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Sample records for disrupts prepulse inhibition

  1. Prepulse inhibition of the acoustic startle reflex in pigs and its disruption by D-amphetamine

    DEFF Research Database (Denmark)

    Lind, N. M.; Arnfred, S. M.; Hemmingsen, R. P.

    2004-01-01

    Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating. The dopamine receptor agonist-mediated disruption of PPI in rats is widely used as a model of the sensorimotor gating deficiencies demonstrated in schizophrenia patients. As a possible tool for valid......Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating. The dopamine receptor agonist-mediated disruption of PPI in rats is widely used as a model of the sensorimotor gating deficiencies demonstrated in schizophrenia patients. As a possible tool....../kg with a paradigm including two levels of prepulses (82 and 88dB) and a prepulse (PP) interval of 60 and 120ms. We found an average PPI of the startle reflex of 25.6% and both of the investigated PP intensities and PP intervals were equally effective in this PP-inhibitive paradigm. AMPH significantly disrupted PPI...... and, in spite of only the 0.5mg/kg dose proved statistically significant, the results indicate this to be dose-related. We have demonstrated the phenomenon of PPI of the startle reflex in landrace pigs and its disruption by d-amphetamine. Studies of sensorimotor gating defects could be a valuable...

  2. Clerodendrum inerme Leaf Extract Alleviates Animal Behaviors, Hyperlocomotion, and Prepulse Inhibition Disruptions, Mimicking Tourette Syndrome and Schizophrenia

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    Hon-Lie Chen

    2012-01-01

    Full Text Available Previously, we found a patient with intractable motor tic disorder, a spectrum of Tourette syndrome (TS, responsive to the ground leaf juice of Clerodendrum inerme (CI. Here, we examined the effect of the ethanol extract of CI leaves (CI extract on animal behaviors mimicking TS, hyperlocomotion, and sensorimotor gating deficit. The latter is also observed in schizophrenic patients and can be reflected by a disruption of prepulse inhibition of acoustic startle response (PPI in animal models induced by methamphetamine and NMDA channel blockers (ketamine or MK-801, based on hyperdopaminergic and hypoglutamatergic hypotheses, respectively. CI extract (10–300 mg/kg, i.p. dose-dependently inhibited hyperlocomotion induced by methamphetamine (2 mg/kg, i.p. and PPI disruptions induced by methamphetamine, ketamine (30 mg/kg, i.p., and MK-801 (0.3 mg/kg, i.p. but did not affect spontaneous locomotor activity, rotarod performance, and grip force. These results suggest that CI extract can relieve hyperlocomotion and improve sensorimotor gating deficit, supporting the therapeutic potential of CI for TS and schizophrenia.

  3. Effects of sigma(1) receptor ligand, MS-377 on apomorphine- or phencyclidine-induced disruption of prepulse inhibition of acoustic startle in rats.

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    Yamada, S; Yamauchi, K; Hisatomi, S; Annoh, N; Tanaka, M

    2000-08-25

    To evaluate the antipsychotic property of a sigma(1) receptor ligand, (R)-(+)-1-(4-chlorophenyl)-3-¿4-(2-methoxyethyl)piperazin-1-yl¿ methyl-2-pyrrolidinone-L-tartrate (MS-377), an antagonistic effect of MS-377 on the disruption of prepulse inhibition (PPI) of the acoustic startle by apomorphine or phencyclidine (PCP) was investigated in rats. MS-377 antagonized the PCP-induced disruption of PPI. The ED(50) value of MS-377 for this effect was 0.66 mg/kg. In contrast, apomorphine-induced disruption of PPI was not attenuated by MS-377. These data indicate that the PCP-induced disruption of PPI in rats would be, at least partially, mediated by sigma receptors and MS-377 could be a novel anti-psychotic agent with clinical efficacy for the sensorimotor-gating deficit in schizophrenia.

  4. Adenosine AA Receptor Antagonists Do Not Disrupt Rodent Prepulse Inhibition: An Improved Side Effect Profile in the Treatment of Parkinson's Disease

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    Carina J. Bleickardt

    2012-01-01

    Full Text Available Parkinson's disease (PD is characterized by loss of dopaminergic neurons in the substantia nigra. Current treatments for PD focus on dopaminergic therapies, including L-dopa and dopamine receptor agonists. However, these treatments induce neuropsychiatric side effects. Psychosis, characterized by delusions and hallucinations, is one of the most serious such side effects. Adenosine A2A receptor antagonism is a nondopaminergic treatment for PD with clinical and preclinical efficacy. The present studies assessed A2A antagonists SCH 412348 and istradefylline in rodent prepulse inhibition (PPI, a model of psychosis. Dopamine receptor agonists pramipexole (0.3–3 mg/kg, pergolide (0.3–3 mg/kg, and apomorphine (0.3–3 mg/kg significantly disrupted PPI; ropinirole (1–30 mg/kg had no effect; L-dopa (100–300 mg/kg disrupted rat but not mouse PPI. SCH 412348 (0.3–3 mg/kg did not disrupt rodent PPI; istradefylline (0.1–1 mg/kg marginally disrupted mouse but not rat PPI. These results suggest that A2A antagonists, unlike dopamine agonists, have an improved neuropsychiatric side effect profile.

  5. Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis

    NARCIS (Netherlands)

    de Koning, Mariken B.; Bloemen, Oswald J. N.; van Duin, Esther D. A.; Booij, Jan; Abel, Kathryn M.; de Haan, Lieuwe; Linszen, Don H.; van Amelsvoort, Thérèse A. M. J.

    2014-01-01

    Reduced prepulse inhibition (PPI) of the acoustic startle response is thought to represent a robust biomarker in schizophrenia. Reduced PPI has been demonstrated in subjects at ultra high risk (UHR) for developing psychosis. Imaging studies report disruption of striatal dopaminergic

  6. Motivated attention and prepulse inhibition of startle in rats: using conditioned reinforcers as prepulses.

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    Baschnagel, Joseph S; Hawk, Larry W; Colder, Craig R; Richards, Jerry B

    2007-12-01

    In humans, prepulse inhibition (PPI) of startle is greater during attended prestimuli than it is during ignored prestimuli, whereas in rats, most work has focused on passive PPI, which does not require attention. In the work described in this article, researchers developed a paradigm to assess attentional modification of PPI in rats using motivationally salient prepulses. Water-deprived rats were either conditioned to attend to a conditioned stimulus (CS; 1-s, 7-dB increase in white noise) paired with water (CS(+) group), or they received uncorrelated presentations of white noise and water (CS0 group). After 10 conditioning sessions, startle probes (50 ms, 115 dB) were introduced, with the CS serving as a continuous prepulse. Three experiments examined PPI across a range of prepulse intensities (4-10 dB) and stimulus onset asynchronies (SOAs; 30-960 ms). PPI was consistently reduced in the CS(+) group, particularly with a 10-dB prepulse and a 60-ms SOA. Thus, PPI in rats differed between attended and ignored prestimuli, but the effect was reversed in the results of research with humans. A fourth study eliminated the group difference by reversing the CS-water contingency. Methodological and motivational hypotheses regarding the current findings are discussed.

  7. Prepulse inhibition of auditory change-related cortical responses

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    Inui Koji

    2012-10-01

    Full Text Available Abstract Background Prepulse inhibition (PPI of the startle response is an important tool to investigate the biology of schizophrenia. PPI is usually observed by use of a startle reflex such as blinking following an intense sound. A similar phenomenon has not been reported for cortical responses. Results In 12 healthy subjects, change-related cortical activity in response to an abrupt increase of sound pressure by 5 dB above the background of 65 dB SPL (test stimulus was measured using magnetoencephalography. The test stimulus evoked a clear cortical response peaking at around 130 ms (Change-N1m. In Experiment 1, effects of the intensity of a prepulse (0.5 ~ 5 dB on the test response were examined using a paired stimulation paradigm. In Experiment 2, effects of the interval between the prepulse and test stimulus were examined using interstimulus intervals (ISIs of 50 ~ 350 ms. When the test stimulus was preceded by the prepulse, the Change-N1m was more strongly inhibited by a stronger prepulse (Experiment 1 and a shorter ISI prepulse (Experiment 2. In addition, the amplitude of the test Change-N1m correlated positively with both the amplitude of the prepulse-evoked response and the degree of inhibition, suggesting that subjects who are more sensitive to the auditory change are more strongly inhibited by the prepulse. Conclusions Since Change-N1m is easy to measure and control, it would be a valuable tool to investigate mechanisms of sensory gating or the biology of certain mental diseases such as schizophrenia.

  8. The effects of increased central serotonergic activity on prepulse inhibition and habituation of the human startle response

    DEFF Research Database (Denmark)

    Frederiksen, Kristian Steen; Oranje, Bob; Wienberg, Malene

    2007-01-01

    Sensorimotor gating is critical to normal brain functioning, and disruptions are associated with certain mental illnesses, such as schizophrenia. Prepulse inhibition of the acoustic startle reflex (ASR) (PPI) is an operational measure of sensorimotor gating, of which evidence for a serotonergic...

  9. Similar effects of attention directed to acoustic and tactile stimuli on prepulse inhibition of acoustic startle.

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    Elden, Ake; Flaten, Magne A

    2003-09-01

    Prepulse inhibition (PPI) is assumed to index automatic and controlled processing. In three experiments (n= 32, 22, and 30) participants were asked to judge the duration of a prepulse in comparison with a stimulus presented 4000 ms before the prepulse. A distracter was presented simultaneously with the prepulse to increase the cognitive demands of the task. PPI was assessed at stimulus onset asynchronies (SOAs) of 30-150 ms, and 420 ms. The prepulse was either a tone (60 dB) or a tactile stimulus (21 kPa), and startle was elicited by 95 dB white noise. Directing attention to the prepulse increased PPI at SOAs of 60 ms and longer in all experiments, but the sensory modality to which attention was directed played only a minor role. We conclude that directing attention to both acoustic and tactile prepulses increased PPI.

  10. Interaction of reelin and stress on immobility in the forced swim test but not dopamine-mediated locomotor hyperactivity or prepulse inhibition disruption: Relevance to psychotic and mood disorders.

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    Notaras, Michael J; Vivian, Billie; Wilson, Carey; van den Buuse, Maarten

    2017-07-13

    Psychotic disorders, such as schizophrenia, as well as some mood disorders, such as bipolar disorder, have been suggested to share common biological risk factors. One such factor is reelin, a large extracellular matrix glycoprotein that regulates neuronal migration during development as well as numerous activity-dependent processes in the adult brain. The current study sought to evaluate whether a history of stress exposure interacts with endogenous reelin levels to modify behavioural endophenotypes of relevance to psychotic and mood disorders. Heterozygous Reeler Mice (HRM) and wildtype (WT) controls were treated with 50mg/L of corticosterone (CORT) in their drinking water from 6 to 9weeks of age, before undergoing behavioural testing in adulthood. We assessed methamphetamine-induced locomotor hyperactivity, prepulse inhibition (PPI) of acoustic startle, short-term spatial memory in the Y-maze, and depression-like behaviour in the Forced-Swim Test (FST). HRM genotype or CORT treatment did not affect methamphetamine-induced locomotor hyperactivity, a model of psychosis-like behaviour. At baseline, HRM showed decreased PPI at the commonly used 100msec interstimulus interval (ISI), but not at the 30msec ISI or following challenge with apomorphine. A history of CORT exposure potentiated immobility in the FST amongst HRM, but not WT mice. In the Y-maze, chronic CORT treatment decreased novel arm preference amongst HRM, reflecting reduced short-term spatial memory. These data confirm a significant role of endogenous reelin levels on stress-related behaviour, supporting a possible role in both bipolar disorder and schizophrenia. However, an interaction of reelin deficiency with dopaminergic regulation of psychosis-like behaviour remains unclear. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Routine post-weaning handling of rats prevents isolation rearing-induced deficit in prepulse inhibition

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    M.L.N.M. Rosa

    2005-11-01

    Full Text Available Rats reared under isolation conditions from weaning present a number of behavioral changes compared to animals reared under social conditions (group housing. These changes include deficits in prepulse inhibition (PPI of the startle reflex to a loud sound. PPI refers to the reduction of the magnitude of the startle reflex when a relatively weak stimulus (the prepulse precedes by an appropriate time interval the intense startle-elicing stimulus (the pulse. PPI is useful for studying sensorimotor integration. The present study evaluated the effect of handling on the impairment of PPI induced by isolation-rearing. Male Wistar rats (N = 11-15/group were housed in groups (5 per cage and handled three times a week or isolated (housed individually since weaning (21 days for 10 weeks when they reach approximately 150 g. The isolated rats were divided into "minimally handled" animals (handled once a week for cleaning purposes only or "handled" animals (handled three times a week. This handling consisted of grasping the rat by the tail and moving it to a clean cage (approximately 5 s. A statistically significant reduction (52% in the PPI test was found only in the isolated group with minimal handling while no difference was seen between grouped animals and isolated handled animals. These results indicate that isolation rearing causes disruption in the PPI at adult age, which serves as an index of attention deficit. This change in the sensory processing of information induced by post-weaning isolation can be prevented by handling during the development of the animal.

  12. Routine post-weaning handling of rats prevents isolation rearing-induced deficit in prepulse inhibition.

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    Rosa, M L N M; Silva, R C B; Moura-de-Carvalho, F T; Brandão, M L; Guimarães, F S; Del Bel, E A

    2005-11-01

    Rats reared under isolation conditions from weaning present a number of behavioral changes compared to animals reared under social conditions (group housing). These changes include deficits in prepulse inhibition (PPI) of the startle reflex to a loud sound. PPI refers to the reduction of the magnitude of the startle reflex when a relatively weak stimulus (the prepulse) precedes by an appropriate time interval the intense startle-elicing stimulus (the pulse). PPI is useful for studying sensorimotor integration. The present study evaluated the effect of handling on the impairment of PPI induced by isolation-rearing. Male Wistar rats (N = 11-15/group) were housed in groups (5 per cage and handled three times a week) or isolated (housed individually) since weaning (21 days) for 10 weeks when they reach approximately 150 g. The isolated rats were divided into "minimally handled" animals (handled once a week for cleaning purposes only) or "handled" animals (handled three times a week). This handling consisted of grasping the rat by the tail and moving it to a clean cage (approximately 5 s). A statistically significant reduction (52%) in the PPI test was found only in the isolated group with minimal handling while no difference was seen between grouped animals and isolated handled animals. These results indicate that isolation rearing causes disruption in the PPI at adult age, which serves as an index of attention deficit. This change in the sensory processing of information induced by post-weaning isolation can be prevented by handling during the development of the animal.

  13. Prepulse inhibition is associated with attention, processing speed, and 123I-FP-CIT SPECT in Parkinson's disease

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    Zoetmulder, Marielle; Biernat, Heidi B; Nikolic, Miki

    2014-01-01

    BACKGROUND: Prepulse inhibition is a measure of sensorimotor gating, which reflects the ability to filter or 'gate' irrelevant information. Prepulse inhibition is dramatically altered in basal ganglia disorders associated with dysfunction in the midbrain dopaminergic system, and corresponding......'s disease have been extensively studied in relation to motor function, less is known about the potential role of sensorimotor processes in cognitive function. OBJECTIVE: We investigated the relationship between prepulse inhibition, cognition and nigrostriatal dysfunction, as measured with 123I......-FP-CIT-SPECT scanning, in patients with Parkinson's disease. METHODS: 38 Parkinson patients were assessed with prepulse inhibition, neuropsychological tests, and neurological investigation. A subset of these patients underwent 123I-FP-CIT-SPECT scanning. RESULTS: Patients with a higher level of prepulse inhibition...

  14. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies.

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    Braff, D L; Geyer, M A; Swerdlow, N R

    2001-07-01

    Since the mid-1970s, cross-species translational studies of prepulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been optimized. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30-500 ms before a strong startle-inducing stimulus, and reduces the magnitude of the startle response. In humans, PPI occurs in a robust, predictable manner when the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous). This review covers three areas of interest in human PPI studies. First, we review the normal influences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopathological disorders that form a family of gating disorders. Third, we review the relatively limited but interesting and rapidly expanding literature on pharmacological influences on PPI in humans. All studies identified by a computerized literature search that addressed the three topics of this review were compiled and evaluated. The principal studies were summarized in appropriate tables. The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domains are similar across species, supporting the value of PPI studies in translational comparisons across species. The most prominent literature describing deficits in PPI in psychiatrically defined groups features schizophrenia-spectrum patients and their clinically unaffected relatives. These findings support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology involving cortico-striato-pallido-pontine circuits exhibit poor gating of motor, sensory, or cognitive information and corresponding PPI deficits. These groups include patients with obsessive compulsive disorder, Tourette's syndrome

  15. Glycine and GABAA receptors mediate tonic and phasic inhibitory processes that contribute to prepulse inhibition in the goldfish startle network

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    Paul C.P. Curtin

    2015-03-01

    Full Text Available Prepulse inhibition (PPI is understood as an inhibitory process that attenuates sensory flow during early stages (20-1000ms of information processing. Here, we applied in vivo electrophysiology and pharmacology to determine if prepulse inhibition (PPI is mediated by glycine receptors (GlyRs and/or GABAA receptors (GABAARs in the goldfish auditory startle circuit. Specifically, we used selective antagonists to dissect the contributions of target receptors on sound-evoked postsynaptic potentials (PSPs recorded in the neurons that initiate startle, the Mauthner-cells (M-cell. We found that strychnine, a GlyR antagonist, disrupted a fast-activated (5 ms and rapidly (< 50ms decaying (feed-forward inhibitory process that disrupts PPI at 20 ms prepulse/pulse inter-stimulus intervals (ISI. Additionally we observed increases of the evoked postsynaptic potential (PSP peak amplitude (+87.43 ± 21.53%; N=9 and duration (+204 ± 48.91%, N=9. In contrast, treatment with bicuculline, a GABAAR antagonist, caused a general reduction in PPI across all tested ISIs (20-500 ms, essentially eliminating PPI at ISIs from 20-100 ms. Bicuculline also increased PSP peak amplitude (+133.8 ± 10.3%, N=5 and PSP duration (+284.95 ± 65.64%, N=5. Treatment with either antagonist also tonically increased post-synaptic excitability in the M-cells, reflected by an increase in the magnitude of antidromically-evoked action potentials (APs by 15.07 ± 3.21%, N=7 and 16.23 ± 7.08%, N=5 for strychnine and bicuculline, respectively. These results suggest that GABAARs and GlyRs are functionally segregated to short- and longer-lasting sound-evoked (phasic inhibitory processes that contribute to PPI, with the mediation of tonic inhibition by both receptor systems being critical for gain control within the M-cell startle circuit.

  16. Effects of postnatal anoxia on striatal dopamine metabolism and prepulse inhibition in rats

    DEFF Research Database (Denmark)

    Sandager-Nielsen, Karin; Andersen, Maibritt B; Sager, Thomas N

    2004-01-01

    in schizophrenic patients. There was no effect of postnatal anoxia on either baseline or d-amphetamine-induced deficit in the prepulse inhibition (PPI) paradigm in adulthood. Accordingly, although oxygen deficiency early in life has been discussed as vulnerability factor in developing schizophrenia, exposure...

  17. Prepulse inhibition and facilitation of the postauricular reflex, a vestigial remnant of pinna startle.

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    Hackley, Steven A; Ren, Xi; Underwood, Amy; Valle-Inclán, Fernando

    2017-04-01

    If the postauricular reflex (PAR) is to be used effectively in studies of emotion and attention, its sensitivity to basic modulatory effects such as prepulse inhibition and facilitation must be determined. Two experiments were carried out with healthy young adults to assess the effects of transient and sustained visual prestimuli on the pinna-flexion response to trains of startle probes. In the first experiment, participants passively viewed a small white square. It was displayed from 1,000 ms prior to onset of a train of noise bursts until the end of that train. Relative to no-prepulse control trials, PAR amplitude was inhibited, possibly due to the withdrawal of attentional resources from the auditory modality. In the second experiment, participants performed a visual oddball task in which irrelevant trains of startle probes followed most briefly displayed task stimuli (checkerboards). Prepulse inhibition was observed when a transient stimulus preceded the first probe at a lead time of 100 ms. Amplitude facilitation was observed at longer lead times. In addition to documenting the existence of prepulse inhibition and facilitation, the data suggest that the PAR is not elicited by visual stimuli, that temporal expectancy does not influence its amplitude or latency, and that this vestigial microreflex is resistant to habituation. Results are interpreted in light of a recent theory that the human PAR is a highly degraded pinna startle, in which the reflex arc no longer includes the startle center (nucleus reticularis pontis caudalis). © 2017 Society for Psychophysiological Research.

  18. BDNF deficiency and young-adult methamphetamine induce sex-specific effects on prepulse inhibition regulation

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    Elizabeth E Manning

    2013-06-01

    Full Text Available Brain-derived neurotrophic factor (BDNF has been implicated in the pathophysiology of schizophrenia, yet its role in the development of specific symptoms is unclear. Methamphetamine (METH users have an increased risk of psychosis and schizophrenia, and METH-treated animals have been used extensively as a model to study the positive symptoms of schizophrenia. We investigated whether METH treatment in BDNF heterozygous mutant mice (HET has cumulative effects on sensorimotor gating, including the disruptive effects of psychotropic drugs. BDNF HETs and WT littermates were treated during young-adulthood with METH and, following a two-week break, prepulse inhibition (PPI was examined. At baseline, BDNF HETs showed reduced PPI compared to WT mice irrespective of METH pre-treatment. An acute challenge with amphetamine (AMPH disrupted PPI but male BDNF HETs were more sensitive to this effect, irrespective of METH pre-treatment. In contrast, female mice treated with METH were less sensitive to the disruptive effects of AMPH, and there were no effects of BDNF genotype. Similar changes were not observed in the response to an acute apomorphine or MK-801 challenge. These results show that genetically-induced reduction of BDNF caused changes in a behavioural endophenotype relevant to the positive symptoms of schizophrenia. However, major sex differences were observed in the effects of a psychotropic drug challenge on this behaviour. These findings suggest sex differences in the effects of BDNF depletion and METH treatment on the monoamine signaling pathways that regulate PPI. Given that these same pathways are thought to contribute to the expression of positive symptoms in schizophrenia, this work suggests that there may be significant sex differences in the pathophysiology underlying these symptoms. Elucidating these sex differences may be important for our understanding of the neurobiology of schizophrenia and developing better treatments strategies for the

  19. Neural circuits containing olfactory neurons are involved in prepulse inhibition of the startle reflex in rats

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    Haichen eNiu

    2015-03-01

    Full Text Available Many neuropsychiatric disorders, such as schizophrenia, have been associated with abnormalities in the function of the olfactory system and prepulse inhibition (PPI of the startle reflex. However, whether these two abnormalities are related is unclear. The present study was designed to determine whether inhibiting olfactory sensory input via the infusion of zinc sulfate (ZnE, 0.17 M, 0.5 ml into the olfactory naris disrupts PPI. Furthermore, lidocaine/MK801 was bilaterally microinjected into the olfactory bulb (OB to examine whether the blockade of olfactory sensory input impairs PPI. To identify the neural projections that connect the olfaction- and PPI-related areas of the CNS, trans-synaptic retrograde tracing using a recombinant pseudorabies virus (PRV was performed. Our results demonstrated that blocking olfactory sensory input altered olfaction-related behavior. At the functional level, we demonstrated that the inhibition of olfactory sensory input impaired PPI of the startle response subsequent to a decrease in c-fos expression in relevant brain regions. Furthermore, the results of a similar and more robust experiment indicated that blocking olfactory sensory input via the microinjection of lidocaine/MK801 into the OB impaired PPI. At the circuit level, based on trans-synaptic retrograde tracing using PRV, we demonstrated that a large portion of the labeled neurons in several regions of the olfactory cortices connected to the pedunculopontine tegmental nucleus (PPTg. Thus, these data suggest that the olfactory system participates in the regulation of PPI and plays a role in the effect of PPI on the startle response in rats.

  20. Prepulse Inhibition of Auditory Cortical Responses in the Caudolateral Superior Temporal Gyrus in Macaca mulatta.

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    Chen, Zuyue; Parkkonen, Lauri; Wei, Jingkuan; Dong, Jin-Run; Ma, Yuanye; Carlson, Synnöve

    2018-04-01

    Prepulse inhibition (PPI) refers to a decreased response to a startling stimulus when another weaker stimulus precedes it. Most PPI studies have focused on the physiological startle reflex and fewer have reported the PPI of cortical responses. We recorded local field potentials (LFPs) in four monkeys and investigated whether the PPI of auditory cortical responses (alpha, beta, and gamma oscillations and evoked potentials) can be demonstrated in the caudolateral belt of the superior temporal gyrus (STGcb). We also investigated whether the presence of a conspecific, which draws attention away from the auditory stimuli, affects the PPI of auditory cortical responses. The PPI paradigm consisted of Pulse-only and Prepulse + Pulse trials that were presented randomly while the monkey was alone (ALONE) and while another monkey was present in the same room (ACCOMP). The LFPs to the Pulse were significantly suppressed by the Prepulse thus, demonstrating PPI of cortical responses in the STGcb. The PPI-related inhibition of the N1 amplitude of the evoked responses and cortical oscillations to the Pulse were not affected by the presence of a conspecific. In contrast, gamma oscillations and the amplitude of the N1 response to Pulse-only were suppressed in the ACCOMP condition compared to the ALONE condition. These findings demonstrate PPI in the monkey STGcb and suggest that the PPI of auditory cortical responses in the monkey STGcb is a pre-attentive inhibitory process that is independent of attentional modulation.

  1. Dissociative identity disorder and prepulse inhibition of the acoustic startle reflex

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    Dale, Karl Yngvar; Flaten, Magne Arve; Elden, Åke; Holte, Arne

    2008-01-01

    A group of persons with dissociative identity disorder (DID) was compared with a group of persons with other dissociative disorders, and a group of nondiagnosed controls with regard to prepulse inhibition (PPI) of the acoustic startle reflex. The findings suggest maladaptive attentional processes at a controlled level, but not at a preattentive automatic level, in persons with DID. The prepulse occupied more controlled attentional resources in the DID group compared with the other two groups. Preattentive automatic processing, on the other hand, was normal in the DID group. Moreover, startle reflexes did not habituate in the DID group. In conclusion, increased PPI and delayed habituation is consistent with increased vigilance in individuals with DID. The present findings of reduced habituation of startle reflexes and increased PPI in persons with DID suggest the operation of a voluntary process that directs attention away from unpleasant or threatening stimuli. Aberrant voluntary attentional processes may thus be a defining characteristic in DID. PMID:18830396

  2. Effects of melatonin on prepulse inhibition, habituation and sensitization of the human startle reflex in healthy volunteers

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    Lehtinen, Emilia K; Ucar, Ebru; Glenthøj, Birte Y

    2014-01-01

    Prepulse inhibition of the startle reflex (PPI) is an operational measure of sensorimotor gating, which is demonstrated to be impaired in patients with schizophrenia. In addition, a disruption of the circadian rhythm together with blunted melatonin secretion is regularly found in patients...... with schizophrenia and it is theorized that these may contribute to their attentional deficits. The aim of this study was to assess the effects of acute melatonin on healthy human sensorimotor gating. Twenty-one healthy male volunteers were administered melatonin or placebo after which their levels of PPI were...... assessed. Melatonin significantly reduced startle magnitude and ratings of alertness, but did not influence PPI, nor sensitization and habituation. However, when taking baseline scores in consideration, melatonin significantly increased PPI in low scoring individuals while significantly decreasing...

  3. White matter hyperintensities and prepulse inhibition in a mixed elderly population

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    Salem, Lise C; Hejl, Anne-Mette; Garde, Ellen

    2011-01-01

    Prepulse inhibition (PPI) of the startle response, a measure for sensorimotor gating, exhibits a relatively high inter-individual variability in elderly subjects. The aim of this study was to investigate whether white matter hyperintensities (WMH), frequently identified on cranial magnetic...... rated visually on craniel MRI FLAIR images using the Fazekas scale. WMH were identified in 70% of all subjects. The latency to peak of the startle response increased significantly with increasing WMH load, whereas the inhibition of the startle response (PPI) was neither significantly related...

  4. Dissociative identity disorder and prepulse inhibition of the acoustic startle reflex

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    Karl Yngvar Dale

    2008-06-01

    Full Text Available Karl Yngvar Dale1, Magne Arve Flaten1, Åke Elden1, Arne Holte21Department of Psychology, University of Tromsø, Norway; 2The Norwegian Institute of Public Health, Department of Mental Health, Oslo, Norway and University of Oslo, NorwayAbstract: A group of persons with dissociative identity disorder (DID was compared with a group of persons with other dissociative disorders, and a group of nondiagnosed controls with regard to prepulse inhibition (PPI of the acoustic startle reflex. The findings suggest maladaptive attentional processes at a controlled level, but not at a preattentive automatic level, in persons with DID. The prepulse occupied more controlled attentional resources in the DID group compared with the other two groups. Preattentive automatic processing, on the other hand, was normal in the DID group. Moreover, startle reflexes did not habituate in the DID group. In conclusion, increased PPI and delayed habituation is consistent with increased vigilance in individuals with DID. The present findings of reduced habituation of startle reflexes and increased PPI in persons with DID suggest the operation of a voluntary process that directs attention away from unpleasant or threatening stimuli. Aberrant voluntary attentional processes may thus be a defining characteristic in DID.Keywords: dissociation, DID, PPI, startle, habituation

  5. Hypnotizability, hypnosis and prepulse inhibition of the startle reflex in healthy women: an ERP analysis.

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    De Pascalis, Vilfredo; Russo, Emanuela

    2013-01-01

    A working model of the neurophysiology of hypnosis suggests that highly hypnotizable individuals (HHs) have more effective frontal attentional systems implementing control, monitoring performance, and inhibiting unwanted stimuli from conscious awareness, than low hypnotizable individuals (LHs). Recent studies, using prepulse inhibition (PPI) of the auditory startle reflex (ASR), suggest that HHs, in the waking condition, may show reduced sensory gating although they may selectively attend and disattend different stimuli. Using a within subject design and a strict subject selection procedure, in waking and hypnosis conditions we tested whether HHs compared to LHs showed a significantly lower inhibition of the ASR and startle-related brain activity in both time and intracerebral source localization domains. HHs, as compared to LH participants, exhibited (a) longer latency of the eyeblink startle reflex, (b) reduced N100 responses to startle stimuli, and (c) higher PPI of eyeblink startle and of the P200 and P300 waves. Hypnosis yielded smaller N100 waves to startle stimuli and greater PPI of this component than in the waking condition. sLORETA analysis revealed that, for the N100 (107 msec) elicited during startle trials, HHs had a smaller activation in the left parietal lobe (BA2/40) than LHs. Auditory pulses of pulse-with prepulse trials in HHs yielded less activity of the P300 (280 msec) wave than LHs, in the cingulate and posterior cingulate gyrus (BA23/31). The present results, on the whole, are in the opposite direction to PPI findings on hypnotizability previously reported in the literature. These results provide support to the neuropsychophysiological model that HHs have more effective sensory integration and gating (or filtering) of irrelevant stimuli than LHs.

  6. Hypnotizability, hypnosis and prepulse inhibition of the startle reflex in healthy women: an ERP analysis.

    Directory of Open Access Journals (Sweden)

    Vilfredo De Pascalis

    Full Text Available A working model of the neurophysiology of hypnosis suggests that highly hypnotizable individuals (HHs have more effective frontal attentional systems implementing control, monitoring performance, and inhibiting unwanted stimuli from conscious awareness, than low hypnotizable individuals (LHs. Recent studies, using prepulse inhibition (PPI of the auditory startle reflex (ASR, suggest that HHs, in the waking condition, may show reduced sensory gating although they may selectively attend and disattend different stimuli. Using a within subject design and a strict subject selection procedure, in waking and hypnosis conditions we tested whether HHs compared to LHs showed a significantly lower inhibition of the ASR and startle-related brain activity in both time and intracerebral source localization domains. HHs, as compared to LH participants, exhibited (a longer latency of the eyeblink startle reflex, (b reduced N100 responses to startle stimuli, and (c higher PPI of eyeblink startle and of the P200 and P300 waves. Hypnosis yielded smaller N100 waves to startle stimuli and greater PPI of this component than in the waking condition. sLORETA analysis revealed that, for the N100 (107 msec elicited during startle trials, HHs had a smaller activation in the left parietal lobe (BA2/40 than LHs. Auditory pulses of pulse-with prepulse trials in HHs yielded less activity of the P300 (280 msec wave than LHs, in the cingulate and posterior cingulate gyrus (BA23/31. The present results, on the whole, are in the opposite direction to PPI findings on hypnotizability previously reported in the literature. These results provide support to the neuropsychophysiological model that HHs have more effective sensory integration and gating (or filtering of irrelevant stimuli than LHs.

  7. Increased Prepulse Inhibition and Sensitization of the Startle Reflex in Autistic Children

    DEFF Research Database (Denmark)

    Madsen, Gitte Falcher; Bilenberg, Niels; Cantio, Cathriona

    2014-01-01

    The relation between autism spectrum disorders (ASD) and schizophrenia is a subject of intense debate and research due to evidence of common neurobiological pathways in the two disorders. The objective of this study was to explore whether deficits in prepulse inhibition (PPI) of the startle reflex......, as usually seen in schizophrenic patients, can be replicated in a group of children with ASD in comparison with a group of matched neuro-typically developed (NTD) controls. An additional aim was to explore possible psychophysiological subgroups within our ASD sample. In a case-control design, 35 ASD patients...... and 40 matched NTD controls were tested in a psychophysiological test battery. The PPI of the acoustic startle reflex was analyzed in 18 ASD subjects and 34 NTD controls. Habituation and sensitization were analyzed in 23 ASD subjects and 39 NTD controls. In trials with less intense prestimuli (76 d...

  8. Methodological optimization of tinnitus assessment using prepulse inhibition of the acoustic startle reflex.

    Science.gov (United States)

    Longenecker, R J; Galazyuk, A V

    2012-11-16

    Recently prepulse inhibition of the acoustic startle reflex (ASR) became a popular technique for tinnitus assessment in laboratory animals. This method confers a significant advantage over the previously used time-consuming behavioral approaches utilizing basic mechanisms of conditioning. Although this technique has been successfully used to assess tinnitus in different laboratory animals, many of the finer details of this methodology have not been described enough to be replicated, but are critical for tinnitus assessment. Here we provide detail description of key procedures and methodological issues that provide guidance for newcomers with the process of learning to correctly apply gap detection techniques for tinnitus assessment in laboratory animals. The major categories of these issues include: refinement of hardware for best performance, optimization of stimulus parameters, behavioral considerations, and identification of optimal strategies for data analysis. This article is part of a Special Issue entitled: Tinnitus Neuroscience. Copyright © 2012. Published by Elsevier B.V.

  9. Disturbed prepulse inhibition in patients with schizophrenia is consequential to dysfunction of selective attention.

    Science.gov (United States)

    Scholes, Kirsty E; Martin-Iverson, Mathew T

    2010-03-01

    Controversy exists as to the cause of disturbed prepulse inhibition (PPI) in patients with schizophrenia. This study aimed to clarify the nature of PPI in schizophrenia using improved methodology. Startle and PPI were measured in 44 patients with schizophrenia and 32 controls across a range of startling stimulus intensities under two conditions, one while participants were attending to the auditory stimuli (ATTEND condition) and one while participants completed a visual task in order to ensure they were ignoring the auditory stimuli (IGNORE condition). Patients showed reduced PPI of R(MAX) (reflex capacity) and increased PPI of Hillslope (reflex efficacy) only under the INGORE condition, and failed to show the same pattern of attentional modulation of the reflex parameters as controls. In conclusion, disturbed PPI in schizophrenia appears to result from deficits in selective attention, rather than from preattentive dysfunction.

  10. The effects of methylphenidate on prepulse inhibition during attended and ignored prestimuli among boys with attention-deficit hyperactivity disorder.

    Science.gov (United States)

    Hawk, Larry W; Yartz, Andrew R; Pelham, William E; Lock, Thomas M

    2003-01-01

    The present study investigated attentional modification of prepulse inhibition of startle among boys with and without attention-deficit hyperactivity disorder (ADHD). Two hypotheses were tested: (1) whether ADHD is associated with diminished prepulse inhibition during attended prestimuli, but not ignored prestimuli, and (2) whether methylphenidate selectively increases prepulse inhibition to attended prestimuli among boys with ADHD. Participants were 17 boys with ADHD and 14 controls. Participants completed a tone discrimination task in each of two sessions separated by 1 week. ADHD boys were administered methylphenidate (0.3 mg/kg) in one session and placebo in the other session in a randomized, double-blind fashion. During each series of 72 tones (75 dB; half 1200-Hz, half 400-Hz), participants were paid to attend to one pitch and ignore the other. Bilateral eyeblink electromyogram startle responses were recorded in response to acoustic probes (50-ms, 102-dB white noise) presented following the onset of two-thirds of tones, and during one-third of intertrial intervals. Relative to controls, boys with ADHD exhibited diminished prepulse inhibition 120 ms after onset of attended but not ignored prestimuli following placebo administration. Methylphenidate selectively increased prepulse inhibition to attended prestimuli at 120 ms among boys with ADHD to a level comparable to that of controls, who did not receive methylphenidate. These data are consistent with the hypothesis that ADHD involves diminished selective attention and suggest that methylphenidate ameliorates the symptoms of ADHD, at least in part, by altering an early attentional mechanism.

  11. Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS.

    Science.gov (United States)

    Swerdlow, Neal R; Light, Gregory A; Sprock, Joyce; Calkins, Monica E; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Nuechterlein, Keith H; Radant, Allen D; Ray, Amrita; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Stone, William S; Sugar, Catherine A; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

    2014-02-01

    Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site "COGS-2" study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data. Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60 ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures. 884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (pschizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures. The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia "endophenotype" of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Repeated forced swimming impairs prepulse inhibition and alters brain-derived neurotrophic factor and astroglial parameters in rats.

    Science.gov (United States)

    Borsoi, Milene; Antonio, Camila Boque; Müller, Liz Girardi; Viana, Alice Fialho; Hertzfeldt, Vivian; Lunardi, Paula Santana; Zanotto, Caroline; Nardin, Patrícia; Ravazzolo, Ana Paula; Rates, Stela Maris Kuze; Gonçalves, Carlos-Alberto

    2015-01-01

    Glutamate perturbations and altered neurotrophin levels have been strongly associated with the neurobiology of neuropsychiatric disorders. Environmental stress is a risk factor for mood disorders, disrupting glutamatergic activity in astrocytes in addition to cognitive behaviours. Despite the negative impact of stress-induced neuropsychiatric disorders on public health, the molecular mechanisms underlying the response of the brain to stress has yet to be fully elucidated. Exposure to repeated swimming has proven useful for evaluating the loss of cognitive function after pharmacological and behavioural interventions, but its effect on glutamate function has yet to be fully explored. In the present study, rats previously exposed to repeated forced swimming were evaluated using the novel object recognition test, object location test and prepulse inhibition (PPI) test. In addition, quantification of brain-derived neurotrophic factor (BDNF) mRNA expression and protein levels, glutamate uptake, glutathione, S100B, GluN1 subunit of N-methyl-D-aspartate receptor and calmodulin were evaluated in the frontal cortex and hippocampus after various swimming time points. We found that swimming stress selectively impaired PPI but did not affect memory recognition. Swimming stress altered the frontal cortical and hippocampal BDNF expression and the activity of hippocampal astrocytes by reducing hippocampal glutamate uptake and enhancing glutathione content in a time-dependent manner. In conclusion, these data support the assumption that astrocytes may regulate the activity of brain structures related to cognition in a manner that alters complex behaviours. Moreover, they provide new insight regarding the dynamics immediately after an aversive experience, such as after behavioural despair induction, and suggest that forced swimming can be employed to study altered glutamatergic activity and PPI disruption in rodents. Copyright © 2014. Published by Elsevier Inc.

  13. Inhibition in Parkinson’s disease: A focus on prepulse inhibition and Rapid eye movement sleep Behavior Disorder (RBD)

    DEFF Research Database (Denmark)

    Zoetmulder, Marielle

    2014-01-01

    Summary Background: α-synucleinopathies are characterized by degeneration of the nigrostriatal pathway and midbrain dopamine function. These disorders, including Parkinson’s disease (PD), are associated with sensorimotor gating deficits and show an increased prevalence of the parasomnia REM sleep...... with daytime motor function in Parkinsonism, the relation to the increased motor activity during REM sleep as seen in RBD is unclear. Aim: The objective of this thesis was 1) to examine prepulse inhibition of the acoustic blink reflex in patients with idiopathic REM sleep behaviour disorder (iRBD), Parkinson...... in the striatum. Moreover, our results support the hypothesis that increased EMG-activity during REM sleep in iRBD is associated with the nigrostriatal dopamine system, while EMG-activity during REM-sleep in PD is associated with dopaminergic medication....

  14. Sleep duration, depression, and oxytocinergic genotype influence prepulse inhibition of the startle reflex in postpartum women.

    Science.gov (United States)

    Comasco, Erika; Gulinello, Maria; Hellgren, Charlotte; Skalkidou, Alkistis; Sylven, Sara; Sundström-Poromaa, Inger

    2016-04-01

    The postpartum period is characterized by a post-withdrawal hormonal status, sleep deprivation, and susceptibility to affective disorders. Postpartum mothering involves automatic and attentional processes to screen out new external as well as internal stimuli. The present study investigated sensorimotor gating in relation to sleep duration, depression, as well as catecholaminergic and oxytocinergic genotypes in postpartum women. Prepulse inhibition (PPI) of the startle reflex and startle reactivity were assessed two months postpartum in 141 healthy and 29 depressed women. The catechol-O-methyltransferase (COMT) Val158Met, and oxytocin receptor (OXTR) rs237885 and rs53576 polymorphisms were genotyped, and data on sleep duration were collected. Short sleep duration (less than four hours in the preceding night) and postpartum depression were independently associated with lower PPI. Also, women with postpartum depression had higher startle reactivity in comparison with controls. The OXTR rs237885 genotype was related to PPI in an allele dose-dependent mode, with T/T healthy postpartum women carriers displaying the lowest PPI. Reduced sensorimotor gating was associated with sleep deprivation and depressive symptoms during the postpartum period. Individual neurophysiological vulnerability might be mediated by oxytocinergic genotype which relates to bonding and stress response. These findings implicate the putative relevance of lower PPI of the startle response as an objective physiological correlate of liability to postpartum depression. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  15. Acoustic startle reflex and pre-pulse inhibition in tinnitus patients

    Institute of Scientific and Technical Information of China (English)

    Kelly Shadwick; Wei Sun

    2014-01-01

    Gap induced pre-pulse inhibition (Gap-PPI) of acoustic startle reflex has been used as a measurement of tinnitus in animal models. However, whether this test is sensitive to detect tinnitus in humans is still unclear. Based on the testing procedure used in animal studies, a human subject testing method was formulated and conducted to investigate if a similar result could be found in tinnitus patients. Audiologic and tinnitus assessments and acoustic startle reflex measurements were performed on seven tinnitus subjects and nine age matched subjects without tinnitus. There was no significant difference found between the control and tinnitus group on the Gap-PPI across the frequencies evaluated. The amplitude of the startle response in the tinnitus group with normal hearing thresholds was significantly higher than the control group and those with tinnitus and hearing loss. This preliminary result suggests that hyperexcitability in the central auditory system may be involved in tinnitus. There was no correlation between hearing thresholds and the increased amplitude of startle response.

  16. Baclofen reverses the reduction in prepulse inhibition of the acoustic startle response induced by dizocilpine, but not by apomorphine.

    Science.gov (United States)

    Bortolato, Marco; Frau, Roberto; Aru, Gian Nicola; Orrù, Marco; Gessa, Gian Luigi

    2004-01-01

    Since baclofen, the prototypical GABA(B) receptor agonist, is known to reduce the activity of dopaminergic mesolimbic neurons, a putative antipsychotic property of this compound has been suggested, but the evidence for this is still controversial. The aim of the present study was to elucidate the effects of baclofen on the prepulse inhibition (PPI) of the acoustic startle response (ASR), a behavioral paradigm considered to be one of the most powerful tools for the evaluation of sensorimotor gating and for the screening of antipsychotics. We tested the effects of baclofen (1.25, 2.5, 5 and 10 mg/kg IP) in rats, per se and in co-treatment with some of the substances known to induce a robust reduction of PPI, such as apomorphine (0.25 mg/kg SC) and dizocilpine (0.1 mg/kg SC). Finally, in order to ascertain whether the effects of baclofen could be ascribed to its activity on GABA(B) receptors, we analyzed whether its action could be prevented by pretreatment with SCH 50911, a selective GABA(B) receptor antagonist (20 mg/kg IP). All the experiments were carried out using standard procedures for the assessment of PPI of the ASR. Baclofen per se produced no significant change in PPI parameters. Moreover, while no effect on apomorphine-mediated alterations in PPI parameters was observed, baclofen proved able to reverse dizocilpine-induced PPI disruption, and this effect was significantly prevented by SCH 50911. On the other hand, this last compound exhibited no effects per se at the same dose. These results indicate that GABA(B) receptors are implicated in the neurobiological circuitry accounting for glutamatergic action in sensorimotor gating, and therefore can be proposed as putative new targets in the pharmacological therapy of psychotic disorders. Further studies should be addressed to evaluate more closely the clinical efficacy of baclofen in this respect.

  17. Subchronic and chronic PCP treatment produces temporally distinct deficits in attentional set shifting and prepulse inhibition in rats.

    Science.gov (United States)

    Egerton, Alice; Reid, Lee; McGregor, Sandie; Cochran, Susan M; Morris, Brian J; Pratt, Judith A

    2008-05-01

    We have previously demonstrated that subchronic (five daily administrations of 2.6 mg/kg PCP) and chronic intermittent administration of 2.6 mg/kg PCP to rats produces hypofrontality and other neurochemical changes akin to schizophrenia pathology (Cochran et al., Neuropsychopharmacology, 28:265-275, 2003). We sought to determine whether behavioral alterations related to discrete aspects of schizophrenia are also induced by these PCP treatment regimes. Following administration of vehicle or PCP according to the protocols described above, rats were assessed for attentional set shifting ability, prepulse inhibition (PPI), or social interaction and the locomotor response to a challenge dose of amphetamine. Ability to shift attentional set was impaired 72 h after the last PCP administration following the subchronic and chronic intermittent treatment regimes. PPI was disrupted after each acute administration of PCP in animals under the subchronic treatment regime. However, PPI deficits were not sustained 72 h after the last of five daily administrations. In subchronic and chronic PCP treated animals, no change was found in social interaction behavior, and there was little change in baseline or amphetamine-stimulated locomotor activity, employed as an indicator of dopaminergic hyperfunction. The temporally distinct behavioral effects of these PCP treatment regimes suggest that PPI deficits relate directly to acute NMDA receptor antagonism, whereas the more enduring set shifting deficits relate to the longer term consequences of NMDA receptor blockade. Therefore, these subchronic and chronic PCP treatment regimes produce hypofrontality (Cochran et al., Neuropsychopharmacology, 28:265-275, 2003) and associated prefrontal cortex-dependent deficits in behavioral flexibility which mirror core deficits in schizophrenia.

  18. Alterations to prepulse inhibition magnitude and latency in adult rats following neonatal treatment with domoic acid and social isolation rearing.

    Science.gov (United States)

    Marriott, Amber L; Tasker, R Andrew; Ryan, Catherine L; Doucette, Tracy A

    2016-02-01

    Deficits in perceptual, informational, and attentional processing are consistently identified as a core feature in schizophrenia and related neuropsychiatric disorders. Neonatal injections of low doses of the AMPA/kainate agonist domoic acid (DOM) have previously been shown to alter various aspects of perceptual and attentional processing in adult rats. The current study investigated the effects of combined neonatal DOM treatment with isolation rearing on prepulse inhibition behaviour and relevant neurochemical measures, to assess the usefulness of these paradigms in modeling neurodevelopmental disorders. Daily subcutaneous injections of DOM (20 μg/kg) or saline were administered to male and female rat pups from postnatal days (PND) 8-14. After weaning, rats were either housed alone or in groups of 4. Both the magnitude and latency of prepulse inhibition were determined in adulthood (approximately 4.5 months of age) and post-mortem brain tissue was assayed using Western blot. Social isolation alone significantly lowered PPI magnitude in male (but not female) rats while DOM treatment appeared to make animals refractory to this effect. Combining social isolation and DOM treatment caused an additive decrease in PPI startle latency. No statistically significant differences were found in the expression of D1, D2, TH, GAD65 or GAD67 protein in either the prefrontal cortex or hippocampus, although some tendencies toward differences were noted. We conclude that both neonatal low-dose DOM and social isolation affect prepulse inhibition in rats but that each paradigm exerts these effects through different neuronal signalling systems. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. The effects of imipramine on P50 suppression, prepulse inhibition and habituation of the startle response in humans

    DEFF Research Database (Denmark)

    Hammer, Trine Bjørg; Oranje, Bob; Glenthoj, Birte Y

    2007-01-01

    Schizophrenic patients exhibit impairments in filtering of sensory information, as can be assessed by use of prepulse inhibition (PPI) of the acoustic startle response and P50 suppression paradigms. In the treatment of negative symptoms or depressive syndromes during the course of schizophrenia...... as well as P50 suppression. No significant differences between the two treatments were observed on habituation of the acoustic startle reflex. Since sensory filtering is usually already reduced in patients with schizophrenia, the current results call for caution in the widespread use of dual......-acting antidepressants in the treatment of depressed or negative symptoms in these patients....

  20. Pre-pulse inhibition of the acoustic startle eye-blink in the Göttingen minipig

    DEFF Research Database (Denmark)

    Arnfred, S. M.; Lind, N. M.; Hansen, A. K.

    2004-01-01

    Pre-pulse inhibition (PPI) of the startle response is a measure of sensorimotor gating which has been frequently shown to be deficient in schizophrenic patients. In humans it is typically measured as the attenuation of the startle eye-blink reflex EMG when a startle eliciting noise is preceded...... by a weak white noise pre-pulse (PP), the interval between the PP and the startle noise stimulus (SNS) determining the degree of inhibition. Aiming at developing a new animal model of schizophrenia, we have investigated the acoustic startle eye-blink and PPI in 10 Göttingen minipigs. The stimuli......, and three other pigs did not have a startle response of a sufficient magnitude to demonstrate the PPI seen in the other six pigs at the expected PP intervals of 60, 120, and 220 ms. Maximal inhibition was seen at the 220 ms interval (mean PPI 58.6%, range -18.4 to 94.6%, N = 9). Most of the results...

  1. The Functional Networks of Prepulse Inhibition: Neuronal Connectivity Analysis Based on FDG-PET in Awake and Unrestrained Rats.

    Directory of Open Access Journals (Sweden)

    Cathrin Rohleder

    2016-07-01

    Full Text Available Prepulse inhibition (PPI is a neuropsychological process during which a weak sensory stimulus (prepulse attenuates the motor response (startle reaction to a subsequent strong startling stimulus. It is measured as a surrogate marker of sensorimotor gating in patients suffering from neuropsychological diseases such as schizophrenia, as well as in corresponding animal models. A variety of studies has shown that PPI of the acoustical startle reaction comprises three brain circuitries for: i startle mediation, ii PPI mediation and iii modulation of PPI mediation. While anatomical connections and information flow in the startle and PPI mediation pathways are well known, spatial and temporal interactions of the numerous regions involved in PPI modulation are incompletely understood.We therefore combined [18F]fluoro-2-deoxyglucose positron-emission-tomography (FDG-PET with PPI and resting state control paradigms in awake rats. A battery of subtractive, correlative as well as seed-based functional connectivity analyses revealed a default mode-like network (DMN active during resting state only. Furthermore, two functional networks were observed during PPI: Metabolic activity in the lateral circuitry was positively correlated with PPI effectiveness and involved the auditory system and emotional regions. The medial network was negatively correlated with PPI effectiveness, i.e. associated with startle, and recruited a spatial/cognitive network. Our study provides evidence for two distinct neuronal networks, whose continuous interplay determines PPI effectiveness in rats, probably by either protecting the prepulse or facilitating startle processing.Discovering similar networks affected in neuropsychological disorders may help to better understand mechanisms of sensorimotor gating deficits and provide new perspectives for therapeutic strategies.

  2. The Functional Networks of Prepulse Inhibition: Neuronal Connectivity Analysis Based on FDG-PET in Awake and Unrestrained Rats.

    Science.gov (United States)

    Rohleder, Cathrin; Wiedermann, Dirk; Neumaier, Bernd; Drzezga, Alexander; Timmermann, Lars; Graf, Rudolf; Leweke, F Markus; Endepols, Heike

    2016-01-01

    Prepulse inhibition (PPI) is a neuropsychological process during which a weak sensory stimulus ("prepulse") attenuates the motor response ("startle reaction") to a subsequent strong startling stimulus. It is measured as a surrogate marker of sensorimotor gating in patients suffering from neuropsychological diseases such as schizophrenia, as well as in corresponding animal models. A variety of studies has shown that PPI of the acoustical startle reaction comprises three brain circuitries for: (i) startle mediation, (ii) PPI mediation, and (iii) modulation of PPI mediation. While anatomical connections and information flow in the startle and PPI mediation pathways are well known, spatial and temporal interactions of the numerous regions involved in PPI modulation are incompletely understood. We therefore combined [(18)F]fluoro-2-deoxyglucose positron-emission-tomography (FDG-PET) with PPI and resting state control paradigms in awake rats. A battery of subtractive, correlative as well as seed-based functional connectivity analyses revealed a default mode-like network (DMN) active during resting state only. Furthermore, two functional networks were observed during PPI: Metabolic activity in the lateral circuitry was positively correlated with PPI effectiveness and involved the auditory system and emotional regions. The medial network was negatively correlated with PPI effectiveness, i.e., associated with startle, and recruited a spatial/cognitive network. Our study provides evidence for two distinct neuronal networks, whose continuous interplay determines PPI effectiveness in rats, probably by either protecting the prepulse or facilitating startle processing. Discovering similar networks affected in neuropsychological disorders may help to better understand mechanisms of sensorimotor gating deficits and provide new perspectives for therapeutic strategies.

  3. Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

    DEFF Research Database (Denmark)

    Oliveras, Ignasi; Sánchez-González, Ana; Sampedro-Viana, Daniel

    2017-01-01

    acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). RESULTS: RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical...... antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70 dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI...

  4. Mice lacking collapsin response mediator protein 1 manifest hyperactivity, impaired learning and memory, and impaired prepulse inhibition

    Directory of Open Access Journals (Sweden)

    Naoya eYamashita

    2013-12-01

    Full Text Available Collapsin response mediator protein 1 (CRMP1 is one of the CRMP family members that are involved in various aspects of neuronal development such as axonal guidance and neuronal migration. Here we provide evidence that crmp1-/- mice exhibited behavioral abnormalities related to schizophrenia. The crmp1-/- mice exhibited hyperactivity and/or impaired emotional behavioral phenotype. These mice also exhibited impaired context-dependent memory and long-term memory retention. Furthermore, crmp1-/- mice exhibited decreased prepulse inhibition, and this phenotype was rescued by administration of chlorpromazine, a typical antipsychotic drug. In addition, in vivo microdialysis revealed that the methamphetamine-induced release of dopamine in prefrontal cortex was exaggerated in crmp1-/- mice, suggesting that enhanced mesocortical dopaminergic transmission contributes to their hyperactivity phenotype. These observations suggest that impairment of CRMP1 function may be involved in the pathogenesis of schizophrenia. We propose that crmp1-/- mouse may model endophenotypes present in this neuropsychiatric disorder.

  5. Disrupted sensory gating in pathological gambling.

    Science.gov (United States)

    Stojanov, Wendy; Karayanidis, Frini; Johnston, Patrick; Bailey, Andrew; Carr, Vaughan; Schall, Ulrich

    2003-08-15

    Some neurochemical evidence as well as recent studies on molecular genetics suggest that pathologic gambling may be related to dysregulated dopamine neurotransmission. The current study examined sensory (motor) gating in pathologic gamblers as a putative measure of endogenous brain dopamine activity with prepulse inhibition of the acoustic startle eye-blink response and the auditory P300 event-related potential. Seventeen pathologic gamblers and 21 age- and gender-matched healthy control subjects were assessed. Both prepulse inhibition measures were recorded under passive listening and two-tone prepulse discrimination conditions. Compared to the control group, pathologic gamblers exhibited disrupted sensory (motor) gating on all measures of prepulse inhibition. Sensory motor gating deficits of eye-blink responses were most profound at 120-millisecond prepulse lead intervals in the passive listening task and at 240-millisecond prepulse lead intervals in the two-tone prepulse discrimination task. Sensory gating of P300 was also impaired in pathologic gamblers, particularly at 500-millisecond lead intervals, when performing the discrimination task on the prepulse. In the context of preclinical studies on the disruptive effects of dopamine agonists on prepulse inhibition, our findings suggest increased endogenous brain dopamine activity in pathologic gambling in line with previous neurobiological findings.

  6. Association between prepulse inhibition of the startle response and latent inhibition of two-way avoidance acquisition: A study with heterogeneous NIH-HS rats.

    Science.gov (United States)

    Sánchez-González, Ana; Esnal, Aitor; Río-Álamos, Cristóbal; Oliveras, Ignasi; Cañete, Toni; Blázquez, Gloria; Tobeña, Adolf; Fernández-Teruel, Alberto

    2016-03-01

    This study presents the first evaluation of the associations between responses in two paradigms related to schizophrenia in the genetically heterogeneous NIH-HS rat stock. NIH-HS rats are a stock of genetically heterogeneous animals that have been derived from eight different inbred strains. A rotational breeding schedule has been followed for more than eighty generations, leading to a high level of genetic recombination that makes the NIH-HS rats a unique tool for studying the genetic basis of (biological, behavioral, disease-related) complex traits. Previous work has dealt with the characterization of coping styles, cognitive and anxiety/fear-related profiles of NIH-HS rats. In the present study we have completed their characterization in two behavioral models, prepulse inhibition (PPI) and latent inhibition (LI) of the two-way active avoidance response, that appear to be related to schizophrenia or to schizophrenia-relevant symptoms. We have found that these rats display PPI for each of the four prepulse intensities tested, allowing their stratification in high, medium and low PPI subgroups. When testing these three subgroups for LI of two-way active avoidance acquisition it has been observed that the LowPPI and MediumPPI subgroups present impaired LI, which, along with the fact that the HighPPI group presents significant LI, allows us to hypothesize that responses in these two paradigms are somehow related and that selection of NIH-HS rats for Low vs HighPPI could make a promising animal model for the study of clusters of schizophrenia-relevant symptoms and their underlying neurobiological mechanisms. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Neuroligin 2 R215H Mutant Mice Manifest Anxiety, Increased Prepulse Inhibition, and Impaired Spatial Learning and Memory

    Directory of Open Access Journals (Sweden)

    Chia-Hsiang Chen

    2017-11-01

    Full Text Available Neuroligin 2 (NLGN2 is a postsynaptic adhesion protein that plays an essential role in synaptogenesis and function of inhibitory neuron. We previously identified a missense mutation R215H of the NLGN2 in a patient with schizophrenia. This missense mutation was shown to be pathogenic in several cell-based assays. The objective of this study was to better understand the behavioral consequences of this mutation in vivo. We generated a line of transgenic mice carrying this mutation using a recombinant-based method. The mice were subjected to a battery of behavioral tests including open field locomotor activity assay, prepulse inhibition (PPI assay, accelerated rotarod test, novel location and novel recognition tests, elevated plus-maze (EPM test, and Morris water maze test. The transgenic animals were viable and fertile, but the Nlgn2 R215H knock-in (KI homozygous mice showed growth retardation, anxiety-like behavior, increased PPI, and impaired spatial learning and memory. There was no significant interaction between sex and genotype in most behavioral tests; however, we observed a significant interaction between sex and genotype in EPM test in this study. Also, we found that the Nlgn2 R215H homozygous KI mice did not express the NLGN2 protein, resembling Nlgn2 knockout mice. Our results demonstrate that Nlgn2 R215H KI homozygous mice manifest several behavioral abnormalities similar to those found in psychiatric patients carrying NLGN2 mutations, indicating that dysfunction of NLGN2 contributes to the pathogenesis of certain psychiatric symptoms commonly present in various mental disorders, not limited to schizophrenia.

  8. White matter hyperintensities and prepulse inhibition in a mixed elderly population

    DEFF Research Database (Denmark)

    Salem, Lise C; Hejl, Anne-Mette; Garde, Ellen

    2011-01-01

    resonance imaging (MRI) in elderly subjects with and without cognitive impairment, may contribute to variations in PPI. A passive acoustic PPI paradigm was applied in 92 human subjects (53 healthy and 39 patients with Alzheimer's disease or mild cognitive impairment) between 60 and 85years of age. WMH were...... rated visually on craniel MRI FLAIR images using the Fazekas scale. WMH were identified in 70% of all subjects. The latency to peak of the startle response increased significantly with increasing WMH load, whereas the inhibition of the startle response (PPI) was neither significantly related...... to the degree of WMH nor to cognitive performance. We conclude that the presence of WMH in the fronto-striatal brain circuit may affect the latency of the startle response, but not information processing in elderly subjects....

  9. Investigation of the effects of head irradiation with gamma rays and protons on startle and pre-pulse inhibition behavior in mice.

    Science.gov (United States)

    Haerich, Paul; Eggers, Cara; Pecaut, Michael J

    2012-05-01

    With the increased international emphasis on manned space exploration, there is a growing need to understand the impact of the spaceflight environment on health and behavior. One particularly important aspect of this environment is low-dose radiation. In the present studies, we first characterized the γ- and proton-irradiation dose effect on acoustic startle and pre-pulse inhibition behaviors in mice exposed to 0-5 Gy brain-localized irradiation, and assessed these effects 2 days later. Subsequently, we used 2 Gy to assess the time course of γ- and proton-radiation effects on startle reactivity 0-8 days after exposure. Exposures targeted the brain to minimize the impact of peripheral inflammation-induced sickness behavior. The effects of radiation on startle were subtle and acute. Radiation reduced the startle response at 2 and 5 Gy. Following a 2-Gy exposure, the response reached a minimum at the 2-day point. Proton and γ-ray exposures did not differ in their impact on startle. We found there were no effects of radiation on pre-pulse inhibition of the startle response.

  10. Assessment of auditory sensory processing in a neurodevelopmental animal model of schizophrenia-Gating of auditory-evoked potentials and prepulse inhibition

    DEFF Research Database (Denmark)

    Broberg, Brian Villumsen; Oranje, Bob; Yding, Birte

    2010-01-01

    The use of translational approaches to validate animal models is needed for the development of treatments that can effectively alleviate cognitive impairments associated with schizophrenia, which are unsuccessfully treated by the current available therapies. Deficits in pre-attentive stages...... of sensory information processing seen in schizophrenia patients, can be assessed by highly homologues methods in both humans and rodents, evident by the prepulse inhibition (PPI) of the auditory startle response and the P50 (termed P1 here) suppression paradigms. Treatment with the NMDA receptor antagonist...... PCP on postnatal days 7, 9, and 11 reliably induce cognitive impairments resembling those presented by schizophrenia patients. Here we evaluate the potential of early postnatal PCP (20mg/kg) treatment in Lister Hooded rats to induce post-pubertal deficits in PPI and changes, such as reduced gating...

  11. Assessment of auditory sensory processing in a neurodevelopmental animal model of schizophrenia-Gating of auditory-evoked potentials and prepulse inhibition

    DEFF Research Database (Denmark)

    Broberg, Brian Villumsen; Oranje, Bob; Yding, Birte

    2010-01-01

    of sensory information processing seen in schizophrenia patients, can be assessed by highly homologues methods in both humans and rodents, evident by the prepulse inhibition (PPI) of the auditory startle response and the P50 (termed P1 here) suppression paradigms. Treatment with the NMDA receptor antagonist...... findings confirm measures of early information processing to show high resemblance between rodents and humans, and indicate that early postnatal PCP-treated rats show deficits in pre-attentional processing, which are distinct from those observed in schizophrenia patients.......The use of translational approaches to validate animal models is needed for the development of treatments that can effectively alleviate cognitive impairments associated with schizophrenia, which are unsuccessfully treated by the current available therapies. Deficits in pre-attentive stages...

