction effect (p < 0.05) was detected, showing that stroke duration (acute versus chronic) and type (cortical versus subcortical) modify the effect of tDCS and robotics on motor function. Patients with chronic and subcortical stroke benefited more from the treatments than patients with acute and cortical stroke, who presented very small changes. Conclusion. The additional use of bilateral tDCS to RAT seems to have a significant beneficial effect depending on the duration and type of stroke. These results should be verified by additional confirmatory studies. PMID:27123448

  2. A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation (tDCS) in Multiple Sclerosis (MS)

    PubMed Central

    Kasschau, Margaret; Sherman, Kathleen; Haider, Lamia; Frontario, Ariana; Shaw, Michael; Datta, Abhishek; Bikson, Marom; Charvet, Leigh

    2015-01-01

    Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low amplitude direct currents to alter cortical excitability. With well-established safety and tolerability, tDCS has been found to have the potential to ameliorate symptoms such as depression and pain in a range of conditions as well as to enhance outcomes of cognitive and physical training. However, effects are cumulative, requiring treatments that can span weeks or months and frequent, repeated visits to the clinic. The cost in terms of time and travel is often prohibitive for many participants, and ultimately limits real-world access. Following guidelines for remote tDCS application, we propose a protocol that would allow remote (in-home) participation that uses specially-designed devices for supervised use with materials modified for patient use, and real-time monitoring through a telemedicine video conferencing platform. We have developed structured training procedures and clear, detailed instructional materials to allow for self- or proxy-administration while supervised remotely in real-time. The protocol is designed to have a series of checkpoints, addressing attendance and tolerability of the session, to be met in order to continue to the next step. The feasibility of this protocol was then piloted for clinical use in an open label study of remotely-supervised tDCS in multiple sclerosis (MS). This protocol can be widely used for clinical study of tDCS. PMID:26780383

  3. A Pilot Study on Effects of 4×1 High-Definition tDCS on Motor Cortex Excitability

    PubMed Central

    Caparelli-Daquer, Egas M.; Zimmermann, Trelawny J.; Mooshagian, Eric; Parra, Lucas C.; Rice, Justin K.; Datta, Abhishek; Bikson, Marom; Wassermann, Eric M.

    2016-01-01

    High-Definition transcranial Direct Current Stimulation (HD-tDCS) using specialized small electrodes has been proposed as a focal, non-invasive neuromodulatory technique. Here we provide the first evidence of a change in cortical excitability after HD-tDCS of the motor cortex, using TMS motor evoked potential (MEP) as the measure of excitability. Stimulation for 20 minutes at 1 mA with an anode centered over the hand area of the motor cortex and four surrounding return electrodes (anodal 4×1 montage) produced a significant increase in MEP amplitude and variability after stimulation, compared to sham stimulation. Stimulation was well tolerated by all subjects with adverse effects limited to transient sensation under the electrodes. A high-resolution computational model confirmed predictions of increased focality using the 4×1 HD tDCS montage compared to conventional tDCS. Simulations also indicated that variability in placement of the center electrode relative to the location of the target (central sulcus) could account for increasing variability. These results provide support for the careful use of this technique where focal tDCS is desired. PMID:23365997

  4. Regulatory Considerations for the Clinical and Research Use of Transcranial Direct Current Stimulation (tDCS): review and recommendations from an expert panel

    PubMed Central

    Fregni, F; Nitsche, MA; Loo, C.K.; Brunoni, AR; Marangolo, P; Leite, J; Carvalho, S; Bolognini, N; Caumo, W; Paik, NJ; Simis, M; Ueda, K; Ekhitari, H; Luu, P; Tucker, DM; Tyler, WJ; Brunelin, J; Datta, A; Juan, CH; Venkatasubramanian, G; Boggio, PS; Bikson, M

    2014-01-01

    The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. We therefore convened a group of research and clinician experts on tDCS to review the research and clinical use of tDCS. In this report, we review the regulatory status of tDCS, and we summarize the results according to research, off-label and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan and United States. Research use, off label treatment and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials. PMID:25983531

  5. The effectiveness of ground level post-flight 100 percent oxygen breathing as therapy for pain-only altitude Decompression Sickness (DCS)

    NASA Technical Reports Server (NTRS)

    Demboski, John T.; Pilmanis, Andrew A.

    1994-01-01

    In both the aviation and space environments, decompression sickness (DCS) is an operational limitation. Hyperbaric recompression is the most efficacious treatment for altitude DCS. However, the inherent recompression of descent to ground level while breathing oxygen is in itself therapy for altitude DCS. If pain-only DCS occurs during a hypobaric exposure, and the symptoms resolver during descent, ground level post-flight breathing of 100% O2 for 2 hours (GLO2) is considered sufficient treatment by USAF Regulation 161-21. The effectiveness of the GLO2 treatment protocol is defined.

  6. Sca-1 expression defines developmental stages of mouse pDCs that show functional heterogeneity in the endosomal but not lysosomal TLR9 response.

    PubMed

    Niederquell, Marina; Kurig, Stefanie; Fischer, Jens A A; Tomiuk, Stefan; Swiecki, Melissa; Colonna, Marco; Johnston, Ian C D; Dzionek, Andrzej

    2013-11-01

    Plasmacytoid dendritic cells (pDCs) play an important role in innate and adaptive immunity and were shown to be identical to previously described natural interferon (IFN)-α-producing cells. Here, we describe two functionally distinct pDC subpopulations that are characterized by the differential expression of stem cell antigen-1 (Sca-1; Ly-6A/E). Sca-1(-) pDCs are mainly found in the BM, appear first during development, show a higher proliferative activity, and represent the more precursor phenotype. Sca-1(+) pDCs are mostly located in secondary lymphoid organs and represent a later developmental stage. Sca-1(-) pDCs give rise to an Sca-1(+) subset upon activation or in response to endogenous type I IFN. Interestingly, in contrast to Sca-1(-) pDCs, Sca-1(+) pDCs are defective in IFN-α production upon endosomal TLR9 stimulation, whereas lysosomal signaling via TLR9 is functional in both subsets. Gene expression analysis revealed that osteopontin is strongly upregulated in Sca-1(-) pDCs. These data provide evidence for the molecular basis of the observed functional heterogeneity, as the intracellular isoform of osteopontin couples TLR9 signaling to IFN-α expression. Taken together, our results indicate that Sca-1(-) pDCs are an early developmental stage of pDCs with distinct innate functions representing the true murine natural IFN-α-producing cells. PMID:23922217

  7. HERG1 Channel Agonists and Cardiac Arrhythmia

    PubMed Central

    Sanguinetti, Michael

    2014-01-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  8. HERG1 channel agonists and cardiac arrhythmia.

    PubMed

    Sanguinetti, Michael C

    2014-04-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  9. The SOFIA DCS Persistent Store: Maintaining Science and Mission Data in the Long Term

    NASA Astrophysics Data System (ADS)

    Krzaczek, R.; Shuping, R.; Lin, L.; Sun, L.; Charcos-Llorens, M.; Alles, R.; Perez, R.

    2014-05-01

    The Stratospheric Observatory for Infrared Astronomy (SOFIA) is an airborne astronomical observatory comprised of a 2.5 meter infrared telescope mounted in the aft section of a Boeing 747SP aircraft that flies at operational altitudes between 37 000 and 45 000 feet, above 99% of atmospheric water vapor. SOFIA is projected to collect data over a 20 year lifetime, using a growing variety of instruments and observational modes. This in turn poses significant challenges for the long term maintenance and storage of science and mission data, as well as the delivery of that data to the astronomical community. Herein we present some aspects from the design of the SOFIA Data Cycle System (DCS) Persistent Store, which collects, maintains, and ultimately delivers all mission, science, and processed data to our end users. Features such as DCS Data Integrity, ensuring that all files are uncorrupted during their entire lifetime, from collection and generation through delivery to a user's desktop, are efficiently enabled by the Persistent Store. Key techniques in its implementation, such as the adoption of content addressable storage and inode indexing, are presented as well. Finally, both planned and unplanned benefits from our adoption of the Persistent Store are briefly detailed.

  10. Cathodal tDCS over the left prefrontal cortex diminishes choice-induced preference change.

    PubMed

    Mengarelli, Flavia; Spoglianti, Silvia; Avenanti, Alessio; di Pellegrino, Giuseppe

    2015-05-01

    In everyday life, people often find themselves facing difficult decisions between options that are equally attractive. Cognitive dissonance theory states that after making a difficult choice between 2 equally preferred options, individuals no longer find the alternatives similarly desirable. Rather, they often change their existing preferences to align more closely with the choice they have just made. Despite the relevance of cognitive dissonance in modulating behavior, little is known about the brain processes crucially involved in choice-induced preference change. In the present study, we applied cathodal transcranial Direct Current Stimulation (tDCS) with the aim of downregulating the activity of the left or the right dorsolateral prefrontal cortex (DLPFC) during a revised version of Brehm's (in 1956. Post-decision changes in the desirability of alternatives. J Abnorm Soc Psychol. 52:384-389) free-choice paradigm. We found that cathodal tDCS over the left, but not over the right, DLPFC caused a reduction of the typical behavior-induced preference change relative to sham stimulation. Our findings highlight the role of prefrontal cortex in cognitive dissonance and provide evidence that left DLPFC plays a necessary role in the implementation of choice-induced preference change. PMID:24275827

  11. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  12. Melanocortin 1 Receptor Agonists Reduce Proteinuria

    PubMed Central

    Ebefors, Kerstin; Johansson, Martin E.; Stefánsson, Bergur; Granqvist, Anna; Arnadottir, Margret; Berg, Anna-Lena; Nyström, Jenny; Haraldsson, Börje

    2010-01-01

    Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. Recent reports suggest that treatment with adrenocorticotropic hormone (ACTH) reduces proteinuria, but the mechanism of action is unknown. Here, we identified gene expression of the melanocortin receptor MC1R in podocytes, glomerular endothelial cells, mesangial cells, and tubular epithelial cells. Podocytes expressed most MC1R protein, which colocalized with synaptopodin but not with an endothelial-specific lectin. We treated rats with passive Heymann nephritis (PHN) with MS05, a specific MC1R agonist, which significantly reduced proteinuria compared with untreated PHN rats (P < 0.01). Furthermore, treatment with MC1R agonists improved podocyte morphology and reduced oxidative stress. In summary, podocytes express MC1R, and MC1R agonism reduces proteinuria, improves glomerular morphology, and reduces oxidative stress in nephrotic rats with PHN. These data may explain the proteinuria-reducing effects of ACTH observed in patients with membranous nephropathy, and MC1R agonists may provide a new therapeutic option for these patients. PMID:20507942

  13. Polarity-Dependent Misperception of Subjective Visual Vertical during and after Transcranial Direct Current Stimulation (tDCS)

    PubMed Central

    Santos-Pontelli, Taiza E. G.; Rimoli, Brunna P.; Favoretto, Diandra B.; Mazin, Suleimy C.; Truong, Dennis Q.; Leite, Joao P.; Pontes-Neto, Octavio M.; Babyar, Suzanne R.; Reding, Michael; Bikson, Marom; Edwards, Dylan J.

    2016-01-01

    Pathologic tilt of subjective visual vertical (SVV) frequently has adverse functional consequences for patients with stroke and vestibular disorders. Repetitive transcranial magnetic stimulation (rTMS) of the supramarginal gyrus can produce a transitory tilt on SVV in healthy subjects. However, the effect of transcranial direct current stimulation (tDCS) on SVV has never been systematically studied. We investigated whether bilateral tDCS over the temporal-parietal region could result in both online and offline SVV misperception in healthy subjects. In a randomized, sham-controlled, single-blind crossover pilot study, thirteen healthy subjects performed tests of SVV before, during and after the tDCS applied over the temporal-parietal region in three conditions used on different days: right anode/left cathode; right cathode/left anode; and sham. Subjects were blind to the tDCS conditions. Montage-specific current flow patterns were investigated using computational models. SVV was significantly displaced towards the anode during both active stimulation conditions when compared to sham condition. Immediately after both active conditions, there were rebound effects. Longer lasting after-effects towards the anode occurred only in the right cathode/left anode condition. Current flow models predicted the stimulation of temporal-parietal regions under the electrodes and deep clusters in the posterior limb of the internal capsule. The present findings indicate that tDCS over the temporal-parietal region can significantly alter human SVV perception. This tDCS approach may be a potential clinical tool for the treatment of SVV misperception in neurological patients. PMID:27031726

  14. A systematic review of the clinical efficacy of transcranial direct current stimulation (tDCS) in psychiatric disorders.

    PubMed

    Kekic, Maria; Boysen, Elena; Campbell, Iain C; Schmidt, Ulrike

    2016-03-01

    Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique, which can be used to selectively disrupt patterns of neural activity that are associated with symptoms of mental illness. tDCS has been implemented in numerous therapeutic trials across a range of patient populations, with a rapidly increasing number of studies being published each year. This systematic review aimed to evaluate the efficacy of tDCS in the treatment of psychiatric disorders. Four electronic databases were searched from inception until December 2015 by two independent reviewers, and 66 eligible studies were identified. Depression was the most extensively researched condition, followed by schizophrenia and substance use disorders. Data on obsessive compulsive disorder, generalised anxiety disorder, and anorexia nervosa were also obtained. The quality of included studies was appraised using a standardised assessment framework, which yielded a median score corresponding to "weak" on the three-point scale. This improved to "moderate" when case reports/series were excluded from the analysis. Overall, data suggested that tDCS interventions comprising multiple sessions can ameliorate symptoms of several major psychiatric disorders, both acutely and in the long-term. Nevertheless, the tDCS field is still in its infancy, and several methodological and ethical issues must be addressed before clinical efficacy can truly be determined. Studies probing the mechanisms of action of tDCS and those facilitating the definition of optimised stimulation protocols are warranted. Furthermore, evidence from large-scale, multi-centre randomised controlled trials is required if the transition of this therapy from the laboratory to the clinic is to be considered. PMID:26765514

  15. Impact of tDCS on performance and learning of target detection: interaction with stimulus characteristics and experimental design.

    PubMed

    Coffman, B A; Trumbo, M C; Flores, R A; Garcia, C M; van der Merwe, A J; Wassermann, E M; Weisend, M P; Clark, V P

    2012-06-01

    We have previously found that transcranial direct current stimulation (tDCS) over right inferior frontal cortex (RIFC) enhances performance during learning of a difficult visual target detection task (Clark et al., 2012). In order to examine the cognitive mechanisms of tDCS that lead to enhanced performance, here we analyzed its differential effects on responses to stimuli that varied by repetition and target presence, differences related to expectancy by comparing performance in single- and double-blind task designs, and individual differences in skin stimulation and mood. Participants were trained for 1h to detect target objects hidden in a complex virtual environment, while anodal tDCS was applied over RIFC at 0.1 mA or 2.0 mA for the first 30 min. Participants were tested immediately before and after training and again 1h later. Higher tDCS current was associated with increased performance for all test stimuli, but was greatest for repeated test stimuli with the presence of hidden-targets. This finding was replicated in a second set of subjects using a double-blind task design. Accuracy for target detection discrimination sensitivity (d'; Z(hits)-Z(false alarms)) was greater for 2.0 mA current (1.77) compared with 0.1 mA (0.95), with no differences in response bias (β). Taken together, these findings indicate that the enhancement of performance with tDCS is sensitive to stimulus repetition and target presence, but not to changes in expectancy, mood, or type of blinded task design. The implications of these findings for understanding the cognitive mechanisms of tDCS are discussed. PMID:22450198

  16. tDCS-Induced Analgesia and Electrical Fields in Pain-Related Neural Networks in Chronic Migraine

    PubMed Central

    DaSilva, Alexandre F.; Mendonca, Mariana E.; Zaghi, Soroush; Lopes, Mariana; DosSantos, Marcos Fabio; Spierings, Egilius L.; Bajwa, Zahid; Datta, Abhishek; Bikson, Marom; Fregni, Felipe

    2014-01-01

    Objective We investigated in a sham-controlled trial the analgesic effects of a 4-week treatment of transcranial direct current stimulation (tDCS) over the primary motor cortex in chronic migraine. In addition, using a high-resolution tDCS computational model, we analyzed the current flow (electric field) through brain regions associated with pain perception and modulation. Methods Thirteen patients with chronic migraine were randomized to receive 10 sessions of active or sham tDCS for 20 minutes with 2 mA over 4 weeks. Data were collected during baseline, treatment and follow-up. For the tDCS computational analysis, we adapted a high-resolution individualized model incorporating accurate segmentation of cortical and subcortical structures of interest. Results There was a significant interaction term (time vs group) for the main outcome (pain intensity) and for the length of migraine episodes (ANOVA, P < .05 for both analyses). Post-hoc analysis showed a significant improvement in the follow-up period for the active tDCS group only. Our computational modeling studies predicted electric current flow in multiple cortical and subcortical regions associated with migraine pathophysiology. Significant electric fields were generated, not only in targeted cortical regions but also in the insula, cingulate cortex, thalamus, and brainstem regions. Conclusions Our findings give preliminary evidence that patients with chronic migraine have a positive, but delayed, response to anodal tDCS of the primary motor cortex. These effects may be related to electrical currents induced in pain-related cortical and subcortical regions. PMID:22512348

  17. Controlling the Emotional Bias: Performance, Late Positive Potentials, and the Effect of Anodal Transcranial Direct Current Stimulation (tDCS)

    PubMed Central

    Faehling, Florian; Plewnia, Christian

    2016-01-01

    Cognitive control of emotional processing is essential for adaptive human behavior. Biased attention toward emotionally salient information is critically linked with affective disorders and is discussed as a promising treatment target. Anodal (activity enhancing) transcranial direct current stimulation (tDCS) has been shown to increase healthy and impaired cognitive control over emotional distraction and is therefore widely used for the investigation and experimental treatment of this disorder. In this study, event-related potential (ERP) were recorded parallel to tDCS to track its online effects. Healthy volunteers (n = 87) performed a delayed working memory paradigm with emotional salient and neutral distractors during stimulation with different intensities (sham, 0.5, 1, 1.5 mA). Measuring the late positive potential (LPP), an ERP that indexes attention allocation, we found that a valence-specific increase of the early portion of the LPP (eLPP, 250–500 ms) was associated with less emotional distraction in the sham group. Of note, stimulation with tDCS exerted an intensity related effect on this correlation. The later part of the LPP (lLPP, 500–1000 ms) was found to be correlated with reaction time, regardless of valence. General effect of tDCS on LPPs and task performance were not observed. These findings demonstrate that ERP recordings parallel to tDCS are feasible to investigate the neuronal underpinnings of stimulation effects on executive functions. Furthermore, they support the notion that the LPP induced by a distractive stimulus during a working memory task mirrors the additional allocation of neuronal resources with a specific sensitivity of the early LPP for highly arousing negative stimuli. Finally, together with the variable magnitude and direction of the emotional bias, the lack of systematic modulations of LPPs and behavior by tDCS further underlines the important influence of the individual brain activity patterns on stimulation effects both on

  18. Polarity-Dependent Misperception of Subjective Visual Vertical during and after Transcranial Direct Current Stimulation (tDCS).

    PubMed

    Santos-Pontelli, Taiza E G; Rimoli, Brunna P; Favoretto, Diandra B; Mazin, Suleimy C; Truong, Dennis Q; Leite, Joao P; Pontes-Neto, Octavio M; Babyar, Suzanne R; Reding, Michael; Bikson, Marom; Edwards, Dylan J

    2016-01-01

    Pathologic tilt of subjective visual vertical (SVV) frequently has adverse functional consequences for patients with stroke and vestibular disorders. Repetitive transcranial magnetic stimulation (rTMS) of the supramarginal gyrus can produce a transitory tilt on SVV in healthy subjects. However, the effect of transcranial direct current stimulation (tDCS) on SVV has never been systematically studied. We investigated whether bilateral tDCS over the temporal-parietal region could result in both online and offline SVV misperception in healthy subjects. In a randomized, sham-controlled, single-blind crossover pilot study, thirteen healthy subjects performed tests of SVV before, during and after the tDCS applied over the temporal-parietal region in three conditions used on different days: right anode/left cathode; right cathode/left anode; and sham. Subjects were blind to the tDCS conditions. Montage-specific current flow patterns were investigated using computational models. SVV was significantly displaced towards the anode during both active stimulation conditions when compared to sham condition. Immediately after both active conditions, there were rebound effects. Longer lasting after-effects towards the anode occurred only in the right cathode/left anode condition. Current flow models predicted the stimulation of temporal-parietal regions under the electrodes and deep clusters in the posterior limb of the internal capsule. The present findings indicate that tDCS over the temporal-parietal region can significantly alter human SVV perception. This tDCS approach may be a potential clinical tool for the treatment of SVV misperception in neurological patients. PMID:27031726

  19. Optimization of focality and direction in dense electrode array transcranial direct current stimulation (tDCS)

    NASA Astrophysics Data System (ADS)

    Guler, Seyhmus; Dannhauer, Moritz; Erem, Burak; Macleod, Rob; Tucker, Don; Turovets, Sergei; Luu, Phan; Erdogmus, Deniz; Brooks, Dana H.

    2016-06-01

    Objective. Transcranial direct current stimulation (tDCS) aims to alter brain function non-invasively via electrodes placed on the scalp. Conventional tDCS uses two relatively large patch electrodes to deliver electrical current to the brain region of interest (ROI). Recent studies have shown that using dense arrays containing up to 512 smaller electrodes may increase the precision of targeting ROIs. However, this creates a need for methods to determine effective and safe stimulus patterns as the number of degrees of freedom is much higher with such arrays. Several approaches to this problem have appeared in the literature. In this paper, we describe a new method for calculating optimal electrode stimulus patterns for targeted and directional modulation in dense array tDCS which differs in some important aspects with methods reported to date. Approach. We optimize stimulus pattern of dense arrays with fixed electrode placement to maximize the current density in a particular direction in the ROI. We impose a flexible set of safety constraints on the current power in the brain, individual electrode currents, and total injected current, to protect subject safety. The proposed optimization problem is convex and thus efficiently solved using existing optimization software to find unique and globally optimal electrode stimulus patterns. Main results. Solutions for four anatomical ROIs based on a realistic head model are shown as exemplary results. To illustrate the differences between our approach and previously introduced methods, we compare our method with two of the other leading methods in the literature. We also report on extensive simulations that show the effect of the values chosen for each proposed safety constraint bound on the optimized stimulus patterns. Significance. The proposed optimization approach employs volume based ROIs, easily adapts to different sets of safety constraints, and takes negligible time to compute. An in-depth comparison study gives

  20. A technical guide to tDCS, and related non-invasive brain stimulation tools.

    PubMed

    Woods, A J; Antal, A; Bikson, M; Boggio, P S; Brunoni, A R; Celnik, P; Cohen, L G; Fregni, F; Herrmann, C S; Kappenman, E S; Knotkova, H; Liebetanz, D; Miniussi, C; Miranda, P C; Paulus, W; Priori, A; Reato, D; Stagg, C; Wenderoth, N; Nitsche, M A

    2016-02-01

    Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain. PMID:26652115

  1. Bandwidth optimization of compact microstrip antenna for PCS/DCS/bluetooth application

    NASA Astrophysics Data System (ADS)

    Singh, Vinod; Ali, Zakir; Ayub, Shahanaz; Singh, Ashutosh

    2014-09-01

    A novel compact broadband microstrip patch antenna is presented for various wireless applications. The proposed antenna has been fabricated and the impedance bandwidth and radiation pattern are measured. The simulated and measured antenna characteristics along with radiation pattern and gain are presented. It is stated that the proposed designed antenna can completely cover the required band widths of Digital communication system (DCS 1.71-1.88 GHz), Personal communication system (PCS 1.85-1.88 GHz) and IEEE 802.11b/g (2.4-2.485 GHz) with satisfactory radiation characteristics. The Experimental result shows that the proposed antenna presents a bandwidth 60.25% covering the range of 1.431-2.665 GHz with the maximum radiation efficiency 90%.

  2. ERTS-1 DCS technical support provided by Wallops Station. [ground truth stations and DCP repair depot

    NASA Technical Reports Server (NTRS)

    Smith, R.

    1975-01-01

    Wallops Station accepted the tasks of providing ground truth to several ERTS investigators, operating a DCP repair depot, designing and building an airborne DCP Data Acquisition System, and providing aircraft underflight support for several other investigators. Additionally, the data bank is generally available for use by ERTS and other investigators that have a scientific interest in data pertaining to the Chesapeake Bay area. Working with DCS has provided a means of evaluating the system as a data collection device possibly applicable to ongoing Earth Resources Program activities in the Chesapeake Bay area as well as providing useful data and services to other ERTS investigators. The two areas of technical support provided by Wallops, ground truth stations and repair for DCPs, are briefly discussed.

  3. Monitoring of streamflow in the Verde River by ERTS-1 Data Collection System (DCS)

    NASA Technical Reports Server (NTRS)

    Schumann, H. H.

    1973-01-01

    The Verde River watershed in central Arizona furnishes municipal, industrial, and agricultural water to the Salt River Valley --an area that contains more than half of Arizona's population and about one-fourth of the State's irrigated land. Water-management decisions related to the operation of large multiple-use reservoirs require accurate and continuous monitoring of moisture conditions over large remote areas. The U.S. Geological Survey in cooperation with the Salt River Valley Water Users' Association installed a specially designed gaging station on the Verde River near the town of Camp Verde to evaluate near-real time streamflow data furnished by the ERTS-1 Data Collection System (DCS). On Nov. 3, 1972, the installation was equipped with a Stevens digital water-level recorder, modified for telemetry, and an ERTS-1 data collection platform operating in the digital-parallel mode.

  4. IFNγ Signaling Endows DCs with the Capacity to Control Type I Inflammation during Parasitic Infection through Promoting T-bet+ Regulatory T Cells

    PubMed Central

    Lee, Hyang-Mi; Fleige, Anne; Forman, Ruth; Cho, Sunglim; Khan, Aly Azeem; Lin, Ling-Li; Nguyen, Duc T.; O'Hara-Hall, Aisling; Yin, Zhinan; Hunter, Christopher A.; Muller, Werner; Lu, Li-Fan

    2015-01-01

    IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population. PMID:25658840

  5. Dopamine agonist: pathological gambling and hypersexuality.

    PubMed

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication. PMID:19536937

  6. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  7. Mechanisms of agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Lin, Hong; Strange, Philip G

    2004-12-01

    In this study, we investigated the biochemical mechanisms of agonist action at the G protein-coupled D2 dopamine receptor expressed in Chinese hamster ovary cells. Stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding by full and partial agonists was determined at different concentrations of [35S]GTPgammaS (0.1 and 10 nM) and in the presence of different concentrations of GDP. At both concentrations of [35S]GTPgammaS, increasing GDP decreased the [35S]GTPgammaS binding observed with maximally stimulating concentrations of agonist, with partial agonists exhibiting greater sensitivity to the effects of GDP than full agonists. The relative efficacy of partial agonists was greater at the lower GDP concentrations. Concentration-response experiments were performed for a range of agonists at the two [35S]GTPgammaS concentrations and with different concentrations of GDP. At 0.1 nM [35S]GTPgammaS, the potency of both full and partial agonists was dependent on the GDP concentration in the assays. At 10 nM [35S]GTPgammaS, the potency of full agonists exhibited a greater dependence on the GDP concentration, whereas the potency of partial agonists was virtually independent of GDP. We concluded that at the lower [35S]GTPgammaS concentration, the rate-determining step in G protein activation is the binding of [35S]GTPgammaS to the G protein. At the higher [35S]GTPgammaS concentration, for full agonists, [35S]GTPgammaS binding remains the slowest step, whereas for partial agonists, another (GDP-independent) step, probably ternary complex breakdown, becomes rate-determining. PMID:15340043

  8. Cerebellum as a forward but not inverse model in visuomotor adaptation task: a tDCS-based and modeling study.

    PubMed

    Yavari, Fatemeh; Mahdavi, Shirin; Towhidkhah, Farzad; Ahmadi-Pajouh, Mohammad-Ali; Ekhtiari, Hamed; Darainy, Mohammad

    2016-04-01

    Despite several pieces of evidence, which suggest that the human brain employs internal models for motor control and learning, the location of these models in the brain is not yet clear. In this study, we used transcranial direct current stimulation (tDCS) to manipulate right cerebellar function, while subjects adapt to a visuomotor task. We investigated the effect of this manipulation on the internal forward and inverse models by measuring two kinds of behavior: generalization of training in one direction to neighboring directions (as a proxy for inverse models) and localization of the hand position after movement without visual feedback (as a proxy for forward model). The experimental results showed no effect of cerebellar tDCS on generalization, but significant effect on localization. These observations support the idea that the cerebellum is a possible brain region for internal forward, but not inverse model formation. We also used a realistic human head model to calculate current density distribution in the brain. The result of this model confirmed the passage of current through the cerebellum. Moreover, to further explain some observed experimental results, we modeled the visuomotor adaptation process with the help of a biologically inspired method known as population coding. The effect of tDCS was also incorporated in the model. The results of this modeling study closely match our experimental data and provide further evidence in line with the idea that tDCS manipulates FM's function in the cerebellum. PMID:26706039

  9. Lessons from D.C.'s Evaluation System: Teachers Give IMPACT Low Marks on Support and Professional Development

    ERIC Educational Resources Information Center

    Headden, Susan; Silva, Elena

    2011-01-01

    IMPACT, Washington, D.C.'s controversial evaluation system, sets clear expectations for instruction and holds teachers to well-defined standards of performance. Now into its third year, the program appears to be meeting its goals of rewarding effective teachers and eliminating educators it considers incompetent. And it has given the public reason…

  10. Increased expression of surface CD44 in hypoxia-DCs skews helper T cells toward a Th2 polarization

    PubMed Central

    Yang, Meixiang; Liu, Yanguo; Ren, Guangwen; Shao, Qianqian; Gao, Wenjuan; Sun, Jintang; Wang, Huayang; Ji, Chunyan; Li, Xingang; Zhang, Yun; Qu, Xun

    2015-01-01

    A low partial oxygen pressure (hypoxia) occurs in many pathological environments, such as solid tumors and inflammatory lesions. Understanding the cellular response to hypoxic stress has broad implications for human diseases. As we previously reported, hypoxia significantly altered dendritic cells (DCs) to a DC2 phenotype and promoted a Th2 polarization of naïve T cells with increased IL-4 production. However, the underlying mechanisms still remain largely unknown. In this study, we found the over-expression of surface CD44 in DCs was involved in this process via ligand binding. Further investigation showed hypoxia could reduce the surface expression of membrane type 1 metalloprotease (MT1-MMP) via down-regulating the kinesin-like protein KIF2A, which subsequently alleviated the shedding of CD44 from DCs. Moreover, KIF2A expression was found negatively regulated by HIF-1α in hypoxic microenvironment. These results suggest a previously uncharacterized mechanism by which hypoxia regulates the function of DCs via KIF2A/MT1-MMP/CD44 axis, providing critical information to understand the immune response under hypoxia. PMID:26323509

  11. tDCS of the Cerebellum: Where Do We Stand in 2016? Technical Issues and Critical Review of the Literature

    PubMed Central

    van Dun, Kim; Bodranghien, Florian C. A. A.; Mariën, Peter; Manto, Mario U.

    2016-01-01

    Transcranial Direct Current Stimulation (tDCS) is an up-and-coming electrical neurostimulation technique increasingly used both in healthy subjects and in selected groups of patients. Due to the high density of neurons in the cerebellum, its peculiar anatomical organization with the cortex lying superficially below the skull and its diffuse connections with motor and associative areas of the cerebrum, the cerebellum is becoming a major target for neuromodulation of the cerebellocerebral networks. We discuss the recent studies based on cerebellar tDCS with a focus on the numerous technical and open issues which remain to be solved. Our current knowledge of the physiological impacts of tDCS on cerebellar circuitry is criticized. We provide a comparison with transcranial Alternating Current Stimulation (tACS), another promising transcranial electrical neurostimulation technique. Although both tDCS and tACS are becoming established techniques to modulate the cerebellocerebral networks, it is surprising that their impacts on cerebellar disorders remains unclear. A major reason is that the literature lacks large trials with a double-blind, sham-controlled, and cross-over experimental design in cerebellar patients. PMID:27242469

  12. Effects of transcranial direct current stimulation (tDCS) on multiscale complexity of dual-task postural control in older adults

    PubMed Central

    Zhou, Diange; Zhou, Junhong; Chen, Hu; Manor, Brad; Lin, Jianhao; Zhang, Jue

    2016-01-01

    Transcranial direct current stimulation (tDCS) targeting the prefrontal cortex reduces the size and speed of standing postural sway in younger adults, particularly when performing a cognitive dual task. Here, we hypothesized that tDCS would alter the complex dynamics of postural sway as quantified by multiscale entropy (MSE). Twenty healthy older adults completed two study visits. Center-of-pressure (COP) fluctuations were recorded during single-task (i.e., quiet standing) and dual-task (i.e., standing while performing serial subtractions) conditions, both before and after a 20-min session of real or sham tDCS. MSE was used to estimate COP complexity within each condition. The percentage change in complexity from single- to dual-task conditions (i.e., dual-task cost) was also calculated. Before tDCS, COP complexity was lower (p = 0.04) in the dual-task condition as compared to the single-task condition. Neither real nor sham tDCS altered complexity in the single-task condition. As compared to sham tDCS, real tDCS increased complexity in the dual-task condition (p = 0.02) and induced a trend toward improved serial subtraction performance (p = 0.09). Moreover, those subjects with lower dual-task COP complexity at baseline exhibited greater percentage increases in complexity following real tDCS (R = −0.39, p = 0.05). Real tDCS also reduced the dual-task cost to complexity (p = 0.02), while sham stimulation had no effect. A single session of tDCS targeting the prefrontal cortex increased standing postural sway complexity with concurrent non-postural cognitive task. This form of noninvasive brain stimulation may be a safe strategy to acutely improve postural control by enhancing the system's capacity to adapt to stressors. PMID:25963755

  13. High Definition Transcranial Direct Current Stimulation Induces Both Acute and Persistent Changes in Broadband Cortical Synchronization: a Simultaneous tDCS-EEG Study

    PubMed Central

    Roy, Abhrajeet; Baxter, Bryan

    2014-01-01

    The goal of this study was to develop methods for simultaneously acquiring electrophysiological data during high definition transcranial direct current stimulation (tDCS) using high resolution electroencephalography (EEG). Previous studies have pointed to the after effects of tDCS on both motor and cognitive performance, and there appears to be potential for using tDCS in a variety of clinical applications. However, little is known about the real-time effects of tDCS on rhythmic cortical activity in humans due to the technical challenges of simultaneously obtaining electrophysiological data during ongoing stimulation. Furthermore, the mechanisms of action of tDCS in humans are not well understood. We have conducted a simultaneous tDCS-EEG study in a group of healthy human subjects. Significant acute and persistent changes in spontaneous neural activity and event related synchronization (ERS) were observed during and after the application of high definition tDCS over the left sensorimotor cortex. Both anodal and cathodal stimulation resulted in acute global changes in broadband cortical activity which were significantly different than the changes observed in response to sham stimulation. For the group of 8 subjects studied, broadband individual changes in spontaneous activity during stimulation were apparent both locally and globally. In addition, we found that high definition tDCS of the left sensorimotor cortex can induce significant ipsilateral and contralateral changes in event related desynchronization (ERD) and ERS during motor imagination following the end of the stimulation period. Overall, our results demonstrate the feasibility of acquiring high resolution EEG during high definition tDCS and provide evidence that tDCS in humans directly modulates rhythmic cortical synchronization during and after its administration. PMID:24956615

  14. Self-Administered Domiciliary tDCS Treatment for Tinnitus: A Double-Blind Sham-Controlled Study

    PubMed Central

    Mäkitie, Antti; Aarnisalo, Antti A.

    2016-01-01

    Transcranial direct current stimulation (tDCS) has shown potential for providing tinnitus relief, although positive effects have usually been observed only during a short time period after treatment. In recent studies the focus has turned from one-session experiments towards multi-session treatment studies investigating long-term outcomes with double-blinded and sham-controlled study designs. Traditionally, tDCS has been administered in a clinical setting by a healthcare professional but in studies involving multiple treatment sessions, often a trade-off has to be made between sample size and the amount of labor needed to run the trial. Also, as the number of required visits to the clinic increases, the dropout rate is likely to rise proportionally.The aim of the current study was to find out if tDCS treatment for tinnitus could be patient-administered in a domiciliary setting and whether the results would be comparable to those from in-hospital treatment studies. Forty-three patients with chronic (> 6 months) tinnitus were involved in the study, and data on 35 out of these patients were included in final analysis. Patients received 20 minutes of left temporal area anodal (LTA) or bifrontal tDCS stimulation (2 mA) or sham stimulation (0.3 mA) for ten consecutive days. An overall reduction in the main outcome measure, Tinnitus Handicap Inventory (THI), was found (mean change −5.0 points, p < 0.05), but there was no significant difference between active and sham treatment outcomes. Patients found the tDCS treatment easy to administer and they all tolerated it well. In conclusion, self-administered domiciliary tDCS treatment for tinnitus was found safe and feasible and gave outcome results similar to recent randomized controlled long-term treatment trials. The results suggest better overall treatment response—as measured by THI—with domiciliary treatment than with in-hospital treatment, but this advantage is not related to the tDCS variant. The study protocol

  15. Computational modeling toward understanding agonist binding on dopamine 3.

    PubMed

    Zhao, Yaxue; Lu, Xuefeng; Yang, Chao-Yie; Huang, Zhimin; Fu, Wei; Hou, Tingjun; Zhang, Jian

    2010-09-27

    The dopamine 3 (D3) receptor is a promising therapeutic target for the treatment of nervous system disorders, such as Parkinson's disease, and current research interests primarily focus on the discovery/design of potent D3 agonists. Herein, a well-designed computational protocol, which combines pharmacophore identification, homology modeling, molecular docking, and molecular dynamics (MD) simulations, was employed to understand the agonist binding on D3 aiming to provide insights into the development of novel potent D3 agonists. We (1) identified the chemical features required in effective D3 agonists by pharmacophore modeling based upon 18 known diverse D3 agonists; (2) constructed the three-dimensional (3D) structure of D3 based on homology modeling and the pharmacophore hypothesis; (3) identified the binding modes of the agonists to D3 by the correlation between the predicted binding free energies and the experimental values; and (4) investigated the induced fit of D3 upon agonist binding through MD simulations. The pharmacophore models of the D3 agonists and the 3D structure of D3 can be used for either ligand- or receptor-based drug design. Furthermore, the MD simulations further give the insight that the long and flexible EL2 acts as a "door" for agonist binding, and the "ionic lock" at the bottom of TM3 and TM6 is essential to transduce the activation signal. PMID:20695484

  16. Stress-induced resistance to the fear memory labilization/reconsolidation process. Involvement of the basolateral amygdala complex.

    PubMed

    Espejo, Pablo Javier; Ortiz, Vanesa; Martijena, Irene Delia; Molina, Victor Alejandro

    2016-10-01

    Consolidated memories can enter into a labile state after reactivation followed by a restabilization process defined as reconsolidation. This process can be interfered with Midazolam (MDZ), a positive allosteric modulator of the GABA-A receptor. The present study has evaluated the influence of prior stress on MDZ's interfering effect. We also assessed the influence of both systemic and intra-basolateral amygdala (BLA) infusion of d-cycloserine (DCS), a partial agonist of the NMDA receptors, on the MDZ effect in previously stressed rats. Furthermore, we analyzed the effect of stress on the expression of Zif-268 and the GluN2B sites, two molecular markers of the labilization/reconsolidation process, following reactivation. The results revealed that prior stress resulted into a memory trace that was insensitive to the MDZ impairing effect. Both systemic and intra-BLA DCS administration previous to reactivation restored MDZ's disruptive effect on memory reconsolidation in stressed animals. Further, reactivation enhanced Zif-268 expression in the BLA in control unstressed rats, whereas no elevation was observed in stressed animals. In agreement with the behavioral findings, DCS restored the increased level of Zif-268 expression in the BLA in stressed animals. Moreover, memory reactivation in unstressed animals elevated GluN2B expression in the BLA, thus suggesting that this effect is involved in memory destabilization, whereas stressed animals did not reveal any changes. These findings are consistent with resistance to the MDZ effect in these rats, indicating that stress exposure prevents the onset of destabilization following reactivation. In summary, prior stress limited both the occurrence of the reactivation-induced destabilization and restabilization. PMID:27378335

  17. Treatment of visuospatial neglect with biparietal tDCS and cognitive training: a single-case study

    PubMed Central

    Brem, Anna-Katharine; Unterburger, Evelyn; Speight, Irving; Jäncke, Lutz

    2014-01-01

    Symptoms of visuospatial neglect occur frequently after unilateral brain damage. Neglect hampers rehabilitation progress and is associated with reduced quality of life. However, existing treatment methods show limited efficacy. Transcranial direct current stimulation (tDCS) is a neuromodulatory technique, which can be used to increase or decrease brain excitability. Its combination with conventional neglect therapy may enhance treatment efficacy. A 72-year-old male with a subacute ischemic stroke of the right posterior cerebral artery suffering from visuospatial neglect, hemianopia, and hemiparesis was treated with biparietal tDCS and cognitive neglect therapy in a double-blind, sham-controlled single-case study. Four weeks of daily treatment sessions (5 days per week, 30 min) were started 26 days post-stroke. During week 1 and 4 the patient received conventional neglect therapy, during week 2, conventional neglect therapy was combined once with sham and once with real biparietal tDCS. Week 3 consisted of daily sessions of real biparietal tDCS (1 mA, 20 min) combined with neglect therapy. Outcome measures were assessed before, immediately after, as well as 1 week and 3 months after the end of treatment. They included subtests of the Test for Attentional Performance (TAP): covert attention (main outcome), alertness, visual field; the Neglect-Test (NET): line bisection, cancelation, copying; and activities of daily living (ADL). After real stimulation, covert attention allocation toward left-sided invalid stimuli was significantly improved, and line bisection and copying improved qualitatively as compared to sham stimulation. ADL were only improved at the 3-month follow-up. This single-case study demonstrates for the first time that combined application of tDCS and cognitive training may enhance training-induced improvements in measures of visuospatial neglect and is applicable in a clinical context. PMID:25324736

  18. Electrodes for high-definition transcutaneous DC stimulation for applications in drug-delivery and electrotherapy, including tDCS

    PubMed Central

    Minhas, Preet; Bansal, Varun; Patel, Jinal; Ho, Johnson S.; Diaz, Julian; Datta, Abhishek; Bikson, Marom

    2010-01-01

    Transcutaneous electrical stimulation is applied in a range of biomedical applications including Transcranial Direct Current Stimulation (tDCS). tDCS is a non-invasive procedure where a weak direct current (<2 mA) is applied across the scalp to modulate brain function. High-Definition tDCS (HD-tDCS) is a technique used to increase the spatial focality of tDCS by passing current across the scalp using <12 mm diameter electrodes. The purpose of this study was to design and optimize “high-definition” electrode-gel parameters for electrode durability, skin safety, and subjective pain. Anode and cathode electrode potential, temperature, pH, and subjective sensation over time were assessed during application of 2 mA direct current, for up to 22 minutes on agar gel or subject forearms. A selection of 5 types of solid-conductors (Ag pellet, Ag/AgCl pellet, Rubber pellet, Ag/AgCl ring, and Ag/AgCl disc) and 7 conductive gels (Signa, Spectra, Tensive, Redux, BioGel, Lectron, and CCNY-4) were investigated. The Ag/AgCl ring in combination with CCNY-4 gel resulted in the most favorable outcomes. Under anode stimulations, electrode potential and temperature rises were generally observed in all electrode-gel combinations except for Ag/AgCl ring and disc electrodes. pH remained constant for all solid-conductors except for both Ag and Rubber pellet electrodes with Signa and CCNY-4 gels. Sensation ratings were independent of stimulation polarity. Ag/AgCl ring electrodes were found to be the most comfortable followed by Ag, Rubber, and Ag/AgCl pellet electrodes across all gels. PMID:20488204

  19. Can tDCS enhance item-specific effects and generalization after linguistically motivated aphasia therapy for verbs?

    PubMed Central

    de Aguiar, Vânia; Bastiaanse, Roelien; Capasso, Rita; Gandolfi, Marialuisa; Smania, Nicola; Rossi, Giorgio; Miceli, Gabriele

    2015-01-01

    Background: Aphasia therapy focusing on abstract properties of language promotes both item-specific effects and generalization to untreated materials. Neuromodulation with transcranial Direct Current Stimulation (tDCS) has been shown to enhance item-specific improvement, but its potential to enhance generalization has not been systematically investigated. Here, we test the efficacy of ACTION (a linguistically motivated protocol) and tDCS in producing item-specific and generalized improvement in aphasia. Method: Nine individuals with post-stroke aphasia participated in this study. Participants were pre-tested with a diagnostic language battery and a cognitive screening. Experimental tasks were administered over multiple baselines. Production of infinitives, of finite verbs and of full sentences were assessed before and after each treatment phase. Nonword repetition was used as a control measure. Each subject was treated in two phases. Ten daily 1-h treatment sessions were provided per phase, in a double-blind, cross-over design. Linguistically-motivated language therapy focusing on verb inflection and sentence construction was provided in both phases. Each session began with 20 min of real or sham tDCS. Stimulation site was determined individually, based on MRI scans. Results: Group data showed improved production of treated and untreated verbs, attesting the efficacy of behavioral treatment, and its potential to yield generalization. Each individual showed significant item-specific improvement. Generalization occurred in the first phase of treatment for all subjects, and in the second phase for two subjects. Stimulation effects at the group level were significant for treated and untreated verbs altogether, but a ceiling effect for Sham cannot be excluded, as scores between real tDCS and Sham differed only before treatment. Conclusion: Our data demonstrate the efficacy of ACTION and suggest that tDCS may enhance both item-specific effects and generalization. PMID

  20. Strategies for designing synthetic immune agonists.

    PubMed

    Wu, Tom Y-H

    2016-08-01

    Enhancing the immune system is a validated strategy to combat infectious disease, cancer and allergy. Nevertheless, the development of immune adjuvants has been hampered by safety concerns. Agents that can stimulate the immune system often bear structural similarities with pathogen-associated molecular patterns found in bacteria or viruses and are recognized by pattern recognition receptors (PRRs). Activation of these PRRs results in the immediate release of inflammatory cytokines, up-regulation of co-stimulatory molecules, and recruitment of innate immune cells. The distribution and duration of these early inflammatory events are crucial in the development of antigen-specific adaptive immunity in the forms of antibody and/or T cells capable of searching for and destroying the infectious pathogens or cancer cells. However, systemic activation of these PRRs is often poorly tolerated. Hence, different strategies have been employed to modify or deliver immune agonists in an attempt to control the early innate receptor activation through temporal or spatial restriction. These approaches include physicochemical manipulation, covalent conjugation, formulation and conditional activation/deactivation. This review will describe recent examples of discovery and optimization of synthetic immune agonists towards clinical application. PMID:27213842

  1. Proglumide exhibits delta opioid agonist properties.

    PubMed

    Rezvani, A; Stokes, K B; Rhoads, D L; Way, E L

    1987-01-01

    Recently, it was reported that proglumide, a cholecystokinin (CCK) antagonist, potentiates the analgetic effects of morphine and endogenous opioid peptides and reverses morphine tolerance by antagonizing the CCK system in the central nervous system of the rat. In order to provide additional insight into the mode of action of this agent, we assessed the effect of proglumide in the isolated guinea pig ileum and the mouse, rat and rabbit vas deferens. Furthermore, we studied the in vitro binding affinity of this substance to mouse brain synaptosomes. Our results show that proglumide inhibits, dose dependently, the electrically stimulated twitches in the mouse vas deferens and guinea pig ileum, but not in the rat or rabbit vas deferens. The inhibitory action of proglumide on the mouse vas deferens, but not on the guinea pig ileum, is antagonized by naloxone and by the selective delta-antagonist, ICI 174,864, in a competitive fashion. Other CCK antagonists were found to be devoid of such activity on the mouse vas deferens. In vitro binding studies showed that proglumide displaces D-ala-D-[leucine]5-enkephalin (DADLE), a delta agonist, but not ethylketocyclazocine (EKC), a preferentially selective kappa agonist. The effect of proglumide appeared to be elicited presynaptically since it did not alter the norepinephrine-induced contractions of the mouse vas deferens. Our results suggest that proglumide might exert its opiate-like effects by activation of delta-opioid receptors. PMID:3030338

  2. Chimpanzees Extract Social Information from Agonistic Screams

    PubMed Central

    Slocombe, Katie E.; Kaller, Tanja; Call, Josep; Zuberbühler, Klaus

    2010-01-01

    Chimpanzee (Pan troglodytes) agonistic screams are graded vocal signals that are produced in a context-specific manner. Screams given by aggressors and victims can be discriminated based on their acoustic structure but the mechanisms of listener comprehension of these calls are currently unknown. In this study, we show that chimpanzees extract social information from these vocal signals that, combined with their more general social knowledge, enables them to understand the nature of out-of-sight social interactions. In playback experiments, we broadcast congruent and incongruent sequences of agonistic calls and monitored the response of bystanders. Congruent sequences were in accordance with existing social dominance relations; incongruent ones violated them. Subjects looked significantly longer at incongruent sequences, despite them being acoustically less salient (fewer call types from fewer individuals) than congruent ones. We concluded that chimpanzees categorised an apparently simple acoustic signal into victim and aggressor screams and used pragmatics to form inferences about third-party interactions they could not see. PMID:20644722

  3. MIF Promotes Classical Activation and Conversion of Inflammatory Ly6C(high) Monocytes into TipDCs during Murine Toxoplasmosis.

    PubMed

    Ruiz-Rosado, Juan de Dios; Olguín, Jonadab E; Juárez-Avelar, Imelda; Saavedra, Rafael; Terrazas, Luis I; Robledo-Avila, Frank H; Vazquez-Mendoza, Alicia; Fernández, Jacquelina; Satoskar, Abhay R; Partida-Sánchez, Santiago; Rodriguez-Sosa, Miriam

    2016-01-01

    Macrophage migration inhibitory factor (MIF) mediates immunity against Toxoplasma gondii infection by inducing inflammatory cytokines required to control the parasite replication. However, the role of this inflammatory mediator in the cell-mediated immune response against this infection is still poorly understood. Here, we used T. gondii-infected WT and Mif (-/-) mice to analyze the role of MIF in the maturation of CD11b(+) and CD8α (+) dendritic cells (DCs). We found that MIF promotes maturation of CD11b(+) but not CD8α (+) DCs, by inducing IL-12p70 production and CD86 expression. Infected Mif (-/-) mice showed significantly lower numbers of TNF and inducible nitric oxide synthase- (iNOS-) producing DCs (TipDCs) compared to infected WT mice. The adoptive transfer of Ly6C(high) monocytes into infected WT or Mif (-/-) mice demonstrated that MIF participates in the differentiation of Ly6C(high) monocytes into TipDCs. In addition, infected Mif (-/-) mice display a lower percentage of IFN-γ-producing natural killer (NK) cells compared to WT mice, which is associated with reducing numbers of TipDCs in Mif (-/-) mice. Furthermore, administration of recombinant MIF (rMIF) into T. gondii-infected Mif (-/-) mice restored the numbers of TipDCs and reversed the susceptible phenotype of Mif (-/-) mice. Collectively, these results demonstrate an important role for MIF inducing cell-mediated immunity to T. gondii infection. PMID:27057101

  4. The effects of prefrontal cortex transcranial direct current stimulation (tDCS) on food craving and temporal discounting in women with frequent food cravings.

    PubMed

    Kekic, Maria; McClelland, Jessica; Campbell, Iain; Nestler, Steffen; Rubia, Katya; David, Anthony S; Schmidt, Ulrike

    2014-07-01

    Bulimia nervosa, binge-eating disorder, and some forms of obesity are characterised by compulsive overeating that is often precipitated by food craving. Transcranial direct current stimulation (tDCS) has been used to suppress food cravings, but there is insufficient evidence to support its application in clinical practice. Furthermore, the potential moderating role of impulsivity has not been considered. This study used a randomised within-subjects crossover design to examine whether a 20-minute session of sham-controlled bilateral tDCS to the dorsolateral prefrontal cortex (anode right/cathode left) would transiently modify food cravings and temporal discounting (TD; a measure of choice impulsivity) in 17 healthy women with frequent food cravings. Whether the effects of tDCS on food craving were moderated by individual differences in TD behaviour was also explored. Participants were exposed to food and a film of people eating, and food cravings and TD were assessed before and after active and sham stimulation. Craving for sweet but not savoury foods was reduced following real tDCS. Participants that exhibited more reflective choice behaviour were more susceptible to the anti-craving effects of tDCS than those that displayed more impulsive choice behaviour. No differences were seen in TD or food consumption after real versus sham tDCS. These findings support the efficacy of tDCS in temporarily lowering food cravings and identify the moderating role of TD behaviour. PMID:24656950

  5. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  6. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  7. "If two witches would watch two watches, which witch would watch which watch?" tDCS over the left frontal region modulates tongue twister repetition in healthy subjects.

    PubMed

    Fiori, V; Cipollari, S; Caltagirone, C; Marangolo, P

    2014-01-01

    Recent studies have demonstrated that transcranial direct current stimulation (tDCS) modulates cortical activity in the human brain. In the language domain, it has already been shown that during a naming task tDCS reduces vocal reaction times in healthy individuals and speeds up the recovery process in left brain-damaged aphasic subjects. In this study, we wondered whether tDCS would influence the ability to articulate tongue twisters during a repetition task. Three groups of 10 healthy individuals were asked to repeat a list of tongue twisters in three different stimulation conditions: one group performed the task during anodal tDCS (atDCS) (20 min, 2 mA) over the left frontal region; a second group during cathodal tDCS delivered over the same region; and, in a third group, sham stimulation was applied. Accuracy and vocal reaction times in repeating each tongue twister before, during and 1h after the stimulation were recorded. Participants were more accurate and faster at repeating the stimuli during atDCS than at baseline, while cathodal tDCS significantly reduced their performance in terms of accuracy and reaction times. No significant differences were observed among the three time points during the sham condition. We believe that these data clearly confirm that the left frontal region is critically involved in the process of speech repetition. They are also in line with recent evidence suggesting that frontal tDCS might be used as a therapeutic tool in patients suffering from articulatory deficits. PMID:24184977

  8. Estrogen receptor beta agonists in neurobehavioral investigations.

    PubMed

    Choleris, Elena; Clipperton, Amy E; Phan, Anna; Kavaliers, Martin

    2008-07-01

    Neurobehavioral investigations into the functions of estrogen receptor (ER)alpha and ERbeta have utilized 'knockout' mice, phytoestrogens and, more recently, ER-specific agonists. Feeding, sexual, aggressive and social behavior, anxiety, depression, drug abuse, pain perception, and learning (and associated synaptic plasticity) are affected by ERalpha and ERbeta in a manner that is dependent upon the specific behavior studied, gender and developmental stage. Overall, ERalpha and ERbeta appear to function together to foster sociosexual behavior while inhibiting behaviors that, if occurring at the time of behavioral estrous, may compete with reproduction (eg, feeding). Recently developed pharmacological tools have limited selectivity and availability to the research community at large, as they are not commercially available. The development of highly selective, commercially available ERbeta-specific antagonists would greatly benefit preclinical and applied research. PMID:18600582

  9. Non-Benzodiazepine Receptor Agonists for Insomnia.

    PubMed

    Becker, Philip M; Somiah, Manya

    2015-03-01

    Because of proven efficacy, reduced side effects, and less concern about addiction, non-benzodiazepine receptor agonists (non-BzRA) have become the most commonly prescribed hypnotic agents to treat onset and maintenance insomnia. First-line treatment is cognitive-behavioral therapy. When pharmacologic treatment is indicated, non-BzRA are first-line agents for the short-term and long-term management of transient and chronic insomnia related to adjustment, psychophysiologic, primary, and secondary causation. In this article, the benefits and risks of non-BzRA are reviewed, and the selection of a hypnotic agent is defined, based on efficacy, pharmacologic profile, and adverse events. PMID:26055674

  10. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  11. Medical aspects of terrorist bombings - a focus on DCS and DCR.