  12. Effects of Cannabinoid Drugs on the Deficit of Prepulse Inhibition of Startle in an Animal Model of Schizophrenia: the SHR Strain

    Directory of Open Access Journals (Sweden)

    Raquel eLevin

    2014-02-01

    Full Text Available Clinical and neurobiological findings suggest that the cannabinoids and the endocannabinoid system may be implicated in the pathophysiology and treatment of schizophrenia. We described that the Spontaneously Hypertensive Rats (SHR strain presents a schizophrenia behavioral phenotype that is specifically attenuated by antipsychotic drugs, and potentiated by proschizophrenia manipulations. Based on these findings, we have suggested this strain as an animal model of schizophrenia. The aim of this study was to evaluate the effects of cannabinoid drugs on the deficit of prepulse inhibition of startle (PPI, the main paradigm used to study sensorimotor gating impairment related to schizophrenia, presented by the SHR strain. The following drugs were used: 1 WIN55212,2 (cannabinoid agonist, 2 rimonabant (CB1 antagonist, 3 AM404 (anandamide uptake inhibitor, and 4 cannabidiol (indirect CB1/CB2 receptor antagonist, among other effects. Wistar rats (WR and SHRs were treated with vehicle or different doses of WIN55212 (0.3, 1 or 3 mg/kg, rimonabant (0.75, 1.5 or 3 mg/kg, AM404 (1, 5 or 10 mg/kg or cannabidiol (15, 30 or 60 mg/kg. Vehicle-treated SHRs showed a decreased PPI when compared to WRs. This PPI deficit was reversed by 1 mg/kg WIN and 30 mg/kg cannabidiol. Conversely, 0.75 mg/kg rimonabant decreased PPI in SHR strain, whereas AM404 did not modify it. Our results reinforce the role of the endocannabinoid system in the sensorimotor gating impairment related to schizophrenia, and point to cannabinoid drugs as potential therapeutic strategies.

  13. The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval.

    Science.gov (United States)

    Vollenweider, Franz X; Csomor, Philipp A; Knappe, Bernhard; Geyer, Mark A; Quednow, Boris B

    2007-09-01

    Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT(2A) receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT(2A) receptor agonist psilocybin increases PPI in healthy humans. Hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on PPI in healthy humans. Sixteen subjects each received placebo or 115, 215, and 315 microg/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. PPI at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (ISIs) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. The effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the Altered States of Consciousness Rating Scale (5D-ASC) and the Frankfurt Attention Inventory (FAIR). Psilocybin dose-dependently reduced PPI at short (30 ms), had no effect at medium (60 ms), and increased PPI at long (120-2000 ms) ISIs, without affecting startle reactivity or habituation. Psilocybin dose-dependently impaired sustained attention and increased all 5D-ASC scores with exception of Auditory Alterations. Moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30 ms ISI and not with the concomitant increases in PPI observed at long ISIs. These results confirm the psilocybin-induced increase in PPI at long ISIs and reveal that psilocybin also produces a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia.

  14. Effects of combined exposure to pyridostigmine bromide and shaker stress on acoustic startle response, pre-pulse inhibition and open field behavior in mice.

    Science.gov (United States)

    Dubovicky, M; Paton, S; Morris, M; Mach, M; Lucot, J B

    2007-01-01

    The present study investigated the effect of combined exposure of pyridostigmine bromide (PB) and chronic shaker stress on acoustic startle responses (ASR), pre-pulse inhibition (PPI) and open field behavior of adult C57BL/6J mice. PB (10 mg kg(-1) day(-1) for 7 days) or saline was administered subcutaneously using osmotic Alzet minipumps implanted under the skin on the back of the mice. At the same time, the mice were exposed to 7 days of intermittent shaker stress. They were tested for ASR (100 dB and 120 dB stimuli) and PPI (70 dB + 100 dB and 70 dB + 120 dB) in the acoustic startle monitor system. The mice were assessed during the shaker stress on days 2 and 7 and 7, 14, 21 and 28 days after discontinuation of treatment. Separate groups of mice were tested in the open field in 15 min sessions on days 1, 3 and 6 during shaker stress and PB treatment. Exposure of mice to PB resulted in an exaggerated ASR, reduced PPI and non-significant decrease in locomotor activity. These behavioral changes were apparent only during exposure to PB. Repeated shaker stress did not have any effect on sensorimotor functions or open field behavior of mice. There was no prolonged or delayed effect of PB and/or stress on individual behavioral variables. The study found C57BL/6J mice to be behaviorally sensitive to PB treatment. (c) 2007 John Wiley & Sons, Ltd.

  15. Differences in P50 and prepulse inhibition of the startle reflex between male smokers and non-smokers with first episode schizophrenia without medical treatment

    Institute of Scientific and Technical Information of China (English)

    Song Lisheng; Chen Xingshi; Chen Meijuan; Tang Yunxiang; Wang Jijun; Zhang Mingdao; Lou Feiying

    2014-01-01

    Backgorund Nicotine may improve schizophrenia patient's cognitive deficit symptoms.This study was to explore the chronic effects of smoking on prepulse inhibition of the startle reflex (PPI) and P50 in the patients with first-episode schizophrenia (FES).Methods The event-related potentials (ERP) recording and analysis instrument made by Brain Products,Germany,was used to detect PPI and P50 in 49 male FES patients (FES group,n=21 for smokers and n=28 for non-smokers) and 43 normal male controls (control group,n=19 for smokers and n=24 for non-smokers).Results Compared with normal controls,the FES group had prolonged PPI latency when elicited by single stronger stimulus (P <0.05); the FES group had prolonged PPI latency and increased PPI amplitude (P <0.05,0.01) when elicited by weak and strong stimuli.The FES group had lower PPI inhibition rate than normal controls (P <0.05).Compared with normal controls,the FES group had increased P50-S2 amplitude and increased amplitude ratio S2/S1 (both P <0.05).In the control group,the smokers had a tendency of increase in P50-S2 amplitude (P >0.05) and shorter P50-S2 latency (P <0.05) than the non-smokers.The smokers had higher PPI amplitude than the non-smokers (P <0.05).In the FES group,the smokers had higher P50-S1 amplitude,shorter P50-S2 latency,and higher amplitude ratio S2/S1 than the non-smokers (P <0.05,0.01).The smokers had higher PPI amplitude than the non-smokers (P <0.05).Conclusions There is obvious PPI and P50 deficits in schizophrenic patients.However,these deficits are relatively preserved in the smokers compared with the non-smokers,which suggests that long-term smoking might partially improve the sensory gating in schizophrenic patients.Whether this conclusion can be deduced to female patients requires further follow-ups.

  16. The maternal immune activation (MIA) model of schizophrenia produces pre-pulse inhibition (PPI) deficits in both juvenile and adult rats but these effects are not associated with maternal weight loss.

    Science.gov (United States)

    Wolff, Amy R; Bilkey, David K

    2010-12-01

    The developmental onset of deficits in sensorimotor-gating was examined in the maternal immune activation (MIA) animal model of schizophrenia. Pre-pulse inhibition (PPI) deficits were evident in juvenile MIA rats. This parallels the sensorimotor-gating deficits observed in groups at high-risk of schizophrenia. PPI deficits were independent of maternal weight loss following the MIA manipulation, suggesting that this measure may not be a useful marker of treatment efficacy. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  17. A New Statistical Approach for the Evaluation of Gap-prepulse Inhibition of the Acoustic Startle Reflex (GPIAS for Tinnitus Assessment

    Directory of Open Access Journals (Sweden)

    Achim Schilling

    2017-10-01

    Full Text Available Background: An increasingly used behavioral paradigm for the objective assessment of a possible tinnitus percept in animal models has been proposed by Turner and coworkers in 2006. It is based on gap-prepulse inhibition (PPI of the acoustic startle reflex (ASR and usually referred to as GPIAS. As it does not require conditioning it became the method of choice to study neuroplastic phenomena associated with the development of tinnitus.Objective: It is still controversial if GPIAS is really appropriate for tinnitus screening, as the hypothesis that a tinnitus percept impairs the gap detection ability (“filling-in interpretation” is still questioned. Furthermore, a wide range of criteria for positive tinnitus detection in GPIAS have been used across different laboratories and there still is no consensus on a best practice for statistical evaluation of GPIAS results. Current approaches are often based on simple averaging of measured PPI values and comparisons on a population level without the possibility to perform valid statistics on the level of the single animal.Methods: A total number of 32 animals were measured using the standard GPIAS paradigm with varying number of measurement repetitions. Based on this data further statistical considerations were performed.Results: We here present a new statistical approach to overcome the methodological limitations of GPIAS. In a first step we show that ASR amplitudes are not normally distributed. Next we estimate the distribution of the measured PPI values by exploiting the full combinatorial power of all measured ASR amplitudes. We demonstrate that the amplitude ratios (1-PPI are approximately lognormally distributed, allowing for parametrical testing of the logarithmized values and present a new statistical approach allowing for a valid and reliable statistical assessment of PPI changes in GPIAS.Conclusion: Based on our statistical approach we recommend using a constant criterion, which does not

  18. An investigation into ‘two hit’ effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice

    Directory of Open Access Journals (Sweden)

    Maren eKlug

    2013-10-01

    Full Text Available Reduced brain-derived neurotrophic factor (BDNF signalling has been shown in the frontal cortex and hippocampus in schizophrenia. The aim of the present study was to investigate whether a BDNF deficit would modulate effects of chronic cannabis intake, a well-described risk factor for schizophrenia development. BDNF heterozygous mice (HET and wild-type controls were chronically treated during weeks 6, 7 and 8 of life with the cannabinoid CB1 receptor agonist, CP55,940 (CP. After a 2-week delay, there were no CP-induced deficits in any of the groups in short-term spatial memory in a Y-maze task or novel object recognition memory. Baseline prepulse inhibition (PPI was lower but average startle was increased in BDNF HET compared to wild-type controls. Acute CP administration before the PPI session caused a marked increase in PPI in male HET mice pre-treated with CP but not in any of the other male groups. In females, there were small increases of PPI in all groups upon acute CP administration. Acute CP administration furthermore reduced startle and this effect was greater in HET mice irrespective of chronic CP pre-treatment. Analysis of the levels of [3H]CP55,940 binding by autoradiography revealed a significant increase in the nucleus accumbens of male BDNF HET mice previously treated with CP but not in any of the other groups or in the caudate nucleus.These results show that BDNF deficiency and chronic young-adult cannabinoid receptor stimulation do not interact in this model on learning and memory later in life. In contrast, male ‘two hit’ mice, but not females, were hypersensitive to the effect of acute CP on sensorimotor gating. These effects may be related to a selective increase of [3H]CP55,940 binding in the nucleus accumbens, reflecting up-regulation of CB1 receptor density in this region. These data could be of relevance to our understanding of differential ‘two hit’ neurodevelopmental mechanisms in schizophrenia.

  19. Stability of prepulse inhibition and habituation of the startle reflex in schizophrenia: a 6-year follow-up study of initially antipsychotic-naive, first-episode schizophrenia patients

    DEFF Research Database (Denmark)

    Hammer, Trine Bjørg; Oranje, Bob; Fagerlund, Birgitte

    2011-01-01

    and is regarded as an endophenotype for schizophrenia. However, reports on the stability of PPI over a longer period of time are lacking, both for patients with schizophrenia and for healthy subjects. The current study examined 25 initially drug-naive, first-episode schizophrenia patients and 23 healthy matched...... not change in patients or controls. The present results show that PPI in drug-naive, first-episode schizophrenia patients can improve significantly over time. As PPI increased in patients over the same period that it decreased in controls, it is likely that the increase was caused by disease-related factors......Deficits in information processing appear to be core features in the pathogenesis of schizophrenia. Prepulse inhibition (PPI) and habituation of the startle reflex are operational measures of early information processing. Impaired PPI in schizophrenia has been replicated in many studies...

  20. Prenatal immune challenge in rats: altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to poly IC.

    Science.gov (United States)

    Vorhees, Charles V; Graham, Devon L; Braun, Amanda A; Schaefer, Tori L; Skelton, Matthew R; Richtand, Neil M; Williams, Michael T

    2012-08-01

    Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic acid (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues were unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, or latent inhibition deficits reported in Poly IC-treated rats but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction). Copyright © 2012 Wiley Periodicals, Inc.

  1. Triazine herbicides inhibit relaxin signaling and disrupt nitric oxide homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Park, Si Eun; Lim, Sa Rang; Choi, Hyung-kyoon; Bae, Jeehyeon, E-mail: jeehyeon@cau.ac.kr

    2016-09-15

    Triazines are herbicides that are widely used worldwide, and we previously observed that the maternal exposure of mice to simazine (50 or 500 μg/kg) resulted in smaller ovaries and uteri of their female offspring. Here, we investigated the underlying mechanism that may account for the reproductive dysfunction induced by simazine. We found that following maternal exposure, simazine is transmitted to the offspring, as evidenced by its presence in the offspring ovaries. Analyses of the simazine-exposed offspring revealed that the expression of the relaxin hormone receptor, relaxin-family peptide receptor 1 (RXFP1), prominently decreased in their ovaries and uteri. In addition, downstream target genes of the relaxin pathway including nitric oxide (NO) synthase 2 (Nos2), Nos3, matrix metallopeptidase 9 (Mmp9), and vascular endothelial growth factor (Vegf) were downregulated in their ovaries. Moreover, AKT and extracellular signal-regulated kinases (ERK) levels and their phosphorylated active forms decreased in simazine-exposed ovaries. In vitro exposure of the human ovarian granulosa cells (KGN) and uterine endometrium cells (Hec-1A) to very low concentrations (0.001 to 1 nM) of triazines including atrazine, terbuthylazine, and propazine repressed NO production with a concurrent reduction in RXFP1, NOS2, and NOS3. The inhibitory action of triazines on NO release was dependent on RXFP1, phosphoinositol 3-kinase (PI3K)/AKT, and ERK. Radioligand-binding assay also confirmed that triazines competitively inhibited the binding of relaxin to its receptor. Therefore, the present study suggests that triazine herbicides act as endocrine disrupters by interfering with relaxin hormone signaling. Thus, further evaluation of their impact on human health is imperative. - Highlights: • Triazines downregulate critical molecules involved in the relaxin signaling pathway. • Triazines act as potent antagonists of binding of relaxin to its receptor. • Triazines disrupt nitric oxide

  2. Reward devaluation disrupts latent inhibition in fear conditioning.

    Science.gov (United States)

    De la Casa, Luís Gonzalo; Mena, Auxiliadora; Ruiz-Salas, Juán Carlos; Quintero, Esperanza; Papini, Mauricio R

    2018-03-01

    Three experiments explored the link between reward shifts and latent inhibition (LI). Using consummatory procedures, rewards were either downshifted from 32% to 4% sucrose (Experiments 1-2), or upshifted from 4% to 32% sucrose (Experiment 3). In both cases, appropriate unshifted controls were also included. LI was implemented in terms of fear conditioning involving a single tone-shock pairing after extensive tone-only preexposure. Nonpreexposed controls were also included. Experiment 1 demonstrated a typical LI effect (i.e., disruption of fear conditioning after preexposure to the tone) in animals previously exposed only to 4% sucrose. However, the LI effect was eliminated by preexposure to a 32%-to-4% sucrose devaluation. Experiment 2 replicated this effect when the LI protocol was administered immediately after the reward devaluation event. However, LI was restored when preexposure was administered after a 60-min retention interval. Finally, Experiment 3 showed that a reward upshift did not affect LI. These results point to a significant role of negative emotion related to reward devaluation in the enhancement of stimulus processing despite extensive nonreinforced preexposure experience.

  3. GluN2C/GluN2D subunit-selective NMDA receptor potentiator CIQ reverses MK-801-induced impairment in prepulse inhibition and working memory in Y-maze test in mice

    Science.gov (United States)

    Suryavanshi, P S; Ugale, R R; Yilmazer-Hanke, D; Stairs, D J; Dravid, S M

    2014-01-01

    Background and Purpose Despite ample evidence supporting the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (d-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.). Experimental Approach The effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test. Key Results We found that systemic administration of CIQ (20 mg·kg−1, i.p.) in mice reversed MK-801 (0.15 mg·kg−1, i.p.)-induced, but not methamphetamine (3 mg·kg−1, i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801- and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze. Conclusion and Implications Together, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia. PMID:24236947

  4. Prepulse suppression and allowable prepulse voltage in Z-pinch experiments

    International Nuclear Information System (INIS)

    Xia Minghe; Xie Weiping; Li Hongtao

    2004-01-01

    The causes of prepulse origin in pulse power machine especially in Blumlein pulser are analyzed in this paper. A method that can reduce the prepulse by an inductance between Marx and zero voltage node has been presented while a calculation example used Pspice is provided. The prepulse switches can be used to reduce the prepulse effects in many fields. The prepulse requests for wire arrays in Z-pinch experiments are analyzed and explained by means of specific reaction quantity and vaporization heat, the results of the calculations are similar. In fact, the results of experiments indicate that the energy deposited in the wires is sufficient to bring the aluminium wires to partial or total vaporization. Because the value of prepulse current is larger than that of calculation, this indicates the calculation method is right

  5. Studying prepulse inhibition in a stressed system

    NARCIS (Netherlands)

    Douma, T.N.

    2013-01-01

    Onset and course of psychotic disorders are thought to be influenced by stress, although there is no consistent evidence that experience of elevated levels of stress triggers disease onset in healthy individuals. In order to better understand the relation between stress and psychosis, these complex

  6. Inhibition of radioemesis by disruption of catecholamines in dogs

    International Nuclear Information System (INIS)

    Luthra, Y.K.; Mattsson, J.L.; Yochmowitz, M.G.

    1981-01-01

    Dogs were treated 30 min to 1 h before x irradiation with α-methyl-p-tyrosine or 6-hydroxydopamine. A third group of dogs was given a known antiradioemetic drug, haloperidol to verify the sensitivity of the procedure. Irradiated but untreated controls were also used. Light methoxyflurane anesthesia was used for restraint during the exposure. Exposure dose was 800 rad kerma delivered at 50 rad/min to a 10 x 10-cm area covering the abdominal area from xiphoid to pubis. Haloperidol and 6-hydroxydopamine significantly reduced the number of emetic episodes and delayed the onset time to the first episode, α-Methyl-p-tyrosine caused no significant changes. The effectiveness of 6-hydroxydopamine indicates that catecholaminergic neurons are involved in radioemesis, whereas haloperidol and phenothiazine-derivative tranquilizers inhibit radiomesis by blocking catecholamine receptor neurons

  7. Disruption?

    DEFF Research Database (Denmark)

    2016-01-01

    This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray......This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray...

  8. Inhibition of phospholipase C disrupts cytoskeletal organization and gravitropic growth in Arabidopsis roots.

    Science.gov (United States)

    Andreeva, Zornitza; Barton, Deborah; Armour, William J; Li, Min Y; Liao, Li-Fen; McKellar, Heather L; Pethybridge, Kylie A; Marc, Jan

    2010-10-01

    The phospholipase protein superfamily plays an important role in hormonal signalling and cellular responses to environmental stimuli. There is also growing evidence for interactions between phospholipases and the cytoskeleton. In this report we used a pharmacological approach to investigate whether inhibiting a member of the phospholipase superfamily, phospholipase C (PLC), affects microtubules and actin microfilaments as well as root growth and morphology of Arabidopsis thaliana seedlings. Inhibiting PLC activity using the aminosteroid U73122 significantly inhibited root elongation and disrupted root morphology in a concentration-dependent manner, with the response being saturated at 5 μM, whereas the inactive analogue U73343 was ineffective. The primary root appeared to lose growth directionality accompanied by root waving and formation of curls. Immunolabelling of roots exposed to increasingly higher U73122 concentrations revealed that the normal transverse arrays of cortical microtubules in the elongation zone became progressively more disorganized or depolymerized, with the disorganization appearing within 1 h of incubation. Likewise, actin microfilament arrays also were disrupted. Inhibiting PLC using an alternative inhibitor, neomycin, caused similar disruptions to both cytoskeletal organization and root morphology. In seedlings gravistimulated by rotating the culture plates by 90°, both U73122 and neomycin disrupted the normal gravitropic growth of roots and etiolated hypocotyls. The effects of PLC inhibitors are therefore consistent with the notion that, as with phospholipases A and D, PLC likewise interacts with the cytoskeleton, alters growth morphology, and is involved in gravitropism.

  9. Lasting Adaptations in Social Behavior Produced by Social Disruption and Inhibition of Adult Neurogenesis

    Science.gov (United States)

    Opendak, Maya; Offit, Lily; Monari, Patrick; Schoenfeld, Timothy J.; Sonti, Anup N.; Cameron, Heather A.

    2016-01-01

    Research on social instability has focused on its detrimental consequences, but most people are resilient and respond by invoking various coping strategies. To investigate cellular processes underlying such strategies, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Social disruption produced a preference for familiar over novel conspecifics, a change that did not involve global memory impairments or increased anxiety. Using the neuropeptide oxytocin as a tool to increase neurogenesis in the hippocampus of disrupted rats restored preference for novel conspecifics to predisruption levels. Conversely, reducing the number of new neurons by limited inhibition of adult neurogenesis in naive transgenic GFAP–thymidine kinase rats resulted in social behavior similar to disrupted rats. Together, these results provide novel mechanistic evidence that social disruption shapes behavior in a potentially adaptive way, possibly by reducing adult neurogenesis in the hippocampus. SIGNIFICANCE STATEMENT To investigate cellular processes underlying adaptation to social instability, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Unexpectedly, these changes were accompanied by changes in social strategies without evidence of impairments in cognition or anxiety regulation. Restoring adult neurogenesis in disrupted rats using oxytocin and conditionally suppressing the production of new neurons in socially naive GFAP–thymidine kinase rats showed that loss of 6-week-old neurons may be responsible for adaptive changes in social behavior. PMID:27358459

  10. Salmonella Disrupts Host Endocytic Trafficking by SopD2-Mediated Inhibition of Rab7

    Directory of Open Access Journals (Sweden)

    Vanessa M. D’Costa

    2015-09-01

    Full Text Available Intracellular bacterial pathogens of a diverse nature share the ability to evade host immunity by impairing trafficking of endocytic cargo to lysosomes for degradation, a process that is poorly understood. Here, we show that the Salmonella enterica type 3 secreted effector SopD2 mediates this process by binding the host regulatory GTPase Rab7 and inhibiting its nucleotide exchange. Consequently, this limits Rab7 interaction with its dynein- and kinesin-binding effectors RILP and FYCO1 and thereby disrupts host-driven regulation of microtubule motors. Our study identifies a bacterial effector capable of directly binding and thereby modulating Rab7 activity and a mechanism of endocytic trafficking disruption that may provide insight into the pathogenesis of other bacteria. Additionally, we provide a powerful tool for the study of Rab7 function, and a potential therapeutic target.

  11. Generalization of fear inhibition by disrupting hippocampal protein synthesis-dependent reconsolidation process.

    Science.gov (United States)

    Yang, Chih-Hao; Huang, Chiung-Chun; Hsu, Kuei-Sen

    2011-09-01

    Repetitive replay of fear memories may precipitate the occurrence of post-traumatic stress disorder and other anxiety disorders. Hence, the suppression of fear memory retrieval may help prevent and treat these disorders. The formation of fear memories is often linked to multiple environmental cues and these interconnected cues may act as reminders for the recall of traumatic experiences. However, as a convenience, a simple paradigm of one cue pairing with the aversive stimulus is usually used in studies of fear conditioning in animals. Here, we built a more complex fear conditioning model by presenting several environmental stimuli during fear conditioning and characterize the effectiveness of extinction training and the disruption of reconsolidation process on the expression of learned fear responses. We demonstrate that extinction training with a single-paired cue resulted in cue-specific attenuation of fear responses but responses to other cures were unchanged. The cue-specific nature of the extinction persisted despite training sessions combined with D-cycloserine treatment reveals a significant weakness in extinction-based treatment. In contrast, the inhibition of the dorsal hippocampus (DH) but not the basolateral amygdala (BLA)-dependent memory reconsolidation process using either protein synthesis inhibitors or genetic disruption of cAMP-response-element-binding protein-mediated transcription comprehensively disrupted the learned connections between fear responses and all paired environmental cues. These findings emphasize the distinct role of the DH and the BLA in the reconsolidation process of fear memories and further indicate that the disruption of memory reconsolidation process in the DH may result in generalization of fear inhibition.

  12. Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4

    International Nuclear Information System (INIS)

    Kucka, Marek; Pogrmic-Majkic, Kristina; Fa, Svetlana; Stojilkovic, Stanko S.; Kovacevic, Radmila

    2012-01-01

    Atrazine, one of the most commonly used herbicides worldwide, acts as an endocrine disruptor, but the mechanism of its action has not been characterized. In this study, we show that atrazine rapidly increases cAMP levels in cultured rat pituitary and testicular Leydig cells in a concentration-dependent manner, but less effectively than 3-isobutyl-1-methylxanthine, a competitive non-specific inhibitor of phosphodiesterases (PDEs). In forskolin (an activator of adenylyl cyclase)- and probenecid (an inhibitor of cyclic nucleotide transporters)-treated cells, but not in 3-isobutyl-1-methylxanthine-treated cells, atrazine further increased cAMP levels, indicating that inhibition of PDEs accounts for accumulation of cAMP. In contrast to cAMP, atrazine did not alter cGMP levels, further indicating that it inhibits cAMP-specific PDEs. Atrazine-induced changes in cAMP levels were sufficient to stimulate prolactin release in pituitary cells and androgen production in Leydig cells, indicating that it acts as an endocrine disrupter both in cells that secrete by exocytosis of prestored hormones and in cells that secrete by de novo hormone synthesis. Rolipram abolished the stimulatory effect of atrazine on cAMP release in both cell types, suggesting that it acts as an inhibitor of PDE4s, isoforms whose mRNA transcripts dominate in pituitary and Leydig cells together with mRNA for PDE8A. In contrast, immortalized lacto-somatotrophs showed low expression of these mRNA transcripts and several fold higher cAMP levels compared to normal pituitary cells, and atrazine was unable to further increase cAMP levels. These results indicate that atrazine acts as a general endocrine disrupter by inhibiting cAMP-specific PDE4s. -- Highlights: ► Atrazine stimulates cAMP accumulation in pituitary and Leydig cells. ► Atrazine also stimulates PRL and androgens secretion. ► Stimulatory effects of atrazine were abolished in cells with IBMX-inhibited PDEs. ► Atrazine specificity toward c

  13. Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition.

    Science.gov (United States)

    Trotta, Andrew P; Gelles, Jesse D; Serasinghe, Madhavika N; Loi, Patrick; Arbiser, Jack L; Chipuk, Jerry E

    2017-07-14

    The mitochondrial network is a major site of ATP production through the coupled integration of the electron transport chain (ETC) with oxidative phosphorylation. In melanoma arising from the V600E mutation in the kinase v-RAF murine sarcoma viral oncogene homolog B (BRAF V600E ), oncogenic signaling enhances glucose-dependent metabolism while reducing mitochondrial ATP production. Likewise, when BRAF V600E is pharmacologically inhibited by targeted therapies ( e.g. PLX-4032/vemurafenib), glucose metabolism is reduced, and cells increase mitochondrial ATP production to sustain survival. Therefore, collateral inhibition of oncogenic signaling and mitochondrial respiration may help enhance the therapeutic benefit of targeted therapies. Honokiol (HKL) is a well tolerated small molecule that disrupts mitochondrial function; however, its underlying mechanisms and potential utility with targeted anticancer therapies remain unknown. Using wild-type BRAF and BRAF V600E melanoma model systems, we demonstrate here that HKL administration rapidly reduces mitochondrial respiration by broadly inhibiting ETC complexes I, II, and V, resulting in decreased ATP levels. The subsequent energetic crisis induced two cellular responses involving cyclin-dependent kinases (CDKs). First, loss of CDK1-mediated phosphorylation of the mitochondrial division GTPase dynamin-related protein 1 promoted mitochondrial fusion, thus coupling mitochondrial energetic status and morphology. Second, HKL decreased CDK2 activity, leading to G 1 cell cycle arrest. Importantly, although pharmacological inhibition of oncogenic MAPK signaling increased ETC activity, co-treatment with HKL ablated this response and vastly enhanced the rate of apoptosis. Collectively, these findings integrate HKL action with mitochondrial respiration and shape and substantiate a pro-survival role of mitochondrial function in melanoma cells after oncogenic MAPK inhibition.

  14. Disruption in a Neurodevelopmental Model of Schizophrenia

    Directory of Open Access Journals (Sweden)

    Benjamin Rolland

    2012-01-01

    Full Text Available Oxidative stress has been implicated in neurodevelopmental theories of schizophrenia. Antioxidant Peroxysome Proliferator-Activated Receptors α (PPARα agonist fenofibrate has neuroprotective properties and could reverse early preclinical infringements that could trigger the illness. We have evaluated the neuroprotective interest of fenofibrate in a neurodevelopmental rat model of schizophrenia. The oxidative lesion induced by Kainic Acid (KA injection at postnatal day (PND 7 has previously been reported to disrupt Prepulse Inhibition (PPI at PND56 but not at PND35. In 4 groups of 15 male rats each, KN (KA-PND7 + normal postweaning food, KF (KA-PND7 + fenofibrate 0.2% food, ON (saline-PND7 + normal food, and OF (saline + fenofibrate food, PPI was recorded at PND35 and PND56. Three levels of prepulse were used: 73 dB, 76 dB, and 82 dB for a pulse at 120 dB. Four PPI scores were analyzed: PPI73, PPI76, PPI82, and mean PPI (PPIm. Two-way ANOVAs were used to evaluate the effects of both factors (KA + fenofibrate, and, in case of significant results, intergroup Student’s t-tests were performed. We notably found a significant difference (P<0.05 in PPIm between groups KN and KF at PND56, which supposes that fenofibrate could be worthy of interest for early neuroprotection in schizophrenia.

  15. Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination

    International Nuclear Information System (INIS)

    Benachour, Nora; Moslemi, Safa; Sipahutar, Herbert; Seralini, Gilles-Eric

    2007-01-01

    Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure, combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p'-DDT, vinclozolin (VZ), p,p'-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic 293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was affected in 24 h by all the xenobiotics with a threshold at 50 μM (except for TBTO and DES, 10 μM threshold), and aromatase was inhibited at non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4-10 μM, and aromatase activity by 50% in some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment

  16. Neutral sphingomyelinase (SMPD3) deficiency disrupts the Golgi secretory pathway and causes growth inhibition

    Science.gov (United States)

    Stoffel, Wilhelm; Hammels, Ina; Jenke, Bitta; Binczek, Erika; Schmidt-Soltau, Inga; Brodesser, Susanne; Schauss, Astrid; Etich, Julia; Heilig, Juliane; Zaucke, Frank

    2016-01-01

    Systemic loss of neutral sphingomyelinase (SMPD3) in mice leads to a novel form of systemic, juvenile hypoplasia (dwarfism). SMPD3 deficiency in mainly two growth regulating cell types contributes to the phenotype, in chondrocytes of skeletal growth zones to skeletal malformation and chondrodysplasia, and in hypothalamic neurosecretory neurons to systemic hypothalamus–pituitary–somatotropic hypoplasia. The unbiased smpd3−/− mouse mutant and derived smpd3−/− primary chondrocytes were instrumental in defining the enigmatic role underlying the systemic and cell autonomous role of SMPD3 in the Golgi compartment. Here we describe the unprecedented role of SMPD3. SMPD3 deficiency disrupts homeostasis of sphingomyelin (SM), ceramide (Cer) and diacylglycerol (DAG) in the Golgi SMPD3-SMS1 (SM-synthase1) cycle. Cer and DAG, two fusogenic intermediates, modify the membrane lipid bilayer for the initiation of vesicle formation and transport. Dysproteostasis, unfolded protein response, endoplasmic reticulum stress and apoptosis perturb the Golgi secretory pathway in the smpd3−/− mouse. Secretion of extracellular matrix proteins is arrested in chondrocytes and causes skeletal malformation and chondrodysplasia. Similarly, retarded secretion of proteo-hormones in hypothalamic neurosecretory neurons leads to hypothalamus induced combined pituitary hormone deficiency. SMPD3 in the regulation of the protein vesicular secretory pathway may become a diagnostic target in the etiology of unknown forms of juvenile growth and developmental inhibition. PMID:27882938

  17. Antimicrobial agent triclosan disrupts mitochondrial structure, revealed by super-resolution microscopy, and inhibits mast cell signaling via calcium modulation.

    Science.gov (United States)

    Weatherly, Lisa M; Nelson, Andrew J; Shim, Juyoung; Riitano, Abigail M; Gerson, Erik D; Hart, Andrew J; de Juan-Sanz, Jaime; Ryan, Timothy A; Sher, Roger; Hess, Samuel T; Gosse, Julie A

    2018-06-15

    The antimicrobial agent triclosan (TCS) is used in products such as toothpaste and surgical soaps and is readily absorbed into oral mucosa and human skin. These and many other tissues contain mast cells, which are involved in numerous physiologies and diseases. Mast cells release chemical mediators through a process termed degranulation, which is inhibited by TCS. Investigation into the underlying mechanisms led to the finding that TCS is a mitochondrial uncoupler at non-cytotoxic, low-micromolar doses in several cell types and live zebrafish. Our aim was to determine the mechanisms underlying TCS disruption of mitochondrial function and of mast cell signaling. We combined super-resolution (fluorescence photoactivation localization) microscopy and multiple fluorescence-based assays to detail triclosan's effects in living mast cells, fibroblasts, and primary human keratinocytes. TCS disrupts mitochondrial nanostructure, causing mitochondria to undergo fission and to form a toroidal, "donut" shape. TCS increases reactive oxygen species production, decreases mitochondrial membrane potential, and disrupts ER and mitochondrial Ca 2+ levels, processes that cause mitochondrial fission. TCS is 60 × more potent than the banned uncoupler 2,4-dinitrophenol. TCS inhibits mast cell degranulation by decreasing mitochondrial membrane potential, disrupting microtubule polymerization, and inhibiting mitochondrial translocation, which reduces Ca 2+ influx into the cell. Our findings provide mechanisms for both triclosan's inhibition of mast cell signaling and its universal disruption of mitochondria. These mechanisms provide partial explanations for triclosan's adverse effects on human reproduction, immunology, and development. This study is the first to utilize super-resolution microscopy in the field of toxicology. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. MicroRNA expression profile and functional analysis reveal their roles in contact inhibition and its disruption switch of rat vascular smooth muscle cells.

    Science.gov (United States)

    Sun, Ye-Ying; Qin, Shan-Shan; Cheng, Yun-Hui; Wang, Chao-Yun; Liu, Xiao-Jun; Liu, Ying; Zhang, Xiu-Li; Zhang, Wendy; Zhan, Jia-Xin; Shao, Shuai; Bian, Wei-Hua; Luo, Bi-Hui; Lu, Dong-Feng; Yang, Jian; Wang, Chun-Hua; Zhang, Chun-Xiang

    2018-05-01

    Contact inhibition and its disruption of vascular smooth muscle cells (VSMCs) are important cellular events in vascular diseases. But the underlying molecular mechanisms are unclear. In this study we investigated the roles of microRNAs (miRNAs) in the contact inhibition and its disruption of VSMCs and the molecular mechanisms involved. Rat VSMCs were seeded at 30% or 90% confluence. MiRNA expression profiles in contact-inhibited confluent VSMCs (90% confluence) and non-contact-inhibited low-density VSMCs (30% confluence) were determined. We found that multiple miRNAs were differentially expressed between the two groups. Among them, miR-145 was significantly increased in contact-inhibited VSMCs. Serum could disrupt the contact inhibition as shown by the elicited proliferation of confluent VSMCs. The contact inhibition disruption accompanied with a down-regulation of miR-145. Serum-induced contact inhibition disruption of VSMCs was blocked by overexpression of miR-145. Moreover, downregulation of miR-145 was sufficient to disrupt the contact inhibition of VSMCs. The downregulation of miR-145 in serum-induced contact inhibition disruption was related to the activation PI3-kinase/Akt pathway, which was blocked by the PI3-kinase inhibitor LY294002. KLF5, a target gene of miR-145, was identified to be involved in miR-145-mediated effect on VSMC contact inhibition disruption, as it could be inhibited by knockdown of KLF5. In summary, our results show that multiple miRNAs are differentially expressed in contact-inhibited VSMCs and in non-contact-inhibited VSMCs. Among them, miR-145 is a critical gene in contact inhibition and its disruption of VSMCs. PI3-kinase/Akt/miR-145/KLF5 is a critical signaling pathway in serum-induced contact inhibition disruption. Targeting of miRNAs related to the contact inhibition of VSMCs may represent a novel therapeutic approach for vascular diseases.

  19. Sleep disruption is related to poor response inhibition in individuals with obsessive-compulsive and repetitive negative thought symptoms.

    Science.gov (United States)

    Nota, Jacob A; Schubert, Jessica R; Coles, Meredith E

    2016-03-01

    Obsessive-compulsive (OC) symptoms and repetitive negative thinking (RNT) are associated with poor inhibitory control. Sleep disruptions may partially mediate these relations and/or act as a "second hit" to individuals with OC symptoms and RNT. Models including habitual (past month) hours slept and bedtimes were tested. We employed a go/no-go task that allowed us to examine the relation between sleep and inhibition with various task contingencies. Sixty-seven unselected individuals were recruited from the participant pool at a public university. Bias-corrected bootstrap estimates did not show that sleep disruption mediated the relation between OC symptoms and response inhibition nor the relation between RNT and response inhibition. Multiple linear regression analyses found significant interactions between hours slept and OC symptom severity and between RNT and hours slept to predict poor response inhibition. Hours slept significantly negatively predicted commission errors when OC symptoms and RNT levels were relatively heightened but not when OC symptoms and RNT levels were relatively low. These effects were present in blocks where task contingencies were designed to shape a no-go bias. No significant relations were found with habitual bedtimes. The cross-sectional study design precludes testing the temporal precedence of symptoms in the "second hit" model. The unselected sample also limits generalization to clinical samples. These findings support a "second hit" model of interaction between sleep disruption and perseverative thoughts and behaviors. Further research on the mechanisms of the relation between sleep disruption and perseverative thought symptoms (OC and RNT) is warranted. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Inhibition in the Human Auditory Cortex.

    Directory of Open Access Journals (Sweden)

    Koji Inui

    Full Text Available Despite their indispensable roles in sensory processing, little is known about inhibitory interneurons in humans. Inhibitory postsynaptic potentials cannot be recorded non-invasively, at least in a pure form, in humans. We herein sought to clarify whether prepulse inhibition (PPI in the auditory cortex reflected inhibition via interneurons using magnetoencephalography. An abrupt increase in sound pressure by 10 dB in a continuous sound was used to evoke the test response, and PPI was observed by inserting a weak (5 dB increase for 1 ms prepulse. The time course of the inhibition evaluated by prepulses presented at 10-800 ms before the test stimulus showed at least two temporally distinct inhibitions peaking at approximately 20-60 and 600 ms that presumably reflected IPSPs by fast spiking, parvalbumin-positive cells and somatostatin-positive, Martinotti cells, respectively. In another experiment, we confirmed that the degree of the inhibition depended on the strength of the prepulse, but not on the amplitude of the prepulse-evoked cortical response, indicating that the prepulse-evoked excitatory response and prepulse-evoked inhibition reflected activation in two different pathways. Although many diseases such as schizophrenia may involve deficits in the inhibitory system, we do not have appropriate methods to evaluate them; therefore, the easy and non-invasive method described herein may be clinically useful.

  1. Enhanced eyeblink conditioning in behaviorally inhibited individuals is disrupted by proactive interference following US alone pre-exposures.

    Directory of Open Access Journals (Sweden)

    Michael Todd Allen

    2016-03-01

    Full Text Available Anxiety vulnerable individuals exhibit enhanced acquisition of conditioned eyeblinks as well as enhanced proactive interference from CS or US alone pre-exposures (Holloway et al., 2012. US alone pre-exposures disrupt subsequent CR acquisition to CS-US paired trials as compared to context pre-exposure controls. While Holloway et al., (2012 reported enhanced acquisition in high trait anxiety individuals in the context condition, anxiety vulnerability effects were not reported for the US alone pre-exposure group. It appears from the published data that there were no differences between high and low anxiety individuals in the US alone condition. In the work reported here, we sought to extend the findings of enhanced proactive interference with US alone pre-exposures to determine if the enhanced conditioning was disrupted by proactive interference procedures. We also were interested in the spontaneous eyeblinks during the pre-exposure phase of training. We categorized individuals as anxiety vulnerability or non-vulnerable individuals based scores on the Adult Measure of Behavioural Inhibition (AMBI. Sixty six participants received 60 trials consisting of 30 US alone or context alone pre-exposures followed by 30 CS-US trials. US alone pre-exposures not only disrupted CR acquisition overall, but behaviorally inhibited (BI individuals exhibited enhanced proactive interference as compared to non-inhibited (NI individuals. In addition, US alone pre-exposures disrupted the enhanced acquisition observed in BI individuals as compared to NI individuals following context alone pre-exposures. Differences were also found in rates of spontaneous eyeblinks between BI and NI individuals during context pre-exposure. Our findings will be discussed in the light of the neural substrates of eyeblink conditioning as well as possible factors such as hypervigilance in the amygdala and hippocampal systems, and possible learned helplessness. Applications of these findings of

  2. Triptolide disrupts the actin-based Sertoli-germ cells adherens junctions by inhibiting Rho GTPases expression

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xiang; Zhao, Fang [Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009 (China); Lv, Zhong-ming; Shi, Wei-qin [Jiangsu Provincial Center for Disease Control and Prevention, Nanjing (China); Zhang, Lu-yong, E-mail: lyzhang@cpu.edu.cn [Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009 (China); Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing (China); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009 (China); Yan, Ming, E-mail: brookming@cpu.edu.cn [Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009 (China)

    2016-11-01

    Triptolide (TP), derived from the medicinal plant Triterygium wilfordii Hook. f. (TWHF), is a diterpene triepoxide with variety biological and pharmacological activities. However, TP has been restricted in clinical application due to its narrow therapeutic window especially in reproductive system. During spermatogenesis, Sertoli cell cytoskeleton plays an essential role in facilitating germ cell movement and cell-cell actin-based adherens junctions (AJ). At Sertoli cell-spermatid interface, the anchoring device is a kind of AJ, known as ectoplasmic specializations (ES). In this study, we demonstrate that β-actin, an important component of cytoskeleton, has been significantly down-regulated after TP treatment. TP can inhibit the expression of Rho GTPase such as, RhoA, RhoB, Cdc42 and Rac1. Downstream of Rho GTPase, Rho-associated protein kinase (ROCKs) gene expressions were also suppressed by TP. F-actin immunofluorescence proved that TP disrupts Sertoli cells cytoskeleton network. As a result of β-actin down-regulation, TP treatment increased expression of testin, which indicating ES has been disassembled. In summary, this report illustrates that TP induces cytoskeleton dysfunction and disrupts cell-cell adherens junctions via inhibition of Rho GTPases. - Highlights: • Triptolide induced the disruption of Sertoli-germ cell adherens junction. • Rho GTPases expression and actin dynamics have been suppressed by triptolide. • Actin-based adherens junction is a potential antifertility target of triptolide. • Rho-Rock is involved in the regulation of actin dynamics.

  3. Triptolide disrupts the actin-based Sertoli-germ cells adherens junctions by inhibiting Rho GTPases expression

    International Nuclear Information System (INIS)

    Wang, Xiang; Zhao, Fang; Lv, Zhong-ming; Shi, Wei-qin; Zhang, Lu-yong; Yan, Ming

    2016-01-01

    Triptolide (TP), derived from the medicinal plant Triterygium wilfordii Hook. f. (TWHF), is a diterpene triepoxide with variety biological and pharmacological activities. However, TP has been restricted in clinical application due to its narrow therapeutic window especially in reproductive system. During spermatogenesis, Sertoli cell cytoskeleton plays an essential role in facilitating germ cell movement and cell-cell actin-based adherens junctions (AJ). At Sertoli cell-spermatid interface, the anchoring device is a kind of AJ, known as ectoplasmic specializations (ES). In this study, we demonstrate that β-actin, an important component of cytoskeleton, has been significantly down-regulated after TP treatment. TP can inhibit the expression of Rho GTPase such as, RhoA, RhoB, Cdc42 and Rac1. Downstream of Rho GTPase, Rho-associated protein kinase (ROCKs) gene expressions were also suppressed by TP. F-actin immunofluorescence proved that TP disrupts Sertoli cells cytoskeleton network. As a result of β-actin down-regulation, TP treatment increased expression of testin, which indicating ES has been disassembled. In summary, this report illustrates that TP induces cytoskeleton dysfunction and disrupts cell-cell adherens junctions via inhibition of Rho GTPases. - Highlights: • Triptolide induced the disruption of Sertoli-germ cell adherens junction. • Rho GTPases expression and actin dynamics have been suppressed by triptolide. • Actin-based adherens junction is a potential antifertility target of triptolide. • Rho-Rock is involved in the regulation of actin dynamics.

  4. Fluoxetine and vitamin C synergistically inhibits blood-spinal cord barrier disruption and improves functional recovery after spinal cord injury.

    Science.gov (United States)

    Lee, Jee Y; Choi, Hae Y; Yune, Tae Y

    2016-10-01

    Recently we reported that fluoxetine (10 mg/kg) improves functional recovery by attenuating blood spinal cord barrier (BSCB) disruption after spinal cord injury (SCI). Here we investigated whether a low-dose of fluoxetine (1 mg/kg) and vitamin C (100 mg/kg), separately not possessing any protective effect, prevents BSCB disruption and improves functional recovery when combined. After a moderate contusion injury at T9 in rat, a low-dose of fluoxetine and vitamin C, or the combination of both was administered intraperitoneally immediately after SCI and further treated once a day for 14 d. Co-treatment with fluoxetine and vitamin C significantly attenuated BSCB permeability at 1 d after SCI. When only fluoxetine or vitamin C was treated after injury, however, there was no effect on BSCB disruption. Co-treatment with fluoxetine and vitamin C also significantly inhibited the expression and activation of MMP-9 at 8 h and 1 d after injury, respectively, and the infiltration of neutrophils (at 1 d) and macrophages (at 5 d) and the expression of inflammatory mediators (at 2 h, 6 h, 8 h or 24 h after injury) were significantly inhibited by co-treatment with fluoxetine and vitamin C. Furthermore, the combination of fluoxetine and vitamin C attenuated apoptotic cell death at 1 d and 5 d and improved locomotor function at 5 weeks after SCI. These results demonstrate the synergistic effect combination of low-dose fluoxetine and vitamin C on BSCB disruption after SCI and furthermore support the effectiveness of the combination treatment regimen for the management of acute SCI. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes.

    Directory of Open Access Journals (Sweden)

    Beth S Zha

    Full Text Available HIV protease inhibitors (PI are core components of Highly Active Antiretroviral Therapy (HAART, the most effective treatment for HIV infection currently available. However, HIV PIs have now been linked to lipodystrophy and dyslipidemia, which are major risk factors for cardiovascular disease and metabolic syndrome. Our previous studies have shown that HIV PIs activate endoplasmic reticulum (ER stress and disrupt lipid metabolism in hepatocytes and macrophages. Yet, little is known on how HIV PIs disrupt lipid metabolism in adipocytes, a major cell type involved in the pathogenesis of metabolic syndrome.Cultured and primary mouse adipocytes and human adipocytes were used to examine the effect of frequently used HIV PIs in the clinic, lopinavir/ritonavir, on adipocyte differentiation and further identify the underlying molecular mechanism of HIV PI-induced dysregulation of lipid metabolism in adipocytes. The results indicated that lopinavir alone or in combination with ritonavir, significantly activated the ER stress response, inhibited cell differentiation, and induced cell apoptosis in adipocytes. In addition, HIV PI-induced ER stress was closely linked to inhibition of autophagy activity. We also identified through the use of primary adipocytes of CHOP(-/- mice that CHOP, the major transcriptional factor of the ER stress signaling pathway, is involved in lopinavir/ritonavir-induced inhibition of cell differentiation in adipocytes. In addition, lopinavir/ritonavir-induced ER stress appears to be associated with inhibition of autophagy activity in adipocytes.Activation of ER stress and impairment of autophagy activity are involved in HIV PI-induced dysregulation of lipid metabolism in adipocytes. The key components of ER stress and autophagy signaling pathways are potential therapeutic targets for HIV PI-induced metabolic side effects in HIV patients.

  6. Enhanced Eyeblink Conditioning in Behaviorally Inhibited Individuals is Disrupted by Proactive Interference Following US Alone Pre-exposures.

    Science.gov (United States)

    Allen, Michael Todd; Miller, Daniel P

    2016-01-01

    Anxiety vulnerable individuals exhibit enhanced acquisition of conditioned eyeblinks as well as enhanced proactive interference from conditioned stimulus (CS) or unconditioned stimulus (US) alone pre-exposures (Holloway et al., 2012). US alone pre-exposures disrupt subsequent conditioned response (CR) acquisition to CS-US paired trials as compared to context pre-exposure controls. While Holloway et al. (2012) reported enhanced acquisition in high trait anxiety individuals in the context condition, anxiety vulnerability effects were not reported for the US alone pre-exposure group. It appears from the published data that there were no differences between high and low anxiety individuals in the US alone condition. In the work reported here, we sought to extend the findings of enhanced proactive interference with US alone pre-exposures to determine if the enhanced conditioning was disrupted by proactive interference procedures. We also were interested in the spontaneous eyeblinks during the pre-exposure phase of training. We categorized individuals as anxiety vulnerability or non-vulnerable individuals based scores on the Adult Measure of Behavioral Inhibition (AMBI). Sixty-six participants received 60 trials consisting of 30 US alone or context alone pre-exposures followed by 30 CS-US trials. US alone pre-exposures not only disrupted CR acquisition overall, but behaviorally inhibited (BI) individuals exhibited enhanced proactive interference as compared to non-inhibited (NI) individuals. In addition, US alone pre-exposures disrupted the enhanced acquisition observed in BI individuals as compared to NI individuals following context alone pre-exposures. Differences were also found in rates of spontaneous eyeblinks between BI and NI individuals during context pre-exposure. Our findings will be discussed in the light of the neural substrates of eyeblink conditioning as well as possible factors such as hypervigilance in the amygdala and hippocampal systems, and possible

  7. Evaluating iodide recycling inhibition as a novel molecular initiating event for thyroid axis disruption

    Science.gov (United States)

    The enzyme iodotyrosine deiodinase (dehalogenase, IYD) catalyzes iodide recycling and promotes iodide retention in thyroid follicular cells. Loss of function or chemical inhibition of IYD reduces available iodide for thyroid hormone synthesis, which leads to hormone insufficiency...

  8. Inhibition of autophagy enhances DNA damage-induced apoptosis by disrupting CHK1-dependent S phase arrest

    Energy Technology Data Exchange (ETDEWEB)

    Liou, Jong-Shian; Wu, Yi-Chen; Yen, Wen-Yen; Tang, Yu-Shuan [Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC (China); Kakadiya, Rajesh B.; Su, Tsann-Long [Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, ROC (China); Yih, Ling-Huei, E-mail: lhyih@gate.sinica.edu.tw [Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC (China)

    2014-08-01

    DNA damage has been shown to induce autophagy, but the role of autophagy in the DNA damage response and cell fate is not fully understood. BO-1012, a bifunctional alkylating derivative of 3a-aza-cyclopenta[a]indene, is a potent DNA interstrand cross-linking agent with anticancer activity. In this study, BO-1012 was found to reduce DNA synthesis, inhibit S phase progression, and induce phosphorylation of histone H2AX on serine 139 (γH2AX) exclusively in S phase cells. Both CHK1 and CHK2 were phosphorylated in response to BO-1012 treatment, but only depletion of CHK1, but not CHK2, impaired BO-1012-induced S phase arrest and facilitated the entry of γH2AX-positive cells into G2 phase. CHK1 depletion also significantly enhanced BO-1012-induced cell death and apoptosis. These results indicate that BO-1012-induced S phase arrest is a CHK1-dependent pro-survival response. BO-1012 also resulted in marked induction of acidic vesicular organelle (AVO) formation and microtubule-associated protein 1 light chain 3 (LC3) processing and redistribution, features characteristic of autophagy. Depletion of ATG7 or co-treatment of cells with BO-1012 and either 3-methyladenine or bafilomycin A1, two inhibitors of autophagy, not only reduced CHK1 phosphorylation and disrupted S phase arrest, but also increased cleavage of caspase-9 and PARP, and cell death. These results suggest that cells initiate S phase arrest and autophagy as pro-survival responses to BO-1012-induced DNA damage, and that suppression of autophagy enhances BO-1012-induced apoptosis via disruption of CHK1-dependent S phase arrest. - Highlights: • Autophagy inhibitors enhanced the cytotoxicity of a DNA alkylating agent, BO-1012. • BO-1012-induced S phase arrest was a CHK1-dependent pro-survival response. • Autophagy inhibition enhanced BO-1012 cytotoxicity via disrupting the S phase arrest.

  9. Low prepulse, high power density water dielectric switching

    International Nuclear Information System (INIS)

    Johnson, D.L.; VanDevender, J.P.; Martin, T.H.

    1979-01-01

    Prepulse voltage suppression has proven difficult in high power, high voltage accelerators employing self-breakdown water dielectric switches. A novel and cost effective water switch has been developed at Sandia Laboratories which reduces prepulse voltage by reducing the capacity across the switch. This prepulse suppression switch causes energy formerly stored in the switch capacity and dissipated in the arc to be useful output energy. The switching technique also allows the pulse forming lines to be stacked in parallel and electrically isolated from the load after the line has been discharged. The switch consists of a ground plane, with several holes, inserted between the switch electrodes. The output line switch electrodes extend through the holes and face electrodes on the pulse forming line (PFL). The capacity between the PFL and the output transmission line is reduced by about 80%. The gap spacing between the output line electrode and the hole in the ground plane is adjusted so that breakdown occurs after the main pulse and provides a crow bar between the load and the source. Performance data from the Proto II, Mite and Ripple test facilities are presented

  10. Ocular Dominance Plasticity Disrupts Binocular Inhibition-Excitation Matching in Visual Cortex

    NARCIS (Netherlands)

    Saiepour, M.H.; Rajendran, R.; Omrani, A.; Ma, W.; Tao, H.W.; Heimel, J.A.; Levelt, C.N.

    2015-01-01

    Background To ensure that neuronal networks function in a stable fashion, neurons receive balanced inhibitory and excitatory inputs. In various brain regions, this balance has been found to change temporarily during plasticity. Whether changes in inhibition have an instructive or permissive role in

  11. Niclosamide inhibits lytic replication of Epstein-Barr virus by disrupting mTOR activation.

    Science.gov (United States)

    Huang, Lu; Yang, Mengtian; Yuan, Yan; Li, Xiaojuan; Kuang, Ersheng

    2017-02-01

    Infection with the oncogenic γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause several severe malignancies in humans. Inhibition of the lytic replication of EBV and KSHV eliminates the reservoir of persistent infection and transmission, consequently preventing the occurrence of diseases from the sources of infection. Antiviral drugs are limited in controlling these viral infectious diseases. Here, we demonstrate that niclosamide, an old anthelmintic drug, inhibits mTOR activation during EBV lytic replication. Consequently, niclosamide effectively suppresses EBV lytic gene expression, viral DNA lytic replication and virion production in EBV-infected lymphoma cells and epithelial cells. Niclosamide exhibits cytotoxicity toward lymphoma cells and induces irreversible cell cycle arrest in lytically EBV-infected cells. The ectopic overexpression of mTOR reverses the inhibition of niclosamide in EBV lytic replication. Similarly, niclosamide inhibits KSHV lytic replication. Thus, we conclude that niclosamide is a promising candidate for chemotherapy against the acute occurrence and transmission of infectious diseases of oncogenic γ-herpesviruses. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. The N Terminus of the Retinoblastoma Protein Inhibits DNA Replication via a Bipartite Mechanism Disrupted in Partially Penetrant Retinoblastomas

    Science.gov (United States)

    Borysov, Sergiy I.; Nepon-Sixt, Brook S.

    2015-01-01

    The N-terminal domain of the retinoblastoma (Rb) tumor suppressor protein (RbN) harbors in-frame exon deletions in partially penetrant hereditary retinoblastomas and is known to impair cell growth and tumorigenesis. However, how such RbN deletions contribute to Rb tumor- and growth-suppressive functions is unknown. Here we establish that RbN directly inhibits DNA replication initiation and elongation using a bipartite mechanism involving N-terminal exons lost in cancer. Specifically, Rb exon 7 is necessary and sufficient to target and inhibit the replicative CMG helicase, resulting in the accumulation of inactive CMGs on chromatin. An independent N-terminal loop domain, which forms a projection, specifically blocks DNA polymerase α (Pol-α) and Ctf4 recruitment without affecting DNA polymerases ε and δ or the CMG helicase. Individual disruption of exon 7 or the projection in RbN or Rb, as occurs in inherited cancers, partially impairs the ability of Rb/RbN to inhibit DNA replication and block G1-to-S cell cycle transit. However, their combined loss abolishes these functions of Rb. Thus, Rb growth-suppressive functions include its ability to block replicative complexes via bipartite, independent, and additive N-terminal domains. The partial loss of replication, CMG, or Pol-α control provides a potential molecular explanation for how N-terminal Rb loss-of-function deletions contribute to the etiology of partially penetrant retinoblastomas. PMID:26711265

  13. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice

    DEFF Research Database (Denmark)

    Koenen, RR; Hundelshausen, P; Nesmelova, IV

    2009-01-01

    Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXC...... monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects......) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities...... compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions. Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating...

  14. Xanthium strumarium extract inhibits mammalian cell proliferation through mitotic spindle disruption mediated by xanthatin.

    Science.gov (United States)

    Sánchez-Lamar, Angel; Piloto-Ferrer, Janet; Fiore, Mario; Stano, Pasquale; Cozzi, Renata; Tofani, Daniela; Cundari, Enrico; Francisco, Marbelis; Romero, Aylema; González, Maria L; Degrassi, Francesca

    2016-12-24

    Xanthium strumarium L. is a member of the Asteraceae family popularly used with multiple therapeutic purposes. Whole extracts of this plant have shown anti-mitotic activity in vitro suggesting that some components could induce mitotic arrest in proliferating cells. Aim of the present work was to characterize the anti-mitotic properties of the X. strumarium whole extract and to isolate and purify active molecule(s). The capacity of the whole extract to inhibit mitotic progression in mammalian cultured cells was investigated to identify its anti-mitotic activity. Isolation of active component(s) was performed using a bioassay-guided multistep separation procedure in which whole extract was submitted to a progressive process of fractionation and fractions were challenged for their anti-mitotic activity. Our results show for the first time that X. strumarium whole extract inhibits assembly of the mitotic spindle and spindle-pole separation, thereby heavily affecting mitosis, impairing the metaphase to anaphase transition and inducing apoptosis. The purification procedure led to a fraction with an anti-mitotic activity comparable to that of the whole extract. Chemical analysis of this fraction showed that its major component was xanthatin. The present work shows a new activity of X. strumarium extract, i.e. the alteration of the mitotic apparatus in cultured cells that may be responsible for the anti-proliferative activity of the extract. Anti-mitotic activity is shown to be mainly exerted by xanthatin. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations.

    Science.gov (United States)

    Mortimer, Leanne; Moreau, France; MacDonald, Justin A; Chadee, Kris

    2016-10-01

    Inflammasomes are positioned to rapidly escalate the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. However, negative regulation of inflammasomes remains poorly understood, as is the signaling cascade that dampens inflammasome activity. We found that rapid NLRP3 inflammasome activation was directly inhibited by protein kinase A (PKA), which was induced by prostaglandin E2 (PGE2) signaling via the PGE2 receptor E-prostanoid 4 (EP4). PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function. We found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation. Mutations in NLRP3-encoding residues adjacent to Ser295 have been linked to the inflammatory disease CAPS (cryopyrin-associated periodic syndromes). NLRP3-S295A phenocopied the human CAPS mutants. These data suggest that negative regulation at Ser295 is critical for restraining the NLRP3 inflammasome and identify a molecular basis for CAPS-associated NLRP3 mutations.

  16. The effects of prepulse-blink reflex trial repetition and prepulse change on blink reflex modification at short and long lead intervals.

    Science.gov (United States)

    Lipp, O V; Siddle, D A

    1998-01-01

    Prepulse inhibition and facilitation of the blink reflex are said to reflect different responses elicited by the lead stimulus, transient detection and orienting response respectively. Two experiments investigated the effects of trial repetition and lead stimulus change on blink modification. It was hypothesized that these manipulations will affect orienting and thus blink facilitation to a greater extent than they will affect transient detection and thus blink inhibition. In Experiment 1 (N = 64), subjects were trained with a sequence of 12 lead stimulus and 12 blink stimulus alone presentations, and 24 lead stimulus-blink stimulus pairings. Lead interval was 120 ms for 12 of the trials and 2000 ms for the other 12. For half the subjects this sequence was followed by a change in pitch of the lead stimulus. In Experiment 2 (N = 64), subjects were trained with a sequence of 36 blink alone stimuli and 36 lead stimulus-blink stimulus pairings. The lead interval was 120 ms for half the subjects and 2000 ms for the other half. The pitch of the lead stimulus on prestimulus trials 31-33 was changed for half the subjects in each group. In both experiments, the amount of blink inhibition decreased during training whereas the amount of blink facilitation remained unchanged. Lead stimulus change had no effect on blink modification in either experiment although it resulted in enhanced skin conductance responses and greater heart rate deceleration in Experiment 2. The present results are not consistent with the notion that blink facilitation is linked to orienting whereas blink inhibition reflects a transient detection mechanism.

  17. Forchlorfenuron disrupts SEPT9_i1 filaments and inhibits HIF-1.

    Directory of Open Access Journals (Sweden)

    Dikla Vardi-Oknin

    Full Text Available Forchlorfenuron (FCF is a synthetic plant cytokinin that has been shown to alter yeast and mammalian septin organization. Septins are a highly conserved family of GTP-binding cytoskeletal proteins. Mammalian septins are involved in diverse cellular processes including tumorigenesis. We have been studying the interaction between septin 9 isoform 1 (SEPT9_i1 and hypoxia inducible factor-1α (HIF-1α, the oxygen regulated subunit of HIF-1. HIF-1 is a key transcription factor in the hypoxic responses pathway, and its activation has been observed in carcinogenesis and numerous cancers. SEPT9_i1/HIF-1α interaction plays an important role in upregulation of HIF-1 transcriptional activity by preventing HIF-1α's ubiquitination and degradation leading to increased tumor growth and angiogenesis. We tested the hypothesis whether FCF affects SEPT9_i1 filamentous structures and consequently HIF-1 pathway in cancer cells. We showed that FCF suppresses tumorigenic properties, including proliferation, migration and transformation, in prostate cancer cells. FCF did not alter SEPT9_i1 steady state protein expression levels but it affected its filamentous structures and subcellular localization. FCF induced degradation of HIF-1α protein in a dose- and time-dependent manner. This inhibition was also shown in other common cancer types tested. Rapid degradation of HIF-1α protein levels was accompanied by respective inhibition in HIF-1α transcriptional activity. Moreover, HIF-1α protein half-life was markedly decreased in the presence of FCF compared with that in the absence of FCF. The FCF-induced degradation of HIF-1α was mediated in a significant part via the proteasome. To the best of our knowledge, this is the first demonstration of specific manipulation of septin filaments by pharmacological means having downstream inhibitory effects on the HIF-1 pathway.

  18. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction.

    Science.gov (United States)

    Nishikawa, Joy L; Boeszoermenyi, Andras; Vale-Silva, Luis A; Torelli, Riccardo; Posteraro, Brunella; Sohn, Yoo-Jin; Ji, Fei; Gelev, Vladimir; Sanglard, Dominique; Sanguinetti, Maurizio; Sadreyev, Ruslan I; Mukherjee, Goutam; Bhyravabhotla, Jayaram; Buhrlage, Sara J; Gray, Nathanael S; Wagner, Gerhard; Näär, Anders M; Arthanari, Haribabu

    2016-02-25

    Eukaryotic transcription activators stimulate the expression of specific sets of target genes through recruitment of co-activators such as the RNA polymerase II-interacting Mediator complex. Aberrant function of transcription activators has been implicated in several diseases. However, therapeutic targeting efforts have been hampered by a lack of detailed molecular knowledge of the mechanisms of gene activation by disease-associated transcription activators. We previously identified an activator-targeted three-helix bundle KIX domain in the human MED15 Mediator subunit that is structurally conserved in Gal11/Med15 Mediator subunits in fungi. The Gal11/Med15 KIX domain engages pleiotropic drug resistance transcription factor (Pdr1) orthologues, which are key regulators of the multidrug resistance pathway in Saccharomyces cerevisiae and in the clinically important human pathogen Candida glabrata. The prevalence of C. glabrata is rising, partly owing to its low intrinsic susceptibility to azoles, the most widely used antifungal agent. Drug-resistant clinical isolates of C. glabrata most commonly contain point mutations in Pdr1 that render it constitutively active, suggesting that this transcriptional activation pathway represents a linchpin in C. glabrata multidrug resistance. Here we perform sequential biochemical and in vivo high-throughput screens to identify small-molecule inhibitors of the interaction of the C. glabrata Pdr1 activation domain with the C. glabrata Gal11A KIX domain. The lead compound (iKIX1) inhibits Pdr1-dependent gene activation and re-sensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models for disseminated and urinary tract C. glabrata infection. Determining the NMR structure of the C. glabrata Gal11A KIX domain provides a detailed understanding of the molecular mechanism of Pdr1 gene activation and multidrug resistance inhibition by iKIX1. We have demonstrated the feasibility of small-molecule targeting of a

  19. Measurements of low-level prepulse on Nike KrF laser

    International Nuclear Information System (INIS)

    Karasik, Max; Mostovych, A.N.; Lehmberg, R.H.; Chan, Y.; Weaver, J.L.; Obenschain, S.P.

    2005-01-01

    The krypton fluoride (KrF) laser is a leading candidate driver for inertial fusion energy. Some of the current fusion target designs call for targets with thin metallic coatings. These targets could be particularly susceptible to preheat by a low-level laser prepulse. Knowledge of the prepulse can be important in understanding and modeling the behavior of such targets. This paper presents measurements of low-level prepulse on target with the Nike KrF laser. Sources of prepulse are discussed and measurements are performed under several specific laser conditions in order to evaluate the relative contribution of these sources to the overall prepulse. Prepulse is found to be ∼2x10 -7 from peak intensity for approximately 120 ns prior to the main laser pulse. Prepulse energy density on target is ∼2 J/cm 2 . The first laser amplifier in the time- and angle-multiplexed section of the laser is found to be the dominant source of prepulse

  20. Evaluation of the effect of prepulses on HF laser-target interactions

    International Nuclear Information System (INIS)

    Matzen, M.K.

    1979-06-01

    We have assessed the effect of multinanosecond, low-power-density prepulses on the interaction of multinanosecond, 10 14 W/cm 2 , approx. 3 -μm HF laser pulses with slab targets. The emphasis is on analyzing absorption and x-ray conversion efficiency. A survey of previous experiments gives no evidence that these prepulses will affect the total absorption. However, prepulses have been observed to cause qualitative changes in both the x-ray spectrum and conversion efficiency. Numerical simulations indicate that the laser-target interaction is effectively insensitive to low-power-density prepulses. These studies imply that basic laser-target experiments with multiplexed, HF laser pulses will provide an important characterization of the interaction of long pulse, multi-line, approx. 3 μm radiation with targets. Future wavelength comparison experiments will require prepulse suppression or target isolation

  1. Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA).

    Science.gov (United States)

    Young, Matthew B; Norrholm, Seth D; Khoury, Lara M; Jovanovic, Tanja; Rauch, Sheila A M; Reiff, Collin M; Dunlop, Boadie W; Rothbaum, Barbara O; Howell, Leonard L

    2017-10-01

    3,4-Methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD, particularly in treatment-resistant patients. However, given MDMA's broad pharmacological profile, further investigation is warranted before moving to a complex clinical population. We aimed to inform clinical research by providing a translational model of MDMA's effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction. We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training. MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA's effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA's effect by 5-HTT inhibition also downregulated 5-HT 2A -mediated behavior, and 5-HT 2A antagonism disrupted MDMA's effect on extinction. We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT 2A receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.

  2. Using prepulsing: a useful way for increasing absorption efficiency of high intensity laser beam

    International Nuclear Information System (INIS)

    Peng Huimin; Zhang Guoping; Sheng Jiatian

    1990-01-01

    Using prepulse to irradiate target for increasing absorption efficiency of high intensity incident laser beam is considered and some theoretical simulations have been done. 1-D non-LTE radiative hydrodynamic code is used to simulate the interactions of laser beam with matter. A gaussian laser prepulse of wavelength 1.06 μm, FWHM 600 ps and peak intensity 1.5 x 10 12 W/cm 2 was used to irradiate 20 μm thick Au plate target, after 3ns a main gaussian pulse with wavelength 1.06 μm, FWHM 600 ps and peak intensity 3.0 x 10 14 W/cm 2 irradiated the expanding Au plasma. The responces of laser-produced plasma conditions are shown. By comparing with without prepulsing, under the condition of same main incident laser pulse, the absorption efficiency is increased from 0.36 to 0.60 and the laser-x-ray conversion efficiency is increased from 0.16 to 0.25. The electron temperature of hot plasma is also higher than without prepulsing, and the x-ray spectrum which is emitted from laser-produced hot plasma is harder and more intense than without prepulsing. The responces of laser-produced plasma for Fe target with prepulsing are shown as well. The conclusion is that using prepulsing is a useful way for getting high absorption laser beam

  3. Prepulse dependence in hard x-ray generation from microdroplets

    International Nuclear Information System (INIS)

    Anand, M.; Kahaly, S.; Kumar, G. Ravindra; Sandhu, A. S.; Gibbon, P.; Krishnamurthy, M.

    2006-01-01

    We report on experiments which show that liquid microdroplets are very efficient in hard x-ray generation. We make a comparative study of hard x-ray emission from 15 μm methanol microdroplets and a plain slab target of similar atomic composition at similar laser intensities. The hard X-ray yield from droplet plasmas is about 35 times more than that obtained from solid plasmas. A prepulse that is about 10ns and at least 2% in intensity of the main pulse is essential for hard x-ray generation from the droplets at about 1015 W cm-2. A hot electron temperature of 36 keV is measured from the droplets at 8 x 1014 W cm-2; three times higher intensity is needed to obtain similar hot electron temperature from solid plasmas that have similar atomic composition. We use 1D-PIC simulation to obtain qualitative correlation to the experimental observations

  4. DISRUPTION OF CONDITIONED REWARD ASSOCIATION BY TYPICAL AND ATYPICAL ANTIPSYCHOTICS

    Science.gov (United States)

    Danna, C.L.; Elmer, G.I.

    2013-01-01

    Antipsychotic drugs are broadly classified into typical and atypical compounds; they vary in their pharmacological profile however a common component is their antagonist effects at the D2 dopamine receptors (DRD2). Unfortunately, diminished DRD2 activation is generally thought to be associated with the severity of neuroleptic-induced anhedonia. The purpose of this study was to determine the effect of the atypical antipsychotic olanzapine and typical antipsychotic haloperidol in a paradigm that reflects the learned transfer of incentive motivational properties to previously neutral stimuli, namely autoshaping. In order to provide a dosing comparison to a therapeutically relevant endpoint, both drugs were tested against amphetamine-induced disruption of prepulse inhibition as well. In the autoshaping task, rats were exposed to repeated pairings of stimuli that were differentially predictive of reward delivery. Conditioned approach to the reward predictive cue (sign-tracking) and to the reward (goal-tracking) increased during repeated pairings in the vehicle treated rats. Haloperidol and olanzapine completely abolished this behavior at relatively low doses (100 μg/kg). This same dose was the threshold dose for each drug to antagonize the sensorimotor gating deficits produced by amphetamine. At lower doses (3–30 μg/kg) both drugs produced a dose-dependent decrease in conditioned approach to the reward predictive cue. There was no difference between drugs at this dose range which indicates that olanzapine disrupts autoshaping at a significantly lower proposed DRD2 receptor occupancy. Interestingly, neither drug disrupted conditioned approach to the reward at the same dose range that disrupted conditioned approach to the reward predictive cue. Thus, haloperidol and olanzapine, at doses well below what is considered therapeutically relevant, disrupts the attribution of incentive motivational value to previously neutral cues. Drug effects on this dimension of reward

  5. Cucurbitacin B inhibits human breast cancer cell proliferation through disruption of microtubule polymerization and nucleophosmin/B23 translocation

    Directory of Open Access Journals (Sweden)

    Duangmano Suwit

    2012-10-01

    Full Text Available Abstract Background Cucurbitacin B, an oxygenated tetracyclic triterpenoid compound extracted from the Thai medicinal plant Trichosanthes cucumerina L., has been reported to have several biological activities including anti-inflammatory, antimicrobial and anticancer. Cucurbitacin B is great of interest because of its biological activity. This agent inhibits growth of various types of human cancer cells lines. Methods In this study, we explored the novel molecular response of cucurbitacin B in human breast cancer cells, MCF-7 and MDA-MB-231. The growth inhibitory effect of cucurbitacin B on breast cancer cells was assessed by MTT assay. The effects of cucurbitacin B on microtubules morphological structure and tubulin polymerization were analyzed using immunofluorescence technique and tubulin polymerization assay kit, respectively. Proteomic analysis was used to identify the target-specific proteins that involved in cucurbitacin B treatment. Some of the differentially expressed genes and protein products were validated by real-time RT-PCR and western blot analysis. Cell cycle distributions and apoptosis were investigated using flow cytometry. Results Cucurbitacin B exhibited strong antiproliferative effects against breast cancer cells in a dose-dependent manner. We show that cucurbitacin B prominently alters the cytoskeletal network of breast cancer cells, inducing rapid morphologic changes and improper polymerization of the microtubule network. Moreover, the results of 2D-PAGE, real-time RT-PCR, and western blot analysis revealed that the expression of nucleophosmin/B23 and c-Myc decreased markedly after cucurbitacin B treatment. Immunofluorescence microscopy showed that cucurbitacin B induced translocation of nucleophosmin/B23 from the nucleolus to nucleoplasm. Treatment with cucurbitacin B resulted in cell cycle arrest at G2/M phase and the enhancement of apoptosis. Conclusions Our findings suggest that cucurbitacin B may inhibit the

  6. The effects of insulating coatings and current prepulse on tungsten planar wire array Z-pinches

    Energy Technology Data Exchange (ETDEWEB)

    Li, M., E-mail: limo@nint.ac.cn; Li, Y. [State Key Laboratory of Electrical Insulation and Power Equipment, Xi' an Jiaotong University, Shaanxi 710049 (China); State Key Laboratory of Intense Pulsed Radiation Simulation and Effect, Northwest Institute of Nuclear Technology, Xi' an 710024 (China); Sheng, L.; Wang, L. P.; Zhao, C.; Yuan, Y.; Zhang, X. J.; Zhang, M.; Peng, B. D.; Zhang, J. H.; Zhang, S. G.; Qiu, M. T. [State Key Laboratory of Intense Pulsed Radiation Simulation and Effect, Northwest Institute of Nuclear Technology, Xi' an 710024 (China); Li, X. W. [State Key Laboratory of Electrical Insulation and Power Equipment, Xi' an Jiaotong University, Shaanxi 710049 (China)

    2015-12-15

    This paper presents experimental results on the effects of insulating coatings and current prepulse on tungsten planar wire array Z-pinches on ∼100 ns main current facility. Optical framing images indicated that without a current prepulse the wire ablation process was asymmetrical and the implosion was zippered. The x-ray peak power was ∼320 GW. By using insulating coatings on the wire surface the asymmetry remained, and the processes of ablation and implosion were delayed by ∼30 ns. The x-ray burst was narrow and decreased to ∼200 GW. When current prepulses were used on both standard and insulated wire arrays, implosion symmetry was improved and the x-ray burst was improved (to ∼520 GW peak power). In addition, there was a strong emitting precursor column for insulated loads with the current prepulse.

  7. Controlling output pulse and prepulse in a resonant microwave pulse compressor

    International Nuclear Information System (INIS)

    Shlapakovski, A.; Artemenko, S.; Chumerin, P.; Yushkov, Yu.

    2013-01-01

    A resonant microwave pulse compressor with a waveguide H-plane-tee-based energy extraction unit was studied in terms of its capability to produce output pulses that comprise a low-power long-duration (prepulse) and a high-power short-duration part. The application of such combined pulses with widely variable prepulse and high-power pulse power and energy ratios is of interest in the research area of electronic hardware vulnerability. The characteristics of output radiation pulses are controlled by the variation of the H-plane tee transition attenuation at the stage of microwave energy storage in the compressor cavity. Results of theoretical estimations of the parameters tuning range and experimental investigations of the prototype S-band compressor (1.5 MW, 12 ns output pulse; ∼13.2 dB gain) are presented. The achievable maximum in the prepulse power is found to be about half the power of the primary microwave source. It has been shown that the energy of the prepulse becomes comparable with that of the short-duration (nanosecond) pulse, while the power of the latter decreases insignificantly. The possible range of variation of the prepulse power and energy can be as wide as 40 dB. In the experiments, the prepulse level control within the range of ∼10 dB was demonstrated.

  8. Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1.

    Science.gov (United States)

    O'Tuathaigh, Colm M P; Fumagalli, Fabio; Desbonnet, Lieve; Perez-Branguli, Francesc; Moloney, Gerard; Loftus, Samim; O'Leary, Claire; Petit, Emilie; Cox, Rachel; Tighe, Orna; Clarke, Gerard; Lai, Donna; Harvey, Richard P; Cryan, John F; Mitchell, Kevin J; Dinan, Timothy G; Riva, Marco A; Waddington, John L

    2017-01-01

    Few studies have addressed likely gene × gene (ie, epistatic) interactions in mediating risk for schizophrenia. Using a preclinical genetic approach, we investigated whether simultaneous disruption of the risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) would produce a disease-relevant phenotypic profile different from that observed following disruption to either gene alone. NRG1 heterozygotes exhibited hyperactivity and disruption to prepulse inhibition, both reversed by antipsychotic treatment, and accompanied by reduced striatal dopamine D2 receptor protein expression, impaired social cognition, and altered glutamatergic synaptic protein expression in selected brain areas. Single gene DISC1 mutants demonstrated a disruption in social cognition and nest-building, altered brain 5-hydroxytryptamine levels and hippocampal ErbB4 expression, and decreased cortical expression of the schizophrenia-associated microRNA miR-29b. Co-disruption of DISC1 and NRG1, indicative of epistasis, evoked an impairment in sociability and enhanced self-grooming, accompanied by changes in hypothalamic oxytocin/vasopressin gene expression. The findings indicate specific behavioral correlates and underlying cellular pathways downstream of main effects of DNA variation in the schizophrenia-associated genes NRG1 and DISC1. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  9. High doses of salicylate causes prepulse facilitation of onset-gap induced acoustic startle response.

    Science.gov (United States)

    Sun, Wei; Doolittle, Lauren; Flowers, Elizabeth; Zhang, Chao; Wang, Qiuju

    2014-01-01

    Prepulse inhibition of acoustic startle reflex (PPI), a well-established method for evaluating sensorimotor gating function, has been used to detect tinnitus in animal models. Reduced gap induced PPI (gap-PPI) was considered as a sign of tinnitus. The silent gap used in the test contains both onset and offset signals. Tinnitus may affect these cues differently. In this experiment, we studied the effects of a high dose of salicylate (250 mg/kg, i.p.), an inducer of reversible tinnitus and sensorineural hearing loss, on gap-PPI induced by three different gaps: an onset-gap with 0.1 ms onset and 25 ms offset time, an offset-gap with 25 ms onset and 0.1 ms offset time, and an onset-offset-gap with 0.1 ms onset and offset time. We found that the onset-gaps induced smaller inhibitions than the offset-gaps before salicylate treatment. The offset-gap induced PPI was significantly reduced 1-3h after salicylate treatment. However, the onset-gap caused a facilitation of startle response. These results suggest that salicylate induced reduction of gap-PPI was not only caused by the decrease of offset-gap induced PPI, but also by the facilitation induced by the onset-gap. Since the onset-gap induced PPI is caused by neural offset response, our results suggest that salicylate may cause a facilitation of neural response to an offset acoustical signal. Treatment of vigabatrin (60 mg/kg/day, 14 days), which elevates the GABA level in the brain, blocked the offset-gap induced PPI and onset-gap induced facilitation caused by salicylate. These results suggest that enhancing GABAergic activities can alleviate salicylate induced tinnitus. Published by Elsevier B.V.

  10. Specialized Information Processing Deficits and Distinct Metabolomic Profiles Following TM-Domain Disruption of Nrg1.

    Science.gov (United States)

    O'Tuathaigh, Colm M P; Mathur, Naina; O'Callaghan, Matthew J; MacIntyre, Lynsey; Harvey, Richard; Lai, Donna; Waddington, John L; Pickard, Benjamin S; Watson, David G; Moran, Paula M

    2017-09-01

    Although there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signaling in schizophrenia. The present study focused on hitherto uncharacterized information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across 2 different sites and protocols, Nrg1 mutants demonstrated deficits in prepulse inhibition, a measure of sensorimotor gating, that is, disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in a "what-where-when" object recognition memory task, Nrg1 mutants displayed sex-specific (males only) disruption of "what-when" performance, indicative of impaired temporal aspects of episodic memory. Differential metabolomic profiling revealed that these behavioral phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioral changes in adulthood. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

  11. Disruption of spinal cord white matter and sciatic nerve geometry inhibits axonal growth in vitro in the absence of glial scarring

    Directory of Open Access Journals (Sweden)

    Crutcher Keith A

    2001-05-01

    Full Text Available Abstract Background Axons within the mature mammalian central nervous system fail to regenerate following injury, usually resulting in long-lasting motor and sensory deficits. Studies involving transplantation of adult neurons into white matter implicate glial scar-associated factors in regeneration failure. However, these studies cannot distinguish between the effects of these factors and disruption of the spatial organization of cells and molecular factors (disrupted geometry. Since white matter can support or inhibit neurite growth depending on the geometry of the fiber tract, the present study sought to determine whether disrupted geometry is sufficient to inhibit neurite growth. Results Embryonic chick sympathetic neurons were cultured on unfixed longitudinal cryostat sections of mature rat spinal cord or sciatic nerve that had been crushed with forceps ex vivo then immediately frozen to prevent glial scarring. Neurite growth on uncrushed portions of spinal cord white matter or sciatic nerve was extensive and highly parallel with the longitudinal axis of the fiber tract but did not extend onto crushed portions. Moreover, neurite growth from neurons attached directly to crushed white matter or nerve tissue was shorter and less parallel compared with neurite growth on uncrushed tissue. In contrast, neurite growth appeared to be unaffected by crushed spinal cord gray matter. Conclusions These observations suggest that glial scar-associated factors are not necessary to block axonal growth at sites of injury. Disruption of fiber tract geometry, perhaps involving myelin-associated neurite-growth inhibitors, may be sufficient to pose a barrier to regenerating axons in spinal cord white matter and peripheral nerves.

  12. A single high dose of escitalopram disrupts sensory gating and habituation, but not sensorimotor gating in healthy volunteers

    DEFF Research Database (Denmark)

    Oranje, Bob; Wienberg, Malene; Glenthøj, Birte Yding

    2011-01-01

    Early mechanisms to limit the input of sensory information to higher brain areas are important for a healthy individual. In previous studies, we found that a low dose of 10mg escitalopram (SSRI) disrupts habituation, without affecting sensory and sensorimotor gating in healthy volunteers. In the ......Early mechanisms to limit the input of sensory information to higher brain areas are important for a healthy individual. In previous studies, we found that a low dose of 10mg escitalopram (SSRI) disrupts habituation, without affecting sensory and sensorimotor gating in healthy volunteers....... In the current study a higher dose of 15mg was used. The hypothesis was that this higher dose of escitalopram would not only disrupt habituation, but also sensory and sensorimotor gating. Twenty healthy male volunteers received either placebo or 15mg escitalopram, after which they were tested in a P50...... suppression, and a habituation and prepulse inhibition (PPI) of the startle reflex paradigm. Escitalopram significantly decreased P50 suppression and habituation, but had no effect on PPI. The results indicate that habituation and sensory gating are disrupted by increased serotonergic activity, while...

  13. Tolerance of laser-driven microshell targets to fluorescence and prepulse energy

    International Nuclear Information System (INIS)

    Leonard, T.; Moncur, N.K.; Sullivan, D.

    1976-01-01

    Glass-shell targets currently being used for laser-fusion experiments are susceptible to damage by preenergy from the laser. This energy can result from amplified spontaneous emission (ASE) throughout the laser chain during the period of high-population inversion or it can take the form of a short prepulse nanoseconds before the main laser pulse. We point out the energy levels which a typical target can tolerate in the form of ASE and prepulses. These energies are low enough that special precautions must be taken to prevent significant perturbations of the target or its environment before the main laser pulse

  14. Glycogen synthase kinase-3 inhibition disrupts nuclear factor-kappaB activity in pancreatic cancer, but fails to sensitize to gemcitabine chemotherapy

    Directory of Open Access Journals (Sweden)

    Mamaghani Shadi

    2009-04-01

    Full Text Available Abstract Background Aberrant activation NF-kappaB has been proposed as a mechanism of drug resistance in pancreatic cancer. Recently, inhibition of glycogen synthase kinase-3 has been shown to exert anti-tumor effects on pancreatic cancer cells by suppressing NF-kappaB. Consequently, we investigated whether inhibition of GSK-3 sensitizes pancreatic cancer cells to the chemotherapeutic agent gemcitabine. Methods GSK-3 inhibition was achieved using the pharmacological agent AR-A014418 or siRNA against GSK-3 alpha and beta isoforms. Cytotoxicity was measured using a Sulphorhodamine B assay and clonogenic survival following exposure of six different pancreatic cancer cell lines to a range of doses of either gemcitabine, AR-A014418 or both for 24, 48 and 72 h. We measured protein expression levels by immunoblotting. Basal and TNF-alpha induced activity of NF-kappaB was assessed using a luciferase reporter assay in the presence or absence of GSK-3 inhibition. Results GSK-3 inhibition reduced both basal and TNF-alpha induced NF-kappaB luciferase activity. Knockdown of GSK-3 beta reduced nuclear factor kappa B luciferase activity to a greater extent than GSK-3 alpha, and the greatest effect was seen with dual knockdown of both GSK-3 isoforms. GSK-3 inhibition also resulted in reduction of the NF-kappaB target proteins XIAP, Bcl-XL, and cyclin D1, associated with growth inhibition and decreased clonogenic survival. In all cell lines, treatment with either AR-A014418, or gemcitabine led to growth inhibition in a dose- and time-dependent manner. However, with the exception of PANC-1 where drug synergy occurred with some dose schedules, the inhibitory effect of combined drug treatment was additive, sub-additive, or even antagonistic. Conclusion GSK-3 inhibition has anticancer effects against pancreatic cancer cells with a range of genetic backgrounds associated with disruption of NF-kappaB, but does not significantly sensitize these cells to the standard

  15. Glycogen synthase kinase-3 inhibition disrupts nuclear factor-kappaB activity in pancreatic cancer, but fails to sensitize to gemcitabine chemotherapy

    International Nuclear Information System (INIS)

    Mamaghani, Shadi; Patel, Satish; Hedley, David W

    2009-01-01

    Aberrant activation NF-kappaB has been proposed as a mechanism of drug resistance in pancreatic cancer. Recently, inhibition of glycogen synthase kinase-3 has been shown to exert anti-tumor effects on pancreatic cancer cells by suppressing NF-kappaB. Consequently, we investigated whether inhibition of GSK-3 sensitizes pancreatic cancer cells to the chemotherapeutic agent gemcitabine. GSK-3 inhibition was achieved using the pharmacological agent AR-A014418 or siRNA against GSK-3 alpha and beta isoforms. Cytotoxicity was measured using a Sulphorhodamine B assay and clonogenic survival following exposure of six different pancreatic cancer cell lines to a range of doses of either gemcitabine, AR-A014418 or both for 24, 48 and 72 h. We measured protein expression levels by immunoblotting. Basal and TNF-alpha induced activity of NF-kappaB was assessed using a luciferase reporter assay in the presence or absence of GSK-3 inhibition. GSK-3 inhibition reduced both basal and TNF-alpha induced NF-kappaB luciferase activity. Knockdown of GSK-3 beta reduced nuclear factor kappa B luciferase activity to a greater extent than GSK-3 alpha, and the greatest effect was seen with dual knockdown of both GSK-3 isoforms. GSK-3 inhibition also resulted in reduction of the NF-kappaB target proteins XIAP, Bcl-X L , and cyclin D1, associated with growth inhibition and decreased clonogenic survival. In all cell lines, treatment with either AR-A014418, or gemcitabine led to growth inhibition in a dose- and time-dependent manner. However, with the exception of PANC-1 where drug synergy occurred with some dose schedules, the inhibitory effect of combined drug treatment was additive, sub-additive, or even antagonistic. GSK-3 inhibition has anticancer effects against pancreatic cancer cells with a range of genetic backgrounds associated with disruption of NF-kappaB, but does not significantly sensitize these cells to the standard chemotherapy agent gemcitabine. This lack of synergy might be

  16. Growth of chronic myeloid leukemia cells is inhibited by infection with Ad-SH2-HA adenovirus that disrupts Grb2-Bcr-Abl complexes.

    Science.gov (United States)

    Peng, Zhi; Luo, Hong-Wei; Yuan, Ying; Shi, Jing; Huang, Shi-Feng; Li, Chun-Li; Cao, Wei-Xi; Huang, Zong-Gan; Feng, Wen-Li

    2011-05-01

    The persistence of Bcr-Abl-positive cells in patients on imatinib therapy indicates that inhibition of the Bcr-Abl kinase activity alone might not be sufficient to eradicate the leukemia cells. Many downstream effectors of Bcr-Abl have been described, including activation of both the Grb2-SoS-Ras-MAPK and Grb2-Gab2-PI3K-Akt pathways. The Bcr-Abl-Grb2 interaction, which is mediated by the direct interaction of the Grb2 SH2 domain with the phospho-Bcr-Abl Y177, is required for activation of these signaling pathways. Therefore, disrupting their interaction represents a potential therapeutic strategy for inhibiting the oncogenic downstream signals of Bcr-Abl. Adenovirus Ad-SH2-HA expressing the Grb2 SH2 domain was constructed and applied in this study. As expected, Ad-SH2-HA efficiently infected CML cells and functioned by binding to the phospho-Bcr-Abl Y177 site, competitively disrupting the Grb2 SH2-phospho-Bcr-Abl Y177 complex. They induced potent anti-proliferation and apoptosis-inducing effects in CML cell lines. Moreover, the Ras, MAPK and Akt activities were significantly reduced in the Ad-SH2-HA treated cells. These were not observed with the point-mutated control adenovirus Ad-Sm-HA with abolished phospho-Bcr-Abl Y177 binding sites. These data indicate that, in addition to the direct targeting of Bcr-Abl, selective inhibition of its downstream signaling pathways may be a therapeutic option for CML, and the Ad-SH2-HA-mediated killing strategy could be explored as a promising anti-leukemia agent in CML.

  17. Use of pre-pulse in laser spot welding of materials with high optical reflection

    Science.gov (United States)

    Mys, Ihor; Geiger, Manfred

    2003-11-01

    Laser micro welding has become a standard manufacturing technique, particularly in industry sectors, such as automotive and aerospace electronics or medical devices, where the requirements for strength, miniaturization and temperature resistance are constantly rising. So far the use of laser micro welding is limited due to the fluctuation of the quality of the welded joints, because the welding results for material with high optical reflection and thermal conductivity, such as copper and copper alloys, depend very strongly on the condition of the material surface. This paper presents investigations on the use of a laser pre-pulse in spot welding of electronic materials with Nd:YAG laser. In order to achieve reproducible joining results two strategies are followed-up. The first one utilizes a reflection-based process control for measuring the reflection during the short pre-pulse. The intensity of the reflected light is used to calculate an appropriated welding pulse power, which corresponds to the measured relative absorption. Adjustment of laser parameters according to the condition of the surface is done in real time before laser main pulse. A second possibility for the stabilization of copper welding is the employment of a short and powerful laser pre-pulse before laser main pulse. This pre-pulse affects the workpiece surface and creates more reproducible absorption conditions for the main pulse, independent from the initial situation on material surface.

  18. Disruptions of working memory and inhibition mediate the association between exposure to institutionalization and symptoms of attention deficit hyperactivity disorder.

    Science.gov (United States)

    Tibu, F; Sheridan, M A; McLaughlin, K A; Nelson, C A; Fox, N A; Zeanah, C H

    2016-02-01

    Young children raised in institutions are exposed to extreme psychosocial deprivation that is associated with elevated risk for psychopathology and other adverse developmental outcomes. The prevalence of attention deficit hyperactivity disorder (ADHD) is particularly high in previously institutionalized children, yet the mechanisms underlying this association are poorly understood. We investigated whether deficits in executive functioning (EF) explain the link between institutionalization and ADHD. A sample of 136 children (aged 6-30 months) was recruited from institutions in Bucharest, Romania, and 72 never institutionalized community children matched for age and gender were recruited through general practitioners' offices. At 8 years of age, children's performance on a number of EF components (working memory, response inhibition and planning) was evaluated. Teachers completed the Health and Behavior Questionnaire, which assesses two core features of ADHD, inattention and impulsivity. Children with history of institutionalization had higher inattention and impulsivity than community controls, and exhibited worse performance on working memory, response inhibition and planning tasks. Lower performances on working memory and response inhibition, but not planning, partially mediated the association between early institutionalization and inattention and impulsivity symptom scales at age 8 years. Institutionalization was associated with decreased EF performance and increased ADHD symptoms. Deficits in working memory and response inhibition were specific mechanisms leading to ADHD in previously institutionalized children. These findings suggest that interventions that foster the development of EF might reduce risk for psychiatric problems in children exposed to early deprivation.

  19. Aspirin disrupts the mTOR-Raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition.

    Science.gov (United States)

    Sun, Danni; Liu, Hongchun; Dai, Xiaoyang; Zheng, Xingling; Yan, Juan; Wei, Rongrui; Fu, Xuhong; Huang, Min; Shen, Aijun; Huang, Xun; Ding, Jian; Geng, Meiyu

    2017-10-10

    Aspirin is associated with a reduced risk of cancer and delayed progression of malignant disease. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mTOR signaling is believed to partially contribute to these anticancer effects, although the mechanism is unclear. In this study, we revealed the mechanism underlying the effects of aspirin on AMPK-mTOR signaling, and described a mechanism-based rationale for the use of aspirin in cancer therapy. We found that aspirin inhibited mTORC1 signaling through AMPK-dependent and -independent manners. Aspirin inhibited the AMPK-TSC pathway, thus resulting in the suppression of mTORC1 activity. In parallel, it directly disrupted the mTOR-raptor interaction. Additionally, the combination of aspirin and sorafenib showed synergetic effects via inhibiting mTORC1 signaling and the PI3K/AKT, MAPK/ERK pathways. Aspirin and sorafenib showed synergetic anticancer efficacy in the SMMC-7721 model. Our study provides mechanistic insights and a mechanism-based rationale for the roles of aspirin in cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Inhibition of PTP1B disrupts cell-cell adhesion and induces anoikis in breast epithelial cells.

    Science.gov (United States)

    Hilmarsdottir, Bylgja; Briem, Eirikur; Halldorsson, Skarphedinn; Kricker, Jennifer; Ingthorsson, Sævar; Gustafsdottir, Sigrun; Mælandsmo, Gunhild M; Magnusson, Magnus K; Gudjonsson, Thorarinn

    2017-05-11

    Protein tyrosine phosphatase 1B (PTP1B) is a well-known inhibitor of insulin signaling pathways and inhibitors against PTP1B are being developed as promising drug candidates for treatment of obesity. PTP1B has also been linked to breast cancer both as a tumor suppressor and as an oncogene. Furthermore, PTP1B has been shown to be a regulator of cell adhesion and migration in normal and cancer cells. In this study, we analyzed the PTP1B expression in normal breast tissue, primary breast cells and the breast epithelial cell line D492. In normal breast tissue and primary breast cells, PTP1B is widely expressed in both epithelial and stromal cells, with highest expression in myoepithelial cells and fibroblasts. PTP1B is widely expressed in branching structures generated by D492 when cultured in 3D reconstituted basement membrane (3D rBM). Inhibition of PTP1B in D492 and another mammary epithelial cell line HMLE resulted in reduced cell proliferation and induction of anoikis. These changes were seen when cells were cultured both in monolayer and in 3D rBM. PTP1B inhibition affected cell attachment, expression of cell adhesion proteins and actin polymerization. Moreover, epithelial to mesenchymal transition (EMT) sensitized cells to PTP1B inhibition. A mesenchymal sublines of D492 and HMLE (D492M and HMLEmes) were more sensitive to PTP1B inhibition than D492 and HMLE. Reversion of D492M to an epithelial state using miR-200c-141 restored resistance to detachment induced by PTP1B inhibition. In conclusion, we have shown that PTP1B is widely expressed in the human breast gland with highest expression in myoepithelial cells and fibroblasts. Inhibition of PTP1B in D492 and HMLE affects cell-cell adhesion and induces anoikis-like effects. Finally, cells with an EMT phenotype are more sensitive to PTP1B inhibitors making PTP1B a potential candidate for further studies as a target for drug development in cancer involving the EMT phenotype.

  1. Inhibition of PTP1B disrupts cell–cell adhesion and induces anoikis in breast epithelial cells

    Science.gov (United States)

    Hilmarsdottir, Bylgja; Briem, Eirikur; Halldorsson, Skarphedinn; Kricker, Jennifer; Ingthorsson, Sævar; Gustafsdottir, Sigrun; Mælandsmo, Gunhild M; Magnusson, Magnus K; Gudjonsson, Thorarinn

    2017-01-01

    Protein tyrosine phosphatase 1B (PTP1B) is a well-known inhibitor of insulin signaling pathways and inhibitors against PTP1B are being developed as promising drug candidates for treatment of obesity. PTP1B has also been linked to breast cancer both as a tumor suppressor and as an oncogene. Furthermore, PTP1B has been shown to be a regulator of cell adhesion and migration in normal and cancer cells. In this study, we analyzed the PTP1B expression in normal breast tissue, primary breast cells and the breast epithelial cell line D492. In normal breast tissue and primary breast cells, PTP1B is widely expressed in both epithelial and stromal cells, with highest expression in myoepithelial cells and fibroblasts. PTP1B is widely expressed in branching structures generated by D492 when cultured in 3D reconstituted basement membrane (3D rBM). Inhibition of PTP1B in D492 and another mammary epithelial cell line HMLE resulted in reduced cell proliferation and induction of anoikis. These changes were seen when cells were cultured both in monolayer and in 3D rBM. PTP1B inhibition affected cell attachment, expression of cell adhesion proteins and actin polymerization. Moreover, epithelial to mesenchymal transition (EMT) sensitized cells to PTP1B inhibition. A mesenchymal sublines of D492 and HMLE (D492M and HMLEmes) were more sensitive to PTP1B inhibition than D492 and HMLE. Reversion of D492M to an epithelial state using miR-200c-141 restored resistance to detachment induced by PTP1B inhibition. In conclusion, we have shown that PTP1B is widely expressed in the human breast gland with highest expression in myoepithelial cells and fibroblasts. Inhibition of PTP1B in D492 and HMLE affects cell–cell adhesion and induces anoikis-like effects. Finally, cells with an EMT phenotype are more sensitive to PTP1B inhibitors making PTP1B a potential candidate for further studies as a target for drug development in cancer involving the EMT phenotype. PMID:28492548

  2. The antituberculosis antibiotic capreomycin inhibits protein synthesis by disrupting interaction between ribosomal proteins L12 and L10.

    Science.gov (United States)

    Lin, Yuan; Li, Yan; Zhu, Ningyu; Han, Yanxing; Jiang, Wei; Wang, Yanchang; Si, Shuyi; Jiang, Jiandong

    2014-01-01

    Capreomycin is a second-line drug for multiple-drug-resistant tuberculosis (TB). However, with increased use in clinics, the therapeutic efficiency of capreomycin is decreasing. To better understand TB resistance to capreomycin, we have done research to identify the molecular target of capreomycin. Mycobacterium tuberculosis ribosomal proteins L12 and L10 interact with each other and constitute the stalk of the 50S ribosomal subunit, which recruits initiation and elongation factors during translation. Hence, the L12-L10 interaction is considered to be essential for ribosomal function and protein synthesis. Here we provide evidence showing that capreomycin inhibits the L12-L10 interaction by using an established L12-L10 interaction assay. Overexpression of L12 and/or L10 in M. smegmatis, a species close to M. tuberculosis, increases the MIC of capreomycin. Moreover, both elongation factor G-dependent GTPase activity and ribosome-mediated protein synthesis are inhibited by capreomycin. When protein synthesis was blocked with thiostrepton, however, the bactericidal activity of capreomycin was restrained. All of these results suggest that capreomycin seems to inhibit TB by interrupting the L12-L10 interaction. This finding might provide novel clues for anti-TB drug discovery.

  3. Disruption of HPV16-E7 by CRISPR/Cas System Induces Apoptosis and Growth Inhibition in HPV16 Positive Human Cervical Cancer Cells

    Directory of Open Access Journals (Sweden)

    Zheng Hu

    2014-01-01

    Full Text Available High-risk human papillomavirus (HR-HPV has been recognized as a major causative agent for cervical cancer. Upon HPV infection, early genes E6 and E7 play important roles in maintaining malignant phenotype of cervical cancer cells. By using clustered regularly interspaced short palindromic repeats- (CRISPR- associated protein system (CRISPR/Cas system, a widely used genome editing tool in many organisms, to target HPV16-E7 DNA in HPV positive cell lines, we showed for the first time that the HPV16-E7 single-guide RNA (sgRNA guided CRISPR/Cas system could disrupt HPV16-E7 DNA at specific sites, inducing apoptosis and growth inhibition in HPV positive SiHa and Caski cells, but not in HPV negative C33A and HEK293 cells. Moreover, disruption of E7 DNA directly leads to downregulation of E7 protein and upregulation of tumor suppressor protein pRb. Therefore, our results suggest that HPV16-E7 gRNA guided CRISPR/Cas system might be used as a therapeutic strategy for the treatment of cervical cancer.

  4. Enhanced Therapeutic Potential of Nano-Curcumin Against Subarachnoid Hemorrhage-Induced Blood-Brain Barrier Disruption Through Inhibition of Inflammatory Response and Oxidative Stress.

    Science.gov (United States)

    Zhang, Zong-Yong; Jiang, Ming; Fang, Jie; Yang, Ming-Feng; Zhang, Shuai; Yin, Yan-Xin; Li, Da-Wei; Mao, Lei-Lei; Fu, Xiao-Yan; Hou, Ya-Jun; Fu, Xiao-Ting; Fan, Cun-Dong; Sun, Bao-Liang

    2017-01-01

    Curcumin and nano-curcumin both exhibit neuroprotective effects in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). However, the mechanism that whether curcumin and its nanoparticles affect the blood-brain barrier (BBB) following SAH remains unclear. This study investigated the effect of curcumin and the poly(lactide-co-glycolide) (PLGA)-encapsulated curcumin nanoparticles (Cur-NPs) on BBB disruption and evaluated the possible mechanism underlying BBB dysfunction in EBI using the endovascular perforation rat SAH model. The results indicated that Cur-NPs showed enhanced therapeutic effects than that of curcumin in improving neurological function, reducing brain water content, and Evans blue dye extravasation after SAH. Mechanically, Cur-NPs attenuated BBB dysfunction after SAH by preventing the disruption of tight junction protein (ZO-1, occludin, and claudin-5). Cur-NPs also up-regulated glutamate transporter-1 and attenuated glutamate concentration of cerebrospinal fluid following SAH. Moreover, inhibition of inflammatory response and microglia activation both contributed to Cur-NPs' protective effects. Additionally, Cur-NPs markedly suppressed SAH-mediated oxidative stress and eventually reversed SAH-induced cell apoptosis in rats. Our findings revealed that the strategy of using Cur-NPs could be a promising way in improving neurological function in EBI after experimental rat SAH.

  5. Reactivation of cocaine reward memory engages the Akt/GSK3/mTOR signaling pathway and can be disrupted by GSK3 inhibition.

    Science.gov (United States)

    Shi, Xiangdang; Miller, Jonathan S; Harper, Lauren J; Poole, Rachel L; Gould, Thomas J; Unterwald, Ellen M

    2014-08-01

    Memories return to a labile state following their retrieval and must undergo a process of reconsolidation to be maintained. Thus, disruption of cocaine reward memories by interference with reconsolidation may be therapeutically beneficial in the treatment of cocaine addiction. The objectives were to elucidate the signaling pathway involved in reconsolidation of cocaine reward memory and to test whether targeting this pathway could disrupt cocaine-associated contextual memory. Using a mouse model of conditioned place preference, regulation of the activity of glycogen synthase kinase-3 (GSK3), mammalian target of Rapamycin complex 1 (mTORC1), P70S6K, β-catenin, and the upstream signaling molecule Akt, was studied in cortico-limbic-striatal circuitry after re-exposure to an environment previously paired with cocaine. Levels of phosporylated Akt-Thr308, GSK3α-Ser21, GSK3β-Ser9, mTORC1, and P70S6K were reduced in the nucleus accumbens and hippocampus 10 min after the reactivation of cocaine cue memories. Levels of pAkt and pGSK3 were also reduced in the prefrontal cortex. Since reduced phosphorylation of GSK3 indicates heightened enzyme activity, the effect of a selective GSK3 inhibitor, SB216763, on reconsolidation was tested. Administration of SB216763 immediately after exposure to an environment previously paired with cocaine abrogated a previously established place preference, suggesting that GSK3 inhibition interfered with reconsolidation of cocaine-associated reward memories. These findings suggest that the Akt/GSK3/mTORC1 signaling pathway in the nucleus accumbens, hippocampus, and/or prefrontal cortex is critically involved in the reconsolidation of cocaine contextual reward memory. Inhibition of GSK3 activity during memory retrieval can erase an established cocaine place preference.

  6. Disruption of Specific RNA-RNA Interactions in a Double-Stranded RNA Virus Inhibits Genome Packaging and Virus Infectivity.

    Science.gov (United States)

    Fajardo, Teodoro; Sung, Po-Yu; Roy, Polly

    2015-12-01

    Bluetongue virus (BTV) causes hemorrhagic disease in economically important livestock. The BTV genome is organized into ten discrete double-stranded RNA molecules (S1-S10) which have been suggested to follow a sequential packaging pathway from smallest to largest segment during virus capsid assembly. To substantiate and extend these studies, we have investigated the RNA sorting and packaging mechanisms with a new experimental approach using inhibitory oligonucleotides. Putative packaging signals present in the 3'untranslated regions of BTV segments were targeted by a number of nuclease resistant oligoribonucleotides (ORNs) and their effects on virus replication in cell culture were assessed. ORNs complementary to the 3' UTR of BTV RNAs significantly inhibited virus replication without affecting protein synthesis. Same ORNs were found to inhibit complex formation when added to a novel RNA-RNA interaction assay which measured the formation of supramolecular complexes between and among different RNA segments. ORNs targeting the 3'UTR of BTV segment 10, the smallest RNA segment, were shown to be the most potent and deletions or substitution mutations of the targeted sequences diminished the RNA complexes and abolished the recovery of viable viruses using reverse genetics. Cell-free capsid assembly/RNA packaging assay also confirmed that the inhibitory ORNs could interfere with RNA packaging and further substitution mutations within the putative RNA packaging sequence have identified the recognition sequence concerned. Exchange of 3'UTR between segments have further demonstrated that RNA recognition was segment specific, most likely acting as part of the secondary structure of the entire genomic segment. Our data confirm that genome packaging in this segmented dsRNA virus occurs via the formation of supramolecular complexes formed by the interaction of specific sequences located in the 3' UTRs. Additionally, the inhibition of packaging in-trans with inhibitory ORNs

  7. Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs.

    Science.gov (United States)

    Zhang, Hai-Tao; Zhang, Ping; Gao, Yi; Li, Chen-Long; Wang, Hong-Jun; Chen, Ling-Chao; Feng, Yan; Li, Rui-Yan; Li, Yong-Li; Jiang, Chuan-Lu

    2017-01-01

    Vascular endothelial growth factor (VEGF) inhibition has been demonstrated to be an effective strategy in preserving the integrity of the blood-brain barrier (BBB) in patients with acute ischemic stroke. Loss of the BBB is the key event associated with morbidity and mortality in these patients. However, the underlying mechanisms remain poorly understood. In the present study, the effects of VEGF inhibition and the possible mechanism that underlies acute cerebral ischemia in rats was investigated. Following the induction of transient middle cerebral artery occlusion for a 90‑min period, either an anti‑VEGF neutralizing antibody (RB‑222; 5 or 10 µg), or IgG (control), was administered by intracerebroventricular injection at 1 h following reperfusion. Functional outcomes, BBB leakage, brain edema, microvessel numbers and the relative protein levels of VEGF, matrix metalloproteinase (MMP)-2, MMP-9, occludin and collagen-IV were then determined using neurological assessments, Evans Blue staining, brain water content, CD31 staining and western blotting. Treatment with RB‑222 at a dose of 5 and 10 µg significantly improved neurological functional outcomes and diminished infarct size, BBB leakage and brain edema compared with the MCAO and IgG groups at 24 h following reperfusion; 10 µg RB‑222 was more effective than a 5 µg dose of the antibody. In addition, RB‑222 reduced the number of immature microvessels, which subsequently attenuated BBB permeability. RB‑222 significantly repressed VEGF expression as well as decreased MMP‑2 and MMP‑9 expression. However, it enhanced occludin and collagen‑IV levels in the ischemic rat brain compared with the MCAO and IgG groups. Taken together, the results indicate that early inhibition of VEGF may have significant potential against cerebral ischemia, partly by regulating the expression of MMPs.

  8. Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias

    Science.gov (United States)

    Cubeddu, Luigi X.

    2016-01-01

    Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interference with IKr is the most common cause of acquired LQTS/TdP. Multiple drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics, antibiotics, antivirals, azole-antifungals, antimalarials, anticancer, antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has been recently added to this list. In addition to direct channel inhibition, some drugs interfere with the traffic of channels from the endoplasmic reticulum to the cell membrane, decreasing mature channel membrane density; e.g., pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil, tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel inhibition and impaired channel trafficking. Although many drugs prolong the QT interval, TdP is a rare event. The following conditions increase the risk of drug-induced TdP: a) Disease states/electrolyte levels (heart failure, structural cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables (presence of congenital LQTS, subclinical ion-channel mutations, history of or having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining two or more QT prolonging drugs, drugs that prolong the QT and increase QT dispersion, and drugs with multiple actions on ion channels). Because most of these conditions are preventable, careful evaluation of risk factors and increased knowledge of drug use associated with repolarization abnormalities are strongly recommended. PMID:26926294

  9. Graphene oxide quantum dots disrupt autophagic flux by inhibiting lysosome activity in GC-2 and TM4 cell lines

    International Nuclear Information System (INIS)

    Ji, Xiaoli; Xu, Bo; Yao, Mengmeng; Mao, Zhilei; Zhang, Yuqing; Xu, Guofeng; Tang, Qiusha; Wang, Xinru; Xia, Yankai

    2016-01-01

    Graphene oxide quantum dots (GOQDs) have broad application prospects in many areas including bioimaging, drug delivery, DNA cleavage system, sensors and photocatalyst. Recently, increasing concerns have been raised about their biocompatibility, but studies about the effects of GOQDs on male reproductive system are still lacking. In this work, we explored the effects and molecular mechanisms of GOQDs on GC-2 and TM4 cells. We found autophagosome accumulation in GC-2 and TM4 cells after GOQDs treatment. Both LC3-II/LC3-I ratio and p62 levels increased, and the chloroquine-induced accumulation of LC3-II didn’t enhance in the presence of GOQDs, which indicated that GOQDs blocked autophagic flux. Further studies found that the fusion between autophagosome and lysosome was not inhibited by GOQDs, but the proteolytic capacity of lysosome was weakened and both the expression and activity of cathepsin B reduced. Taken together, these results suggested that GOQDs blocked autophagic flux by decreasing the amount and enzymatic activity of cathepsin B and inhibiting lysosome proteolytic capacity in GC-2 and TM4 cells, which might have a potential hazard to male reproduction.

  10. Disruption of contact inhibition in rat liver epithelial cells by various types of AhR ligands

    Energy Technology Data Exchange (ETDEWEB)

    Vondracek, J.; Chramostova, K.; Kozubik, A. [Institute of Biophysics, Brno (Czech Republic); Krcmar, P.; Machala, M. [Veterinary Research Institute, Brno (Czech Republic)

    2004-09-15

    The maintenance of a balance between cell gain and cell loss is essential for proper liver function. The exact role of aryl hydrocarbon receptor (AhR) in regulating cell proliferation and apoptosis of liver cells remains unclear, since ligand-dependent activation of AhR has been shown to induce cell cycle arrest, proliferation, differentiation or apoptosis, depending on the cellular model used. AhR can directly interact with retinoblastoma protein in hepatic cells, forming protein complexes that can efficiently block cell cycle progression by inducing G1 arrest, or to induce the expression of inhibitors of cyclin-dependent kinases, such as p271. On the other hand, it has been suggested that AhR could play a stimulatory role in cell proliferation, either directly or by mediating a release from contact inhibition. It is now generally accepted that progenitor cells exist in the liver, are activated in various liver diseases and can form a potential target cell population for both tumor initiating and tumor promoting chemicals4. 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) has been found to release rat liver epithelial cells from contact inhibition by upregulating cyclin A expression and cyclin A/cdk2 activity. Our previous studies have shown that a number of AhR ligands5,6 can stimulate proliferation of confluent of rat liver epithelial ''stem-like'' WB-F344 cells. Such mechanism could play a role in liver tumor promotion. In the present study, we used flavonoid compounds that have been reported to act either as pure agonists, such as beta-naphthoflavone (BNF), or as partial/complete antagonists of AhR - alpha-naphthoflavone (ANF) and 3'-methoxy-4'-nitroflavone (3'M4'NF), in order to investigate effects of AhR agonists/antagonists on confluent rat liver epithelial cells. The present study aimed to investigate the effects of model flavonoids on the release of rat liver epithelial cells from contact inhibition, and on inducibility of

  11. Hohlraum glint and laser pre-pulse detector for NIF experiments using velocity interferometer system for any reflector.

    Science.gov (United States)

    Moody, J D; Clancy, T J; Frieders, G; Celliers, P M; Ralph, J; Turnbull, D P

    2014-11-01

    Laser pre-pulse and early-time laser reflection from the hohlraum wall onto the capsule (termed "glint") can cause capsule imprint and unwanted early-time shocks on indirect drive implosion experiments. In a minor modification to the existing velocity interferometer system for any reflector diagnostic on NIF a fast-response vacuum photodiode was added to detect this light. The measurements show evidence of laser pre-pulse and possible light reflection off the hohlraum wall and onto the capsule.

  12. Inhibition of projections from the basolateral amygdala to the entorhinal cortex disrupts the acquisition of contextual fear

    Directory of Open Access Journals (Sweden)

    Dennis R. Sparta

    2014-05-01

    Full Text Available The development of excessive fear and/or stress responses to environmental cues such as contexts associated with a traumatic event is a hallmark of post-traumatic stress disorder (PTSD. The basolateral amygdala (BLA has been implicated as a key structure mediating contextual fear conditioning. In addition, the hippocampus has an integral role in the encoding and processing of contexts associated with strong, salient stimuli such as fear. Given that both the BLA and hippocampus play an important role in the regulation of contextual fear conditioning, examining the functional connectivity between these two structures may elucidate a role for this pathway in the development of PTSD. Here, we used optogenetic strategies to demonstrate that the BLA sends a strong glutamatergic projection to the hippocampal formation through the entorhinal cortex (EC. Next, we photoinhibited glutamatergic fibers from the BLA terminating in the EC during the acquisition or expression of contextual fear conditioning. In mice that received optical inhibition of the BLA-to-EC pathway during the acquisition session, we observed a significant decrease in freezing behavior in a context re-exposure session. In contrast, we observed no differences in freezing behavior in mice that were only photoinhibited during the context re-exposure session. These data demonstrate an important role for the BLA-to-EC glutamatergic pathway in the acquisition of contextual fear conditioning.

  13. Plasma formation and target preheating by prepulse of PW laser light

    Science.gov (United States)

    Sentoku, Yasuhiko; Iwata, Natsumi; Koga, James; Dover, Nicholas; Nishiuchi, Mamiko

    2017-10-01

    An intense short pulse laser with intensity over 1021 W/cm2 has become available, i.e. J-KAREN-P at QST. Although the contrast of the short pulse is improved to be of the order of 10-11, there is an unavoidable prepulse, which has multiple spikes (ps) on top of an exponential profile with intensity greater than 1014 W/cm2 about 50 ps in front of the main pulse. The prepulse preheats the target and also produces tenuous plasmas in front of a target before the main pulse arrives. It is critical to understand such preheating of the target, where the nonlocal heat transport is essential at intensity >1014 W/cm2, since the target condition might totally change before the interaction with the main pulse. Using a hydro code, FLASH, and a collisional particle-in-cell code, PICLS, we study the preplasma formation and target preheating over tens of picoseconds timescale, and discuss the prepulse effects on the main pulse interaction. Work supported by the JSPS KAKENHI under Grant No. JP15K21767.

  14. Use of microsecond current prepulse for dramatic improvements of wire array Z-pinch implosion

    International Nuclear Information System (INIS)

    Calamy, H.; Lassalle, F.; Loyen, A.; Zucchini, F.; Chittenden, J. P.; Hamann, F.; Maury, P.; Georges, A.; Bedoch, J. P.; Morell, A.

    2008-01-01

    The Sphinx machine [F. Lassalle et al., 'Status on the SPHINX machine based on the 1microsecond LTD technology'] based on microsecond linear transformer driver (LTD) technology is used to implode an aluminium wire array with an outer diameter up to 140 mm and maximum current from 3.5 to 5 MA. 700 to 800 ns implosion Z-pinch experiments are performed on this driver essentially with aluminium. Best results obtained before the improvement described in this paper were 1-3 TW radial total power, 100-300 kJ total yield, and 20-30 kJ energy above 1 keV. An auxiliary generator was added to the Sphinx machine in order to allow a multi microsecond current to be injected through the wire array load before the start of the main current. Amplitude and duration of this current prepulse are adjustable, with maxima ∼10 kA and 50 μs. This prepulse dramatically changes the ablation phase leading to an improvement of the axial homogeneity of both the implosion and the final radiating column. Total power was multiplied by a factor of 6, total yield by a factor of 2.5 with a reproducible behavior. This paper presents experimental results, magnetohydrodynamic simulations, and analysis of the effect of such a long current prepulse

  15. Assessing the Comprehensive Soldier Fitness Program: Measuring Startle Response and Prepulse Inhibition

    Science.gov (United States)

    2011-04-01

    increase PPI, but dopamine agonists can have the opposite effect by reducing PPI. Fortunately, caffeine appears to have no significant effect on PPI...violent behavior, and sexual risk behavior. Landis, C., & Hunt, W.A. (1939). The Startle Pattern. New York: Farrar. An example of early research on

  16. Effects of postnatal anoxia on striatal dopamine metabolism and prepulse inhibition in rats

    DEFF Research Database (Denmark)

    Sandager-Nielsen, Karin; Andersen, Maibritt B; Sager, Thomas N

    2004-01-01

    (DOPAC) and homovanillic acid (HVA) concentrations. Furthermore, in the anoxic group only, striatal HVA concentrations were negatively correlated to prefrontal cortical N-acetylaspartate (NAA) levels. Similar findings of distorted prefrontal-subcortical interactions have recently been reported...

  17. Inhibition of human melanoma cell growth by dietary flavonoid fisetin is associated with disruption of Wnt/β-catenin signaling and decreased Mitf levels

    Science.gov (United States)

    Syed, Deeba N.; Afaq, Farrukh; Maddodi, Nityanand; Johnson, Jeremy J.; Sarfaraz, Sami; Ahmad, Adeel; Setaluri, Vijayasaradhi; Mukhtar, Hasan

    2011-01-01

    The prognosis of advanced melanoma remains poor in spite of treatment advances, emphasizing the importance of additional preventive measures. Flavonoids, natural components of our diet are being investigated for their chemopreventive/therapeutic properties. Microphthalmia-associated transcription factor (Mitf), downstream of Wnt/β-catenin pathway has become an important prognostic marker of melanoma. Here, we show that treatment of 451Lu melanoma cells with the dietary flavonoid fisetin resulted in decreased cell viability with G1-phase arrest and disruption of Wnt/β-catenin signaling. This was accompanied with a decrease in expression of Wnt protein and its co-receptors and a parallel increase in the expression of endogenous Wnt inhibitors. Fisetin-treated cells showed increased cytosolic levels of Axin and β-TrCP and decreased phosphorylation of GSK3-β assocaited with decreased β-catenin stabilization. Fisetin-mediated interference with the functional cooperation between β-catenin and LEF/TCF-2 resulted in downregulation of positively regulated TCF targets such as c-myc, Brn-2 and Mitf. Flowcytometric analysis of Mitf overexpressing cells showed that fisetin repressed Mitf-induced cell proliferation. Finally, administration of fisetin to 451Lu xenografted nude mice resulted in inhibition of tumor development and decreased Mitf expression. Our data suggest that fisetin can be developed as an effective agent against melanoma due to its potential inhibitory effect on β-catenin/Mitf signaling. PMID:21346776

  18. Primate-specific microRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting signal transducer and activator of transcription 3 signaling.

    Science.gov (United States)

    Zhang, Jin-fang; He, Ming-liang; Fu, Wei-ming; Wang, Hua; Chen, Lian-zhou; Zhu, Xiao; Chen, Ying; Xie, Dan; Lai, Paul; Chen, Gong; Lu, Gang; Lin, Marie C M; Kung, Hsiang-fu

    2011-12-01

    MiR-637 (microRNA-637) is a primate-specific miRNA belonging to the small noncoding RNA family, which represses gene regulation at the post-transcriptional expression level. Although it was discovered approximately 5 years ago, its biomedical significance and regulatory mechanism remain obscure. Our preliminary data showed that miR-637 was significantly suppressed in four HCC cell lines and, also, in most of the hepatocellular carcinoma (HCC) specimens, thereby suggesting that miR-637 would be a tumor suppressor in HCC. Simultaneously, the enforced overexpression of miR-637 dramatically inhibited cell growth and induced the apoptosis of HCC cells. The transcription factor, signal transducer and activator of transcription 3 (Stat3), is constitutively activated in multiple tumors, and aberrant Stat3 activation is linked to the promotion of growth and desensitization of apoptosis. Our study showed that Stat3 tyrosine 705 phosphorylation and several Stat3-regulated antiapoptotic genes were down-regulated in miR-637 mimics-transfected and Lv-miR637-infected HCC cells. In addition, miR-637 overexpression negatively regulated Stat3 phosphorylation by suppressing autocrine leukemia inhibitory factor (LIF) expression and exogenous LIF-triggered Stat3 activation and rescued cell growth in these cells. A nude mice model also demonstrated the above-described results, which were obtained from the cell model. Furthermore, we found that LIF was highly expressed in a large proportion of HCC specimens, and its expression was inversely associated with miR-637 expression. Our data indicate that miR-637 acted as a tumor suppressor in HCC, and the suppressive effect was mediated, at least in part, by the disruption of Stat3 activation. Copyright © 2011 American Association for the Study of Liver Diseases.

  19. pp32 (ANP32A expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs.

    Directory of Open Access Journals (Sweden)

    Timothy K Williams

    Full Text Available The expression of protein phosphatase 32 (PP32, ANP32A is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1, a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C, but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the mRNA encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK, causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR, while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy.

  20. Femtosecond laser-plasma interaction with prepulse-generated liquid metal microjets

    Energy Technology Data Exchange (ETDEWEB)

    Uryupina, D. S.; Ivanov, K. A.; Savel' ev, A. B.; Volkov, R. V. [Faculty of Physics and International Laser Center of M.V. Lomonosov Moscow State University, 119991 Moscow, Leninskie Gory (Russian Federation); Brantov, A. V.; Bychenkov, V. Yu. [P. N. Lebedev Physical Institute, Russian Academy of Sciences, 119991 Moscow (Russian Federation); Povarnitsyn, M. E. [Joint Institute for High Temperatures, Russian Academy of Sciences, 125412 Moscow (Russian Federation); Tikhonchuk, V. T. [CELIA, University of Bordeaux - CNRS - CEA, 33405 Talence (France)

    2012-01-15

    Ultrashort laser pulse interaction with a microstructured surface of a melted metal is a promising source of hard x-ray radiation. Microstructuring is achieved by a weak prepulse that produces narrow high-density microjets. As an x-ray source, the interaction of the main laser pulse with such jets is shown to be nearly two orders of magnitude more efficient than the interaction with ordinary metal targets. This paper presents the results of optical and x-ray studies of laser-plasma interaction physics under such conditions supported by numerical simulations of microjet formation and fast-electron generation.

  1. Femtosecond laser-plasma interaction with prepulse-generated liquid metal microjets

    International Nuclear Information System (INIS)

    Uryupina, D. S.; Ivanov, K. A.; Savel'ev, A. B.; Volkov, R. V.; Brantov, A. V.; Bychenkov, V. Yu.; Povarnitsyn, M. E.; Tikhonchuk, V. T.

    2012-01-01

    Ultrashort laser pulse interaction with a microstructured surface of a melted metal is a promising source of hard x-ray radiation. Microstructuring is achieved by a weak prepulse that produces narrow high-density microjets. As an x-ray source, the interaction of the main laser pulse with such jets is shown to be nearly two orders of magnitude more efficient than the interaction with ordinary metal targets. This paper presents the results of optical and x-ray studies of laser-plasma interaction physics under such conditions supported by numerical simulations of microjet formation and fast-electron generation.

  2. Investigating Disruption

    DEFF Research Database (Denmark)

    Lundgaard, Stine Schmieg; Rosenstand, Claus Andreas Foss

    This book shares knowledge collected from 2015 and onward within the Consortium for Digital Disruption anchored at Aalborg University (www.dd.aau.dk). Evidenced by this publication, the field of disruptive innovation research has gone through several stages of operationalizing the theory. In recent...... years, researchers are increasingly looking back towards the origins of the theory in attempts to cure it from its most obvious flaws. This is especially true for the use of the theory in making predictions about future disruptions. In order to continue to develop a valuable theory of disruption, we...... find it useful to first review what the theory of disruptive innovation initially was, how it has developed, and where we are now. A cross section of disruptive innovation literature has been reviewed in order to form a general foundation from which we might better understand the changing world...

  3. Disruption model

    International Nuclear Information System (INIS)

    Murray, J.G.; Bronner, G.

    1982-07-01

    Calculations of disruption time and energy dissipation have been obtained by simulating the plasma as an electrical conducting loop that varies in resistivity, current density, major radius. The calculations provide results which are in good agreement with experimental observations. It is believed that this approach allows engineering designs for disruptions to be completed in large tokamaks such as INTOR or FED

  4. Psilocybin-induced deficits in automatic and controlled inhibition are attenuated by ketanserin in healthy human volunteers.

    Science.gov (United States)

    Quednow, Boris B; Kometer, Michael; Geyer, Mark A; Vollenweider, Franz X

    2012-02-01

    The serotonin-2A receptor (5-HT(2A)R) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT(2A)R or 5-HT(1A)R agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT(2A/2C)R antagonist ketanserin. A total of 16 healthy participants received placebo, ketanserin (40 mg p.o.), psilocybin (260 μg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioral inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test. Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects. These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT(2A)R stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT(2A)R system.

  5. Psilocybin-Induced Deficits in Automatic and Controlled Inhibition are Attenuated by Ketanserin in Healthy Human Volunteers

    Science.gov (United States)

    Quednow, Boris B; Kometer, Michael; Geyer, Mark A; Vollenweider, Franz X

    2012-01-01

    The serotonin-2A receptor (5-HT2AR) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT2AR or 5-HT1AR agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT2A/2CR antagonist ketanserin. A total of 16 healthy participants received placebo, ketanserin (40 mg p.o.), psilocybin (260 μg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioral inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test. Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects. These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT2AR stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT2AR system. PMID:21956447

  6. Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by d-serine.

    Directory of Open Access Journals (Sweden)

    Hiroko Hagiwara

    Full Text Available D-Serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA receptor, is synthesized from L-serine by serine racemase (SRR. Given the role of D-serine in both neurodevelopment and the pathophysiology of schizophrenia, we examined whether neonatal disruption of D-serine synthesis by SRR inhibition could induce behavioral abnormalities relevant to schizophrenia, in later life.Neonatal mice (7-9 days were injected with vehicle or phenazine methosulfate (Met-Phen: 3 mg/kg/day, an SRR inhibitor. Behavioral evaluations, such as spontaneous locomotion, novel object recognition test (NORT, and prepulse inhibition (PPI were performed at juvenile (5-6 weeks old and adult (10-12 weeks old stages. In addition, we tested the effects of D-serine on PPI deficits in adult mice after neonatal Met-Phen exposure. Finally, we assessed whether D-serine could prevent the onset of schizophrenia-like behavior in these mice. Neonatal Met-Phen treatment reduced D-serine levels in the brain, 24 hours after the final dose. Additionally, this treatment caused behavioral abnormalities relevant to prodromal symptoms in juveniles and to schizophrenia in adults. A single dose of D-serine improved PPI deficits in adult mice. Interestingly, chronic administration of D-serine (900 mg/kg/day from P35 to P70 significantly prevented the onset of PPI deficits after neonatal Met-Phen exposure.This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life. Furthermore, early pharmacological intervention with D-serine may prevent the onset of psychosis in adult.

  7. The influence of plasma density decreasement by pre-pulse on the laser wakefield acceleration

    Directory of Open Access Journals (Sweden)

    Ke-Gong Dong

    2011-12-01

    Full Text Available In the laser wakefield acceleration, the generation of electron beam is very sensitive to the plasma density. Not only the laser-wakefield interaction, but also the electron trapping and acceleration would be effected by the plasma density. However, the plasma density could be changed in the experiment by different reasons, which will result in the mismatch of parameters arranged initially. Forward Raman scattering spectrum demonstrated that the interaction density was decreased obviously in the experiment, which was verified by the pre-pulse conditions and two-dimensional particle-in-cell simulations. It was demonstrated that the plasma density was very important on the self-evolutions and energy coupling of laser pulse and wakefield, and eventually the energy spectrum of electron beam.