    PubMed

    Mutafchiyski, Ventsislav M; Popivanov, Georgi I; Kjossev, Kirien C

    2014-01-01

    Although terrorist bombings have tormented the world for a long time, currently they have reached unprecedented levels and become a continuous threat without borders, race or age. Almost all of them are caused by improvised explosive devices. The unpredictability of the terrorist bombings, leading to simultaneous generation of a large number of casualties and severe "multidimensional" blast trauma require a constant vigilance and preparedness of every hospital worldwide. Approximately 1-2.6% of all trauma patients and 7% of the combat casualties require a massive blood transfusion. Coagulopathy is presented in 65% of them with mortality exceeding 50%. Damage control resuscitation is a novel approach, developed in the military practice for treatment of this subgroup of trauma patients. The comparison with the conventional approach revealed mortality reduction with 40-74%, lower frequency of abdominal compartment syndrome (8% vs. 16%), sepsis (9% vs. 20%), multiorgan failure (16% vs. 37%) and a significant reduction of resuscitation volumes, both crystalloids and blood products. DCS and DCR are promising new approaches, contributing for the mortality reduction among the most severely wounded patients. Despite the lack of consensus about the optimal ratio of the blood products and the possible influence of the survival bias, we think that DCR carries survival benefit and recommend it in trauma patients with exsanguinating bleeding. PMID:25722871

  12. DCS: A Case Study of Identification of Knowledge and Disposition Gaps Using Principles of Continuous Risk Management

    NASA Technical Reports Server (NTRS)

    Norcross, Jason; Steinberg, Susan; Kundrot, Craig; Charles, John

    2011-01-01

    The Human Research Program (HRP) is formulated around the program architecture of Evidence-Risk-Gap-Task-Deliverable. Review of accumulated evidence forms the basis for identification of high priority risks to human health and performance in space exploration. Gaps in knowledge or disposition are identified for each risk, and a portfolio of research tasks is developed to fill them. Deliverables from the tasks inform the evidence base with the ultimate goal of defining the level of risk and reducing it to an acceptable level. A comprehensive framework for gap identification, focus, and metrics has been developed based on principles of continuous risk management and clinical care. Research towards knowledge gaps improves understanding of the likelihood, consequence or timeframe of the risk. Disposition gaps include development of standards or requirements for risk acceptance, development of countermeasures or technology to mitigate the risk, and yearly technology assessment related to watching developments related to the risk. Standard concepts from clinical care: prevention, diagnosis, treatment, monitoring, rehabilitation, and surveillance, can be used to focus gaps dealing with risk mitigation. The research plan for the new HRP Risk of Decompression Sickness (DCS) used the framework to identify one disposition gap related to establishment of a DCS standard for acceptable risk, two knowledge gaps related to DCS phenomenon and mission attributes, and three mitigation gaps focused on prediction, prevention, and new technology watch. These gaps were organized in this manner primarily based on target for closure and ease of organizing interim metrics so that gap status could be quantified. Additional considerations for the knowledge gaps were that one was highly design reference mission specific and the other gap was focused on DCS phenomenon.

  13. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. PMID:22269613

  14. [PPAR receptors and insulin sensitivity: new agonists in development].

    PubMed

    Pégorier, J-P

    2005-04-01

    Thiazolidinediones (or glitazones) are synthetic PPARgamma (Peroxisome Proliferator-Activated Receptors gamma) ligands with well recognized effects on glucose and lipid metabolism. The clinical use of these PPARgamma agonists in type 2 diabetic patients leads to an improved glycemic control and an inhanced insulin sensitivity, and at least in animal models, to a protective effect on pancreatic beta-cell function. However, they can produce adverse effects, generally mild or moderate, but some of them (mainly peripheral edema and weight gain) may conduct to treatment cessation. Several pharmacological classes are currently in pre-clinical or clinical development, with the objective to retain the beneficial metabolic properties of PPARgamma agonists, either alone or in association with the PPARalpha agonists (fibrates) benefit on lipid profile, but devoid of the side-effects on weight gain and fluid retention. These new pharmacological classes: partial PPARgamma agonists, PPARgamma antagonists, dual PPARalpha/PPARgamma agonists, pan PPARalpha/beta(delta)/gamma agonists, RXR receptor agonists (rexinoids), are presented in this review. Main results from in vitro cell experiments and animal model studies are discussed, as well as the few published short-term studies in type 2 diabetic patients. PMID:15959400

  15. Risk versus benefit considerations for the beta(2)-agonists.

    PubMed

    Kelly, H William

    2006-09-01

    Short-acting beta(2)-agonists are the mainstay of therapy for acute bronchospasm associated with asthma and chronic obstructive pulmonary disease, whereas long-acting beta(2)-agonists are used in maintaining disease control in these respiratory disorders. This review describes and compares the pharmacology of the beta(2)-agonists and explains how these differences translate into differences in efficacy and beta(2)-adrenergic-mediated adverse effects. Questions commonly asked by clinicians regarding the efficacy and safety of short- and long-acting beta(2)-agonists include issues about cardiovascular effects, tolerance to their bronchodilator and bronchoprotective effects, blunting of albuterol response by long-acting beta(2)-agonists, potential masking of worsening asthma control, and the role of long-acting beta(2)-agonists as adjunctive therapy with inhaled corticosteroids in maintaining asthma control. Pharmacogenetics may play a role in determining which patients may be at risk for a reduced response to a beta(2)-agonist. The continued use of racemic albuterol, which contains a mixture of R-albuterol and S-albuterol, has been questioned because of data from preclinical and clinical studies suggesting that S-albuterol causes proinflammatory effects and may increase bronchial hyperreactivity. The preclinical and clinical effects of these two stereoisomers are reviewed. Data describing the efficacy and safety of levalbuterol (R-albuterol) and racemic albuterol are presented. PMID:16945063

  16. FIXATION OF SUPRACONDYLAR FEMORAL FRACTURES: A BIOMECHANICAL ANALYSIS COMPARING 95° BLADE PLATES AND DYNAMIC CONDYLAR SCREWS (DCS)

    PubMed Central

    Percope Andrade, Marco Antônio; Rodrigues, André Soares; Mendonça, Celso Junio; Santos Portela, Luiz Gustavo

    2015-01-01

    Objective: To determine, by means of comparative biomechanical tests, whether greater compressive load resistance and flexion is presented by 95° angled blade plates or by dynamic condylar screws (DCS), and to correlate the failure type presented during the tests with each type of plate. Methods: Sixty-five porcine femurs were subjected to 1 cm medial wedge osteotomy, in the metaphysis, to simulate an unstable supracondylar femoral fracture. Osteosynthesis was performed on these pieces: 35 were fixed using 95° lateral blade plates and 30 with DCS plates. Another variable studied was the failure type presented in each group, in an attempt to correlate this with the type of plate. Results: There were no statistically significant differences in biomechanical resistance between the two types of plates, or between the failure type and the plate type used for the osteosynthesis. Conclusion: The two types of plate behaved in a similar fashion. However, the angled blade plate proved to be superior to the DCS in the flexion test. No statistical difference in failure type or type of plate used was observed. PMID:27022525

  17. Enhancing verbal creativity: modulating creativity by altering the balance between right and left inferior frontal gyrus with tDCS.

    PubMed

    Mayseless, N; Shamay-Tsoory, S G

    2015-04-16

    Creativity is the production of novel ideas that have value. Previous research indicated that while regions in the right hemisphere are implicated in the production of new ideas, damage to the left inferior frontal gyrus (IFG) is associated with increased creativity, indicating that the left IFG damage may have a "releasing" effect on creativity. To examine this, in the present study we used transcranial direct current stimulation (tDCS) to modulate activity of the right and the left IFG. In the first experiment we show that whereas anodal tDCS over the right IFG coupled with cathodal tDCS over the left IFG increases creativity as measured by a verbal divergent thinking task, the reverse stimulation does not affect creative production. To further confirm that only altering the balance between the two hemispheres is crucial in modulating creativity, in the second experiment we show that stimulation targeting separately the left IFG (cathodal stimulation) or the right IFG (anodal stimulation) did not result in changes in creativity as measured by verbal divergent thinking. These findings support the balance hypothesis, according to which verbal creativity requires a balance of activation between the right and the left frontal lobes, and more specifically, between the right and the left IFG. PMID:25659343

  18. Brain mechanisms of semantic interference in spoken word production: An anodal transcranial Direct Current Stimulation (atDCS) study.

    PubMed

    Meinzer, Marcus; Yetim, Özlem; McMahon, Katie; de Zubicaray, Greig

    2016-01-01

    When naming pictures, categorically-related compared to unrelated contexts typically slow production. We investigated proposed roles for the left inferior frontal gyrus (LIFG) and posterior middle and superior temporal gyri (pMTG/STG) in mediating this semantic interference effect. In a three-way, cross-over, sham-controlled study, we applied online anodal transcranial Direct Current Stimulation (atDCS) to LIFG or pMTG/STG while 24 participants performed parallel versions of the blocked cyclic naming paradigm. Significant effects of semantic context and cycle, and interactions of context and cycle, were observed on naming latencies in all three stimulation sessions. Additionally, atDCS over left pMTG/STG facilitated naming in related blocks from the second cycle onward, significantly reducing but not eliminating the interference effect. Applying atDCS over left LIFG likewise reduced the magnitude of interference compared to sham stimulation, although the facilitation was limited to the first few cycles of naming. We interpret these results as indicating semantic interference in picture naming reflects contributions of two complementary mechanisms: a relatively short-lived, top-down mechanism to bias selection and a more persistent lexical-level activation mechanism. PMID:27180210

  19. Safety review of the DCS (Distributed Control System) controlled full scale SRAT/SME (Sludge Receipt Adjustment Tank/Slurry Mix Evaporator) for water runs

    SciTech Connect

    Hacker, B.A.

    1988-01-29

    This memorandum addresses safety concerns of the Full Scale Sludge Receipt Adjustment Tank/Slurry Mix Evaporator (SRAT/SME) resulting from the installation of the new Distributed Control System (DCS). The present configuration of the SRAT/SME with DCS has been determined to be safe for operational testing with water. Another memorandum will be written after experience has been gained during water runs for actual operation. Previous safety evaluations and process hazard reviews for this facility have addressed normal industrial safety hazards and hazards associated with formic acid handling and operation with organics in the feed. Process operation with the new DCS controls will be very similar to the earlier operation controlled by the Modicon programmable logic controller (PLC). The interlocks for the SRAT/SME that were in the PLC have been programmed into the new DCS and will be reviewed here. 6 refs.

  20. Dopamine agonist withdrawal syndrome: implications for patient care.

    PubMed

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper. PMID:23686524

  1. In Vivo Approaches Reveal a Key Role for DCs in CD4+ T Cell Activation and Parasite Clearance during the Acute Phase of Experimental Blood-Stage Malaria

    PubMed Central

    Borges da Silva, Henrique; Fonseca, Raíssa; Cassado, Alexandra dos Anjos; Machado de Salles, Érika; de Menezes, Maria Nogueira; Langhorne, Jean; Perez, Katia Regina; Cuccovia, Iolanda Midea; Ryffel, Bernhard; Barreto, Vasco M.; Marinho, Cláudio Romero Farias; Boscardin, Silvia Beatriz; Álvarez, José Maria; D’Império-Lima, Maria Regina; Tadokoro, Carlos Eduardo

    2015-01-01

    Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection. PMID:25658925

  2. Supra-physiological efficacy at GPCRs: superstition or super agonists?

    PubMed

    Langmead, Christopher J; Christopoulos, Arthur

    2013-05-01

    The concept of 'super agonism' has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. PMID:23441648

  3. Effects of a common transcranial direct current stimulation (tDCS) protocol on motor evoked potentials found to be highly variable within individuals over 9 testing sessions.

    PubMed

    Horvath, Jared Cooney; Vogrin, Simon J; Carter, Olivia; Cook, Mark J; Forte, Jason D

    2016-09-01

    Transcranial direct current stimulation (tDCS) uses a weak electric current to modulate neuronal activity. A neurophysiologic outcome measure to demonstrate reliable tDCS modulation at the group level is transcranial magnetic stimulation engendered motor evoked potentials (MEPs). Here, we conduct a study testing the reliability of individual MEP response patterns following a common tDCS protocol. Fourteen participants (7m/7f) each underwent nine randomized sessions of 1 mA, 10 min tDCS (3 anode; 3 cathode; 3 sham) delivered using an M1/orbito-frontal electrode montage (sessions separated by an average of ~5.5 days). Fifteen MEPs were obtained prior to, immediately following and in 5 min intervals for 30 min following tDCS. TMS was delivered at 130 % resting motor threshold using neuronavigation to ensure consistent coil localization. A number of non-experimental variables were collected during each session. At the individual level, considerable variability was seen among different testing sessions. No participant demonstrated an excitatory response ≥20 % to all three anodal sessions, and no participant demonstrated an inhibitory response ≥20 % to all three cathodal sessions. Intra-class correlation revealed poor anodal and cathodal test-retest reliability [anode: ICC(2,1) = 0.062; cathode: ICC(2,1) = 0.055] and moderate sham test-retest reliability [ICC(2,1) = 0.433]. Results also revealed no significant effect of tDCS at the group level. Using this common protocol, we found the effects of tDCS on MEP amplitudes to be highly variable at the individual level. In addition, no significant effects of tDCS on MEP amplitude were found at the group level. Future studies should consider utilizing a more strict experimental protocol to potentially account for intra-individual response variations. PMID:27150317

  4. M-cell targeted polymeric lipid nanoparticles containing a Toll-like receptor agonist to boost oral immunity.

    PubMed

    Ma, Tongtong; Wang, Lianyan; Yang, Tingyuan; Ma, Guanghui; Wang, Siling

    2014-10-01

    Oral delivery of antigens is patient-friendly and efficient way of treating intestinal infections. However, the efficacy of oral vaccines is limited by degradation in the gastrointestinal (GI) tract and poor absorption by enterocytes and antigen-presenting cells (APC). Here we report ulex europaeus agglutinin-1 (UEA-1) conjugated poly (D,L-lactide-co-glycolide) (PLGA)-lipid nanoparticles (NP) containing a Toll-like receptor (TLR)-agonist monophosphoryl lipid A (MPL) as an oral vaccine delivery system. The uniform-sized PLGA-lipid NPs (simplified as lipid NPs) were produced by the premix membrane emulsification method. They can protect the entrapped model antigen ovalbumin (OVA) from exposure to the GI tract and release the OVA in a controlled manner. With UEA-1 and MPL modification, the UEA-MPL/lipid NPs can be effectively transported by M-cells and captured by mucosal dendritic cells (DCs). After in vivo vaccination, the OVA-UEA-MPL/lipid NPs stimulated the most effective mucosal IgA and serum IgG antibodies during the oral formulations. These results suggest that this MPL containing M-cell targeted lipid NP can potentially be used as a universally robust oral vaccine delivery system. PMID:24984067

  5. Wearable functional near infrared spectroscopy (fNIRS) and transcranial direct current stimulation (tDCS): expanding vistas for neurocognitive augmentation

    PubMed Central

    McKendrick, Ryan; Parasuraman, Raja; Ayaz, Hasan

    2015-01-01

    Contemporary studies with transcranial direct current stimulation (tDCS) provide a growing base of evidence for enhancing cognition through the non-invasive delivery of weak electric currents to the brain. The main effect of tDCS is to modulate cortical excitability depending on the polarity of the applied current. However, the underlying mechanism of neuromodulation is not well understood. A new generation of functional near infrared spectroscopy (fNIRS) systems is described that are miniaturized, portable, and include wearable sensors. These developments provide an opportunity to couple fNIRS with tDCS, consistent with a neuroergonomics approach for joint neuroimaging and neurostimulation investigations of cognition in complex tasks and in naturalistic conditions. The effects of tDCS on complex task performance and the use of fNIRS for monitoring cognitive workload during task performance are described. Also explained is how fNIRS + tDCS can be used simultaneously for assessing spatial working memory. Mobile optical brain imaging is a promising neuroimaging tool that has the potential to complement tDCS for realistic applications in natural settings. PMID:25805976

  6. Transcranial direct current stimulation (tDCS) in behavioral and food addiction: a systematic review of efficacy, technical, and methodological issues

    PubMed Central

    Sauvaget, Anne; Trojak, Benoît; Bulteau, Samuel; Jiménez-Murcia, Susana; Fernández-Aranda, Fernando; Wolz, Ines; Menchón, José M.; Achab, Sophia; Vanelle, Jean-Marie; Grall-Bronnec, Marie

    2015-01-01

    Objectives: Behavioral addictions (BA) are complex disorders for which pharmacological and psychotherapeutic treatments have shown their limits. Non-invasive brain stimulation, among which transcranial direct current stimulation (tDCS), has opened up new perspectives in addiction treatment. The purpose of this work is to conduct a critical and systematic review of tDCS efficacy, and of technical and methodological considerations in the field of BA. Methods: A bibliographic search has been conducted on the Medline and ScienceDirect databases until December 2014, based on the following selection criteria: clinical studies on tDCS and BA (namely eating disorders, compulsive buying, Internet addiction, pathological gambling, sexual addiction, sports addiction, video games addiction). Study selection, data analysis, and reporting were conducted according to the PRISMA guidelines. Results: Out of 402 potential articles, seven studies were selected. So far focusing essentially on abnormal eating, these studies suggest that tDCS (right prefrontal anode/left prefrontal cathode) reduces food craving induced by visual stimuli. Conclusions: Despite methodological and technical differences between studies, the results are promising. So far, only few studies of tDCS in BA have been conducted. New research is recommended on the use of tDCS in BA, other than eating disorders. PMID:26500478

  7. Siglec-1-positive plasmacytoid dendritic cells (pDCs) in human peripheral blood: A semi-mature and myeloid-like subset imbalanced during protective and autoimmune responses.

    PubMed

    Wilhelm, Theresa R; Taddeo, Adriano; Winter, Oliver; Schulz, Axel Ronald; Mälzer, Julia-Nora; Domingo, Cristina; Biesen, Robert; Alexander, Tobias; Thiel, Andreas; Radbruch, Andreas; Hiepe, Falk; Gerl, Velia

    2016-02-01

    Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of systemic lupus erythematosus (SLE) as IFN-α producers and promoters of T-cell activation or tolerance. Here, we demonstrated by flow-cytometry and confocal microscopy that Siglec-1, a molecule involved in the regulation of adaptive immunoresponses, is expressed in a subset of semi-mature, myeloid-like pDCs in human blood. These pDCs express lower BDCA-2 and CD123 and higher HLA-DR and CD11c than Siglec-1-negative pDCs and do not produce IFN-α via TLR7/TLR9 engagement. In vitro, Siglec-1 expression was induced in Siglec-1-negative pDCs by influenza virus. Proportions of Siglec-1-positive/Siglec-1-negative pDCs were higher in SLE than in healthy controls and correlated with disease activity. Healthy donors immunized with yellow fever vaccine YFV-17D displayed different kinetics of the two pDC subsets during protective immune response. PDCs can be subdivided into two subsets according to Siglec-1 expression. These subsets may play specific roles in (auto)immune responses. PMID:26674280

  8. Relamorelin: A Novel Gastrocolokinetic Synthetic Ghrelin Agonist

    PubMed Central

    Camilleri, Michael; Acosta, Andres

    2015-01-01

    Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately 6-fold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin. In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a pre-specified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders. PMID:25545036

  9. Selecting agonists from single cells infected with combinatorial antibody libraries.

    PubMed

    Zhang, Hongkai; Yea, Kyungmoo; Xie, Jia; Ruiz, Diana; Wilson, Ian A; Lerner, Richard A

    2013-05-23

    We describe a system for direct selection of antibodies that are receptor agonists. Combinatorial antibody libraries in lentiviruses are used to infect eukaryotic cells that contain a fluorescent reporter system coupled to the receptor for which receptor agonist antibodies are sought. In this embodiment of the method, very large numbers of candidate antibodies expressing lentivirus and eukaryotic reporter cells are packaged together in a format where each is capable of replication, thereby forging a direct link between genotype and phenotype. Following infection, cells that fluoresce are sorted and the integrated genes encoding the agonist antibodies recovered. We validated the system by illustrating its ability to generate rapidly potent antibody agonists that are complete thrombopoietin phenocopies. The system should be generalizable to any pathway where its activation can be linked to production of a selectable phenotype. PMID:23706638

  10. Therapeutic Potential of 5-HT6 Receptor Agonists.

    PubMed

    Karila, Delphine; Freret, Thomas; Bouet, Valentine; Boulouard, Michel; Dallemagne, Patrick; Rochais, Christophe

    2015-10-22

    Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox. PMID:26099069

  11. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    PubMed

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. PMID:20579229

  12. Selective 5-HT2C agonists as potential antidepressants.

    PubMed

    Leysen, D C

    1999-02-01

    The antidepressants currently used need improvement, especially in terms of efficacy, relapse rate and onset of action. In this review the clinical and experimental data which support the rationale for 5-HT2C agonists in the treatment of depression are listed. Next, the results obtained with the non-selective 5-HT2C agonists on the market and in clinical development are described. Finally, the preclinical data on the more selective 5-HT2C agonists are summarized. These recent preclinical results reveal a greater potency and effect size compared to fluoxetine, good tolerability and no evidence of tolerance development. Selective 5-HT2C agonists might become innovative drugs for the treatment of depression, panic, obsessive-compulsive disorder (OCD), some forms of aggression and eating disorders. PMID:16160946

  13. Agonist pharmacology of two Drosophila GABA receptor splice variants.

    PubMed Central

    Hosie, A. M.; Sattelle, D. B.

    1996-01-01

    1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of

  14. Sleep attacks in patients taking dopamine agonists: review

    PubMed Central

    Homann, Carl Nikolaus; Wenzel, Karoline; Suppan, Klaudia; Ivanic, Gerd; Kriechbaum, Norbert; Crevenna, Richard; Ott, Erwin

    2002-01-01

    Objectives To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. Design Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinson's disease. Results 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. Conclusion Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinson's disease. Prospective population based studies are needed to provide this information. What is already known on this topicCar crashes in patients with Parkinson's disease have been associated with sleep attacks caused by the dopamine agonists pramipexole and ropiniroleWhether sleep attacks exist, their connection with certain agonists, prevention or treatment, and the justification of legal actions are controversialWhat this study addsSleep attacks as a phenomenon distinct from normal somnolence really do existThey are a class effect of all dopamine drugsEffective prevention and treatment

  15. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  16. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25326839

  17. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25437461

  18. PPAR dual agonists: are they opening Pandora's Box?

    PubMed

    Balakumar, Pitchai; Rose, Madhankumar; Ganti, Subrahmanya S; Krishan, Pawan; Singh, Manjeet

    2007-08-01

    Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in

  19. Mechanisms of inverse agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Strange, Philip G

    2005-05-01

    Mechanisms of inverse agonist action at the D2(short) dopamine receptor have been examined. Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [3H]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. Competition of inverse agonists versus [3H]NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. K(i) values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. K(coupled) and K(uncoupled) were statistically different for the set of compounds tested (ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. These observations were supported by simulations of these competition experiments according to the extended ternary complex model. Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [35S]GTP gamma S binding to varying degrees in concentration-response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (-)-sulpiride was unaffected. These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism. PMID:15735658

  20. Differential effects of AMPK agonists on cell growth and metabolism

    PubMed Central

    Vincent, Emma E.; Coelho, Paula P.; Blagih, Julianna; Griss, Takla; Viollet, Benoit; Jones, Russell G.