  8. kW-class picosecond thin-disc prepulse laser Perla for efficient EUV generation

    Czech Academy of Sciences Publication Activity Database

    Endo, Akira; Smrž, Martin; Mužík, Jiří; Novák, Ondřej; Chyla, Michal; Mocek, Tomáš

    2017-01-01

    Roč. 16, č. 4 (2017), s. 1-6, č. článku 041011. ISSN 1932-5150 R&D Projects: GA MŠk LO1602; GA ČR GA16-12960S; GA MŠk LM2015086 EU Projects: European Commission(XE) 739573 - HiLASE CoE Grant - others:OP VVV - HiLASE-CoE(XE) CZ.02.1.01/0.0/0.0/15_006/0000674 Institutional support: RVO:68378271 Keywords : EUV source * laser produced plasma * FEL * prepulse * thin-disc laser Subject RIV: BH - Optics, Masers, Laser s OBOR OECD: Optics (including laser optics and quantum optics) Impact factor: 1.350, year: 2016

  9. Disrupted Disclosure

    DEFF Research Database (Denmark)

    Krause Hansen, Hans; Uldam, Julie

    appearances become challenged through disruptive disclosures in mediaenvironments characterized by multiple levels of visibility, with companies both observing andbeing observed by civil society groups that criticize them; (c) why and how the mobilization aroundtransparency and ensuing practices...

  10. Family Disruptions

    Science.gov (United States)

    ... Spread the Word Shop AAP Find a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care ... Life Listen Español Text Size Email Print Share Family Disruptions Page Content Article Body No matter how ...

  11. Inhibition of somatosensory-evoked cortical responses by a weak leading stimulus.

    Science.gov (United States)

    Nakagawa, Kei; Inui, Koji; Yuge, Louis; Kakigi, Ryusuke

    2014-11-01

    We previously demonstrated that auditory-evoked cortical responses were suppressed by a weak leading stimulus in a manner similar to the prepulse inhibition (PPI) of startle reflexes. The purpose of the present study was to investigate whether a similar phenomenon was present in the somatosensory system, and also whether this suppression reflected an inhibitory process. We recorded somatosensory-evoked magnetic fields following stimulation of the median nerve and evaluated the extent by which they were suppressed by inserting leading stimuli at an intensity of 2.5-, 1.5-, 1.1-, or 0.9-fold the sensory threshold (ST) in healthy participants (Experiment 1). The results obtained demonstrated that activity in the secondary somatosensory cortex in the hemisphere contralateral to the stimulated side (cSII) was significantly suppressed by a weak leading stimulus with the intensity larger than 1.1-fold ST. This result implied that the somatosensory system had an inhibitory process similar to that of PPI. We then presented two successive leading stimuli before the test stimulus, and compared the extent of suppression between the test stimulus-evoked responses and those obtained with the second prepulse alone and with two prepulses (first and second) (Experiment 2). When two prepulses were preceded, cSII responses to the second prepulse were suppressed by the first prepulse, whereas the ability of the second prepulse to suppress the test stimulus remained unchanged. These results suggested the presence of at least two individual pathways; response-generating and inhibitory pathways. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Digital Disruption

    DEFF Research Database (Denmark)

    Rosenstand, Claus Andreas Foss

    det digitale domæne ud over det niveau, der kendetegner den nuværende debat, så præsenteres der ny viden om digital disruption. Som noget nyt udlægges Clayton Christens teori om disruptiv innovation med et særligt fokus på små organisationers mulighed for eksponentiel vækst. Specielt udfoldes...... forholdet mellem disruption og den stadig accelererende digitale udvikling i konturerne til ny teoridannelse om digital disruption. Bogens undertitel ”faretruende og fascinerende forandringer” peger på, at der er behov for en nuanceret debat om digital disruption i modsætning til den tone, der er slået an i...... videre kalder et ”disruption-råd”. Faktisk er rådet skrevet ind i 2016 regeringsgrundlaget for VLK-regeringen. Disruption af organisationer er ikke et nyt fænomen; men hastigheden, hvormed det sker, er stadig accelererende. Årsagen er den globale mega-trend: Digitalisering. Og derfor er specielt digital...

  13. Monitoring-induced disruption in skilled typewriting.

    Science.gov (United States)

    Snyder, Kristy M; Logan, Gordon D

    2013-10-01

    It is often disruptive to attend to the details of one's expert performance. The current work presents four experiments that utilized a monitor to report protocol to evaluate the sufficiency of three accounts of monitoring-induced disruption. The inhibition hypothesis states that disruption results from costs associated with preparing to withhold inappropriate responses. The dual-task hypothesis states that disruption results from maintaining monitored information in working memory. The implicit-explicit hypothesis states that disruption results from explicitly monitoring details of performance that are normally implicit. The findings suggest that all three hypotheses are sufficient to produce disruption, but inhibition and dual-task costs are not necessary. Experiment 1 showed that monitoring to report was disruptive even when there was no requirement to inhibit. Experiment 2 showed that maintaining information in working memory caused some disruption but much less than monitoring to report. Experiment 4 showed that monitoring to inhibit was more disruptive than monitoring to report, suggesting that monitoring is more disruptive when it is combined with other task requirements, such as inhibition. PsycINFO Database Record (c) 2013 APA, all rights reserved.

  14. Politisk disruption

    DEFF Research Database (Denmark)

    Tække, Jesper

    2018-01-01

    Dette blogindlæg giver en kort analyse af hvordan de sociale medier ved at give en ny tid har åbnet for den disruption af de politiske processer som især Trump stå som et eksempel på.......Dette blogindlæg giver en kort analyse af hvordan de sociale medier ved at give en ny tid har åbnet for den disruption af de politiske processer som især Trump stå som et eksempel på....

  15. Disrupting Business

    DEFF Research Database (Denmark)

    Cox, Geoff; Bazzichelli, Tatiana

    Disruptive Business explores some of the interconnections between art, activism and the business concept of disruptive innovation. With a backdrop of the crisis of financial capitalism, austerity cuts in the cultural sphere, the idea is to focus on potential art strategies in relation to a broken...... economy. In a perverse way, we ask whether this presents new opportunities for cultural producers to achieve more autonomy over their production process. If it is indeed possible, or desirable, what alternative business models emerge? The book is concerned broadly with business as material for reinvention...

  16. The effect of prepulse on x-ray laser development using a powerful subpicosecond KrF* laser

    International Nuclear Information System (INIS)

    Nam, C.H.; Tighe, W.; Valeo, E.; Suckewer, S.

    1990-03-01

    A high power uv laser has been developed as a pump source for short wavelength (down to 1 nm) x-ray lasers. Various schemes are considered and theoretical analysis is discussed. Spectroscopic studies of laser-target interaction have been performed and, in particular, the effect of a prepulse on plasma generation has been investigated. Analysis of the observed spectra indicates that reduction of the prepulse energy results in a higher temperature plasma. Investigation of the interaction using thin layered targets is also presented. These data provide evidence for initially hot plasma conditions generated from target layers ≤150 angstrom. Discussions of proposed laser schemes at 1-5 nm are presented. 45 refs., 8 figs., 1 tab

  17. Prepulse and amplified spontaneous emission effects on the interaction of a petawatt class laser with thin solid targets

    Energy Technology Data Exchange (ETDEWEB)

    Esirkepov, Timur Zh. [QuBS, Japan Atomic Energy Agency, Kizugawa, Kyoto 619-0215 (Japan); Koga, James K., E-mail: koga.james@jaea.go.jp [QuBS, Japan Atomic Energy Agency, Kizugawa, Kyoto 619-0215 (Japan); Sunahara, Atsushi [Institute for Laser Technology, 2-6 Yamadaoka Suita, Osaka 565-0871 (Japan); Morita, Toshimasa; Nishikino, Masaharu [QuBS, Japan Atomic Energy Agency, Kizugawa, Kyoto 619-0215 (Japan); Kageyama, Kei [Graduate School of Engineering, Osaka University, Osaka 565-0871 (Japan); Nagatomo, Hideo; Nishihara, Katsunobu [Institute of Laser Engineering, 2-6 Yamadaoka Suita, Osaka 565-0871 (Japan); Sagisaka, Akito; Kotaki, Hideyuki; Nakamura, Tatsufumi; Fukuda, Yuji; Okada, Hajime; Pirozhkov, Alexander S.; Yogo, Akifumi; Nishiuchi, Mamiko; Kiriyama, Hiromitsu; Kondo, Kiminori; Kando, Masaki [QuBS, Japan Atomic Energy Agency, Kizugawa, Kyoto 619-0215 (Japan); Bulanov, Sergei V. [QuBS, Japan Atomic Energy Agency, Kizugawa, Kyoto 619-0215 (Japan); A.M. Prokhorov Institute of General Physics of RAS, Vavilova st. 38, Moscow 117942 (Russian Federation); Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141700 (Russian Federation)

    2014-05-01

    When a finite contrast petawatt laser pulse irradiates a micron-thick foil, a prepulse (including amplified spontaneous emission) creates a preplasma, where an ultrashort relativistically strong portion of the laser pulse (the main pulse) acquires higher intensity due to relativistic self-focusing and undergoes fast depletion transferring energy to fast electrons. If the preplasma thickness is optimal, the main pulse can reach the target accelerating fast ions more efficiently than an ideal, infinite contrast, laser pulse. A simple analytical model of a target with preplasma formation is developed and the radiation pressure dominant acceleration of ions in this target is predicted. The preplasma formation by a nanosecond prepulse is analyzed with dissipative hydrodynamic simulations. The main pulse interaction with the preplasma is studied with multi-parametric particle-in-cell simulations. The optimal conditions for hundreds of MeV ion acceleration are found with accompanying effects important for diagnostics, including high-order harmonics generation.

  18. Inhibition of di(2-ethylhexyl) phthalate (DEHP)-induced endocrine disruption by co-treatment of vitamins C and E and their mechanism of action.

    Science.gov (United States)

    Choi, Seul Min; Lim, Duck Soo; Kim, Min Kook; Yoon, Sungpil; Kacew, Sam; Kim, Hyung Sik; Lee, Byung-Mu

    2018-05-29

    The endocrine disrupting actions of di(2-ethylhexyl) phthalate (DEHP) on testicular functions are postulated to involve excess free radical generation. Thus the aim of this study was to examine the ability of antioxidant vitamins C and E to prevent DEHP-induced testicular disruption in male Sprague-Dawley (SD) rats. SD male rats were administered DEHP alone or DEHP with vitamin C and/or vitamin E for 30 days. DEHP alone increased the levels of testosterone (T) and reduced estradiol (E 2 ) concentrations. Supplementation with antioxidant vitamins diminished or restored serum T levels noted in DEHP-treated rats to control values. In contrast vitamins C and E increased E 2 levels to control in rats administered DEHP. Antioxidants significantly improved the decreased testicular levels of reduced glutathione and activity of superoxide dismutase compared to DEHP-treatment alone. Co-treatment of vitamins C and E also markedly improved the reduced epididymal sperm head counts and elevated levels of malondialdehyde (MDA) or 8-hydroxydeoxyguanosine (8-OHdG) induced by DEHP treatment. These results support the concept that the adverse actions of DEHP may be related to increased free radical generation while co-treatment with vitamins C and E significantly blocked the actions of DEHP on male testicular functions.

  19. Antimicrobial peptide AMPNT-6 from Bacillus subtilis inhibits biofilm formation by Shewanella putrefaciens and disrupts its preformed biofilms on both abiotic and shrimp shell surfaces.

    Science.gov (United States)

    Deng, Qi; Pu, Yuehua; Sun, Lijun; Wang, Yaling; Liu, Yang; Wang, Rundong; Liao, Jianmeng; Xu, Defeng; Liu, Ying; Ye, Riying; Fang, Zhijia; Gooneratne, Ravi

    2017-12-01

    Shewanella putrefaciens biofilm formation is of great concern for the shrimp industry because it adheres easily to food and food-contact surfaces and is a source of persistent and unseen contamination that causes shrimp spoilage and economic losses to the shrimp industry. Different concentrations of an antimicrobial lipopeptide, the fermentation product of Bacillus subtilis, AMPNT-6, were tested for the ability to reduce adhesion and disrupt S. putrefaciens preformed biofilms on two different contact surfaces (shrimp shell, stainless steel sheet). AMPNT-6 displayed a marked dose- and time-dependent anti-adhesive effect>biofilm removal. 3MIC AMPNT-6 was able both to remove biofilm and prevent bacteria from forming biofilm in a 96-well polystyrene microplate used as the model surface. 2MIC AMPNT-6 prevented bacteria from adhering to the microplate surface to form biofilm for 3h and removed already existing biofilm within 24h. Secretion of extracellular polymeric substances incubated in LB broth for 24h by S. putrefaciens was minimal at 3× MIC AMPNT-6. Scanning electron microscopy showed that damage to S. putrefaciens bacteria by AMPNT-6 possibly contributed to the non-adherence to the surfaces. Disruption of the mature biofilm structure by AMPNT-6 contributed to biofilm removal. It is concluded that AMPNT-6 can be used effectively to prevent attachment and also detach S. putrefaciens biofilms from shrimp shells, stainless steel sheets and polystyrene surfaces. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Laser Giant Ion Source and the Prepulse Effects for Picosecond Interaction for High Gain Laser Fusion

    International Nuclear Information System (INIS)

    Hora, Heinrich; Badziak, J.; Parys, P.; Wolowski, J.; Woryna, E.; Boody, F.P.; Hoepfl, R.; Jungwirth, K.; Ullschmied, J.; Kralikova, B.; Krasa, J.; Laska, L.; Pfeifer, M.; Rohlena, K.; Skala, J.; Perina, V.

    2003-01-01

    By studying laser driven ion sources which produce giant ion emission current densities exceeding the few mA/cm2 of classical ion sources (MEVVA or ECR) by more than six orders of magnitude, we unexpectedly measured an anomalous low ion energy with ps laser pulses.The emission is basically different from that with the fastest ion energies in the MeV to GeV range due to relativistic self focusing and from the second fastest ion group due to quiver-thermalization processes. We report on specifically designed experiments with gold targets where 0.5 ns laser pulses produce MeV Au-ions in accordance with relativistic self focusing in strong contrast to ps pulses where a 400 times higher intensity from TW pulses is needed to arrive at the same ion energies. These can be explained by a basically new model without self-focusing as a skin layer effect where the absence of a prepulse is essential. This has consequences for the application of laser driven ion sources and may improve the hitherto highest published laser fusion gains with 50 TW-ps laser pulses without the usual spherical precompression

  1. OSU-A9 inhibits angiogenesis in human umbilical vein endothelial cells via disrupting Akt–NF-κB and MAPK signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Omar, Hany A. [Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210 (United States); Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514 (Egypt); Arafa, El-Shaimaa A. [Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514 (Egypt); Salama, Samir A. [Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11511 (Egypt); Arab, Hany H. [Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562 (Egypt); Wu, Chieh-Hsi, E-mail: chhswu@mail.cmu.edu.tw [School of Pharmacy, China Medical University, Taichung 40402, Taiwan (China); Weng, Jing-Ru, E-mail: columnster@gmail.com [Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan (China)

    2013-11-01

    Since the introduction of angiogenesis as a useful target for cancer therapy, few agents have been approved for clinical use due to the rapid development of resistance. This problem can be minimized by simultaneous targeting of multiple angiogenesis signaling pathways, a potential strategy in cancer management known as polypharmacology. The current study aimed at exploring the anti-angiogenic activity of OSU-A9, an indole-3-carbinol-derived pleotropic agent that targets mainly Akt–nuclear factor-kappa B (NF-κB) signaling which regulates many key players of angiogenesis such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Human umbilical vein endothelial cells (HUVECs) were used to study the in vitro anti-angiogenic effect of OSU-A9 on several key steps of angiogenesis. Results showed that OSU-A9 effectively inhibited cell proliferation and induced apoptosis and cell cycle arrest in HUVECs. Besides, OSU-A9 inhibited angiogenesis as evidenced by abrogation of migration/invasion and Matrigel tube formation in HUVECs and attenuation of the in vivo neovascularization in the chicken chorioallantoic membrane assay. Mechanistically, Western blot, RT-PCR and ELISA analyses showed the ability of OSU-A9 to inhibit MMP-2 production and VEGF expression induced by hypoxia or phorbol-12-myristyl-13-acetate. Furthermore, dual inhibition of Akt–NF-κB and mitogen-activated protein kinase (MAPK) signaling, the key regulators of angiogenesis, was observed. Together, the current study highlights evidences for the promising anti-angiogenic activity of OSU-A9, at least in part through the inhibition of Akt–NF-κB and MAPK signaling and their consequent inhibition of VEGF and MMP-2. These findings support OSU-A9's clinical promise as a component of anticancer therapy. - Highlights: • The antiangiogenic activity of OSU-A9 in HUVECs was explored. • OSU-A9 inhibited HUVECs proliferation, migration, invasion and tube formation. • OSU-A9

  2. Disruption of Aneuploidy and Senescence Induced by Aurora Inhibition Promotes Intrinsic Apoptosis in Double Hit or Double Expressor Diffuse Large B-cell Lymphomas.

    Science.gov (United States)

    Islam, Shariful; Qi, Wenqing; Morales, Carla; Cooke, Laurence; Spier, Catherine; Weterings, Eric; Mahadevan, Daruka

    2017-10-01

    Double hit (DH) or double expressor (DE) diffuse large B-cell lymphomas (DLBCL) are aggressive non-Hodgkin's lymphomas (NHL) with translocations and/or overexpressions of MYC and BCL-2 , which are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in ∼30%, while ∼70% are aneuploid and senescent cells (AASC), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. Combinations of alisertib + ibrutinib or alisertib + ibrutinib + rituximab significantly reduced AASCs with enhanced intrinsic cell death. Inhibition of AK + BTK reduced phosphorylation of AKT/mTOR and ERK-1/2, upregulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6, and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage. In a DE-DLBCL SCID mouse xenograft model, ibrutinib alone was inactive, while alisertib + ibrutinib was additive with a tumor growth inhibition (TGI) rate of ∼25%. However, TGI for ibrutinib + rituximab was ∼50% to 60%. In contrast, triple therapy showed a TGI rate of >90%. Kaplan-Meier survival analysis showed that 67% of mice were alive at day 89 with triple therapy versus 20% with ibrutinib + rituximab. All treatments were well tolerated with no changes in body weights. A novel triple therapy consisting of alisertib + ibrutinib + rituximab inhibits AASCs induced by AK inhibition in DH/DE-DLBCL leading to a significant antiproliferative signal, enhanced intrinsic apoptosis and may be of therapeutic potential in these lymphomas. Mol Cancer Ther; 16(10); 2083-93. ©2017 AACR . ©2017 American Association for Cancer Research.

  3. Genetic disruption of tubulin acetyltransferase, αTAT1, inhibits proliferation and invasion of colon cancer cells through decreases in Wnt1/β-catenin signaling

    International Nuclear Information System (INIS)

    Oh, Somi; You, Eunae; Ko, Panseon; Jeong, Jangho; Keum, Seula; Rhee, Sangmyung

    2017-01-01

    Microtubules are required for diverse cellular processes, and abnormal regulation of microtubule dynamics is closely associated with severe diseases including malignant tumors. In this study, we report that α-tubulin N-acetyltransferase (αTAT1), a regulator of α-tubulin acetylation, is required for colon cancer proliferation and invasion via regulation of Wnt1 and its downstream genes expression. Public transcriptome analysis showed that expression of ATAT1 is specifically upregulated in colon cancer tissue. A knockout (KO) of ATAT1 in the HCT116 colon cancer cell line, using the CRISPR/Cas9 system showed profound inhibition of proliferative and invasive activities of these cancer cells. Overexpression of αTAT1 or the acetyl-mimic K40Q α-tubulin mutant in αTAT1 KO cells restored the invasiveness, indicating that microtubule acetylation induced by αTAT1 is critical for HCT116 cell invasion. Analysis of colon cancer-related gene expression in αTAT1 KO cells revealed that the loss of αTAT1 decreased the expression of WNT1. Mechanistically, abrogation of tubulin acetylation by αTAT1 knockout inhibited localization of β-catenin to the plasma membrane and nucleus, thereby resulting in the downregulation of Wnt1 and of its downstream genes including CCND1, MMP-2, and MMP-9. These results suggest that αTAT1-mediated Wnt1 expression via microtubule acetylation is important for colon cancer progression. - Highlights: • Ablation of αTAT1 inhibits HCT116 colon cancer cell invasion. • αTAT1/acetylated microtubules regulate expression of Wnt1/β-catenin target genes. • Acetylated microtubules regulate cellular localization of β-catenin. • Loss of αTAT1 prevents Wnt1 from inducing β-catenin-dependent and -independent pathways.

  4. Rapid high resolution MR neurography with a diffusion-weighted pre-pulse

    International Nuclear Information System (INIS)

    Yoneyama, Masami; Nakamura, Masanobu; Tabuchi, Takashi; Takahara, Taro; Kwee, T.C.

    2013-01-01

    The purpose of this study was to introduce, optimize, and assess the feasibility of a new scheme to rapidly acquire high-resolution volumetric neurographic images using a three-dimensional turbo spin-echo sequence combined with a diffusion-weighted pre-pulse called improved motion-sensitized driven equilibrium (iMSDE): Diffusion-prepared magnetic resonance (MR) Neurography (D-prep MRN). In order to optimize the signal suppression of blood vessels and muscle at D-prep MRN, coronal lumbosacral plexus images were acquired in five volunteers at 3T, and the following parameters were examined: iMSDE gradient-strength (b-value) of 0, 2 and 10 s/mm 2 (with the aim to suppress blood vessels) and iMSDE preparation duration (iMSDE prep-time ) of 18, 50 and 100 ms (with the aim to suppress muscle signal). Subsequently, the feasibility of the optimized D-prep MRN sequence in visualizing the brachial plexus, lumbosacral plexus, and cranial nerves was evaluated in 5 healthy volunteers. A higher b-value of 10 s/mm 2 was better in signal suppression of blood vessels, whereas an intermediate iMSDE prep-time of 50 ms provided the best compromise between suppression of muscle signal and minimization of signal loss of nerves. With these parameters, the normal nerve structures showed high signal intensity, while the blood vessels and muscles were effectively suppressed. The optimized D-prep MRN sequence clearly showed the three-dimensional trajectory of the brachial plexus, lumbosacral plexus, and cranial nerves. D-prep MRN was introduced and optimized, and clearly showed detailed anatomy of the brachial plexus, lumbosacral plexus, and cranial nerves. These results suggest that the D-prep MRN can be used for fast, high-resolution, volumetric imaging of the peripheral nervous system. (author)

  5. The inhibition of myometrial contractions by chlorinated herbicides (atrazine and linuron), and their disruptive effect on the secretory functions of uterine and ovarian cells in cow, in vitro.

    Science.gov (United States)

    Wrobel, Michał H; Mlynarczuk, Jaroslaw

    2017-10-01

    The effect of atrazine and linuron, the popular and widely used chlorinated herbicides, on both myometrial contractions and secretory functions of bovine uterus and ovaries in vitro, was investigated. The pesticides inhibited (Pherbicides affected PGs secretion from myometrium and PGF2α from endometrium. Only the lowest dose of both tested compounds decreased PGE2 secretion from endometrium. The pesticides increased (P<0.05) the OT secretion from granulosa. However, only linuron stimulated (P<0.05) the OT secretion from the luteal cells, and it increased (P<0.05) the expression of mRNA for the OT precursor. Both compounds stimulated (P<0.05) the secretion of testosterone and atrazine increased (P<0.05) also the secretion of estradiol from the granulosa cells. While atrazine and linuron reduced (P<0.05) the progesterone secretion from the luteal cells. The data show that atrazine and linuron altered the secretory functions of ovarian cells and inhibited the myometrial contractions in vitro. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Fisetin inhibits growth, induces G2/M arrest and apoptosis of human epidermoid carcinoma A431 cells: Role of mitochondrial membrane potential disruption and consequent caspases activation

    Science.gov (United States)

    Pal, Harish C.; Sharma, Samriti; Elmets, Craig A.; Athar, Mohammad; Afaq, Farrukh

    2013-01-01

    Non-melanoma skin cancers (NMSCs) one of the most common neoplasms causes serious morbidity and mortality. Therefore, identification of non-toxic phytochemicals for prevention/treatment of NMSCs is highly desirable. Fisetin (3,3′,4′,7-tetrahydroxyflavone), a dietary flavonoid, present in fruits and vegetables possesses anti-oxidant and anti-proliferative properties. The aim of this study was to investigate the chemotherapeutic potential of fisetin in cultured human epidermoid carcinoma A431 cells. Treatment of A431 cells with fistein (5-80 μM) resulted in a significant decrease in cell viability in a dose- and time-dependent manner. Employing clonogenic assay, we found that fisetin treatment significantly reduced colony formation in A431 cells. Fisetin treatment of A431 cells resulted in G2/M arrest and induction of apoptosis. Furthermore, treatment of A431 cells with fisetin resulted in (i) decreased expression of anti-apoptotic proteins (Bcl2, Bcl-xL and Mcl-1), (ii) increased expression of pro-apoptotic proteins (Bax, Bak and Bad), (iii) disruption of mitochondrial potential, (iv) release of cytchrome c and Smac/DIABLO from mitochondria, (v) activation of caspases, and (vi) cleavage of PARP protein. Pretreatment of A431 cells with the pan-caspase inhibitor (Z-VAD-FMK) blocked fisetin-induced cleavage of caspases and PARP. Taken together, these data provide evidence that fisetin possesses chemotherapeutic potential against human epidermoid carcinoma A431 cells. Overall, these results suggest that fisetin could be developed as a novel therapeutic agent for the management of NMSCs. PMID:23800058

  7. Locostatin, a disrupter of Raf kinase inhibitor protein, inhibits extracellular matrix production, proliferation, and migration in human uterine leiomyoma and myometrial cells.

    Science.gov (United States)

    Janjusevic, Milijana; Greco, Stefania; Islam, Md Soriful; Castellucci, Clara; Ciavattini, Andrea; Toti, Paolo; Petraglia, Felice; Ciarmela, Pasquapina

    2016-11-01

    To investigate the presence of Raf kinase inhibitor protein (RKIP) in human myometrium and leiomyoma as well as to determine the effect of locostatin (RKIP inhibitor) on extracellular matrix (ECM) production, proliferation, and migration in human myometrial and leiomyoma cells. Laboratory study. Human myometrium and leiomyoma. Thirty premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. Myometrial and leiomyoma tissues were used to investigate the localization and the expression level of RKIP through immunohistochemistry and Western blotting. Myometrial and leiomyoma cells were treated with locostatin (10 μM) to measure ECM expression by real-time polymerase chain reaction, GSK3β expression by Western blotting, cell migration by wound-healing assay, and cell proliferation by MTT assay and immunocytochemistry. The expression of RKIP in human myometrial and leiomyoma tissue; ECM components and GSK3β expression, migration, and proliferation in myometrial and leiomyoma cells. RKIP is expressed in human myometrial and leiomyoma tissue. Locostatin treatment resulted in the activation of the mitogen-activated protein kinase (MAPK) signal pathway (ERK phosphorylation), providing a powerful validation of our targeting protocol. Further, RKIP inhibition by locostatin reduces ECM components. Moreover, the inhibition of RKIP by locostatin impaired cell proliferation and migration in both leiomyoma and myometrial cells. Finally, locostatin treatment reduced GSK3β expression. Therefore, even if the activation of MAPK pathway should increase proliferation and migration, the destabilization of GSK3β leads to the reduction of proliferation and migration of myometrial and leiomyoma cells. Our results indicate that RKIP may be involved in leiomyoma pathophysiology. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  8. Dependence of the cutoff in lithium plasma harmonics on the delay between the prepulse and the main pulse

    International Nuclear Information System (INIS)

    Suzuki, M; Baba, M; Kuroda, H; Ganeev, R A; Bom, L B Elouga; Ozaki, T

    2012-01-01

    We demonstrated the generation of the 43rd harmonic at the wavelength of 18.49 nm (67 eV photon energy) by using laser-ablation lithium plasma irradiated by a Ti:sapphire laser pulse. We found that for low-Z material, such as lithium, the cutoff energy depends strongly on the delay time between the prepulse and the main pulse, due to rapid recombination. As a result, the maximum cutoff energy was obtained at a relatively short delay of 24 ns. From the theoretical cutoff rule and hydrodynamic simulations, we show that these harmonics were generated from singly charged lithium ions. (paper)

  9. Sustainable Disruptions

    DEFF Research Database (Denmark)

    Friis, Silje Alberthe Kamille; Kjær, Lykke Bloch

    2016-01-01

    Since 2012 the Sustainable Disruptions (SD) project at the Laboratory for Sustainability at Design School Kolding (DK) has developed and tested a set of design thinking tools, specifically targeting the barriers to economically, socially, and environmentally sustainable business development....... The tools have been applied in practice in collaboration with 11 small and medium sized companies (SMEs). The study investigates these approaches to further understand how design thinking can contribute to sustainable transition in a business context. The study and the findings are relevant to organizations...... invested in the issue of sustainable business development, in particular the leaders and employees of SMEs, but also to design education seeking new ways to consciously handle and teach the complexity inherent in sustainable transformation. Findings indicate that the SD design thinking approach contributes...

  10. 1,25(OH)2D3 disrupts glucose metabolism in prostate cancer cells leading to a truncation of the TCA cycle and inhibition of TXNIP expression.

    Science.gov (United States)

    Abu El Maaty, Mohamed A; Alborzinia, Hamed; Khan, Shehryar J; Büttner, Michael; Wölfl, Stefan

    2017-10-01

    Prostate cell metabolism exhibits distinct profiles pre- and post-malignancy. The malignant metabolic shift converts prostate cells from "citrate-producing" to "citrate-oxidizing" cells, thereby enhancing glucose metabolism, a phenotype that contrasts classical tumoral Warburg metabolism. An on-line biosensor chip system (BIONAS 2500) was used to monitor metabolic changes (glycolysis and respiration) in response to the putative anti-cancer nutraceutical 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], in different prostate cancer (PCa) cell lines (LNCaP, VCaP, DU145 and PC3). LNCaP cells exhibited profound metabolic responsiveness to the treatment and thus extensive analysis of metabolism-modulating effects of 1,25(OH) 2 D 3 were performed, including mRNA expression analysis of key metabolic genes (e.g. GLUT1 and PDHK1), analysis of TCA cycle metabolites, glucose uptake/consumption measurements, ATP production, and mitochondrial biogenesis/activity. Altogether, data demonstrate a vivid disruption of glucose metabolism by 1,25(OH) 2 D 3 , illustrated by a decreased glucose uptake and an accumulation of citrate/isocitrate due to TCA cycle truncation. Depletion of glycolytic intermediates led to a consistent decrease in TXNIP expression in response to 1,25(OH) 2 D 3 , an effect that coincided with the activation of AMPK signaling and a reduction in c-MYC expression. Reduction in TXNIP levels in response to 1,25(OH) 2 D 3 was rescued by an AMPK signaling inhibitor and mimicked by a MYC inhibitor highlighting the possible involvement of both pathways in mediating 1,25(OH) 2 D 3 's metabolic effects in PCa cells. Furthermore, pharmacological and genetic modulation of the androgen receptor showed similar and disparate effects on metabolic parameters compared to 1,25(OH) 2 D 3 treatment, highlighting the AR-independent nature of 1,25(OH) 2 D 3 's metabolism-modulating effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. The effects of increased central serotonergic activity on prepulse inhibition and habituation of the human startle response

    DEFF Research Database (Denmark)

    Jensen, Kristian S; Oranje, Bob; Wienberg, Malene

    2007-01-01

    modulation is currently inconsistent. In a double-blind placebo-controlled crossover design, 18 healthy male volunteers received either placebo or a dose of 10 mg of escitalopram (SSRI), after which they were tested in both PPI and habituation of the startle reflex paradigms. No significant differences...... between the two treatments were observed on PPI, although escitalopram was found to significantly delay habituation of the ASR. In the current study, escitalopram was found to delay habituation, but it did not affect PPI in healthy male volunteers. As escitalopram is a highly specific SSRI, the results...

  12. Interactions of Stress and Nicotine on Amplitude, Pre-Pulse Inhibition and Habituation of the Acoustic Startle Reflex

    Science.gov (United States)

    1992-09-24

    Marquez , Armario , & Gelpi, 1988) consistent with a stress response . Restraint stress has been reported to increase the amplitude of sensory...and NE in the brain (Adell , Garcia- Marquez , Armario , & Gelpi , 1988) consistent with a stress response. Restraint stress has been reported t o...and non- reactive strains. Al coholism. Clinical and Experimental Research, ~(2), 170-174. Adell, A., Garcia - Marquez, C., Armario , A. , & Gelpi , E

  13. Gap-prepulse inhibition of the startle reflex (GPIAS for tinnitus assessment: current status and future directions

    Directory of Open Access Journals (Sweden)

    Alexander eGalazyuk

    2015-04-01

    Full Text Available The progress in the field of tinnitus largely depends on the development of a reliable tinnitus animal model. Recently a new method based on the acoustic startle reflex modification was introduced for tinnitus screening in laboratory animals. This method was enthusiastically adopted and now widely used by many scientists in the field due to its seeming simplicity and a number of advantages over the other methods of tinnitus assessment. Furthermore, this method opened an opportunity for tinnitus assessment in humans as well. Unfortunately multiple modifications of data collection and interpretation implemented in different labs make comparisons across studies very difficult. In addition, recent animal and human studies have challenged the original filling-in interpretation of the paradigm. Here we review the current literature to emphasize on the commonalities and differences in data collection and interpretation across laboratories that are using this method for tinnitus assessment. We also propose future research directions that could be taken in order to establish whether or not this method is warranted as an indicator of the presence of tinnitus.

  14. ADAMTS9 is Silenced by Epigenetic Disruption in Colorectal Cancer and Inhibits Cell Growth and Metastasis by Regulating Akt/p53 Signaling

    Directory of Open Access Journals (Sweden)

    Ling Chen

    2017-11-01

    Full Text Available Background/Aims: ADAMTS (disintegrin-like and metalloproteinase with thrombospondin motifs proteins are extracellular zinc metalloproteinases that play an important role in extracellular matrix assembly and degradation, connective tissue structuring, angiogenesis, and cell migration. Multiple studies suggest that ADAMTS proteins (e.g. ADAMTS9 can act as tumor suppressors. In gastric, esophageal, and nasopharyngeal carcinomas ADAMTS9 is frequently down-regulated by promoter methylation. Whether ADAMTS9 can function as a tumor suppressor gene (TSG in colorectal cancer is still unclear. Methods: We performed immunohistochemistry, RT-PCR, and qRT-PCR, to examine the expression of ADAMTS9 in colorectal cancer cell lines and primary colorectal cancer tissues. Methylation-specific PCR was also carried out to investigate the promoter methylation status of ADAMTS9. We also explored the functions of ADAMTS9 in colorectal cancer cell lines through in vitro experiments. Results: ADAMTS9 expression was down-requlated or silenced in 83.3% (5/6 of colorectal cancer cell lines, and frequently repressed in 65.6% (21/32 of colorectal cancer tissues. Down-regulation of ADAMTS9 was partially due to promoter methylation. Exogenous expression of ADAMTS9 in colorectal cancer cell lines inhibited cell proliferation and migration through the regulation of cell cycle and apoptosis. In addition, ADAMTS9 prevented the activation of Akt, and its downstream targets in colorectal cancer cell lines. Conclusion: Our findings suggest ADAMTS9 is a TSG in colorectal cancer.

  15. Control of laser-beam propagation and absorption in a nanoplasma gas by programming of a transient complex refractive index with a prepulse

    International Nuclear Information System (INIS)

    Chu, H.-E.; Xiao, Y.-F.; Tsai, H.-E.; Lee, C.-H.; Lin, J.-Y.; Wang, J.; Chen, S.-Y.

    2004-01-01

    By utilizing the intensity- and duration-dependent heating and expansion rate of nanoplasma to generate a transient transverse gradient of the refractive index, prepulse controlled laser-beam propagation is demonstrated. The dynamical response of the macroscopic optical refractive index is traced back to the microscopic polarizability of nanoplasmas experimentally, in accordance with hydrodynamic nanoplasma models. In particular, the delay between the prepulse and the main pulse for maximum Rayleigh scattering is found to be longer than that for maximum x-ray emission, supporting the more refined one-dimensional self-consistent hydrodynamic nanoplasma model

  16. Endocrine Disrupting Chemicals (EDCs)

    Science.gov (United States)

    ... Center Pacientes y Cuidadores Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ... Hormones and Health › Endocrine Disrupting Chemicals (EDCs) The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) EDCs Myth vs. ...

  17. Status On Multi-microsecond Prepulse Technique On Sphinx Machine Going From Nested To Single Wire Array For 800 ns Implosion Time Z-pinch

    Science.gov (United States)

    Maury, P.; Calamy, H.; Grunenwald, J.; Lassalle, F.; Zucchini, F.; Loyen, A.; Georges, A.; Morell, A.; Bedoch, J. P.

    2009-01-01

    The Sphinx machine[1] is a 6 MA, 1 μS driver based on the LTD technology, used for Z-pinch experiments. Important improvements of Sphinx radiation output were recently obtained using a multi-microsecond current prepulse[2]. Total power per unit of length is multiplied by a factor of 6 and FWHM divided by a factor of 2.5. Early breakdown of the wires during the prepulse phase dramatically changes the ablation phase leading to an improvement of axial homogeneity of both the implosion and the final radiating column. As a consequence, the cathode bubble observed on classical shots is definitively removed. The implosion is then centered and zippering effect is reduced, leading to simultaneous x-ray emission of the whole length. A great reproducibility is obtained. Nested arrays were used before to mitigate the Rayleigh-Taylor instabilities during the implosion phase. Further experiments with pre-pulse technique are described here were inner array was removed. The goal of these experiments was to see if long prepulse could give stable enough implosion with single array and at the same time increase the η parameter by reducing the mass of the load. Experimental results of single wire array loads of typical dimension 5 cm in height with implosion time between 700 and 900 ns and diameter varying between 80 and 140 mm are given. Parameters of the loads were varying in term of radius and number of wires. Comparisons with nested wire array loads are done and trends are proposed. Characteristics of both the implosion and the final radiating column are shown. 2D MHD numerical simulations of single wire array become easier as there is no interaction between outer and inner array anymore. A systematic study was done using injection mass model to benchmark simulation with experiments.

  18. Status On Multi-microsecond Prepulse Technique On Sphinx Machine Going From Nested To Single Wire Array For 800 ns Implosion Time Z-pinch

    International Nuclear Information System (INIS)

    Maury, P.; Calamy, H.; Grunenwald, J.; Lassalle, F.; Zucchini, F.; Loyen, A.; Georges, A.; Morell, A.; Bedoch, J. P.

    2009-01-01

    The Sphinx machine [1] is a 6 MA, 1 μS driver based on the LTD technology, used for Z-pinch experiments. Important improvements of Sphinx radiation output were recently obtained using a multi-microsecond current prepulse [2] . Total power per unit of length is multiplied by a factor of 6 and FWHM divided by a factor of 2.5. Early breakdown of the wires during the prepulse phase dramatically changes the ablation phase leading to an improvement of axial homogeneity of both the implosion and the final radiating column. As a consequence, the cathode bubble observed on classical shots is definitively removed. The implosion is then centered and zippering effect is reduced, leading to simultaneous x-ray emission of the whole length. A great reproducibility is obtained. Nested arrays were used before to mitigate the Rayleigh-Taylor instabilities during the implosion phase. Further experiments with pre-pulse technique are described here were inner array was removed. The goal of these experiments was to see if long prepulse could give stable enough implosion with single array and at the same time increase the η parameter by reducing the mass of the load. Experimental results of single wire array loads of typical dimension 5 cm in height with implosion time between 700 and 900 ns and diameter varying between 80 and 140 mm are given. Parameters of the loads were varying in term of radius and number of wires. Comparisons with nested wire array loads are done and trends are proposed. Characteristics of both the implosion and the final radiating column are shown. 2D MHD numerical simulations of single wire array become easier as there is no interaction between outer and inner array anymore. A systematic study was done using injection mass model to benchmark simulation with experiments.

  19. Plasma conditions generated by interaction of a high brightness, prepulse free Raman amplified KrF laser pulse with solid targets

    International Nuclear Information System (INIS)

    Riley, D.; Gizzi, L.A.; Khattak, F.Y.; Mackinnon, A.J.; Viana, S.M.; Willi, O.

    1992-01-01

    A high brightness, Raman amplified KrF laser has been used to irradiate solid targets with 12 ps laser pulses at intensities above 10 15 W/cm 2 without the presence of a preformed plasma caused by low level amplified spontaneous emission prepulse. Time-resolved x-ray spectroscopy of the K-shell emission from aluminum was used to infer electron densities in excess of 10 23 cm -3 at temperatures of several hundred electronvolts

  20. Internal disruption in tokamaks

    International Nuclear Information System (INIS)

    Kuvshinov, B.N.; Savrukhin, P.V.

    1990-01-01

    A review of results of experimental and theoretical investigations of internal disruption in tokamaks is given. Specific features of various types of saw-tooth oscillations are described and their classification is performed. Theoretical models of the process of development of internal disruption instability are discussed. Effect of internal disruption on parameters of plasma, confined in tokamak, is considered. Scalings of period and amplitude of saw-tooth oscillations, as well as version radius are presented. Different methods for stabilizing instability of internal disruption are described

  1. Internal disruptions in tokamaks

    International Nuclear Information System (INIS)

    Kuvshinov, B.N.; Savrukhin, P.V.

    1990-01-01

    Experimental and theoretical studies of the phenomenon of internal disruptions in tokamaks are reviewed. A classification scheme is introduced and the features of different types of sawtooth oscillations are described. A theoretical model for the development of the internal disruption instability is discussed. The effect of internal disruptions on the parameters of plasma confined in tokamaks is discussed. Scaling laws for the period and amplitude of sawtooth oscillations, as well as for the inversion radius, are presented. Different methods of stabilizing the internal disruption instability are described

  2. Disruptions in JET

    International Nuclear Information System (INIS)

    Wesson, J.A.; Gill, R.D.; Hugon, M.

    1989-01-01

    In JET, both high density and low-q operation are limited by disruptions. The density limit disruptions are caused initially by impurity radiation. This causes a contraction of the plasma temperature profile and leads to an MHD unstable configuration. There is evidence of magnetic island formation resulting in minor disruptions. After several minor disruptions, a major disruption with a rapid energy quench occurs. This event takes place in two stages. In the first stage there is a loss of energy from the central region. In the second stage there is a more rapid drop to a very low temperature, apparently due to a dramatic increase in impurity radiation. The final current decay takes place in the resulting cold plasma. During the growth of the MHD instability the initially rotating mode is brought to rest. This mode locking is believed to be due to an electromagnetic interaction with the vacuum vessel and external magnetic field asymmetries. The low-q disruptions are remarkable for the precision with which they occur at q ψ = 2. These disruptions do not have extended precursors or minor disruptions. The instability grows and locks rapidly. The energy quench and current decay are generally similar to those of the density limit. (author). 43 refs, 35 figs, 3 tabs

  3. Disruptions in Tokamaks

    International Nuclear Information System (INIS)

    Bondeson, A.

    1987-01-01

    This paper discusses major and minor disruptions in Tokamaks. A number of models and numerical simulations of disruptions based on resistive MHD are reviewed. A discussion is given of how disruptive current profiles are correlated with the experimentally known operational limits in density and current. It is argued that the q a =2 limit is connected with stabilization of the m=2/n=1 tearing mode for a approx.< 2.7 by resistive walls and mode rotation. Experimental and theoretical observations indicate that major disruptions usually occur in at least two phases, first a 'predisruption', or loss of confinement in the region 1 < q < 2, leaving the q approx.= 1 region almost unaffected, followed by a final disruption of the central part, interpreted here as a toroidal n = 1 external kink mode. (author)

  4. In vitro evidence for endocrine-disrupting chemical (EDC)'s ...

    African Journals Online (AJOL)

    docrine-disrupting chemical (EDC)'s inhibition of drug metabolism. Materials .... serotonin (5-HT) and 4-methylumbelliferone (4-MU) as the probe substrates ... Hu CM, et al. Structure-. 16. inhibition relationship of ginsenosides towards UDP-.

  5. Understanding disruptions in tokamaksa)

    Science.gov (United States)

    Zakharov, Leonid E.; Galkin, Sergei A.; Gerasimov, Sergei N.; contributors, JET-EFDA

    2012-05-01

    This paper describes progress achieved since 2007 in understanding disruptions in tokamaks, when the effect of plasma current sharing with the wall was introduced into theory. As a result, the toroidal asymmetry of the plasma current measurements during vertical disruption event (VDE) on the Joint European Torus was explained. A new kind of plasma equilibria and mode coupling was introduced into theory, which can explain the duration of the external kink 1/1 mode during VDE. The paper presents first results of numerical simulations using a free boundary plasma model, relevant to disruptions.

  6. Disruptive Mood Dysregulation Disorder

    Science.gov (United States)

    ... Application Process Managing Grants Clinical Research Training Small Business Research Labs at NIMH Labs at NIMH Home Research ... Chat on Disruptive Mood Dysregulation Disorder (Archived Transcript) Research and ... Journal Articles: References and abstracts from MEDLINE/PubMed (National ...

  7. Disruption Rose Tinted II

    OpenAIRE

    Livingstone, Andrew

    2009-01-01

    'Disruption - Rose Tinted II' continues to engage narratives of historical English china as previously explored in the work 'Rose Tinted'. This work engages the sleepy rural idyll which is overlaid with visual contemporary social commentary.

  8. Digital disruption ?syndromes.

    Science.gov (United States)

    Sullivan, Clair; Staib, Andrew

    2017-05-18

    The digital transformation of hospitals in Australia is occurring rapidly in order to facilitate innovation and improve efficiency. Rapid transformation can cause temporary disruption of hospital workflows and staff as processes are adapted to the new digital workflows. The aim of this paper is to outline various types of digital disruption and some strategies for effective management. A large tertiary university hospital recently underwent a rapid, successful roll-out of an integrated electronic medical record (EMR). We observed this transformation and propose several digital disruption "syndromes" to assist with understanding and management during digital transformation: digital deceleration, digital transparency, digital hypervigilance, data discordance, digital churn and post-digital 'depression'. These 'syndromes' are defined and discussed in detail. Successful management of this temporary digital disruption is important to ensure a successful transition to a digital platform. What is known about this topic? Digital disruption is defined as the changes facilitated by digital technologies that occur at a pace and magnitude that disrupt established ways of value creation, social interactions, doing business and more generally our thinking. Increasing numbers of Australian hospitals are implementing digital solutions to replace traditional paper-based systems for patient care in order to create opportunities for improved care and efficiencies. Such large scale change has the potential to create transient disruption to workflows and staff. Managing this temporary disruption effectively is an important factor in the successful implementation of an EMR. What does this paper add? A large tertiary university hospital recently underwent a successful rapid roll-out of an integrated electronic medical record (EMR) to become Australia's largest digital hospital over a 3-week period. We observed and assisted with the management of several cultural, behavioural and

  9. Search and Disrupt

    DEFF Research Database (Denmark)

    Ørding Olsen, Anders

    . However, incumbent sources engaged in capability reconfiguration to accommodate disruption improve search efforts in disruptive technologies. The paper concludes that the value of external sources is contingent on more than their knowledge. Specifically, interdependence of sources in search gives rise...... to influence from individual strategic interests on the outcomes. More generally, this points to the need for understanding the two-way influence of sources, rather than viewing external search as one-way knowledge accessing....

  10. Disruption prediction at JET

    International Nuclear Information System (INIS)

    Milani, F.

    1998-12-01

    The sudden loss of the plasma magnetic confinement, known as disruption, is one of the major issue in a nuclear fusion machine as JET (Joint European Torus). Disruptions pose very serious problems to the safety of the machine. The energy stored in the plasma is released to the machine structure in few milliseconds resulting in forces that at JET reach several Mega Newtons. The problem is even more severe in the nuclear fusion power station where the forces are in the order of one hundred Mega Newtons. The events that occur during a disruption are still not well understood even if some mechanisms that can lead to a disruption have been identified and can be used to predict them. Unfortunately it is always a combination of these events that generates a disruption and therefore it is not possible to use simple algorithms to predict it. This thesis analyses the possibility of using neural network algorithms to predict plasma disruptions in real time. This involves the determination of plasma parameters every few milliseconds. A plasma boundary reconstruction algorithm, XLOC, has been developed in collaboration with Dr. D. O'Brien and Dr. J. Ellis capable of determining the plasma wall/distance every 2 milliseconds. The XLOC output has been used to develop a multilayer perceptron network to determine plasma parameters as l i and q ψ with which a machine operational space has been experimentally defined. If the limits of this operational space are breached the disruption probability increases considerably. Another approach for prediction disruptions is to use neural network classification methods to define the JET operational space. Two methods have been studied. The first method uses a multilayer perceptron network with softmax activation function for the output layer. This method can be used for classifying the input patterns in various classes. In this case the plasma input patterns have been divided between disrupting and safe patterns, giving the possibility of

  11. The disruption management model.

    Science.gov (United States)

    McAlister, James

    2011-10-01

    Within all organisations, business continuity disruptions present a set of dilemmas that managers may not have dealt with before in their normal daily duties. The disruption management model provides a simple but effective management tool to enable crisis management teams to stay focused on recovery in the midst of a business continuity incident. The model has four chronological primary headlines, which steer the team through a quick-time crisis decision-making process. The procedure facilitates timely, systematic, rationalised and justified decisions, which can withstand post-event scrutiny. The disruption management model has been thoroughly tested within an emergency services environment and is proven to significantly support clear and concise decision making in a business continuity context.

  12. Emerging and Disruptive Technologies.

    Science.gov (United States)

    Kricka, Larry J

    2016-08-01

    Several emerging or disruptive technologies can be identified that might, at some point in the future, displace established laboratory medicine technologies and practices. These include increased automation in the form of robots, 3-D printing, technology convergence (e.g., plug-in glucose meters for smart phones), new point-of-care technologies (e.g., contact lenses with sensors, digital and wireless enabled pregnancy tests) and testing locations (e.g., Retail Health Clinics, new at-home testing formats), new types of specimens (e.g., cell free DNA), big biology/data (e.g., million genome projects), and new regulations (e.g., for laboratory developed tests). In addition, there are many emerging technologies (e.g., planar arrays, mass spectrometry) that might find even broader application in the future and therefore also disrupt current practice. One interesting source of disruptive technology may prove to be the Qualcomm Tricorder XPrize, currently in its final stages.

  13. Sustainable Disruption Management

    DEFF Research Database (Denmark)

    Vaaben, Bo Valdemar

    The world we live in is globalized. Goods are seldom made in the place where they are used or consumed, and we do increasingly travel to other countries for either business or pleasure. In our everyday lives we rely on well-functioning global transportations systems to continue the standard...... in the same way, when operation is disrupted. Never the less, we may recall that the Suez Canal was closed due to riots in Egypt, that the fuel price was impacted by threats of closing of the Strait of Hormuz, and we do from time to time hear about acts of piracy outside the coast of Somalia. All...... papers combining disruption management and flight planning through an integrated optimization approach. An additional contribution of the thesis is to show how flexible flight speeds can be used to improve recovery from disruptions, while at the same time allowing an airline to trade off fuel costs...

  14. Erosion of melt layers developed during a plasma disruption

    International Nuclear Information System (INIS)

    Hassanein, A.; Konkashbaev, A.; Konkashbaev, I.

    1995-01-01

    Material erosion of plasma-facing components during a tokamak disruption is a serious problem that limits reactor operation and economical reactor lifetime. In particular, metallic low-Z components such as Be will be subjected to severe melting during disruptions and edge localized modes (ELMs). Loss of the developed melt layer will critically shorten the lifetime of these components, severely contaminate the plasma, and seriously inhibit successful and reliable operation of the reactor. In this study mechanisms responsible for melt-layer loss during a disruption are modeled and evaluated. Implications of melt-layer loss on the performance of metallic facing components in the reactor environment are discussed. (orig.)

  15. Erosion of melt layers developed during a plasma disruption

    International Nuclear Information System (INIS)

    Hassanein, A.; Konkashbaev, A.; Konkashbaev, I.

    1994-08-01

    Material erosion of plasma-facing components during a tokamak disruption is a serious problem that limits reactor operation and economical reactor lifetime. In particular, metallic low-Z components such as Be will be subjected to severe melting during disruptions and edge localized models (ELMs). Loss of the developed melt layer will critically shorten the lifetime of these components, severely contaminate the plasma, and seriously inhibit successful and reliable operation of the reactor. In this study mechanisms responsible for melt-layer loss during a disruption are modeled and evaluated. Implications of melt-layer loss on the performance of metallic facing components in the reactor environment are discussed

  16. Statistical analysis of JET disruptions

    International Nuclear Information System (INIS)

    Tanga, A.; Johnson, M.F.

    1991-07-01

    In the operation of JET and of any tokamak many discharges are terminated by a major disruption. The disruptive termination of a discharge is usually an unwanted event which may cause damage to the structure of the vessel. In a reactor disruptions are potentially a very serious problem, hence the importance of studying them and devising methods to avoid disruptions. Statistical information has been collected about the disruptions which have occurred at JET over a long span of operations. The analysis is focused on the operational aspects of the disruptions rather than on the underlining physics. (Author)

  17. Disruptive instabilities in the TBR-1

    International Nuclear Information System (INIS)

    Vannucci, A.

    1987-01-01

    The disruptive instabilities in the TBR-1 tokamak of the Plasma Physics Laboratory of the Institute of Physics-USP were investigated by using surface-barrier detectors and Mirnov magnetic coils, measuring soft X-ray emited by the plasma and poloidal magnetic fluctuations, respectively. Minor and major disruptions, as well sawteeth oscillations, were identified at the TBR-1 discharges, and their main characteristics were studied. Comparing the measured period of the internal disruptions (sawteeth) with the ones expected from scaling laws, good agreements is reached. The measured sawteeth crashes agree with the values expected from the Kadomtsev's model. External helical fields (CHR), corresponding to m/n=2/1 helicity were produced in order to inhibit or criate disruptive instabilities. A strong weakening of the mhd activity, present in the TBR-1 discharges, was clearly detected. The soft X-ray detection system, projected and constructed for this work, was used to obtain the electron temperatures of regions close to the center of the plasma column (T(r=0) ∼ 205 eV and T(r ± 3,8) ∼ 85 eV), using the absorbing foils method. Using the Spitzer formula, Z sub (eff) values were also obtained. (author) [pt

  18. Emerging and Disruptive Technologies

    OpenAIRE

    Kricka, Larry J.

    2016-01-01

    Several emerging or disruptive technologies can be identified that might, at some point in the future, displace established laboratory medicine technologies and practices. These include increased automation in the form of robots, 3-D printing, technology convergence (e.g., plug-in glucose meters for smart phones), new point-of-care technologies (e.g., contact lenses with sensors, digital and wireless enabled pregnancy tests) and testing locations (e.g., Retail Health Clinics, new at-home test...

  19. Disrupting the Industry with Play

    DEFF Research Database (Denmark)

    Lund, Henrik Hautop

    2016-01-01

    or two ago. This is significantly disrupting the industry in several market sectors. This paper describes the components of the playware and embodied artificial intelligence research that has led to disruption in the industrial robotics sector, and which points to the next disruption of the health care...

  20. Wound Disruption Following Colorectal Operations.

    Science.gov (United States)

    Moghadamyeghaneh, Zhobin; Hanna, Mark H; Carmichael, Joseph C; Mills, Steven; Pigazzi, Alessio; Nguyen, Ninh T; Stamos, Michael J

    2015-12-01

    Postoperative wound disruption is associated with high morbidity and mortality. We sought to identify the risk factors and outcomes of wound disruption following colorectal resection. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was used to examine the clinical data of patients who underwent colorectal resection from 2005 to 2013. Multivariate regression analysis was performed to identify risk factors of wound disruption. We sampled a total of 164,297 patients who underwent colorectal resection. Of these, 2073 (1.3 %) had wound disruption. Patients with wound disruption had significantly higher mortality (5.1 vs. 1.9 %, AOR: 1.46, P = 0.01). The highest risk of wound disruption was seen in patients with wound infection (4.8 vs. 0.9 %, AOR: 4.11, P disruption such as chronic steroid use (AOR: 1.71, P disruption compared to open surgery (AOR: 0.61, P disruption occurs in 1.3 % of colorectal resections, and it correlates with mortality of patients. Wound infection is the strongest predictor of wound disruption. Chronic steroid use, obesity, severe COPD, prolonged operation, non-elective admission, and serum albumin level are strongly associated with wound disruption. Utilization of the laparoscopic approach may decrease the risk of wound disruption when possible.

  1. Disruptive Space Technology

    OpenAIRE

    Benson, Jim

    2004-01-01

    In 1997 "The Innovator’s Dilemma" by Clayton M. Christensen became a popular book in the small satellite and launch vehicle communities. But like the weather, every one talks about “Disruptive Technology” but few do anything about it. In the ‘70s and ‘80s, people were looking for “Paradigm Shifts,” and since the resurrection of Donald Rumsfeld, a recent watchword has been “Transformational Technology.” But today’s buzzword is now “Responsive Space Systems.”

  2. Disruption - Access cards service

    CERN Multimedia

    2014-01-01

    We would like to inform you that between 10 November and 15 December 2014, the access cards service in Building 55 will be disrupted, as the GS Department has decided to improve the facilities for users of this building. During the work, you will find the registration, biometric registration and dosimeter exchange services on the second floor of Building 55 and the vehicle sticker service on the ground floor along with the access cards service. We thank you for your understanding and apologise for any inconvenience caused.

  3. Disruptions in the TFTR tokamak

    International Nuclear Information System (INIS)

    Janos, A.; Fredrickson, E.D.; McGuire, K.; Batha, S.H.; Bell, M.G.; Bitter, M.; Budny, R.; Bush, C.E.; Efthimion, P.C.; Hawryluk, R.J.; Hill, K.W.; Hosea, J.; Jobes, F.C.; Johnson, D.W.; Levinton, F.; Mansfield, D.; Meade, D.; Medley, S.S.; Monticello, D.; Mueller, D.; Nagayama, Y.; Owens, D.K.; Park, H.; Park, W.; Post, D.E.; Schivell, J.; Strachan, J.D.; Taylor, G.; Ulrickson, M.; Goeler, S. von; Wilfrid, E.; Wong, K.L.; Yamada, M.; Young, K.M.; Zarnstorff, M.C.; Zweben, S.J.; Drake, J.F.; Kleva, R.G.; Fleischmann, H.H.

    1993-03-01

    For a successful reactor, it will be useful to predict the occurrence of disruptions and to understand disruption effects including how a plasma disrupts onto the wall and how reproducibly it does so. Studies of disruptions on TFTR at both high-β pol and high-density have shown that, in both types, a fast growing m/n=1/1 mode plays an important role. In highdensity disruptions, a newly observed fast m/n = 1/1 mode occurs early in the thermal decay phase. For the first time in TFTR q-profile measurements just prior to disruptions have been made. Experimental studies of heat deposition patterns on the first wall of TFTR due to disruptions have provided information on MHD phenomena prior to or during the disruption, how the energy is released to the wall, and the reproducibility of the heat loads from disruptions. This information is important in the design of future devices such as ITER. Several new processes of runaway electron generation are theoretically suggested and their application to TFTR and ITER is considered, together with a preliminary assessment of x-ray data from runaways generated during disruptions

  4. Cell disruption for microalgae biorefineries.

    Science.gov (United States)

    Günerken, E; D'Hondt, E; Eppink, M H M; Garcia-Gonzalez, L; Elst, K; Wijffels, R H

    2015-01-01

    Microalgae are a potential source for various valuable chemicals for commercial applications ranging from nutraceuticals to fuels. Objective in a biorefinery is to utilize biomass ingredients efficiently similarly to petroleum refineries in which oil is fractionated in fuels and a variety of products with higher value. Downstream processes in microalgae biorefineries consist of different steps whereof cell disruption is the most crucial part. To maintain the functionality of algae biochemicals during cell disruption while obtaining high disruption yields is an important challenge. Despite this need, studies on mild disruption of microalgae cells are limited. This review article focuses on the evaluation of conventional and emerging cell disruption technologies, and a comparison thereof with respect to their potential for the future microalgae biorefineries. The discussed techniques are bead milling, high pressure homogenization, high speed homogenization, ultrasonication, microwave treatment, pulsed electric field treatment, non-mechanical cell disruption and some emerging technologies. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Disruptions in DIII-D

    International Nuclear Information System (INIS)

    Reiman, A.; Taylor, P.; Kellman, A.; LaHaye, R.

    1996-01-01

    We report on the results of a statistical analysis of the DIII-D disruption data base, and on an examination of a selected subset of the shots to determine the likely causes of disruptions. The statistical analysis focuses on the dependence of the disruption rate on key dimensionless parameters. We find that the disruption frequency is high at modest values of the parameters, and that it can be relatively low at operational limits. For example, the disruption frequency in an ITER relevant regime (β N /l i ∼ 2, 3 G > 0.6, where n G is the Greenwald limit) is approximately 23%. For this range of q, the disruption frequency rises only modestly to about 35% at the β limit, consistent with previous observations of a soft β limit for this q regime. For the range 6 95 G G < .9) in all q regimes we have studied. The location of the minimum moves to higher density with increasing q

  6. Overview of core disruptive accidents

    International Nuclear Information System (INIS)

    Marchaterre, J.F.

    1977-01-01

    An overview of the analysis of core-disruptive accidents is given. These analyses are for the purpose of understanding and predicting fast reactor behavior in severe low probability accident conditions, to establish the consequences of such conditions and to provide a basis for evaluating consequence limiting design features. The methods are used to analyze core-disruptive accidents from initiating event to complete core disruption, the effects of the accident on reactor structures and the resulting radiological consequences are described

  7. Fat suppression with short inversion time inversion-recovery and chemical-shift selective saturation: a dual STIR-CHESS combination prepulse for turbo spin echo pulse sequences.

    Science.gov (United States)

    Tanabe, Koji; Nishikawa, Keiichi; Sano, Tsukasa; Sakai, Osamu; Jara, Hernán

    2010-05-01

    To test a newly developed fat suppression magnetic resonance imaging (MRI) prepulse that synergistically uses the principles of fat suppression via inversion recovery (STIR) and spectral fat saturation (CHESS), relative to pure CHESS and STIR. This new technique is termed dual fat suppression (Dual-FS). To determine if Dual-FS could be chemically specific for fat, the phantom consisted of the fat-mimicking NiCl(2) aqueous solution, porcine fat, porcine muscle, and water was imaged with the three fat-suppression techniques. For Dual-FS and STIR, several inversion times were used. Signal intensities of each image obtained with each technique were compared. To determine if Dual-FS could be robust to magnetic field inhomogeneities, the phantom consisting of different NiCl(2) aqueous solutions, porcine fat, porcine muscle, and water was imaged with Dual-FS and CHESS at the several off-resonance frequencies. To compare fat suppression efficiency in vivo, 10 volunteer subjects were also imaged with the three fat-suppression techniques. Dual-FS could suppress fat sufficiently within the inversion time of 110-140 msec, thus enabling differentiation between fat and fat-mimicking aqueous structures. Dual-FS was as robust to magnetic field inhomogeneities as STIR and less vulnerable than CHESS. The same results for fat suppression were obtained in volunteers. The Dual-FS-STIR-CHESS is an alternative and promising fat suppression technique for turbo spin echo MRI. Copyright 2010 Wiley-Liss, Inc.

  8. Disrupted Refugee Family Life

    DEFF Research Database (Denmark)

    Shapiro, Ditte Krogh

    2017-01-01

    Fleeing civil war involves managing life threatening events and multiple disruptions of everyday life. The theoretical potentials of analysing the recreation of everyday family life among Syrian refugees in Denmark is explored based on conceptualizations that emphasize the collective agency...... of family members in social historical contexts. Studying the multiple perspectives of family members shows how social support conceptualized as care practises is conflictual in the changing everyday family practices that are transformed by policy. The purpose of studying how families manage to flee civil...... war and struggle to recreate an everyday life in exile is to contribute with contextualization and expansion of mainstream understandings of family life, suffering, and resilience in refugee family trajectories in multiple contexts....

  9. Disruptive Technology: An Uncertain Future

    Science.gov (United States)

    2005-05-21

    Technology that overturns market -- Military - Technology that causes a fundamental change in force structure, basing, and capability balance * Disruptive Technologies may arise from systems or enabling technology.