    2016-01-01

    As a sensor of cellular energy status, the AMP-activated protein kinase (AMPK) is believed to act in opposition to the metabolic phenotypes favored by proliferating tumor cells. Consequently, compounds known to activate AMPK have been proposed as cancer therapeutics. However, the extent to which the anti-neoplastic properties of these agonists are mediated by AMPK is unclear. Here we examined the AMPK-dependence of six commonly used AMPK agonists (metformin, phenformin, AICAR, 2DG, salicylate and A-769662) and their influence on cellular processes often deregulated in tumor cells. We demonstrate that the majority of these agonists display AMPK-independent effects on cell proliferation and metabolism with only the synthetic activator, A-769662, exerting AMPK-dependent effects on these processes. We find that A-769662 promotes an AMPK-dependent increase in mitochondrial spare respiratory capacity (SRC). Finally, contrary to the view of AMPK activity being tumor suppressive, we find A-769662 confers a selective proliferative advantage to tumor cells growing under nutrient deprivation. Our results indicate that many of the anti-growth properties of these agonists cannot be attributed to AMPK activity in cells, and thus any observed effects using these agonists should be confirmed using AMPK-deficient cells. Ultimately, our data urge caution, not only regarding the type of AMPK agonist proposed for cancer treatment, but also the context in which they are used. PMID:25241895

  1. Perception of specific trigeminal chemosensory agonists

    PubMed Central

    Frasnelli, J; Albrecht, J; Bryant, B; Lundström, JN

    2011-01-01

    The intranasal trigeminal system is a third chemical sense in addition to olfaction and gustation. As opposed to smell and taste, we still lack knowledge on the relationship between receptor binding and perception for the trigeminal system. We therefore investigated the sensitivity of the intranasal trigeminal system towards agonists of the trigeminal receptors TRPM8 and TRPA1 by assessing subjects’ ability to identify which nostril has been stimulated in a monorhinal stimulation design. We summed the number of correct identifications resulting in a lateralization score. Stimuli were menthol (activating TRPM8 receptors), eucalyptol (TRPM8), mustard oil (TRPA1) and two mixtures thereof (menthol/eucalyptol and menthol/mustard oil). In addition, we examined the relationship between intensity and lateralization scores and investigated whether intensity evaluation and lateralization scores of the mixtures show additive effects. All stimuli were correctly lateralized significantly above chance. Across subjects the lateralization scores for single compounds activating the same receptor showed a stronger correlation than stimuli activating different receptors. Although single compounds were isointense, the mixture of menthol and eucalyptol (activating only TRPM8) was perceived as weaker and was lateralized less accurately than the mixture of menthol and mustard oil (activating both TRPM8 and TRPA1) suggesting suppression effects in the former mixture. In conclusion, sensitivity of different subpopulations of trigeminal sensory neurons seems to be related, but only to a certain degree. The large coherence in sensitivity between various intranasal trigeminal stimuli suggests that measuring sensitivity to one single trigeminal chemical stimulus may be sufficient to generally assess the trigeminal system’s chemosensitivity. Further, for stimuli activating the same receptor a mixture suppression effect appears to occur similar to that observed in the other chemosensory

  2. Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

    PubMed Central

    Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Cöster, Maxi; Wittkopf, Doreen; Meiler, Jens

    2013-01-01

    The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3′-OH of the 2′-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID:23093496

  3. Computational Pipeline for NIRS-EEG Joint Imaging of tDCS-Evoked Cerebral Responses—An Application in Ischemic Stroke

    PubMed Central

    Guhathakurta, Debarpan; Dutta, Anirban

    2016-01-01

    Transcranial direct current stimulation (tDCS) modulates cortical neural activity and hemodynamics. Electrophysiological methods (electroencephalography-EEG) measure neural activity while optical methods (near-infrared spectroscopy-NIRS) measure hemodynamics coupled through neurovascular coupling (NVC). Assessment of NVC requires development of NIRS-EEG joint-imaging sensor montages that are sensitive to the tDCS affected brain areas. In this methods paper, we present a software pipeline incorporating freely available software tools that can be used to target vascular territories with tDCS and develop a NIRS-EEG probe for joint imaging of tDCS-evoked responses. We apply this software pipeline to target primarily the outer convexity of the brain territory (superficial divisions) of the middle cerebral artery (MCA). We then present a computational method based on Empirical Mode Decomposition of NIRS and EEG time series into a set of intrinsic mode functions (IMFs), and then perform a cross-correlation analysis on those IMFs from NIRS and EEG signals to model NVC at the lesional and contralesional hemispheres of an ischemic stroke patient. For the contralesional hemisphere, a strong positive correlation between IMFs of regional cerebral hemoglobin oxygen saturation and the log-transformed mean-power time-series of IMFs for EEG with a lag of about −15 s was found after a cumulative 550 s stimulation of anodal tDCS. It is postulated that system identification, for example using a continuous-time autoregressive model, of this coupling relation under tDCS perturbation may provide spatiotemporal discriminatory features for the identification of ischemia. Furthermore, portable NIRS-EEG joint imaging can be incorporated into brain computer interfaces to monitor tDCS-facilitated neurointervention as well as cortical reorganization. PMID:27378836

  4. Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: A basis for high-definition tDCS

    PubMed Central

    Edwards, Dylan; Cortes, Mar; Datta, Abhishek; Minhas, Preet; Wassermann, Eric M.; Bikson, Marom

    2015-01-01

    Transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost, well-tolerated technique producing lasting modulation of cortical excitability. Behavioral and therapeutic outcomes of tDCS are linked to the targeted brain regions, but there is little evidence that current reaches the brain as intended. We aimed to: (1) validate a computational model for estimating cortical electric fields in human transcranial stimulation, and (2) assess the magnitude and spread of cortical electric field with a novel High-Definition tDCS (HD-tDCS) scalp montage using a 4×1-Ring electrode configuration. In three healthy adults, Transcranial Electrical Stimulation (TES) over primary motor cortex (M1) was delivered using the 4×1 montage (4× cathode, surrounding a single central anode; montage radius ~3 cm) with sufficient intensity to elicit a discrete muscle twitch in the hand. The estimated current distribution in M1 was calculated using the individualized MRI-based model, and compared with the observed motor response across subjects. The response magnitude was quantified with stimulation over motor cortex as well as anterior and posterior to motor cortex. In each case the model data were consistent with the motor response across subjects. The estimated cortical electric fields with the 4×1 montage were compared (area, magnitude, direction) for TES and tDCS in each subject. We provide direct evidence in humans that TES with a 4×1-Ring configuration can activate motor cortex and that current does not substantially spread outside the stimulation area. Computational models predict that both TES and tDCS waveforms using the 4×1-Ring configuration generate electric fields in cortex with comparable gross current distribution, and preferentially directed normal (inward) currents. The agreement of modeling and experimental data for both current delivery and focality support the use of the HD-tDCS 4×1-Ring montage for cortically targeted neuromodulation. PMID:23370061

  5. Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (HD-tDCS).

    PubMed

    Villamar, Mauricio F; Volz, Magdalena Sarah; Bikson, Marom; Datta, Abhishek; Dasilva, Alexandre F; Fregni, Felipe

    2013-01-01

    High-definition transcranial direct current stimulation (HD-tDCS) has recently been developed as a noninvasive brain stimulation approach that increases the accuracy of current delivery to the brain by using arrays of smaller "high-definition" electrodes, instead of the larger pad-electrodes of conventional tDCS. Targeting is achieved by energizing electrodes placed in predetermined configurations. One of these is the 4x1-ring configuration. In this approach, a center ring electrode (anode or cathode) overlying the target cortical region is surrounded by four return electrodes, which help circumscribe the area of stimulation. Delivery of 4x1-ring HD-tDCS is capable of inducing significant neurophysiological and clinical effects in both healthy subjects and patients. Furthermore, its tolerability is supported by studies using intensities as high as 2.0 milliamperes for up to twenty minutes. Even though 4x1 HD-tDCS is simple to perform, correct electrode positioning is important in order to accurately stimulate target cortical regions and exert its neuromodulatory effects. The use of electrodes and hardware that have specifically been tested for HD-tDCS is critical for safety and tolerability. Given that most published studies on 4x1 HD-tDCS have targeted the primary motor cortex (M1), particularly for pain-related outcomes, the purpose of this article is to systematically describe its use for M1 stimulation, as well as the considerations to be taken for safe and effective stimulation. However, the methods outlined here can be adapted for other HD-tDCS configurations and cortical targets. PMID:23893039

  6. Differential response to anodal tDCS and PAS is indicative of impaired focal LTP-like plasticity in schizophrenia.

    PubMed

    Strube, Wolfgang; Bunse, Tilmann; Nitsche, Michael A; Palm, Ulrich; Falkai, Peter; Hasan, Alkomiet

    2016-09-15

    Increasing evidence suggests that neural plasticity impairments, observed in schizophrenia patients, are driven by dysfunctional integration of neural signaling. However, what is less clear is whether this impairment is resultant from a general deficit in plastic induction or whether a specific plastic mechanism is affected. In the current study we aimed to assess whether schizophrenia has a selective impact on focal or non-focal plasticity induction. To pursue this goal we utilized two non-invasive stimulation techniques that differ in the mechanism of long-term potentiation (LTP)-like plasticity induction: focal paired associative stimulation (PAS) and non-focal anodal transcranial direct current stimulation (a-tDCS). 20 schizophrenia patients and 20 matched healthy controls received PAS and a-tDCS in two separate sessions. Cortical excitability and cortical plasticity were assessed by transcranial magnetic stimulation (TMS)-elicited motor evoked potentials (MEP). In both study groups, non-focal a-tDCS resulted in a significant increase of mean MEP magnitude indicating the successful induction of non-focal LTP-like plasticity. In contrast, an increase in mean MEP magnitude following PAS was only observed in the control group, suggesting impaired focal LTP-like plasticity in schizophrenia. Additionally, we observed significantly impaired short-latency intracortical inhibition (SICI) in schizophrenia. This is the first study to comparatively evaluate non-focal and focal plasticity mechanisms in schizophrenia patients. The differential patterns of LTP-like plasticity responses indicate that reduced plasticity in schizophrenia could be ascribed to impairments in spatially and temporally restricted signal integration. This impairment, coupled with an observed reduction of inhibitory circuit efficacy, might further contribute to impairments in coordinating focal signals. PMID:27185738

  7. Carcinogenicity study of GSM and DCS wireless communication signals in B6C3F1 mice.

    PubMed

    Tillmann, Thomas; Ernst, Heinrich; Ebert, Sven; Kuster, Niels; Behnke, Wolfgang; Rittinghausen, Susanne; Dasenbrock, Clemens

    2007-04-01

    The purpose of this study using a total of 1170 B6C3F1 mice was to detect and evaluate possible carcinogenic effects in mice exposed to radio-frequency-radiation (RFR) from Global System for Mobile Communication (GSM) and Digital Personal Communications System (DCS) handsets as emitted by handsets operating in the center of the communication band, that is, at 902 MHz (GSM) and 1747 MHz (DCS). Restrained mice were exposed for 2 h per day, 5 days per week over a period of 2 years to three different whole-body averaged specific absorption rate (SAR) levels of 0.4, 1.3, 4.0 mW/g bw (SAR), or were sham exposed. Regarding the organ-related tumor incidence, pairwise Fisher's test did not show any significant increase in the incidence of any particular tumor type in the RF exposed groups as compared to the sham exposed group. Interestingly, while the incidences of hepatocellular carcinomas were similar in EMF and sham exposed groups, in both studies the incidences of liver adenomas in males decreased with increasing dose levels; the incidences in the high dose groups were statistically significantly different from those in the sham exposed groups. Comparison to published tumor rates in untreated mice revealed that the observed tumor rates were within the range of historical control data. In conclusion, the present study produced no evidence that the exposure of male and female B6C3F1 mice to wireless GSM and DCS radio frequency signals at a whole body absorption rate of up to 4.0 W/kg resulted in any adverse health effect or had any cumulative influence on the incidence or severity of neoplastic and non-neoplastic background lesions, and thus the study did not provide any evidence of RF possessing a carcinogenic potential. PMID:17019729

  8. Effect of mirror therapy with tDCS on functional recovery of the upper extremity of stroke patients

    PubMed Central

    Cho, Hyuk-Shin; Cha, Hyun-gyu

    2015-01-01

    [Purpose] This study aimed to determine the effect of mirror therapy (MT) with transcranial direct current stimulation (tDCS) on the recovery of the upper extremity function of chronic stroke patients. [Subjects] Twenty-seven patients at least 6 months after stroke onset were divided randomly into an experimental group (14 patients) and a control group (13 patients). [Methods] All subjects received tDCS for 20 min followed by a 5 min rest. Then the experimental group received MT while the control group conducted the same exercises as the experimental group using a mirror that did not show the non-paretic upper extremity. The groups performed the same exercises for 20 min. All subjects received this intervention for 45-min three times a week for 6 weeks. [Results] After the intervention, the experimental group showed significant improvements in the box and block test (BBT), grip strength, and the Fugl-Meyer assessment (FMA), and a significant decrease in the Jebsen-Taylor test. The control group showed a significant increase in grip strength after the intervention, and a significant decrease in the Jebsen-Taylor test. Comparison of the result after the intervention revealed that the experimental group showed more significant increases in the BBT and grip strength than the control group. [Conclusion] These results show that MT with tDCS has a positive effect on the functional recovery of the upper extremity of stroke patients, through activating motor regions in the brain, and thus plays an important role in recovery of neuroplasticity. PMID:25995552

  9. Effect of mirror therapy with tDCS on functional recovery of the upper extremity of stroke patients.

    PubMed

    Cho, Hyuk-Shin; Cha, Hyun-Gyu

    2015-04-01

    [Purpose] This study aimed to determine the effect of mirror therapy (MT) with transcranial direct current stimulation (tDCS) on the recovery of the upper extremity function of chronic stroke patients. [Subjects] Twenty-seven patients at least 6 months after stroke onset were divided randomly into an experimental group (14 patients) and a control group (13 patients). [Methods] All subjects received tDCS for 20 min followed by a 5 min rest. Then the experimental group received MT while the control group conducted the same exercises as the experimental group using a mirror that did not show the non-paretic upper extremity. The groups performed the same exercises for 20 min. All subjects received this intervention for 45-min three times a week for 6 weeks. [Results] After the intervention, the experimental group showed significant improvements in the box and block test (BBT), grip strength, and the Fugl-Meyer assessment (FMA), and a significant decrease in the Jebsen-Taylor test. The control group showed a significant increase in grip strength after the intervention, and a significant decrease in the Jebsen-Taylor test. Comparison of the result after the intervention revealed that the experimental group showed more significant increases in the BBT and grip strength than the control group. [Conclusion] These results show that MT with tDCS has a positive effect on the functional recovery of the upper extremity of stroke patients, through activating motor regions in the brain, and thus plays an important role in recovery of neuroplasticity. PMID:25995552

  10. Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist

    PubMed Central

    Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

    2015-01-01

    BACKGROUND AND PURPOSE The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg−1), unmasked etorphine (3 mg·kg−1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg−1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg−1) and diazepam (1 mg·kg−1). CONCLUSIONS AND IMPLICATIONS Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles

  11. Dihydrocodeine/Agonists for Alcohol Dependents

    PubMed Central

    Ulmer, Albrecht; Müller, Markus; Frietsch, Bernhard

    2012-01-01

    Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients. Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6 weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details. Conclusion: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further

  12. Agonists and antagonists for P2 receptors

    PubMed Central

    Jacobson, Kenneth A.; Costanzi, Stefano; Joshi, Bhalchandra V.; Besada, Pedro; Shin, Dae Hong; Ko, Hyojin; Ivanov, Andrei A.; Mamedova, Liaman

    2015-01-01

    Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. PMID:16805423

  13. Transcranial Direct Current Stimulation (tDCS) of the visual cortex: a proof-of-concept study based on interictal electrophysiological abnormalities in migraine

    PubMed Central

    2013-01-01

    Background Preventive pharmacotherapy for migraine is not satisfactory because of the low efficacy/tolerability ratio of many available drugs. Novel and more efficient preventive strategies are therefore warranted. Abnormal excitability of cortical areas appears to play a pivotal role in migraine pathophysiology. Transcranial direct current stimulation (tDCS) is a non-invasive and safe technique that is able to durably modulate the activity of the underlying cerebral cortex, and is being tested in various medical indications. The results of small open studies using tDCS in migraine prophylaxis are conflicting, possibly because the optimal stimulation settings and the brain targets were not well chosen. We have previously shown that the cerebral cortex, especially the visual cortex, is hyperresponsive in migraine patients between attacks and provided evidence from evoked potential studies that this is due to a decreased cortical preactivation level. If one accepts this concept, anodal tDCS over the visual cortex may have therapeutic potentials in migraine prevention, as it is able to increase neuronal firing. Objective To study the effects of anodal tDCS on visual cortex activity in healthy volunteers (HV) and episodic migraine without aura patients (MoA), and its potentials for migraine prevention. Methods We recorded pattern-reversal visual evoked potentials (VEP) before and after a 15-min session of anodal tDCS over the visual cortex in 11 HV and 13 MoA interictally. Then 10 MoA patients reporting at least 4 attacks/month subsequently participated in a therapeutic study, and received 2 similar sessions of tDCS per week for 8 weeks as migraine preventive therapy. Results In HV as well as in MoA, anodal tDCS transiently increased habituation of the VEP N1P1 component. VEP amplitudes were not modified by tDCS. Preventive treatment with anodal tDCS turned out to be beneficial in MoA: migraine attack frequency, migraine days, attack duration and acute medication

  14. State-of-art neuroanatomical target analysis of high-definition and conventional tDCS montages used for migraine and pain control.

    PubMed

    DaSilva, Alexandre F; Truong, Dennis Q; DosSantos, Marcos F; Toback, Rebecca L; Datta, Abhishek; Bikson, Marom

    2015-01-01

    Although transcranial direct current stimulation (tDCS) studies promise to modulate cortical regions associated with pain, the electric current produced usually spreads beyond the area of the electrodes' placement. Using a forward-model analysis, this study compared the neuroanatomic location and strength of the predicted electric current peaks, at cortical and subcortical levels, induced by conventional and High-Definition-tDCS (HD-tDCS) montages developed for migraine and other chronic pain disorders. The electrodes were positioned in accordance with the 10-20 or 10-10 electroencephalogram (EEG) landmarks: motor cortex-supraorbital (M1-SO, anode and cathode over C3 and Fp2, respectively), dorsolateral prefrontal cortex (PFC) bilateral (DLPFC, anode over F3, cathode over F4), vertex-occipital cortex (anode over Cz and cathode over Oz), HD-tDCS 4 × 1 (one anode on C3, and four cathodes over Cz, F3, T7, and P3) and HD-tDCS 2 × 2 (two anodes over C3/C5 and two cathodes over FC3/FC5). M1-SO produced a large current flow in the PFC. Peaks of current flow also occurred in deeper brain structures, such as the cingulate cortex, insula, thalamus and brainstem. The same structures received significant amount of current with Cz-Oz and DLPFC tDCS. However, there were differences in the current flow to outer cortical regions. The visual cortex, cingulate and thalamus received the majority of the current flow with the Cz-Oz, while the anterior parts of the superior and middle frontal gyri displayed an intense amount of current with DLPFC montage. HD-tDCS montages enhanced the focality, producing peaks of current in subcortical areas at negligible levels. This study provides novel information regarding the neuroanatomical distribution and strength of the electric current using several tDCS montages applied for migraine and pain control. Such information may help clinicians and researchers in deciding the most appropriate tDCS montage to treat each pain disorder. PMID:26236199

  15. State-of-art neuroanatomical target analysis of high-definition and conventional tDCS montages used for migraine and pain control

    PubMed Central

    DaSilva, Alexandre F.; Truong, Dennis Q.; DosSantos, Marcos F.; Toback, Rebecca L.; Datta, Abhishek; Bikson, Marom

    2015-01-01

    Although transcranial direct current stimulation (tDCS) studies promise to modulate cortical regions associated with pain, the electric current produced usually spreads beyond the area of the electrodes’ placement. Using a forward-model analysis, this study compared the neuroanatomic location and strength of the predicted electric current peaks, at cortical and subcortical levels, induced by conventional and High-Definition-tDCS (HD-tDCS) montages developed for migraine and other chronic pain disorders. The electrodes were positioned in accordance with the 10–20 or 10–10 electroencephalogram (EEG) landmarks: motor cortex-supraorbital (M1-SO, anode and cathode over C3 and Fp2, respectively), dorsolateral prefrontal cortex (PFC) bilateral (DLPFC, anode over F3, cathode over F4), vertex-occipital cortex (anode over Cz and cathode over Oz), HD-tDCS 4 × 1 (one anode on C3, and four cathodes over Cz, F3, T7, and P3) and HD-tDCS 2 × 2 (two anodes over C3/C5 and two cathodes over FC3/FC5). M1-SO produced a large current flow in the PFC. Peaks of current flow also occurred in deeper brain structures, such as the cingulate cortex, insula, thalamus and brainstem. The same structures received significant amount of current with Cz-Oz and DLPFC tDCS. However, there were differences in the current flow to outer cortical regions. The visual cortex, cingulate and thalamus received the majority of the current flow with the Cz-Oz, while the anterior parts of the superior and middle frontal gyri displayed an intense amount of current with DLPFC montage. HD-tDCS montages enhanced the focality, producing peaks of current in subcortical areas at negligible levels. This study provides novel information regarding the neuroanatomical distribution and strength of the electric current using several tDCS montages applied for migraine and pain control. Such information may help clinicians and researchers in deciding the most appropriate tDCS montage to treat each pain disorder. PMID

  16. Dissociable effects of anodal and cathodal tDCS reveal distinct functional roles for right parietal cortex in the detection of single and competing stimuli.

    PubMed

    Filmer, Hannah L; Dux, Paul E; Mattingley, Jason B

    2015-07-01

    Spatial attention can be used to direct neural processing resources to a subset of task-relevant or otherwise salient items within the environment. Such selective processes are particularly important for resolving competition between multiple stimuli. Deficits in processing single stimuli can arise after damage to parietal, frontal and temporal brain regions, as is typical in patients with contralesional spatial neglect. By contrast, deficits in processing multiple competing stimuli may arise specifically following lesions of the posterior parietal cortex (PPC), as occurs in the disorder of spatial extinction. It remains unclear, however, whether mechanisms involved in selecting single and competing stimuli reflect the same or dissociable neural operations within the PPC. To address this issue, in separate sessions, we applied transcranial direct current stimulation (tDCS) to the left or right PPC and measured the effect on detecting and discriminating single and competing visual stimulus events. Our results revealed reliable tDCS modulations of stimulus processing, specific to the right PPC, as well as a dissociation in the detection of single and competing stimuli. For the right PPC only, single stimuli presented to the left (contralateral) visual field were affected selectively by anodal tDCS, whereas competing stimuli across the two visual fields were affected by both anodal and cathodal tDCS. These contrasting effects of anodal and cathodal tDCS on perception of single and competing stimuli suggest dissociable neural coding properties within the right PPC. PMID:25637773

  17. Paradigm Shift in Dendritic Cell-Based Immunotherapy: From in vitro Generated Monocyte-Derived DCs to Naturally Circulating DC Subsets

    PubMed Central

    Wimmers, Florian; Schreibelt, Gerty; Sköld, Annette E.; Figdor, Carl G.; De Vries, I. Jolanda M.

    2014-01-01

    Dendritic cell (DC)-based immunotherapy employs the patients’ immune system to fight neoplastic lesions spread over the entire body. This makes it an important therapy option for patients suffering from metastatic melanoma, which is often resistant to chemotherapy. However, conventional cellular vaccination approaches, based on monocyte-derived DCs (moDCs), only achieved modest response rates despite continued optimization of various vaccination parameters. In addition, the generation of moDCs requires extensive ex vivo culturing conceivably hampering the immunogenicity of the vaccine. Recent studies, thus, focused on vaccines that make use of primary DCs. Though rare in the blood, these naturally circulating DCs can be readily isolated and activated thereby circumventing lengthy ex vivo culture periods. The first clinical trials not only showed increased survival rates but also the induction of diversified anti-cancer immune responses. Upcoming treatment paradigms aim to include several primary DC subsets in a single vaccine as pre-clinical studies identified synergistic effects between various antigen-presenting cells. PMID:24782868

  18. A BTLA-mediated bait and switch strategy permits Listeria expansion in CD8α(+) DCs to promote long-term T cell responses.

    PubMed

    Yang, Xuanming; Zhang, Xunmin; Sun, Yonglian; Tu, Tony; Fu, May Lynne; Miller, Mendy; Fu, Yang-Xin

    2014-07-01

    Listeria monocytogenes infected CD8α(+) DCs in the spleen are essential for CD8(+) T cell generation. CD8α(+) DCs are also necessary for Listeria expansion and dissemination within the host. The mechanisms that regulate CD8α(+) DCs to allow Listeria expansion are unclear. We find that activating the B and T lymphocyte attenuator (BTLA), a coinhibitory receptor for T cells, suppresses, while blocking BTLA enhances, both the primary and memory CD8 T cell responses against Listeria. Btla(-/-) mice have lower effector and memory CD8(+) T cells while paradoxically also being more resistant to Listeria. Although bacterial entry into Btla(-/-) CD8α(+) DCs is unaffected, Listeria fails to expand within these cells. BTLA signaling limits Fas/FasL-mediated suppression of Listeria expansion within CD8α(+) DCs to more effectively alert adaptive immune cells. This study uncovers a BTLA-mediated strategy used by the host that permits Listeria proliferation to enable increasing T cell responses for long-term protection. PMID:25011109

  19. Applications of ERTS-1 Data Collection System (DCS) in the Arizona Regional Ecological Test Site (ARETS). [water management, streamflow rates, flood control

    NASA Technical Reports Server (NTRS)

    Schumann, H. H. (Principal Investigator)

    1973-01-01

    The author has identified the following significant results. The DCS water-stage data from the USGS streamflow gaging station on the Verde River near Camp Verde furnished information sufficient for the accurate computation of daily mean streamflow rates during the first 2 months of operation. Daily mean flow rates computed from the DCS data agreed with those computed from the digital recorder data within + or - 5% during periods of stable or slowly changing flow and within + or - 10% during periods of rapidly changing high flow. The SRP was furnished near-real time DCS information on snow moisture content and streamflow rates for use in the management and operation of the multiple-use reservoir system. The SRP, by prudent water management and the use of near-real time hydrologic data furnished by microwave and ERTS DCS telemetry, was successful in anticipating the amount of flow into the Salt and Verde Rivers and in the subsequent release of water at rates that did not create flooding in metropolitan Phoenix. Only minor flooding occurred along the Gila River west of Phoenix. According to the Maricopa County Civil Defense agency, wage and salary losses of about $11,400,000 resulted from closing of roads across the Salt River in the winter and spring of 1972-73; however, the number and duration of the closing were minimized by use of DCS data.

  20. Honokiol: A non-adipogenic PPARγ agonist from nature☆

    PubMed Central

    Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H.

    2013-01-01

    Background Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators. Methods We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists. Results The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. PMID:23811337

  1. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  2. Radiation therapy generates platelet-activating factor agonists

    PubMed Central

    Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.

    2016-01-01

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  3. Radiation therapy generates platelet-activating factor agonists.

    PubMed

    Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan; Murphy, Robert C; Konger, Raymond L; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F; Travers, Jeffrey B

    2016-04-12

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  4. Self-assembling peptide for co-delivery of HIV-1 CD8+ T cells epitope and Toll-like receptor 7/8 agonists R848 to induce maturation of monocyte derived dendritic cell and augment polyfunctional cytotoxic T lymphocyte (CTL) response.

    PubMed

    Ding, Yong; Liu, Jun; Lu, Sheng; Igweze, Justice; Xu, Wen; Kuang, Da; Zealey, Chris; Liu, Daheng; Gregor, Alex; Bozorgzad, Ardalan; Zhang, Lei; Yue, Elizabeth; Mujib, Shariq; Ostrowski, Mario; Chen, P

    2016-08-28

    Peptide based vaccine that incorporates one or several highly conserved CD8+ T cells epitopes to induce potent cytotoxic T lymphocyte (CTL) response is desirable for some infectious diseases, such as HIV-1 (human immunodeficiency virus-1), and cancers. However, the CD8+ T cells epitope is often weakly immunogenic, and thus requires a specific adjuvant or delivery system to enhance the efficiency. Here we investigated the use of self-assembling peptide EAK16-II based platform to achieve the co-delivery of CD8+ T cells epitope and TLR7/8 agonists (R848 or R837) for augmenting DCs maturation and HIV-1 specific CTL response. HIV-1 CTL epitope SL9 was conjugated with EAK16-II to obtain SL9-EAK16-II, which further spontaneously co-assembled with R848 or R837 in aqueous solution, forming co-assembled nanofibers. Fluorescence spectra and calorimetrical titration revealed the interaction between SL9-EAK16-II assemblies and R848 or R837 via hydrogen bonding and hydrophobic interaction, with the binding affinity (dissociation constant Kd) of 0.62μM or 0.53μM, respectively. Ex vivo generated DCs from HIV-1+ patients pulsed with the SL9-EAK16-II/R848 nanofibers stimulated significantly more polyfunctional SL9 specific CTLs, compared to the DCs pulsed with SL9 alone or the mixture of SL9 and TLR agonist. Furthermore, the nanofibers elicited stronger SL9 specific CTL response in vaccinated mice. Our findings suggest the self-assembling peptide EAK16-II might be used as a new delivery system for peptide based vaccines. PMID:27297778

  5. Switching off perceptual learning: Anodal transcranial direct current stimulation (tDCS) at Fp3 eliminates perceptual learning in humans.