  10. Major disruption process in tokamak

    International Nuclear Information System (INIS)

    Kurita, Gen-ichi; Azumi, Masafumi; Tuda, Takashi; Takizuka, Tomonori; Tsunematsu, Toshihide; Tokuda, Shinji; Itoh, Kimitaka; Takeda, Tatsuoki

    1981-11-01

    The major disruption in a cylindrical tokamak is investigated by using the multi-helicity code, and the destabilization of the 3/2 mode by the mode coupling with the 2/1 mode is confirmed. The evolution of the magnetic field topology caused by the major disruption is studied in detail. The effect of the internal disruption on the 2/1 magnetic island width is also studied. The 2/1 magnetic island is not enhanced by the flattening of the q-profile due to the internal disruption. (author)

  11. Disrupting Ethnography through Rhizoanalysis

    Directory of Open Access Journals (Sweden)

    Diana Masny

    2014-10-01

    Full Text Available This article interrogates principles of ethnography in education proposed by Mills and Morton: raw tellings, analytic pattern, vignette and empathy. This article adopts a position that is uncomfortable, unconventional and interesting. It involves a deterritorialization/ rupture of ethnography in education in order to reterritorialize a different concept: rhizoanalysis, a way to position theory and data that is multilayered, complex and messy. Rhizoanalysis, the main focus of this article is not a method. It is an approach to research conditioned by a reality in which Deleuze and Guattari disrupt representation, interpretation and subjectivity. In this article, Multiple Literacies Theory, a theoretical and practical framework, becomes a lens to examine a rhizomatic study of a Korean family recently arrived to Australia and attending English as a second language classes. Observations and interviews recorded the daily lives of the family. The vignettes were selected by reading data intensively and immanently through a process of palpation, an innovative approach to educational research. Rhizoanalysis proposes to abandon the given and invent different ways of thinking about and doing research and what might happen when reading data differently, intensively and immanently, through Multiple Literacies Theory. Rhizoanalysis, a game-changer in the way research can be conducted, affords a different lens to tackle issues in education through research.

  12. Thigmotaxis Mediates Trail Odour Disruption.

    Science.gov (United States)

    Stringer, Lloyd D; Corn, Joshua E; Sik Roh, Hyun; Jiménez-Pérez, Alfredo; Manning, Lee-Anne M; Harper, Aimee R; Suckling, David M

    2017-05-10

    Disruption of foraging using oversupply of ant trail pheromones is a novel pest management application under investigation. It presents an opportunity to investigate the interaction of sensory modalities by removal of one of the modes. Superficially similar to sex pheromone-based mating disruption in moths, ant trail pheromone disruption lacks an equivalent mechanistic understanding of how the ants respond to an oversupply of their trail pheromone. Since significant compromise of one sensory modality essential for trail following (chemotaxis) has been demonstrated, we hypothesised that other sensory modalities such as thigmotaxis could act to reduce the impact on olfactory disruption of foraging behaviour. To test this, we provided a physical stimulus of thread to aid trailing by Argentine ants otherwise under disruptive pheromone concentrations. Trail following success was higher using a physical cue. While trail integrity reduced under continuous over-supply of trail pheromone delivered directly on the thread, provision of a physical cue in the form of thread slightly improved trail following and mediated trail disruption from high concentrations upwind. Our results indicate that ants are able to use physical structures to reduce but not eliminate the effects of trail pheromone disruption.

  13. Sleep disruption in chronic rhinosinusitis.

    Science.gov (United States)

    Mahdavinia, Mahboobeh; Schleimer, Robert P; Keshavarzian, Ali

    2017-05-01

    Chronic rhinosinusitis (CRS) is a common disease of the upper airways and paranasal sinuses with a marked decline in quality of life (QOL). CRS patients suffer from sleep disruption at a significantly higher proportion (60 to 75%) than in the general population (8-18 %). Sleep disruption in CRS causes decreased QOL and is linked to poor functional outcomes such as impaired cognitive function and depression. Areas covered: A systematic PubMed/Medline search was done to assess the results of studies that have investigated sleep and sleep disturbances in CRS. Expert commentary: These studies reported sleep disruption in most CRS patients. The main risk factors for sleep disruption in CRS include allergic rhinitis, smoking, and high SNOT-22 total scores. The literature is inconsistent with regard to the prevalence of sleep-related disordered breathing (e.g. obstructive sleep apnea) in CRS patients. Although nasal obstruction is linked to sleep disruption, the extent of sleep disruption in CRS seems to expand beyond that expected from physical blockage of the upper airways alone. Despite the high prevalence of sleep disruption in CRS, and its detrimental effects on QOL, the literature contains a paucity of studies that have investigated the mechanisms underlying this major problem in CRS.

  14. When Disruptive Approaches Meet Disruptive Technologies: Learning at a Distance.

    Science.gov (United States)

    Gibson, Chere Campbell

    2000-01-01

    Reviews research on constructivism in learning and selection of learning strategies. Suggests linking constructivism with instructional technologies for continuing medical education in order to "disrupt" reactive, habitual ways of learning and encourage active engagement. (SK)

  15. Plasma disruption modeling and simulation

    International Nuclear Information System (INIS)

    Hassanein, A.

    1994-01-01

    Disruptions in tokamak reactors are considered a limiting factor to successful operation and reliable design. The behavior of plasma-facing components during a disruption is critical to the overall integrity of the reactor. Erosion of plasma facing-material (PFM) surfaces due to thermal energy dump during the disruption can severely limit the lifetime of these components and thus diminish the economic feasibility of the reactor. A comprehensive understanding of the interplay of various physical processes during a disruption is essential for determining component lifetime and potentially improving the performance of such components. There are three principal stages in modeling the behavior of PFM during a disruption. Initially, the incident plasma particles will deposit their energy directly on the PFM surface, heating it to a very high temperature where ablation occurs. Models for plasma-material interactions have been developed and used to predict material thermal evolution during the disruption. Within a few microseconds after the start of the disruption, enough material is vaporized to intercept most of the incoming plasma particles. Models for plasma-vapor interactions are necessary to predict vapor cloud expansion and hydrodynamics. Continuous heating of the vapor cloud above the material surface by the incident plasma particles will excite, ionize, and cause vapor atoms to emit thermal radiation. Accurate models for radiation transport in the vapor are essential for calculating the net radiated flux to the material surface which determines the final erosion thickness and consequently component lifetime. A comprehensive model that takes into account various stages of plasma-material interaction has been developed and used to predict erosion rates during reactor disruption, as well during induced disruption in laboratory experiments

  16. Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

    DEFF Research Database (Denmark)

    Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine Marie Laure

    2011-01-01

    Background: Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine disrupting compounds (EDCs) share a high...... suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades....

  17. Symposium on disruptive instabilities at Garching

    International Nuclear Information System (INIS)

    Lackner, K.

    1979-01-01

    The phenomenon of disruptive instabilities was investigated with a special care at the IPP at Garching. After lectures and panel sessions it appears suitable, to subdivide the disruptive phenomena into four classes: 1. The internal disruption (the socalled saw-tooth oscillators). 2. the socalled reconnection disruptions. 3. The large disruptions. 4. The small disruptions. The four appearance forms of the phenomena are briefly explained. (GG) [de

  18. A Network Disruption Modeling Tool

    National Research Council Canada - National Science Library

    Leinart, James

    1998-01-01

    Given that network disruption has been identified as a military objective and C2-attack has been identified as the mechanism to accomplish this objective, a target set must be acquired and priorities...

  19. DISRUPTIVE TECHNOLOGIES: AN EXPANDED VIEW

    OpenAIRE

    JAMES M. UTTERBACK; HAPPY J. ACEE

    2005-01-01

    The term "disruptive technology" as coined by Christensen (1997, The Innovator's Dilemma; How New Technologies Cause Great Firms to Fail. Harvard Business School Press) refers to a new technology having lower cost and performance measured by traditional criteria, but having higher ancillary performance. Christensen finds that disruptive technologies may enter and expand emerging market niches, improving with time and ultimately attacking established products in their traditional markets. This...

  20. Improvements in disruption prediction at ASDEX Upgrade

    Energy Technology Data Exchange (ETDEWEB)

    Aledda, R., E-mail: raffaele.aledda@diee.unica.it; Cannas, B., E-mail: cannas@diee.unica.it; Fanni, A., E-mail: fanni@diee.unica.it; Pau, A., E-mail: alessandro.pau@diee.unica.it; Sias, G., E-mail: giuliana.sias@diee.unica.it

    2015-10-15

    Highlights: • A disruption prediction system for AUG, based on a logistic model, is designed. • The length of the disruptive phase is set for each disruption in the training set. • The model is tested on dataset different from that used during the training phase. • The generalization capability and the aging of the model have been tested. • The predictor performance is compared with the locked mode detector. - Abstract: In large-scale tokamaks disruptions have the potential to create serious damage to the facility. Hence disruptions must be avoided, but, when a disruption is unavoidable, minimizing its severity is mandatory. A reliable detection of a disruptive event is required to trigger proper mitigation actions. To this purpose machine learning methods have been widely studied to design disruption prediction systems at ASDEX Upgrade. The training phase of the proposed approaches is based on the availability of disrupted and non-disrupted discharges. In literature disruptive configurations were assumed appearing into the last 45 ms of each disruption. Even if the achieved results in terms of correct predictions were good, it has to be highlighted that the choice of such a fixed temporal window might have limited the prediction performance. In fact, it generates confusing information in cases of disruptions with disruptive phase different from 45 ms. The assessment of a specific disruptive phase for each disruptive discharge represents a relevant issue in understanding the disruptive events. In this paper, the Mahalanobis distance is applied to define a specific disruptive phase for each disruption, and a logistic regressor has been trained as disruption predictor. The results show that enhancements on the achieved performance on disruption prediction are possible by defining a specific disruptive phase for each disruption.

  1. Improvements in disruption prediction at ASDEX Upgrade

    International Nuclear Information System (INIS)

    Aledda, R.; Cannas, B.; Fanni, A.; Pau, A.; Sias, G.

    2015-01-01

    Highlights: • A disruption prediction system for AUG, based on a logistic model, is designed. • The length of the disruptive phase is set for each disruption in the training set. • The model is tested on dataset different from that used during the training phase. • The generalization capability and the aging of the model have been tested. • The predictor performance is compared with the locked mode detector. - Abstract: In large-scale tokamaks disruptions have the potential to create serious damage to the facility. Hence disruptions must be avoided, but, when a disruption is unavoidable, minimizing its severity is mandatory. A reliable detection of a disruptive event is required to trigger proper mitigation actions. To this purpose machine learning methods have been widely studied to design disruption prediction systems at ASDEX Upgrade. The training phase of the proposed approaches is based on the availability of disrupted and non-disrupted discharges. In literature disruptive configurations were assumed appearing into the last 45 ms of each disruption. Even if the achieved results in terms of correct predictions were good, it has to be highlighted that the choice of such a fixed temporal window might have limited the prediction performance. In fact, it generates confusing information in cases of disruptions with disruptive phase different from 45 ms. The assessment of a specific disruptive phase for each disruptive discharge represents a relevant issue in understanding the disruptive events. In this paper, the Mahalanobis distance is applied to define a specific disruptive phase for each disruption, and a logistic regressor has been trained as disruption predictor. The results show that enhancements on the achieved performance on disruption prediction are possible by defining a specific disruptive phase for each disruption.

  2. Disrupting neuronal transmission: Mechanism of DBS?

    Directory of Open Access Journals (Sweden)

    Satomi eChiken

    2014-03-01

    Full Text Available Applying high-frequency stimulation to deep brain rain structure, known as deep brain stimulation (DBS, has now been recognized an effective therapeutic option for a wide range of neurological and psychiatric disorders. DBS targeting the basal ganglia thalamo-cortical loop, especially the internal segment of the globus pallidus, subthalamic nucleus and thalamus, has been widely employed as a successful surgical therapy for movement disorders, such as Parkinson’s disease, dystonia and tremor. However, the neurophysiological mechanism underling the action of DBS remains unclear and is still under debate: does DBS inhibit or excite local neuronal elements? In this review, we will examine this question and propose the alternative interpretation: DBS dissociates inputs and outputs, resulting in disruption of abnormal signal transmission.

  3. Modeling Steroidogenesis Disruption Using High-Throughput ...

    Science.gov (United States)

    Environmental chemicals can elicit endocrine disruption by altering steroid hormone biosynthesis and metabolism (steroidogenesis) causing adverse reproductive and developmental effects. Historically, a lack of assays resulted in few chemicals having been evaluated for effects on steroidogenesis. The steroidogenic pathway is a series of hydroxylation and dehydrogenation steps carried out by CYP450 and hydroxysteroid dehydrogenase enzymes, yet the only enzyme in the pathway for which a high-throughput screening (HTS) assay has been developed is aromatase (CYP19A1), responsible for the aromatization of androgens to estrogens. Recently, the ToxCast HTS program adapted the OECD validated H295R steroidogenesis assay using human adrenocortical carcinoma cells into a high-throughput model to quantitatively assess the concentration-dependent (0.003-100 µM) effects of chemicals on 10 steroid hormones including progestagens, androgens, estrogens and glucocorticoids. These results, in combination with two CYP19A1 inhibition assays, comprise a large dataset amenable to clustering approaches supporting the identification and characterization of putative mechanisms of action (pMOA) for steroidogenesis disruption. In total, 514 chemicals were tested in all CYP19A1 and steroidogenesis assays. 216 chemicals were identified as CYP19A1 inhibitors in at least one CYP19A1 assay. 208 of these chemicals also altered hormone levels in the H295R assay, suggesting 96% sensitivity in the

  4. Disruptive event analysis: volcanism and igneous intrusion

    International Nuclear Information System (INIS)

    Crowe, B.M.

    1979-01-01

    Three basic topics are addressed for the disruptive event analysis: first, the range of disruptive consequences of a radioactive waste repository by volcanic activity; second, the possible reduction of the risk of disruption by volcanic activity through selective siting of a repository; and third, the quantification of the probability of repository disruption by volcanic activity

  5. Disruption studies on ASDEX upgrade

    International Nuclear Information System (INIS)

    Pautasso, G.; Egorov, S.; Finken, K.H.

    2003-01-01

    Disruptions generate large thermal and mechanical stresses on the tokamak components and are occasionally responsible for damages to the machine. For a future reactor disruptions have a significant impact on the design since all loading conditions must be analyzed in accordance with stricter design criteria (due to safety or difficult maintenance). Therefore the uncertainties affecting the predicted stresses must be reduced as much as possible with a more comprehensive set of measurements and analyses in this generation of experimental machines, and avoidance/predictive methods must be developed further. Disruption studies on ASDEX Upgrade are focused on these subjects, namely on: (1) understanding the physical mechanisms leading to this phenomenon in order to learn to avoid it or to predict its occurrence and to mitigate its effects; (2) analyzing the effects of disruptions on the machine to determine the functional dependence of the thermal and mechanical loads upon the discharge parameters. This allows, firstly, to dimension or reinforce the machine components to withstand these loads and, secondly, to extrapolate them to tokamaks still in the design phase; (3) learning to mitigate the consequence of disruptions, i.e. thermal loads, mechanical forces and runaways with injection of impurity pellets or gas. This paper is focused on most recent results concerning points, i.e. on the analysis of the degree of asymmetry of the forces and on the use of impurity puff for mitigation

  6. Disruption studies in ASDEX Upgrade

    International Nuclear Information System (INIS)

    Pautasso, G.

    2002-01-01

    Disruption generate large thermal and mechanical stresses on the tokamak components. For a future reactor disruptions have a significant impact on the design since all loading conditions must be analyzed in accordance with stricter design criteria (due to safety or difficult maintenance). Therefore the uncertainties affecting the predicted stresses must be reduced as much as possible with a more comprehensive set of measurements and analyses in this generation of experimental machines, and avoidance/ predictive methods must be developed further. The study of disruptions on ASDEX Upgrade is focused on these subjects, namely on: (1) understanding the physical mechanisms leading to this phenomenon and learning to avoid it or to predict its occurrence (with neural networks, for example) and to mitigate its effects; (2) analyzing the effects of disruptions on the machine to determine the functional dependence of the thermal and mechanical loads upon the discharge parameters. This allows to dimension or reinforce the machine components to withstand these loads and to extrapolate them to tokamaks still in the design phase; (3) learning to mitigate the consequence of disruptions. (author)

  7. IN UTERO EXPOSURE TO THE FUNGICIDE PROCYMIDONE AND DIBUTYL PHTHALATE PRODUCE DOSE ADDITIVE DISRUPTIONS OF MALE RAT SEXUAL DIFFERENTIATION

    Science.gov (United States)

    Procymidone (PRO) and dibutyl phthalate (DBP) alter male rat sexual differentiation by disrupting the androgen-signaling pathway via distinctly different cellular mechanisms of toxicity. DBP inhibits fetal Leydig cell androgen production whereas PRO binds AR and blocks androgen a...

  8. TAD disruption as oncogenic driver.

    Science.gov (United States)

    Valton, Anne-Laure; Dekker, Job

    2016-02-01

    Topologically Associating Domains (TADs) are conserved during evolution and play roles in guiding and constraining long-range regulation of gene expression. Disruption of TAD boundaries results in aberrant gene expression by exposing genes to inappropriate regulatory elements. Recent studies have shown that TAD disruption is often found in cancer cells and contributes to oncogenesis through two mechanisms. One mechanism locally disrupts domains by deleting or mutating a TAD boundary leading to fusion of the two adjacent TADs. The other mechanism involves genomic rearrangements that break up TADs and creates new ones without directly affecting TAD boundaries. Understanding the mechanisms by which TADs form and control long-range chromatin interactions will therefore not only provide insights into the mechanism of gene regulation in general, but will also reveal how genomic rearrangements and mutations in cancer genomes can lead to misregulation of oncogenes and tumor suppressors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Heterozygous Disruption of Autism susceptibility candidate 2 Causes Impaired Emotional Control and Cognitive Memory.

    Directory of Open Access Journals (Sweden)

    Kei Hori

    Full Text Available Mutations in the Autism susceptibility candidate 2 gene (AUTS2 have been associated with a broad range of psychiatric illnesses including autism spectrum disorders, intellectual disability and schizophrenia. We previously demonstrated that the cytoplasmic AUTS2 acts as an upstream factor for the Rho family small GTPase Rac1 and Cdc42 that regulate the cytoskeletal rearrangements in neural cells. Moreover, genetic ablation of the Auts2 gene in mice has resulted in defects in neuronal migration and neuritogenesis in the developing cerebral cortex caused by inactivation of Rac1-signaling pathway, suggesting that AUTS2 is required for neural development. In this study, we conducted a battery of behavioral analyses on Auts2 heterozygous mutant mice to examine the involvement of Auts2 in adult cognitive brain functions. Auts2-deficient mice displayed a decrease in exploratory behavior as well as lower anxiety-like behaviors in the absence of any motor dysfunction. Furthermore, the capability for novel object recognition and cued associative memory were impaired in Auts2 mutant mice. Social behavior and sensory motor gating functions were, however, normal in the mutant mice as assessed by the three-chamber test and prepulse inhibition test, respectively. Together, our findings indicate that AUTS2 is critical for the acquisition of neurocognitive function.

  10. Disruptive Technologies in Higher Education

    Science.gov (United States)

    Flavin, Michael

    2012-01-01

    This paper analyses the role of "disruptive" innovative technologies in higher education. In this country and elsewhere, Higher Education Institutions (HEIs) have invested significant sums in learning technologies, with Virtual Learning Environments (VLEs) being more or less universal, but these technologies have not been universally…

  11. Disruption mitigation on Tore Supra

    International Nuclear Information System (INIS)

    Martin, G.; Sourd, F.; Saint-Laurent, F.; Bucalossi, J.; Eriksson, L.G.

    2005-01-01

    During disruptions, the plasma energy is lost on the first wall within 1 ms, forces up to hundred tons are applied to the structures and kA of electrons are accelerated up to 50 MeV (runaway electrons). Already sources of concern in present day tokamaks, extrapolation to ITER shows the necessity of mitigation procedures, to avoid serious damages to in-vessel components. Massive gas injection was proposed, and encouraging tests have been done on Textor and DIII-D. Similar experiments where performed on Tore Supra, with the goal to validate their effect on runaway electrons, observed during the majority of disruptions. 0.1 mole of helium was injected within 5 ms in ohmic plasmas, up to 1.2 MA, either stable, or in a pre-disruptive phase (argon puffing). Beneficial effects where obtained: reduction of the current fall rate and eddy currents, total disappearance of runaway electrons and easy recovery for the next pulse, without noticeable helium pollution of following plasmas. Analysis of the 4 ms period between injection and disruption indicates that to reach these goals, one need to inject enough helium to keep it only partially ionised. It correspond to 0.1 g for Tore Supra, and extrapolate to hundred's of grams for ITER. (author)

  12. Disruptive Pupils and Teacher Stress.

    Science.gov (United States)

    Dunham, Jack

    1981-01-01

    Teachers have identified a number of stress situations in their work with disruptive children: insecurity due to student unpredictability, doubting their effectiveness, frustrated attempts at communication with other professionals, and feelings of isolation and limited social relationships (expressed by residential workers). (CT)

  13. JET and COMPASS asymmetrical disruptions

    Czech Academy of Sciences Publication Activity Database

    Gerasimov, S.N.; Abreu, P.; Baruzzo, M.; Drozdov, V.; Dvornova, A.; Havlíček, Josef; Hender, T.C.; Hronová-Bilyková, Olena; Kruezi, U.; Li, X.; Markovič, Tomáš; Pánek, Radomír; Rubinacci, G.; Tsalas, M.; Ventre, S.; Villone, F.; Zakharov, L.E.

    2015-01-01

    Roč. 55, č. 11 (2015), s. 113006-113006 ISSN 0029-5515 R&D Projects: GA MŠk(CZ) LM2011021 Institutional support: RVO:61389021 Keywords : tokamak * asymmetrical disruption * JET * COMPASS Subject RIV: BL - Plasma and Gas Discharge Physics Impact factor: 4.040, year: 2015

  14. Disruption mitigation on Tore Supra

    International Nuclear Information System (INIS)

    Martin, G.; Sourd, F.; Saint-Laurent, F.; Bucalossi, J.; Eriksson, L.G.

    2004-01-01

    During disruptions, the plasma energy is lost on the first wall within 1 ms, forces up to hundred tons are applied to the structures and kA of electrons are accelerated up to 50 MeV (runaway electrons). Already sources of concern in present day tokamaks, extrapolation to ITER shows the necessity of mitigation procedures, to avoid serious damages to in-vessel components. Massive gas injection was proposed, and encouraging tests have been done on Textor and DIII-D. Similar experiments where performed on Tore Supra, with the goal to validate their effect on runaway electrons, observed during the majority of disruptions. 0.1 mole of helium was injected within 5 ms in ohmic plasmas, up to 1.2 MA, either stable, or in a pre-disruptive phase (argon puffing). Beneficial effects where obtained: reduction of the current fall rate and eddy currents, total disappearance of runaway electrons and easy recovery for the next pulse, without noticeable helium pollution of following plasmas. Analysis of the 4 ms period between injection and disruption indicates that to reach these goals, one need to inject enough helium to keep it only partially ionised. It corresponds to 0.1 g for Tore Supra, and extrapolate to hundreds of grams for ITER. (authors)

  15. Marital Alternatives and Marital Disruption.

    Science.gov (United States)

    Udry, J. Richard

    1981-01-01

    Explores the usefulness of "marital alternatives" as a dimension in explaining marital stability, using longitudinal data from a panel of married, White, urban couples from 16 urban areas. Results indicated the dimension of marital alternatives appeared to be a better predictor of marital disruption than marital satisfaction. (Author/RC)

  16. Will blockchain disrupt your business?

    OpenAIRE

    Schmeiss, Jessica

    2018-01-01

    Blockchain has been praised to be “the technology most likely to change the next decade of business”. The disruptive power of the blockchain technology is yet limited, says HIIG-researcher Jessica Schmeiss. Beyond the hype, there a opportunities for companies to make their current business models more cost-effective and more efficient.

  17. Supply disruption cost for power network planning

    International Nuclear Information System (INIS)

    Kjoelle, G.H.

    1992-09-01

    A description is given of the method of approach to calculate the total annual socio-economic cost of power supply disruption and non-supplied energy, included the utilities' cost for planning. The total socio-economic supply disruption cost is the sum of the customers' disruption cost and the utilities' cost for failure and disruption. The mean weighted disruption cost for Norway for one hour disruption is NOK 19 per kWh. The customers' annual disruption cost is calculated with basis in the specific disruption cost referred to heavy load (January) and dimensioning maximum loads. The loads are reduced by factors taking into account the time variations of the failure frequency, duration, the loads and the disruption cost. 6 refs

  18. Survey of disruption causes at JET

    International Nuclear Information System (INIS)

    De Vries, P.C.; Johnson, M.F.; Alper, B.; Hender, T.C.; Riccardo, V.; Buratti, P.; Koslowski, H.R.

    2011-01-01

    A survey has been carried out into the causes of all 2309 disruptions over the last decade of JET operations. The aim of this survey was to obtain a complete picture of all possible disruption causes, in order to devise better strategies to prevent or mitigate their impact. The analysis allows the effort to avoid or prevent JET disruptions to be more efficient and effective. As expected, a highly complex pattern of chain of events that led to disruptions emerged. It was found that the majority of disruptions had a technical root cause, for example due to control errors, or operator mistakes. These bring a random, non-physics, factor into the occurrence of disruptions and the disruption rate or disruptivity of a scenario may depend more on technical performance than on physics stability issues. The main root cause of JET disruptions was nevertheless due to neo-classical tearing modes that locked, closely followed in second place by disruptions due to human error. The development of more robust operational scenarios has reduced the JET disruption rate over the last decade from about 15% to below 4%. A fraction of all disruptions was caused by very fast, precursorless unpredictable events. The occurrence of these disruptions may set a lower limit of 0.4% to the disruption rate of JET. If one considers on top of that human error and all unforeseen failures of heating or control systems this lower limit may rise to 1.0% or 1.6%, respectively.

  19. Structured Literature Review of digital disruption literature

    DEFF Research Database (Denmark)

    Vesti, Helle; Rosenstand, Claus Andreas Foss; Gertsen, Frank

    2018-01-01

    Digital disruption is a term/phenomenon frequently appearing in innovation management literature. However, no academic consensus exists as to what it entails; conceptual nor theoretical. We use the SLR-method (Structured Literature Review) to investigate digital disruption literature. A SLR......-study conducted in 2017 revealed some useful information on how disruption and digital disruption literature has developed over a specific period. However, this study was less representative of papers addressing digital disruption; which is the in-depth subject of this paper. To accommodate this, we intend...... to conduct a similar SLR-study assembling a body literature having digital disruption as the only common denominator...

  20. Biosensor discovery of thyroxine transport disrupting chemicals

    International Nuclear Information System (INIS)

    Marchesini, Gerardo R.; Meimaridou, Anastasia; Haasnoot, Willem; Meulenberg, Eline; Albertus, Faywell; Mizuguchi, Mineyuki; Takeuchi, Makoto; Irth, Hubertus; Murk, Albertinka J.

    2008-01-01

    Ubiquitous chemicals may interfere with the thyroid system that is essential in the development and physiology of vertebrates. We applied a surface plasmon resonance (SPR) biosensor-based screening method for the fast screening of chemicals with thyroxine (T4) transport disrupting activity. Two inhibition assays using the main thyroid hormone transport proteins, T4 binding globulin (TBG) and transthyretin (TTR), in combination with a T4-coated biosensor chip were optimized and automated for screening chemical libraries. The transport protein-based biosensor assays were rapid, high throughput and bioeffect-related. A library of 62 chemicals including the natural hormones, polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and metabolites, halogenated bisphenol A (BPA), halogenated phenols, pharmaceuticals, pesticides and other potential environmentally relevant chemicals was tested with the two assays. We discovered ten new active compounds with moderate to high affinity for TBG with the TBG assay. Strikingly, the most potent binding was observed with hydroxylated metabolites of the brominated diphenyl ethers (BDEs) BDE 47, BDE 49 and BDE 99, that are commonly found in human plasma. The TTR assay confirmed the activity of previously identified hydroxylated metabolites of PCBs and PBDEs, halogenated BPA and genistein. These results show that the hydroxylated metabolites of the ubiquitous PBDEs not only target the T4 transport at the TTR level, but also, and to a great extent, at the TBG level where most of the T4 in humans is circulating. The optimized SPR biosensor-based transport protein assay is a suitable method for high throughput screening of large libraries for potential thyroid hormone disrupting compounds

  1. Biosensor discovery of thyroxine transport disrupting chemicals.

    Science.gov (United States)

    Marchesini, Gerardo R; Meimaridou, Anastasia; Haasnoot, Willem; Meulenberg, Eline; Albertus, Faywell; Mizuguchi, Mineyuki; Takeuchi, Makoto; Irth, Hubertus; Murk, Albertinka J

    2008-10-01

    Ubiquitous chemicals may interfere with the thyroid system that is essential in the development and physiology of vertebrates. We applied a surface plasmon resonance (SPR) biosensor-based screening method for the fast screening of chemicals with thyroxine (T4) transport disrupting activity. Two inhibition assays using the main thyroid hormone transport proteins, T4 binding globulin (TBG) and transthyretin (TTR), in combination with a T4-coated biosensor chip were optimized and automated for screening chemical libraries. The transport protein-based biosensor assays were rapid, high throughput and bioeffect-related. A library of 62 chemicals including the natural hormones, polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and metabolites, halogenated bisphenol A (BPA), halogenated phenols, pharmaceuticals, pesticides and other potential environmentally relevant chemicals was tested with the two assays. We discovered ten new active compounds with moderate to high affinity for TBG with the TBG assay. Strikingly, the most potent binding was observed with hydroxylated metabolites of the brominated diphenyl ethers (BDEs) BDE 47, BDE 49 and BDE 99, that are commonly found in human plasma. The TTR assay confirmed the activity of previously identified hydroxylated metabolites of PCBs and PBDEs, halogenated BPA and genistein. These results show that the hydroxylated metabolites of the ubiquitous PBDEs not only target the T4 transport at the TTR level, but also, and to a great extent, at the TBG level where most of the T4 in humans is circulating. The optimized SPR biosensor-based transport protein assay is a suitable method for high throughput screening of large libraries for potential thyroid hormone disrupting compounds.

  2. Disruptive technologies and transportation : final report.

    Science.gov (United States)

    2016-06-01

    Disruptive technologies refer to innovations that, at first, may be considered unproven, lacking refinement, relatively unknown, or even impractical, but ultimately they supplant existing technologies and/or applications. In general, disruptive techn...

  3. Disrupting reconsolidation: pharmacological and behavioral manipulations

    NARCIS (Netherlands)

    Soeter, M.; Kindt, M.

    2011-01-01

    We previously demonstrated that disrupting reconsolidation by pharmacological manipulations "deleted" the emotional expression of a fear memory in humans. If we are to target reconsolidation in patients with anxiety disorders, the disruption of reconsolidation should produce content-limited

  4. Disrupting the habit of interviewing

    Directory of Open Access Journals (Sweden)

    Eileen Honan

    2014-06-01

    Full Text Available This paper contributes to the growing domain of ‘post-qualitative’ research and experiments with a new (representational form to move away from traditional and clichéd descriptions of research methods. In this paper, I want to interrogate the category of interview, and the habit of interviewing, to disrupt the clichés, so as to allow thinking of different ways of writing/speaking/representing the interactions between researcher and researched that will breathe new life into qualitative inquiries. I will attempt to flatten and shred, destabilise and disrupt our common-sense ideas about interview, including those held most sacred to the qualitative community, that of anonymity and confidentiality, as well as the privilege of the ‘transcript’ in re-presenting interview data.

  5. Bodily illusions disrupt tactile sensations.

    Science.gov (United States)

    D'Amour, Sarah; Pritchett, Lisa M; Harris, Laurence R

    2015-02-01

    To accurately interpret tactile information, the brain needs to have an accurate representation of the body to which to refer the sensations. Despite this, body representation has only recently been incorporated into the study of tactile perception. Here, we investigate whether distortions of body representation affect tactile sensations. We perceptually altered the length of the arm and the width of the waist using a tendon vibration illusion and measured spatial acuity and sensitivity. Surprisingly, we found reduction in both tactile acuity and sensitivity thresholds when the arm or waist was perceptually altered, which indicates a general disruption of low-level tactile processing. We postulate that the disruptive changes correspond to the preliminary stage as the body representation starts to change and may give new insights into sensory processing in people with long-term or sudden abnormal body representation such as are found in eating disorders or following amputation.

  6. Disruptive technologies - widening the scope -

    OpenAIRE

    Ruhlig, Klaus; Wiemken, Uwe

    2006-01-01

    The term „disruptive technologies” was introduced 1997 by Clayton Christensen in the context of innovations in the business world based upon technological developments. It was meant to sharpen the view for new technologies which can „disrupt” the economic context of a business. Since then it inspired other communities like so many terms in English (or American) language. One of these is the domain of international Research & Technology (R&T) cooperation and technological forecasting for publi...

  7. Disruptive technologies in higher education

    Directory of Open Access Journals (Sweden)

    Michael Flavin

    2012-08-01

    Full Text Available This paper analyses the role of “disruptive” innovative technologies in higher education. In this country and elsewhere, Higher Education Institutions (HEIs have invested significant sums in learning technologies, with Virtual Learning Environments (VLEs being more or less universal, but these technologies have not been universally adopted and used by students and staff. Instead, other technologies not owned or controlled by HEIs are widely used to support learning and teaching. According to Christensen's theory of Disruptive Innovation, these disruptive technologies are not designed explicitly to support learning and teaching in higher education, but have educational potential. This study uses Activity Theory and Expansive Learning to analyse data regarding the impact of disruptive technologies. The data were obtained through a questionnaire survey about awareness and use of technologies, and through observation and interviews, exploring participants’ actual practice. The survey answers tended to endorse Disruptive Innovation theory, with participants establishing meanings for technologies through their use of them, rather than in keeping with a designer's intentions. Observation revealed that learners use a narrow range of technologies to support learning, but with a tendency to use resources other than those supplied by their HEIs. Interviews showed that participants use simple and convenient technologies to support their learning and teaching. This study identifies a contradiction between learning technologies made available by HEIs, and technologies used in practice. There is no evidence to suggest that a wide range of technologies is being used to support learning and teaching. Instead, a small range of technologies is being used for a wide range of tasks. Students and lecturers are not dependent on their HEIs to support learning and teaching. Instead, they self-select technologies, with use weighted towards established brands. The

  8. Thyroid effects of endocrine disrupting chemicals

    DEFF Research Database (Denmark)

    Boas, Malene; Feldt-Rasmussen, Ulla; Main, Katharina M

    2012-01-01

    In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert ...... thyroid-disrupting effects, and there is emerging evidence that also phthalates, bisphenol A, brominated flame retardants and perfluorinated chemicals may have thyroid disrupting properties....

  9. Sideways Force Produced During Disruptions

    Science.gov (United States)

    Strauss, H. R.; Paccagnella, R.; Breslau, J.; Jardin, S.; Sugiyama, L.

    2012-10-01

    We extend previous studies [1] of vertical displacement events (VDE) which can produce disruptions. The emphasis is on the non axisymmetric ``sideways'' wall force Fx. Simulations are performed using the M3D [2] code. A VDE expels magnetic flux through the resistive wall until the last closed flux surface has q VDE is presented. The wall force depends strongly on γτw, where γ is the mode growth rate and τw is the wall resistive penetration time. The force Fx is largest when γτw is a constant of order unity, which depends on the initial conditions. For large values of γτw, the wall force asymptotes to a relatively smaller value, well below the critical value ITER is designed to withstand. The principle of disruption mitigation by massive gas injection is to cause a disruption with large γτw. [4pt] [1] H. R. Strauss, R. Paccagnella, and J. Breslau,Phys. Plasmas 17, 082505 (2010) [2] W. Park, E.V. Belova, G.Y. Fu, X. Tang, H.R. Strauss, L.E. Sugiyama, Phys. Plasmas 6, 1796 (1999).

  10. Engineering analysis of TFTR disruption

    International Nuclear Information System (INIS)

    Murray, J.G.; Rothe, K.E.; Bronner, G.

    1984-09-01

    This report covers an engineering approach quantifying the currents, forces, and times, as well as plasma position, for the worst-case disruption based on engineerign circuit assumptions for the plasma. As the plasma moves toward the wall during the current-decay phase of disruption, the wall currents affect the rate of movement and, hence, the decay time. The calculated structure-induced currents differ considerably from those calculated using a presently available criterion, which specifies that the plasma remains stationary in the center of the torus while decaying in 10 ms. This report outlines the method and basis for the engineering calculation used to determine the current and forces as a function of the circuit characteristics. It provides specific calculations for the Tokamak Fusion Test Reactor (TFTR) with variations in parameters such as the thermal decay time, the torus resistance, and plasma temperature during the current decay. The study reviews possible ways to reduce the disruption damage of TFTR by reducing the magnitude of the plasma external field energy that is absorbed by the plasma during the current decay

  11. Engineering analysis of TFTR disruption

    Energy Technology Data Exchange (ETDEWEB)

    Murray, J.G.; Rothe, K.E.; Bronner, G.

    1984-09-01

    This report covers an engineering approach quantifying the currents, forces, and times, as well as plasma position, for the worst-case disruption based on engineerign circuit assumptions for the plasma. As the plasma moves toward the wall during the current-decay phase of disruption, the wall currents affect the rate of movement and, hence, the decay time. The calculated structure-induced currents differ considerably from those calculated using a presently available criterion, which specifies that the plasma remains stationary in the center of the torus while decaying in 10 ms. This report outlines the method and basis for the engineering calculation used to determine the current and forces as a function of the circuit characteristics. It provides specific calculations for the Tokamak Fusion Test Reactor (TFTR) with variations in parameters such as the thermal decay time, the torus resistance, and plasma temperature during the current decay. The study reviews possible ways to reduce the disruption damage of TFTR by reducing the magnitude of the plasma external field energy that is absorbed by the plasma during the current decay.

  12. Probabilistic analysis of tokamak plasma disruptions

    International Nuclear Information System (INIS)

    Sanzo, D.L.; Apostolakis, G.E.

    1985-01-01

    An approximate analytical solution to the heat conduction equations used in modeling component melting and vaporization resulting from plasma disruptions is presented. This solution is then used to propagate uncertainties in the input data characterizing disruptions, namely, energy density and disruption time, to obtain a probabilistic description of the output variables of interest, material melted and vaporized. (orig.)

  13. Disruptive innovation as an entrepreneurial process

    NARCIS (Netherlands)

    Chandra, Y.; Yang, S.-J.S.; Singh, P.; Prajogo, D.; O'Neill, P.; Rahman, S.

    2008-01-01

    Research on conditions and causal mechanisms that influence disruptive innovation has been relatively unexplored in the extant research in disruptive innovation. By re-conceptualizing disruptive innovation as an entrepreneurial process at product, firm and industry levels, this paper draws on

  14. 3rd Annual Disruptive Technology Conference

    Science.gov (United States)

    2006-09-07

    Panel -- The Warfighter’s Perspective The Impact of Disruptive Technologies on Joint Warfighting MG Michael Vane, USA, Vice Director for Force...Structure, Resources & Assessment, Joint Staff, J-8 Panel -- Perspectives of Change: Identifying the Emerging Commercial Disruptive Technologies Decision...Mark Lucas, Board Member OSGeo, RadiantBlue Technologies Panel -- The Search for Disruptive Technologies - a “Blue Force” Multiplier Advanced

  15. Disruption and Distinctiveness in Higher Education

    Science.gov (United States)

    Purcell, Wendy

    2014-01-01

    "Disruption"--while an evocative word triggering feelings of anxiety and perhaps even fear--also signals renewal and growth. The Higher Education (HE) sector in England has experienced some profound disruption over the years, and yet has emerged stronger and renewed in many ways. The impact of recent disruptive forces, from fees to the…

  16. Statistical analysis of disruptions in JET

    International Nuclear Information System (INIS)

    De Vries, P.C.; Johnson, M.F.; Segui, I.

    2009-01-01

    The disruption rate (the percentage of discharges that disrupt) in JET was found to drop steadily over the years. Recent campaigns (2005-2007) show a yearly averaged disruption rate of only 6% while from 1991 to 1995 this was often higher than 20%. Besides the disruption rate, the so-called disruptivity, or the likelihood of a disruption depending on the plasma parameters, has been determined. The disruptivity of plasmas was found to be significantly higher close to the three main operational boundaries for tokamaks; the low-q, high density and β-limit. The frequency at which JET operated close to the density-limit increased six fold over the last decade; however, only a small reduction in disruptivity was found. Similarly the disruptivity close to the low-q and β-limit was found to be unchanged. The most significant reduction in disruptivity was found far from the operational boundaries, leading to the conclusion that the improved disruption rate is due to a better technical capability of operating JET, instead of safer operations close to the physics limits. The statistics showed that a simple protection system was able to mitigate the forces of a large fraction of disruptions, although it has proved to be at present more difficult to ameliorate the heat flux.

  17. Routine Responses to Disruption of Routines

    Science.gov (United States)

    Guha, Mahua

    2015-01-01

    "Organisational routines" is a widely studied research area. However, there is a dearth of research on disruption of routines. The few studies on disruption of routines discussed problem-solving activities that are carried out in response to disruption. In contrast, this study develops a theory of "solution routines" that are a…

  18. Dissociation in undergraduate students: disruptions in executive functioning.

    Science.gov (United States)

    Giesbrecht, Timo; Merckelbach, Harald; Geraerts, Elke; Smeets, Ellen

    2004-08-01

    The concept of dissociation refers to disruptions in attentional control. Attentional control is an executive function. Few studies have addressed the link between dissociation and executive functioning. Our study investigated this relationship in a sample of undergraduate students (N = 185) who completed the Dissociative Experiences Scale and the Random Number Generation Task. We found that minor disruptions in executive functioning were related to a subclass of dissociative experiences, notably dissociative amnesia and the Dissociative Experiences Scale Taxon. However, the two other subscales of the Dissociative Experiences Scale, measuring depersonalization and absorption, were unrelated to executive functioning. Our findings suggest that a failure to inhibit previous responses might contribute to the pathological memory manifestations of dissociation.

  19. Corrosion inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, A O

    1965-12-29

    An acid corrosion-inhibiting composition consists essentially of a sugar, and an alkali metal salt selected from the group consisting of iodides and bromides. The weight ratio of the sugar to the alkali metal salt is between 2:1 and about 20,000:1. Also, a corrosion- inhibited phosphoric acid composition comprising at least about 20 wt% of phosphoric acid and between about 0.1 wt% and about 10 wt% of molasses, and between about 0.0005 wt% and about 1 wt% of potassium iodide. The weight ratio of molasses to iodide is greater than about 2:1. (11 claims)

  20. A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission

    DEFF Research Database (Denmark)

    Nielsen, Jacob; Fejgin, Kim; Sotty, Florence

    2017-01-01

    on schizophrenia-related assays. Df(h1q21)/+ mice displayed increased hyperactivity in response to amphetamine challenge and increased sensitivity to the disruptive effects of amphetamine and phencyclidine hydrochloride (PCP) on prepulse inhibition. Probing of the direct dopamine (DA) pathway using the DA D1...... and basic functions such as reflexes, ASR, thermal pain sensitivity, and motor performance were unaltered. Similarly, anxiety related measures, baseline prepulse inhibition, and seizure threshold were unaltered. In addition to the central nervous system-related phenotypes, Df(h1q21)/+ mice exhibited reduced...

  1. From Digital Disruption to Business Model Scalability

    DEFF Research Database (Denmark)

    Nielsen, Christian; Lund, Morten; Thomsen, Peter Poulsen

    2017-01-01

    This article discusses the terms disruption, digital disruption, business models and business model scalability. It illustrates how managers should be using these terms for the benefit of their business by developing business models capable of achieving exponentially increasing returns to scale...... will seldom lead to business model scalability capable of competing with digital disruption(s)....... as a response to digital disruption. A series of case studies illustrate that besides frequent existing messages in the business literature relating to the importance of creating agile businesses, both in growing and declining economies, as well as hard to copy value propositions or value propositions that take...

  2. Towards a Disruptive Digital Platform Model

    DEFF Research Database (Denmark)

    Kazan, Erol

    that digital platforms leverage on three strategic design elements (i.e., business, architecture, and technology design) to create supportive conditions for facilitating disruption. To shed light on disruptive digital platforms, I opted for payment platforms as my empirical context and unit of analysis......Digital platforms are layered modular information technology architectures that support disruption. Digital platforms are particularly disruptive, as they facilitate the quick release of digital innovations that may replace established innovations. Yet, despite their support for disruption, we have...... not fully understood how such digital platforms can be strategically designed and configured to facilitate disruption. To that end, this thesis endeavors to unravel disruptive digital platforms from the supply perspective that are grounded on strategic digital platform design elements. I suggest...

  3. Professional Disruption in Health Regulation

    DEFF Research Database (Denmark)

    Hasselbalch, Jacob

    2016-01-01

    How do professions respond to fast-moving technological changes? Disruptive innovations overturn expectations about how markets function and develop, and they often raise moral, legal and scientific concerns among professionals. Sudden technological changes can result in a state of professional...... recent revision to the Tobacco Products Directive. Medical and public health professionals that control tobacco issues were challenged by a coalition of e-cigarette industry representatives, e-cigarette users, and liberal politicians. The challengers drew on the contending norm of harm reduction...

  4. Disruptive Innovation in Numerical Hydrodynamics

    Energy Technology Data Exchange (ETDEWEB)

    Waltz, Jacob I. [Los Alamos National Laboratory

    2012-09-06

    We propose the research and development of a high-fidelity hydrodynamic algorithm for tetrahedral meshes that will lead to a disruptive innovation in the numerical modeling of Laboratory problems. Our proposed innovation has the potential to reduce turnaround time by orders of magnitude relative to Advanced Simulation and Computing (ASC) codes; reduce simulation setup costs by millions of dollars per year; and effectively leverage Graphics Processing Unit (GPU) and future Exascale computing hardware. If successful, this work will lead to a dramatic leap forward in the Laboratory's quest for a predictive simulation capability.

  5. The left hand doesn't know what the right hand is doing: the disruptive effects of attention to the hands in skilled typewriting.

    Science.gov (United States)

    Logan, Gordon D; Crump, Matthew J C

    2009-10-01

    Everyone knows that attention to the details disrupts skilled performance, but little empirical evidence documents this fact. We show that attention to the hands disrupts skilled typewriting. We had skilled typists type words preceded by cues that told them to type only the letters assigned to one hand or to type all of the letters. Cuing the hands disrupted performance markedly, slowing typing and increasing the error rate (Experiment 1); these deleterious effects were observed even when no keystrokes were actually inhibited (Experiment 3). However, cuing the same letters with colors was not disruptive (Experiment 2). We account for the disruption with a hierarchical control model, in which an inner loop controls the hands and an outer loop controls what is typed. Typing letters using only one hand requires the outer loop to monitor the inner loop's output; the outer loop slows inner-loop cycle time to increase the likelihood of inhibiting responses with the unwanted hand. This produces the disruption.

  6. Designing Endocrine Disruption Out of the Next Generation of Chemicals.

    Science.gov (United States)

    Schug, T T; Abagyan, R; Blumberg, B; Collins, T J; Crews, D; DeFur, P L; Dickerson, S M; Edwards, T M; Gore, A C; Guillette, L J; Hayes, T; Heindel, J J; Moores, A; Patisaul, H B; Tal, T L; Thayer, K A; Vandenberg, L N; Warner, J; Watson, C S; Saal, F S Vom; Zoeller, R T; O'Brien, K P; Myers, J P

    2013-01-01

    A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical's potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at "the drawing board." It consists of five testing tiers ranging from broad in silico evaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a 'proof-of-principle' test, we ran 6 endocrine disrupting chemicals (EDCs) that act via

  7. Ion heating at the disruptive instability in the LT-3 Tokamak

    International Nuclear Information System (INIS)

    Bell, M.G.; Hutchinson, I.H.

    1976-01-01

    Measurements of the ion temperature and the toroidal current density and electric field during the disruptive instability in LT-3 are presented. Rapid ion heating and strong current inhibition have been observed. Fluctuation measurements suggest that these effects may be attributable to the excitation of ion cyclotron drift waves in the plasma

  8. Disruptive innovation for social change.

    Science.gov (United States)

    Christensen, Clayton M; Baumann, Heiner; Ruggles, Rudy; Sadtler, Thomas M

    2006-12-01

    Countries, organizations, and individuals around the globe spend aggressively to solve social problems, but these efforts often fail to deliver. Misdirected investment is the primary reason for that failure. Most of the money earmarked for social initiatives goes to organizations that are structured to support specific groups of recipients, often with sophisticated solutions. Such organizations rarely reach the broader populations that could be served by simpler alternatives. There is, however, an effective way to get to those underserved populations. The authors call it "catalytic innovation." Based on Clayton Christensen's disruptive-innovation model, catalytic innovations challenge organizational incumbents by offering simpler, good-enough solutions aimed at underserved groups. Unlike disruptive innovations, though, catalytic innovations are focused on creating social change. Catalytic innovators are defined by five distinct qualities. First, they create social change through scaling and replication. Second, they meet a need that is either overserved (that is, the existing solution is more complex than necessary for many people) or not served at all. Third, the products and services they offer are simpler and cheaper than alternatives, but recipients view them as good enough. Fourth, they bring in resources in ways that initially seem unattractive to incumbents. And fifth, they are often ignored, put down, or even encouraged by existing organizations, which don't see the catalytic innovators' solutions as viable. As the authors show through examples in health care, education, and economic development, both nonprofit and for-profit groups are finding ways to create catalytic innovation that drives social change.

  9. Modeling SOL evolution during disruptions

    International Nuclear Information System (INIS)

    Rognlien, T.D.; Cohen, R.H.; Crotinger, J.A.

    1996-01-01

    We present the status of our models and transport simulations of the 2-D evolution of the scrape-off layer (SOL) during tokamak disruptions. This evolution is important for several reasons: It determines how the power from the core plasma is distributed on material surfaces, how impurities from those surfaces or from gas injection migrate back to the core region, and what are the properties of the SOL for carrying halo currents. We simulate this plasma in a time-dependent fashion using the SOL transport code UEDGE. This code models the SOL plasma using fluid equations of plasma density, parallel momentum (along the magnetic field), electron energy, ion energy, and neutral gas density. A multispecies model is used to follow the density of different charge-states of impurities. The parallel transport is classical but with kinetic modifications; these are presently treated by flux limits, but we have initiated more sophisticated models giving the correct long-mean-free path limit. The cross-field transport is anomalous, and one of the results of this work is to determine reasonable values to characterize disruptions. Our primary focus is on the initial thermal quench phase when most of the core energy is lost, but the total current is maintained. The impact of edge currents on the MHD equilibrium will be discussed

  10. Potential of a lytic bacteriophage to disrupt Acinetobacter baumannii biofilms in vitro.

    Science.gov (United States)

    Liu, Yannan; Mi, Zhiqiang; Niu, Wenkai; An, Xiaoping; Yuan, Xin; Liu, Huiying; Wang, Yong; Feng, Yuzhong; Huang, Yong; Zhang, Xianglilan; Zhang, Zhiyi; Fan, Hang; Peng, Fan; Li, Puyuan; Tong, Yigang; Bai, Changqing

    2016-10-01

    The ability of Acinetobacter baumannii to form biofilms and develop antibiotic resistance makes it difficult to control infections caused by this bacterium. In this study, we explored the potential of a lytic bacteriophage to disrupt A. baumannii biofilms. The potential of the lytic bacteriophage to disrupt A. baumannii biofilms was assessed by performing electron microscopy, live/dead bacterial staining, crystal violet staining and by determining adenosine triphosphate release. The bacteriophage inhibited the formation of and disrupted preformed A. baumannii biofilms. Results of disinfection assay showed that the lytic bacteriophage lysed A. baumannii cells suspended in blood or grown on metal surfaces. These results suggest the potential of the lytic bacteriophage to disrupt A. baumannii biofilms.

  11. Suppression of Runaway Electrons by Resonant Magnetic Perturbations in TEXTOR Disruptions

    International Nuclear Information System (INIS)

    Lehnen, M.; Bozhenkov, S. A.; Abdullaev, S. S.; TEXTOR Team,; Jakubowski, M. W.

    2008-01-01

    The generation of runaway electrons in the international fusion experiment ITER disruptions can lead to severe damage at plasma facing components. Massive gas injection might inhibit the generation process, but the amount of gas needed can affect, e.g., vacuum systems. Alternatively, magnetic perturbations can suppress runaway generation by increasing the loss rate. In TEXTOR disruptions runaway losses were enhanced by the application of resonant magnetic perturbations with toroidal mode number n=1 and n=2. The disruptions are initiated by fast injection of about 3x10 21 argon atoms, which leads to a reliable generation of runaway electrons. At sufficiently high perturbation levels a reduction of the runaway current, a shortening of the current plateau, and the suppression of high energetic runaways are observed. These findings indicate the suppression of the runaway avalanche during disruptions

  12. Prefrontal cortex modulates desire and dread generated by nucleus accumbens glutamate disruption.

    Science.gov (United States)

    Richard, Jocelyn M; Berridge, Kent C

    2013-02-15

    Corticolimbic circuits, including direct projections from prefrontal cortex to nucleus accumbens (NAc), permit top-down control of intense motivations generated by subcortical circuits. In rats, localized disruptions of glutamate signaling within medial shell of NAc generate desire or dread, anatomically organized along a rostrocaudal gradient analogous to a limbic keyboard. At rostral locations in shell, these disruptions generate appetitive eating, but at caudal locations the disruptions generate progressively fearful behaviors (distress vocalizations, escape attempts, and antipredator reactions). Here, we asked whether medial prefrontal cortex can modulate intense motivations generated by subcortical NAc disruptions. We used simultaneous microinjections in medial prefrontal cortex regions and in NAc shell to examine whether the desire or dread generated by NAc shell disruptions is modulated by activation/inhibition of three specific regions of prefrontal cortex: medial orbitofrontal cortex, infralimbic cortex (homologous to area 25 or subgenual anterior cingulate in the human), or prelimbic cortex (midventral anterior cingulate). We found that activation of medial orbitofrontal cortex biased intense bivalent motivation in an appetitive direction by amplifying generation of eating behavior by middle to caudal NAc disruptions, without altering fear. In contrast, activation of infralimbic prefrontal cortex powerfully and generally suppressed both appetitive eating and fearful behaviors generated by NAc shell disruptions. These results suggest that corticolimbic projections from discrete prefrontal regions can either bias motivational valence or generally suppress subcortically generated intense motivations of desire or fear. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  13. β limit disruptions in the TFTR tokamak

    International Nuclear Information System (INIS)

    Fredrickson, E.D.; McGuire, K.; Janos, A.; Bell, M.; Budny, R.V.; Bush, C.E.; Manickam, J.; Mynick, H.; Nazikian, R.; Taylor, G.

    1994-11-01

    A disruptive β limit (β = plasma pressure/magnetic pressure) is observed in high performance plasmas in TFTR. The MHD character of these disruptions differs substantially from the disruptions in high density plasmas (density limit disruptions) on TFTR. The high β disruptions can occur with less than a milliseconds warning in the form of a fast growing precursor. The precursor appears to be an external kink or internal (m,n)=(1,1) kink strongly coupled through finite β effects and toroidal terms to higher m components. It does not have the open-quote cold bubble close-quote structure found in density limit disruptions. There is also no evidence for a change in the internal inductance, i.e., a major reconnection of the flux, at the time of the thermal quench

  14. The Effects of Disruption on Strategic Management

    DEFF Research Database (Denmark)

    Drejer, Anders

    2017-01-01

    There is a lot of interest in Disruption these days even though the concept itself is still under formation. Disruption can be traced back to the idea of disruptive technological change and the late 1990s but has reemerged in the public eye in current years under guises such as Big Data......, Digitalization, Globalization and much more. Furthermore, the effects of disruption are now being felt by organizations and industries all over the world. In this paper, we will try to outline and illustrate some of those effects using the case-study of an international, Danish, SME. The case company has been...... forced to face some challenges caused by disruption and in the process of doing so has changed its strategy process significantly towards a more learning based approach to strategic management. Keywords: disruption; case- study; SME; strategy process....

  15. Multistage Logistic Network Optimization under Disruption Risk

    OpenAIRE

    Rusman, Muhammad

    2013-01-01

    Getting over disruptions risk has been a challenging issue for many companies under the globalization that will link to potential external source such as demand uncertainties, natural disasters, and terrorist attacks. The disruption is an unexpected event that disturbs normal flows of products and materials within a supply chain. The disruption at one members of supply chain will propagate the offers and finally affect significant impacts on the entire chain. If we look back...

  16. CATASTROPHIC DISRUPTION OF COMET ISON

    Energy Technology Data Exchange (ETDEWEB)

    Keane, Jacqueline V.; Kleyna, Jan T.; Riesen, Timm-Emmanuel; Meech, Karen J. [Institute for Astronomy, University of Hawaii, 2680 Woodlawn Drive, Honolulu, HI 96822 (United States); Milam, Stefanie N.; Charnley, Steven B. [Astrochemistry Laboratory, NASA GSFC, MS 690, Greenbelt, MD 20771 (United States); Coulson, Iain M. [Joint Astronomy Center, 660 North Aohoku Place, Hilo, HI 96720 (United States); Sekanina, Zdenek [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Pasadena, CA 91109 (United States); Kracht, Rainer, E-mail: keane@ifa.hawaii.edu [Ostlandring 53, D-25335 Elmshorn, Schleswig-Holstein (Germany)

    2016-11-10

    We report submillimeter 450 and 850 μ m dust continuum observations for comet C/2012 S1 (ISON) obtained at heliocentric distances 0.31–0.08 au prior to perihelion on 2013 November 28 ( r {sub h} = 0.0125 au). These observations reveal a rapidly varying dust environment in which the dust emission was initially point-like. As ISON approached perihelion, the continuum emission became an elongated dust column spread out over as much as 60″ (>10{sup 5} km) in the anti-solar direction. Deconvolution of the November 28.04 850 μ m image reveals numerous distinct clumps consistent with the catastrophic disruption of comet ISON, producing ∼5.2 × 10{sup 10} kg of submillimeter-sized dust. Orbital computations suggest that the SCUBA-2 emission peak coincides with the comet's residual nucleus.

  17. Current disruption in toroidal devices

    International Nuclear Information System (INIS)

    1979-07-01

    Attempts at raising the density or the plasma current in a tokamak above certain critical values generally result in termination of the discharge by a disruption. This sudden end of the plasma current and plasma confinement is accompanied by large induced voltages and currents in the outer structures which, in large tokamaks, can only be handled with considerable effort, and which will probably only be tolerable in reactors as rare accidents. Because of its crucial importance for the construction and operation of tokamaks, this phenomenon and its theoretical interpretation were the subject of a three-day symposium organized by the International Atomic Energy Agency and Max-Planck-Institut fuer Plasmaphysik at Garching from February 14 to 16. (orig./HT)

  18. Catastrophic Disruption of Comet ISON

    Science.gov (United States)

    Keane, Jacqueline V.; Milam, Stefanie N.; Coulson, Iain M.; Kleyna, Jan T.; Sekanina, Zdenek; Kracht, Rainer; Riesen, Timm-Emmanuel; Meech, Karen J.; Charnley, Steven B.

    2016-01-01

    We report submillimeter 450 and 850 microns dust continuum observations for comet C/2012 S1 (ISON) obtained at heliocentric distances 0.31-0.08 au prior to perihelion on 2013 November 28 (rh?=?0.0125 au). These observations reveal a rapidly varying dust environment in which the dust emission was initially point-like. As ISON approached perihelion, the continuum emission became an elongated dust column spread out over as much as 60? (greater than 10(exp 5) km in the anti-solar direction. Deconvolution of the November 28.04 850 microns image reveals numerous distinct clumps consistent with the catastrophic disruption of comet ISON, producing approximately 5.2?×?10(exp 10) kg of submillimeter-sized dust. Orbital computations suggest that the SCUBA-2 emission peak coincides with the comet's residual nucleus.

  19. Incumbent response to disruptive innovation

    DEFF Research Database (Denmark)

    Kaulio, Matti; Thorén, Kent; Rohrbeck, René

    in relation to disruptive change. In relation to technical change the case company has successfully in transferred its technology from one generation to the next during more than 20 years. In relation to business model change the case company has been proactive but not successful in major business model......This article presents a preliminary analysis of a retrospective longitudinal case study of an incumbent, the Swedish-Finnish Telecom operator TeliaSonera AB, with focus on its responses to technical and business model change. Findings nuance the general understanding of Telco’s as passive actors...... changes, however successful in minor business model adaptions. An implication hereof is that the business model concept as such has low predictive power in explaining success and failure and is in the need of an operationalization. In addition, the article discusses the relationship between technological...

  20. Automatic location of disruption times in JET

    Science.gov (United States)

    Moreno, R.; Vega, J.; Murari, A.

    2014-11-01

    The loss of stability and confinement in tokamak plasmas can induce critical events known as disruptions. Disruptions produce strong electromagnetic forces and thermal loads which can damage fundamental components of the devices. Determining the disruption time is extremely important for various disruption studies: theoretical models, physics-driven models, or disruption predictors. In JET, during the experimental campaigns with the JET-C (Carbon Fiber Composite) wall, a common criterion to determine the disruption time consisted of locating the time of the thermal quench. However, with the metallic ITER-like wall (JET-ILW), this criterion is usually not valid. Several thermal quenches may occur previous to the current quench but the temperature recovers. Therefore, a new criterion has to be defined. A possibility is to use the start of the current quench as disruption time. This work describes the implementation of an automatic data processing method to estimate the disruption time according to this new definition. This automatic determination allows both reducing human efforts to locate the disruption times and standardizing the estimates (with the benefit of being less vulnerable to human errors).

  1. Automatic location of disruption times in JET.

    Science.gov (United States)

    Moreno, R; Vega, J; Murari, A

    2014-11-01

    The loss of stability and confinement in tokamak plasmas can induce critical events known as disruptions. Disruptions produce strong electromagnetic forces and thermal loads which can damage fundamental components of the devices. Determining the disruption time is extremely important for various disruption studies: theoretical models, physics-driven models, or disruption predictors. In JET, during the experimental campaigns with the JET-C (Carbon Fiber Composite) wall, a common criterion to determine the disruption time consisted of locating the time of the thermal quench. However, with the metallic ITER-like wall (JET-ILW), this criterion is usually not valid. Several thermal quenches may occur previous to the current quench but the temperature recovers. Therefore, a new criterion has to be defined. A possibility is to use the start of the current quench as disruption time. This work describes the implementation of an automatic data processing method to estimate the disruption time according to this new definition. This automatic determination allows both reducing human efforts to locate the disruption times and standardizing the estimates (with the benefit of being less vulnerable to human errors).

  2. Disruptive colouration and perceptual grouping.

    Science.gov (United States)

    Espinosa, Irene; Cuthill, Innes C

    2014-01-01

    Camouflage is the primary defence of many animals and includes multiple strategies that interfere with figure-ground segmentation and object recognition. While matching background colours and textures is widespread and conceptually straightforward, less well explored are the optical 'tricks', collectively called disruptive colouration, that exploit perceptual grouping mechanisms. Adjacent high contrast colours create false edges, but this is not sufficient for an object's shape to be broken up; some colours must blend with the background. We test the novel hypothesis that this will be particularly effective when the colour patches on the animal appear to belong to, not merely different background colours, but different background objects. We used computer-based experiments where human participants had to find cryptic targets on artificial backgrounds. Creating what appeared to be bi-coloured foreground objects on bi-coloured backgrounds, we generated colour boundaries that had identical local contrast but either lay within or between (illusory) objects. As predicted, error rates for targets matching what appeared to be different background objects were higher than for targets which had otherwise identical local contrast to the background but appeared to belong to single background objects. This provides evidence for disruptive colouration interfering with higher-level feature integration in addition to previously demonstrated low-level effects involving contour detection. In addition, detection was impeded in treatments where targets were on or in close proximity to multiple background colour or tone boundaries. This is consistent with other studies which show a deleterious influence of visual 'clutter' or background complexity on search.

  3. Disruptive colouration and perceptual grouping.

    Directory of Open Access Journals (Sweden)

    Irene Espinosa

    Full Text Available Camouflage is the primary defence of many animals and includes multiple strategies that interfere with figure-ground segmentation and object recognition. While matching background colours and textures is widespread and conceptually straightforward, less well explored are the optical 'tricks', collectively called disruptive colouration, that exploit perceptual grouping mechanisms. Adjacent high contrast colours create false edges, but this is not sufficient for an object's shape to be broken up; some colours must blend with the background. We test the novel hypothesis that this will be particularly effective when the colour patches on the animal appear to belong to, not merely different background colours, but different background objects. We used computer-based experiments where human participants had to find cryptic targets on artificial backgrounds. Creating what appeared to be bi-coloured foreground objects on bi-coloured backgrounds, we generated colour boundaries that had identical local contrast but either lay within or between (illusory objects. As predicted, error rates for targets matching what appeared to be different background objects were higher than for targets which had otherwise identical local contrast to the background but appeared to belong to single background objects. This provides evidence for disruptive colouration interfering with higher-level feature integration in addition to previously demonstrated low-level effects involving contour detection. In addition, detection was impeded in treatments where targets were on or in close proximity to multiple background colour or tone boundaries. This is consistent with other studies which show a deleterious influence of visual 'clutter' or background complexity on search.

  4. Endocrine disruptive effects in vitro of conazole antifungals used as pesticides and pharmaceutical

    DEFF Research Database (Denmark)

    Kjærstad, Mia Birkhøj; Taxvig, Camilla; Nellemann, Christine Lydia

    2010-01-01

    Widely used conazole antifungals were tested for endocrine disruptive effects using a panel of in vitro assays. They all showed endocrine disrupting potential and ability to act via several different mechanisms. Overall the imidazoles (econazole, ketoconazole, miconazole, prochloraz) were more...... inhibition of enzymes involved in the conversion of progesterone to testosterone. Prochloraz was most potent followed by econazole~miconazole>ketoconazole>tebuconazole>epoxiconazole>propiconazole. In the MCF-7 cell proliferation assay, the conazoles showed anti-estrogenic effect, including aromatase...... inhibition, since they inhibited the response induced by both 17β-estradiol (miconazole>econazole~ketoconazole>prochloraz>tebuconazole>epoxiconazole>propiconazole) and testosterone (econazole>miconazole>prochloraz>ketoconazole>tebuconazole>epoxiconazole>propiconazole). The triazoles were anti...

  5. Disrupting Jagged1-Notch signaling impairs spatial memory formation in adult mice.

    Science.gov (United States)

    Sargin, Derya; Botly, Leigh C P; Higgs, Gemma; Marsolais, Alexander; Frankland, Paul W; Egan, Sean E; Josselyn, Sheena A

    2013-07-01

    It is well-known that Notch signaling plays a critical role in brain development and growing evidence implicates this signaling pathway in adult synaptic plasticity and memory formation. The Notch1 receptor is activated by two subclasses of ligands, Delta-like (including Dll1 and Dll4) and Jagged (including Jag1 and Jag2). Ligand-induced Notch1 receptor signaling is modulated by a family of Fringe proteins, including Lunatic fringe (Lfng). Although Dll1, Jag1 and Lfng are critical regulators of Notch signaling, their relative contribution to memory formation in the adult brain is unknown. To investigate the roles of these important components of Notch signaling in memory formation, we examined spatial and fear memory formation in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 plus Lfng. We also examined motor activity, anxiety-like behavior and sensorimotor gating using the acoustic startle response in these mice. Of the lines of mutant mice tested, we found that only mice with reduced Jag1 expression (mice heterozygous for a null mutation in Jag1, Jag1(+/-)) showed a selective impairment in spatial memory formation. Importantly, all other behavior including open field activity, conditioned fear memory (both context and discrete cue), acoustic startle response and prepulse inhibition, was normal in this line of mice. These results provide the first in vivo evidence that Jag1-Notch signaling is critical for memory formation in the adult brain. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

  6. TIE2-expressing macrophages limit the therapeutic efficacy of the vascular disrupting agent, combretastatin A4 phosphate in mice.

    OpenAIRE

    Welford, Abigail F.; Biziato, Daniela; Coffelt, Seth B.; Nucera, Silvia; Fisher, Matthew; Pucci, Ferdinando; Di Serio, Clelia; Naldini, Luigi; De Palma, Michele; Tozer, Gillian M.; Lewis, Claire E.

    2011-01-01

    Vascular-disrupting agents (VDAs) such as combretastatin A4 phosphate (CA4P) selectively disrupt blood vessels in tumors and induce tumor necrosis. However, tumors rapidly repopulate after treatment with such compounds. Here, we show that CA4P-induced vessel narrowing, hypoxia, and hemorrhagic necrosis in murine mammary tumors were accompanied by elevated tumor levels of the chemokine CXCL12 and infiltration by proangiogenic TIE2-expressing macrophages (TEMs). Inhibiting TEM recruitment to CA...

  7. Prenatal immune challenge in rats: Altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to Poly IC

    OpenAIRE

    Vorhees, Charles V.; Graham, Devon L.; Braun, Amanda A.; Schaefer, Tori L.; Skelton, Matthew R.; Richtand, Neil M.; Williams, Michael T.

    2012-01-01

    Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into th...

  8. Criteria for initiation of tokamak disruptions

    International Nuclear Information System (INIS)

    Hopcraft, K.I.; Turner, M.F.

    1986-01-01

    The process by which a tokamak plasma evolves from an equilibrium state containing a saturated magnetic island to one which is disruptively unstable is discussed and illustrated by numerical simulation of a resistive magnetoplasma. Those elements which are required to initiate a disruption are delineated

  9. Disruption simulation for the EAST plasma

    International Nuclear Information System (INIS)

    Niu Xingping; Wu Bin

    2007-01-01

    The disruptions due to vertical displacement event for the EAST plasma are simulated in this article by using the TSC program. Meanwhile, the evolutions of the halo current and stress on vacuum vessel are calculated; the disruptions at different initial conditions are compared with each other, and killer pellet injection is simulated for the device fast shutting-down. (authors)

  10. Network Formation under the Threat of Disruption

    NARCIS (Netherlands)

    Hoyer, B.

    2013-01-01

    The studies in this thesis are focused on the impact the presence of a network disruptor has on network formation models. In particular, we build two theoretical models to study the effect of network disruption on network formation and test the effect network disruption has on equilibrium selection

  11. Inventory strategies to manage supply disruptions

    NARCIS (Netherlands)

    Atan, Z.; Snyder, L.V.; Gurnani, H.; Mehrotra, H.; Ray, S.

    2012-01-01

    Disruptions in supply chains occur routinely—both large ones, due to natural disasters, labor strikes, or terrorist attacks, and small ones, due to machine breakdowns, supplier stockouts, or quality problems (to name a few examples). Companies whose supply processes are affected by disruptions may

  12. Simulation of a major tokamak disruption

    International Nuclear Information System (INIS)

    White, R.B.; Monticello, D.A.; Rosenbluth, M.N.

    1977-08-01

    It is known that the internal tokamak disruption leads to a current profile which is flattened inside the surface where the safety factor equals unity. It is shown that such a profile can lead to m = 2 magnetic islands which grow to fill a substantial part of the tokamak cross section in a time consistent with the observations of the major disruption

  13. Disruptive technologies and networking in telecom industries

    DEFF Research Database (Denmark)

    Madsen, Erik Strøjer; Hartington, Simon

    in the telecommunication industry and finds significant similarities between the industry development and the literature on disruptive technology, which finds that incumbent companies are not able to react in a successful way when disruptions occur in their industry. By studying how the telecommunication industry...

  14. Disrupted Sleep: From Molecules to Cognition

    NARCIS (Netherlands)

    van Someren, E.J.; Cirelli, C.; Dijk, D.J.; Van Cauter, E.; Schwartz, S.; Chee, M.W.L.

    2015-01-01

    Although the functions of sleep remain to be fully elucidated, it is clear that there are far-reaching effects of its disruption, whether by curtailment for a single night, by a few hours each night over a long period, or by disruption in sleep continuity. Epidemiological and experimental studies of

  15. Disrupted Sleep : From Molecules to Cognition

    NARCIS (Netherlands)

    Van Someren, Eus J W; Cirelli, Chiara; Dijk, Derk-Jan; Van Cauter, Eve; Schwartz, Sophie; Chee, Michael W L

    2015-01-01

    UNLABELLED: Although the functions of sleep remain to be fully elucidated, it is clear that there are far-reaching effects of its disruption, whether by curtailment for a single night, by a few hours each night over a long period, or by disruption in sleep continuity. Epidemiological and

  16. Disruption Management in Passenger Railway Transportation

    DEFF Research Database (Denmark)

    Groth, Julie Jespersen; Potthoff, Daniel; Clausen, Jens

    2009-01-01

    This paper deals with disruption management in passenger railway transportation. In the disruption management process, many actors belonging to different organizations play a role. In this paper we therefore describe the process itself and the roles of the different actors. Furthermore, we discuss...

  17. Resistance to Disruption in a Classroom Setting

    Science.gov (United States)

    Parry-Cruwys, Diana E.; Neal, Carrie M.; Ahearn, William H.; Wheeler, Emily E.; Premchander, Raseeka; Loeb, Melissa B.; Dube, William V.

    2011-01-01

    Substantial experimental evidence indicates that behavior reinforced on a denser schedule is more resistant to disruption than is behavior reinforced on a thinner schedule. The present experiment studied resistance to disruption in a natural educational environment. Responding during familiar activities was reinforced on a multiple…

  18. Disruption of Retinol (Vitamin A Signaling by Phthalate Esters: SAR and Mechanism Studies.

    Directory of Open Access Journals (Sweden)

    Yanling Chen

    Full Text Available A spectrum of reproductive system anomalies (cryptorchidism, hypospadias, dysgenesis of Wolffian duct-derived tissues and prostate, and reduced sperm production in male rats exposed in utero to phthalate esters (PEs are thought to be caused by PE inhibition of fetal testosterone production. Recently, dibutyl and dipentyl phthalate (DBuP, DPnP were shown to disrupt the retinol signaling pathway (RSP in mouse pluripotent P19 embryonal carcinoma cells in vitro. The RSP regulates the synthesis and cellular levels of retinoic acid (RA, the active metabolite of retinol (vitamin A. In this new study, a total of 26 di- and mono-esters were screened to identify additional phthalate structures that disrupt the RSP and explore their mechanisms of action. The most potent PEs, those causing > 50% inhibition, contained aryl and cycloalkane groups or C4-C6 alkyl ester chains and were the same PEs reported to cause malformations in utero. They shared similar lipid solubility; logP values were between 4 and 6 and, except for PEs with butyl and phenyl groups, were stable for prolonged periods in culture. Mono- and cognate di-esters varied in ability to disrupt the RSP; e.g., DEHP was inactive but its monoester was active while DBuP was active yet its monoester was inactive. DBuP and dibenzyl phthalate both disrupted the synthesis of RA from retinol but not the ability of RA to activate gene transcription. Both PEs also disrupted the RSP in C3H10T1/2 multipotent mesenchymal stem cells. Based on this in vitro study showing that some PEs disrupt retinol signaling and previous in vivo studies that vitamin A/RA deficiency and PEs both cause strikingly similar anomalies in the male rat reproductive system, we propose that PE-mediated inhibition of testosterone and RA synthesis in utero are both causes of malformations in male rat offspring.

  19. Sideways wall force produced during tokamak disruptions

    Science.gov (United States)

    Strauss, H.; Paccagnella, R.; Breslau, J.; Sugiyama, L.; Jardin, S.

    2013-07-01

    A critical issue for ITER is to evaluate the forces produced on the surrounding conducting structures during plasma disruptions. We calculate the non-axisymmetric ‘sideways’ wall force Fx, produced in disruptions. Simulations were carried out of disruptions produced by destabilization of n = 1 modes by a vertical displacement event (VDE). The force depends strongly on γτwall, where γ is the mode growth rate and τwall is the wall penetration time, and is largest for γτwall = constant, which depends on initial conditions. Simulations of disruptions caused by a model of massive gas injection were also performed. It was found that the wall force increases approximately offset linearly with the displacement from the magnetic axis produced by a VDE. These results are also obtained with an analytical model. Disruptions are accompanied by toroidal variation of the plasma current Iφ. This is caused by toroidal variation of the halo current, as verified computationally and analytically.

  20. Towards a Framework of Digital Platform Disruption

    DEFF Research Database (Denmark)

    Kazan, Erol; Tan, Chee-Wee; Lim, Eric T. K.

    2014-01-01

    Digital platforms are disruptive information technology (IT) artifacts that erode conventional business logic associated with traditional market structures. This paper presents a framework for examining the disruptive potential of digital platforms whereby we postulate that the strategic interplay...... digital platforms purposely decouple platform layers, to foster open innovation and accelerate market disruption. This paper therefore represents a first concrete step aimed at unravelling the disruptive potential of digital platforms....... of governance regimes and platform layers is deterministic of whether disruptive derivatives are permitted to flourish. This framework has been employed in a comparative case study between centralized (i.e., PayPal) and decentralized (i.e., Coinkite) digital payment platforms to illustrate its applicability...

  1. Plasma membrane disruption: repair, prevention, adaptation

    Science.gov (United States)

    McNeil, Paul L.; Steinhardt, Richard A.

    2003-01-01

    Many metazoan cells inhabit mechanically stressful environments and, consequently, their plasma membranes are frequently disrupted. Survival requires that the cell rapidly repair or reseal the disruption. Rapid resealing is an active and complex structural modification that employs endomembrane as its primary building block, and cytoskeletal and membrane fusion proteins as its catalysts. Endomembrane is delivered to the damaged plasma membrane through exocytosis, a ubiquitous Ca2+-triggered response to disruption. Tissue and cell level architecture prevent disruptions from occurring, either by shielding cells from damaging levels of force, or, when this is not possible, by promoting safe force transmission through the plasma membrane via protein-based cables and linkages. Prevention of disruption also can be a dynamic cell or tissue level adaptation triggered when a damaging level of mechanical stress is imposed. Disease results from failure of either the preventive or resealing mechanisms.

  2. Applying a Cognitive Neuroscience Perspective to Disruptive Behavior Disorders: Implications for Schools.

    Science.gov (United States)

    Tyler, Patrick M; White, Stuart F; Thompson, Ronald W; Blair, R J R

    2018-02-12

    A cognitive neuroscience perspective seeks to understand behavior, in this case disruptive behavior disorders (DBD), in terms of dysfunction in cognitive processes underpinned by neural processes. While this type of approach has clear implications for clinical mental health practice, it also has implications for school-based assessment and intervention with children and adolescents who have disruptive behavior and aggression. This review articulates a cognitive neuroscience account of DBD by discussing the neurocognitive dysfunction related to emotional empathy, threat sensitivity, reinforcement-based decision-making, and response inhibition. The potential implications for current and future classroom-based assessments and interventions for students with these deficits are discussed.

  3. Microalgal cell disruption via ultrasonic nozzle spraying.

    Science.gov (United States)

    Wang, M; Yuan, W

    2015-01-01

    The objective of this study was to understand the effect of operating parameters, including ultrasound amplitude, spraying pressure, nozzle orifice diameter, and initial cell concentration on microalgal cell disruption and lipid extraction in an ultrasonic nozzle spraying system (UNSS). Two algal species including Scenedesmus dimorphus and Nannochloropsis oculata were evaluated. Experimental results demonstrated that the UNSS was effective in the disruption of microalgal cells indicated by significant changes in cell concentration and Nile red-stained lipid fluorescence density between all treatments and the control. It was found that increasing ultrasound amplitude generally enhanced cell disruption and lipid recovery although excessive input energy was not necessary for best results. The effect of spraying pressure and nozzle orifice diameter on cell disruption and lipid recovery was believed to be dependent on the competition between ultrasound-induced cavitation and spraying-generated shear forces. Optimal cell disruption was not always achieved at the highest spraying pressure or biggest nozzle orifice diameter; instead, they appeared at moderate levels depending on the algal strain and specific settings. Increasing initial algal cell concentration significantly reduced cell disruption efficiency. In all UNSS treatments, the effectiveness of cell disruption and lipid recovery was found to be dependent on the algal species treated.

  4. Summary report for ITER Task - T226B: Evaluation of ITER disruption erosion

    International Nuclear Information System (INIS)

    Hassanein, A.

    1995-02-01

    The behavior of divertor materials during a major disruption in a tokamak reactor is very important to successful and reliable operation of the device. Erosion of material surfaces due to a thermal energy dump can severely limit the lifetimes of plasma-facing components and thus diminish the reactor's economic feasibility. A comprehensive numerical model has been developed and used in this analysis, which includes all major physical processes taking place during plasma/material interactions. Models to account for material thermal evolution, plasma/vapor interaction physics, and models for hydrodynamic radiation transport in the developed vapor cloud above the exposed surface are implemented in a self-consistent manner to realistically assess disruption damage. The extent of self-protection from the developed vapor cloud in front of the incoming plasma particles is critically important in determining the overall disruption lifetime. Models to study detailed effects of the strong magnetic field on the behavior of the vapor cloud and on the net erosion rate have also been developed and analyzed. Candidate materials such as beryllium and carbon are considered in this analysis. The dependence of divertor disruption lifetime on disruption physics and reactor conditions is analyzed and discussed. In addition, material erosion from melting of plasma-facing components during a tokamak disruption is also a serious problem that limits reactor operation and economical reactor lifetime. In particular, metallic low-Z components such as Be will be subjected to severe melting during disruptions and edge localized modes (ELMs). Loss of the developed melt layer will critically shorten the lifetime of these components, severely contaminate the plasma, and seriously inhibit successful and reliable operation of the reactor. In this study mechanisms responsible for melt-layer loss during a disruption are also modeled and evaluated

  5. Erosion products in disruption simulation experiments

    International Nuclear Information System (INIS)

    Safronov, V.; Arkhipov, N.; Bakhtin, V.; Barsuk, V.; Kurkin, S.; Mironova, E.; Toporkov, D.; Vasenin, S.; Zhitlukhin, A.; Arkhipov, I.; Werle, H.; Wuerz, H.

    1998-01-01

    Erosion of divertor materials under tokamak disruption event presents a serious problem of ITER technology. Erosion restricts the divertor lifetime and leads to production of redeposited layers of the material retaining large amount of tritium, which is a major safety issue for future fusion reactor. Since ITER disruptive heat loads are not achievable in existing tokamaks, material erosion is studied in special simulation experiments. Till now the simulation experiments have focused mainly on investigation of shielding effect and measurement of erosion rate. In the present work the properties of eroded and redeposited graphite are studied under condition typical for hard ITER disruption. (author)

  6. Disruptions and Their Mitigation in TEXTOR

    International Nuclear Information System (INIS)

    Finken, K.H.; Jaspers, R.; Kraemer-Flecken, A.; Savtchkov, A.; Lehnen, M.; Waidmann, G.

    2005-01-01

    Disruptions remain a major concern for tokamak devices, particularly for large machines. The critical issues are the induced (halo) currents and the resulting forces, the excessive heating of exposed surfaces by the instantaneous power release, and the possible occurrence of highly energetic runaway electrons. The key topics of the investigations on TEXTOR in the recent years concerned (a) the power deposition pattern recorded by a fast infrared scanner, (b) the runaway generation measured by synchrotron radiation in the infrared spectral region, (c) method development for 'healing' discharges that are going to disrupt, and (d) massive gas puffing for mitigating the adverse effects of disruptions

  7. Visual in-pile fuel disruption experiments

    International Nuclear Information System (INIS)

    Cano, G.L.; Ostensen, R.W.; Young, M.F.

    1978-01-01

    In a loss-of-flow (LOF) accident in an LMFBR, the mode of disruption of fuel may determine the probability of a subsequent energetic excursion. To investigate these phenomena, in-pile disruption of fission-heated irradiated fuel pellets was recorded by high speed cinematography. Instead of fuel frothing or dust-cloud breakup (as used in the SAS code) massive and very rapid fuel swelling, not predicted by analytical models, occurred. These tests support massive fuel swelling as the initial mode of fuel disruption in a LOF accident. (author)

  8. Periodic disruptions in the MT-1 tokamak

    International Nuclear Information System (INIS)

    Zoletnik, S.

    1988-11-01

    Disruptive instabilities are common phenomena in toroidal devices, especially in tokamaks. Three types can be distinguished: internal, minor and major disruptions. Periodic minor disruptions in the MT-1 tokamak were measured systematically with values of the limiter safety factor between 4 and 10. The density limit as a function of plasma current and horizontal displacement was investigated. Precursor oscillations always appear before the instability with increasing amplitude but can be observed at the density limit with quasi-stationary amplitude. Phase correlation between precursor oscillations were measured with Mirnov coils and x-ray detectors, and they show good agreement with a simple magnetic island model. (R.P.) 11 refs.; 6 figs

  9. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. G.; Krægpøth, Morten; Nielsen, Helena Skyt

    2015-01-01

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving school-cohort. We...... identify three groups of potentially disruptive and emotionally sensitive children from detailed Danish register data: children with divorced parents, children with parents convicted of crime, and children with a psychiatric diagnosis. We find that adding potentially disruptive children lowers the academic...

  10. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. Grøne; Krægpøth, Morten; Nielsen, Helena Skyt

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving school-cohort. We...... identify three groups of potentially disruptive and emotionally sensitive children from detailed Danish register data: children with divorced parents, children with parents convicted of crime, and children with a psychiatric diagnosis. We find that adding potentially disruptive children lowers the academic...

  11. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. G.; Krægpøth, Morten Visby; Skyt Nielsen, Helena

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving schoolcohort. We...... identify three groups of potentially disruptive and emotionally sensitive children from detailed Danish register data: children with divorced parents, children with parents convicted of crime, and children with a psychiatric diagnosis. We find that adding potentially disruptive children lowers the academic...

  12. The immediate effects of acoustic trauma on excitation and inhibition in the inferior colliculus : A Wiener-kernel analysis

    NARCIS (Netherlands)

    Heeringa, Amarins Nieske; van Dijk, Pim

    Noise-induced tinnitus and hyperacusis are thought to correspond to a disrupted balance between excitation and inhibition in the central auditory system. Excitation and inhibition are often studied using pure tones; however, these responses do not reveal inhibition within the excitatory pass band.

  13. Glaciological parameters of disruptive event analysis

    International Nuclear Information System (INIS)

    Bull, C.

    1979-01-01

    The following disruptive events caused by ice sheets are considered: continental glaciation, erosion, loading and subsidence, deep ground water recharge, flood erosion, isostatic rebound rates, melting, and periodicity of ice ages

  14. Disruptive Innovation in Chinese and Indian Businesses

    DEFF Research Database (Denmark)

    markets, has made these emerging economies fertile ground for developing and applying disruptive innovations. A novel mix of key attributes distinctive from those of established technologies or business models, disruptive innovations are typically inferior, yet affordable and "good-enough" products...... or services, which originate in lower-end market segments, but later move up to compete with those provided by incumbent firms. This book sheds new light on disruptive innovations both from and for the bottom of the pyramid in China and India, from the point of view of local entrepreneurs and international...... firms seeking to operate their businesses there. It covers both the theoretical and practical implications of disruptive innovation using conceptual frameworks alongside detailed case studies, whilst also providing a comparison of conditions and strategic options in India and China. Further, unlike...

  15. Disruption mitigation studies in DIII-D

    International Nuclear Information System (INIS)

    Taylor, P.L.; Kellman, A.G.; Evans, T.E.

    1999-01-01

    Data on the discharge behavior, thermal loads, halo currents, and runaway electrons have been obtained in disruptions on the DIII-D tokamak. These experiments have also evaluated techniques to mitigate the disruptions while minimizing runaway electron production. Experiments injecting cryogenic impurity killer pellets of neon and argon and massive amounts of helium gas have successfully reduced these disruption effects. The halo current generation, scaling, and mitigation are understood and are in good agreement with predictions of a semianalytic model. Results from killer pellet injection have been used to benchmark theoretical models of the pellet ablation and energy loss. Runaway electrons are often generated by the pellets and new runaway generation mechanisms, modifications of the standard Dreicer process, have been found to explain the runaways. Experiments with the massive helium gas puff have also effectively mitigated disruptions without the formation of runaway electrons that can occur with killer pellets

  16. Runaway electron generation in tokamak disruptions

    International Nuclear Information System (INIS)

    Helander, P.; Andersson, F.; Fueloep, T.; Smith, H.; Anderson, D.; Lisak, M.; Eriksson, L.-G.

    2005-01-01

    The time evolution of the plasma current during a tokamak disruption is calculated by solving the equations for runaway electron production simultaneously with the induction equation for the toroidal electric field. The resistive diffusion time in a post-disruption plasma is typically comparable to the runaway avalanche growth time. Accordingly, the toroidal electric field induced after the thermal quench of a disruption diffuses radially through the plasma at the same time as it accelerates runaway electrons, which in turn back-react on the electric field. When these processes are accounted for in a self-consistent way, it is found that (1) the efficiency and time scale of runaway generation agrees with JET experiments; (2) the runaway current profile typically becomes more peaked than the pre-disruption current profile; and (3) can easily become radially filamented. It is also shown that higher runaway electron generation is expected if the thermal quench is sufficiently fast. (author)

  17. Disrupted functional brain networks in autistic toddlers

    NARCIS (Netherlands)

    Boersma, M.; Kemner, C.; Reus, M.A. de; Collin, G; Snijders, T.M.; Hofman, D.; Buitelaar, J.K.; Stam, C.J.; Heuvel, M.P. van den

    2013-01-01

    Communication and integration of information between brain regions plays a key role in healthy brain function. Conversely, disruption in brain communication may lead to cognitive and behavioral problems. Autism is a neurodevelopmental disorder that is characterized by impaired social interactions

  18. Integrated disruption avoidance and mitigation in KSTAR

    International Nuclear Information System (INIS)

    Kim, Jayhyun; Woo, M.H.; Han, H.; In, Y.; Bak, J.G.; Eidietis, N.W.

    2014-01-01

    The final target of Korea Superconducting Tokamak Advanced Research (KSTAR) aims advanced tokamak operation at plasma current 2 MA and toroidal field 3.5 T. In order to safely achieve the target, disruption counter-measures are unavoidable when considering the disruption risks, inevitably accompanied with high performance discharges, such as electro-magnetic load on conducting structures, collisional damage by run-away electrons, and thermal load on plasma facing components (PFCs). In this reason, the establishment of integrated disruption mitigation system (DMS) has been started for routine mega-ampere class operations of KSTAR since 2013 campaign. The DMS mainly consists of the disruption prediction and its avoidance/mitigation in company with logical/technical integration of them. We present the details of KSTAR DMS and the related experimental results in this article. (author)

  19. Disruption Management in Passenger Railway Transportation

    DEFF Research Database (Denmark)

    Jespersen-Groth, Julie; Potthoff, Daniel; Clausen, Jens

    This paper deals with disruption management in passenger railway transportation. In the disruption management process, many actors belonging to different organizations play a role. In this paper we therefore describe the process itself and the roles of the different actors. Furthermore, we discuss...... the three main subproblems in railway disruption management: timetable adjustment, and rolling stock and crew re-scheduling. Next to a general description of these problems, we give an overview of the existing literature and we present some details of the specific situations at DSB S-tog and NS....... These are the railway operators in the suburban area of Copenhagen, Denmark, and on the main railway lines in the Netherlands, respectively. Since not much research has been carried out yet on Operations Research models for disruption management in the railway context, models and techniques that have been developed...

  20. The Logic of Digital Platform Disruption

    DEFF Research Database (Denmark)

    Kazan, Erol; Tan, Chee-Wee; Lim, Eric T. K.

    Digital platforms are disruptive IT artifacts, because they facilitate the quick release of innovative platform derivatives from third parties (e.g., apps). This study endeavours to unravel the disruptive potential, caused by distinct designs and configurations of digital platforms on market...... environments. We postulate that the disruptive potential of digital platforms is determined by the degree of alignment among the business, technology and platform profiles. Furthermore, we argue that the design and configuration of the aforementioned three elements dictates the extent to which open innovation...... is permitted. To shed light on the disruptive potential of digital platforms, we opted for payment platforms as our unit of analysis. Through interviews with experts and payment providers, we seek to gain an in-depth appreciation of how contemporary digital payment platforms are designed and configured...

  1. Resonant Tidal Disruption in Galactic Nuclei

    OpenAIRE

    Rauch, Kevin P.; Ingalls, Brian

    1997-01-01

    It has recently been shown that the rate of angular momentum relaxation in nearly-Keplerian star clusters is greatly increased by a process termed resonant relaxation (Rauch & Tremaine 1996), who also argued that tidal disruption of stars in galactic nuclei containing massive black holes could be noticeably enhanced by this process. We describe here the results of numerical simulations of resonant tidal disruption which quantitatively test the predictions made by Rauch & Tremaine. The simulat...

  2. Disruptions, loads, and dynamic response of ITER

    International Nuclear Information System (INIS)

    Nelson, B.; Riemer, B.; Sayer, R.; Strickler, D.; Barabaschi, P.; Ioki, K.; Johnson, G.; Shimizu, K.; Williamson, D.

    1995-01-01

    Plasma disruptions and the resulting electromagnetic loads are critical to the design of the vacuum vessel and in-vessel components of the International Thermonuclear Experimental Reactor (ITER). This paper describes the status of plasma disruption simulations and related analysis, including the dynamic response of the vacuum vessel and in-vessel components, stresses and deflections in the vacuum vessel, and reaction loads in the support structures

  3. BUSINESS MODEL PATTERNS FOR DISRUPTIVE TECHNOLOGIES

    OpenAIRE

    BENJAMIN AMSHOFF; CHRISTIAN DÜLME; JULIAN ECHTERFELD; JÜRGEN GAUSEMEIER

    2015-01-01

    Companies nowadays face a myriad of business opportunities as a direct consequence of manifold disruptive technology developments. As a basic characteristic, disruptive technologies lead to a severe shift in value-creation networks giving rise to new market segments. One of the key challenges is to anticipate the business logics within these nascent and formerly unknown markets. Business model patterns promise to tackle this challenge. They can be interpreted as proven business model elements...

  4. RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines.

    Science.gov (United States)

    Narendrula, Rashmi; Mispel-Beyer, Kyle; Guo, Baoqing; Parissenti, Amadeo M; Pritzker, Laura B; Pritzker, Ken; Masilamani, Twinkle; Wang, Xiaohui; Lannér, Carita

    2016-02-24

    Cellular stressors and apoptosis-inducing agents have been shown to induce ribosomal RNA (rRNA) degradation in eukaryotic cells. Recently, RNA degradation in vivo was observed in patients with locally advanced breast cancer, where mid-treatment tumor RNA degradation was associated with complete tumor destruction and enhanced patient survival. However, it is not clear how widespread chemotherapy induced "RNA disruption" is, the extent to which it is associated with drug response or what the underlying mechanisms are. Ovarian (A2780, CaOV3) and breast (MDA-MB-231, MCF-7, BT474, SKBR3) cancer cell lines were treated with several cytotoxic chemotherapy drugs and total RNA was isolated. RNA was also prepared from docetaxel resistant A2780DXL and carboplatin resistant A2780CBN cells following drug exposure. Disruption of RNA was analyzed by capillary electrophoresis. Northern blotting was performed using probes complementary to the 28S and 18S rRNA to determine the origins of degradation bands. Apoptosis activation was assessed by flow cytometric monitoring of annexin-V and propidium iodide (PI) binding to cells and by measuring caspase-3 activation. The link between apoptosis and RNA degradation (disruption) was investigated using a caspase-3 inhibitor. All chemotherapy drugs tested were capable of inducing similar RNA disruption patterns. Docetaxel treatment of the resistant A2780DXL cells and carboplatin treatment of the A2780CBN cells did not result in RNA disruption. Northern blotting indicated that two RNA disruption bands were derived from the 3'-end of the 28S rRNA. Annexin-V and PI staining of docetaxel treated cells, along with assessment of caspase-3 activation, showed concurrent initiation of apoptosis and RNA disruption, while inhibition of caspase-3 activity significantly reduced RNA disruption. Supporting the in vivo evidence, our results demonstrate that RNA disruption is induced by multiple chemotherapy agents in cell lines from different tissues and is

  5. BINARY DISRUPTION BY MASSIVE BLACK HOLES: HYPERVELOCITY STARS, S STARS, AND TIDAL DISRUPTION EVENTS

    Energy Technology Data Exchange (ETDEWEB)

    Bromley, Benjamin C. [Department of Physics and Astronomy, University of Utah, 115 S 1400 E, Rm 201, Salt Lake City, UT 84112 (United States); Kenyon, Scott J.; Geller, Margaret J.; Brown, Warren R., E-mail: bromley@physics.utah.edu, E-mail: skenyon@cfa.harvard.edu, E-mail: mgeller@cfa.harvard.edu, E-mail: wbrown@cfa.harvard.edu [Smithsonian Astrophysical Observatory, 60 Garden Street, Cambridge, MA 02138 (United States)

    2012-04-20

    We examine whether disrupted binary stars can fuel black hole growth. In this mechanism, tidal disruption produces a single hypervelocity star (HVS) ejected at high velocity and a former companion star bound to the black hole. After a cluster of bound stars forms, orbital diffusion allows the black hole to accrete stars by tidal disruption at a rate comparable to the capture rate. In the Milky Way, HVSs and the S star cluster imply similar rates of 10{sup -5} to 10{sup -3} yr{sup -1} for binary disruption. These rates are consistent with estimates for the tidal disruption rate in nearby galaxies and imply significant black hole growth from disrupted binaries on 10 Gyr timescales.

  6. Mechanistic evaluation of endocrine disrupting chemicals

    DEFF Research Database (Denmark)

    Taxvig, Camilla

    BACKGROUND: This PhD project is part of the research area concerning effects of endocrine disrupters at the National Food Institute at DTU in Denmark. Endocrine disrupting chemicals (EDCs) have proved to be important for improper development of the male reproductive organs and subsequent for the ...... metabolising system using liver S9 mixtures or hepatic rat microsomes could be a convenient method for the incorporation of metabolic aspects into in vitro testing for endocrine disrupting effects.......BACKGROUND: This PhD project is part of the research area concerning effects of endocrine disrupters at the National Food Institute at DTU in Denmark. Endocrine disrupting chemicals (EDCs) have proved to be important for improper development of the male reproductive organs and subsequent......, to be able to detect effects and predict mixture effects. In addition, a new hypothesis have emerge concerning a potential role of exposure to endocrine disrupting chemicals, and the development of obesity and obesity related diseases. AIM: This PhD project aimed to gain more information regarding...

  7. Disruption modeling in support of ITER

    International Nuclear Information System (INIS)

    Bandyopadhyay, I.

    2015-01-01

    Plasma current disruptions and Vertical Displacement Events (VDEs) are one of the major concerns in any tokamak as they lead to large electromagnetic forces to tokamak first wall components and vacuum vessel. Their occurrence also means disruption to steady state operations of tokamaks. Thus future fusion reactors like ITER must ensure that disruptions and VDEs are minimized. However, since there is still finite probability of their occurrence, one must be able to characterize disruptions and VDEs and able to predict, for example, the plasma current quench time and halo current amplitude, which mainly determine the magnitude of the electromagnetic forces. There is a concerted effort globally to understand and predict plasma and halo current evolution during disruption in tokamaks through MHD simulations. Even though Disruption and VDEs are often 3D MHD perturbations in nature, presently they are mostly simulated using 2D axisymmetric MHD codes like the Tokamak Simulation Code (TSC) and DINA. These codes are also extensively benchmarked against experimental data in present day tokamaks to improve these models and their ability to predict these events in ITER. More detailed 3D models like M3D are only recently being developed, but they are yet to be benchmarked against experiments, as also they are massively computationally exhaustive

  8. Voluntary eyeblinks disrupt iconic memory.

    Science.gov (United States)

    Thomas, Laura E; Irwin, David E

    2006-04-01

    In the present research, we investigated whether eyeblinks interfere with cognitive processing. In Experiment 1, the participants performed a partial-report iconic memory task in which a letter array was presented for 106 msec, followed 50, 150, or 750 msec later by a tone that cued recall of onerow of the array. At a cue delay of 50 msec between array offset and cue onset, letter report accuracy was lower when the participants blinked following array presentation than under no-blink conditions; the participants made more mislocation errors under blink conditions. This result suggests that blinking interferes with the binding of object identity and object position in iconic memory. Experiment 2 demonstrated that interference due to blinks was not due merely to changes in light intensity. Experiments 3 and 4 demonstrated that other motor responses did not interfere with iconic memory. We propose a new phenomenon, cognitive blink suppression, in which blinking inhibits cognitive processing. This phenomenon may be due to neural interference. Blinks reduce activation in area V1, which may interfere with the representation of information in iconic memory.

  9. Disruption prediction with adaptive neural networks for ASDEX Upgrade

    International Nuclear Information System (INIS)

    Cannas, B.; Fanni, A.; Pautasso, G.; Sias, G.

    2011-01-01

    In this paper, an adaptive neural system has been built to predict the risk of disruption at ASDEX Upgrade. The system contains a Self Organizing Map, which determines the 'novelty' of the input of a Multi Layer Perceptron predictor module. The answer of the MLP predictor will be inhibited whenever a novel sample is detected. Furthermore, it is possible that the predictor produces a wrong answer although it is fed with known samples. In this case, a retraining procedure will be performed to update the MLP predictor in an incremental fashion using data coming from both the novelty detection, and from wrong predictions. In particular, a new update is performed whenever a missed alarm is triggered by the predictor. The performance of the adaptive predictor during the more recent experimental campaigns until November 2009 has been evaluated.

  10. Intracellular renin disrupts chemical communication between heart cells. Pathophysiological implications

    Directory of Open Access Journals (Sweden)

    Walmor eDe Mello

    2015-01-01

    Full Text Available The influence of intracellular renin on the process of chemical communication between cardiac cells was investigated in cell pairs isolated from the left ventricle of adult Wistar Kyoto rats. The enzyme together with Lucifer yellow CH was dialyzed into one cell of the pair using the whole cell clamp technique. The diffusion of the dye in the dialyzed and in non-dialyzed cell was followed by measuring the intensity of fluorescence in both cells as a function of time. The results indicated that; 1 under normal conditions, Lucifer Yellow flows from cell-to-cell through gap junctions; 2 the intracellular dialysis of renin (100nM disrupts chemical communication-an effect enhanced by simultaneous administration of angiotensinogen (100nM; 3 enalaprilat (10-9M administered to the cytosol together with renin reduced drastically the uncoupling action of the enzyme; 4 aliskiren (10-8M inhibited the effect of renin on chemical communication;5 the possible role of intracellular renin independently of angiotensin II (Ang II was evaluated including the increase of the inward calcium current elicited by the enzyme and the possible role of oxidative stress on the disruption of cell communication; 6 the possible harmful versus the beneficial effect of intracellular renin during myocardial infarction was discussed;7 the present results indicate that intracellular renin due to internalization or in situ synthesis, causes a severe impairment of chemical communication in the heart resulting in derangement of metabolic cooperation with serious consequences for heart function.

  11. Comparative toxicity and endocrine disruption potential of urban and rural atmospheric organic PM1 in JEG-3 human placental cells

    International Nuclear Information System (INIS)

    Drooge, Barend L. van; Marqueño, Anna; Grimalt, Joan O.; Fernández, Pilar; Porte, Cinta

    2017-01-01

    Outdoor ambient air particulate matter and air pollution are related to adverse effects on human health. The present study assesses the cytotoxicity and ability to disrupt aromatase activity of organic PM 1 extracts from rural and urban areas at equivalent air volumes from 2 to 30 m 3 , in human placental JEG-3 cells. Samples were chemically analyzed for particle bounded organic compounds with endocrine disrupting potential, i.e. PAH, O-PAH, phthalate esters, but also for organic molecular tracer compounds for the emission source identification. Rural samples collected in winter were cytotoxic at the highest concentration tested and strongly inhibited aromatase activity in JEG-3 cells. No cytotoxicity was detected in summer samples from the rural site and the urban samples, while aromatase activity was moderately inhibited in these samples. In the urban area, the street site samples, collected close to intensive traffic, showed stronger inhibition of aromatase activity than the samples simultaneously collected at a roof site, 50 m above ground level. The cytotoxicity and endocrine disruption potential of the samples were linked to combustion products, i.e. PAH and O-PAH, especially from biomass burning in the rural site in winter. - Highlights: • Organic extracts of outdoor ambient air PM1 showed aromatase activity inhibition in exposed human placental JEG-3 cells. • Cytotoxicity and strongest endocrine disruption was observed in rural winter samples, while lowest inhibition was observed in urban background site 50 m above a busy street. • Cytotoxicity and aromatase activity inhibition in the samples were linked to combustion products, i.e. PAH and O-PAH, especially from biomass burning. - Organic extracts from ambient air PM 1 related to biomass burning are more cytotoxic and have stronger endocrine disruption potential than urban PM 1 .

  12. MHD stability, operational limits and disruptions

    International Nuclear Information System (INIS)

    1999-01-01

    The present physics understandings of magnetohydrodynamic (MHD) stability of tokamak plasmas, the threshold conditions for onset of MHD instability, and the resulting operational limits on attainable plasma pressure (beta limit) and density (density limit), and the consequences of plasma disruption and disruption related effects are reviewed and assessed in the context of their application to a future DT burning reactor prototype tokamak experiment such as ITER. The principal considerations covered within the MHD stability and beta limit assessments are (i) magnetostatic equilibrium, ideal MHD stability and the resulting ideal MHD beta limit; (ii) sawtooth oscillations and the coupling of sawtooth activity to other types of MHD instability; (iii) neoclassical island resistive tearing modes and the corresponding limits on beta and energy confinement; (iv) wall stabilization of ideal MHD instabilities and resistive wall instabilities; (v) mode locking effects of non-axisymmetric error fields; (vi) edge localized MHD instabilities (ELMs, etc.); and (vii) MHD instabilities and beta/pressure gradient limits in plasmas with actively modified current and magnetic shear profiles. The principal considerations covered within the density limit assessments are (i) empirical density limits; (ii) edge power balance/radiative density limits in ohmic and L-mode plasmas; and (iii) edge parameter related density limits in H-mode plasmas. The principal considerations covered in the disruption assessments are (i) disruption causes, frequency and MHD instability onset; (ii) disruption thermal and current quench characteristics; (iii) vertical instabilities (VDEs), both before and after disruption, and plasma and in-vessel halo currents; (iv) after disruption runaway electron formation, confinement and loss; (v) fast plasma shutdown (rapid externally initiated dissipation of plasma thermal and magnetic energies); (vi) means for disruption avoidance and disruption effect mitigation; and

  13. Enhancing Tumor Drug Delivery by Laser-Activated Vascular Barrier Disruption

    Science.gov (United States)

    2009-12-01

    diabetic retinopathy . Therefore, se- lectively targeting existing blood vessels (vascular- disrupting therapy) and/or inhibiting the forma- tion of new...adhesion led to the formation of thrombi that can occlude blood vessels, causing vascular shutdown. However, viable tumor cells were often detected at...tumor sections (Fig. 4). However, viable tumor cells were commonly detected at tumor periphery. Because of the existence of viable peripheral tumor cells

  14. Endocrine Disrupting Contaminants—Beyond the Dogma

    Science.gov (United States)

    Guillette, Louis J.

    2006-01-01

    Descriptions of endocrine disruption have largely been associated with wildlife and driven by observations documenting estrogenic, androgenic, antiandrogenic, and antithyroid actions. These actions, in response to exposure to ecologically relevant concentrations of various environmental contaminants, have now been established in numerous vertebrate species. However, many potential mechanisms and endocrine actions have not been studied. For example, the DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] metabolite, p,p′-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] is known to disrupt prostaglandin synthesis in the uterus of birds, providing part of the explanation for DDT-induced egg shell thinning. Few studies have examined prostaglandin synthesis as a target for endocrine disruption, yet these hormones are active in reproduction, immune responses, and cardiovascular physiology. Future studies must broaden the basic science approach to endocrine disruption, thereby expanding the mechanisms and endocrine end points examined. This goal should be accomplished even if the primary influence and funding continue to emphasize a narrower approach based on regulatory needs. Without this broader approach, research into endocrine disruption will become dominated by a narrow dogma, focusing on a few end points and mechanisms. PMID:16818240

  15. Effect of music on mealtime disruptions.

    Science.gov (United States)

    Hooper, Jeff; Carson, Derek; Lindsay, Bill

    People with learning disabilities can disrupt mealtimes with non-cooperative, aggressive and self-injurious behaviours that challenge other people to tolerate and manage them. These behaviours appear to arise because the proximity of other people, and the heightened activity and noise of a dining room, causes anxiety and agitation. To examine how delivering calming background music via headphones affected anxiety-driven behaviours that disrupted mealtimes. A sample of 30 adults with mild, moderate or severe learning disabilities were videotaped during mealtimes on two consecutive days. On the first day, half the group ate without any calming music while the other half sat opposite them wearing earphones and listening to calming music. On the second day, the non-music and music groups swapped around. Of the participants who tolerated the earphones, only three showed disruptive behaviour; all three had been sitting at the table waiting for their food. With so few examples, meaningful inferential analysis was not possible. However, there were signs that calming music had a positive effect on disruptive mealtime behaviours. It eliminated physical harm, complaining and verbal repetition in one person, and stopped another from shouting/swearing. It also reduced the incidence of shouting/swearing, restlessness and vocalising. Calming music and reduced waiting at tables for food may reduce disruptive behaviours.

  16. RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines

    International Nuclear Information System (INIS)

    Narendrula, Rashmi; Mispel-Beyer, Kyle; Guo, Baoqing; Parissenti, Amadeo M.; Pritzker, Laura B.; Pritzker, Ken; Masilamani, Twinkle; Wang, Xiaohui; Lannér, Carita

    2016-01-01

    Cellular stressors and apoptosis-inducing agents have been shown to induce ribosomal RNA (rRNA) degradation in eukaryotic cells. Recently, RNA degradation in vivo was observed in patients with locally advanced breast cancer, where mid-treatment tumor RNA degradation was associated with complete tumor destruction and enhanced patient survival. However, it is not clear how widespread chemotherapy induced “RNA disruption” is, the extent to which it is associated with drug response or what the underlying mechanisms are. Ovarian (A2780, CaOV3) and breast (MDA-MB-231, MCF-7, BT474, SKBR3) cancer cell lines were treated with several cytotoxic chemotherapy drugs and total RNA was isolated. RNA was also prepared from docetaxel resistant A2780DXL and carboplatin resistant A2780CBN cells following drug exposure. Disruption of RNA was analyzed by capillary electrophoresis. Northern blotting was performed using probes complementary to the 28S and 18S rRNA to determine the origins of degradation bands. Apoptosis activation was assessed by flow cytometric monitoring of annexin-V and propidium iodide (PI) binding to cells and by measuring caspase-3 activation. The link between apoptosis and RNA degradation (disruption) was investigated using a caspase-3 inhibitor. All chemotherapy drugs tested were capable of inducing similar RNA disruption patterns. Docetaxel treatment of the resistant A2780DXL cells and carboplatin treatment of the A2780CBN cells did not result in RNA disruption. Northern blotting indicated that two RNA disruption bands were derived from the 3’-end of the 28S rRNA. Annexin-V and PI staining of docetaxel treated cells, along with assessment of caspase-3 activation, showed concurrent initiation of apoptosis and RNA disruption, while inhibition of caspase-3 activity significantly reduced RNA disruption. Supporting the in vivo evidence, our results demonstrate that RNA disruption is induced by multiple chemotherapy agents in cell lines from different tissues

  17. Disruptive Intelligence - How to gather Information to deal with disruptive innovations

    NARCIS (Netherlands)

    Vriens, D.J.; Solberg Søilen, K.

    2014-01-01

    Disruptive innovations are innovations that have the capacity to transform a whole business into one with products that are more accessible and affordable (cf. Christensen et al. 2009). As Christensen et al. argue no business is immune to such disruptive innovations. If these authors are right, it

  18. Why Two Heads Apart Are Better than Two Heads Together: Multiple Mechanisms Underlie the Collaborative Inhibition Effect in Memory

    Science.gov (United States)

    Barber, Sarah J.; Harris, Celia B.; Rajaram, Suparna

    2015-01-01

    Although a group of people working together remembers more than any one individual, they recall less than their predicted potential. This finding is known as collaborative inhibition and is generally thought to arise due to retrieval disruption. However, there is growing evidence that is inconsistent with the retrieval disruption account,…

  19. Mechanical algal disruption for efficient biodiesel extraction

    Science.gov (United States)

    Krehbiel, Joel David

    Biodiesel from algae provides several benefits over current biodiesel feedstocks, but the energy requirements of processing algae into a useable fuel are currently so high as to be prohibitive. One route to improving this is via disruption of the cells prior to lipid extraction, which can significantly increase energy recovery. Unfortunately, several obvious disruption techniques require more energy than can be gained. This dissertation examines the use of microbubbles to improve mechanical disruption of algal cells using experimental, theoretical, and computational methods. New laboratory experiments show that effective ultrasonic disruption of algae is achieved by adding microbubbles to an algal solution. The configuration studied flows the solution through a tube and insonifies a small section with a high-pressure ultrasound wave. Previous biomedical research has shown effective cell membrane damage on animal cells with similar methods, but the present research is the first to extend such study to algal cells. Results indicate that disruption increases with peak negative pressure between 1.90 and 3.07 MPa and with microbubble concentration up to 12.5 x 107 bubbles/ml. Energy estimates of this process suggest that it requires only one-fourth the currently most-efficient laboratory-scale disruption process. Estimates of the radius near each bubble that causes disruption (i.e. the disruption radius) suggest that it increases with peak negative pressure and is near 9--20 microm for all cases tested. It is anticipated that these procedures can be designed for better efficiency and efficacy, which will be facilitated by identifying the root mechanisms of the bubble-induced disruption. We therefore examine whether bubble expansion alone creates sufficient cell deformation for cell rupture. The spherically-symmetric Marmottant model for bubble dynamics allows estimation of the flow regime under experimental conditions. Bubble expansion is modeled as a point source of

  20. Mating Disruption for the 21st Century: Matching Technology With Mechanism.

    Science.gov (United States)

    Miller, James R; Gut, Larry J

    2015-06-01

    Progress toward proof of the principal cause of insect mating disruption under a particular set of conditions has been hindered by a lack of logical rigor and clean falsifications of possible explanations. Here we make the case that understanding of mating disruption and optimization of particular formulations can be significantly advanced by rigorous application of the principles of strong inference. To that end, we offer a dichotomous key for eight distinct categories of mating disruption and detail criteria and methodologies for differentiating among them. Mechanisms of mating disruption closely align with those established for enzyme inhibition, falling into two major categories-competitive and noncompetitive. Under competitive disruption, no impairments are experienced by males, females, or the signal of females. Therefore, males can respond to females and traps. Competitive disruption is entirely a numbers game where the ratio of dispensers to females and traps is highly consequential and renders the control pest-density-dependent. Under noncompetitive disruption, males, females, or the signal from females are already impaired when sexual activity commences. The control achieved noncompetitively offers the notable advantage of being pest-density-independent. Dosage-response curves are the best way to distinguish competitive from noncompetitive disruption. Purely competitive disruption produces: a smoothly concave curve when untransformed capture data are plotted on the y-axis against density of dispensers on the x-axis; a straight line with positive slope when the inverse of catch is plotted against density of pheromone dispensers; and, a straight line with negative slope when catch is plotted against density of pheromone dispensers × catch. Disruption operating only noncompetitively produces: a straight line with negative slope when untransformed capture data are plotted on the y-axis against density of dispensers on the x-axis; an upturning curve when the

  1. Heat load material studies: Simulated tokamak disruptions

    International Nuclear Information System (INIS)

    Gahl, J.M.; McDonald, J.M.; Zakharov, A.; Tserevitinov, S.; Barabash, V.; Guseva, M.

    1991-01-01

    It is clear that an improved understanding of the effects of tokamak disruptions on plasma facing component materials is needed for the ITER program. very large energy fluxes are predicted to be deposited in ITER and could be very damaging to the machine. During 1991, Sandia National Laboratories and the University of New Mexico conducted cooperative tokamak disruption simulation experiments at several Soviet facilities. These facilities were located at the Efremov Institute in Leningrad, the Kurchatov Atomic Energy Institute (Troisk and Moscow) and the Institute for Physical Chemistry of the Soviet Adademy of Sciences in Moscow. Erosion of graphite from plasma stream impact is seen to be much less than that observed with laser or electron beams with similar energy fluxes. This, along with other data obtained, seem to suggest that the ''vapor shielding'' effect is a very important phenomenon in the study of graphite erosion during tokamak disruption

  2. Maternal Characteristics Predicting Young Girls’ Disruptive Behavior

    Science.gov (United States)

    van der Molen, Elsa; Hipwell, Alison E.; Vermeiren, Robert; Loeber, Rolf

    2011-01-01

    Little is known about the relative predictive utility of maternal characteristics and parenting skills on the development of girls’ disruptive behavior. The current study used five waves of parent and child-report data from the ongoing Pittsburgh Girls Study to examine these relationships in a sample of 1,942 girls from age 7 to 12 years. Multivariate Generalized Estimating Equation (GEE) analyses indicated that European American race, mother’s prenatal nicotine use, maternal depression, maternal conduct problems prior to age 15, and low maternal warmth explained unique variance. Maladaptive parenting partly mediated the effects of maternal depression and maternal conduct problems. Both current and early maternal risk factors have an impact on young girls’ disruptive behavior, providing support for the timing and focus of the prevention of girls’ disruptive behavior. PMID:21391016

  3. Tidal Disruption Events from Eccentric Nuclear Disks

    Science.gov (United States)

    Wernke, Heather N.; Madigan, Ann-Marie

    2018-04-01

    Stars that get too close to a supermassive black hole are in danger of being tidally disrupted. Stellar two-body relaxation is commonly assumed to be the main driver of these events. Recent work has shown, however, that secular gravitational torques from eccentric nuclear disks can push stars to extreme eccentricities at much higher rates than predicted by two-body relaxation. This work did not include the effects of general relativity, however, which could quench secular torques via rapid apsidal precession. Here we show that, for a star in danger of disruption, general relativity acts on a timescale of less than an orbital period. This short timescale means that general relativity does not have enough time to have a major effect on the orbit. When driven by secular torques from eccentric nuclear disks, tidal disruption event rates are not affected by general relativity.

  4. A model for disruption generated runaway electrons

    International Nuclear Information System (INIS)

    Russo, A.J.; Campbell, R.B.

    1993-01-01

    One of the possible consequences of disruptions in tokamaks is the generation of runaway electrons which can impact plasma facing components and cause damage, owing to high local energy deposition. This problem becomes more serious as the machine size and plasma current increase. Since large size and high currents are characteristics of proposed future machines, control of runaway generation is an important design consideration. A lumped circuit model for disruption runaway electron generation indicates that impurity concentration and type, as well as plasma motion, can strongly influence runaway behaviour. A comparison of disruption data from several runs on JET and DIII-D with model results demonstrate the effects of impurities, and plasma motion, on runaway number density and energy. The model is also applied to the calculation of runaway currents for ITER. (author). 16 refs, 13 figs

  5. Energy flow during disruptions in JET

    International Nuclear Information System (INIS)

    Paley, J.I.; Andrew, P.; Cowley, S.C.; Fundamenski, W.; Huber, A.

    2005-01-01

    Disruptions place severe limitations on the materials selected for plasma facing components in fusion devices. In a disruption, the plasma stored thermal and magnetic energy is dissipated leading to predicted power loadings in the current quench of up to 10 MW m -2 in JET. In the thermal quench very high power loads of up to 10 G Wm -2 would be expected if all the power flowed to the steady state strike points, however this is not observed. In this paper the energy balance associated with both events is investigated. The magnetic energy is found to balance well with radiated energy. Circumstantial evidence for limiter interaction during the thermal quench of plasmas in divertor configuration is presented and a possible mechanism for limiter interaction in disruptions resulting from the collapse of an internal transport barrier is discussed

  6. Density turbulence and disruption phenomena in TEXTOR

    International Nuclear Information System (INIS)

    Waidmann, G.; Kuang, G.; Jadoul, M.

    1992-01-01

    Disruptive processes are observed in tokamak plasmas not only at the operating limits (density limit or q-limit) but can be found under a variety of experimental conditions. Large forces are exerted then on vessel components and support structures. The sudden release of stored plasma energy presents a serious erosion problem for the first wall already in the next generation of large tokamak machines. Strong energy losses from the plasma and an influx of impurities are already present in minor plasma disruptions which do not immediately lead to a plasma current termination. The rapid loss of energy confinement was investigated within the framework of a systematic study on plasma disruption phenomena in TEXTOR. (author) 4 refs., 4 figs

  7. Disruption effects on the beam size measurement

    International Nuclear Information System (INIS)

    Raimondi, P.; Decker, F.J.; Chen, P.

    1995-01-01

    At the SLC Final Focus with higher currents and smaller beam sizes, the disruption parameter D y is close to one and so the pinch effect should produce a luminosity enhancement. Since a flat beam-beam function is fit to deflection scan data to measure the beam size, disruption can affect the measurement. Here the authors discuss the quantitative effects of disruption for typical SLC beam parameters. With 3.5 10 10 particles per pulse, bunch length of 0.8 mm and beam sizes of 2.1 μm horizontally and 0.55 μm vertically, the measured vertical size can be as much as 25% bigger than the real one. Furthermore during the collision the spot size actually decrease, producing an enhancement factor H D of about 1.25. This would yield to a true luminosity which is 1.6 times that which is estimated from the beam-beam deflection fit

  8. Airline Disruption Management - Perspectives, Experiences and Outlook

    DEFF Research Database (Denmark)

    Kohl, Niklas; Larsen, Allan; Larsen, Jesper

    2007-01-01

    Over the past decade, airlines have become more concerned with developing an optimal flight schedule, with very little slack left to accommodate for any form of variation from the optimal solution. During operation the planned schedules often have to be revised due to disruptions caused...... part we report on experiences from a large research and development project on airline disruption management. Within the project the first prototype of a multiple resource decision support system at the operations control center in a major airline, has been implemented....... by for example severe weather, technical problems and crew sickness. Thus, the field of Airline Disruption Management has emerged within the past few years. The increased focus on cutting cost at the major airlines has intensified the interest in the development of new and cost efficient methods to handle...

  9. Airline Disruption Management - Perspectives, Experiences and Outlook

    DEFF Research Database (Denmark)

    Kohl, Niklas; Larsen, Allan; Larsen, Jesper

    2004-01-01

    Over the past decade, airlines have become more concerned with developing an optimal flight schedule, with very little slack left to accommodate for any form of variation from the optimal solution. During operation the planned schedules often have to be revised due to disruptions caused...... report on experiences from a large research and development project on airline disruption management. Within the project the first prototype of a multiple resource decision support system at the operations control center in a major airline, has been implemented....... by for example severe weather, technical problems and crew sickness. Thus, the field of Airline Disruption Management has emerged within the past few years. The increased focus on cutting cost at the major airlines has intensified the interest in the development of new and cost e cient methods to handle airline...

  10. Analytic modeling of axisymmetric disruption halo currents

    International Nuclear Information System (INIS)

    Humphreys, D.A.; Kellman, A.G.

    1999-01-01

    Currents which can flow in plasma facing components during disruptions pose a challenge to the design of next generation tokamaks. Induced toroidal eddy currents and both induced and conducted poloidal ''halo'' currents can produce design-limiting electromagnetic loads. While induction of toroidal and poloidal currents in passive structures is a well-understood phenomenon, the driving terms and scalings for poloidal currents flowing on open field lines during disruptions are less well established. A model of halo current evolution is presented in which the current is induced in the halo by decay of the plasma current and change in enclosed toroidal flux while being convected into the halo from the core by plasma motion. Fundamental physical processes and scalings are described in a simplified analytic version of the model. The peak axisymmetric halo current is found to depend on halo and core plasma characteristics during the current quench, including machine and plasma dimensions, resistivities, safety factor, and vertical stability growth rate. Two extreme regimes in poloidal halo current amplitude are identified depending on the minimum halo safety factor reached during the disruption. A 'type I' disruption is characterized by a minimum safety factor that remains relatively high (typically 2 - 3, comparable to the predisruption safety factor), and a relatively low poloidal halo current. A 'type II' disruption is characterized by a minimum safety factor comparable to unity and a relatively high poloidal halo current. Model predictions for these two regimes are found to agree well with halo current measurements from vertical displacement event disruptions in DIII-D [T. S. Taylor, K. H. Burrell, D. R. Baker, G. L. Jackson, R. J. La Haye, M. A. Mahdavi, R. Prater, T. C. Simonen, and A. D. Turnbull, open-quotes Results from the DIII-D Scientific Research Program,close quotes in Proceedings of the 17th IAEA Fusion Energy Conference, Yokohama, 1998, to be published in

  11. Disruptive event analysis: volcanism and igneous intrusion

    International Nuclear Information System (INIS)

    Crowe, B.M.

    1980-08-01

    An evaluation is made of the disruptive effects of volcanic activity with respect to long term isolation of radioactive waste through deep geologic storage. Three major questions are considered. First, what is the range of disruption effects of a radioactive waste repository by volcanic activity. Second, is it possible, by selective siting of a repository, to reduce the risk of disruption by future volcanic activity. And third, can the probability of repository disruption by volcanic activity be quantified. The main variables involved in the evaluation of the consequences of repository disruption by volcanic activity are the geometry of the magma-repository intersection (partly controlled by depth of burial) and the nature of volcanism. Potential radionuclide dispersal by volcanic transport within the biosphere ranges in distance from several kilometers to global. Risk from the most catastrophic types of eruptions can be reduced by careful site selection to maximize lag time prior to the onset of activity. Certain areas or volcanic provinces within the western United States have been sites of significant volcanism and should be avoided as potential sites for a radioactive waste repository. Examples of projection of future sites of active volcanism are discussed for three areas of the western United States. Probability calculations require two types of data: a numerical rate or frequency of volcanic activity and a numerical evaluation of the areal extent of volcanic disruption for a designated region. The former is clearly beyond the current state of art in volcanology. The latter can be approximated with a reasonable degree of satisfaction. In this report, simplified probability calculations are attempted for areas of past volcanic activity

  12. Energetics of LMFBR core disruptive accidents

    International Nuclear Information System (INIS)

    Marchaterre, J.F.

    1979-01-01

    In general, in the design of fast reactor systems, containment design margins are specified by investigating the response of the containment to core disruptive accidents. The results of these analyses are then translated into criteria which the designers must meet. Currently, uniform and agreed upon criteria are lacking, and in this time while they are being developed, the designer should be aware of the considerations which go into the particular criteria he must work with, and participate in their development. This paper gives an overview of the current state of the art in assessing core disruptive accidents and the design implications of this process. (orig.)

  13. Disruption problematics in segmented blanket concepts

    International Nuclear Information System (INIS)

    Crutzen, Y.; Fantechi, S.; Farfaletti-Casali, F.

    1994-01-01

    In Tokamaks, the hostile operating environment originated by plasma disruption events requires that the first wall/blanket/shield components sustain the large induced electromagnetic (EM) forces without significant structural deformation and within allowable material stresses. As a consequence there is a need to improve the safety features of the blanket design concepts satisfying the disruption problematics and to formulate guidelines on the required internal reinforcements of the blanket components. The present paper describes the recent investigations on blanket reinforcement systems needed in order to optimize the first-wall/blanket/shield structural design for next step and commercial fusion reactors in the context of ITER, DEMO and SEAFP activities

  14. Engineering aspects of disruption current decay

    International Nuclear Information System (INIS)

    Murray, J.G.

    1983-11-01

    Engineering features associated with the configuration of a tokamak can affect the amount of energy that produces melting and damage to the limiters or internal wall surfaces as the result of a major disruption. During the current decay period of a major thermal disruption, the energy that can damage a wall or limiter comes from the external magnetic field. By providing a good conducting torus near the plasma and increasing the plasma circuit resistance, this magnetic energy (transferred by way of the plasma circuit) can be minimized. This report addresses engineering design features to reduce the energy deposited on the inner torus surface that produces melting of the structures

  15. Manufacturing doubt about endocrine disrupter science

    DEFF Research Database (Denmark)

    Bergman, Åke; Becher, Georg; Blumberg, Bruce

    2015-01-01

    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption......) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers...

  16. Development of disruption thermal analysis code DREAM

    Energy Technology Data Exchange (ETDEWEB)

    Yamazaki, Seiichiro; Kobayahsi, Takeshi [Kawasaki Heavy Industries Ltd., Kobe (Japan); Seki, Masahiro

    1989-07-01

    When a plasma disruption takes place in a tokamak type fusion reactor, plasma facing componenets such as first wall and divertor/limiter are subjected to a intensse heat load in a short duration. At the surface of the wall, temperature rapidly rises, and melting and evaporation occurs. It causes reduction of wall thickness and crack initiation/propagation. As lifetime of the components is significantly affected by them, the transient analysis in consideration of phase changes and radiation heat loss in required in the design of these components. This paper describes the computer code DREAM, developed to perform the disruption thermal analysis, taking phase changes and radiation into account. (author).

  17. Development of disruption thermal analysis code DREAM

    International Nuclear Information System (INIS)

    Yamazaki, Seiichiro; Kobayahsi, Takeshi; Seki, Masahiro.