    PubMed

    Civile, Ciro; Verbruggen, Frederick; McLaren, Rossy; Zhao, Di; Ku, Yixuan; McLaren, I P L

    2016-07-01

    Perceptual learning can be acquired as a result of experience with stimuli that would otherwise be difficult to tell apart, and is often explained in terms of the modulation of feature salience by an error signal based on how well that feature can be predicted by the others that make up the stimulus. In this article we show that anodal transcranial Direct Current Stimulation (tDCS) at Fp3 directly influences this modulation process so as to eliminate and possibly reverse perceptual learning. In 2 experiments, anodal stimulation disrupted perceptual learning (indexed by an inversion effect) compared with sham (Experiment 1) or cathodal (Experiment 2) stimulation. Our findings can be interpreted as showing that anodal tDCS severely reduced or even abolished the modulation of salience based on error, greatly increasing generalization between stimuli. This result supports accounts of perceptual learning based on variations in salience as a consequence of pre-exposure, and opens up the possibility of controlling this phenomenon. (PsycINFO Database Record PMID:27379720

  6. Association between psychosocial job characteristics and sickness absence due to low back symptoms using combined DCS and ERI models

    PubMed Central

    Yu, Shanfa; Lu, Ming-Lun; Gu, Guizhen; Zhou, Wenhui; He, Lihua; Wang, Sheng

    2015-01-01

    Objective To evaluate the combined demand-control-support (DCS) and effort-reward-overcommitment (ERI-OC) stress models in association with sickness absence due to low back symptoms (SA-LBS). Methods A total of 2,737 blue-collar workers recruited from 13 companies in the most populous province (Henan) of China were included in the study. Personal and physical job characteristics, psychosocial scales of the stress models, and SA-LBS data in the preceding year were collected by a self-reported questionnaire and analyzed by a multivariable logistic regression model. Tertile exposure levels (low, medium and high) were constructed to discriminate a risk level. Odds ratios (OR) with 95% confidence intervals (CI) were used as the association with SA-LBS. Results A large percentage (84.5%) of the Chinese workers did not take sick leave after reporting low back symptoms during the preceding year. High job demand or medium–high reward was associated with SA-LBS. The association of the combined stress models and SA-LBS was not evident. Conclusions The ERI-OC model appeared to be more predictive of SA-LBS than the DCS model in the study population. The advantage of using combined stress models for predicting SA-LBS is not evident. PMID:24939110

  7. Transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex affects stimulus conflict but not response conflict.

    PubMed

    Zmigrod, S; Zmigrod, L; Hommel, B

    2016-05-13

    When the human brain encounters a conflict, performance is often impaired. Two tasks that are widely used to induce and measure conflict-related interference are the Eriksen flanker task, whereby the visual target stimulus is flanked by congruent or incongruent distractors, and the Simon task, where the location of the required spatial response is either congruent or incongruent with the location of the target stimulus. Interestingly, both tasks share the characteristic of inducing response conflict but only the flanker task induces stimulus conflict. We used a non-invasive brain stimulation technique to explore the role of the right dorsolateral prefrontal cortex (DLPFC) in dealing with conflict in the Eriksen flanker and Simon tasks. In different sessions, participants received anodal, cathodal, or sham transcranial direct current stimulation (tDCS) (2 mA, 20 min) on the right DLPFC while performing these tasks. The results indicate that cathodal tDCS over the right DLPFC increased the flanker interference effect while having no impact on the Simon effect. This finding provides empirical support for the role of the right DLPFC in stimulus-stimulus rather than stimulus-response conflict, which suggests the existence of multiple, domain-specific control mechanisms underlying conflict resolution. In addition, methodologically, the study also demonstrates the way in which brain stimulation techniques can reveal subtle yet important differences between experimental paradigms that are often assumed to tap into a single process. PMID:26924018

  8. Supra-physiological efficacy at GPCRs: superstition or super agonists?

    PubMed Central

    Langmead, Christopher J; Christopoulos, Arthur

    2013-01-01

    The concept of ‘super agonism’ has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. Linked Article This article is a commentary on Schrage et al., pp. 357–370 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12003 PMID:23441648

  9. Principles of agonist recognition in Cys-loop receptors

    PubMed Central

    Lynagh, Timothy; Pless, Stephan A.

    2014-01-01

    Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine, and GABA. After the term “chemoreceptor” emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies, and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands. PMID:24795655

  10. Alpha-2 agonists as pain therapy in horses.

    PubMed

    Valverde, Alexander

    2010-12-01

    Alpha-2 agonists, such as xylazine, clonidine, romifidine, detomidine, medetomidine, and dexmedetomidine, are potent analgesic drugs that also induce physiologic and behavioral changes, such as hypertension, bradycardia, atrioventricular block, excessive sedation and ataxia, all of which can potentially limit their systemic use as analgesics in some clinical cases. The use of medetomidine and dexmetomidine has been introduced for equine anesthesia/analgesia, and although not approved in this species, their increased specificity for alpha-2 receptors may offer some potential advantages over the traditional alpha-2 agonists. Similarly, other routes of administration and benefits of alpha-2 agonists are recognized in the human and laboratory animal literature, which may prove useful in the equine patient if validated in the near future. This review presents this relevant information. PMID:21056297

  11. Agonist treatment in opioid use: advances and controversy.

    PubMed

    Viswanath, Biju; Chand, Prabhat; Benegal, Vivek; Murthy, Pratima

    2012-06-01

    Opioid dependence is a chronic relapsing condition which requires comprehensive care; pharmacological agents form the mainstay of its long term treatment. The two most popular approaches are the harm reduction method using agonists and the complete abstinence method using antagonists. Currently, particularly from the harm minimization perspective and the low feasibility of an abstinence based approach, there is an increasing trend toward agonist treatment. The use of buprenorphine has gained popularity in view of its safety profile and the availability of the buprenorphine-naloxone combination has made it popular as a take-home treatment. This review outlines the pharmacological advances and controversies in this area. PMID:22813654

  12. Insect Nicotinic Receptor Agonists as Flea Adulticides in Small Animals

    PubMed Central

    Vo, Dai Tan; Hsu, Walter H.; Martin, Richard J.

    2013-01-01

    Fleas are significant ectoparasites of small animals. They can be a severe irritant to animals and serve as a vector for a number of infectious diseases. In this article, we discuss the pharmacological characteristics of four insect nicotinic acetylcholine receptor (nAChR) agonists used as fleacides in dogs and cats, which include three neonicotinoids (imidacloprid, nitenpyram, and dinotefuran) and spinosad. Insect nAChR agonists are one of the most important new classes of insecticides, which are used to control sucking insects both on plants and on companion animals. These new compounds provide a new approach for practitioners to safely and effectively eliminate fleas. PMID:20646191

  13. Piperidine derivatives as nonprostanoid IP receptor agonists 2.

    PubMed

    Hayashi, Ryoji; Ito, Hiroaki; Ishigaki, Takeshi; Morita, Yasuhiro; Miyamoto, Mitsuko; Isogaya, Masafumi

    2016-06-15

    We searched for a strong and selective nonprostanoid IP agonist bearing piperidine and benzanilide moieties. Through optimization of substituents on the benzanilide moiety, the crucial part of the agonist, 43 (2-((1-(2-(N-(4-tolyl)benzo[d][1,3]dioxole-5-carboxamido)ethyl)piperidin-4-yl)oxy)acetic acid monohydrate monohydrochloride) was discovered and exhibited strong platelet aggregation inhibition (IC50=21nM) and 100-fold selectivity for IP receptor over other PG receptors. The systemic exposure level and bioavailability after oral administration of 43 were also good in dog. PMID:27133594

  14. Canine Recombinant Adenovirus Vector Induces an Immunogenicity-Related Gene Expression Profile in Skin-Migrated CD11b+ -Type DCs

    PubMed Central

    Jouneau, Luc; Bourge, Mickael; Bouet-Cararo, Coraline; Bonneau, Michel; Zientara, Stephan; Klonjkowski, Bernard; Schwartz-Cornil, Isabelle

    2012-01-01

    Gene expression profiling of the blood cell response induced early after vaccination has previously been demonstrated to predict the immunogenicity of vaccines. In this study, we evaluated whether the analysis of the gene expression profile of skin-migrated dendritic cells (DCs) could be informative for the in vitro prediction of immunogenicity of vaccine, using canine adenovirus serotype 2 (CAV2) as vaccine vector. CAV2 has been shown to induce immunity to transgenes in several species including sheep and is an interesting alternative to human adenovirus-based vectors, based on the safety records of the parental strain in dogs and the lack of pre-existing immunity in non-host species. Skin-migrated DCs were collected from pseudo-afferent lymph in sheep. Both the CD11b+ -type and CD103+ -type skin-migrated DCs were transduced by CAV2. An analysis of the global gene response to CAV2 in the two skin DC subsets showed that the gene response in CD11b+ -type DCs was far higher and broader than in the CD103+ -type DCs. A newly released integrative analytic tool from Ingenuity systems revealed that the CAV2-modulated genes in the CD11b+ -type DCs clustered in several activated immunogenicity-related functions, such as immune response, immune cell trafficking and inflammation. Thus gene profiling in skin-migrated DC in vitro indicates that the CD11b+ DC type is more responsive to CAV2 than the CD103+ DC type, and provides valuable information to help in evaluating and possibly improving viral vector vaccine effectiveness. PMID:23300693

  15. Canine recombinant adenovirus vector induces an immunogenicity-related gene expression profile in skin-migrated CD11b⁺ -type DCs.

    PubMed

    Contreras, Vanessa; Urien, Céline; Jouneau, Luc; Bourge, Mickael; Bouet-Cararo, Coraline; Bonneau, Michel; Zientara, Stephan; Klonjkowski, Bernard; Schwartz-Cornil, Isabelle

    2012-01-01

    Gene expression profiling of the blood cell response induced early after vaccination has previously been demonstrated to predict the immunogenicity of vaccines. In this study, we evaluated whether the analysis of the gene expression profile of skin-migrated dendritic cells (DCs) could be informative for the in vitro prediction of immunogenicity of vaccine, using canine adenovirus serotype 2 (CAV2) as vaccine vector. CAV2 has been shown to induce immunity to transgenes in several species including sheep and is an interesting alternative to human adenovirus-based vectors, based on the safety records of the parental strain in dogs and the lack of pre-existing immunity in non-host species. Skin-migrated DCs were collected from pseudo-afferent lymph in sheep. Both the CD11b(+) -type and CD103(+) -type skin-migrated DCs were transduced by CAV2. An analysis of the global gene response to CAV2 in the two skin DC subsets showed that the gene response in CD11b(+) -type DCs was far higher and broader than in the CD103(+) -type DCs. A newly released integrative analytic tool from Ingenuity systems revealed that the CAV2-modulated genes in the CD11b(+) -type DCs clustered in several activated immunogenicity-related functions, such as immune response, immune cell trafficking and inflammation. Thus gene profiling in skin-migrated DC in vitro indicates that the CD11b(+) DC type is more responsive to CAV2 than the CD103(+) DC type, and provides valuable information to help in evaluating and possibly improving viral vector vaccine effectiveness. PMID:23300693

  16. Pyrrolo- and Pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

    PubMed Central

    Kumar, V.; Clark, M.J.; Traynor, J.R.; Lewis, J.W.; Husbands, S.M.

    2014-01-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  17. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    PubMed

    Kumar, V; Clark, M J; Traynor, J R; Lewis, J W; Husbands, S M

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  18. Brief Report: HIV-1 Infection Results in Increased Frequency of Active and Inflammatory SlanDCs that Produce High Level of IL-1β.

    PubMed

    Tufa, Dejene M; Ahmad, Fareed; Chatterjee, Debanjana; Ahrenstorf, Gerrit; Schmidt, Reinhold E; Jacobs, Roland

    2016-09-01

    HIV infection is marked by phenotypic and functional alterations of immune cells. Different studies have shown both numerical and functional deterioration of dendritic cells in HIV-1-infected patients. In this study, we report an increase of inflammatory 6-sulfo LacNAc dendritic cells (slanDCs) that are more activated and produce higher amounts of interleukin (IL)-1β during HIV-1 infection as compared with healthy controls. IL-1β plays a regulatory role in chronic inflammatory disorders. Therefore, our findings might reveal a compensatory regulatory function of slanDCs during HIV-1 infection. PMID:27243902

  19. Key Role of Splenic Myeloid DCs in the IFN-αβ Response to Adenoviruses In Vivo

    PubMed Central

    Fejer, György; Drechsel, Lisa; Liese, Jan; Schleicher, Ulrike; Ruzsics, Zsolt; Imelli, Nicola; Greber, Urs F.; Keck, Simone; Hildenbrand, Bernd; Krug, Anne; Bogdan, Christian; Freudenberg, Marina A.

    2008-01-01

    The early systemic production of interferon (IFN)-αβ is an essential component of the antiviral host defense mechanisms, but is also thought to contribute to the toxic side effects accompanying gene therapy with adenoviral vectors. Here we investigated the IFN-αβ response to human adenoviruses (Ads) in mice. By comparing the responses of normal, myeloid (m)DC- and plasmacytoid (p)DC-depleted mice and by measuring IFN-αβ mRNA expression in different organs and cells types, we show that in vivo, Ads elicit strong and rapid IFN-αβ production, almost exclusively in splenic mDCs. Using knockout mice, various strains of Ads (wild type, mutant and UV-inactivated) and MAP kinase inhibitors, we demonstrate that the Ad-induced IFN-αβ response does not require Toll-like receptors (TLR), known cytosolic sensors of RNA (RIG-I/MDA-5) and DNA (DAI) recognition and interferon regulatory factor (IRF)-3, but is dependent on viral endosomal escape, signaling via the MAP kinase SAPK/JNK and IRF-7. Furthermore, we show that Ads induce IFN-αβ and IL-6 in vivo by distinct pathways and confirm that IFN-αβ positively regulates the IL-6 response. Finally, by measuring TNF-α responses to LPS in Ad-infected wild type and IFN-αβR−/− mice, we show that IFN-αβ is the key mediator of Ad-induced hypersensitivity to LPS. These findings indicate that, like endosomal TLR signaling in pDCs, TLR-independent virus recognition in splenic mDCs can also produce a robust early IFN-αβ response, which is responsible for the bulk of IFN-αβ production induced by adenovirus in vivo. The signaling requirements are different from known TLR-dependent or cytosolic IFN-αβ induction mechanisms and suggest a novel cytosolic viral induction pathway. The hypersensitivity to components of the microbial flora and invading pathogens may in part explain the toxic side effects of adenoviral gene therapy and contribute to the pathogenesis of adenoviral disease. PMID:19008951

  20. Synthetic RORγt Agonists Enhance Protective Immunity.

    PubMed

    Chang, Mi Ra; Dharmarajan, Venkatasubramanian; Doebelin, Christelle; Garcia-Ordonez, Ruben D; Novick, Scott J; Kuruvilla, Dana S; Kamenecka, Theodore M; Griffin, Patrick R

    2016-04-15

    The T cell specific RORγ isoform RORγt has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of TH17 and TC17 cells, cells that have demonstrated antitumor efficacy. RORγt controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of RORγt have been shown to increase the basal activity of RORγt enhancing TH17 cell proliferation. Here, we show that activation of RORγt using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-1, a mechanism that should enhance antitumor immunity while blunting tumor associated adaptive immune resistance. Interestingly, putative endogenous agonists drive proliferation of TH17 cells but do not repress PD-1. These findings suggest that synthetic agonists of RORγt should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer). Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment; thus such a molecule would provide a unique approach for the treatment of cancer. PMID:26785144

  1. Amphetamine- type reinforcement by dopaminergic agonists in the rat.

    PubMed

    Yokel, R A; Wise, R A

    1978-07-19

    Intravenous self-administration of d-amphetamine (0.25 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and piribedil. The dopaminergic agonists appear to suppress amphetamine intake in the same way as do 'free' amphetamine injections, by extending drug satiation in a given interresponse period. Clonidine, an alpha noradrenergic agonist, did not have similar effects. Apomorphine and piribedil did not increase 14C-amphetamine levels in rat brains, nor did they retard disappearance of 14C-amphetamine; thus their amphetamine-like effects are not due to alterations of amphetamine metabolism. Rats responding for amphetamine continued to respond for apomorphine or peribedil when the latter drugs were substituted for the former. Rats experienced in amphetamine self-administration readily initiated and maintained responding for apomorphine and piribedil. The dopaminergic blocker (+)-butaclamol disrupted responding for apomorphine and piribedil, although it produced no marked increase in responding for the dopaminergic agonists, as it does for amphetamine. These data add to the evidence that actions in the dopaminergic synapse account for amphetamine's reinforcing properties. PMID:98800

  2. Alkaloid delta agonist BW373U86 increases hypoxic tolerance.

    PubMed

    Bofetiado, D M; Mayfield, K P; D'Alecy, L G

    1996-06-01

    Activation of delta opioid receptors increases survival time during acute, lethal hypoxia in mice. delta Agonists therefore present a promising avenue for therapeutic application to reduce the morbidity and mortality associated with clinical hypoxia in settings such as drowning, head injury apnea, and complicated childbirths. However, most delta agonists now available are peptides, and may have limited clinical utility. In the present study, we evaluate the neuroprotective ability of an alkaloid delta agonist, BW373U86. Alkaloid compounds, due to increased stability and increased systemic distribution, may be more favorable for clinical use. We found that BW373U86, like the peptide delta agonist, DPDPE ([D-Pen2, D-Pen5]-enkephalin), increases survival time of mice during lethal hypoxia. The mechanism of neuroprotection induced by delta receptor activation appears to involve decreasing body temperature. Further, using selective opioid receptor antagonists, it appears that BW373U86 exerts these neuroprotective effects by acting at delta-opioid receptors. PMID:8638797

  3. The Agonistic Approach: Reframing Resistance in Qualitative Research

    ERIC Educational Resources Information Center

    Vitus, Kathrine

    2008-01-01

    The agonistic approach--aimed at embracing opposing perspectives as part of a qualitative research process and acknowledging that process as fundamentally political--sheds light on both the construction of and the resistance to research identities. This approach involves reflexively embedding interview situations into the ethnographic context as a…

  4. [Alpha-2 adrenoreceptor agonists in anaesthesia and intensive care medicine].

    PubMed

    Mavropoulos, G; Minguet, G; Brichant, J F

    2014-02-01

    Alpha-2 adrenoreceptor agonists have long been used in the treatment of arterial hypertension. However, in that indication they have progressively been replaced by antihypertensive drugs with a more interesting therapeutic profile. Nonetheless, pharmacological activation of alpha-2 adrenoreceptors leads to a variety of clinical effects that are of major interest for anaesthesia and intensive care practice. Indeed, the sedative and analgesic properties of alpha-2 adrenoreceptor agonists allow a reduction of hypnotic and opioid needs during general anaesthesia. In addition, they induce a down-regulation of the level of consciousness comparable to that of natural slow-wave sleep during post-anaesthesia and intensive care unit stay. These drugs may also prevent some deleterious effects of the sympathetic discharge in response to surgical stress. Furthermore, alpha-2 adrenoreceptor agonists are potent adjuncts for locoregional anaesthesia. In this article, we will summarize the most frequent applications of alpha-2 adrenoreceptor agonists in anaesthesia and intensive care medicine. We will focus on the clinical data available for the two most representative molecules of this pharmacological class: clonidine and dexmedetomidine. PMID:24683831

  5. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents. PMID:27194194

  6. Physician perceptions of GLP-1 receptor agonists in the UK.

    PubMed

    Matza, Louis S; Curtis, Sarah E; Jordan, Jessica B; Adetunji, Omolara; Martin, Sherry A; Boye, Kristina S

    2016-05-01

    Objectives Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetes for almost a decade, and new treatments in this class have recently been introduced. The purpose of this study was to examine perceptions of GLP-1 receptor agonists among physicians who treat patients with type 2 diabetes in the UK. Methods A total of 670 physicians (226 diabetes specialists; 444 general practice [GP] physicians) completed a survey in 2014. Results Almost all physicians had prescribed GLP-1 receptor agonists (95.4% total sample; 99.1% specialists; 93.5% GP), most frequently to patients whose glucose levels are not adequately controlled with oral medications (85.9% of physicians) and obese/overweight patients (83.7%). Physicians' most common reasons for prescribing a GLP-1 receptor agonist were: associated with weight loss (65.8%), good efficacy (55.7%), less hypoglycemia risk than insulin (55.2%), not associated with weight gain (34.5%), and better efficacy than oral medications (32.7%). Factors that most commonly cause hesitation when prescribing this class were: not considered first line therapy according to guidelines (56.9%), injectable administration (44.6%), cost (36.7%), gastrointestinal side effects (33.4%), and risk of pancreatitis (26.7%). Almost all specialists (99.1%) believed they had sufficient knowledge to prescribe a GLP-1 receptor agonist, compared with 76.1% of GPs. Conclusions Results highlight the widespread use of GLP-1 receptor agonists for treatment of type 2 diabetes in the UK. However, almost a quarter of GPs reported that they do not have enough knowledge to prescribe GLP-1s, suggesting a need for increased dissemination of information to targeted groups of physicians. Study limitations were that the generalizability of the clinician sample is unknown; survey questions required clinicians to select answers from multiple response options rather than generating the responses themselves; and responses to this survey conducted

  7. Activation of endplate nicotinic acetylcholine receptors by agonists.

    PubMed

    Auerbach, Anthony

    2015-10-15

    The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ∼300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by αY190) that behaves similarly at all sites and a coupled pair (led by γW55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of α(1) and one each of β, δ, and either γ (fetal) or ϵ (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at αδ and either αγ or αϵ subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C→O opening rate constant and C↔O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly

  8. Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists.

    PubMed

    Yang, Ting; Liu, Qian; Cheng, Yaobang; Cai, Wei; Ma, Yingli; Yang, Liuqing; Wu, Qianqian; Orband-Miller, Lisa A; Zhou, Ling; Xiang, Zhijun; Huxdorf, Melanie; Zhang, Wei; Zhang, Jing; Xiang, Jia-Ning; Leung, Stewart; Qiu, Yang; Zhong, Zhong; Elliott, John D; Lin, Xichen; Wang, Yonghui

    2014-01-01

    A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists. PMID:24900774

  9. Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.

    PubMed

    Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C

    2013-10-01

    SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594

  10. Sex differences in opioid antinociception: kappa and 'mixed action' agonists.

    PubMed

    Craft, R M; Bernal, S A

    2001-08-01

    A number of investigators have shown that male animals are more sensitive than females to the antinociceptive effects of mu-opioid agonists. The present study was conducted to examine sex differences in opioid antinociception in the rat using agonists known to differ in selectivity for and efficacy at kappa- versus mu-receptors. Dose- and time-effect curves were obtained for s.c. U69593, U50488, ethylketazocine, (-)-bremazocine, (-)-pentazocine, butorphanol and nalbuphine on the 50 or 54 degrees C hotplate and warm water tail withdrawal assays; spontaneous locomotor activity was measured 32-52 min post-injection in the same rats. On the hotplate assay, only butorphanol (54 degrees C) and nalbuphine (50 degrees C) were significantly more potent in males than females. On the tail withdrawal assay, all agonists were significantly more potent or efficacious in males than females at one or both temperatures. In contrast, no agonist was consistently more potent in one sex or the other in decreasing locomotor activity. Estrous stage in female rats only slightly influenced opioid effects, accounting for an average of 2.6% of the variance in females' antinociceptive and locomotor responses to drug (50 degrees C experiment). These results suggest that (1) sex differences in antinociceptive effects of opioids are not mu-receptor-dependent, as they may occur with opioids known to have significant kappa-receptor-mediated activity; (2) the mechanisms underlying sex differences in kappa-opioid antinociception may be primarily spinal rather than supraspinal; (3) sex differences in antinociceptive effects of opioid agonists are not secondary to sex differences in their sedative effects. PMID:11418226

  11. A novel rabies virus lipopeptide provides a better protection by improving the magnitude of DCs activation and T cell responses.

    PubMed

    Liu, Rui; Wang, Jingbo; Yang, Yan; Khan, Inamullah; Dong, Yue; Zhu, Naishuo

    2016-08-01

    Besides rabies virus neutralizing antibody, non-neutralizing antibody to internal vital proteins, interferon, and possibly cell-mediated immunity also have a critical role in preventing the infection by rabies virus (RV). We identified novel CTL and Th epitopes which could induce lymphocyte proliferation and IFN-γ, IL-4 production, and designed linear and branched lipopeptides with these selected CTL and Th epitopes. Compared to linear construct, branched lipopeptides, especially Lipo C, stimulate stronger phenotypic and functional maturation of DCs, as well as more efficient CD8(+) T cell responses, evaluating by using FACS, G333-341 tetramer staining and specific CTL assay. Lipo C could also assist rabies vaccine to induce an instant rabies virus neutralizing antibody production, and better protection against rabies virus challenge at early stage. These data reveal that Lipo C could be a promising component for developing novel rabies vaccines. PMID:27182006

  12. The combined effects of neurostimulation and priming on creative thinking. A preliminary tDCS study on dorsolateral prefrontal cortex

    PubMed Central

    Colombo, Barbara; Bartesaghi, Noemi; Simonelli, Luisa; Antonietti, Alessandro

    2015-01-01

    The role of prefrontal cortex (PFC) in influencing creative thinking has been investigated by many researchers who, while succeeding in proving an effective involvement of PFC, reported suggestive but sometimes conflicting results. In order to better understand the relationships between creative thinking and brain activation in a more specific area of the PFC, we explored the role of dorsolateral PFC (DLPFC). We devised an experimental protocol using transcranial direct-current stimulation (tDCS). The study was based on a 3 (kind of stimulation: anodal vs. cathodal vs. sham) × 2 (priming: divergent vs. convergent) design. Forty-five healthy adults were randomly assigned to one stimulation condition. Participants’ creativity skills were assessed using the Product Improvement subtest from the Torrance Tests of Creative Thinking (TTCT). After 20 min of tDCS stimulation, participants were presented with visual images of common objects. Half of the participants were instructed to visualize themselves using the object in an unusual way (divergent priming), whereas the other half were asked to visualize themselves while using the object in a common way (convergent priming). Priming was aimed at inducing participants to adopt different attitudes toward the creative task. Afterwards, participants were asked to describe all of the possible uses of the objects that were presented. Participants’ physiological activation was recorded using a biofeedback equipment. Results showed a significant effect of anodal stimulation that enhanced creative performance, but only after divergent priming. Participants showed lower skin temperature values after cathodal stimulation, a finding which is coherent with studies reporting that, when a task is not creative or creative thinking is not prompted, people show lower levels of arousal. Differences in individual levels of creativity as assessed by the Product Improvement test were not influential. The involvement of DLPFC in creativity

  13. The combined effects of neurostimulation and priming on creative thinking. A preliminary tDCS study on dorsolateral prefrontal cortex.

    PubMed

    Colombo, Barbara; Bartesaghi, Noemi; Simonelli, Luisa; Antonietti, Alessandro

    2015-01-01

    The role of prefrontal cortex (PFC) in influencing creative thinking has been investigated by many researchers who, while succeeding in proving an effective involvement of PFC, reported suggestive but sometimes conflicting results. In order to better understand the relationships between creative thinking and brain activation in a more specific area of the PFC, we explored the role of dorsolateral PFC (DLPFC). We devised an experimental protocol using transcranial direct-current stimulation (tDCS). The study was based on a 3 (kind of stimulation: anodal vs. cathodal vs. sham) × 2 (priming: divergent vs. convergent) design. Forty-five healthy adults were randomly assigned to one stimulation condition. Participants' creativity skills were assessed using the Product Improvement subtest from the Torrance Tests of Creative Thinking (TTCT). After 20 min of tDCS stimulation, participants were presented with visual images of common objects. Half of the participants were instructed to visualize themselves using the object in an unusual way (divergent priming), whereas the other half were asked to visualize themselves while using the object in a common way (convergent priming). Priming was aimed at inducing participants to adopt different attitudes toward the creative task. Afterwards, participants were asked to describe all of the possible uses of the objects that were presented. Participants' physiological activation was recorded using a biofeedback equipment. Results showed a significant effect of anodal stimulation that enhanced creative performance, but only after divergent priming. Participants showed lower skin temperature values after cathodal stimulation, a finding which is coherent with studies reporting that, when a task is not creative or creative thinking is not prompted, people show lower levels of arousal. Differences in individual levels of creativity as assessed by the Product Improvement test were not influential. The involvement of DLPFC in creativity has

  14. Pulmonary Allergic Responses Augment IL-13 Secretion by Circulating Basophils yet Suppress IFN-alpha from Plasmacytoid DCs

    PubMed Central

    Schroeder, John T.; Bieneman, Anja P.; Chichester, Kristin L.; Breslin, Linda; Xiao, HuiQing; Liu, Mark C.