    1989-01-01

    When a plasma disruption takes place in a tokamak type fusion reactor, plasma facing componenets such as first wall and divertor/limiter are subjected to a intensse heat load in a short duration. At the surface of the wall, temperature rapidly rises, and melting and evaporation occurs. It causes reduction of wall thickness and crack initiation/propagation. As lifetime of the components is significantly affected by them, the transient analysis in consideration of phase changes and radiation heat loss in required in the design of these components. This paper describes the computer code DREAM, developed to perform the disruption thermal analysis, taking phase changes and radiation into account. (author)

  18. Inhibition of Cell Growth and Induction of Apoptosis by Antrodia camphorata in HER-2/neu-Overexpressing Breast Cancer Cells through the Induction of ROS, Depletion of HER-2/neu, and Disruption of the PI3K/Akt Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Chuan-Chen Lee

    2012-01-01

    Full Text Available Previously, we demonstrated that a submerged fermentation culture of Antrodia camphorata (AC promotes cell-cycle arrest and apoptosis in human estrogen receptor-positive/negative breast cancer cells. However, whether AC is effective against HER-2/neu-overexpressing breast cancers has not been thoroughly elucidated. In the present study, we showed that AC exhibited a significant cytotoxic effect against HER-2/neu-overexpressing MDA-MB-453 and BT-474 cells. Immunoblot analysis demonstrated that HER-2/neu and their tyrosine phosphorylation were inhibited by AC in a dose-dependent manner. An increase in intracellular reactive oxygen species (ROS was observed in AC-treated cells, whereas antioxidant N-acetylcysteine (NAC significantly prevented AC induced HER-2/neu depletion and cell death, which directly indicates that AC-induced HER-2/neu depletion and cell death was mediated by ROS generation. Also, AC significantly downregulated the expression of cyclin D1, cyclin E, and CDK4 followed by the suppression of PI3K/Akt, and their downstream effectors GSK-3β and β-catenin. Notably, AC-treatment induced apoptotic cell death, which was associated with sub-G1 accumulation, DNA fragmentation, mitochondrial dysfunction, cytochrome c release, caspase-3/-9 activation, PARP degradation, and Bcl-2/Bax dysregulation. Assays for colony formation also confirmed the growth-inhibitory effects of AC. This is the first report confirming the anticancer activity of this potentially beneficial mushroom against human HER-2/neu-overexpressing breast cancers.

  19. Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth

    International Nuclear Information System (INIS)

    Liu, Shicheng; Yuan, Yiming; Okumura, Yutaka; Shinkai, Norihiro; Yamauchi, Hitoshi

    2010-01-01

    The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser 81 and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [ 3 H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.

  20. Pesticides Provoke Endocrine Disruption A Review

    International Nuclear Information System (INIS)

    Aly, M.A.S.

    2006-01-01

    Increasing numbers of environmental chemicals,including pesticides, have the ability to produce endocrine disruption by various mechanisms. such substances may affect hormone secretion from an endocrine gland and may alter the rate of hormone elimination from the body. environmental chemicals may also disrupt regulatory feedback mechanisms that exist between two endocrine organs; or may interact with a hormone receptor either by mimicking or antagonizing the actions of the natural hormone. these chemicals are referred to endocrine disruptive chemicals (EDC's). EDC's act to alter the blood hormone levels or the subsequent action of hormones . the use of radioimmunoassay(RIA) constitutes a superior and unrivalled tool for the determination and quantification of hormones.the endocrine system participates in virtually all important functions of an organism, such as sexual differentiation before birth, sexual maturation during puberty, reproduction in adulthood, growth, metabolism, digestion, cardiovascular function and excretion. hormones are also implicated in the etiology of certain cancers of hormone- dependent tissues, such as those of the breast, uterus, and prostate gland. therefore, endocrine disruption can potentially produce widespread effects. scientists should not stick to the past belief which presumes that pesticides have limited effect on some hormones. A paradigm shift in which a wider vision of understanding of the wholesome complex effects of pesticides on the whole body rather than a narrow limited understanding should take place

  1. Time scales in tidal disruption events

    Directory of Open Access Journals (Sweden)

    Krolik J.

    2012-12-01

    Full Text Available We explore the temporal structure of tidal disruption events pointing out the corresponding transitions in the lightcurves of the thermal accretion disk and of the jet emerging from such events. The hydrodynamic time scale of the disrupted star is the minimal time scale of building up the accretion disk and the jet and it sets a limit on the rise time. This suggest that Swift J1644+57, that shows several flares with a rise time as short as a few hundred seconds could not have arisen from a tidal disruption of a main sequence star whose hydrodynamic time is a few hours. The disrupted object must have been a white dwarf. A second important time scale is the Eddington time in which the accretion rate changes form super to sub Eddington. It is possible that such a transition was observed in the light curve of Swift J2058+05. If correct this provides interesting constraints on the parameters of the system.

  2. Thyroid effects of endocrine disrupting chemicals.

    Science.gov (United States)

    Boas, Malene; Feldt-Rasmussen, Ulla; Main, Katharina M

    2012-05-22

    In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert thyroid effects through a variety of mechanisms of action, and some animal experiments and in vitro studies have focused on elucidating the mode of action of specific chemical compounds. Long-term human studies on effects of environmental chemicals on thyroid related outcomes such as growth and development are still lacking. The human exposure scenario with life long exposure to a vast mixture of chemicals in low doses and the large physiological variation in thyroid hormone levels between individuals render human studies very difficult. However, there is now reasonably firm evidence that PCBs have thyroid-disrupting effects, and there is emerging evidence that also phthalates, bisphenol A, brominated flame retardants and perfluorinated chemicals may have thyroid disrupting properties. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  3. Analysis of recent fuel-disruption experiments

    International Nuclear Information System (INIS)

    Kramer, J.M.; Kraft, T.E.; DiMelfi, R.J.; Fenske, G.R.; Gruber, E.E.

    1982-01-01

    Recent USDOE-sponsored DEH, FGR, and TREAT F series fuel-disruption experiments are analyzed with existing analytical models. The experiments are interpreted and the results used to evaluate the models. Calculations are presented using the FRAS3 fission-gas-behavior code and the DiMelfi-Deitrich fuel-response model

  4. Operational limits and disruptions in ITER

    Energy Technology Data Exchange (ETDEWEB)

    Tsunematsu, T; Mizoguchi, T; Yoshino, R [Japan Atomic Energy Research Inst., Tokyo (Japan); Borrass, K; Engelmann, F; Pacher, G; Pacher, H [Max-Planck-Institut fuer Plasmaphysik, Garching (Germany, F.R.). NET Design Team; Cohen, S; Post, D [Princeton Univ., NJ (USA). Plasma Physics Lab.; Hogan, J; Uckan, N A [Oak Ridge National Lab., TN (USA); Krasheninnikov, S; Mukhovatov, V; Parail, V

    1990-12-15

    Detailed knowledge of the operational limits for beta, q and the plasma density will be required for successful and flexible operation of ITER. In this paper, the present data base and guidelines on operational limits and disruptions in the ITER design are presented. 10 refs., 1 fig.

  5. Maternal Characteristics Predicting Young Girls' Disruptive Behavior

    Science.gov (United States)

    van der Molen, Elsa; Hipwell, Alison E.; Vermeiren, Robert; Loeber, Rolf

    2011-01-01

    Little is known about the relative predictive utility of maternal characteristics and parenting skills on the development of girls' disruptive behavior. The current study used five waves of parent- and child-report data from the ongoing Pittsburgh Girls Study to examine these relationships in a sample of 1,942 girls from age 7 to 12 years.…

  6. Management of posterior urethral disruption injuries.

    Science.gov (United States)

    Myers, Jeremy B; McAninch, Jack W

    2009-03-01

    Posterior urethral disruption is a traumatic injury to the male urethra, which most often results from pelvic fracture. After trauma, the distraction defect between the two ends of the urethra often scars and becomes fibrotic, blocking the urethra and bladder emptying. Increasing evidence suggests that many posterior urethral disruptions occur at the junction between the membranous urethra and the bulbar urethra, which is distal to the rhabdosphincter. In the acute setting, when a posterior urethral disruption is suspected, retrograde urethrography should be performed. Posterior urethral disruptions can be managed acutely by realignment of the urethra over a urethral catheter or by placement of a suprapubic catheter for bladder drainage only. Once fibrosis has stabilized, the patient can undergo posterior urethroplasty. In most cases, this procedure can be performed via a perineal approach in a single-stage surgery. The results of this single-stage perineal urethroplasty are excellent, and a patent urethra can be re-established in the majority of men who undergo surgery.

  7. Development of Disruptive Open Access Journals

    Science.gov (United States)

    Anderson, Terry; McConkey, Brigette

    2009-01-01

    Open access (OA) publication has emerged, with disruptive effects, as a major outlet for scholarly publication. OA publication is usually associated with on-line distribution and provides access to scholarly publications to anyone, anywhere--regardless of their ability to pay subscription fees or their association with an educational institution.…

  8. Disrupting Educational Inequalities through Youth Digital Activism

    Science.gov (United States)

    Stornaiuolo, Amy; Thomas, Ebony Elizabeth

    2017-01-01

    This article reviews scholarship on youth and young adult activism in digital spaces, as young users of participatory media sites are engaging in political, civic, social, or cultural action and advocacy online to create social change. The authors argue that youth's digital activism serves as a central mechanism to disrupt inequality, and that…

  9. An analysis of recent fuel disruption experiments

    International Nuclear Information System (INIS)

    Kramer, J.M.; Kraft, T.E.; Dimelfi, R.J.; Fenske, G.R.; Gruber, E.E.

    1982-01-01

    Recent USDOE-Sponsored DEH, FGR, and TREAT F series fuel disruption experiments are analyzed with existing analytical models. The experiments are interpreted and the results used to evaluate the models. Calculations are presented using the FRAS3 fission gas behavior code and the DiMelfi-Deitrich fuel response model

  10. Endocrine Disrupting Chemicals and Disease Susceptibility

    Science.gov (United States)

    Schug, Thaddeus T.; Janesick, Amanda; Blumberg, Bruce; Heindel, Jerrold J.

    2011-01-01

    Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products– including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption. PMID:21899826

  11. Natural and Professional Help during Marital Disruption.

    Science.gov (United States)

    Toro, Paul A.; Zax, Melvin

    Although few people bring their psychological problems to mental health professionals, research in the area of 'natural' help is rudimentary. To investigate the process and effectiveness of natural professional groups in helping individuals experiencing marital disruption, 42 helpers (14 mental health professionals, 14 divorce lawyers, and 14…

  12. Five disruptive technology directions for 5G

    DEFF Research Database (Denmark)

    Boccardi, Federico; W. Heath Jr., Robert; Lozano, Angel

    2014-01-01

    New research directions will lead to fundamental changes in the design of future fifth generation (5G) cellular networks. This article describes five technologies that could lead to both architectural and component disruptive design changes: device-centric architectures, millimeter wave, massive ...

  13. Disrupted functional connectivity in adolescent obesity

    Directory of Open Access Journals (Sweden)

    Laura Moreno-Lopez

    2016-01-01

    Conclusions: These findings suggest that adolescent obesity is linked to disrupted functional connectivity in brain networks relevant to maintaining balance between reward, emotional memories and cognitive control. Our findings may contribute to reconceptualization of obesity as a multi-layered brain disorder leading to compromised motivation and control, and provide a biological account to target prevention strategies for adolescent obesity.

  14. Traffic disruption route Einstein near building 170

    CERN Multimedia

    A Lopez - TS/CE

    2005-01-01

    The TS/CE Group informs you that, for the duration of the work at Building 170, there may be some disruption to traffic on route Einstein in the vicinity of Building 170. The work is due to take place from the 14th to 18th February. For more information, please contact 165029. A. Lopez TS/CE

  15. New directions for mating disruption in Wisconsin

    Science.gov (United States)

    Mating Disruption (MD) is an alternative to insecticide for control of three major pests -Sparganthois fruitworm, Cranberry fruitworm and Blackheaded fireworm. MD functions by sending out false plumes of the insect's sex pheromones – this interferes with the insect’s ability to find a mate, preempti...

  16. The Relative Ineffectiveness of Criminal Network Disruption

    Science.gov (United States)

    Duijn, Paul A. C.; Kashirin, Victor; Sloot, Peter M. A.

    2014-01-01

    Researchers, policymakers and law enforcement agencies across the globe struggle to find effective strategies to control criminal networks. The effectiveness of disruption strategies is known to depend on both network topology and network resilience. However, as these criminal networks operate in secrecy, data-driven knowledge concerning the effectiveness of different criminal network disruption strategies is very limited. By combining computational modeling and social network analysis with unique criminal network intelligence data from the Dutch Police, we discovered, in contrast to common belief, that criminal networks might even become ‘stronger’, after targeted attacks. On the other hand increased efficiency within criminal networks decreases its internal security, thus offering opportunities for law enforcement agencies to target these networks more deliberately. Our results emphasize the importance of criminal network interventions at an early stage, before the network gets a chance to (re-)organize to maximum resilience. In the end disruption strategies force criminal networks to become more exposed, which causes successful network disruption to become a long-term effort. PMID:24577374

  17. Anomalous periodic disruptions in tokamak plasma

    International Nuclear Information System (INIS)

    Montvai, A.; Tegze, M.; Valyi, I.

    1982-09-01

    Anomalously strong, periodic instabilities were observed in the MT-1 tokamak. Characteristics of these instabilities were partly similar to those of internal disruptions, but there were features making them different from the normal relaxational oscillations. Basic characteristics of the phenomenon were studied with the aid of generally used diagnostics. (author)

  18. Biosensor discovery of thyroxine transport disrupting chemicals

    NARCIS (Netherlands)

    Marchesini, G.R.; Meimaridou, A.; Haasnoot, W.; Meulenberg, E.; Albertus, F.; Mizuguchi, M.; Takeuchi, M.; Irth, H.; Murk, A.J.

    2008-01-01

    Ubiquitous chemicals may interfere with the thyroid system that is essential in the development and physiology of vertebrates. We applied a surface plasmon resonance (SPR) biosensor-based screening method for the fast screening of chemicals with thyroxine (T4) transport disrupting activity. Two

  19. The Structure of Childhood Disruptive Behaviors

    Science.gov (United States)

    Martel, Michelle M.; Gremillion, Monica; Roberts, Bethan; von Eye, Alexander; Nigg, Joel T.

    2010-01-01

    Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) frequently co-occur. Comorbidity of these 2 childhood disruptive behavior domains has not been satisfactorily explained at either a structural or etiological level. The current study evaluated a bifactor model, which allows for a "g" factor in addition to…

  20. Disruption of Spectrin-Like Cytoskeleton in Differentiating Keratinocytes by PKCδ Activation Is Associated with Phosphorylated Adducin

    Science.gov (United States)

    Zhao, Kong-Nan; Masci, Paul P.; Lavin, Martin F.

    2011-01-01

    Spectrin is a central component of the cytoskeletal protein network in a variety of erythroid and non-erythroid cells. In keratinocytes, this protein has been shown to be pericytoplasmic and plasma membrane associated, but its characteristics and function have not been established in these cells. Here we demonstrate that spectrin increases dramatically in amount and is assembled into the cytoskeleton during differentiation in mouse and human keratinocytes. The spectrin-like cytoskeleton was predominantly organized in the granular and cornified layers of the epidermis and disrupted by actin filament inhibitors, but not by anti-mitotic drugs. When the cytoskeleton was disrupted PKCδ was activated by phosphorylation on Thr505. Specific inhibition of PKCδ(Thr505) activation with rottlerin prevented disruption of the spectrin-like cytoskeleton and the associated morphological changes that accompany differentiation. Rottlerin also inhibited specific phosphorylation of the PKCδ substrate adducin, a cytoskeletal protein. Furthermore, knock-down of endogenous adducin affected not only expression of adducin, but also spectrin and PKCδ, and severely disrupted organization of the spectrin-like cytoskeleton and cytoskeletal distribution of both adducin and PKCδ. These results demonstrate that organization of a spectrin-like cytoskeleton is associated with keratinocytes differentiation, and disruption of this cytoskeleton is mediated by either PKCδ(Thr505) phosphorylation associated with phosphorylated adducin or due to reduction of endogenous adducin, which normally connects and stabilizes the spectrin-actin complex. PMID:22163289

  1. The mass disruption of Jupiter Family comets

    Science.gov (United States)

    Belton, Michael J. S.

    2015-01-01

    I show that the size-distribution of small scattered-disk trans-neptunian objects when derived from the observed size-distribution of Jupiter Family comets (JFCs) and other observational constraints implies that a large percentage (94-97%) of newly arrived active comets within a range of 0.2-15.4 km effective radius must physically disrupt, i.e., macroscopically disintegrate, within their median dynamical lifetime. Additional observational constraints include the numbers of dormant and active nuclei in the near-Earth object (NEO) population and the slope of their size distributions. I show that the cumulative power-law slope (-2.86 to -3.15) of the scattered-disk TNO hot population between 0.2 and 15.4 km effective radius is only weakly dependent on the size-dependence of the otherwise unknown disruption mechanism. Evidently, as JFC nuclei from the scattered disk evolve into the inner Solar System only a fraction achieve dormancy while the vast majority of small nuclei (e.g., primarily those with effective radius <2 km) break-up. The percentage disruption rate appears to be comparable with that of the dynamically distinct Oort cloud and Halley type comets (Levison, H.F., Morbidelli, A., Dones, L., Jedicke, R., Wiegert, P.A., Bottke Jr., W.F. [2002]. Science 296, 2212-2215) suggesting that all types of comet nuclei may have similar structural characteristics even though they may have different source regions and thermal histories. The typical disruption rate for a 1 km radius active nucleus is ∼5 × 10-5 disruptions/year and the dormancy rate is typically 3 times less. We also estimate that average fragmentation rates range from 0.01 to 0.04 events/year/comet, somewhat above the lower limit of 0.01 events/year/comet observed by Chen and Jewitt (Chen, J., Jewitt, D.C. [1994]. Icarus 108, 265-271).

  2. Perceptual consequences of disrupted auditory nerve activity.

    Science.gov (United States)

    Zeng, Fan-Gang; Kong, Ying-Yee; Michalewski, Henry J; Starr, Arnold

    2005-06-01

    Perceptual consequences of disrupted auditory nerve activity were systematically studied in 21 subjects who had been clinically diagnosed with auditory neuropathy (AN), a recently defined disorder characterized by normal outer hair cell function but disrupted auditory nerve function. Neurological and electrophysical evidence suggests that disrupted auditory nerve activity is due to desynchronized or reduced neural activity or both. Psychophysical measures showed that the disrupted neural activity has minimal effects on intensity-related perception, such as loudness discrimination, pitch discrimination at high frequencies, and sound localization using interaural level differences. In contrast, the disrupted neural activity significantly impairs timing related perception, such as pitch discrimination at low frequencies, temporal integration, gap detection, temporal modulation detection, backward and forward masking, signal detection in noise, binaural beats, and sound localization using interaural time differences. These perceptual consequences are the opposite of what is typically observed in cochlear-impaired subjects who have impaired intensity perception but relatively normal temporal processing after taking their impaired intensity perception into account. These differences in perceptual consequences between auditory neuropathy and cochlear damage suggest the use of different neural codes in auditory perception: a suboptimal spike count code for intensity processing, a synchronized spike code for temporal processing, and a duplex code for frequency processing. We also proposed two underlying physiological models based on desynchronized and reduced discharge in the auditory nerve to successfully account for the observed neurological and behavioral data. These methods and measures cannot differentiate between these two AN models, but future studies using electric stimulation of the auditory nerve via a cochlear implant might. These results not only show the unique

  3. Dissociating Effects of Global SWS Disruption and Healthy Aging on Waking Performance and Daytime Sleepiness

    Science.gov (United States)

    Groeger, John A.; Stanley, Neil; Deacon, Stephen; Dijk, Derk-Jan

    2014-01-01

    Study Objective: To contrast the effects of slow wave sleep (SWS) disruption and age on daytime functioning. Design: Daytime functioning was contrasted in three age cohorts, across two parallel 4-night randomized groups (baseline, two nights of SWS disruption or control, recovery sleep). Setting: Sleep research laboratory. Participants: 44 healthy young (20-30 y), 35 middle-aged (40-55 y), and 31 older (66-83 y) men and women. Interventions: Acoustic stimulation contingent on appearance of slow waves. Measurements and Results: Cognitive performance was assessed before sleep latency tests at five daily time-points. SWS disruption resulted in less positive affect, slower or impaired information processing and sustained attention, less precise motor control, and erroneous implementation, rather than inhibition, of well-practiced actions. These performance impairments had far smaller effect sizes than the increase in daytime sleepiness and differed from baseline to the same extent for each age group. At baseline, younger participants performed better than older participants across many cognitive domains, with largest effects on executive function, response time, sustained attention, and motor control. At baseline, the young were sleepier than other age groups. Conclusions: SWS has been considered a potential mediator of age-related decline in performance, although the effects of SWS disruption on daytime functioning have not been quantified across different cognitive domains nor directly compared to age-related changes in performance. The data imply that two nights of SWS disruption primarily leads to an increase in sleepiness with minor effects on other aspects of daytime functioning, which are different from the substantial effects of age. Citation: Groeger JA, Stanley N, Deacon S, Dijk DJ. Dissociating effects of global sws disruption and healthy aging on waking performance and daytime sleepiness. SLEEP 2014;37(6):1127-1142. PMID:24882908

  4. Phenomenology of high density disruptions in the TFTR tokamak

    International Nuclear Information System (INIS)

    Fredrickson, E.D.; McGuire, K.M.; Bell, M.G.

    1993-01-01

    Studies of high density disruptions on TFTR, including a comparison of minor and major disruptions at high density, provide important new information regarding the nature of the disruption mechanism. Further, for the first time, an (m,n)=(1,1) 'cold bubble' precursor to high density disruptions has been experimentally observed in the electron temperature profile. The precursor to major disruptions resembles the 'vacuum bubble' model of disruptions first proposed by B.B. Kadomtsev and O.P. Pogutse (Sov. Phys. - JETP 38 (1974) 283). (author). Letter-to-the-editor. 25 refs, 3 figs

  5. BAX channel activity mediates lysosomal disruption linked to Parkinson disease.

    Science.gov (United States)

    Bové, Jordi; Martínez-Vicente, Marta; Dehay, Benjamin; Perier, Celine; Recasens, Ariadna; Bombrun, Agnes; Antonsson, Bruno; Vila, Miquel

    2014-05-01

    Lysosomal disruption is increasingly regarded as a major pathogenic event in Parkinson disease (PD). A reduced number of intraneuronal lysosomes, decreased levels of lysosomal-associated proteins and accumulation of undegraded autophagosomes (AP) are observed in PD-derived samples, including fibroblasts, induced pluripotent stem cell-derived dopaminergic neurons, and post-mortem brain tissue. Mechanistic studies in toxic and genetic rodent PD models attribute PD-related lysosomal breakdown to abnormal lysosomal membrane permeabilization (LMP). However, the molecular mechanisms underlying PD-linked LMP and subsequent lysosomal defects remain virtually unknown, thereby precluding their potential therapeutic targeting. Here we show that the pro-apoptotic protein BAX (BCL2-associated X protein), which permeabilizes mitochondrial membranes in PD models and is activated in PD patients, translocates and internalizes into lysosomal membranes early following treatment with the parkinsonian neurotoxin MPTP, both in vitro and in vivo, within a time-frame correlating with LMP, lysosomal disruption, and autophagosome accumulation and preceding mitochondrial permeabilization and dopaminergic neurodegeneration. Supporting a direct permeabilizing effect of BAX on lysosomal membranes, recombinant BAX is able to induce LMP in purified mouse brain lysosomes and the latter can be prevented by pharmacological blockade of BAX channel activity. Furthermore, pharmacological BAX channel inhibition is able to prevent LMP, restore lysosomal levels, reverse AP accumulation, and attenuate mitochondrial permeabilization and overall nigrostriatal degeneration caused by MPTP, both in vitro and in vivo. Overall, our results reveal that PD-linked lysosomal impairment relies on BAX-induced LMP, and point to small molecules able to block BAX channel activity as potentially beneficial to attenuate both lysosomal defects and neurodegeneration occurring in PD.

  6. Disrupt mig vel: Fire gode råd om disruption

    DEFF Research Database (Denmark)

    Rydén, Pernille; Ringberg, Torsten; Østergaard Jacobsen, Per

    2017-01-01

    Forandring. Ønsket om at være teknologisk foran, kommer ofte til at ske på bekostning af fokus på kundernes oplevelser. Lighedstegnet mellem disruption og ny teknologi er kun den halve sandhed.......Forandring. Ønsket om at være teknologisk foran, kommer ofte til at ske på bekostning af fokus på kundernes oplevelser. Lighedstegnet mellem disruption og ny teknologi er kun den halve sandhed....

  7. INHIBITION IN SPEAKING PERFORMANCE

    OpenAIRE

    Humaera, Isna

    2015-01-01

    The most common problem encountered by the learner in the languageacquisition process is learner inhibition. Inhibition refers to a temperamentaltendency to display wariness, fearfulness, or restrain in response tounfamiliar people, objects, and situations. There are some factors that causeinhibition, such as lack of motivation, shyness, self-confidence, self-esteem,and language ego. There are also levels of inhibition, it refers to kinds ofinhibition and caused of inhibition itself. Teacher ...

  8. Self-restraint spillover: Inhibitory control disrupts appetite regulation among ruminators.

    Science.gov (United States)

    Schlinkert, Caroline; Koole, Sander L

    2017-10-23

    People can use inhibitory control to temporarily inhibit their personal preferences to achieve their long-term goals. According to the ego fixation model (Koole et al., 2014), ruminators have difficulties relaxing inhibitory control, leading them to continue inhibiting their personal needs, even when this is no longer required by the situation. Inhibitory control may thus disrupt healthy appetite regulation among ruminators. Among 324 Dutch undergraduate students (218 women; M age  = 21.5), different inhibitory control states were manipulated by varying whether or not participants exerted inhibitory control (Study 1) or priming high versus low inhibitory control (Study 2). All participants then performed a food-tasting task. Healthy appetite regulation was defined as a positive correlation between level of food deprivation and preference for high-calorie foods. For taste ratings, the interaction between inhibitory control and rumination was significant in each study: Inhibitory control disrupted healthy appetite regulation in taste preferences among ruminators, but not among non-ruminators. For eating behavior, the same interaction effect was significant when the two studies were combined. Inhibitory control disrupts healthy appetite regulation among ruminators. These findings suggest the need for caution in interventions that rely on inhibitory control, especially among samples with compulsive thought tendencies. © 2017 Wiley Periodicals, Inc.

  9. Longitudinal association between marital disruption and child BMI and obesity.

    Science.gov (United States)

    Arkes, Jeremy

    2012-08-01

    This research examines whether family disruptions (i.e., divorces and separation) contribute to children's weight problems. The sample consists of 7,299 observations for 2,333 children, aged 5-14, over the 1986-2006 period, from a US representative sample from the Child and Young Adult Survey accompanying the National Longitudinal Survey of Youth (NLSY). The study uses individual-fixed-effects models in a longitudinal framework to compare children's BMI and weight problems before and after a disruption. Furthermore, besides doing a before-after comparison for children, the study also estimates the effects at various periods relative to the disruption in order to examine whether children are affected before the disruption and whether any effects change as time passes from the disruption, as some effects may be temporary or slow to develop. Despite having a larger sample than the previous studies, the results provide no evidence that, on average, children's BMI and BMI percentile scores (measured with continuous outcomes) are affected before the disruption, after the disruption, and as time passes from the disruption, relative to a baseline period a few years before the disruption. However, children experiencing a family disruption do have an increased risk of obesity (having a BMI percentile score of 95 or higher) in the two years leading up to the disruption as well as after the disruption, and as time passes from the disruption.

  10. Disruption of circumstellar discs by large-scale stellar magnetic fields

    Science.gov (United States)

    ud-Doula, Asif; Owocki, Stanley P.; Kee, Nathaniel Dylan

    2018-05-01

    Spectropolarimetric surveys reveal that 8-10% of OBA stars harbor large-scale magnetic fields, but thus far no such fields have been detected in any classical Be stars. Motivated by this, we present here MHD simulations for how a pre-existing Keplerian disc - like that inferred to form from decretion of material from rapidly rotating Be stars - can be disrupted by a rotation-aligned stellar dipole field. For characteristic stellar and disc parameters of a near-critically rotating B2e star, we find that a polar surface field strength of just 10 G can significantly disrupt the disc, while a field of 100 G, near the observational upper limit inferred for most Be stars, completely destroys the disc over just a few days. Our parameter study shows that the efficacy of this magnetic disruption of a disc scales with the characteristic plasma beta (defined as the ratio between thermal and magnetic pressure) in the disc, but is surprisingly insensitive to other variations, e.g. in stellar rotation speed, or the mass loss rate of the star's radiatively driven wind. The disc disruption seen here for even a modest field strength suggests that the presumed formation of such Be discs by decretion of material from the star would likely be strongly inhibited by such fields; this provides an attractive explanation for why no large-scale fields are detected from such Be stars.

  11. Disruption of Microtubules Post-Virus Entry Enhances Adeno-Associated Virus Vector Transduction

    Science.gov (United States)

    Xiao, Ping-Jie; Mitchell, Angela M.; Huang, Lu; Li, Chengwen; Samulski, R. Jude

    2016-01-01

    Perinuclear retention of viral particles is a poorly understood phenomenon observed during many virus infections. In this study, we investigated whether perinuclear accumulation acts as a barrier to limit recombinant adeno-associated virus (rAAV) transduction. After nocodazole treatment to disrupt microtubules at microtubule-organization center (MT-MTOC) after virus entry, we observed higher rAAV transduction. To elucidate the role of MT-MTOC in rAAV infection and study its underlying mechanisms, we demonstrated that rAAV's perinuclear localization was retained by MT-MTOC with fluorescent analysis, and enhanced rAAV transduction from MT-MTOC disruption was dependent on the rAAV capsid's nuclear import signals. Interestingly, after knocking down RhoA or inhibiting its downstream effectors (ROCK and Actin), MT-MTOC disruption failed to increase rAAV transduction or nuclear entry. These data suggest that enhancement of rAAV transduction is the result of increased trafficking to the nucleus via the RhoA-ROCK-Actin pathway. Ten-fold higher rAAV transduction was also observed by disrupting MT-MTOC in brain, liver, and tumor in vivo. In summary, this study indicates that virus perinuclear accumulation at MT-MTOC is a barrier-limiting parameter for effective rAAV transduction and defines a novel defense mechanism by which host cells restrain viral invasion. PMID:26942476

  12. Temperamental correlates of disruptive behavior disorders in young children: preliminary findings.

    Science.gov (United States)

    Hirshfeld-Becker, Dina R; Biederman, Joseph; Faraone, Stephen V; Violette, Heather; Wrightsman, Jessica; Rosenbaum, Jerrold F

    2002-04-01

    Our objective was to test the hypothesis that temperamental behavioral disinhibition measured in early childhood would be associated with disruptive behavior disorders. We used variables from laboratory-based behavioral observations originally devised to assess behavioral inhibition to construct a theory-based a priori definition of "behavioral disinhibition" in 200 young children at-risk for panic disorder, depression, or both and 84 children of parents without anxiety or major depressive disorder. We then compared behaviorally disinhibited and nonbehaviorally disinhibited children on rates of DSM-III-R disorders and measures of academic and social dysfunction. Behavioral disinhibition was significantly associated with higher rates of disruptive behavior disorders and mood disorders. Children with behavioral disinhibition were significantly more likely than nondisinhibited, noninhibited children to have attention-deficit/hyperactivity disorder (ADHD) and to have comorbid mood and disruptive behavior disorders. Moreover, disinhibited children had lower Global Assessment of Functioning Scale scores and were more likely to have been in special classes and to have problems with school behavior and leisure activities. These results suggest that behavioral disinhibition may represent a temperamental precursor to disruptive behavior problems, particularly ADHD. Longitudinal studies using behavioral assessments of behavioral disinhibition are needed to confirm these findings.

  13. Make disruptive technological change happen - The case of additive manufacturing

    DEFF Research Database (Denmark)

    Maresch, Daniela; Gartner, Johannes

    2018-01-01

    Disruptive technological change can contribute to a more abundant world. However, potentially disruptive technologies often struggle to significantly influence practice. One prominent example is additive manufacturing (AM). Although AM is often regarded as the next great technological revolution...

  14. Disruptive behaviour in the Foundation Phase of schooling | Marais ...

    African Journals Online (AJOL)

    Data collection was done by conducting interviews comprising semistructured questions with Foundation Phase teachers. Strategies purposely devised to deal specifically with the identified types and causes of disruptive behaviour are explained. Keywords: disciplinary procedures; discipline problems; disruptive behaviour;

  15. CUMULATIVE DEVELOPMENTAL EFFECTS OF ENDOCRINE DISRUPTERS: SYNERGY OR ADDITIVITY?

    Science.gov (United States)

    Exposure to chemicals with hormonal activity during critical developmental periods can disrupt reproductive function and development. Within the last decade, several classes of pesticides and toxic substances have been shown to disrupt differentiation of the male rat reproductive...

  16. Science and policy on endocrine disrupters must not be mixed

    DEFF Research Database (Denmark)

    Bergman, Åke; Andersson, Anna-Maria; Becher, Georg

    2013-01-01

    The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a r...

  17. Conversion of homothallic yeast to heterothallism trough HO gene disruption

    CSIR Research Space (South Africa)

    Van Zyl, WH

    1993-04-01

    Full Text Available A simple method was developed for the conversion of homothallic Saccharomyces cerevisiae yeaststrains to heterothallism through HO gene disruption. An integrative ho:: neo disrupted allele was constructed by cloning a dominant selectable marker...

  18. Neural net prediction of tokamak plasma disruptions

    International Nuclear Information System (INIS)

    Hernandez, J.V.; Lin, Z.; Horton, W.; McCool, S.C.

    1994-10-01

    The computation based on neural net algorithms in predicting minor and major disruptions in TEXT tokamak discharges has been performed. Future values of the fluctuating magnetic signal are predicted based on L past values of the magnetic fluctuation signal, measured by a single Mirnov coil. The time step used (= 0.04ms) corresponds to the experimental data sampling rate. Two kinds of approaches are adopted for the task, the contiguous future prediction and the multi-timescale prediction. Results are shown for comparison. Both networks are trained through the back-propagation algorithm with inertial terms. The degree of this success indicates that the magnetic fluctuations associated with tokamak disruptions may be characterized by a relatively low-dimensional dynamical system

  19. The hexagon hypothesis: Six disruptive scenarios.

    Science.gov (United States)

    Burtles, Jim

    2015-01-01

    This paper aims to bring a simple but effective and comprehensive approach to the development, delivery and monitoring of business continuity solutions. To ensure that the arguments and principles apply across the board, the paper sticks to basic underlying concepts rather than sophisticated interpretations. First, the paper explores what exactly people are defending themselves against. Secondly, the paper looks at how defences should be set up. Disruptive events tend to unfold in phases, each of which invites a particular style of protection, ranging from risk management through to business continuity to insurance cover. Their impact upon any business operation will fall into one of six basic scenarios. The hexagon hypothesis suggests that everyone should be prepared to deal with each of these six disruptive scenarios and it provides them with a useful benchmark for business continuity.

  20. Disruption studies in DIII-D

    International Nuclear Information System (INIS)

    Kellman, A.G.; Evans, T.E.; Cuthbertson, J.W.

    1996-09-01

    Characteristics of disruptions in the DIII-D tokamak including the current decay rate, halo current magnitude and toroidal asymmetry, and heat pulse to the divertor are described. Neon and argon pellet injection is shown to be an effective method for mitigating the halo currents and the heat pulse with a 50% reduction in both quantities achieved. The injection of these impurity pellets frequently gives rise to runaway electrons

  1. Disruption Studies in JT-60U

    International Nuclear Information System (INIS)

    Kawano, Y.; Yoshino, R.; Neyatani, Y.; Nakamura, Y.; Tokuda, S.; Tamai, H.

    2002-01-01

    Intensive studies on the physics of disruptions and developments of avoidance/mitigation methods of disruption-related phenomena have being carried out in JT-60U. The characteristics of the disruption sequence were well understood from the observation of the relationship between the heat pulse onto divertor plates during thermal quench and the impurity influx into the plasma, which determined the speed of the following current quench. A fast shutdown was first demonstrated by injecting impurity ice pellets to the plasma and intensively reducing the heat flux on first wall. The halo current and its toroidal asymmetry were precisely measured, and the halo current database was made for ITER in a wide parameter range. It was found that TPF x I h /I p0 was 0.52 at the maximum in a large tokamak like the JT-60U, whereas the higher factor of 0.75 had been observed in medium-sized tokamaks such as Alcator C-Mod and ASDEX-Upgrade. The vertical displacement event (VDE) at the start of the current quench was carefully investigated, and the neutral point where the VDE hardly occurs was discovered. MHD simulations clarified the onset mechanisms of the VDE, in which the eddy current effect of the up-down asymmetric resistive shell was essential. The real-time Z j measurement was improved for avoiding VDEs during slow current quench, and plasma-wall interaction was avoided by a well-optimized plasma equilibrium control. Magnetic fluctuations that were spontaneously generated at the disruption and/or enhanced by the externally applied helical field have been shown to avoid the generation of runaway electrons. Numerical analysis clarified an adequate rate of collisionless loss of runaway electrons in turbulent magnetic fields, which was consistent with the avoidance of runaway electron generation by magnetic fluctuations observed in JT-60U. Once generated, runaway electrons were suppressed when the safety factor at the plasma surface was reduced to 3 or 2

  2. Internal disruptions in Tokamak: a turbulent interpretation

    International Nuclear Information System (INIS)

    Dubois, M.A.; Pecquet, A.L.; Reverdin, C.

    1982-07-01

    High speed X-ray data of sawteeth in TFR are interpreted using a kinematic model. It is shown that the internal disruption begins for a small size of the q = 1 island, and that the sharp details observed on different chords are not reproduced by a total reconnection model. Conversely they are well simulated by a model where the temperature flattening is due to the propagation of a turbulent region starting from the q = 1 surface

  3. Disrupting Mating Behavior of Diaphorina citri (Liviidae).

    Science.gov (United States)

    Lujo, S; Hartman, E; Norton, K; Pregmon, E A; Rohde, B B; Mankin, R W

    2016-12-01

    Severe economic damage from citrus greening disease, caused by 'Candidatus Liberibacter asiaticus' bacteria, has stimulated development of methods to reduce mating and reproduction in populations of its insect vector, Diaphorina citri (Hemiptera: Liviidae). Male D. citri find mating partners by walking on host plants, intermittently producing vibrational calls that stimulate duetting replies by receptive females. The replies provide orientational feedback, assisting the search process. To test a hypothesis that D. citri mating can be disrupted using vibrational signals that compete with and/or mask female replies, courtship bioassays were conducted in citrus trees with or without interference from female reply mimics produced by a vibrating buzzer. Statistically significant reductions occurred in the rates and proportions of mating when the buzzer produced reply mimics within 0.4 s after male courtship calls compared with undisturbed controls. Observations of courtship behaviors in the two bioassays revealed activity patterns that likely contributed to the reductions. In both disruption and control tests, males reciprocated frequently between structural bifurcations and other transition points where signal amplitudes changed. Males in the disruption bioassay had to select among vibrational signals combined from the buzzer and the female at each transition point. They often turned towards the buzzer instead of the female. There was a statistically significant reduction in the proportion of males mating if they contacted the buzzer, possibly due to its higher vibration amplitude and duration in comparison with female replies. Potential applications of D. citri mating disruption technology in citrus groves are discussed. Published by Oxford University Press on behalf of Entomological Society of America 2016. This work is written by US Government employees and is in the public domain in the US.

  4. Literature Review on Disruption Recovery in the Supply Chain

    OpenAIRE

    Ivanov , Dmitry; Dolgui , Alexandre; Sokolov , Boris; Ivanova , Marina

    2017-01-01

    International audience; Recent research underlines the crucial role of disruption events and recovery policies in supply chains. Despite a wealth of literature on supply chain design with disruption considerations, to the best of our knowledge there is no survey on supply chain with disruptions and recovery considerations. We analyse state-of-the-art research streams on supply chain design and planning with both disruptions and recovery considerations with the aim of relating the existing qua...

  5. Cost Sharing in the Prevention of Supply Chain Disruption

    OpenAIRE

    Wen Wang; Kelei Xue; Xiaochen Sun

    2017-01-01

    We examine the influence of cost-sharing mechanism on the disruption prevention investment in a supply chain with unreliable suppliers. When a supply chain faces considerable loss following a disruption, supply chain members are motivated toward investing in manners that reduce their disruption probability. In improving supply chain reliability, the cost-sharing mechanism must be set appropriately to realize the efficiency of the disruption prevention investment. In a supply chain where the f...

  6. A case for change: disruption in academic medicine.

    Science.gov (United States)

    Kahn, Marc J; Maurer, Ralph; Wartman, Steven A; Sachs, Benjamin P

    2014-09-01

    Disruptive technologies allow less expensive and more efficient processes to eventually dominate a market sector. The academic health center's tripartite mission of education, clinical care, and research is threatened by decreasing revenues and increasing expenses and is, as a result, ripe for disruption. The authors describe current disruptive technologies that threaten traditional operations at academic health centers and provide a prescription not only to survive, but also to prosper, in the face of disruptive forces.

  7. Antecedents and implications of disruptive innovation: Evidence from China

    OpenAIRE

    Wan, Feng; Williamson, Peter; Yin, Eden

    2015-01-01

    A growing recognition of the importance of disruptive innovation has led researchers to examine the question of how disruptive innovation comes about and to what extent it reflects "discovery" versus "creation" of opportunities. Earlier research has focused on the organisational preconditions for disruptive innovation to arise. Much less attention has been paid to the role of innovation processes, including their goals and design, in promoting disruptive innovation. In this paper we aim to be...

  8. Tokamak plasma current disruption infrared control system

    International Nuclear Information System (INIS)

    Kugel, H.W.; Ulrickson, M.

    1987-01-01

    This patent describes a device for magnetically confining a plasma driven by a plasma current and contained within a toroidal vacuum chamber, the device having an inner toroidal limiter on an inside wall of the vacuum chamber and an arrangement for the rapid prediction and control in real time of a major plasma disruption. The arrangement is described which includes: scanning means sensitive to infrared radiation emanating from within the vacuum chamber, the infrared radiation indicating the temperature along a vertical profile of the inner toroidal limiter. The scanning means is arranged to observe the infrared radiation and to produce in response thereto an electrical scanning output signal representative of a time scan of temperature along the vertical profile; detection means for analyzing the scanning output signal to detect a first peaked temperature excursion occurring along the profile of the inner toroidal limiter, and to produce a detection output signal in repsonse thereto, the detection output signal indicating a real time prediction of a subsequent major plasma disruption; and plasma current reduction means for reducing the plasma current driving the plasma, in response to the detection output signal and in anticipation of a subsequent major plasma disruption

  9. Disruptive Innovation Can Prevent the Next Pandemic.

    Science.gov (United States)

    Shaikh, Affan T; Ferland, Lisa; Hood-Cree, Robert; Shaffer, Loren; McNabb, Scott J N

    2015-01-01

    Public health surveillance (PHS) is at a tipping point, where the application of novel processes, technologies, and tools promise to vastly improve efficiency and effectiveness. Yet twentieth century, entrenched ideology and lack of training results in slow uptake and resistance to change. The term disruptive innovation - used to describe advances in technology and processes that change existing markets - is useful to describe the transformation of PHS. Past disruptive innovations used in PHS, such as distance learning, the smart phone, and field-based laboratory testing have outpaced older services, practices, and technologies used in the traditional classroom, governmental offices, and personal communication, respectively. Arguably, the greatest of these is the Internet - an infrastructural innovation that continues to enable exponential benefits in seemingly limitless ways. Considering the Global Health Security Agenda and facing emerging and reemerging infectious disease threats, evolving environmental and behavioral risks, and ever changing epidemiologic trends, PHS must transform. Embracing disruptive innovation in the structures and processes of PHS can be unpredictable. However, it is necessary to strengthen and unlock the potential to prevent, detect, and respond.

  10. Disruptive Innovation Can Prevent the Next Pandemic

    Directory of Open Access Journals (Sweden)

    Affan eShaikh

    2015-09-01

    Full Text Available Public health surveillance (PHS is at a tipping point, where the application of novel processes, technologies, and tools promise to vastly improve efficiency and effectiveness. Yet 20th-century, entrenched ideology and lack of training results in slow uptake and resistance to change. The term disruptive innovation – used to describe advances in technology and processes that change existing markets, is useful to describe the transformation of PHS. Past disruptive innovations used in PHS, such as distance learning, the smart phone, and field-based laboratory testing have outpaced older services, practices, and technologies used in the traditional classroom, governmental offices, and personal communication, respectively. Arguably, the greatest of these is the Internet – an infrastructural innovation that continues to enable exponential benefits in seemingly limitless ways. Considering the Global Health Security Agenda and facing emerging and reemerging infectious disease threats, evolving environmental and behavioral risks, and ever changing epidemiologic trends, PHS must transform. Embracing disruptive innovation in the structures and processes of PHS can be unpredictable. However it is necessary to strengthen and unlock the potential to prevent, detect, and respond.

  11. Disruption effects on the beam size measurement

    Energy Technology Data Exchange (ETDEWEB)

    Raimondi, P.; Decker, F.J.; Chen, P.

    1995-06-01

    At the SLC Final Focus with higher currents and smaller beam sizes, the disruption parameter D{sub y} is close to one and so the pinch effect should produce a luminosity enhancement. Since a flat beam-beam function is fit to deflection scan data to measure the beam size, disruption can affect the measurement. Here the authors discuss the quantitative effects of disruption for typical SLC beam parameters. With 3.5 10{sup 10} particles per pulse, bunch length of 0.8 mm and beam sizes of 2.1 {mu}m horizontally and 0.55 {mu}m vertically, the measured vertical size can be as much as 25% bigger than the real one. Furthermore during the collision the spot size actually decrease, producing an enhancement factor H{sub D} of about 1.25. This would yield to a true luminosity which is 1.6 times that which is estimated from the beam-beam deflection fit.

  12. Natural Hazards and Supply Chain Disruptions

    Science.gov (United States)

    Haraguchi, M.

    2016-12-01

    Natural hazards distress the global economy through disruptions in supply chain networks. Moreover, despite increasing investment to infrastructure for disaster risk management, economic damages and losses caused by natural hazards are increasing. Manufacturing companies today have reduced inventories and streamlined logistics in order to maximize economic competitiveness. As a result, today's supply chains are profoundly susceptible to systemic risks, which are the risk of collapse of an entire network caused by a few node of the network. For instance, the prolonged floods in Thailand in 2011 caused supply chain disruptions in their primary industries, i.e. electronic and automotive industries, harming not only the Thai economy but also the global economy. Similar problems occurred after the Great East Japan Earthquake and Tsunami in 2011, the Mississippi River floods and droughts during 2011 - 2013, and the Earthquake in Kumamoto Japan in 2016. This study attempts to discover what kind of effective measures are available for private companies to manage supply chain disruptions caused by floods. It also proposes a method to estimate potential risks using a Bayesian network. The study uses a Bayesian network to create synthetic networks that include variables associated with the magnitude and duration of floods, major components of supply chains such as logistics, multiple layers of suppliers, warehouses, and consumer markets. Considering situations across different times, our study shows desirable data requirements for the analysis and effective measures to improve Value at Risk (VaR) for private enterprises and supply chains.

  13. Runaway electrons beams in ITER disruptions

    International Nuclear Information System (INIS)

    Fleischmann, H.H.

    1993-01-01

    In agreement with the initial projections, the potential generation of runaway beams in disruptions of ITER discharges was performed. This analysis was based on the best-available present projections of plasma parameters existing in large-tokamak disruptions. Using these parameters, the potential contributions from various basic mechanisms for the generation of runway electrons were estimated. The envisioned mechanisms included (i) the well-known Dreicer process (assuming an evaporation of the runways from the thermal distribution), (ii) the seeding of runaway beams resulting from the potential presence of trapped high-temperature electrons from the original discharge still remaining in the disruption plasma at time of reclosure of the magnetic surfaces, and (iii) the generation of runaway beams through avalanche exponentiation of low-level seed runaways resulting via close collisions of existing runaways with cold plasma electrons. Finally, the prospective behavior of the any generated runaway beams -- in particular during their decay -- as well as their potential avoidance and/or damage controlled extraction through the use of magnetic perturbation fields also was considered in some detail

  14. Circadian Rhythm Disruption Promotes Lung Tumorigenesis.

    Science.gov (United States)

    Papagiannakopoulos, Thales; Bauer, Matthew R; Davidson, Shawn M; Heimann, Megan; Subbaraj, Lakshmipriya; Bhutkar, Arjun; Bartlebaugh, Jordan; Vander Heiden, Matthew G; Jacks, Tyler

    2016-08-09

    Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Dynamic shortest path problems : hybrid routing policies considering network disruptions

    NARCIS (Netherlands)

    Sever, D.; Dellaert, N.P.; Woensel, van T.; Kok, de A.G.

    2013-01-01

    Traffic network disruptions lead to significant increases in transportation costs. We consider networks in which a number of links are vulnerable to these disruptions leading to a significantly higher travel time on these links. For these vulnerable links, we consider known link disruption

  16. Feature extraction for improved disruption prediction analysis at JET

    International Nuclear Information System (INIS)

    Ratta, G. A.; Vega, J.; Murari, A.; Johnson, M.

    2008-01-01

    Disruptions are major instabilities and remain one of the main problems in tokomaks. Using Joint European Torus database, a disruption predictor is developed by computational methods including supervised learning techniques. The main objectives of the work are to develop accurate automatic classifiers, to test their performances, and to determine how much in advance of the disruption they can operate with acceptable reliability.

  17. Practice Oriented Algorithmic Disruption Management in Passenger Railways

    NARCIS (Netherlands)

    J.C. Wagenaar (Joris)

    2016-01-01

    markdownabstractHow to deal with a disruption is a question railway companies face on a daily basis. This thesis focusses on the subject how to handle a disruption such that the passenger service is upheld as much as possible. The current mathematical models for disruption management can not yet be

  18. Mechanisms of quorum sensing and strategies for quorum sensing disruption in aquaculture pathogens.

    Science.gov (United States)

    Zhao, J; Chen, M; Quan, C S; Fan, S D

    2015-09-01

    In many countries, infectious diseases are a considerable threat to aquaculture. The pathogenicity of micro-organisms that infect aquaculture systems is closely related to the release of virulence factors and the formation of biofilms, both of which are regulated by quorum sensing (QS). Thus, QS disruption is a potential strategy for preventing disease in aquaculture systems. QS inhibitors (QSIs) not only inhibit the expression of virulence-associated genes but also attenuate the virulence of aquaculture pathogens. In this review, we discuss QS systems in important aquaculture pathogens and focus on the relationship between QS mechanisms and bacterial virulence in aquaculture. We further elucidate QS disruption strategies for targeting aquaculture pathogens. Four main types of QSIs that target aquaculture pathogens are discussed based on their mechanisms of action. © 2014 John Wiley & Sons Ltd.

  19. Non-Host Plant Volatiles Disrupt Sex Pheromone Communication in a Specialist Herbivore

    Science.gov (United States)

    Wang, Fumin; Deng, Jianyu; Schal, Coby; Lou, Yonggen; Zhou, Guoxin; Ye, Bingbing; Yin, Xiaohui; Xu, Zhihong; Shen, Lize

    2016-01-01

    The ecological effects of plant volatiles on herbivores are manifold. Little is known, however, about the impacts of non-host plant volatiles on intersexual pheromonal communication in specialist herbivores. We tested the effects of several prominent constitutive terpenoids released by conifers and Eucalyptus trees on electrophysiological and behavioral responses of an oligophagous species, Plutella xylostella, which feeds on Brassicaceae. The non-host plant volatile terpenoids adversely affected the calling behavior (pheromone emission) of adult females, and the orientation responses of adult males to sex pheromone were also significantly inhibited by these terpenoids in a wind tunnel and in the field. We suggest that disruption of both pheromone emission and orientation to sex pheromone may explain, at least in part, an observed reduction in herbivore attack in polyculture compared with monoculture plantings. We also propose that mating disruption of both male and female moths with non-host plant volatiles may be a promising alternative pest management strategy. PMID:27585907

  20. Non-Host Plant Volatiles Disrupt Sex Pheromone Communication in a Specialist Herbivore.

    Science.gov (United States)

    Wang, Fumin; Deng, Jianyu; Schal, Coby; Lou, Yonggen; Zhou, Guoxin; Ye, Bingbing; Yin, Xiaohui; Xu, Zhihong; Shen, Lize

    2016-09-02

    The ecological effects of plant volatiles on herbivores are manifold. Little is known, however, about the impacts of non-host plant volatiles on intersexual pheromonal communication in specialist herbivores. We tested the effects of several prominent constitutive terpenoids released by conifers and Eucalyptus trees on electrophysiological and behavioral responses of an oligophagous species, Plutella xylostella, which feeds on Brassicaceae. The non-host plant volatile terpenoids adversely affected the calling behavior (pheromone emission) of adult females, and the orientation responses of adult males to sex pheromone were also significantly inhibited by these terpenoids in a wind tunnel and in the field. We suggest that disruption of both pheromone emission and orientation to sex pheromone may explain, at least in part, an observed reduction in herbivore attack in polyculture compared with monoculture plantings. We also propose that mating disruption of both male and female moths with non-host plant volatiles may be a promising alternative pest management strategy.

  1. RNA interference targeting raptor inhibits proliferation of gastric cancer cells

    International Nuclear Information System (INIS)

    Wu, William Ka Kei; Lee, Chung Wa; Cho, Chi Hin; Chan, Francis Ka Leung; Yu, Jun; Sung, Joseph Jao Yiu

    2011-01-01

    Mammalian target of rapamycin complex 1 (mTORC1) is dysregulated in gastric cancer. The biologic function of mTORC1 in gastric carcinogenesis is unclear. Here, we demonstrate that disruption of mTORC1 function by RNA interference-mediated downregulation of raptor substantially inhibited gastric cancer cell proliferation through induction of G 0 /G 1 -phase cell cycle arrest. The anti-proliferative effect was accompanied by concomitant downregulation of activator protein-1 and upregulation of Smad2/3 transcriptional activities. In addition, the expression of cyclin D 3 and p21 Waf1 , which stabilizes cyclin D/cdk4 complex for G 1 -S transition, was reduced by raptor knockdown. In conclusion, disruption of mTORC1 inhibits gastric cancer cell proliferation through multiple pathways. This discovery may have an implication in the application of mTORC1-directed therapy for the treatment of gastric cancer.

  2. Disruptive coloration in woodland camouflage: evaluation of camouflage effectiveness due to minor disruptive patches

    Science.gov (United States)

    Selj, Gorm K.; Heinrich, Daniela H.

    2016-10-01

    We present results from an observer based photosimulation study of generic camouflage patterns, intended for military uniforms, where three near-identical patterns have been compared. All the patterns were prepared with similar effective color, but were different in how the individual pattern patches were distributed throughout the target. We did this in order to test if high contrast (black) patches along the outline of the target would enhance the survivability when exposed to human observers. In the recent years it has been shown that disruptive coloration in the form of high contrast patches are capable of disturbing an observer by creating false edges of the target and consequently enhance target survivability. This effect has been shown in different forms in the Animal Kingdom, but not to the same extent in camouflaged military targets. The three patterns in this study were i) with no disruptive preference, ii) with a disruptive patch along the outline of the head and iii) with a disruptive patch on the outline of one of the shoulders. We used a high number of human observers to assess the three targets in 16 natural (woodland) backgrounds by showing images of one of the targets at the time on a high definition pc screen. We found that the two patterns that were thought to have a minor disruptive preference to the remaining pattern were more difficult to detect in some (though not all) of the 16 scenes and were also better in overall performance when all the scenes were accounted for.

  3. Neural-net disruption predictor in JT-60U

    International Nuclear Information System (INIS)

    Yoshino, R.

    2003-01-01

    The prediction of major disruptions caused by the density limit, the plasma current ramp-down with high internal inductance l i , the low density locked mode and the β-limit has been investigated in JT-60U. The concept of 'stability level', newly proposed in this paper to predict the occurrence of a major disruption, is calculated from nine input parameters every 2 ms by the neural network and the start of a major disruption is predicted when the stability level decreases to a certain level, the 'alarm level'. The neural network is trained in two steps. It is first trained with 12 disruptive and six non-disruptive shots (total of 8011 data points). Second, the target output data for 12 disruptive shots are modified and the network is trained again with additional data points generated by the operator. The 'neural-net disruption predictor' obtained has been tested for 300 disruptive shots (128 945 data points) and 1008 non-disruptive shots (982 800 data points) selected from nine years of operation (1991-1999) of JT-60U. Major disruptions except for those caused by the -limit have been predicted with a prediction success rate of 97-98% at 10 ms prior to the disruption and higher than 90% at 30 ms prior to the disruption while the false alarm rate is 2.1% for non-disruptive shots. This prediction performance has been confirmed for 120 disruptive shots (56 163 data points), caused by the density limit, as well as 1032 non-disruptive shots (1004 611 data points) in the last four years of operation (1999-2002) of JT-60U. A careful selection of the input parameters supplied to the network and the newly developed two-step training of the network have reduced the false alarm rate resulting in a considerable improvement of the prediction success rate. (author)

  4. An organizational assessment of disruptive clinician behavior: findings and implications.

    Science.gov (United States)

    Walrath, Jo M; Dang, Deborah; Nyberg, Dorothy

    2013-01-01

    This study investigated registered nurses' (RNs) and physicians' (MD) experiences with disruptive behavior, triggers, responses, and impacts on clinicians, patients, and the organization. Using the Disruptive Clinician Behavior Survey for Hospital Settings, it was found that RNs experienced a significantly higher frequency of disruptive behaviors and triggers than MDs; MDs (45% of 295) and RNs (37% of 689) reported that their peer's disruptive behavior affected them most negatively. The most frequently occurring trigger was pressure from high census, volume, and patient flow; 189 incidences of harm to patients as a result of disruptive behavior were reported. Findings provide organizational leaders with evidence to customize interventions to strengthen the culture of safety.

  5. Disruption characteristics in PDX with limiter and divertor discharges

    International Nuclear Information System (INIS)

    Couture, P.; McGuire, K.

    1986-09-01

    A comparison has been made between the characteristics of disruptions with limiter and divertor configurations in PDX. A large data base on disruptions has been collected over four years of machine operation, and a total of 15,000 discharges are contained in the data file. It was found that divertor discharges have less disruptions during ramp up and flattop of the plasma current. However, for divertor discharges a large number of fast, low current disruptions take place during the current ramp down. These disruptions are probably caused by the deformation of the plasma shape

  6. Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption.

    Directory of Open Access Journals (Sweden)

    Marsha C Lampi

    Full Text Available Arterial stiffening accompanies both aging and atherosclerosis, and age-related stiffening of the arterial intima increases RhoA activity and cell contractility contributing to increased endothelium permeability. Notably, statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase inhibitors whose pleiotropic effects include disrupting small GTPase activity; therefore, we hypothesized the statin simvastatin could be used to attenuate RhoA activity and inhibit the deleterious effects of increased age-related matrix stiffness on endothelial barrier function. Using polyacrylamide gels with stiffnesses of 2.5, 5, and 10 kPa to mimic the physiological stiffness of young and aged arteries, endothelial cells were grown to confluence and treated with simvastatin. Our data indicate that RhoA and phosphorylated myosin light chain activity increase with matrix stiffness but are attenuated when treated with the statin. Increases in cell contractility, cell-cell junction size, and indirect measurements of intercellular tension that increase with matrix stiffness, and are correlated with matrix stiffness-dependent increases in monolayer permeability, also decrease with statin treatment. Furthermore, we report that simvastatin increases activated Rac1 levels that contribute to endothelial barrier enhancing cytoskeletal reorganization. Simvastatin, which is prescribed clinically due to its ability to lower cholesterol, alters the endothelial cell response to increased matrix stiffness to restore endothelial monolayer barrier function, and therefore, presents a possible therapeutic intervention to prevent atherogenesis initiated by age-related arterial stiffening.

  7. Disrupted cortical function underlies behavior dysfunction due to social isolation

    Science.gov (United States)

    Miyazaki, Tomoyuki; Takase, Kenkichi; Nakajima, Waki; Tada, Hirobumi; Ohya, Daisuke; Sano, Akane; Goto, Takahisa; Hirase, Hajime; Malinow, Roberto; Takahashi, Takuya

    2012-01-01

    Stressful events during early childhood can have a profound lifelong influence on emotional and cognitive behaviors. However, the mechanisms by which stress affects neonatal brain circuit formation are poorly understood. Here, we show that neonatal social isolation disrupts molecular, cellular, and circuit developmental processes, leading to behavioral dysfunction. Neonatal isolation prevented long-term potentiation and experience-dependent synaptic trafficking of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors normally occurring during circuit formation in the rodent barrel cortex. This inhibition of AMPA receptor trafficking was mediated by an increase of the stress glucocorticoid hormone and was associated with reduced calcium/calmodulin-dependent protein kinase type II (CaMKII) signaling, resulting in attenuated whisker sensitivity at the cortex. These effects led to defects in whisker-dependent behavior in juvenile animals. These results indicate that neonatal social isolation alters neuronal plasticity mechanisms and perturbs the initial establishment of a normal cortical circuit, which potentially explains the long-lasting behavioral effects of neonatal stress. PMID:22706303

  8. Application of the Disruption Predictor Feature Developer to developing a machine-portable disruption predictor

    Science.gov (United States)

    Parsons, Matthew; Tang, William; Feibush, Eliot

    2016-10-01

    Plasma disruptions pose a major threat to the operation of tokamaks which confine a large amount of stored energy. In order to effectively mitigate this damage it is necessary to predict an oncoming disruption with sufficient warning time to take mitigative action. Machine learning approaches to this problem have shown promise but require further developments to address (1) the need for machine-portable predictors and (2) the availability of multi-dimensional signal inputs. Here we demonstrate progress in these two areas by applying the Disruption Predictor Feature Developer to data from JET and NSTX, and discuss topics of focus for ongoing work in support of ITER. The author is also supported under the Fulbright U.S. Student Program as a graduate student in the department of Nuclear, Plasma and Radiological Engineering at the University of Illinois at Urbana-Champaign.

  9. Disruption Physics and Mitigation on DIII-D

    International Nuclear Information System (INIS)

    Whyte, D.G.; Humphreys, D.A.; Kellman, A.G.

    2005-01-01

    The contributions of the DIII-D tokamak toward the understanding and control of disruptions are reviewed. Disruptions are found to be deterministic, and the underlying causes of disruption can therefore be predicted and avoided. With sufficiently rapid detection, possible damage from disruptions can be mitigated using an understanding of disruption phenomenology and plasma physics. Regimes of high β are readily available in DIII-D and provide access to relatively high energy density disruptions, despite DIII-D's moderate magnetic field and size. DIII-D, with all-graphite wall armor and wall conditioning between discharges, has proven highly resilient to the deleterious effects that disruptions can have on plasma operations. Simultaneously, exploitation and adaptation of DIII-D's extensive core and edge plasma diagnostic set have allowed for unique plasma measurements during disruptions. These measurements have tied into the development of several physical models used to understand aspects of disruptions, such as magnetohydrodynamic growth at the disruption onset, radiation energy balance through the thermal quench, and halo currents during the current quench. Based on this fundamental understanding, DIII-D has developed techniques to mitigate the harmful effects of disruptions by radiative dissipation of the plasma energy and extrapolated these techniques for possible use on larger devices like ITER

  10. An overview on plasma disruption mitigation and avoidance in tokamak

    International Nuclear Information System (INIS)

    He Kaihui; Pan Chuanhong; Feng Kaiming

    2002-01-01

    Plasma disruption, which seems to be unavoidable in Tokamak operation, occurs very fast and uncontrolled. In order to keep Tokamak plasma from disruption and mitigate the disruption frequency, the research on Tokamak plasma major disruption constitutes one of the main topics in plasma physics. The phenomena and processes of the precursor, thermal quench, current quench, VDE, halo current and runaway electrons generation during plasma disruption are analyzed in detail and systematically based on the data obtained from current Tokamaks such as TFTR, JET, JT-60U and ASDEX-U, etc. The methods to mitigate and avoid disruption in Tokamak are also highlighted schematically. Therefore, it is helpful and instructive for plasma disruption research in next generation large Tokamak such as ITER-FEAT

  11. Pheromone disruption of Argentine ant trail integrity

    Science.gov (United States)

    Suckling, D.M.; Peck, R.W.; Manning, L.M.; Stringer, L.D.; Cappadonna, J.; El-Sayed, A. M.

    2008-01-01

    Disruption of Argentine ant trail following and reduced ability to forage (measured by bait location success) was achieved after presentation of an oversupply of trail pheromone, (Z)-9-hexadecenal. Experiments tested single pheromone point sources and dispersion of a formulation in small field plots. Ant walking behavior was recorded and digitized by using video tracking, before and after presentation of trail pheromone. Ants showed changes in three parameters within seconds of treatment: (1) Ants on trails normally showed a unimodal frequency distribution of walking track angles, but this pattern disappeared after presentation of the trail pheromone; (2) ants showed initial high trail integrity on a range of untreated substrates from painted walls to wooden or concrete floors, but this was significantly reduced following presentation of a point source of pheromone; (3) the number of ants in the pheromone-treated area increased over time, as recruitment apparently exceeded departures. To test trail disruption in small outdoor plots, the trail pheromone was formulated with carnuba wax-coated quartz laboratory sand (1 g quartz sand/0.2 g wax/1 mg pheromone). The pheromone formulation, with a half-life of 30 h, was applied by rotary spreader at four rates (0, 2.5, 7.5, and 25 mg pheromone/m2) to 1- and 4-m2 plots in Volcanoes National Park, Hawaii. Ant counts at bait cards in treated plots were significantly reduced compared to controls on the day of treatment, and there was a significant reduction in ant foraging for 2 days. These results show that trail pheromone disruption of Argentine ants is possible, but a much more durable formulation is needed before nest-level impacts can be expected. ?? 2008 Springer Science+Business Media, LLC.

  12. Estrogens can disrupt amphibian mating behavior.

    Directory of Open Access Journals (Sweden)

    Frauke Hoffmann

    Full Text Available The main component of classical contraceptives, 17α-ethinylestradiol (EE2, has high estrogenic activity even at environmentally relevant concentrations. Although estrogenic endocrine disrupting compounds are assumed to contribute to the worldwide decline of amphibian populations by adverse effects on sexual differentiation, evidence for EE2 affecting amphibian mating behaviour is lacking. In this study, we demonstrate that EE2 exposure at five different concentrations (0.296 ng/L, 2.96 ng/L, 29.64 ng/L, 2.96 µg/L and 296.4 µg/L can disrupt the mating behavior of adult male Xenopus laevis. EE2 exposure at all concentrations lowered male sexual arousal, indicated by decreased proportions of advertisement calls and increased proportions of the call type rasping, which characterizes a sexually unaroused state of a male. Additionally, EE2 at all tested concentrations affected temporal and spectral parameters of the advertisement calls, respectively. The classical and highly sensitive biomarker vitellogenin, on the other hand, was only induced at concentrations equal or higher than 2.96 µg/L. If kept under control conditions after a 96 h EE2 exposure (2.96 µg/L, alterations of male advertisement calls vanish gradually within 6 weeks and result in a lower sexual attractiveness of EE2 exposed males toward females as demonstrated by female choice experiments. These findings indicate that exposure to environmentally relevant EE2 concentrations can directly disrupt male mate calling behavior of X. laevis and can indirectly affect the mating behavior of females. The results suggest the possibility that EE2 exposure could reduce the reproductive success of EE2 exposed animals and these effects might contribute to the global problem of amphibian decline.

  13. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice

    DEFF Research Database (Denmark)

    Koenen, Rory R; von Hundelshausen, Philipp; Nesmelova, Irina V

    2009-01-01

    Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXC...

  14. Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrine loop

    Czech Academy of Sciences Publication Activity Database

    Stapelberg, M.; Gellert, N.; Swettenham, E.; Tomasetti, M.; Witting, P. K.; Procopio, A.; Neužil, Jiří

    2005-01-01

    Roč. 280, č. 27 (2005), s. 25369-25376 ISSN 0021-9258 Institutional research plan: CEZ:AV0Z50520514 Keywords : alpha-tocopheryl succinate * malignant mesothelioma * fibroblast growth factor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.854, year: 2005

  15. alpha-Tocopheryl succinate inhibits angiogenesis by disrupting paracrine FGF2 signalling

    Czech Academy of Sciences Publication Activity Database

    Neužil, Jiří; Swettenham, E.; Wang, X.F.; Dong, L.F.; Stapelberg, M.

    2007-01-01

    Roč. 581, č. 24 (2007), s. 4611-4615 ISSN 0014-5793 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : mitocans * proliferating endothelial cells * apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.263, year: 2007

  16. Pseudomonas aeruginosa extracellular products inhibit staphylococcal growth, and disrupt established biofilms produced by Staphylococcus epidermidis

    DEFF Research Database (Denmark)

    Qin, Zhiqiang; Yang, Liang; Qu, Di

    2009-01-01

    Multiple bacterial species often coexist as communities, and compete for environmental resources. Here, we describe how an opportunistic pathogen, Pseudomonas aeruginosa, uses extracellular products to interact with the nosocomial pathogen Staphylococcus epidermidis. S. epidermidis biofilms and p...... of a novel strategy for controlling S. epidermidis biofilms....

  17. Sustained Angiopoietin-2 Expression Disrupts Vessel Formation and Inhibits Glioma Growth

    Directory of Open Access Journals (Sweden)

    Ok-Hee Lee

    2006-05-01

    Full Text Available Systematic analyses of the expression of angiogenic regulators in cancer models should yield useful information for the development of novel therapies for malignant gliomas. In this study, we analyzed tumor growth, vascularization, and angiopoietin-2 (Ang2 expression during the development of U-87 MG xenografts. We found that tumoral angiogenesis in this model follows a multistage process characterized by avascular, prolific peripheral angiogenesis, and late vascular phases. On day 4, we observed an area of central necrosis, a peripheral ring of Ang2-positive glioma cells, and reactive Ang2-positive vascular structures in the tumor/brain interface. When the tumor had developed a vascular network, Ang2 was expressed only in peripheral vascular structures. Because Ang2 expression was downmodulated in the late stages of development, probably to maintain a stable tumoral vasculature, we next studied whether sustained Ang2 expression might impair vascular development and, ultimately, tumor growth. Ang2 prevented the formation of capillary-like structures and impaired angiogenesis in a chorioallantoic membrane chicken model. Finally, we tested the effect of sustained Ang2 expression on U-87 MG xenograff development. Ang2 significantly prolonged the survival of intracranial U-87 MG tumor-bearing animals. Examination of Ang2treated xenograffs revealed areas of tumor necrosis and vascular damage. We therefore conclude that deregulated Ang2 expression during gliomagenesis hindered successful angiogenesis and that therapies that sustain Ang2 expression might be effective against malignant gliomas.

  18. Generalization of Fear Inhibition by Disrupting Hippocampal Protein Synthesis-Dependent Reconsolidation Process

    OpenAIRE

    Yang, Chih-Hao; Huang, Chiung-Chun; Hsu, Kuei-Sen

    2011-01-01

    Repetitive replay of fear memories may precipitate the occurrence of post-traumatic stress disorder and other anxiety disorders. Hence, the suppression of fear memory retrieval may help prevent and treat these disorders. The formation of fear memories is often linked to multiple environmental cues and these interconnected cues may act as reminders for the recall of traumatic experiences. However, as a convenience, a simple paradigm of one cue pairing with the aversive stimulus is usually used...

  19. Disrupting the Scaffold to Improve Focal Adhesion Kinase–Targeted Cancer Therapeutics

    Science.gov (United States)

    Cance, William G.; Kurenova, Elena; Marlowe, Timothy; Golubovskaya, Vita

    2013-01-01

    Focal adhesion kinase (FAK) is emerging as a promising cancer target because it is highly expressed at both the transcriptional and translational level in cancer and is involved in many aspects of tumor growth, invasion, and metastasis. Existing FAK-based therapeutics focus on inhibiting the kinase's catalytic function and not the large scaffold it creates that includes many oncogenic receptor tyrosine kinases and tumor suppressor proteins. Targeting the FAK scaffold is a feasible and promising approach for developing highly specific therapeutics that disrupt FAK signaling pathways in cancer. PMID:23532331

  20. Disrupting the scaffold to improve focal adhesion kinase-targeted cancer therapeutics.

    Science.gov (United States)

    Cance, William G; Kurenova, Elena; Marlowe, Timothy; Golubovskaya, Vita

    2013-03-26

    Focal adhesion kinase (FAK) is emerging as a promising cancer target because it is highly expressed at both the transcriptional and translational level in cancer and is involved in many aspects of tumor growth, invasion, and metastasis. Existing FAK-based therapeutics focus on inhibiting the kinase's catalytic function and not the large scaffold it creates that includes many oncogenic receptor tyrosine kinases and tumor suppressor proteins. Targeting the FAK scaffold is a feasible and promising approach for developing highly specific therapeutics that disrupt FAK signaling pathways in cancer.

  1. Physics and observations of tidal disruption events

    Science.gov (United States)

    Mangalam, Arun; Mageshwaran, Tamilan

    2018-04-01

    We describe a model of tidal disruption events (TDEs) with input physical parameters that include the black hole (BH) mass M•, the specific orbital energy E, the angular momentum J, the star mass M⊙ and radius R⊙. We calculate the rise time of the TDEs, the peak bolometric luminosity in terms of these physical parameters and a typical light curve of TDEs for various All Sky Survey (ASS) and Deep Sky Survey (DSS) missions. We then derive the expected detection rates and discuss the follow up of TDEs through observations in various spectral bands from X-rays to radio wavelengths.

  2. Disruptive Innovation by Emerging Multinational Latecomers

    DEFF Research Database (Denmark)

    Li, Peter Ping

    Despite the growing interest in the emerging-economy multinational enterprise (EMNE), there is little knowledge about the underlying mechanism for EMNEs as latecomers to catch up with and even leapfrog the traditional MNEs as early-movers. The cross-fertilization between the research streams...... of latecomer innovation as a special DI by EMNE at BOP to provide insights into the mechanisms underlying the trajectories of catching up and leapfrogging. Built upon latecomer innovation, EMNEs at BOP can emerge as the most disruptive challengers to the MNE incumbents at TOP. The implications of reframed...... constructs, integrative typology, and emerging theory for research and practice are also discussed....

  3. Moore's Law, disruptive technologies, and the clinician.

    Science.gov (United States)

    Vosburgh, Kirby G; Newbower, Ronald S

    2002-01-01

    The advancement of technical power described by Moore's Law offers great potential for enabling more cost-effective medical devices and systems. However, progress has been slow. Many factors for this failure have been cited, including the anti-rational economic structure of healthcare and the complexity and long time scale of medical development. Christensen et al. suggest that "disruptive technologies" may circumvent some of these difficulties. "Disruptive Technologies" are defined as those that are established in one market, but then penetrate and overwhelm another market. These incursions are accelerated by economic factors, and capitalize on functionality, reliability, and advancements supported by the original market. Christensen has cited many examples from industrial and service businesses, but few examples can be found yet in healthcare. We argue that positive technology impacts in medicine occur most readily when innovators augment the skills of and collaborate with caregivers, rather than seeking to displace them. In the short term, a new approach may improve efficiency or quality. In the longer term, such approaches may obviate human tasks at lower-skill levels, and even permit task automation. One successful example has been the introduction of flexible monitoring for physiologic information. Systems for computer-aided diagnosis, which have failed to impact complex decision making, have succeeded in simpler specialty areas such as the interpretation of EKG's and mammograms, and may do the same with analysis of some pathology images. The next frontier may the operating room, and the adoption of such systemic technologies by caregivers in emergency medicine and general care may then have an even wider "disruptive" effect. Responding to time and cost pressures, and the desire to move care to the patient, other workers, such as radiologists, will drive the trend away from isolated, complex, large-scale devices, and toward integrated, modular, and simpler

  4. Traumatic ureteropelvic disruption in the child

    International Nuclear Information System (INIS)

    Reda, E.T.; Lebowitz, R.L.

    1986-01-01

    Traumatic disruption of the ureter from the renal pelvis is a rare injury because the ureteropelvic junction is situated deep in the retroperitoneum and is thus protected by the spine and paraspinal muscles. The mechanism for this injury is thought to be the stretching of the proximal ureter by sudden extreme hyperextension of the trunk. As a non-fatal injury, this occurs only in the child because of the greater elasticity and mobility of the young skeleton. At The Children's Hospital we have seen 3 cases of avulsion of the ureter from the pelvis following blunt trauma. (orig.)

  5. Electrical disruption in toroidal plasma of hydrogen

    International Nuclear Information System (INIS)

    Roberto, M.; Silva, C.A.B.; Goes, L.C.S.; Sudano, J.P.

    1991-01-01

    The initial phase of ionization of a toroidal plasma produced in hydrogen was investigated using zero-dimensional model. The model describes the temporal evolution of plasma by spatial medium of particle density and temperature, on whole plasma volume. The energy and particle (electrons and ions) balance equations are considered. The electron loss is due to ambipolar diffusion in the presence of magnetic field. The electron energy loss involves ionization, Coulomb interaction and diffusion. The ohmic heating converter gives the initial voltage necessary to disruption. (M.C.K.)

  6. Disruptive Innovation in Air Measurement Technology: Reality ...

    Science.gov (United States)

    This presentation is a big picture overview on the changing state of air measurement technology in the world, with a focus on the introduction of low-cost sensors into the market place. The presentation discusses how these new technologies may be a case study in disruptive innovation for the air pollution measurement field. The intended audience is primarily those with experience in air pollution measurement methods, but much of the talk is accessible to the general public. This is a keynote presentation on emerging air monitoring technology, to be provided at the AWMA measurements conference in March, 2016.

  7. Multimedia data mining and analytics disruptive innovation

    CERN Document Server

    Baughman, Aaron; Pan, Jia-Yu; Petrushin, Valery A

    2015-01-01

    This authoritative text/reference provides fresh insights into the cutting edge of multimedia data mining, reflecting how the research focus has shifted towards networked social communities, mobile devices and sensors. Presenting a detailed exploration into the progression of the field, the book describes how the history of multimedia data processing can be viewed as a sequence of disruptive innovations. Across the chapters, the discussion covers the practical frameworks, libraries, and open source software that enable the development of ground-breaking research into practical applications.

  8. Collaborative Memory and Part-Set Cuing Impairments: The Role of Executive Depletion in Modulating Retrieval Disruption

    Science.gov (United States)

    Barber, Sarah J.; Rajaram, Suparna

    2011-01-01

    When people are exposed to a subset of previously studied list items they recall fewer of the remaining items compared to a condition where none of the studied items are provided during recall. This occurs both when the subset of items is provided by the experimenter (i.e., the part-set cuing deficit in individual recall) and when they are provided during the course of a collaborative discussion (i.e., the collaborative inhibition effect in group recall). Previous research has identified retrieval disruption as a common mechanism underlying both effects; however, less is known about the factors that may make individuals susceptible to such retrieval disruption. In the current studies we tested one candidate factor, namely, executive control. Using an executive depletion paradigm we directly manipulated an individual’s level of executive control during retrieval. Results revealed no direct role of executive depletion in modulating retrieval disruption. In contrast, executive control abilities were indirectly related to retrieval disruption through their influence at encoding. Together, these results suggest that executive control does not directly affect retrieval disruption at the retrieval stage, and that the role of this putative mechanism may be limited to the encoding stage. PMID:21678155

  9. An AOP-based alternative testing strategy to predict the impact of thyroid hormone disruption on swim bladder inflation in zebrafish (poster)

    Science.gov (United States)

    Within the field of chemical safety assessment, there is a desire to replace costly whole organism testing with more efficient and cost-effective alternatives based on in vitro test systems. Disruption of thyroid hormone signaling via inhibition of enzymes called deiodinases is o...

  10. An AOP-based alternative testing strategy to predict the impact of thyroid hormone disruption on swim bladder inflation in zebrafish

    Science.gov (United States)

    Within the field of chemical safety assessment, there is a desire to replace costly whole organism testing with more efficient and cost-effective alternatives based on in vitro test systems. Disruption of thyroid hormone signaling via inhibition of enzymes called deiodinases is o...

  11. Smog induces oxidative stress and microbiota disruption.

    Science.gov (United States)

    Wong, Tit-Yee

    2017-04-01

    Smog is created through the interactions between pollutants in the air, fog, and sunlight. Air pollutants, such as carbon monoxide, heavy metals, nitrogen oxides, ozone, sulfur dioxide, volatile organic vapors, and particulate matters, can induce oxidative stress in human directly or indirectly through the formation of reactive oxygen species. The outermost boundary of human skin and mucous layers are covered by a complex network of human-associated microbes. The relation between these microbial communities and their human host are mostly mutualistic. These microbes not only provide nutrients, vitamins, and protection against other pathogens, they also influence human's physical, immunological, nutritional, and mental developments. Elements in smog can induce oxidative stress to these microbes, leading to community collapse. Disruption of these mutualistic microbiota may introduce unexpected health risks, especially among the newborns and young children. Besides reducing the burning of fossil fuels as the ultimate solution of smog formation, advanced methods by using various physical, chemical, and biological means to reduce sulfur and nitrogen contains in fossil fuels could lower smog formation. Additionally, information on microbiota disruption, based on functional genomics, culturomics, and general ecological principles, should be included in the risk assessment of prolonged smog exposure to the health of human populations. Copyright © 2017. Published by Elsevier B.V.

  12. Features, Events, and Processes: Disruptive Events

    Energy Technology Data Exchange (ETDEWEB)

    P. Sanchez

    2004-11-08

    The purpose of this analysis report is to evaluate and document the inclusion or exclusion of the disruptive events features, events, and processes (FEPs) with respect to modeling used to support the total system performance assessment for license application (TSPA-LA). A screening decision, either ''Included'' or ''Excluded,'' is given for each FEP, along with the technical basis for screening decisions. This information is required by the U.S. Nuclear Regulatory Commission (NRC) at 10 CFR 63.114 (d), (e), and (f) [DIRS 156605]. The FEPs addressed in this report deal with both seismic and igneous disruptive events, such as fault displacements through the repository and an igneous intrusion into the repository. For included FEPs, this analysis summarizes the implementation of the FEP in TSPA-LA (i.e., how the FEP is included). For excluded FEPs, this analysis provides the technical basis for exclusion from TSPA-LA (i.e., why the FEP is excluded). Previous versions of this report were developed to support the total system performance assessments (TSPA) for various prior repository designs. This revision addresses the repository design for the license application (LA).

  13. Features, Events, and Processes: Disruptive Events

    International Nuclear Information System (INIS)

    P. Sanchez

    2004-01-01

    The purpose of this analysis report is to evaluate and document the inclusion or exclusion of the disruptive events features, events, and processes (FEPs) with respect to modeling used to support the total system performance assessment for license application (TSPA-LA). A screening decision, either ''Included'' or ''Excluded,'' is given for each FEP, along with the technical basis for screening decisions. This information is required by the U.S. Nuclear Regulatory Commission (NRC) at 10 CFR 63.114 (d), (e), and (f) [DIRS 156605]. The FEPs addressed in this report deal with both seismic and igneous disruptive events, such as fault displacements through the repository and an igneous intrusion into the repository. For included FEPs, this analysis summarizes the implementation of the FEP in TSPA-LA (i.e., how the FEP is included). For excluded FEPs, this analysis provides the technical basis for exclusion from TSPA-LA (i.e., why the FEP is excluded). Previous versions of this report were developed to support the total system performance assessments (TSPA) for various prior repository designs. This revision addresses the repository design for the license application (LA)

  14. Turbulence associated with the sawtooth internal disruption

    International Nuclear Information System (INIS)

    Andreoletti, J.; Laviron, C.; Olivain, J.; Pecquet, A.L.

    1989-05-01

    Specific turbulence associated with the sawtooth internal disruption has been observed on TFR tokamak plasmas by analyzing density fluctuations with CO 2 laser light scattering. The time localization is clearly connected with the successive phases of the relaxation process. Some specific turbulence appears in relation to the kink motion, but the main burst corresponds to the collapse phase. We concentrate our study on this strong burst and show first its frequency and wave number spectral properties and the corresponding pseudo dispersion relation. The specific turbulence is spatially localized. It is within the interior of the q = 1 surface and extends approximately 120 0 azimuthally. Taking into account the twisting of the central plasma during the turbulent kink phase, this location agrees with the azimuthal position of the ''sooner and faster'' outgoing heat flux. The power level of this turbulence is two orders of magnitude larger than the local quasi-stationary turbulence. These observations are in fair agreement with the predictions of the sawtooth disruption model previously proposed by Andreoletti. The observed specific turbulence shows several similarities with the so called ''magnetodrift turbulence'' described in the model

  15. Disruptive mood dysregulation disorder: current insights

    Directory of Open Access Journals (Sweden)

    Baweja R

    2016-08-01

    Full Text Available Raman Baweja, Susan D Mayes, Usman Hameed, James G Waxmonsky Department of Psychiatry, Penn State University College of Medicine, Hershey, PA, USA Abstract: Disruptive mood dysregulation disorder (DMDD was introduced as a new diagnostic entity under the category of depressive disorders in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5. It was included in DSM-5 primarily to address concerns about the misdiagnosis and consequent overtreatment of bipolar disorder in children and adolescents. DMDD does provide a home for a large percentage of referred children with severe persistent irritability that did not fit well into any DSM, Fourth Edition (DSM-IV diagnostic category. However, it has been a controversial addition to the DSM-5 due to lack of published validity studies, leading to questions about its validity as a distinct disorder. In this article, the authors discuss the diagnostic criteria, assessment, epidemiology, criticism of the diagnosis, and pathophysiology, as well as treatment and future directions for DMDD. They also review the literature on severe mood dysregulation, as described by the National Institute of Mental Health, as the scientific support for DMDD is based primarily on studies of severe mood dysregulation. Keywords: disruptive mood dysregulation disorder, persistent irritability, temper outbursts 

  16. Overvoltage protection for magnetic system during disruption in tokamak

    International Nuclear Information System (INIS)

    Zhang, Ming; Li, Xiaolong; He, Yang; Zhang, Jun; Chen, Zhongyong; Yu, Kexun

    2015-01-01

    Highlights: • We investigate the way to limit the plasma disruption overvoltage by using the MOVs. • An overvoltage model of plasma disruption is introduced. • The overvoltage protection scheme has been verified by disruption experiments. • The overvoltage during plasma disruption can be limited to 330 V. - Abstract: During a plasma disruption the magnetic flux in the tokamak changes rapidly, which in most cases will cause high-voltage surges among the magnetic systems and may bring severe damage to the components if there is no overvoltage protection. This paper investigates the way to limit the plasma disruption overvoltage and absorb the energy with the use of metal oxide varistors (MOVs). An overvoltage model of plasma disruption is introduced which can be used for the simulation of plasma disruption and the analysis of the overvoltage. The effectiveness of the overvoltage protection system is validated with disruption experiments. It shows that by optimizing the varistors voltage, the overvoltage during plasma disruption can be limited to an ideal low value. Now the overvoltage protection system has been deployed in J-TEXT tokamak and serves well for daily experiments.

  17. Fuel disruption mechanisms determined in-pile in the ACRR

    International Nuclear Information System (INIS)

    Wright, S.A.; Fischer, E.A.

    1984-09-01

    Over thirty in-pile experiments were performed to investigate fuel disruption behavior for LMFBR loss of flow (LOF) accidents. These experiments reproduced the heating transients for a variety of accidents ranging from slow LOF accidents to rapid LOF-driven-TOP accidents. In all experiments the timing and mode of the fuel disruption were observed with a high speed camera, enabling detailed comparisons with a fuel pin code, SANDPIN. This code transient intra- and inter-granular fission gas behavior to predict the macroscopic fuel behavior, such as fission gas induced swelling and frothing, cracking and breakup of solid fuel, and fuel vapor pressure driven dispersal. This report reviews the different modes of fuel disruption as seen in the experiments and then describes the mechanism responsible for the disruption. An analysis is presented that describes a set of conditions specifying the mode of fuel disruption and the heating conditions required to produce the disruption. The heating conditions are described in terms of heating rate (K/s), temperature gradient, and fuel temperature. A fuel disruption map is presented which plots heating rate as a function of fuel temperature to illustrate the different criteria for disruption. Although this approach to describing fuel disruption oversimplifies the fission gas processes modeled by SANDPIN, it does illustrate the criteria used to determine which fuel disruption mechanism is dominant and on what major fission gas parameters it depends

  18. Comparative toxicity and endocrine disruption potential of urban and rural atmospheric organic PM1 in JEG-3 human placental cells.

    Science.gov (United States)

    van Drooge, Barend L; Marqueño, Anna; Grimalt, Joan O; Fernández, Pilar; Porte, Cinta

    2017-11-01

    Outdoor ambient air particulate matter and air pollution are related to adverse effects on human health. The present study assesses the cytotoxicity and ability to disrupt aromatase activity of organic PM 1 extracts from rural and urban areas at equivalent air volumes from 2 to 30 m 3 , in human placental JEG-3 cells. Samples were chemically analyzed for particle bounded organic compounds with endocrine disrupting potential, i.e. PAH, O-PAH, phthalate esters, but also for organic molecular tracer compounds for the emission source identification. Rural samples collected in winter were cytotoxic at the highest concentration tested and strongly inhibited aromatase activity in JEG-3 cells. No cytotoxicity was detected in summer samples from the rural site and the urban samples, while aromatase activity was moderately inhibited in these samples. In the urban area, the street site samples, collected close to intensive traffic, showed stronger inhibition of aromatase activity than the samples simultaneously collected at a roof site, 50 m above ground level. The cytotoxicity and endocrine disruption potential of the samples were linked to combustion products, i.e. PAH and O-PAH, especially from biomass burning in the rural site in winter. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Tactile acuity is disrupted in osteoarthritis but is unrelated to disruptions in motor imagery performance.

    NARCIS (Netherlands)

    Stanton, T.R.; Lin, C.W.; Bray, H.; Smeets, R.J.P.; Taylor, D.; Law, R.Y.; Moseley, G.L.

    2013-01-01

    OBJECTIVE: To determine whether tactile acuity is disrupted in people with knee OA and to determine whether tactile acuity, a clinical signature of primary sensory cortex representation, is related to motor imagery performance (MIP; evaluates working body schema) and pain. METHODS: Experiment 1:

  20. Disruptive Conduct: The Impact of Disruptive Technologies on Social Relations in Higher Education

    Science.gov (United States)

    Flavin, Michael

    2016-01-01

    Higher education institutions (HEIs) have invested significantly in digital technologies for learning and teaching. However, technologies provided by HEIs have not been universally successful in terms of adoption and usage. Meanwhile, both students and lecturers use disruptive technologies to support learning and teaching. This article examines…

  1. Comparison of Advanced Machine Learning Tools for Disruption Prediction and Disruption Studies

    Czech Academy of Sciences Publication Activity Database

    Odstrčil, Michal; Murari, A.; Mlynář, Jan

    2013-01-01

    Roč. 41, č. 7 (2013), s. 1751-1759 ISSN 0093-3813 R&D Projects: GA ČR GAP205/10/2055 Institutional support: RVO:61389021 Keywords : Learning Machines * Support Vector Machines * Neural Network * ASDEX Upgrade * JET * Disruption mitigation * Tokamaks * ITER Subject RIV: BL - Plasma and Gas Discharge Physics Impact factor: 0.950, year: 2013

  2. Disrupting Law School: How Disruptive Innovation Will Revolutionize the Legal World

    Science.gov (United States)

    Pistone, Michele R.; Horn, Michael B.

    2016-01-01

    Facing dramatic declines in enrollment, revenue, and student quality at the same time that their cost structure continues to rise and public support has waned, law schools are in crisis. A key driver of the crisis is shrinking employment opportunities for recent graduates, which stem in part from the disruption of the traditional business model…

  3. Effects of triazole fungicides on androgenic disruption and CYP3A4 enzyme activity.

    Science.gov (United States)

    Lv, Xuan; Pan, Liumeng; Wang, Jiaying; Lu, Liping; Yan, Weilin; Zhu, Yanye; Xu, Yiwen; Guo, Ming; Zhuang, Shulin

    2017-03-01

    Triazole fungicides are widely used as broad-spectrum fungicides, non-steroidal antiestrogens and for various industrial applications. Their residues have been frequently detected in multiple environmental and human matrices. The increasingly reported toxicity incidents have led triazole fungicides as emerging contaminants of environmental and public health concern. However, whether triazole fungicides behave as endocrine disruptors by directly mimicking environmental androgens/antiandrogens or exerting potential androgenic disruption indirectly through the inhibition of cytochrome P450 (CYP450) enzyme activity is yet an unresolved question. We herein evaluated five commonly used triazole fungicides including bitertanol, hexaconazole, penconazole, tebuconazole and uniconazole for the androgenic and anti-androgenic activity using two-hybrid recombinant human androgen receptor (AR) yeast bioassay and comparatively evaluated their effects on enzymatic activity of CYP3A4 by P450-Glo™ CYP3A4 bioassay. All five fungicides showed moderate anti-androgenic activity toward human AR with the IC 50 ranging from 9.34 μM to 79.85 μM. The anti-androgenic activity remained no significant change after the metabolism mediated by human liver microsomes. These fungicides significantly inhibited the activity of CYP3A4 at the environmental relevant concentrations and the potency ranks as tebuconazole > uniconazole > hexaconazole > penconazole > bitertanol with the corresponding IC 50 of 0.81 μM, 0.93 μM, 1.27 μM, 2.22 μM, and 2.74 μM, respectively. We found that their anti-androgenic activity and the inhibition potency toward CYP3A4 inhibition was significantly correlated (R 2 between 0.83 and 0.97, p pesticides and structurally similar chemicals should fully consider potential androgenic disrupting effects and the influences on the activity of CYP450s. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Inhibition of enveloped viruses infectivity by curcumin.

    Directory of Open Access Journals (Sweden)

    Tzu-Yen Chen

    Full Text Available Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter than for the pseudorabies virus (approximately 180 nm and the vaccinia virus (roughly 335 × 200 × 200 nm. These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses.

  5. Inhibition of Enveloped Viruses Infectivity by Curcumin

    Science.gov (United States)

    Wen, Hsiao-Wei; Ou, Jun-Lin; Chiou, Shyan-Song; Chen, Jo-Mei; Wong, Min-Liang; Hsu, Wei-Li

    2013-01-01

    Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA) activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB)-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter) than for the pseudorabies virus (approximately 180 nm) and the vaccinia virus (roughly 335 × 200 × 200 nm). These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses. PMID:23658730

  6. Scaling Up Cortical Control Inhibits Pain

    Directory of Open Access Journals (Sweden)

    Jahrane Dale

    2018-05-01

    Full Text Available Summary: Acute pain evokes protective neural and behavioral responses. Chronic pain, however, disrupts normal nociceptive processing. The prefrontal cortex (PFC is known to exert top-down regulation of sensory inputs; unfortunately, how individual PFC neurons respond to an acute pain signal is not well characterized. We found that neurons in the prelimbic region of the PFC increased firing rates of the neurons after noxious stimulations in free-moving rats. Chronic pain, however, suppressed both basal spontaneous and pain-evoked firing rates. Furthermore, we identified a linear correlation between basal and evoked firing rates of PFC neurons, whereby a decrease in basal firing leads to a nearly 2-fold reduction in pain-evoked response in chronic pain states. In contrast, enhancing basal PFC activity with low-frequency optogenetic stimulation scaled up prefrontal outputs to inhibit pain. These results demonstrate a cortical gain control system for nociceptive regulation and establish scaling up prefrontal outputs as an effective neuromodulation strategy to inhibit pain. : Dale et al. find that acute pain increases activity levels in the prefrontal cortex. Chronic pain reduces both basal spontaneous and pain-evoked activity in this region, whereas neurostimulation to restore basal activities can in turn enhance nociception-evoked prefrontal activities to inhibit pain. Keywords: chronic pain, neuromodulation, prefrontal cortex, PFC, cortical gain control

  7. Abnormal energy deposition on the wall through plasma disruptions

    International Nuclear Information System (INIS)

    Yamazaki, K.; Schmidt, G.L.

    1984-01-01

    The dissipation of plasma kinetic and magnetic energy during sawtooth oscillations and disruptions in tokamak is analyzed using Kadomtsev's disruption model and the plasma-circuit equations. New simple scalings of several characteristic times are obtained for sawteeth and for thermal and magnetic energy quenches of disruptions. The abnormal energy deposition on the wall during major or minor disruptions, estimated from this analysis, is compared with bolometric measurements in the PDX tokamak. Especially, magnetic energy dissipation during the current termination period is shown to be reduced by the strong coupling of the plasma current with external circuits. These analyses are found to be useful to predict the phenomenological behavior of plasma disruptions in large future tokamaks, and to estimate abnormal heat deposition on the wall during plasma disruptions. (orig.)

  8. Abnormal energy deposition on the wall through plasma disruptions

    International Nuclear Information System (INIS)

    Yamazaki, K.; Schmidt, G.L.

    1984-07-01

    The dissipation of plasma kinetic and magnetic energy during sawtooth oscillstions and disruptions in tokamaks is analyzed using Kadomtsev's disruption model and the plasma-circuit equations. New simple scalings of several characteristic times are obtained for sawteeth and for thermal and magnetic energy quenches of disruptions. The abnormal energy deposition on the wall during major or minor disruptions, estimated from this analysis, is compared with bolometric measurements in the PDX tokamak. Especially, magnetic energy dissipation during current termination period is shown to be reduced by the strong coupling of the plasma current with external circuits. These analyses are found to be useful to predict the phenomenological behavior of plasma disruptions in large future tokamaks, and to estimate abnormal heat deposition on the wall during plasma disruptions. (author)

  9. Power loading on the first wall during disruptions in TFTR

    International Nuclear Information System (INIS)

    Janos, A.; Fredrickson, E.D.; McGuire, K.M.; Nagayama, Y.; Owens, D.K.; Wilfrid, E.

    1992-01-01

    Heating of the first wall of TFTR due to disruptions is investigated experimentally using an extensive array of thermocouples. By comparing results from discharges with and without disruptions, we extract effects due to the disruption alone. Disruptions preferentially heat the same areas which are heated during discharges without disruptions. Hot areas are inward protrusions or regions unshielded by neighboring areas. Peaking factors in the toroidal direction, defined as peak temperature divided by average toroidal temperature, as a function of poloidal angle, are calculated. For nondisruptive discharges, the peaking factor varies between 2 and 4. For the disruptive portion of a discharge only, the peaking factor near the midplane, where most of the energy is deposited, ranges from 3 to 5. Further away from the midplane, the peaking factor can reach 28, although the heat load is less in that region. (orig.)

  10. Disrupting astrocyte–neuron lactate transfer persistently reduces conditioned responses to cocaine

    KAUST Repository

    Boury-Jamot, B

    2015-10-27

    A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte–neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine.

  11. Deletion of Melanin Concentrating Hormone Receptor-1 disrupts overeating in the presence of food cues.

    Science.gov (United States)

    Sherwood, Andrew; Holland, Peter C; Adamantidis, Antoine; Johnson, Alexander W

    2015-12-01

    Exposure to environmental cues associated with food can evoke eating behavior in the absence of hunger. This capacity for reward cues to promote feeding behaviors under sated conditions can be examined in the laboratory using cue-potentiated feeding (CPF). The orexigenic neuropeptide Melanin Concentrating Hormone (MCH) is expressed throughout brain circuitry critical for CPF. We examined whether deletion of the MCH receptor, MCH-1R, would in KO mice disrupt overeating in the presence of a Pavlovian CS+ associated with sucrose delivery. While both wild-type controls and KO mice showed comparable food magazine approach responses during the CPF test, MCH-1R deletion significantly impaired the ability of the CS+ to evoke overeating of sucrose under satiety. Through the use of a refined analysis of meal intake, it was revealed that this disruption to overeating behavior in KO mice reflected a reduction in the capacity for the CS+ to initiate and maintain bursts of licking behavior. These findings suggest that overeating during CPF requires intact MCH-1R signaling and may be due to an influence of the CS+ on the palatability of food and on regulatory mechanisms of peripheral control. Thus, disruptions to MCH-1R signaling may be a useful pharmacological tool to inhibit this form of overeating behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Tributyltin induces disruption of microfilament in HL7702 cells via MAPK-mediated hyperphosphorylation of VASP.

    Science.gov (United States)

    Tu, Wei-Wei; Ji, Lin-Dan; Qian, Hai-Xia; Zhou, Mi; Zhao, Jin-Shun; Xu, Jin

    2016-11-01

    Tributyltin (TBT) has been widely used for various industrial purposes, and it has toxic effects on multiple organs and tissues. Previous studies have found that TBT could induce cytoskeletal disruption, especially of the actin filaments. However, the underlying mechanisms remain unclear. The aim of the present study was to determine whether TBT could induce microfilament disruption using HL7702 cells and then to assess for the total levels of various microfilament-associated proteins; finally, the involvement of the MAPK pathway was investigated. The results showed that after TBT treatment, F-actin began to depolymerize and lost its characteristic filamentous structure. The protein levels of Ezrin and Cofilin remained unchanged, the actin-related protein (ARP) 2/3 levels decreased slightly, and the vasodilator-stimulated phosphoprotein (VASP) decreased dramatically. However, the phosphorylation levels of VASP increased 2.5-fold, and the ratio of phosphorylated-VASP/unphosphorylated-VASP increased 31-fold. The mitogen-activated protein kinases (MAPKs) ERK and JNK were discovered to be activated. Inhibition of ERK and JNK not only largely diminished the TBT-induced hyperphosphorylation of VASP but also recovered the cellular morphology and rescued the cells from death. In summary, this study demonstrates that TBT-induced disruption of actin filaments is caused by the hyperphosphorylation of VASP through MAPK pathways. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1530-1538, 2016. © 2015 Wiley Periodicals, Inc.

  13. Disrupting astrocyte–neuron lactate transfer persistently reduces conditioned responses to cocaine

    KAUST Repository

    Boury-Jamot, B; Carrard, A; Martin, J L; Halfon, O; Magistretti, Pierre J.; Boutrel, B

    2015-01-01

    A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte–neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine.

  14. Can we disrupt the sensing of honey bees by the bee parasite Varroa destructor?

    Science.gov (United States)

    Eliash, Nurit; Singh, Nitin Kumar; Kamer, Yosef; Pinnelli, Govardhana Reddy; Plettner, Erika; Soroker, Victoria

    2014-01-01

    The ectoparasitic mite, Varroa destructor, is considered to be one of the most significant threats to apiculture around the world. Chemical cues are known to play a significant role in the host-finding behavior of Varroa. The mites distinguish between bees from different task groups, and prefer nurses over foragers. We examined the possibility of disrupting the Varroa--honey bee interaction by targeting the mite's olfactory system. In particular, we examined the effect of volatile compounds, ethers of cis 5-(2'-hydroxyethyl) cyclopent-2-en-1-ol or of dihydroquinone, resorcinol or catechol. We tested the effect of these compounds on the Varroa chemosensory organ by electrophysiology and on behavior in a choice bioassay. The electrophysiological studies were conducted on the isolated foreleg. In the behavioral bioassay, the mite's preference between a nurse and a forager bee was evaluated. We found that in the presence of some compounds, the response of the Varroa chemosensory organ to honey bee headspace volatiles significantly decreased. This effect was dose dependent and, for some of the compounds, long lasting (>1 min). Furthermore, disruption of the Varroa volatile detection was accompanied by a reversal of the mite's preference from a nurse to a forager bee. Long-term inhibition of the electrophysiological responses of mites to the tested compounds was a good predictor for an alteration in the mite's host preference. These data indicate the potential of the selected compounds to disrupt the Varroa--honey bee associations, thus opening new avenues for Varroa control.

  15. Disruption generated secondary runaway electrons in present day tokamaks

    International Nuclear Information System (INIS)

    Pankratov, I.M.; Jaspers, R.

    2000-01-01

    An analysis of the runaway electron secondary generation during disruptions in present day tokamaks (JET, JT-60U, TEXTOR) was made. It was shown that even for tokamaks with the plasma current I approx 100 kA the secondary generation may dominate the runaway production during disruptions. In the same time in tokamaks with I approx 1 MA the runaway electron secondary generation during disruptions may be suppressed

  16. Identifikasi Pembayaran Bergerak (Mobile Payment) yang Mengganggu (Disruptive) di Indonesia

    OpenAIRE

    Mawarrini, Robertta Indira

    2017-01-01

    This research aims to identify disruptive mobile payment in Indonesia. Mobile payment as a sector of financial technology is enabling the lifestyle transformation of electronic banking. The future of retail banking is a smartphone experience that gladden and customers also aspire for a “bank in my pocket”. Mobile payment as the second sector most likely to be disrupted in the intersection of finance and technology industry. The promising approach of disruptive innovations is proposed by Profe...

  17. A Production Model for Deteriorating Inventory Items with Production Disruptions

    OpenAIRE

    Yong He; Ju He

    2010-01-01

    Disruption management has recently become an active area of research. In this study, an extension is made to consider the fact that some products may deteriorate during storage. A production-inventory model for deteriorating items with production disruptions is developed. Then the optimal production and inventory plans are provided, so that the manufacturer can reduce the loss caused by disruptions. Finally, a numerical example is used to illustrate the model.

  18. Plasma diffusion in systems with disrupted magnetic surfaces

    International Nuclear Information System (INIS)

    Morozov, D.K.; Pogutse, O.P.

    1982-01-01

    Plasma diffusion is analyzed in the case in which the system of magnetic surfaces is disrupted by a stochastic perturbation of the magnetic field. The diffusion coefficient is related to the statistical properties of the field. The statistical characteristics of the field are found when the magnetic surfaces near the separatrix are disrupted by an external perturbation. The diffusion coefficient is evaluated in the region in which the magnetic surfaces are disrupted. In this region the diffusion coefficient is of the Bohm form

  19. Disruption of Trophic Inhibitory Signaling in Autism Sepctrum Disorders

    Science.gov (United States)

    2016-12-01

    1 AWARD NUMBER: W81XWH-14-1-0433 TITLE: Disruption of Trophic Inhibitory Signaling in Autism Sepctrum Disorders PRINCIPAL INVESTIGATOR: Anis...SUBTITLE 5a. CONTRACT NUMBER Disruption of Trophic Inhibitory Signaling in Autism Sepctrum Disorders 5b. GRANT NUMBER W81XWH-14-1-0433 5c. PROGRAM...chloride co-transporters that control EGABA could be used as a corrective strategy for the synaptic and circuit disruptions demonstrated in the

  20. Cost Consequences of a Port-Related Supply Chain Disruption

    OpenAIRE

    Hui Shan LOH; Vinh Van THAI

    2015-01-01

    Port functionality is a significant and important aspect of cargo transportation. Previous studies have identified a list of port-related supply chain disruption threats and developed a management model that seeks to address these threats. This paper adds value to these related studies by comparing four consequences of an example of these threats: (1) avoidance of disruption, (2) mitigation of disruption, (3) deviation of transportation plan and (4) delays and deviation of transportation plan...

  1. Features, Events, and Processes: Disruptive Events

    International Nuclear Information System (INIS)

    J. King

    2004-01-01

    The primary purpose of this analysis is to evaluate seismic- and igneous-related features, events, and processes (FEPs). These FEPs represent areas of natural system processes that have the potential to produce disruptive events (DE) that could impact repository performance and are related to the geologic processes of tectonism, structural deformation, seismicity, and igneous activity. Collectively, they are referred to as the DE FEPs. This evaluation determines which of the DE FEPs are excluded from modeling used to support the total system performance assessment for license application (TSPA-LA). The evaluation is based on the data and results presented in supporting analysis reports, model reports, technical information, or corroborative documents that are cited in the individual FEP discussions in Section 6.2 of this analysis report

  2. Endocrine disrupting chemicals and growth of children.

    Science.gov (United States)

    Botton, Jérémie; Kadawathagedara, Manik; de Lauzon-Guillain, Blandine

    2017-06-01

    According to the "environmental obesogen hypothesis", early-life (including in utero) exposure to endocrine disrupting chemicals (EDCs) may disturb the mechanisms involved in adipogenesis or energy storage, and thus may increase the susceptibility to overweight and obesity. Animal models have shown that exposure to several of these chemicals could induce adipogenesis and mechanisms have been described. Epidemiological studies are crucial to know whether this effect could also be observed in humans. We aimed at summarizing the literature in epidemiology on the relationship between EDCs exposure and child's growth. Overall, epidemiological studies suggest that pre- and/or early postnatal exposure to some EDCs may increase the risk of overweight or obesity during childhood. In that review, we present some limitations of these studies, mainly in exposure assessment, that currently prevent to conclude about causality. Recent advances in epidemiology should bring further knowledge. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. The Disruptive Effect of Think Aloud

    DEFF Research Database (Denmark)

    Nielsen, Janni; Yssing, Carsten

    Thinking Aloud Thinking Aloud is the most commonly used technique used to test users´ interaction with computers. The assumption is that Think Aloud gives access to what goes on in the users´ minds. However, interfaces are multi modal and play heavily on user´s visual perception. Reflecting upon...... Think Aloud (TA), we ask the question: what happens when users are required to verbalise their visual perceptions and interactions? We argue that TA may have a disruptive effect, suggesting that other techniques be considered. With a theoretical distinction between focal and subsidiary awareness...... and a focus on the sense making process, we develop a frame for test of user´s visual interaction which rely on the coordination between hand/mouse and eye/cursor.Author Keywords: Think Aloud, visual perception, interaction, test...

  4. Features, Events, and Processes: Disruptive Events

    Energy Technology Data Exchange (ETDEWEB)

    J. King

    2004-03-31

    The primary purpose of this analysis is to evaluate seismic- and igneous-related features, events, and processes (FEPs). These FEPs represent areas of natural system processes that have the potential to produce disruptive events (DE) that could impact repository performance and are related to the geologic processes of tectonism, structural deformation, seismicity, and igneous activity. Collectively, they are referred to as the DE FEPs. This evaluation determines which of the DE FEPs are excluded from modeling used to support the total system performance assessment for license application (TSPA-LA). The evaluation is based on the data and results presented in supporting analysis reports, model reports, technical information, or corroborative documents that are cited in the individual FEP discussions in Section 6.2 of this analysis report.

  5. Disruption of Conscious Access in Schizophrenia.

    Science.gov (United States)

    Berkovitch, Lucie; Dehaene, Stanislas; Gaillard, Raphaël

    2017-11-01

    Schizophrenia is a severe and complex psychiatric disorder resulting in delusions, hallucinations, and cognitive impairments. Across a variety of paradigms, an elevated threshold for conscious perception has been repeatedly observed in persons with schizophrenia. Remarkably, even subtle measures of subliminal processing appear to be preserved. We argue here that the dissociation between impaired conscious access and intact unconscious processing may be due to a specific disruption of top-down attentional amplification. This proposal is compatible with the neurophysiological disturbances observed in schizophrenia, including dysconnectivity, abnormal neural oscillations, and glutamatergic and cholinergic dysregulation. Therefore, placing impaired conscious access as a central feature of schizophrenia can help researchers develop a coherent and parsimonious pathophysiological framework of the disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Childhood obesity and endocrine disrupting chemicals

    Directory of Open Access Journals (Sweden)

    Jin Taek Kim

    2017-12-01

    Full Text Available The prevalence of obesity around the world has increased sharply. Strong evidence has emerged over the last decades that human exposure to numerous endocrine disrupting chemicals (EDCs is the cause of obesity and obesity-related metabolic diseases. Many EDCs are manmade chemicals that are released into the environment. EDCs are exogenous compounds that interfere with hormonal regulation and normal endocrine systems, thereby affecting the health of animals and humans. The number of chemicals belonging to EDCs is increasing and some of them are very stable; they persist in the environment (persistent organic pollutants. Although they are banned, their concentrations have been continuously increasing over time. This review gives a brief introduction to common EDCs, and evidence of harmful effects of EDCs on obesity-related diseases; we focus in particular on EDCs’ role in causing mitochondrial dysfunction.

  7. Toroidal current asymmetry in tokamak disruptions

    Science.gov (United States)

    Strauss, H. R.

    2014-10-01

    It was discovered on JET that disruptions were accompanied by toroidal asymmetry of the toroidal plasma current I ϕ. It was found that the toroidal current asymmetry was proportional to the vertical current moment asymmetry with positive sign for an upward vertical displacement event (VDE) and negative sign for a downward VDE. It was observed that greater displacement leads to greater measured I ϕ asymmetry. Here, it is shown that this is essentially a kinematic effect produced by a VDE interacting with three dimensional MHD perturbations. The relation of toroidal current asymmetry and vertical current moment is calculated analytically and is verified by numerical simulations. It is shown analytically that the toroidal variation of the toroidal plasma current is accompanied by an equal and opposite variation of the toroidal current flowing in a thin wall surrounding the plasma. These currents are connected by 3D halo current, which is π/2 radians out of phase with the n = 1 toroidal current variations.

  8. Assessment of CRBR core disruptive accident energetics

    International Nuclear Information System (INIS)

    Theofanous, T.G.; Bell, C.R.

    1984-03-01

    The results of an independent assessment of core disruptive accident energetics for the Clinch River Breeder Reactor are presented in this document. This assessment was performed for the Nuclear Regulatory Commission under the direction of the CRBR Program Office within the Office of Nuclear Reactor Regulation. It considered in detail the accident behavior for three accident initiators that are representative of three different classes of events; unprotected loss of flow, unprotected reactivity insertion, and protected loss of heat sink. The primary system's energetics accommodation capability was realistically, yet conservatively, determined in terms of core events. This accommodation capability was found to be equivalent to an isentropic work potential for expansion to one atmosphere of 2550 MJ or a ramp rate of about 200 $/s applied to a classical two-phase disassembly

  9. Stabilization of tearing modes to suppress major disruptions in tokamaks

    International Nuclear Information System (INIS)

    Holmes, J.A.; Carreras, B.; Hicks, H.R.; Lynch, S.J.; Waddell, B.V.

    1979-02-01

    It is shown, for q-profiles which lead to a disruption, that the control of the amplitude of the 2/1 tearing mode avoids the disruption. Q-profiles measured in T-4 and PLT before a major disruption were studied. Two methods of controlling the 2/1 mode amplitude have been considered: (1) Feedback stabilization with the feedback signal locked in phase with the 2/1 mode. (2) Heating slightly outside the q = 2 surface. In both cases it is only necessary to decrease the 2/1 mode amplitude to suppress the disruption. It is not always necessary to stabilize the unstable modes fully

  10. Disruption mitigation experiment with massive gas injection of HT-7

    International Nuclear Information System (INIS)

    Zhuang Huidong; Zhang Xiaodong

    2013-01-01

    Massive gas injection (MGI) is a promising method on disruption mitigation. The working principle of the fast valve for disruption mitigation was introduced. The disruption mitigation experiments by MGI on HT-7 were described. The experiment shows that the impurities radiation is improved by injecting appropriate amount of gas, and the current quench rate is slow down, so the electromagnetic load on the device is mitigated. The experiments show that the fast valve can completely satisfy the requirement of disruption mitigation on HT-7. (authors)

  11. Technology and plasma-materials interaction processes of tokamak disruptions

    International Nuclear Information System (INIS)

    McGrath, R.T.; Kellman, A.G.

    1992-01-01

    A workshop on the technology and plasma-materials interaction processes of tokamak disruptions was held April 3, 1992 in Monterey, California, as a satellite meeting of the 10th International Conference on Plasma-Surface Interactions. The objective was to bring together researchers working on disruption measurements in operating tokamaks, those performing disruption simulation experiments using pulsed plasma gun, electron beam and laser systems, and computational physicists attempting to model the evolution and plasma-materials interaction processes of tokamak disruptions. This is a brief report on the workshop. 4 refs

  12. Analysis of disruptive instabilities in Aditya tokamak discharges

    International Nuclear Information System (INIS)

    Chattopadhyay, Asim Kumar; Anand, Arun; Rao, C.V.S.; Joisa, Shankar; Aditya team

    2006-01-01

    Major disruptions and sawteeth oscillations (internal disruptions) are routinely observed in ohmically heated Aditya tokamak discharges and their characteristics have been investigated with the help of soft x-ray (SXR) tomography along with other diagnostics. The SXR tomography is carried out with the help of single array of detectors assuming rigid rotation of the modes to analyse the mode structure of sawtooth internal disruptions. Coupling of m/n = 2/1 and m/n=1/1 modes could be the main mechanism for the major disruption. Sawteeth periods were measured and compared with the scaling laws and found to be in good agreement. (author)

  13. Disruptions in ITER and strategies for their control and mitigation

    Energy Technology Data Exchange (ETDEWEB)

    Lehnen, M., E-mail: michael.lehnen@iter.org [ITER Organization, Route de Vinon sur Verdon, 13115 St Paul Lez Durance (France); Aleynikova, K.; Aleynikov, P.B.; Campbell, D.J. [ITER Organization, Route de Vinon sur Verdon, 13115 St Paul Lez Durance (France); Drewelow, P. [Max-Planck-Institut für Plasmaphysik, Greifswald branch, EURATOM Ass., D-17491 Greifswald (Germany); Eidietis, N.W. [General Atomics, P.O. Box 85608, San Diego, CA 92186-5608 (United States); Gasparyan, Yu. [National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), Kashirskoe sh. 31, Moscow 115409 (Russian Federation); Granetz, R.S. [MIT Plasma Science and Fusion Center, Cambridge, MA 02139 (United States); Gribov, Y. [ITER Organization, Route de Vinon sur Verdon, 13115 St Paul Lez Durance (France); Hartmann, N. [Forschungszentrum Jülich GmbH, Institute of Energy and Climate Research—Plasma Physics, Association EURATOM-FZJ, Trilateral Euregio Cluster, 52425 Jülich (Germany); Hollmann, E.M. [University of California-San Diego, La Jolla, CA 92093 (United States); Izzo, V.A. [ITER Organization, Route de Vinon sur Verdon, 13115 St Paul Lez Durance (France); Jachmich, S. [Laboratory for Plasma Physics, ERM/KMS, Association EURATOM – Belgian State, B-1000 Brussels (Belgium); Kim, S.-H.; Kočan, M. [ITER Organization, Route de Vinon sur Verdon, 13115 St Paul Lez Durance (France); Koslowski, H.R. [Forschungszentrum Jülich GmbH, Institute of Energy and Climate Research—Plasma Physics, Association EURATOM-FZJ, Trilateral Euregio Cluster, 52425 Jülich (Germany); Kovalenko, D. [SRC RF TRINITI, ul. Pushkovykh, vladenie 12, Troitsk, Moscow 142190 (Russian Federation); Kruezi, U. [CCFE, Culham Science Centre, Abingdon, Oxon, OX14 3DB (United Kingdom); and others

    2015-08-15

    The thermal and electromagnetic loads related to disruptions in ITER are substantial and require careful design of tokamak components to ensure they reach the projected lifetime and to ensure that safety relevant components fulfil their function for the worst foreseen scenarios. The disruption load specifications are the basis for the design process of components like the full-W divertor, the blanket modules and the vacuum vessel and will set the boundary conditions for ITER operations. This paper will give a brief overview on the disruption loads and mitigation strategies for ITER and will discuss the physics basis which is continuously refined through the current disruption R&D programs.

  14. Disrupted Working Memory Circuitry in Adolescent Psychosis

    Directory of Open Access Journals (Sweden)

    Ariel Eckfeld

    2017-08-01

    Full Text Available Individuals with schizophrenia (SZ consistently show deficits in spatial working memory (WM and associated atypical patterns of neural activity within key WM regions, including the dorsolateral prefrontal cortex (dlPFC and parietal cortices. However, little research has focused on adolescent psychosis (AP and potential age-associated disruptions of WM circuitry that may occur in youth with this severe form of illness. Here we utilized each subject’s individual spatial WM capacity to investigate task-based neural dysfunction in 17 patients with AP (16.58 ± 2.60 years old as compared to 17 typically developing, demographically comparable adolescents (18.07 ± 3.26 years old. AP patients showed lower behavioral performance at higher WM loads and lower overall WM capacity compared to healthy controls. Whole-brain activation analyses revealed greater bilateral precentral and right postcentral activity in controls relative to AP patients, when controlling for individual WM capacity. Seed-based psychophysiological interaction (PPI analyses revealed significantly greater co-activation between the left dlPFC and left frontal pole in controls relative to AP patients. Significant group-by-age interactions were observed in both whole-brain and PPI analyses, with AP patients showing atypically greater neural activity and stronger coupling between WM task activated brain regions as a function of increasing age. Additionally, AP patients demonstrated positive relationships between right dlPFC neural activity and task performance, but unlike healthy controls, failed to show associations between neural activity and out-of-scanner neurocognitive performance. Collectively, these findings are consistent with atypical WM-related functioning and disrupted developmental processes in youth with AP.

  15. Disrupting established tumor blood vessels: an emerging therapeutic strategy for cancer.

    Science.gov (United States)

    McKeage, Mark J; Baguley, Bruce C

    2010-04-15

    The unique characteristics of tumor vasculature represent an attractive target that may be exploited by vascular-targeting anticancer agents. A promising strategy involves the selective disruption of established tumor blood vessels by tumor-vascular disrupting agents (tumor-VDAs), which exhibit antivascular activity, resulting in inhibition of tumor blood flow and extensive necrosis within the tumor core. The tumor-VDA class can be subdivided into flavonoid compounds, which are related to flavone acetic acid, and tubulin-binding compounds. ASA404, of the flavonoid class, is the most advanced tumor-VDA in clinical development and has been evaluated preclinically and in several phase 1 and phase 2 studies. Preclinical studies have demonstrated the selective apoptosis of tumor endothelial cells and the inhibition of tumor blood flow. Synergistic activity was observed with ASA404 and with several chemotherapeutic agents, particularly taxanes. In clinical trials, compared with chemotherapy alone, ASA404 was tolerated well and produced improved activity in patients with nonsmall cell lung cancer when combined with paclitaxel and carboplatin. Phase 3 clinical trials are ongoing. Selectively targeting established tumor vasculature with tumor-VDAs represents a promising and innovative approach to improving the efficacy of standard anticancer therapies. (c) 2010 American Cancer Society.

  16. S-nitrosylation of the IGF-1 receptor disrupts the cell proliferative action of IGF-1.

    Science.gov (United States)

    Okada, Kazushi; Zhu, Bao-Ting

    2017-09-30

    The insulin-like growth factor 1 receptor (IGF-1R) is a disulfide-linked heterotetramer containing two α-subunits and two β-subunits. Earlier studies demonstrate that nitric oxide (NO) can adversely affect IGF-1 action in the central nervous system. It is known that NO can induce S-nitrosylation of the cysteine residues in proteins, thereby partly contributing to the regulation of protein function. In the present study, we sought to determine whether S-nitrosylation of the cysteine residues in IGF-1R is an important post-translational modification that regulates its response to IGF-1. Using cultured SH-SY5Y human neuroblastoma cells as an in vitro model, we found that treatment of cells with S-nitroso-cysteine (SNOC), a NO donor that can nitrosylate the cysteine residues in proteins, induces S-nitrosylation of the β subunit of IGF-1R but not its α-subunit. IGF-1Rβ S-nitrosylation by SNOC is coupled with increased dissociation of the IGF-1R protein complex. In addition, disruption of the IGF-1R function resulting from S-nitrosylation of the IGF-1Rβ subunit is associated with disruption of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. Further, we observed that SNOC-induced IGF-1Rβ S-nitrosylation results in a dose-dependent inhibition of cell proliferation and survival. Together, these results suggest that elevated nitrosative stress may result in dysfunction of cellular IGF-1R signaling through S-nitrosylation of the cysteine residues in the IGF-1Rβ subunit, thereby disrupting the downstream PI3K and MAPK signaling functions and ultimately resulting in inhibition of cell proliferation and survival. Copyright © 2017. Published by Elsevier Inc.

  17. Maternal exposure to di-(2-ethylhexyl) phthalate disrupts placental growth and development in pregnant mice

    Energy Technology Data Exchange (ETDEWEB)

    Zong, Teng; Lai, Lidan [Department of Physiology, School of Medicine, Nanchang University, Nanchang, Jiangxi 330006 (China); Hu, Jia [Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi (China); Guo, Meijun; Li, Mo; Zhang, Lu; Zhong, Chengxue; Yang, Bei; Wu, Lei; Zhang, Dalei; Tang, Min [Department of Physiology, School of Medicine, Nanchang University, Nanchang, Jiangxi 330006 (China); Kuang, Haibin, E-mail: kuanghaibin@ncu.edu.cn [Department of Physiology, School of Medicine, Nanchang University, Nanchang, Jiangxi 330006 (China)

    2015-10-30

    Highlights: • The influence of DEHP on the development of placenta was investigated. • DEHP disrupts the growth and development of placenta. • DEHP disrupts the formation of labyrinth vascularization. • DEHP inhibits the proliferation of ectoplacental cone and placenta. • DEHP induces the apoptosis of placenta via activated MAPK signaling pathway. - Abstract: Di-(2-ethylhexyl) phthalate (DEHP) is used as a plasticizer and widely dispersed in the environment. DEHP exposure reduces embryo implantations, increases embryonic loss, and decreases fetal body weights. However, no detailed information is available about the effect of DEHP on the placentation during pregnancy. Thus, our aim was to explore the effect of DEHP on the growth and development of placenta in vivo. Mice were administered DEHP by gavages at 125, 250, 500 mg/kg/day from gestational days (GD) 1 until sacrifice. Results showed that DEHP treatment significantly reduced the weight of placenta at GD 13. Histopathologically, in DEHP-treated group, the ectoplacental cones significantly became smaller at GD9, and total area of placenta and area of spongiotrophoblast were significantly reduced at GD 13. Expression levels of Ascl2, Esx1 and Fosl1 mRNA dramatically decreased in DEHP-treated placenta at GD 13. DEHP administration disrupted labyrinth vascularization of placentas, and inhibited proliferation and induced apoptosis of placenta by the activation of caspase-3 and -8, up-regulation of Bax and down-regulation of Bcl-2 mRNA and protein at GD 13. In conclusion, these results suggest that adverse pregnancy outcomes including low birth-weight and pregnancy loss exposed to DEHP are possibly mediated, at least in part, via the suppression of placental growth and development.

  18. Microtubule Binding and Disruption and Induction of Premature Senescence by Disorazole C1S⃞

    Science.gov (United States)

    Tierno, Marni Brisson; Kitchens, Carolyn A.; Petrik, Bethany; Graham, Thomas H.; Wipf, Peter; Xu, Fengfeng L.; Saunders, William S.; Raccor, Brianne S.; Balachandran, Raghavan; Day, Billy W.; Stout, Jane R.; Walczak, Claire E.; Ducruet, Alexander P.; Reese, Celeste E.; Lazo, John S.

    2009-01-01

    Disorazoles comprise a family of 29 macrocyclic polyketides isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. The major fermentation product, disorazole A1, was found previously to irreversibly bind to tubulin and to have potent cytotoxic activity against tumor cells, possibly because of its highly electrophilic epoxide moiety. To test this hypothesis, we synthesized the epoxide-free disorazole C1 and found it retained potent antiproliferative activity against tumor cells, causing prominent G2/M phase arrest and inhibition of in vitro tubulin polymerization. Furthermore, disorazole C1 produced disorganized microtubules at interphase, misaligned chromosomes during mitosis, apoptosis, and premature senescence in the surviving cell populations. Using a tubulin polymerization assay, we found disorazole C1 inhibited purified bovine tubulin polymerization, with an IC50 of 11.8 ± 0.4 μM, and inhibited [3H]vinblastine binding noncompetitively, with a Ki of 4.5 ± 0.6 μM. We also found noncompetitive inhibition of [3H]dolastatin 10 binding by disorazole C1, with a Ki of 10.6 ± 1.5 μM, indicating that disorazole C1 bound tubulin uniquely among known antimitotic agents. Disorazole C1 could be a valuable chemical probe for studying the process of mitotic spindle disruption and its relationship to premature senescence. PMID:19066338

  19. Safe taste memory consolidation is disrupted by a protein synthesis inhibitor in the nucleus accumbens shell.

    Science.gov (United States)

    Pedroza-Llinás, R; Ramírez-Lugo, L; Guzmán-Ramos, K; Zavala-Vega, S; Bermúdez-Rattoni, F

    2009-07-01

    Consolidation is the process by which a new memory is stabilized over time, and is dependent on de novo protein synthesis. A useful model for studying memory formation is gustatory memory, a type of memory in which a novel taste may become either safe by not being followed by negative consequences (attenuation of neophobia, AN), or aversive by being followed by post-digestive malaise (conditioned taste aversion, CTA). Here we evaluated the effects of the administration of a protein synthesis inhibitor in the nucleus accumbens (NAc) shell for either safe or aversive taste memory trace consolidation. To test the effects on CTA and AN of protein synthesis inhibition, anisomycin (100microg/microl) was bilaterally infused into the NAc shell of Wistar rats' brains. We found that post-trial protein synthesis blockade impaired the long-term safe taste memory. However, protein synthesis inhibition failed to disrupt the long-term memory of CTA. In addition, we infused anisomycin in the NAc shell after the pre-exposure to saccharin in a latent inhibition of aversive taste. We found that the protein synthesis inhibition impaired the consolidation of safe taste memory, allowing the aversive taste memory to form and consolidate. Our results suggest that protein synthesis is required in the NAc shell for consolidation of safe but not aversive taste memories, supporting the notion that consolidation of taste memory is processed in several brain regions in parallel, and implying that inhibitory interactions between both taste memory traces do occur.

  20. Inhibition of lactation.

    Science.gov (United States)

    Llewellyn-Jones, D

    1975-01-01

    The mechanism and hormonal regulation of lactation is explained and illustrated with a schematic representation. Circulating estrogen above a critical amount seems to be the inhibitory factor controlling lactation during pregnancy. Once delivery occurs, the level of estrogen falls, that of prolactin rises, and lactation begins. Nonsuckling can be used to inhibit lactation. Estrogens can also be used to inhibit lactation more quickly and with less pain. The reported association between estrogens and puerperal thromboembolism cannot be considered conclusive due to defects in the reporting studies. There is no reason not to use estrogens in lactation inhibition except for women over 35 who experienced a surgical delivery. Alternative therapy is available for these women. The recently-developed drug, brom-ergocryptine, may replace other methods of lactation inhibition.