    2011-01-01

    Background Allergic inflammatory processes may have the capacity to propagate systemically through the actions of circulating leukocytes. Consequently, basophils from allergic individuals are often “primed”, as evidenced by their hyper-responsiveness in vitro. IFN-α, secreted predominately by plasmacytoid DCs, suppresses basophil priming for IL-13 production in vitro. Objective This study sought in vivo correlates, arising during experimental allergen challenge, that support an “axis-interplay” between basophils and pDCs. Methods Using segmental allergen challenge in the lung, the immune responses of both cell types from blood were investigated in volunteers (n=10) before and 24h after allergen exposure. These responses were then correlated with inflammatory parameters measured in bronchoalveolar lavage fluids. Results In blood, segmental allergen challenge significantly augmented IL-13 secretion by basophils induced by IL-3 (p=0.009) yet reduced IFN-α secreted by plasmacytoid dendritic cells stimulated with CpG (p=0.018). Both parameters were negatively correlated (p=0.0015), at least among those subjects secreting the latter. Circulating basophil IL-13 responses further correlated with post-segmental allergen challenge bronchoalveolar lavage parameters including IL-13 protein (p=0.04), basophil (p=0.051), eosinophil (p=0.0018) and total cell counts (p<0.003). Basophil and IL-13 levels in bronchoalveolar lavage likewise correlated (p=0.0002). Conclusions These results support a mechanism of immune regulation whereby allergen reduces innate immune responses and IFN-α production by plasmacytoid dendritic cells, resulting in enhanced inflammation and basophil cytokine production at sites of allergen exposure. PMID:20184608

  15. Synthesis and SAR of potent LXR agonists containing an indole pharmacophore

    SciTech Connect

    Washburn, David G.; Hoang, Tram H.; Campobasso, Nino; Smallwood, Angela; Parks, Derek J.; Webb, Christine L.; Frank, Kelly A.; Nord, Melanie; Duraiswami, Chaya; Evans, Christopher; Jaye, Michael; Thompson, Scott K.

    2009-03-27

    A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXR{alpha} will be disclosed.

  16. Glucagon-Like Peptide-1 Receptor Agonists: Beta-Cell Protection or Exhaustion?

    PubMed

    van Raalte, Daniël H; Verchere, C Bruce

    2016-07-01

    Glucagon-like peptide (GLP)-1 receptor agonists enhance insulin secretion and may improve pancreatic islet cell function. However, GLP-1 receptor (GLP-1R) agonist treatment may have more complex, and sometimes deleterious, effects on beta cells. We discuss the concepts of beta cell protection versus exhaustion for different GLP-1R agonists based on recent data. PMID:27160799

  17. The effects of anodal-tDCS on corticospinal excitability enhancement and its after-effects: conventional vs. unihemispheric concurrent dual-site stimulation

    PubMed Central

    Vaseghi, Bita; Zoghi, Maryam; Jaberzadeh, Shapour

    2015-01-01

    Previous researchers have approved the ability of anodal transcranial direct current stimulation (a-tDCS) of the primary motor cortex (M1) to enhance corticospinal excitability (CSE). The primary aim of the current study was to investigate the effect of concurrent stimulation of M1 and a functionally connected cortical site of M1 on CSE modulation. This new technique is called unihemispheric concurrent dual-site a-tDCS (a-tDCSUHCDS). The secondary aim was to investigate the mechanisms underlying the efficacy of this new approach in healthy individuals. In a randomized crossover study, 12 healthy right-handed volunteers received a-tDCS under five conditions: a-tDCS of M1, a-tDCSUHCDS of M1-dorsolateral prefrontal cortex (DLPFC), a-tDCSUHCDS of M1-primary sensory cortex (S1), a-tDCSUHCDS of M1-primary visual cortex (V1), and sham a-tDCSUHCDS. Peak-to-peak amplitude of transcranial magnetic stimulation (TMS) induced MEPs, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were assessed before and four times after each condition. A-tDCSUHCDS conditions induced larger MEPs than conventional a-tDCS. The level of M1 CSE was significantly higher following a-tDCSUHCDS of M1-DLPFC than other a-tDCSUHCDS conditions (p < 0.001), and lasted for over 24 h. The paired-pulse TMS results after a-tDCS of M1-DLPFC showed significant facilitatory increase and inhibitory change. A-tDCSUHCDS of M1-DLPFC increases M1 CSE twofold that of conventional a-tDCS. A-tDCSUHCDS of M1-DLPFC enhances the activity of glutamergic mechanisms for at least 24 h. Such long-lasting M1 CSE enhancement induced by a-tDCSUHCDS of M1-DLPFC could be a valuable finding in clinical scenarios such as learning, motor performance, or pain management. The present study has been registered on the Australian New Zealand Clinical Trial at http://www.anzctr.org.au/ with registry number of ACTRN12614000817640. PMID:27242498

  18. Spared Primary Motor Cortex and The Presence of MEP in Cerebral Palsy Dictate the Responsiveness to tDCS during Gait Training.

    PubMed

    Grecco, Luanda A Collange; Oliveira, Claudia Santos; Galli, Manuela; Cosmo, Camila; Duarte, Natália de Almeida Carvalho; Zanon, Nelci; Edwards, Dylan J; Fregni, Felipe

    2016-01-01

    The current priority of investigations involving transcranial direct current stimulation (tDCS) and neurorehabilitation is to identify biomarkers associated with the positive results of the interventions such that respondent and non-respondent patients can be identified in the early phases of treatment. The aims were to determine whether: (1) present motor evoked potential (MEP); and (2) injuries involving the primary motor cortex, are associated with tDCS-enhancement in functional outcome following gait training in children with cerebral palsy (CP). We reviewed the data from our parallel, randomized, sham-controlled, double-blind studies. Fifty-six children with spastic CP received gait training (either treadmill training or virtual reality training) and tDCS (active or sham). Univariate and multivariate logistic regression analyses were employed to identify clinical, neurophysiologic and neuroanatomic predictors associated with the responsiveness to treatment with tDCS. MEP presence during the initial evaluation and the subcortical injury were associated with positive effects in the functional results. The logistic regression revealed that present MEP was a significant predictor for the six-minute walk test (6MWT; p = 0.003) and gait speed (p = 0.028), whereas the subcortical injury was a significant predictor of gait kinematics (p = 0.013) and gross motor function (p = 0.021). In this preliminary study involving children with CP, two important prediction factors of good responses to anodal tDCS combined with gait training were identified. Apparently, MEP (integrity of the corticospinal tract) and subcortical location of the brain injury exerted different influences on aspects related to gait, such as velocity and kinematics. PMID:27486393

  19. Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway.

    PubMed

    Anipindi, Varun C; Bagri, Puja; Roth, Kristy; Dizzell, Sara E; Nguyen, Philip V; Shaler, Christopher R; Chu, Derek K; Jiménez-Saiz, Rodrigo; Liang, Hong; Swift, Stephanie; Nazli, Aisha; Kafka, Jessica K; Bramson, Jonathan; Xing, Zhou; Jordana, Manel; Wan, Yonghong; Snider, Denis P; Stampfli, Martin R; Kaushic, Charu

    2016-05-01

    Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway. PMID:27148737

  20. Spared Primary Motor Cortex and The Presence of MEP in Cerebral Palsy Dictate the Responsiveness to tDCS during Gait Training

    PubMed Central

    Grecco, Luanda A. Collange; Oliveira, Claudia Santos; Galli, Manuela; Cosmo, Camila; Duarte, Natália de Almeida Carvalho; Zanon, Nelci; Edwards, Dylan J.; Fregni, Felipe

    2016-01-01

    The current priority of investigations involving transcranial direct current stimulation (tDCS) and neurorehabilitation is to identify biomarkers associated with the positive results of the interventions such that respondent and non-respondent patients can be identified in the early phases of treatment. The aims were to determine whether: (1) present motor evoked potential (MEP); and (2) injuries involving the primary motor cortex, are associated with tDCS-enhancement in functional outcome following gait training in children with cerebral palsy (CP). We reviewed the data from our parallel, randomized, sham-controlled, double-blind studies. Fifty-six children with spastic CP received gait training (either treadmill training or virtual reality training) and tDCS (active or sham). Univariate and multivariate logistic regression analyses were employed to identify clinical, neurophysiologic and neuroanatomic predictors associated with the responsiveness to treatment with tDCS. MEP presence during the initial evaluation and the subcortical injury were associated with positive effects in the functional results. The logistic regression revealed that present MEP was a significant predictor for the six-minute walk test (6MWT; p = 0.003) and gait speed (p = 0.028), whereas the subcortical injury was a significant predictor of gait kinematics (p = 0.013) and gross motor function (p = 0.021). In this preliminary study involving children with CP, two important prediction factors of good responses to anodal tDCS combined with gait training were identified. Apparently, MEP (integrity of the corticospinal tract) and subcortical location of the brain injury exerted different influences on aspects related to gait, such as velocity and kinematics. PMID:27486393

  1. Beta Band Transcranial Alternating (tACS) and Direct Current Stimulation (tDCS) Applied After Initial Learning Facilitate Retrieval of a Motor Sequence

    PubMed Central

    Krause, Vanessa; Meier, Anna; Dinkelbach, Lars; Pollok, Bettina

    2016-01-01

    The primary motor cortex (M1) contributes to the acquisition and early consolidation of a motor sequence. Although the relevance of M1 excitability for motor learning has been supported, the significance of M1 oscillations remains an open issue. This study aims at investigating to what extent retrieval of a newly learned motor sequence can be differentially affected by motor-cortical transcranial alternating (tACS) and direct current stimulation (tDCS). Alpha (10 Hz), beta (20 Hz) or sham tACS was applied in 36 right-handers. Anodal or cathodal tDCS was applied in 30 right-handers. Participants learned an eight-digit serial reaction time task (SRTT; sequential vs. random) with the right hand. Stimulation was applied to the left M1 after SRTT acquisition at rest for 10 min. Reaction times were analyzed at baseline, end of acquisition, retrieval immediately after stimulation and reacquisition after eight further sequence repetitions. Reaction times during retrieval were significantly faster following 20 Hz tACS as compared to 10 Hz and sham tACS indicating a facilitation of early consolidation. tDCS yielded faster reaction times, too, independent of polarity. No significant differences between 20 Hz tACS and tDCS effects on retrieval were found suggesting that 20 Hz effects might be associated with altered motor-cortical excitability. Based on the behavioral modulation yielded by tACS and tDCS one might speculate that altered motor-cortical beta oscillations support early motor consolidation possibly associated with neuroplastic reorganization. PMID:26834593

  2. Transcranial Direct Current Stimulation (tDCS) of the Right Inferior Frontal Gyrus Attenuates Skin Conductance Responses to Unpredictable Threat Conditions.

    PubMed

    Herrmann, Martin J; Beier, Jennifer S; Simons, Bibiane; Polak, Thomas

    2016-01-01

    Patients with panic and post-traumatic stress disorders seem to show increased psychophysiological reactions to conditions of unpredictable (U) threat, which has been discussed as a neurobiological marker of elevated levels of sustained fear in these disorders. Interestingly, a recent study found that the right inferior frontal gyrus (rIFG) is correlated to the successful regulation of sustained fear during U threat. Therefore this study aimed to examine the potential use of non-invasive brain stimulation to foster the rIFG by means of anodal transcranial direct current stimulation (tDCS) in order to reduce psychophysiological reactions to U threat. Twenty six participants were randomly assigned into an anodal and sham stimulation group in a double-blinded manner. Anodal and cathodal electrodes (7 * 5 cm) were positioned right frontal to target the rIFG. Stimulation intensity was I = 2 mA applied for 20 min during a task including U threat conditions (NPU-task). The effects of the NPU paradigm were measured by assessing the emotional startle modulation and the skin conductance response (SCR) at the outset of the different conditions. We found a significant interaction effect of condition × tDCS for the SCR (F (2,48) = 6.3, p < 0.01) without main effects of condition and tDCS. Post hoc tests revealed that the increase in SCR from neutral (N) to U condition was significantly reduced in verum compared to the sham tDCS group (t (24) = 3.84, p < 0.001). Our results emphasize the causal role of rIFG for emotional regulation and the potential use of tDCS to reduce apprehension during U threat conditions and therefore as a treatment for anxiety disorders. PMID:27462211

  3. Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway

    PubMed Central

    Anipindi, Varun C.; Dizzell, Sara E.; Nguyen, Philip V.; Shaler, Christopher R.; Chu, Derek K.; Jiménez-Saiz, Rodrigo; Liang, Hong; Swift, Stephanie; Nazli, Aisha; Kafka, Jessica K.; Bramson, Jonathan; Xing, Zhou; Jordana, Manel; Wan, Yonghong; Snider, Denis P.; Stampfli, Martin R.; Kaushic, Charu

    2016-01-01

    Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway. PMID:27148737

  4. Transcranial Direct Current Stimulation (tDCS) of the Right Inferior Frontal Gyrus Attenuates Skin Conductance Responses to Unpredictable Threat Conditions

    PubMed Central

    Herrmann, Martin J.; Beier, Jennifer S.; Simons, Bibiane; Polak, Thomas

    2016-01-01

    Patients with panic and post-traumatic stress disorders seem to show increased psychophysiological reactions to conditions of unpredictable (U) threat, which has been discussed as a neurobiological marker of elevated levels of sustained fear in these disorders. Interestingly, a recent study found that the right inferior frontal gyrus (rIFG) is correlated to the successful regulation of sustained fear during U threat. Therefore this study aimed to examine the potential use of non-invasive brain stimulation to foster the rIFG by means of anodal transcranial direct current stimulation (tDCS) in order to reduce psychophysiological reactions to U threat. Twenty six participants were randomly assigned into an anodal and sham stimulation group in a double-blinded manner. Anodal and cathodal electrodes (7 * 5 cm) were positioned right frontal to target the rIFG. Stimulation intensity was I = 2 mA applied for 20 min during a task including U threat conditions (NPU-task). The effects of the NPU paradigm were measured by assessing the emotional startle modulation and the skin conductance response (SCR) at the outset of the different conditions. We found a significant interaction effect of condition × tDCS for the SCR (F(2,48) = 6.3, p < 0.01) without main effects of condition and tDCS. Post hoc tests revealed that the increase in SCR from neutral (N) to U condition was significantly reduced in verum compared to the sham tDCS group (t(24) = 3.84, p < 0.001). Our results emphasize the causal role of rIFG for emotional regulation and the potential use of tDCS to reduce apprehension during U threat conditions and therefore as a treatment for anxiety disorders. PMID:27462211

  5. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor.

    PubMed

    Bock, Andreas; Bermudez, Marcel; Krebs, Fabian; Matera, Carlo; Chirinda, Brian; Sydow, Dominique; Dallanoce, Clelia; Holzgrabe, Ulrike; De Amici, Marco; Lohse, Martin J; Wolber, Gerhard; Mohr, Klaus

    2016-07-29

    G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site. PMID:27298318

  6. A Potent and Site-Selective Agonist of TRPA1.

    PubMed

    Takaya, Junichiro; Mio, Kazuhiro; Shiraishi, Takuya; Kurokawa, Tatsuki; Otsuka, Shinya; Mori, Yasuo; Uesugi, Motonari

    2015-12-23

    TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation. PMID:26630251

  7. β2-adrenoceptor agonists in the regulation of mitochondrial biogenesis

    PubMed Central

    Peterson, Yuri K.; Cameron, Robert B.; Wills, Lauren P.; Trager, Richard E.; Lindsey, Chris C.; Beeson, Craig C.; Schnellmann, Rick G.

    2014-01-01

    The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of β2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of β2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB. PMID:23954364

  8. A Human Platelet Calcium Calculator Trained by Pairwise Agonist Scanning

    PubMed Central

    Lee, Mei Yan; Diamond, Scott L.

    2015-01-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  9. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    PubMed Central

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa

    2003-01-01

    The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor. Abbreviation: AEA arylethanolamine AII 2-(arylimino)imidazolidine AIO 2-(arylimino)oxazolidine AIT 2-(arylimino)thiazolidine APAT 2-(α-phenylethylamino)-2-thiazoline BPAT 2-(β-phenylethylamino)-2-thiazoline CAO 2-(3-chlorobenzylamino)-2-oxazoline DCAO 2-(3,5-dichlorobenzylamino)-2-oxazoline DET5 2-(2,6-diethylphenylimino)-5-methylthiazolidine DET6 2-(2,6-diethylphenylimino)thiazine EGTA ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid GFA genetic function approximation G/PLS genetic partial least squares IND 2-aminomethyl-2-indanol LAH lithium aluminum hydride MCSG maximum common subgroup MCT6 2-(2-methyl-4-chlorophenylimino)thiazine OA octopamine PLS partial least squares QSAR quantitative structure-activity relationship SBAT 2-(substituted benzylamino)-2-thiazoline SD the sum of squared deviations of the dependent variable values from their mean SPIT 3-(substituted phenyl)imidazolidine-2-thione THI 2-amino-1-(2-thiazoyl)ethanol TMS tetramethyl silane PMID:15841226

  10. A human platelet calcium calculator trained by pairwise agonist scanning.

    PubMed

    Lee, Mei Yan; Diamond, Scott L

    2015-02-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  11. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    SciTech Connect

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K.

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  12. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    PubMed

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline. PMID:20030735

  13. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    PubMed Central

    Keane, Fergus; Navin, Patrick; Brett, Francesca; Dennedy, Michael C

    2016-01-01

    Summary Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH) agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour. Learning points While non-functioning gonadotropinomas represent the most common form of pituitary macroadenoma, functioning gonadotropinomas are exceedingly rare. Acute tumour enlargement, with potential pituitary apoplexy, is a rare but important adverse effect arising from GNRH agonist therapy in the presence of both functioning and non-functioning pituitary gonadotropinomas. GNRH antagonist therapy represents an alternative treatment option for patients with hormonal therapy-requiring prostate cancer, who also have diagnosed with a pituitary gonadotropinoma. PMID:27284452

  14. Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor 1.

    PubMed

    Aliouane, Lucie; Chao, Sovy; Brizuela, Leyre; Pfund, Emmanuel; Cuvillier, Olivier; Jean, Ludovic; Renard, Pierre-Yves; Lequeux, Thierry

    2014-09-01

    The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported. PMID:25047939

  15. Newspapers and newspaper ink contain agonists for the ah receptor.

    PubMed

    Bohonowych, Jessica E S; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T; Denison, Michael S

    2008-04-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [(3)H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed. PMID:18203687

  16. Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan

    PubMed Central

    Doyle, Carolyn A.; McDougle, Christopher J.

    2012-01-01

    This review outlines pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders (ASDs) in children, adolescents, and adults. Symptom domains include repetitive and stereotyped behaviors, irritability and aggression, hyperactivity and inattention, and social impairment. Medications covered include serotonin reuptake inhibitors (SRIs), mirtazapine, antipsychotics, psychostimulants, atomoxetine, α-2 agonists, D-cycloserine, and memantine. Overall, SRIs are less efficacious and more poorly tolerated in children with ASDs than in adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in ASDs, and may be useful in the treatment of other symptoms. Psychostimulants demonstrate some benefit for the treatment of hyperactivity and inattention in individuals with ASDs, but are less efficacious and associated with more adverse effects compared with individuals with ADHD. D-cycloserine and memantine appear helpful in the treatment of social impairment, although further research is needed. PMID:23226952

  17. Covalent agonists for studying G protein-coupled receptor activation

    PubMed Central

    Weichert, Dietmar; Kruse, Andrew C.; Manglik, Aashish; Hiller, Christine; Zhang, Cheng; Hübner, Harald; Kobilka, Brian K.; Gmeiner, Peter

    2014-01-01

    Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating Gs-, Gi-, and Gq-coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the β2-adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis. PMID:25006259

  18. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    PubMed

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes. PMID:24038158

  19. Biased signaling: potential agonist and antagonist of PAR2.

    PubMed

    Kakarala, Kavita Kumari; Jamil, Kaiser

    2016-06-01

    Protease activated receptor 2 (PAR2) has emerged as one of the promising therapeutic targets to inhibit rapidly metastasizing breast cancer cells. However, its elusive molecular mechanism of activation and signaling has made it a difficult target for drug development. In this study, in silico methods were used to unfold PAR2 molecular mechanism of signaling based on the concept of GPCR receptor plasticity. Although, there are no conclusive evidences of the presence of specific endogenous ligands for PAR2, the efficacy of synthetic agonist and antagonist in PAR2 signaling has opened up the possibilities of ligand-mediated signaling. Furthermore, it has been proved that ligands specific for one GPCR can induce signaling in GPCRs belonging to other subfamilies. Therefore, the aim of this study was to identify potential agonists and antagonists from the GPCR ligand library (GLL), which may induce biased signaling in PAR2 using the concept of existence of multiple ligand-stabilized receptor conformations. The results of our in silico study suggest that PAR2 may show biased signaling mainly with agonists of serotonin type 1, β-adrenergic type 1,3 and antagonists of substance K (NK1), serotonin type 2, dopamine type 4, and thromboxane receptors. Further, this study also throws light on the putative ligand-specific conformations of PAR2. Thus, the results of this study provide structural insights to putative conformations of PAR2 and also gives initial clues to medicinal chemists for rational drug design targeting this challenging receptor. PMID:26295578

  20. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    PubMed

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  1. Cryptochinones from Cryptocarya chinensis act as farnesoid X receptor agonists.

    PubMed

    Lin, Hsiang-Ru; Chou, Tsung-Hsien; Huang, Din-Wen; Chen, Ih-Sheng

    2014-09-01

    Cryptochinones A-D are tetrahydroflavanones isolated from the leaves of Cryptocarya chinensis, an evergreen tree whose extracts are believed to have a variety of health benefits. The origin of their possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and for hyperglycemia. We studied whether cryptochinones A-D, which are structurally similar to known FXR ligands, may act at this target. Indeed, in mammalian one-hybrid and transient transfection reporter assays, cryptochinones A-D transactivated FXR to modulate promoter action including GAL4, SHP, CYP7A1, and PLTP promoters in dose-dependent manner, while they exhibited similar agonistic activity as chenodeoxycholic acid (CDCA), an endogenous FXR agonist. Through molecular modeling docking studies we evaluated their ability to bind to the FXR ligand binding pocket. Our results indicate that cryptochinones A-D can behave as FXR agonists. PMID:25127166

  2. Dopamine-deficient mice are hypersensitive to dopamine receptor agonists.

    PubMed

    Kim, D S; Szczypka, M S; Palmiter, R D

    2000-06-15

    Dopamine-deficient (DA-/-) mice were created by targeted inactivation of the tyrosine hydroxylase gene in dopaminergic neurons. The locomotor activity response of these mutants to dopamine D1 or D2 receptor agonists and l-3,4-dihydroxyphenylalanine (l-DOPA) was 3- to 13-fold greater than the response elicited from wild-type mice. The enhanced sensitivity of DA-/- mice to agonists was independent of changes in steady-state levels of dopamine receptors and the presynaptic dopamine transporter as measured by ligand binding. The acute behavioral response of DA-/- mice to a dopamine D1 receptor agonist was correlated with c-fos induction in the striatum, a brain nucleus that receives dense dopaminergic input. Chronic replacement of dopamine to DA-/- mice by repeated l-DOPA administration over 4 d relieved the hypersensitivity of DA-/- mutants in terms of induction of both locomotion and striatal c-fos expression. The results suggest that the chronic presence of dopaminergic neurotransmission is required to dampen the intracellular signaling response of striatal neurons. PMID:10844009

  3. Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer

    PubMed Central

    Shukla, Nikunj M.; Salunke, Deepak B.; Balakrishna, Rajalakshmi; Mutz, Cole A.; Malladi, Subbalakshmi S.; David, Sunil A.

    2012-01-01

    Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-γ induction in human PBMCs, with preservation of TLR7-driven IFN-α induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine α-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen. PMID:22952720

  4. Emerging strategies for exploiting cannabinoid receptor agonists as medicines

    PubMed Central

    Pertwee, Roger G

    2009-01-01

    Medicines that activate cannabinoid CB1 and CB2 receptor are already in the clinic. These are Cesamet® (nabilone), Marinol® (dronabinol; Δ9-tetrahydrocannabinol) and Sativex® (Δ9-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol® can also be prescribed to stimulate appetite, while Sativex® is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB2 receptors; or (v) ‘multi-targeting’. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  5. Highly selective agonists for substance P receptor subtypes.

    PubMed Central

    Wormser, U; Laufer, R; Hart, Y; Chorev, M; Gilon, C; Selinger, Z

    1986-01-01

    The existence of a third tachykinin receptor (SP-N) in the mammalian nervous system was demonstrated by development of highly selective agonists. Systematic N-methylation of individual peptide bonds in the C-terminal hexapeptide of substance P gave rise to agonists which specifically act on different receptor subtypes. The most selective analog of this series, succinyl-[Asp6,Me-Phe8]SP6-11, elicits half-maximal contraction of the guinea pig ileum through the neuronal SP-N receptor at a concentration of 0.5 nM. At least 60,000-fold higher concentrations of this peptide are required to stimulate the other two tachykinin receptors (SP-P and SP-E). The action of selective SP-N agonists in the guinea pig ileum is antagonized by opioid peptides, suggesting a functional counteraction between opiate and SP-N receptors. These results indicate that the tachykinin receptors are distinct entities which may mediate different physiological functions. PMID:2431898

  6. Suppression of atherosclerosis by synthetic REV-ERB agonist

    SciTech Connect

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  7. Development of specific dopamine D-1 agonists and antagonists

    SciTech Connect

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo(a,d)cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo(1,2)cyclohepta(3,4,5d,e)isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC{sub 50} of compound 11 for displacement of {sup 3}H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of {sup 3}H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor.

  8. Relationships between IL-17(+) subsets, Tregs and pDCs that distinguish among SIV infected elite controllers, low, medium and high viral load rhesus macaques.

    PubMed

    Khowawisetsut, Ladawan; Pattanapanyasat, Kovit; Onlamoon, Nattawat; Mayne, Ann E; Little, Dawn M; Villinger, Francois; Ansari, Aftab A

    2013-01-01

    Comprehensive studies of the frequencies and absolute numbers of the various cell lineages that synthesize IL-17 in the blood and corresponding gastrointestinal (GI) tissues, their correlation with CD4(+) Tregs, CD8(+) Tregs, total and IFN-α synthesizing plasmacytoid dendritic cells (pDC) relative to plasma viral load in SIV infection has been lacking. The unique availability of SIV infected rhesus macaques (RM) classified as Elite Controllers (EC), and those with Low, Intermediate and High Viral Loads (HVL) provided a unique opportunity to address this issue. Results of these studies showed that EC demonstrated a remarkable ability to reverse changes that are induced acutely by SIV in the various cell lineages. Highlights of the differences between EC and HVL RM within Gastro-intestinal tissues (GIT) was the maintenance and/or increases in the levels of IL-17 synthesizing CD4, CD8, and NK cells and pDCs associated with slight decreases in the levels of CD4(+) Tregs and IFN-α synthesizing pDCs in EC as compared with decreases in the levels of IL-17 synthesizing CD4, CD8 and NK cells associated with increases in pDCs and IFN-α synthesizing pDCs in HVL monkeys. A previously underappreciated role for CD8(+) Tregs was also noted with a moderate increase in ECs but further increases of CD8(+) Tregs with increasing VL in viremic monkeys. Positive correlations between plasma VL and decreases in the levels of Th17, Tc17, NK-17, CD4(+) Tregs and increases in the levels of CD8(+) Tregs, total and IFN-α synthesizing pDCs were also noted. This study also identified 2 additional IL-17(+) subsets in GIT as CD3(-/)CD8(+)/NKG2a(-) and CD3(+)/CD8(+)/NKG2a(+) subsets. Studies also suggest a limited role for IFN-α synthesizing pDCs in chronic immune activation despite persistent up-regulation of ISGs. Finally, elevated persistent innate immune responses appear associated with poor prognosis. These findings provide an initial foundation for markers important to follow for vaccine

  9. 2-Triazole-Substituted Adenosines: A New Class of Selective A3 Adenosine Receptor Agonists, Partial Agonists, and Antagonists

    PubMed Central

    Cosyn, Liesbet; Palaniappan, Krishnan K.; Kim, Soo-Kyung; Duong, Heng T.; Gao, Zhan-Guo; Jacobson, Kenneth A.; Van Calenbergh, Serge

    2016-01-01

    “Click chemistry” was explored to synthesize two series of 2-(1,2,3-triazolyl)adenosine derivatives (1–14). Binding affinity at the human A1, A2A, and A3ARs (adenosine receptors) and relative efficacy at the A3AR were determined. Some triazol-1-yl analogues showed A3AR affinity in the low nanomolar range, a high ratio of A3/A2A selectivity, and a moderate-to-high A3/A1 ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A3AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative A3AR efficacy. Thus, several 5′-OH derivatives appeared to be selective A3AR antagonists, i.e., 10, with 260-fold binding selectivity in comparison to the A1AR and displaying a characteristic docking mode in an A3AR model. The corresponding 5′-ethyluronamide analogues generally showed increased A3AR affinity and behaved as full agonists, i.e., 17, with 910-fold A3/A1 selectivity. Thus, N6-substituted 2-(1,2,3-triazolyl)-adenosine analogues constitute a novel class of highly potent and selective nucleoside-based A3AR antagonists, partial agonists, and agonists. PMID:17149867

  10. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR.

    PubMed

    Huang, Wendong; Zhang, Jun; Wei, Ping; Schrader, William T; Moore, David D

    2004-10-01

    The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans. PMID:15272053

  11. Different serotonin receptor agonists have distinct effects on sound-evoked responses in inferior colliculus.

    PubMed

    Hurley, Laura M

    2006-11-01

    The neuromodulator serotonin has a complex set of effects on the auditory responses of neurons within the inferior colliculus (IC), a midbrain auditory nucleus that integrates a wide range of inputs from auditory and nonauditory sources. To determine whether activation of different types of serotonin receptors is a source of the variability in serotonergic effects, four selective agonists of serotonin receptors in the serotonin (5-HT) 1 and 5-HT2 families were iontophoretically applied to IC neurons, which were monitored for changes in their responses to auditory stimuli. Different agonists had different effects on neural responses. The 5-HT1A agonist had mixed facilitatory and depressive effects, whereas 5-HT1B and 5-HT2C agonists were both largely facilitatory. Different agonists changed threshold and frequency tuning in ways that reflected their effects on spike count. When pairs of agonists were applied sequentially to the same neurons, selective agonists sometimes affected neurons in ways that were similar to serotonin, but not to other selective agonists tested. Different agonists also differentially affected groups of neurons classified by the shapes of their frequency-tuning curves, with serotonin and the 5-HT1 receptors affecting proportionally more non-V-type neurons relative to the other agonists tested. In all, evidence suggests that the diversity of serotonin receptor subtypes in the IC is likely to account for at least some of the variability of the effects of serotonin and that receptor subtypes fulfill specialized roles in auditory processing. PMID:16870843

  12. Alternative approaches to myeloid suppressor cell therapy in transplantation: comparing regulatory macrophages to tolerogenic DCs and MDSCs.

    PubMed

    Riquelme, Paloma; Geissler, Edward K; Hutchinson, James A

    2012-01-01

    Several types of myeloid suppressor cell are currently being developed as cell-based immunosuppressive agents. Despite detailed knowledge about the molecular and cellular functions of these cell types, expert opinions differ on how to best implement such therapies in solid organ transplantation. Efforts in our laboratory to develop a cell-based medicinal product for promoting tolerance in renal transplant patients have focused on a type of suppressor macrophage, which we call the regulatory macrophage (M reg). Our favoured clinical strategy is to administer donor-derived M regs to recipients one week prior to transplantation. In contrast, many groups working with tolerogenic dendritic cells (DCs) advocate post-transplant administration of recipient-derived cells. A third alternative, using myeloid-derived suppressor cells, presumably demands that cells are given around the time of transplantation, so that they can infiltrate the graft to create a suppressive environment. On present evidence, it is not possible to say which cell type and treatment strategy might be clinically superior. This review seeks to position our basic scientific and early-stage clinical studies of human regulatory macrophages within the broader context of myeloid suppressor cell therapy in transplantation. PMID:23369628

  13. Selective alteration of human value decisions with medial frontal tDCS is predicted by changes in attractor dynamics

    PubMed Central

    Hämmerer, D.; Bonaiuto, J.; Klein-Flügge, M.; Bikson, M.; Bestmann, S.

    2016-01-01

    During value-based decision making, ventromedial prefrontal cortex (vmPFC) is thought to support choices by tracking the expected gain from different outcomes via a competition-based process. Using a computational neurostimulation approach we asked how perturbing this region might alter this competition and resulting value decisions. We simulated a perturbation of neural dynamics in a biophysically informed model of decision-making through in silico depolarization at the level of neuronal ensembles. Simulated depolarization increased baseline firing rates of pyramidal neurons, which altered their susceptibility to background noise, and thereby increased choice stochasticity. These behavioural predictions were compared to choice behaviour in healthy participants performing similar value decisions during transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique. We placed the soma depolarizing electrode over medial frontal PFC. In line with model predictions, this intervention resulted in more random choices. By contrast, no such effect was observed when placing the depolarizing electrode over lateral PFC. Using a causal manipulation of ventromedial and lateral prefrontal function, these results provide support for competition-based choice dynamics in human vmPFC, and introduce computational neurostimulation as a mechanistic assay for neurostimulation studies of cognition. PMID:27146700

  14. Selective alteration of human value decisions with medial frontal tDCS is predicted by changes in attractor dynamics.

    PubMed

    Hämmerer, D; Bonaiuto, J; Klein-Flügge, M; Bikson, M; Bestmann, S

    2016-01-01

    During value-based decision making, ventromedial prefrontal cortex (vmPFC) is thought to support choices by tracking the expected gain from different outcomes via a competition-based process. Using a computational neurostimulation approach we asked how perturbing this region might alter this competition and resulting value decisions. We simulated a perturbation of neural dynamics in a biophysically informed model of decision-making through in silico depolarization at the level of neuronal ensembles. Simulated depolarization increased baseline firing rates of pyramidal neurons, which altered their susceptibility to background noise, and thereby increased choice stochasticity. These behavioural predictions were compared to choice behaviour in healthy participants performing similar value decisions during transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique. We placed the soma depolarizing electrode over medial frontal PFC. In line with model predictions, this intervention resulted in more random choices. By contrast, no such effect was observed when placing the depolarizing electrode over lateral PFC. Using a causal manipulation of ventromedial and lateral prefrontal function, these results provide support for competition-based choice dynamics in human vmPFC, and introduce computational neurostimulation as a mechanistic assay for neurostimulation studies of cognition. PMID:27146700

  15. MHC Class I-Restricted Myelin Epitopes Are Cross-Presented by Tip-DCs That Promote Determinant Spreading to CD8+ T Cells

    PubMed Central

    Ji, Qingyong; Castelli, Luca; Goverman, Joan M.

    2013-01-01

    Myelin presentation to T cells within the central nervous system (CNS) sustains inflammation in multiple sclerosis (MS). CD4+ and CD8+ T cells contribute to MS; however, only cells that present myelin to CD4+ T cells have been identified. We show that MHC class I-restricted myelin basic protein (MBP) was presented by oligodendrocytes and cross-presented by Tip-dendritic cells (DCs) during experimental autoimmune encephalomyelitis (EAE), an animal model of MS initiated by CD4+ T cells. Tip-DCs activated naïve and effector CD8+ T cells ex vivo, and naïve MBP-specific CD8+ T cells were activated within the CNS during CD4+ T cell-induced EAE. These results demonstrate that CD4+ T cell-mediated CNS autoimmunity leads to determinant spreading to myelin-specific CD8+ T cells that are capable of direct recognition of oligodendrocytes. PMID:23291597

  16. Cytokines plasma levels during antidepressant treatment with sertraline and transcranial direct current stimulation (tDCS): results from a factorial, randomized, controlled trial

    PubMed Central

    Machado-Vieira, Rodrigo; Zarate, Carlos A.; Valiengo, Leandro; Vieira, Erica LM; Benseñor, Isabela M; Lotufo, Paulo A.; Gattaz, Wagner F.; Teixeira, Antonio L

    2014-01-01

    Rationale The inflammatory hypothesis of depression states that increased levels of pro-inflammatory cytokines triggered by external and internal stressors are correlated to the acute depressive state. This hypothesis also suggests that pharmacotherapy partly acts in depression through anti-inflammatory effects. Transcranial direct current stimulation (tDCS) is a novel, promising, non-invasive somatic treatment for depression, although its antidepressant mechanisms are only partly understood. Objectives We explored the effects of tDCS and sertraline over the immune system during an antidepressant treatment trial. Methods In a 6-week, double-blind, placebo-controlled trial, 73 antidepressant-free patients with unipolar depression were randomized to active/sham tDCS and sertraline/placebo (2×2 design). Plasma levels of several cytokines (IL-2, IL-4, IL-6, IL-10, IL-17a, IFN-γ, and TNF-α) were determined to investigate the effects of the interventions and of clinical response on them. Results All cytokines, except TNF-α, decreased over time, these effects being similar across the different intervention-groups and in responders vs. non-responders. Conclusions tDCS and sertraline (separately and combined) acute antidepressant effects might not specifically involve normalization of the immune system. In addition, being one of the first placebo-controlled trials measuring cytokines over an antidepressant treatment course, our study showed that the decrease in cytokine levels during the acute depressive episode could involve a placebo effect, highlighting the need of further placebo-controlled trials and observational studies examining cytokine changes during depression treatment and also after remission of the acute depressive episode. PMID:24150249

  17. Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders.

    PubMed

    Geoffroy, Pierre Alexis; Etain, Bruno; Franchi, Jean-Arthur Micoulaud; Bellivier, Frank; Ritter, Philipp

    2015-01-01

    Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psychiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this comprehensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in patients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and delineate the routine use of melatonin-agonists in the treatment of BD. PMID:26088111

  18. Comparative endpoint sensitivity of in vitro estrogen agonist assays.

    PubMed

    Dreier, David A; Connors, Kristin A; Brooks, Bryan W

    2015-07-01

    Environmental and human health implications of endocrine disrupting chemicals (EDCs), particularly xenoestrogens, have received extensive study. In vitro assays are increasingly employed as diagnostic tools to comparatively evaluate chemicals, whole effluent toxicity and surface water quality, and to identify causative EDCs during toxicity identification evaluations. Recently, the U.S. Environmental Protection Agency (USEPA) initiated ToxCast under the Tox21 program to generate novel bioactivity data through high throughput screening. This information is useful for prioritizing chemicals requiring additional hazard information, including endocrine active chemicals. Though multiple in vitro and in vivo techniques have been developed to assess estrogen agonist activity, the relative endpoint sensitivity of these approaches and agreement of their conclusions remain unclear during environmental diagnostic applications. Probabilistic hazard assessment (PHA) approaches, including chemical toxicity distributions (CTD), are useful for understanding the relative sensitivity of endpoints associated with in vitro and in vivo toxicity assays by predicting the likelihood of chemicals eliciting undesirable outcomes at or above environmentally relevant concentrations. In the present study, PHAs were employed to examine the comparative endpoint sensitivity of 16 in vitro assays for estrogen agonist activity using a diverse group of compounds from the USEPA ToxCast dataset. Reporter gene assays were generally observed to possess greater endpoint sensitivity than other assay types, and the Tox21 ERa LUC BG1 Agonist assay was identified as the most sensitive in vitro endpoint for detecting an estrogenic response. When the sensitivity of this most sensitive ToxCast in vitro endpoint was compared to the human MCF-7 cell proliferation assay, a common in vitro model for biomedical and environmental monitoring applications, the ERa LUC BG1 assay was several orders of magnitude less

  19. Pharmacological properties of acid N-thiazolylamide FFA2 agonists

    PubMed Central

    Brown, Andrew J; Tsoulou, Christina; Ward, Emma; Gower, Elaine; Bhudia, Nisha; Chowdhury, Forhad; Dean, Tony W; Faucher, Nicolas; Gangar, Akanksha; Dowell, Simon J

    2015-01-01

    FFA2 is a receptor for short-chain fatty acids. Propionate (C3) and 4-chloro-α-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide (4-CMTB), the prototypical synthetic FFA2 agonist, evoke calcium mobilization in neutrophils and inhibit lipolysis in adipocytes via this G-protein-coupled receptor. 4-CMTB contains an N-thiazolylamide motif but no acid group, and 4-CMTB and C3 bind to different sites on FFA2 and show allosteric cooperativity. Recently, FFA2 agonists have been described that contain both N-thiazolylamide and carboxylate groups, reminiscent of bitopic ligands. These are thought to engage the carboxylate-binding site on FFA2, but preliminary evidence suggests they do not bind to the same site as 4-CMTB even though both contain N-thiazolylamide. Here, we describe the characterization of four FFA2 ligands containing both N-thiazolylamide and carboxylate. (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid (compound 14) exhibits allosteric agonism with 4-CMTB but not C3. Three other compounds agonize FFA2 in [35S]GTPγS-incorporation or cAMP assays but behave as inverse agonists in yeast-based gene-reporter assays, showing orthosteric antagonism of C3 responses but allosteric antagonism of 4-CMTB responses. Thus, the bitopic-like FFA2 ligands engage the orthosteric site but do not compete at the site of 4-CMTB binding on an FFA2 receptor molecule. Compound 14 activates FFA2 on human neutrophils and mouse adipocytes, but appears not to inhibit lipolysis upon treatment of human primary adipocytes in spite of the presence of a functional FFA2 receptor in these cells. Hence, these new ligands may reveal differences in coupling of FFA2 between human and rodent adipose tissues. PMID:26236484

  20. Defining Nicotinic Agonist Binding Surfaces through Photoaffinity Labeling†

    PubMed Central

    Tomizawa, Motohiro; Maltby, David; Medzihradszky, Katalin F.; Zhang, Nanjing; Durkin, Kathleen A.; Presley, Jack; Talley, Todd T.; Taylor, Palmer; Burlingame, Alma L.; Casida, John E.

    2016-01-01

    Nicotinic acetylcholine (ACh) receptor (nAChR) agonists are potential therapeutic agents for neurological dysfunction. In the present study, the homopentameric mollusk ACh binding protein (AChBP), used as a surrogate for the extracellular ligand-binding domain of the nAChR, was specifically derivatized by the highly potent agonist azidoepibatidine (AzEPI) prepared as a photoaffinity probe and radioligand. One EPI-nitrene photoactivated molecule was incorporated in each subunit interface binding site based on analysis of the intact derivatized protein. Tryptic fragments of the modified AChBP were analyzed by collision-induced dissociation and Edman sequencing of radiolabeled peptides. Each specific EPI-nitrene-modified site involved either Tyr195 of loop C on the principal or (+)-face or Met116 of loop E on the complementary or (−)-face. The two derivatization sites were observed in similar frequency, providing evidence of the reactivity of the azido/nitrene probe substituent and close proximity to both residues. [3H]AzEPI binds to the α4β2 nAChR at a single high-affinity site and photoaffinity-labels only the α4 subunit, presumably modifying Tyr225 spatially corresponding to Tyr195 of AChBP. Phe137 of the β2 nAChR subunit, equivalent to Met116 of AChBP, conceivably lacks sufficient reactivity with the nitrene generated from the probe. The present photoaffinity labeling in a physiologically relevant condition combined with the crystal structure of AChBP allows development of precise structural models for the AzEPI interactions with AChBP and α4β2 nAChR. These findings enabled us to use AChBP as a structural surrogate to define the nAChR agonist site. PMID:17614369

  1. AGONISTIC AUTOANTIBODIES AS VASODILATORS IN ORTHOSTATIC HYPOTENSION: A NEW MECHANISM

    PubMed Central

    Li, Hongliang; Kem, David C.; Reim, Sean; Khan, Muneer; Vanderlinde-Wood, Megan; Zillner, Caitlin; Collier, Daniel; Liles, Campbell; Hill, Michael A.; Cunningham, Madeleine W.; Aston, Christopher E.; Yu, Xichun

    2012-01-01

    Agonistic autoantibodies to the β-adrenergic and muscarinic receptors are a novel investigative and therapeutic target for certain orthostatic disorders. We have identified the presence of autoantibodies to β2-adrenergic and/or M3 muscarinic receptors by enzyme-linked immunosorbent assay in 75% (15 of 20) of patients with significant orthostatic hypotension. Purified serum IgG from all 20 patients and 10 healthy control subjects were examined in a receptor-transfected cell-based cAMP assay for β2 receptor activation and β-arrestin assay for M3 receptor activation. There was a significant increase in IgG-induced activation of β2 and M3 receptors in the patient group compared to controls. A dose response was observed for both IgG activation of β2 and M3 receptors and inhibition of their activation with the non-selective β blocker propranolol and muscarinic blocker atropine. The antibody effects on β2 and/or M3 (via production of nitric oxide) receptor-mediated vasodilation were studied in a rat cremaster resistance arteriole assay. Infusion of IgG from patients with documented β2 and/or M3 receptor agonistic activity produced a dose-dependent vasodilation. Sequential addition of the β blocker propranolol and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester partially inhibited IgG-induced vasodilation (% of maximal dilatory response: from 57.7±10.4 to 35.3±4.6 and 24.3±5.8, respectively, p<0.01, n=3), indicating antibody activation of vascular β2 and/or M3 receptors may contribute to systemic vasodilation. These data support the concept that circulating agonistic autoantibodies serve as vasodilators and may cause or exacerbate orthostatic hypotension. PMID:22215709

  2. Antinociceptive properties of selective MT(2) melatonin receptor partial agonists.

    PubMed

    López-Canul, Martha; Comai, Stefano; Domínguez-López, Sergio; Granados-Soto, Vinicio; Gobbi, Gabriella

    2015-10-01

    Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5-40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT2 partial agonists were blocked by the pre-treatment with the MT2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT2 melatonin receptor may be a novel target for analgesic drug development. PMID:26162699

  3. Integrated Advanced Microwave Sounding Unit-A (AMSU-A). Engineering Test Report: Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A1, S/N 108 2

    NASA Technical Reports Server (NTRS)

    Valdez, A.

    2000-01-01

    This is the Engineering Test Report, Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A1 SIN 108, for the Integrated Advanced Microwave Sounding Unit-A (AMSU-A).

  4. Integrated Advanced Microwave Sounding Unit-A (AMSU-A). Engineering Test Report: Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A2, S/N 108, 08

    NASA Technical Reports Server (NTRS)

    Valdez, A.

    2000-01-01

    This is the Engineering Test Report, Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A2, S/N 108, for the Integrated Advanced Microwave Sounding Unit-A (AMSU-A).

  5. Integrated Advanced Microwave Sounding Unit-A (AMSU-A). Engineering Test Report: Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A1, S/N 109

    NASA Technical Reports Server (NTRS)

    Valdez, A.

    2000-01-01

    This is the Engineering Test Report, Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A1, S/N 109, for the Integrated Advanced Microwave Sounding Unit-A (AMSU-A).

  6. Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine.

    PubMed

    Simeon, D; Hollander, E; Stein, D J; DeCaria, C; Cohen, L J; Saoud, J B; Islam, N; Hwang, M

    1995-09-29

    Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization. PMID:8570768

  7. INSIGHT AGONISTES: A READING OF SOPHOCLES'S OEDIPUS THE KING.

    PubMed

    Mahon, Eugene J

    2015-07-01

    In this reading of Sophocles's Oedipus the King, the author suggests that insight can be thought of as the main protagonist of the tragedy. He personifies this depiction of insight, calling it Insight Agonistes, as if it were the sole conflicted character on the stage, albeit masquerading at times as several other characters, including gods, sphinxes, and oracles. This psychoanalytic reading of the text lends itself to an analogy between psychoanalytic process and Sophocles's tragic hero. The author views insight as always transgressing against, always at war with a conservative, societal, or intrapsychic chorus of structured elements. A clinical vignette is presented to illustrate this view of insight. PMID:26198605

  8. Clenbuterol, a beta(2)-agonist, retards atrophy in denervated muscles

    NASA Technical Reports Server (NTRS)

    Zeman, Richard J.; Ludemann, Robert; Etlinger, Joseph D.

    1987-01-01

    The effects of a beta(2) agonist, clenbuterol, on the protein content as well as on the contractile strength and the muscle fiber cross-sectional area of various denervated muscles from rats were investigated. It was found that denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, of rats treated for 2-3 weeks with clenbuterol contained 95-110 percent more protein than denervated controls. The twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area.

  9. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    PubMed

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter. PMID:26585147

  10. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

    SciTech Connect

    Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  11. Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists.

    PubMed

    Sheppeck, James E; Gilmore, John L; Xiao, Hai-Yun; Dhar, T G Murali; Nirschl, David; Doweyko, Arthur M; Sack, Jack S; Corbett, Martin J; Malley, Mary F; Gougoutas, Jack Z; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Dodd, John H; Nadler, Steven G; Somerville, John E; Barrish, Joel C

    2013-10-01

    Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure. PMID:23953070

  12. [Combination of TLR7 agonist T7-ethacrynic acid conjugate with ROR1 has a stronger anti-breast cancer effect].

    PubMed

    Zhang, Na; Jin, Guangyi; Jin, Zhenchao; Liu, Bing; Peng, Boya; Gao, Ningning; Hu, Yunlong; Tang, Li

    2016-07-01

    Objective To investigate the synergistic anti-breast cancer effect of Toll-like receptor 7 agonist T7-ethacrynic acid conjugate (T7-EA) in combination with receptor-tyrosine-kinase-like orphan receptor 1 (ROR1). Methods ROR1 cytotoxic T lymphocyte (CTL) epitope was predicted using Syfpeithi online software. Mouse spleen lymphocytes and bone marrow dendritic cells (DCs) were separately stimulated with 4 μmol/L T7-EA and 4 μmol/L ROR1 alone or in combination. ELISA assay was used to measure the levels of interferon-γ (IFN-γ), interleukin 12 (IL-12) and tumor necrosis factor-α (TNF-α). Xenograft model was established via subcutaneous injection of mouse breast cancer 4T1 cells. The mice were weekly treated through intraperitoneal administration of 3 mg/kg T7-EA, 15 mg/kg ROR1 or the combination of T7-EA and ROR1. After four rounds of treatment, tumor tissues were weighed. Serum level of anti-4T1 tumor protein IgG was measured by ELISA. Specific CTL activity was detected by lactate dehydrogenase (LDH) assay. Results The peptide PYCDETSSV was chosen as an antigen epitope of breast cancer. The T7-EA highly activated in vitro lymphocytes in a dose-dependent manner, which wasn't affected by other relevant peptides. The combination of T7-EA and ROR1 stimulated the secretion of IFN-γ and IL-12 by lymphocytes and TNF-α by bone marrow DCs. The growth of tumor in vivo was significantly inhibited by T7-EA combined with ROR1 compared with T7-EA or ROR1 alone. The specific CTL activity triggered by T7-EA combined with ROR1 was much stronger than that triggered by T7-EA or ROR1 alone. The titer of anti-4T1 tumor protein IgG induced by T7-EA combined with ROR1 was higher than that induced by T7-EA or ROR1. Conclusion The combination of T7-EA and ROR1 has a better killing effect on breast cancer. PMID:27363264

  13. Site of action of a pentapeptide agonist at the glucagon-like peptide-1 receptor. Insight into a small molecule agonist-binding pocket

    PubMed Central

    Dong, Maoqing; Pinon, Delia I.; Miller, Laurence J.

    2011-01-01

    The development of small molecule agonists for class B G protein-coupled receptors (GPCRs) has been quite challenging. With proof-of-concept that exenatide, the parenterally administered peptide agonist of the glucagon-like peptide-1 (GLP1) receptor, is an effective treatment for patients with diabetes mellitus, the development of small molecule agonists could have substantial advantages. We previously reported a lead for small molecule GLP1 receptor agonist development representing the pentapeptide NRTFD. In this work, we have prepared an NRTFD derivative incorporating a photolabile benzoylphenylalanine and used it to define its site of action. This peptide probe was a full agonist with potency similar to NRTFD, which bound specifically and saturably to a single, distinct site within the GLP1 receptor. Peptide mapping using cyanogen bromide and endoproteinase Lys-C cleavage of labeled wild type and M397L mutant receptor constructs identified the site of covalent attachment of NRTFD within the third extracellular loop above the sixth transmembrane segment. This region is the same as that identified using an analogous photolabile probe based on secretin receptor sequences, and has been shown in mutagenesis studies to be important for natural agonist action of several members of this family. While these observations suggest that small molecule ligands can act at a site bordering the third extracellular loop to activate this class B GPCR, the relationship of this site to the site of action of the amino-terminal end of the natural agonist peptide is unclear. PMID:22079758

  14. No Effect of 2 mA Anodal tDCS Over the M1 on Performance and Practice Effect on Grooved Pegboard Test and Trail Making Test B1,2,3

    PubMed Central

    Freili, Janita L.; Danielsen, Therese L.; Aslaksen, Per M.

    2015-01-01

    Abstract Previous studies suggest that transcranial direct current stimulation (tDCS) can facilitate motor performance and learning. In this double-blind experiment, 60 healthy human subjects (29 females) were randomized into three groups (active tDCS, sham tDCS, and no-treatment control group) in order to investigate the effect of a 20 min session of 2 mA tDCS over the motor cortex contralateral to the dominant hand on practice effect and performance on the Grooved Pegboard Test (GPT) and Trail Making Test (TMT). Performance was operationalized as the time to complete the tests before, during, and after stimulation. The practice effect was termed as the difference in time to complete the tests from pretest to post-test. Data on body mass index (BMI), head circumference, sleep status, interelectrode impedance, and caffeine and nicotine use were sampled to control for the influence of individual differences on the effect of tDCS. Adverse effects were registered using a standardized form. The results indicated no effect of tDCS on performance and practice effects on the GPT and TMT. For all groups, BMI was a predictor for a practice effect on the TMT. In the active tDCS group, high caffeine intake and low impedance predicted a practice effect on the GPT for the dominant hand. The present results suggest that impedance levels in tDCS studies should be routinely reported in future studies, as it might not only provide valuable information on the efficacy of the blinding conditions and participant discomfort, but also correlate with individual differences that are relevant to the outcome of the stimulation. PMID:26465001

  15. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy

    PubMed Central

    Iribarren, Kristina; Bloy, Norma; Buqué, Aitziber; Cremer, Isabelle; Eggermont, Alexander; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Špíšek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2016-01-01

    ABSTRACT Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy. PMID:27141345

  16. Synthesis and biological activities of indolizine derivatives as alpha-7 nAChR agonists.

    PubMed

    Xue, Yu; Tang, Jingshu; Ma, Xiaozhuo; Li, Qing; Xie, Bingxue; Hao, Yuchen; Jin, Hongwei; Wang, Kewei; Zhang, Guisen; Zhang, Liangren; Zhang, Lihe

    2016-06-10

    Human α7 nicotinic acetylcholine receptor (nAChR) is a promising therapeutic target for the treatment of schizophrenia accompanied with cognitive impairment. Herein, we report the synthesis and agonistic activities of a series of indolizine derivatives targeting to α7 nAChR. The results show that all synthesized compounds have affinity to α7 nAChR and some give strong agonistic activity, particularly most active agonists show higher potency than control EVP-6124. The docking and structure-activity relationship studies provide insights to develop more potent novel α7 nAChR agonists. PMID:26994846

  17. Dopamine agonist-induced substance addiction: the next piece of the puzzle.

    PubMed

    Evans, Andrew

    2011-02-01

    Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminergic drugs with the avoidance of motor response complications. Dopamine agonists have an established role in delaying the emergence of motor response complications or reducing motor "off" periods. The recent recognition of a range of "behavioural addictions" that are linked to dopamine agonist use has highlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamine agonists have now even been linked occasionally to new substance addictions. The challenge now for the Parkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effects with avoiding the harm from behavioural compulsions. PMID:20980151

  18. Sustained wash-resistant receptor activation responses of GPR119 agonists.

    PubMed

    Hothersall, J Daniel; Bussey, Charlotte E; Brown, Alastair J; Scott, James S; Dale, Ian; Rawlins, Philip

    2015-09-01

    G protein-coupled receptor 119 (GPR119) is involved in regulating metabolic homoeostasis, with GPR119 agonists targeted for the treatment of type-2 diabetes and obesity. Using the endogenous agonist oleoylethanolamide and a number of small molecule synthetic agonists we have investigated the temporal dynamics of receptor signalling. Using both a dynamic luminescence biosensor-based assay and an endpoint cAMP accumulation assay we show that agonist-driven desensitization is not a major regulatory mechanism for GPR119 despite robust activation responses, regardless of the agonist used. Temporal analysis of the cAMP responses demonstrated sustained signalling resistant to washout for some, but not all of the agonists tested. Further analysis indicated that the sustained effects of one synthetic agonist AR-231,453 were consistent with a role for slow dissociation kinetics. In contrast, the sustained responses to MBX-2982 and AZ1 appeared to involve membrane deposition. We also detect wash-resistant responses to AR-231,453 at the level of physiologically relevant responses in an endogenous expression system (GLP-1 secretion in GLUTag cells). In conclusion, our findings indicate that in a recombinant expression system GPR119 activation is sustained, with little evidence of pronounced receptor desensitization, and for some ligands persistent agonist responses continue despite removal of excess agonist. This provides novel understanding of the temporal responses profiles of potential drug candidates targetting GPR119, and highlights the importance of carefully examining the the mechanisms through which GPCRs generate sustained responses. PMID:26101059

  19. Mapping the agonist binding site of the nicotinic acetylcholine receptor. Orientation requirements for activation by covalent agonist.

    PubMed

    Sullivan, D A; Cohen, J B

    2000-04-28

    To characterize the structural requirements for ligand orientation compatible with activation of the Torpedo nicotinic acetylcholine receptor (nAChR), we used Cys mutagenesis in conjunction with sulfhydryl-reactive reagents to tether primary or quaternary amines at defined positions within the agonist binding site of nAChRs containing mutant alpha- or gamma-subunits expressed in Xenopus oocytes. 4-(N-Maleimido)benzyltrimethylammonium and 2-aminoethylmethanethiosulfonate acted as irreversible antagonists when tethered at alphaY93C, alphaY198C, or gammaE57C, as well as at alphaN94C (2-aminoethylmethanethiosulfonate only). [2-(Trimethylammonium)-ethyl]-methanethiosulfonate (MTSET), which attaches thiocholine to binding site Cys, also acted as an irreversible antagonist when tethered at alphaY93C, alphaN94C, or gammaE57C. However, MTSET modification of alphaY198C resulted in prolonged activation of the nAChR not reversible by washing but inhibitable by subsequent exposure to non-competitive antagonists. Modification of alphaY198C (or any of the other positions tested) by [(trimethylammonium)methyl]methanethiosulfonate resulted only in irreversible inhibition, while modification of alphaY198C by [3-(trimethylammonium)propyl]methanethiosulfonate resulted in irreversible activation of nAChR, but at lower efficacy than by MTSET. Thus changing the length of the tethering arm by less than 1 A in either direction markedly effects the ability of the covalent trimethylammonium to activate the nAChR, and agonist activation depends on a very selective orientation of the quaternary ammonium within the agonist binding site. PMID:10777557

  20. DCs Pulsed with Novel HLA-A2-Restricted CTL Epitopes against Hepatitis C Virus Induced a Broadly Reactive Anti-HCV-Specific T Lymphocyte Response

    PubMed Central

    Guo, Zhongsheng; Zhang, Henghui; Rao, Huiying; Jiang, Dong; Cong, Xu; Feng, Bo; Wang, Jianghua; Wei, Lai; Chen, Hongsong

    2012-01-01

    Objective To determine the capacity of dendritic cells (DCs) loaded with single or multiple-peptide mixtures of novel hepatitis C virus (HCV) epitopes to stimulate HCV-specific cytotoxic T lymphocyte (CTL) effector functions. Methods A bioinformatics approach was used to predict HLA-A2-restricted HCV-specific CTL epitopes, and the predicted peptides identified from this screen were synthesized. Subsequent IFN-γ ELISPOT analysis detected the stimulating function of these peptides in peripheral blood mononuclear cells (PBMCs) from both chronic and self-limited HCV infected subjects (subjects exhibiting spontaneous HCV clearance). Mature DCs, derived in vitro from CD14+ monocytes harvested from the study subjects by incubation with appropriate cytokine cocktails, were loaded with novel peptide or epitope peptide mixtures and co-cultured with autologous T lymphocytes. Granzyme B (GrB) and IFN-γ ELISPOT analysis was used to test for epitope-specific CTL responses. T-cell-derived cytokines contained in the co-cultured supernatant were detected by flow cytometry. Results We identified 7 novel HLA-A2-restricted HCV-specific CTL epitopes that increased the frequency of IFN-γ-producing T cells compared to other epitopes, as assayed by measuring spot forming cells (SFCs). Two epitopes had the strongest stimulating capability in the self-limited subjects, one found in the E2 and one in the NS2 region of HCV; five epitopes had a strong stimulating capacity in both chronic and self-limited HCV infection, but were stronger in the self-limited subjects. They were distributed in E2, NS2, NS3, NS4, and NS5 regions of HCV, respectively. We also found that mDCs loaded with novel peptide mixtures could significantly increase GrB and IFN-γ SFCs as compared to single peptides, especially in chronic HCV infection subjects. Additionally, we found that DCs pulsed with multiple epitope peptide mixtures induced a Th1-biased immune response. Conclusions Seven novel and strongly stimulating

  1. Novel approaches in treatment of pediatric anxiety

    PubMed Central

    Park, Jennifer M.

    2014-01-01

    Pediatric anxiety disorders have high prevalence rates and morbidity and are associated with considerable functional impairment and distress. They may be predictors for the development of other psychiatric disorders and, without intervention, are more likely to persist into adulthood. While evidence-based pharmacological and behavioral interventions are currently available, there remains a sizable subset of youth who remain only partially treatment-responsive and therefore symptomatic following treatment. Novel methods of treatment, pharmacologic and non-pharmacologic, including acceptance and commitment therapy (ACT), attention bias modification (ABM), d-cycloserine (DCS) augmentation of cognitive behavioral treatment (CBT), and glutamatergic agents such as riluzole, are briefly introduced and discussed. PMID:24860652

  2. Isothiouronium compounds as gamma-aminobutyric acid agonists.

    PubMed Central

    Allan, R. D.; Dickenson, H. W.; Hiern, B. P.; Johnston, G. A.; Kazlauskas, R.

    1986-01-01

    Analogues of gamma-aminobutyric acid (GABA) incorporating an isothiouronium salt as a replacement for a protonated amino functional group have been investigated for activity on: GABA receptors in the guinea-pig ileum; [3H]-GABA and [3H]-diazepam binding to rat brain membranes; and GABA uptake and transamination. For the homologous series of omega-isothiouronium alkanoic acids, maximum GABA-mimetic activity was found at 3-[(aminoiminomethyl)thio]propanoic acid. Introduction of unsaturation into this compound gave two isomeric conformationally restricted analogues. The trans isomer was inactive at GABA receptors while the cis compound ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA)) was more potent than muscimol and GABA as a GABA agonist with respect to low affinity GABA receptor sites. Both isomers were moderately potent at inhibiting the uptake of [3H]-GABA into rat brain slices. Comparison of possible conformations of the two unsaturated isomers by interactive computer graphics modelling and comparison with muscimol has led to a plausible active conformation of ZAPA, which may be a selective and potent agonist for low affinity GABA binding sites. PMID:3015310

  3. Cold Suppresses Agonist-induced Activation of TRPV1

    PubMed Central

    Chung, M.-K.; Wang, S.

    2011-01-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction. PMID:21666106

  4. Antidiabetic Actions of an Estrogen Receptor β Selective Agonist

    PubMed Central

    Alonso-Magdalena, Paloma; Ropero, Ana B.; García-Arévalo, Marta; Soriano, Sergi; Quesada, Iván; Muhammed, Sarheed J.; Salehi, Albert; Gustafsson, Jan-Ake; Nadal, Ángel

    2013-01-01

    The estrogen receptor β (ERβ) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ERβ selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic β-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide–induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic β-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic β-cell mass. We conclude that ERβ agonists should be considered as new targets for the treatment of diabetes. PMID:23349481

  5. Anti-cancer flavonoids are mouse selective STING agonists

    PubMed Central

    Kim, Sujeong; Li, Lingyin; Maliga, Zoltan; Yin, Qian; Wu, Hao; Mitchison, Timothy J.

    2013-01-01

    The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice, but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor-specific vascular damage and other anti-tumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the anti-tumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy. PMID:23683494

  6. Aging changes agonist induced contractile responses in permeabilized rat bladder.

    PubMed

    Durlu-Kandilci, N Tugba; Denizalti, Merve; Sahin-Erdemli, Inci

    2015-08-01

    Aging alters bladder functions where a decrease in filling, storage and emptying is observed. These changes cause urinary incontinence, especially in women. The aim of this study is to examine how aging affects the intracellular calcium movements due to agonist-induced contractions in permeabilized female rat bladder. Urinary bladder isolated from young and old female Sprague-Dawley rats were used. Small detrusor strips were permeabilized with β-escin. The contractile responses induced with agonists were compared between young and old groups. Carbachol-induced contractions were decreased in permeabilized detrusor from old rats compared to young group. Heparin and ryanodine decreased carbachol-induced contractions in young rats where only heparin inhibited these contractions in olds. Caffeine-induced contractions but not inositol triphosphate (IP3)-induced contractions were decreased in old group compared to youngs. The cumulative calcium response curves (pCa 8-4) were also decreased in old rats. Carbachol-induced calcium sensitization responses did not alter by age where GTP-β-S and GF-109203X but not Y-27632 inhibited these responses. Carbachol-induced contractions decrease with aging in rat bladder detrusor. It can be postulated as IP3-induced calcium release (IICR) is primarily responsible for the contractions in older rats where the decrease in carbachol contractions in aging may be as a result of a decrease in calcium-induced calcium release (CICR), rather than carbachol-induced calcium sensitization. PMID:26153091

  7. A Sphingosine 1-phosphate receptor 2 selective allosteric agonist

    PubMed Central

    Satsu, Hideo; Schaeffer, Marie-Therese; Guerrero, Miguel; Saldana, Adrian; Eberhart, Christina; Hodder, Peter; Cayanan, Charmagne; Schürer, Stephan; Bhhatarai, Barun; Roberts, Ed; Rosen, Hugh; Brown, Steven J.

    2013-01-01

    Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound. PMID:23849205

  8. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    PubMed

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists. PMID:19832688

  9. Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets

    SciTech Connect

    Schaechter, M.; Godfrey, P.P.; Minchin, M.C.W.; McClue, S.J.; Young, M.M.

    1985-10-28

    The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with (/sup 3/H)-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT/sub 2/ antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT/sub 2/ type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors. 30 references, 4 figures.

  10. Suppression of atherosclerosis by synthetic REV-ERB agonist.

    PubMed

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M; Solt, Laura A; Burris, Thomas P

    2015-05-01

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. PMID:25800870

  11. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways. PMID:24752777

  12. How does agonistic behaviour differ in albino and pigmented fish?

    PubMed Central

    Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics. PMID:27114883

  13. Long-Acting Beta Agonists Enhance Allergic Airway Disease

    PubMed Central

    Knight, John M.; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O.; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A.; Milner, Joshua D.; Zhang, Yuan; Mandal, Pijus K.; Luong, Amber; Kheradmand, Farrah

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  14. Cariprazine:New dopamine biased agonist for neuropsychiatric disorders.

    PubMed

    De Deurwaerdère, P

    2016-02-01

    Cariprazine (RGH-188, MP-214, Vraylar[TM]) is a new dopamine receptor ligand developed for the treatment of several neuropsychiatric diseases including schizophrenia and bipolar disorders. Cariprazine displays higher affinity at dopamine D3 receptors and a similar affinity at D2 and 5-HT2B receptors. At variance with some atypical antipsychotics, its affinity at 5-HT1A, 5-HT2A and histamine H1 receptors is modest compared with its three main targets. Cariprazine could correspond to a biased agonist at dopamine receptors, displaying either antagonist or partial agonist properties depending on the signaling pathways linked to D2/D3 receptors. The compound crosses the blood-brain barrier, as revealed by positron emission tomography and pharmacokinetic studies in various species. Two main metabolites result mainly from the activity of CYP34A and display properties similar to those of the parent drug. Behavioral data report that cariprazine is efficacious in animal models addressing positive, negative and cognitive symptoms of schizophrenia with no extrapyramidal side effects. In September 2015, the FDA approved the use of cariprazine for the treatment of schizophrenia and type I bipolar disorder. The efficacy of cariprazine in other neuropsychiatric diseases is currently being evaluated in preclinical and clinical studies. Side effects have been observed in humans, including extrapyramidal side effects and akathisia of mild to moderate intensity. PMID:27092339

  15. Long-Acting Beta Agonists Enhance Allergic Airway Disease.

    PubMed

    Knight, John M; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A; Milner, Joshua D; Zhang, Yuan; Mandal, Pijus K; Luong, Amber; Kheradmand, Farrah; McMurray, John S; Corry, David B

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  16. Cerebellar cathodal tDCS interferes with recalibration and spatial realignment during prism adaptation procedure in healthy subjects.

    PubMed

    Panico, Francesco; Sagliano, Laura; Grossi, Dario; Trojano, Luigi

    2016-06-01

    The aim of this study is to clarify the specific role of the cerebellum during prism adaptation procedure (PAP), considering its involvement in early prism exposure (i.e., in the recalibration process) and in post-exposure phase (i.e., in the after-effect, related to spatial realignment). For this purpose we interfered with cerebellar activity by means of cathodal transcranial direct current stimulation (tDCS), while young healthy individuals were asked to perform a pointing task on a touch screen before, during and after wearing base-left prism glasses. The distance from the target dot in each trial (in terms of pixels) on horizontal and vertical axes was recorded and served as an index of accuracy. Results on horizontal axis, that was shifted by prism glasses, revealed that participants who received cathodal stimulation showed increased rightward deviation from the actual position of the target while wearing prisms and a larger leftward deviation from the target after prisms removal. Results on vertical axis, in which no shift was induced, revealed a general trend in the two groups to improve accuracy through the different phases of the task, and a trend, more visible in cathodal stimulated participants, to worsen accuracy from the first to the last movements in each phase. Data on horizontal axis allow to confirm that the cerebellum is involved in all stages of PAP, contributing to early strategic recalibration process, as well as to spatial realignment. On vertical axis, the improving performance across the different stages of the task and the worsening accuracy within each task phase can be ascribed, respectively, to a learning process and to the task-related fatigue. PMID:27031676

  17. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification.

    PubMed

    Zaware, Pandurang; Shah, Shailesh R; Pingali, Harikishore; Makadia, Pankaj; Thube, Baban; Pola, Suresh; Patel, Darshit; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Jamili, Jeevankumar; Sairam, Kalapatapu V V M; Giri, Suresh; Patel, Lala; Patel, Harilal; Sudani, Hareshkumar; Patel, Hiren; Jain, Mukul; Patel, Pankaj; Bahekar, Rajesh

    2011-01-15

    A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders. PMID:21195611

  18. Impact of Efficacy at the μ-Opioid Receptor on Antinociceptive Effects of Combinations of μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

    PubMed Central

    Maguire, David R.

    2014-01-01

    Cannabinoid receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ9-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ9-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain. PMID:25194020

  19. 1,4-Benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonists.

    PubMed

    Sherrill, R G; Berman, J M; Birkemo, L; Croom, D K; Dezube, M; Ervin, G N; Grizzle, M K; James, M K; Johnson, M F; Queen, K L; Rimele, T J; Vanmiddlesworth, F; Sugg, E E

    2001-05-01

    A series of 1,4-benzodiazepines, N-1-substituted with an N-isopropyl-N-phenylacetamide moiety, was synthesized and screened for CCK-A agonist activity. In vitro agonist activity on isolated guinea pig gallbladder along with in vivo induction of satiety following intraperitoneal administration in a rat feeding assay was demonstrated. PMID:11354363

  20. The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

    PubMed

    Kotani, Manato; Kiyoshi, Akihiko; Murai, Takeshi; Nakako, Tomokazu; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Ogi, Yuji; Ikeda, Kazuhito

    2016-03-01

    Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics. PMID:26675887

  1. Functional desensitization of the β2 adrenoceptor is not dependent on agonist efficacy

    PubMed Central

    Rosethorne, Elizabeth M; Bradley, Michelle E; Kent, Toby C; Charlton, Steven J

    2015-01-01

    Chronic treatment with β2 adrenoceptor agonists is recommended as a first-line maintenance therapy for chronic obstructive pulmonary disease (COPD). However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time. In this study, we have investigated the tendency of such agonists, with a range of efficacies, to develop functional desensitization to cAMP responses in primary human bronchial smooth muscle cells following prolonged agonist exposure. The data show that upon repeat exposure, all agonists produced functional desensitization to the same degree and rate. In addition, β2 adrenoceptor internalization and β-arrestin-2 recruitment were monitored using β2·eGFP visualization and the PathHunter™ β-arrestin-2 assay, respectively. All agonists were capable of causing robust receptor internalization and β-arrestin-2 recruitment, the rate of which was influenced by agonist efficacy, as measured in those assays. In summary, although a relationship exists between agonist efficacy and the rate of both receptor internalization and β-arrestin-2 recruitment, there is no correlation between agonist efficacy and the rate or extent of functional desensitization. PMID:25692019

  2. Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms.

    PubMed

    Randáková, Alena; Dolejší, Eva; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; El-Fakahany, Esam E; Jakubík, Jan

    2015-07-01

    We mutated key amino acids of the human variant of the M1 muscarinic receptor that target ligand binding, receptor activation, and receptor-G protein interaction. We compared the effects of these mutations on the action of two atypical M1 functionally preferring agonists (N-desmethylclozapine and xanomeline) and two classical non-selective orthosteric agonists (carbachol and oxotremorine). Mutations of D105 in the orthosteric binding site and mutation of D99 located out of the orthosteric binding site decreased affinity of all tested agonists that was translated as a decrease in potency in accumulation of inositol phosphates and intracellular calcium mobilization. Mutation of D105 decreased the potency of the atypical agonist xanomeline more than that of the classical agonists carbachol and oxotremorine. Mutation of the residues involved in receptor activation (D71) and coupling to G-proteins (R123) completely abolished the functional responses to both classical and atypical agonists. Our data show that both classical and atypical agonists activate hM1 receptors by the same molecular switch that involves D71 in the second transmembrane helix. The principal difference among the studied agonists is rather in the way they interact with D105 in the orthosteric binding site. Furthermore, our data demonstrate a key role of D105 in xanomeline wash-resistant binding and persistent activation of hM1 by wash-resistant xanomeline. PMID:25882246

  3. Prolonging Survival of Corneal Transplantation by Selective Sphingosine-1-Phosphate Receptor 1 Agonist

    PubMed Central

    Gao, Min; Liu, Yong; Xiao, Yang; Han, Gencheng; Jia, Liang; Wang, Liqiang; Lei, Tian; Huang, Yifei

    2014-01-01

    Corneal transplantation is the most used therapy for eye disorders. Although the cornea is somewhat an immune privileged organ, immune rejection is still the major problem that reduces the success rate. Therefore, effective chemical drugs that regulate immunoreactions are needed to improve the outcome of corneal transplantations. Here, a sphingosine-1-phosphate receptor 1 (S1P1) selective agonist was systematically evaluated in mouse allogeneic corneal transplantation and compared with the commonly used immunosuppressive agents. Compared with CsA and the non-selective sphingosine 1-phosphate (S1P) receptor agonist FTY720, the S1P1 selective agonist can prolong the survival corneal transplantation for more than 30 days with a low immune response. More importantly, the optimal dose of the S1P1 selective agonist was much less than non-selective S1P receptor agonist FTY720, which would reduce the dose-dependent toxicity in drug application. Then we analyzed the mechanisms of the selected S1P1 selective agonist on the immunosuppression. The results shown that the S1P1 selective agonist could regulate the distribution of the immune cells with less CD4+ T cells and enhanced Treg cells in the allograft, moreover the expression of anti-inflammatory cytokines TGF-β1 and IL-10 unregulated which can reduce the immunoreactions. These findings suggest that S1P1 selective agonist may be a more appropriate immunosuppressive compound to effectively prolong mouse allogeneic corneal grafts survival. PMID:25216235

  4. Hyperthermia induced by the dopamine D1 receptor agonist SK&F38393 in combination with the dopamine D2 receptor agonist talipexole in the rat.

    PubMed

    Nagashima, M; Yamada, K; Kimura, H; Matsumoto, S; Furukawa, T

    1992-12-01

    The present experiments were performed to investigate the effects of dopamine D1 receptor agonists given alone or in combination with dopamine D2 receptor agonists on body temperature in rats. The selective dopamine D1 receptor agonist, 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SK&F38393), produced hyperthermia. However, the dopamine D2 receptor agonist, B-HT 920 (talipexole), and the newly synthesized dopamine D2 receptor agonist, (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (SND 919), did not change the temperature. Interestingly, the SK&F38393-induced hyperthermia was enhanced by talipexole and SND 919. The drastic hyperthermia induced by combined administration of dopamine D1 and D2 receptor agonists was blocked by either the dopamine D1 receptor antagonist, SCH23390, or the dopamine D2 receptor antagonist, spiperone. On the other hand, treatment with prazosin, yohimbine, propranolol, scopolamine, or methysergide failed to affect the marked hyperthermia. The present results suggest that a functional link between dopamine D1 and D2 receptors may be synergistic in the regulation of body temperature and that concurrent stimulation of both dopamine D1 and D2 receptors thereby produces marked hyperthermia in the rat. PMID:1361996

  5. Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis

    PubMed Central

    Pitari, Giovanni M

    2013-01-01

    Agonists of the transmembrane intestinal receptor guanylyl cyclase C (GCC) have recently attracted interest as promising human therapeutics. Peptide ligands that can specifically induce GCC signaling in the intestine include endogenous hormones guanylin and uroguanylin, diarrheagenic bacterial enterotoxins (ST), and synthetic drugs linaclotide, plecanatide, and SP-333. These agonists bind to GCC at intestinal epithelial surfaces and activate the receptor’s intracellular catalytic domain, an event initiating discrete biological responses upon conversion of guanosine-5′-triphosphate to cyclic guanosine monophosphate. A principal action of GCC agonists in the colon is the promotion of mucosal homeostasis and its dependent barrier function. Herein, GCC agonists are being developed as new medications to treat inflammatory bowel diseases, pathological conditions characterized by mucosal barrier hyperpermeability, abnormal immune reactions, and chronic local inflammation. This review will present important concepts underlying the pharmacology and therapeutic utility of GCC agonists for patients with ulcerative colitis, one of the most prevalent inflammatory bowel disease disorders. PMID:23637522

  6. Voltage dependence of agonist effectiveness at the frog neuromuscular junction: resolution of a paradox.

    PubMed Central

    Dionne, V E; Stevens, C F

    1975-01-01

    1. End-plate currents produced by nerve-released acetylcholine and iontophoretically applied acetylcholine and carbachol have been recorded from voltage-clamped frog cutaneous pectoris neuromuscular junctions made visible with Nomarski differential interference contrast optics. 2. The effectiveness of agonists - that is, the end-plate conductance change produced by a given dose-has been determined as a function of post-junctional membrane potential. 3. As the post-junctional membrane potential is made more negative, nerve-released acetylcholine becomes less effective whereas iontophoretically-applied agonists become more effective. 4. This voltage dependence of agonist effectiveness is mediated neither by end-plate current iontophoresis of agonist into the cleft nor through electric field effects on the esterase. 5. Influences of membrane potential on the opening and closing of end-plate channel gates can account quantitatively for the voltage-dependent effectiveness of both nerve-released and iontophoretically applied agonist. PMID:1081139

  7. The link between non-ergot-derived dopamine agonists and heart failure: how strong is it?

    PubMed

    Lockett, Katrina; DeBacker, Danielle; Cauthon, Kimberly A B

    2015-03-01

    Dopamine agonists are commonly used as initial monotherapy and adjunct treatment for Parkinson's disease. However, the Food and Drug Administration recently linked pramipexole use with an increased risk of heart failure (HF). Several case-control studies demonstrate a possible increased risk of the development of HF in patients taking non-ergot-derived dopamine agonists compared with patients not taking dopamine agonists. In patients taking non-ergot-derived dopamine agonists, the studies associated the risk of increased HF with pramipexole. These studies did not find a possible increased risk with ropinirole, but to date no randomized, controlled trials have been conducted to directly compare ropinirole with pramipexole and the risk of HF. The mechanism by which HF occurs is unknown, but the development of edema after dopamine agonist use could increase the risk of HF. If patients with a history of cardiovascular disease or edema are prescribed pramipexole, additional monitoring for HF signs and symptoms is recommended. PMID:25760663

  8. [Is the LHRH Agonist Recommended for Fertility Preservation ?].

    PubMed

    Kimura, Kosei; Iwamoto, Mitsuhiko; Tanaka, Satoru; Watanabe, Toru; Aihara, Tomohiko; Sugimoto, Takeki; Miyara, Kyuichiro; Hayashi, Mitsuhiro; Kouno, Tsutomu; Baba, Shinichi; Kawashima, Hiroaki; Hashimoto, Naoki; Uchiyama, Kazuhisa

    2015-08-01

    The POEMS reportedan effect of goserelin for fertility preservation. The Clinical Practice Guideline for Breast Cancer by The Japanese Breast Cancer Society indicates that the use of the LHRH agonist (LHRHa) for preventing chemotherapy-induced early menopause is a grade C-1 recommendation, and its use for fertility preservation is a grade C-2 recommendation. Results from previous studies on the effects of LHRHa for fertility preservation have varied owing to differences in chemotherapy regimens, definitions of ovarian failure, and dosages of tamoxifen. In the POEMS, the primary endpoint of ovarian failure at 2 years was significantly lower, and the secondary endpoint of pregnancy outcomes was better in the combination group; however, precise interpretation is difficult because many cases were excluded. Currently, it is not necessary to revise The Clinical Practice Guideline; however, desirable results from future studies may allow the recommendation of a specific dosage of LHRHa for fertility preservation. PMID:26321722

  9. The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity

    PubMed Central

    Crane, James; McGowan, Barbara

    2015-01-01

    There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID:26977279

  10. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist.

    PubMed

    Kühnen, Peter; Clément, Karine; Wiegand, Susanna; Blankenstein, Oliver; Gottesdiener, Keith; Martini, Lea L; Mai, Knut; Blume-Peytavi, Ulrike; Grüters, Annette; Krude, Heiko

    2016-07-21

    Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2). PMID:27468060

  11. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis

    PubMed Central

    Dietrich, Johannes W.; Landgrafe, Gabi; Fotiadou, Elisavet H.

    2012-01-01

    This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic be