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Sample records for regulating phasic activation

  1. Brainstem circuitry regulating phasic activation of trigeminal motoneurons during REM sleep.

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    Christelle Anaclet

    2010-01-01

    Full Text Available Rapid eye movement sleep (REMS is characterized by activation of the cortical and hippocampal electroencephalogram (EEG and atonia of non-respiratory muscles with superimposed phasic activity or twitching, particularly of cranial muscles such as those of the eye, tongue, face and jaw. While phasic activity is a characteristic feature of REMS, the neural substrates driving this activity remain unresolved. Here we investigated the neural circuits underlying masseter (jaw phasic activity during REMS. The trigeminal motor nucleus (Mo5, which controls masseter motor function, receives glutamatergic inputs mainly from the parvocellular reticular formation (PCRt, but also from the adjacent paramedian reticular area (PMnR. On the other hand, the Mo5 and PCRt do not receive direct input from the sublaterodorsal (SLD nucleus, a brainstem region critical for REMS atonia of postural muscles. We hypothesized that the PCRt-PMnR, but not the SLD, regulates masseter phasic activity during REMS.To test our hypothesis, we measured masseter electromyogram (EMG, neck muscle EMG, electrooculogram (EOG and EEG in rats with cell-body specific lesions of the SLD, PMnR, and PCRt. Bilateral lesions of the PMnR and rostral PCRt (rPCRt, but not the caudal PCRt or SLD, reduced and eliminated REMS phasic activity of the masseter, respectively. Lesions of the PMnR and rPCRt did not, however, alter the neck EMG or EOG. To determine if rPCRt neurons use glutamate to control masseter phasic movements, we selectively blocked glutamate release by rPCRt neurons using a Cre-lox mouse system. Genetic disruption of glutamate neurotransmission by rPCRt neurons blocked masseter phasic activity during REMS.These results indicate that (1 premotor glutamatergic neurons in the medullary rPCRt and PMnR are involved in generating phasic activity in the masseter muscles, but not phasic eye movements, during REMS; and (2 separate brainstem neural circuits control postural and cranial muscle

  2. Influence of phasic and tonic dopamine release on receptor activation

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Herrik, Kjartan F; Berg, Rune W

    2010-01-01

    Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we...... develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation...

  3. Role of SM22 in the differential regulation of phasic vs. tonic smooth muscle

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    Ali, Mehboob

    2015-01-01

    Preliminary proteomics studies between tonic vs. phasic smooth muscles identified three distinct protein spots identified to be those of transgelin (SM22). The latter was found to be distinctly downregulated in the internal anal sphincter (IAS) vs. rectal smooth muscle (RSM) SMC. The major focus of the present studies was to examine the differential molecular control mechanisms by SM22 in the functionality of truly tonic smooth muscle of the IAS vs. the adjoining phasic smooth muscle of the RSM. We monitored SMC lengths before and after incubation with pFLAG-SM22 (for SM22 overexpression), and SM22 small-interfering RNA. pFLAG-SM22 caused concentration-dependent and significantly greater relaxation in the IAS vs. the RSM SMCs. Conversely, temporary silencing of SM22 caused contraction in both types of the SMCs. Further studies revealed a significant reverse relationship between the levels of SM22 phosphorylation and the amount of SM22-actin binding in the IAS and RSM SMC. Data showed higher phospho-SM22 levels and decreased SM22-actin binding in the IAS, and reverse to be the case in the RSM SMCs. Experiments determining the mechanism for SM22 phosphorylation in these smooth muscles revealed that Y-27632 (Rho kinase inhibitor) but not Gö-6850 (protein kinase C inhibitor) caused concentration-dependent decreased phosphorylation of SM22. We speculate that SM22 plays an important role in the regulation of basal tone via Rho kinase-induced phosphorylation of SM22. PMID:25617350

  4. Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine.

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    Bai, Qiufang; Song, Dan; Gu, Li; Verkhratsky, Alexei; Peng, Liang

    2017-04-01

    Here, we present the data indicating that chronic treatment with fluoxetine regulates Cav-1/PTEN/PI3K/AKT/GSK-3β signalling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At lower concentrations, fluoxetine downregulates gene expression of Cav-1, decreases membrane content of PTEN, increases activity of PI3K/AKT, and elevates GSK-3β phosphorylation thus suppressing its activity. At higher concentrations, fluoxetine acts in an inverse fashion. As expected, fluoxetine at lower concentrations increased while at higher concentrations decreased glycogen content in astrocytes. Our findings indicate that bi-phasic regulation of glycogen content via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine may be responsible for both therapeutic and side effects of the drug.

  5. Impairment of GABA transporter GAT-1 terminates cortical recurrent network activity via enhanced phasic inhibition

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    Daniel Simon Razik

    2013-09-01

    Full Text Available In the central nervous system, GABA transporters (GATs very efficiently clear synaptically released GABA from the extracellular space, and thus exert a tight control on GABAergic inhibition. In neocortex, GABAergic inhibition is heavily recruited during recurrent phases of spontaneous action potential activity which alternate with neuronally quiet periods. Therefore, such activity should be quite sensitive to minute alterations of GAT function. Here, we explored the effects of a gradual impairment of GAT-1 and GAT-2/3 on spontaneous recurrent network activity – termed network bursts and silent periods – in organotypic slice cultures of rat neocortex. The GAT-1 specific antagonist NO-711 depressed activity already at nanomolar concentrations (IC50 for depression of spontaneous multiunit firing rate of 42 nM, reaching a level of 80% at 500-1000 nM. By contrast, the GAT-2/3 preferring antagonist SNAP-5114 had weaker and less consistent effects. Several lines of evidence pointed towards an enhancement of phasic GABAergic inhibition as the dominant activity-depressing mechanism: network bursts were drastically shortened, phasic GABAergic currents decayed slower, and neuronal excitability during ongoing activity was diminished. In silent periods, NO-711 had little effect on neuronal excitability or membrane resistance, quite in contrast to the effects of muscimol, a GABA mimetic which activates GABAA receptors tonically. Our results suggest that an enhancement of phasic GABAergic inhibition efficiently curtails cortical recurrent activity and may mediate antiepileptic effects of therapeutically relevant concentrations of GAT-1 antagonists.

  6. Diagnostic thresholds for quantitative REM sleep phasic burst duration, phasic and tonic muscle activity, and REM atonia index in REM sleep behavior disorder with and without comorbid obstructive sleep apnea.

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    McCarter, Stuart J; St Louis, Erik K; Duwell, Ethan J; Timm, Paul C; Sandness, David J; Boeve, Bradley F; Silber, Michael H

    2014-10-01

    We aimed to determine whether phasic burst duration and conventional REM sleep without atonia (RSWA) methods could accurately diagnose REM sleep behavior disorder (RBD) patients with comorbid OSA. We visually analyzed RSWA phasic burst durations, phasic, "any," and tonic muscle activity by 3-s mini-epochs, phasic activity by 30-s (AASM rules) epochs, and conducted automated REM atonia index (RAI) analysis. Group RSWA metrics were analyzed and regression models fit, with receiver operating characteristic (ROC) curves determining the best diagnostic cutoff thresholds for RBD. Both split-night and full-night polysomnographic studies were analyzed. N/A. Parkinson disease (PD)-RBD (n = 20) and matched controls with (n = 20) and without (n = 20) OSA. N/A. All mean RSWA phasic burst durations and muscle activities were higher in PD-RBD patients than controls (P sleep without atonia diagnostic thresholds applicable in Parkinson disease-REM sleep behavior disorder (PD-RBD) patient populations with comorbid OSA that may be useful toward distinguishing PD-RBD in typical outpatient populations. © 2014 Associated Professional Sleep Societies, LLC.

  7. Phasic dopamine release drives rapid activation of striatal D2-receptors

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    Marcott, Pamela F; Mamaligas, Aphroditi A; Ford, Christopher P

    2014-01-01

    Summary Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G-protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory post-synaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals. PMID:25242218

  8. Transient inhibition and long-term facilitation of locomotion by phasic optogenetic activation of serotonin neurons

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    Correia, Patrícia A; Lottem, Eran; Banerjee, Dhruba; Machado, Ana S; Carey, Megan R; Mainen, Zachary F

    2017-01-01

    Serotonin (5-HT) is associated with mood and motivation but the function of endogenous 5-HT remains controversial. Here, we studied the impact of phasic optogenetic activation of 5-HT neurons in mice over time scales from seconds to weeks. We found that activating dorsal raphe nucleus (DRN) 5-HT neurons induced a strong suppression of spontaneous locomotor behavior in the open field with rapid kinetics (onset ≤1 s). Inhibition of locomotion was independent of measures of anxiety or motor impairment and could be overcome by strong motivational drive. Repetitive place-contingent pairing of activation caused neither place preference nor aversion. However, repeated 15 min daily stimulation caused a persistent increase in spontaneous locomotion to emerge over three weeks. These results show that 5-HT transients have strong and opposing short and long-term effects on motor behavior that appear to arise from effects on the underlying factors that motivate actions. DOI: http://dx.doi.org/10.7554/eLife.20975.001 PMID:28193320

  9. Tonic and phasic changes in anteromedial globus pallidus activity in Tourette syndrome.

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    Israelashvili, Michal; Smeets, Anouk Y J M; Bronfeld, Maya; Zeef, Dagmar H; Leentjens, Albert F G; van Kranen-Mastenbroek, Vivianne; Janssen, Marcus L F; Temel, Yasin; Ackermans, Linda; Bar-Gad, Izhar

    2017-07-01

    Tourette syndrome is a hyperkinetic neurodevelopmental disorder characterized by tics. Assess the neuronal changes in the associative/limbic GP associated with Tourette syndrome. Neurophysiological recordings were performed from the anterior (associative/limbic) GPe and GPi of 8 awake patients during DBS electrode implantation surgeries. The baseline firing rate of the neurons was low in a state-dependent manner in both segments of the GP. Tic-dependent transient rate changes were found in the activity of individual neurons of both segments around the time of the tic. Neither oscillatory activity of individual neurons nor correlations in their interactions were observed. The results demonstrate the involvement of the associative/limbic pathway in the underlying pathophysiology of Tourette syndrome and point to tonic and phasic modulations of basal ganglia output as a key mechanisms underlying the abnormal state of the disorder and the expression of individual tics, respectively. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  10. Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core.

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    Fortin, Samantha M; Roitman, Mitchell F

    2017-07-01

    Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. NS309 decreases rat detrusor smooth muscle membrane potential and phasic contractions by activating SK3 channels

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    Parajuli, Shankar P; Hristov, Kiril L; Soder, Rupal P; Kellett, Whitney F; Petkov, Georgi V

    2013-01-01

    Background and Purpose Overactive bladder (OAB) is often associated with abnormally increased detrusor smooth muscle (DSM) contractions. We used NS309, a selective and potent opener of the small or intermediate conductance Ca2+-activated K+ (SK or IK, respectively) channels, to evaluate how SK/IK channel activation modulates DSM function. Experimental Approach We employed single-cell RT-PCR, immunocytochemistry, whole cell patch-clamp in freshly isolated rat DSM cells and isometric tension recordings of isolated DSM strips to explore how the pharmacological activation of SK/IK channels with NS309 modulates DSM function. Key Results We detected SK3 but not SK1, SK2 or IK channels expression at both mRNA and protein levels by RT-PCR and immunocytochemistry in DSM single cells. NS309 (10 μM) significantly increased the whole cell SK currents and hyperpolarized DSM cell resting membrane potential. The NS309 hyperpolarizing effect was blocked by apamin, a selective SK channel inhibitor. NS309 inhibited the spontaneous phasic contraction amplitude, force, frequency, duration and tone of isolated DSM strips in a concentration-dependent manner. The inhibitory effect of NS309 on spontaneous phasic contractions was blocked by apamin but not by TRAM-34, indicating no functional role of the IK channels in rat DSM. NS309 also significantly inhibited the pharmacologically and electrical field stimulation-induced DSM contractions. Conclusions and Implications Our data reveal that SK3 channel is the main SK/IK subtype in rat DSM. Pharmacological activation of SK3 channels with NS309 decreases rat DSM cell excitability and contractility, suggesting that SK3 channels might be potential therapeutic targets to control OAB associated with detrusor overactivity. PMID:23145946

  12. Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

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    Daberkow, DP; Brown, HD; Bunner, KD; Kraniotis, SA; Doellman, MA; Ragozzino, ME; Garris, PA; Roitman, MF

    2013-01-01

    Drugs of abuse hijack brain reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting non-exocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties - which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to two hours. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration and frequency of spontaneous dopamine transients, the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify up-regulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926

  13. Activity changes of the cat paraventricular hypothalamus during phasic respiratory events

    DEFF Research Database (Denmark)

    Kristensen, Morten Pilgaard; Poe, G R; Rector, D M

    1997-01-01

    We monitored the spatiotemporal organization of cellular activity in the medial paraventricular hypothalamus during spontaneously-occurring periods of increased inspiratory effort followed by prolonged respiratory pauses (sigh/apnea) in the freely-behaving cat. Paraventricular hypothalamic activity...

  14. Selective Activation of Cholinergic Interneurons Enhances Accumbal Phasic Dopamine Release: Setting the Tone for Reward Processing

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    Roger Cachope

    2012-07-01

    Full Text Available Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior.

  15. Locus coeruleus phasic discharge is essential for stimulus-induced gamma oscillations in the prefrontal cortex.

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    Neves, Ricardo M; van Keulen, Silvia; Yang, Mingyu; Logothetis, Nikos K; Eschenko, Oxana

    2018-03-01

    The locus coeruleus (LC) noradrenergic (NE) neuromodulatory system is critically involved in regulation of neural excitability via its diffuse ascending projections. Tonic NE release in the forebrain is essential for maintenance of vigilant states and increases the signal-to-noise ratio of cortical sensory responses. The impact of phasic NE release on cortical activity and sensory processing is less explored. We previously reported that LC microstimulation caused a transient desynchronization of population activity in the medial prefrontal cortex (mPFC), similar to noxious somatosensory stimuli. The LC receives nociceptive information from the medulla and therefore may mediate sensory signaling to its forebrain targets. Here we performed extracellular recordings in LC and mPFC while presenting noxious stimuli in urethane-anesthetized rats. A brief train of foot shocks produced a robust phasic response in the LC and a transient change in the mPFC power spectrum, with the strongest modulation in the gamma (30-90 Hz) range. The LC phasic response preceded prefrontal gamma power increase, and cortical modulation was proportional to the LC excitation. We also quantitatively characterized distinct cortical states and showed that sensory responses in both LC and mPFC depend on the ongoing cortical state. Finally, cessation of the LC firing by bilateral local iontophoretic injection of clonidine, an α 2 -adrenoreceptor agonist, completely eliminated sensory responses in the mPFC without shifting cortex to a less excitable state. Together, our results suggest that the LC phasic response induces gamma power increase in the PFC and is essential for mediating sensory information along an ascending noxious pathway. NEW & NOTEWORTHY Our study shows linear relationships between locus coeruleus phasic excitation and the amplitude of gamma oscillations in the prefrontal cortex. Results suggest that the locus coeruleus phasic response is essential for mediating sensory information

  16. Phasic Triplet Markov Chains.

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    El Yazid Boudaren, Mohamed; Monfrini, Emmanuel; Pieczynski, Wojciech; Aïssani, Amar

    2014-11-01

    Hidden Markov chains have been shown to be inadequate for data modeling under some complex conditions. In this work, we address the problem of statistical modeling of phenomena involving two heterogeneous system states. Such phenomena may arise in biology or communications, among other fields. Namely, we consider that a sequence of meaningful words is to be searched within a whole observation that also contains arbitrary one-by-one symbols. Moreover, a word may be interrupted at some site to be carried on later. Applying plain hidden Markov chains to such data, while ignoring their specificity, yields unsatisfactory results. The Phasic triplet Markov chain, proposed in this paper, overcomes this difficulty by means of an auxiliary underlying process in accordance with the triplet Markov chains theory. Related Bayesian restoration techniques and parameters estimation procedures according to the new model are then described. Finally, to assess the performance of the proposed model against the conventional hidden Markov chain model, experiments are conducted on synthetic and real data.

  17. An integrative theory of the phasic and tonic modes of dopamine modulation in the prefrontal cortex.

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    Dreher, Jean-Claude; Burnod, Yves

    2002-01-01

    This paper presents a model of both tonic and phasic dopamine (DA) effects on maintenance of working memory representations in the prefrontal cortex (PFC). The central hypothesis is that DA modulates the efficacy of inputs to prefrontal pyramidal neurons to prevent interferences for active maintenance. Phasic DA release, due to DA neurons discharges, acts at a short time-scale (a few seconds), while the tonic mode of DA release, independent of DA neurons firing, acts at a long time-scale (a few minutes). The overall effect of DA modulation is modeled as a threshold restricting incoming inputs arriving on PFC neurons. Phasic DA release temporary increases this threshold while tonic DA release progressively increases the basal level of this threshold. Thus, unlike the previous gating theory of phasic DA release, proposing that it facilitates incoming inputs at the time of their arrival, the effect of phasic DA release is supposed to restrict incoming inputs during a period of time after DA neuron discharges. The model links the cellular and behavioral levels during performance of a working memory task. It allows us to understand why a critical range of DA D1 receptors stimulation is required for optimal working memory performance and how D1 receptor agonists (respectively antagonists) increase perseverations (respectively distractability). Finally, the model leads to several testable predictions, including that the PFC regulates DA neurons firing rate to adapt to the delay of the task and that increase in tonic DA release may either improve or decrease performance, depending on the level of DA receptors stimulation at the beginning of the task.

  18. Phasic firing in vasopressin cells: understanding its functional significance through computational models.

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    Duncan J MacGregor

    Full Text Available Vasopressin neurons, responding to input generated by osmotic pressure, use an intrinsic mechanism to shift from slow irregular firing to a distinct phasic pattern, consisting of long bursts and silences lasting tens of seconds. With increased input, bursts lengthen, eventually shifting to continuous firing. The phasic activity remains asynchronous across the cells and is not reflected in the population output signal. Here we have used a computational vasopressin neuron model to investigate the functional significance of the phasic firing pattern. We generated a concise model of the synaptic input driven spike firing mechanism that gives a close quantitative match to vasopressin neuron spike activity recorded in vivo, tested against endogenous activity and experimental interventions. The integrate-and-fire based model provides a simple physiological explanation of the phasic firing mechanism involving an activity-dependent slow depolarising afterpotential (DAP generated by a calcium-inactivated potassium leak current. This is modulated by the slower, opposing, action of activity-dependent dendritic dynorphin release, which inactivates the DAP, the opposing effects generating successive periods of bursting and silence. Model cells are not spontaneously active, but fire when perturbed by random perturbations mimicking synaptic input. We constructed one population of such phasic neurons, and another population of similar cells but which lacked the ability to fire phasically. We then studied how these two populations differed in the way that they encoded changes in afferent inputs. By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input. Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response

  19. Design and Synthesis of Mono- and Bi-phasic Nano hybrids for Simultaneous Release of Two Active Agents

    International Nuclear Information System (INIS)

    Mohd Zobir Hussein; Abdul Rahman, N.S.S.; Siti Halimah Sarijo

    2011-01-01

    Organic-Inorganic nano hybrid materials, especially of host-guest types exhibit an excellent opportunity for a wide range of organic active agents for the formation of organic-inorganic nano hybrids which may find potential uses with tailor made application. A number of groups have studied the agrochemical intercalates of LDHs as potential reservoir and controlled release system. Agrochemicals, in particular herbicides such as 4-(2,4-dichlorophenoxy)butyrate (DPBA) and 2-(3- chlorophenoxy)propionate (CPPA) are commonly used in agriculture sector. Simultaneous incorporation of both phenoxy herbicides anions into Zn-Al-LDH (ZAL) have been successfully prepared by direct co-precipitation method, labeled as NCDD. Both anions were intercalated simultaneously into the inorganic ZAL interlayers and X-ray diffraction data reveal that the basal spacing increased from 8.9 to 25.1 Angstrom upon the intercalation. PXRD patterns of single anion intercalation using CPPA and DPBA labeled as NC and ND nano hybrid, respectively was simulated and found that the PXRD patterns composed of 90 % ND and 10 % NC and this show relatively similar PXRD features to that of NCDD nano hybrid. This indicates that NCDD is possibly composed of mixed phases of each of NC and ND. UV-VIS spectroscopy study shows the percentage loading of CPPA and DPBA is 2.5 % (w/w) and 41.4 % (w/w), respectively. These values are equivalent to about 5.7 % and 94.3 % contribution of CPPA and DPBA, which agree nicely with the values obtained from simulated PXRD patterns. The simultaneous release of the two herbicides from its nano hybrid exhibit different release kinetics, where DPBA shows higher percentage release than CPPA. The release process was found to be controlled by pseudo-second order kinetic. The results presented show that the intercalation and release of the dual herbicides are influenced by the anion size. The abundance of DPBA anion between the ZAL interlayer is due to its higher affinity towards LDH

  20. Noise-enhanced coding in phasic neuron spike trains.

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    Ly, Cheng; Doiron, Brent

    2017-01-01

    The stochastic nature of neuronal response has lead to conjectures about the impact of input fluctuations on the neural coding. For the most part, low pass membrane integration and spike threshold dynamics have been the primary features assumed in the transfer from synaptic input to output spiking. Phasic neurons are a common, but understudied, neuron class that are characterized by a subthreshold negative feedback that suppresses spike train responses to low frequency signals. Past work has shown that when a low frequency signal is accompanied by moderate intensity broadband noise, phasic neurons spike trains are well locked to the signal. We extend these results with a simple, reduced model of phasic activity that demonstrates that a non-Markovian spike train structure caused by the negative feedback produces a noise-enhanced coding. Further, this enhancement is sensitive to the timescales, as opposed to the intensity, of a driving signal. Reduced hazard function models show that noise-enhanced phasic codes are both novel and separate from classical stochastic resonance reported in non-phasic neurons. The general features of our theory suggest that noise-enhanced codes in excitable systems with subthreshold negative feedback are a particularly rich framework to study.

  1. The Cortisol Paradox of Trauma-Related Disorders: Lower Phasic Responses but Higher Tonic Levels of Cortisol Are Associated with Sexual Abuse in Childhood

    OpenAIRE

    Schalinski, Inga; Elbert, Thomas; Steudte-Schmiedgen, Susann; Kirschbaum, Clemens

    2015-01-01

    ObjectivesInconsistent findings exist for the activity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with stress related disorders. Recent studies point towards early life stress as a potential modulator.MethodsWe investigated the impact of childhood sexual abuse on phasic (saliva cortisol reactivity) and tonic (hair cortisol) regulation. Furthermore, we assessed predictors on cortisol accumulation in hair. Women (N = 43) with stress-related disorders underwent a standardized a...

  2. The impact of luminance on tonic and phasic pupillary responses to sustained cognitive load.

    Science.gov (United States)

    Peysakhovich, Vsevolod; Vachon, François; Dehais, Frédéric

    2017-02-01

    Pupillary reactions independent of light conditions have been linked to cognition for a long time. However, the light conditions can impact the cognitive pupillary reaction. Previous studies underlined the impact of luminance on pupillary reaction, but it is still unclear how luminance modulates the sustained and transient components of pupillary reaction - tonic pupil diameter and phasic pupil response. In the present study, we investigated the impact of the luminance on these two components under sustained cognitive load. Fourteen participants performed a novel working memory task combining mathematical computations with a classic n-back task. We studied both tonic pupil diameter and phasic pupil response under low (1-back) and high (2-back) working memory load and two luminance levels (gray and white). We found that the impact of working memory load on the tonic pupil diameter was modulated by the level of luminance, the increase in tonic pupil diameter with the load being larger under lower luminance. In contrast, the smaller phasic pupil response found under high load remained unaffected by luminance. These results showed that luminance impacts the cognitive pupillary reaction - tonic pupil diameter (phasic pupil response) being modulated under sustained (respectively, transient) cognitive load. These findings also support the relationship between the locus-coeruleus system, presumably functioning in two firing modes - tonic and phasic - and the pupil diameter. We suggest that the tonic pupil diameter tracks the tonic activity of the locus-coeruleus while phasic pupil response reflects its phasic activity. Besides, the designed novel cognitive paradigm allows the simultaneous manipulation of sustained and transient components of the cognitive load and is useful for dissociating the effects on the tonic pupil diameter and phasic pupil response. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Human telomerase activity regulation

    OpenAIRE

    Wojtyla, Aneta; Gladych, Marta; Rubis, Blazej

    2010-01-01

    Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells. Thus, it has become a very promising target for anticancer therapy. The cell proliferative potential can be limited by replication end problem, due to telomeres shortening, which is overcome in cancer cells by telomerase activity or by alternative telomeres lengthening (ALT) mechanism. However, this multisubunit enzymatic complex can be regulated at various levels, including expression control b...

  4. Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder.

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    Rajendra D Badgaiyan

    Full Text Available It is unclear whether attention deficit hyperactive disorder (ADHD is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen's flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET camera and administered a dopamine receptor ligand (11C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments or performed the flanker task (phasic release experiments. PET data were analyzed to measure dynamic changes in ligand binding potential (BP and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.

  5. Bi-phasic activation of the primary motor cortex by pain and its relation to pain-evoked potentials - an exploratory study.

    Science.gov (United States)

    Kisler, Lee-Bareket; Weissman-Fogel, Irit; Sinai, Alon; Sprecher, Elliot; Chistyakov, Andrei V; Shamay-Tsoory, Simone; Moscovitz, Nadav; Granovsky, Yelena

    2017-06-15

    The primary motor cortex (M1) is a known target for brain stimulation aimed at pain alleviation in chronic pain patients, yet the mechanisms through which analgesia occurs, and the exact pain-motor interrelations are not fully understood. We used noxious contact heat evoked potentials (CHEPs) and cortical source analysis to further explore the relevance of M1 in pain processing. Twenty-four healthy young females received brief noxious heat stimuli to their left non-dominant volar forearm, simultaneously with CHEPs recordings. Thereafter, the pain-evoked activity of M1 and a control area in the occipital cortex (OC) was analyzed and estimated using sLORETA (standardized low-resolution brain electromagnetic tomography). This analysis revealed two phases of M1 pain-evoked activation (phase 1: the peak at 261.5±25.7ms; phase 2: the peak at 381.3±28.3ms). Canonical correlations revealed that M1, but not the OC, was the main factor contributing to the relation with the CHEPs components. In detail, the activity magnitude of M1 first and second phases was related to the N2 and P2 amplitude, respectively. The latency of the second phase was associated with both N2 and P2 latencies. In relation to pain, the latency of M1's first activity phase was positively correlated with pain ratings, suggesting pain interference to synchronized activity in M1. Our results confirm the established relevance of the primary motor cortex to pain processing. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Tri-phasic fever in dengue fever.

    Science.gov (United States)

    D, Pradeepa H; Rao, Sathish B; B, Ganaraj; Bhat, Gopalakrishna; M, Chakrapani

    2018-04-01

    Dengue fever is an acute febrile illness with a duration of 2-12 days. Our observational study observed the 24-h continuous tympanic temperature pattern of 15 patients with dengue fever and compared this with 26 others with fever due to a non-dengue aetiology. A tri-phasic fever pattern was seen among two-thirds of dengue fever patients, but in only one with an inflammatory disease. One-third of dengue fever patients exhibited a single peak temperature. Continuous temperature monitoring and temperature pattern analysis in clinical settings can aid in the early differentiation of dengue fever from non-dengue aetiology.

  7. Phasic spike patterning in rat supraoptic neurones in vivo and in vitro

    Science.gov (United States)

    Sabatier, Nancy; Brown, Colin H; Ludwig, Mike; Leng, Gareth

    2004-01-01

    In vivo, most vasopressin cells of the hypothalamic supraoptic nucleus fire action potentials in a ‘phasic’ pattern when the systemic osmotic pressure is elevated, while most oxytocin cells fire continuously. The phasic firing pattern is believed to arise as a consequence of intrinsic activity-dependent changes in membrane potential, and these have been extensively studied in vitro. Here we analysed the discharge patterning of supraoptic nucleus neurones in vivo, to infer the characteristics of the post-spike sequence of hyperpolarization and depolarization from the observed spike patterning. We then compared patterning in phasic cells in vivo and in vitro, and we found systematic differences in the interspike interval distributions, and in other statistical parameters that characterized activity patterns within bursts. Analysis of hazard functions (probability of spike initiation as a function of time since the preceding spike) revealed that phasic firing in vitro appears consistent with a regenerative process arising from a relatively slow, late depolarizing afterpotential that approaches or exceeds spike threshold. By contrast, in vivo activity appears to be dominated by stochastic rather than deterministic mechanisms, and appears consistent with a relatively early and fast depolarizing afterpotential that modulates the probability that random synaptic input exceeds spike threshold. Despite superficial similarities in the phasic firing patterns observed in vivo and in vitro, there are thus fundamental differences in the underlying mechanisms. PMID:15146047

  8. Relationship between tonic and phasic craving for alcohol

    Directory of Open Access Journals (Sweden)

    Emily E. Hartwell

    2018-06-01

    Full Text Available Background: Multiple measures are utilized to assess alcohol craving, often interchangeably. Little is known about the relationship between tonic and phasic craving. This study fills this gap in the literature by examining the association between tonic levels of alcohol craving and phasic craving for alcohol that is provoked by alcohol administration. Methods: Forty-three non-treatment seeking problem drinkers underwent an initial interview and two laboratory testing sessions, where either alcohol or a saline placebo was administered intravenously. Tonic craving was assessed via the Penn Alcohol Craving Scale (PACS and Obsessive Compulsive Drinking Scale (OCDS at the initial interview. Phasic craving was assessed during the laboratory sessions (i.e., alcohol and saline administrations, single blinded at baseline and at 3 subsequent breath alcohol concentrations (0.02, 0.04, and 0.06 g/dl. Results: There was a main effect of PACS in predicting phasic craving across both saline and alcohol administration conditions (p  0.10, predicted phasic craving during alcohol, as compared to saline administration. Conclusion: In sum, tonic craving captured by the OCDS was predictive of phasic craving during alcohol administration whereas the PACS more generally captured the increase in phasic craving. Therefore, these measures of tonic craving may function differently in capturing the experience of phasic craving. Implications for the utilization of the PACS and OCDS as well as assessments of craving in alcoholism research are discussed. Keywords: Alcohol, Craving, Assessment

  9. The effect of phasic auditory alerting on visual perception

    DEFF Research Database (Denmark)

    Petersen, Anders; Petersen, Annemarie Hilkjær; Bundesen, Claus

    2017-01-01

    /no-alerting design with a pure accuracy-based single-letter recognition task. Computational modeling based on Bundesen’s Theory of Visual Attention was used to examine the effect of phasic alertness on visual processing speed and threshold of conscious perception. Results show that phasic auditory alertness affects...

  10. Regulating prefrontal cortex activation

    DEFF Research Database (Denmark)

    Aznar, Susana; Klein, Anders Bue

    2013-01-01

    The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala...... of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings...... of a regulatory effect of the PFC on the emotional control of our actions....

  11. The Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors.

    Science.gov (United States)

    Fortin, Samantha M; Chartoff, Elena H; Roitman, Mitchell F

    2016-02-01

    Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiCl-mediated suppression of NAc dopamine release.

  12. Alpha alumina synthesis by laser treatment of bi-phasic nanowires

    Energy Technology Data Exchange (ETDEWEB)

    Aktas, Cenk, E-mail: cenk.aktas@inm-gmbh.de [Leibniz Institute for New Materials, D2 2 Campus, 66123 Saarbrücken (Germany); Lee, Juseok; Míro, Marina Martinez [Leibniz Institute for New Materials, D2 2 Campus, 66123 Saarbrücken (Germany); Barnoush, Afrooz [Norwegian University of Science and Technology, Trondheim (Norway); Saarland University, D2 2 Campus, 66123 Saarbrücken (Germany); Veith, Michael [Leibniz Institute for New Materials, D2 2 Campus, 66123 Saarbrücken (Germany)

    2013-08-01

    Al/Al{sub 2}O{sub 3} bi-phasic nanowires (Al-core/Al{sub 2}O{sub 3} shell) are prepared by chemical vapor deposition (CVD) using single source precursor (SSP) approach. Such bi-phasic nanostructures were heat-treated using an argon laser operating at visible wavelengths. Al core seems to act as an active binder, which might decrease the inhomogeneous heating and thermal gradients. Nanoindentation method is used to estimate the hardness of the laser treated surfaces. Hardness values and pop-in behaviour in loading-curve indicate a formation of α-Al{sub 2}O{sub 3} with very low defect density. It is believed that Al/Al{sub 2}O{sub 3} bi-phasic layers exhibit a dynamic change by transforming into alumina after the laser irradiation and this leads to alteration of the optical absorption especially in the visible wavelength region. Following the full transformation to alumina, the surface reflects back the laser light which hinders inhomogeneous and excessive heating. In this context, laser treatment of Al/Al{sub 2}O{sub 3} bi-phasic nanowires provides a controlled sintering process which can open up various applications in different fields.

  13. Disease progression and phasic changes in gene expression in a mouse model of osteoarthritis.

    Directory of Open Access Journals (Sweden)

    Richard F Loeser

    Full Text Available Osteoarthritis (OA is the most common form of arthritis and has multiple risk factors including joint injury. The purpose of this study was to characterize the histologic development of OA in a mouse model where OA is induced by destabilization of the medial meniscus (DMM model and to identify genes regulated during different stages of the disease, using RNA isolated from the joint "organ" and analyzed using microarrays. Histologic changes seen in OA, including articular cartilage lesions and osteophytes, were present in the medial tibial plateaus of the DMM knees beginning at the earliest (2 week time point and became progressively more severe by 16 weeks. 427 probe sets (371 genes from the microarrays passed consistency and significance filters. There was an initial up-regulation at 2 and 4 weeks of genes involved in morphogenesis, differentiation, and development, including growth factor and matrix genes, as well as transcription factors including Atf2, Creb3l1, and Erg. Most genes were off or down-regulated at 8 weeks with the most highly down-regulated genes involved in cell division and the cytoskeleton. Gene expression increased at 16 weeks, in particular extracellular matrix genes including Prelp, Col3a1 and fibromodulin. Immunostaining revealed the presence of these three proteins in cartilage and soft tissues including ligaments as well as in the fibrocartilage covering osteophytes. The results support a phasic development of OA with early matrix remodeling and transcriptional activity followed by a more quiescent period that is not maintained. This implies that the response to an OA intervention will depend on the timing of the intervention. The quiescent period at 8 weeks may be due to the maturation of the osteophytes which are thought to temporarily stabilize the joint.

  14. Automaticity of phasic alertness: Evidence for a three-component model of visual cueing.

    Science.gov (United States)

    Lin, Zhicheng; Lu, Zhong-Lin

    2016-10-01

    The automaticity of phasic alertness is investigated using the attention network test. Results show that the cueing effect from the alerting cue-double cue-is strongly enhanced by the task relevance of visual cues, as determined by the informativeness of the orienting cue-single cue-that is being mixed (80 % vs. 50 % valid in predicting where the target will appear). Counterintuitively, the cueing effect from the alerting cue can be negatively affected by its visibility, such that masking the cue from awareness can reveal a cueing effect that is otherwise absent when the cue is visible. Evidently, then, top-down influences-in the form of contextual relevance and cue awareness-can have opposite influences on the cueing effect from the alerting cue. These findings lead us to the view that a visual cue can engage three components of attention-orienting, alerting, and inhibition-to determine the behavioral cueing effect. We propose that phasic alertness, particularly in the form of specific response readiness, is regulated by both internal, top-down expectation and external, bottom-up stimulus properties. In contrast to some existing views, we advance the perspective that phasic alertness is strongly tied to temporal orienting, attentional capture, and spatial orienting. Finally, we discuss how translating attention research to clinical applications would benefit from an improved ability to measure attention. To this end, controlling the degree of intraindividual variability in the attentional components and improving the precision of the measurement tools may prove vital.

  15. Distinct phasic and sustained brain responses and connectivity of amygdala and bed nucleus of the stria terminalis during threat anticipation in panic disorder.

    Science.gov (United States)

    Brinkmann, L; Buff, C; Feldker, K; Tupak, S V; Becker, M P I; Herrmann, M J; Straube, T

    2017-11-01

    Panic disorder (PD) patients are constantly concerned about future panic attacks and exhibit general hypersensitivity to unpredictable threat. We aimed to reveal phasic and sustained brain responses and functional connectivity of the amygdala and the bed nucleus of the stria terminalis (BNST) during threat anticipation in PD. Using functional magnetic resonance imaging (fMRI), we investigated 17 PD patients and 19 healthy controls (HC) during anticipation of temporally unpredictable aversive and neutral sounds. We used a phasic and sustained analysis model to disentangle temporally dissociable brain activations. PD patients compared with HC showed phasic amygdala and sustained BNST responses during anticipation of aversive v. neutral stimuli. Furthermore, increased phasic activation was observed in anterior cingulate cortex (ACC), insula and prefrontal cortex (PFC). Insula and PFC also showed sustained activation. Functional connectivity analyses revealed partly distinct phasic and sustained networks. We demonstrate a role for the BNST during unpredictable threat anticipation in PD and provide first evidence for dissociation between phasic amygdala and sustained BNST activation and their functional connectivity. In line with a hypersensitivity to uncertainty in PD, our results suggest time-dependent involvement of brain regions related to fear and anxiety.

  16. Phasic and tonic neuron ensemble codes for stimulus-environment conjunctions in the lateral entorhinal cortex.

    Science.gov (United States)

    Pilkiw, Maryna; Insel, Nathan; Cui, Younghua; Finney, Caitlin; Morrissey, Mark D; Takehara-Nishiuchi, Kaori

    2017-07-06

    The lateral entorhinal cortex (LEC) is thought to bind sensory events with the environment where they took place. To compare the relative influence of transient events and temporally stable environmental stimuli on the firing of LEC cells, we recorded neuron spiking patterns in the region during blocks of a trace eyeblink conditioning paradigm performed in two environments and with different conditioning stimuli. Firing rates of some neurons were phasically selective for conditioned stimuli in a way that depended on which room the rat was in; nearly all neurons were tonically selective for environments in a way that depended on which stimuli had been presented in those environments. As rats moved from one environment to another, tonic neuron ensemble activity exhibited prospective information about the conditioned stimulus associated with the environment. Thus, the LEC formed phasic and tonic codes for event-environment associations, thereby accurately differentiating multiple experiences with overlapping features.

  17. The Cortisol Paradox of Trauma-Related Disorders: Lower Phasic Responses but Higher Tonic Levels of Cortisol Are Associated with Sexual Abuse in Childhood.

    Directory of Open Access Journals (Sweden)

    Inga Schalinski

    Full Text Available Inconsistent findings exist for the activity of the hypothalamic-pituitary-adrenal (HPA axis in patients with stress related disorders. Recent studies point towards early life stress as a potential modulator.We investigated the impact of childhood sexual abuse on phasic (saliva cortisol reactivity and tonic (hair cortisol regulation. Furthermore, we assessed predictors on cortisol accumulation in hair. Women (N = 43 with stress-related disorders underwent a standardized assessment of idiographic adverse and traumatic experiences and psychopathology, while measuring salivary cortisol and, heart rate and blood pressure.Comparing women with and without childhood sexual abuse revealed lower rates of responders and distinct levels of salivary cortisol to the interview in conjunction with a lower heart rate for the abused group. Childhood adversities, traumatic experiences, and depression contributed to higher hair cortisol levels.Our finding of lower response rate and distinct salivary cortisol pattern in individuals with childhood sexual abuse compared to individuals without early sexual abuse supports the role of environmental programming for the HPA axis. Both, childhood adversities and traumatic stress emerge as crucial factors for long-term cortisol secretion. Lower or suppressed phasic cortisol responses to trauma-related stimuli may therefore be associated with higher tonic values. Thus, early exposure to adversities may result in a biological distinct phenotype in adult patients with stress-related disorders.

  18. The Cortisol Paradox of Trauma-Related Disorders: Lower Phasic Responses but Higher Tonic Levels of Cortisol Are Associated with Sexual Abuse in Childhood.

    Science.gov (United States)

    Schalinski, Inga; Elbert, Thomas; Steudte-Schmiedgen, Susann; Kirschbaum, Clemens

    2015-01-01

    Inconsistent findings exist for the activity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with stress related disorders. Recent studies point towards early life stress as a potential modulator. We investigated the impact of childhood sexual abuse on phasic (saliva cortisol reactivity) and tonic (hair cortisol) regulation. Furthermore, we assessed predictors on cortisol accumulation in hair. Women (N = 43) with stress-related disorders underwent a standardized assessment of idiographic adverse and traumatic experiences and psychopathology, while measuring salivary cortisol and, heart rate and blood pressure. Comparing women with and without childhood sexual abuse revealed lower rates of responders and distinct levels of salivary cortisol to the interview in conjunction with a lower heart rate for the abused group. Childhood adversities, traumatic experiences, and depression contributed to higher hair cortisol levels. Our finding of lower response rate and distinct salivary cortisol pattern in individuals with childhood sexual abuse compared to individuals without early sexual abuse supports the role of environmental programming for the HPA axis. Both, childhood adversities and traumatic stress emerge as crucial factors for long-term cortisol secretion. Lower or suppressed phasic cortisol responses to trauma-related stimuli may therefore be associated with higher tonic values. Thus, early exposure to adversities may result in a biological distinct phenotype in adult patients with stress-related disorders.

  19. Muscarinic Long-Term Enhancement of Tonic and Phasic GABAA Inhibition in Rat CA1 Pyramidal Neurons

    Science.gov (United States)

    Domínguez, Soledad; Fernández de Sevilla, David; Buño, Washington

    2016-01-01

    Acetylcholine (ACh) regulates network operation in the hippocampus by controlling excitation and inhibition in rat CA1 pyramidal neurons (PCs), the latter through gamma-aminobutyric acid type-A receptors (GABAARs). Although, the enhancing effects of ACh on GABAARs have been reported (Dominguez et al., 2014, 2015), its role in regulating tonic GABAA inhibition has not been explored in depth. Therefore, we aimed at determining the effects of the activation of ACh receptors on responses mediated by synaptic and extrasynaptic GABAARs. Here, we show that under blockade of ionotropic glutamate receptors ACh, acting through muscarinic type 1 receptors, paired with post-synaptic depolarization induced a long-term enhancement of tonic GABAA currents (tGABAA) and puff-evoked GABAA currents (pGABAA). ACh combined with depolarization also potentiated IPSCs (i.e., phasic inhibition) in the same PCs, without signs of interactions of synaptic responses with pGABAA and tGABAA, suggesting the contribution of two different GABAA receptor pools. The long-term enhancement of GABAA currents and IPSCs reduced the excitability of PCs, possibly regulating plasticity and learning in behaving animals. PMID:27833531

  20. The effect of four-phasic versus three-phasic contrast media injection protocols on extravasation rate in coronary CT angiography. A randomized controlled trial

    Energy Technology Data Exchange (ETDEWEB)

    Karady, Julia; Panajotu, Alexisz; Kolossvary, Marton; Szilveszter, Balint; Jermendy, Adam L.; Bartykowszki, Andrea; Karolyi, Mihaly; Celeng, Csilla; Merkely, Bela; Maurovich-Horvat, Pal [Semmelweis University, MTA-SE Cardiovascular Imaging Research Group, Heart and Vascular Center, Budapest (Hungary)

    2017-11-15

    Contrast media (CM) extravasation is a well-known complication of CT angiography (CTA). Our prospective randomized control study aimed to assess whether a four-phasic CM administration protocol reduces the risk of extravasation compared to the routinely used three-phasic protocol in coronary CTA. Patients referred to coronary CTA due to suspected coronary artery disease were included in the study. All patients received 400 mg/ml iomeprol CM injected with dual-syringe automated injector. Patients were randomized into a three-phasic injection-protocol group, with a CM bolus of 85 ml followed by 40 ml of 75%:25% saline/CM mixture and 30 ml saline chaser bolus; and a four-phasic injection-protocol group, with a saline pacer bolus of 10 ml injected at a lower flow rate before the three-phasic protocol. 2,445 consecutive patients were enrolled (mean age 60.6 ± 12.1 years; females 43.6%). Overall rate of extravasation was 0.9% (23/2,445): 1.4% (17/1,229) in the three-phasic group and 0.5% (6/1,216) in the four-phasic group (p = 0.034). Four-phasic CM administration protocol is easy to implement in the clinical routine at no extra cost. The extravasation rate is reduced by 65% with the application of the four-phasic protocol compared to the three-phasic protocol in coronary CTA. (orig.)

  1. The effect of four-phasic versus three-phasic contrast media injection protocols on extravasation rate in coronary CT angiography: a randomized controlled trial.

    Science.gov (United States)

    Karády, Júlia; Panajotu, Alexisz; Kolossváry, Márton; Szilveszter, Bálint; Jermendy, Ádám L; Bartykowszki, Andrea; Károlyi, Mihály; Celeng, Csilla; Merkely, Béla; Maurovich-Horvat, Pál

    2017-11-01

    Contrast media (CM) extravasation is a well-known complication of CT angiography (CTA). Our prospective randomized control study aimed to assess whether a four-phasic CM administration protocol reduces the risk of extravasation compared to the routinely used three-phasic protocol in coronary CTA. Patients referred to coronary CTA due to suspected coronary artery disease were included in the study. All patients received 400 mg/ml iomeprol CM injected with dual-syringe automated injector. Patients were randomized into a three-phasic injection-protocol group, with a CM bolus of 85 ml followed by 40 ml of 75%:25% saline/CM mixture and 30 ml saline chaser bolus; and a four-phasic injection-protocol group, with a saline pacer bolus of 10 ml injected at a lower flow rate before the three-phasic protocol. 2,445 consecutive patients were enrolled (mean age 60.6 ± 12.1 years; females 43.6%). Overall rate of extravasation was 0.9% (23/2,445): 1.4% (17/1,229) in the three-phasic group and 0.5% (6/1,216) in the four-phasic group (p = 0.034). Four-phasic CM administration protocol is easy to implement in the clinical routine at no extra cost. The extravasation rate is reduced by 65% with the application of the four-phasic protocol compared to the three-phasic protocol in coronary CTA. • Four-phasic CM injection-protocol reduces extravasation rate by 65% compared to three-phasic. • The saline pacer bolus substantially reduces the risk of CM extravasation. • The implementation of four-phasic injection-protocol is at no cost.

  2. The effect of phasic auditory alerting on visual perception.

    Science.gov (United States)

    Petersen, Anders; Petersen, Annemarie Hilkjær; Bundesen, Claus; Vangkilde, Signe; Habekost, Thomas

    2017-08-01

    Phasic alertness refers to a short-lived change in the preparatory state of the cognitive system following an alerting signal. In the present study, we examined the effect of phasic auditory alerting on distinct perceptual processes, unconfounded by motor components. We combined an alerting/no-alerting design with a pure accuracy-based single-letter recognition task. Computational modeling based on Bundesen's Theory of Visual Attention was used to examine the effect of phasic alertness on visual processing speed and threshold of conscious perception. Results show that phasic auditory alertness affects visual perception by increasing the visual processing speed and lowering the threshold of conscious perception (Experiment 1). By manipulating the intensity of the alerting cue, we further observed a positive relationship between alerting intensity and processing speed, which was not seen for the threshold of conscious perception (Experiment 2). This was replicated in a third experiment, in which pupil size was measured as a physiological marker of alertness. Results revealed that the increase in processing speed was accompanied by an increase in pupil size, substantiating the link between alertness and processing speed (Experiment 3). The implications of these results are discussed in relation to a newly developed mathematical model of the relationship between levels of alertness and the speed with which humans process visual information. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Opposite effect of ATP on contraction force of tonic and phasic skeletal muscles in frogs.

    Science.gov (United States)

    Grishin, S N; Kamaliev, R R; Teplov, A Yu; Ziganshin, A U

    2011-07-01

    Experiments in vitro showed that ATP and adenosine equally suppressed contractions of frog m. sartorius, which belongs to the phasic type muscles. Adenosine receptors antagonist 8-SPT abolished the effect of adenosine, but did not change the effect of ATP. This fact proves the independence of signaling pathways of these purines. ATP produced an opposite effect on the tonic muscle m. cruralis and increased the force of its contraction. Adenosine produced an inhibitory effect on the force of m. cruralis contration. In this case, 8-SPT also eliminated the effect of adenosine, but did not change the effect of ATP. The potentiating effect of ATP was blocked by suramin, a nonselective antagonist of P2 receptors, which attests to their involvement into the effects of this purine. The opposite effects of purinergic regulation reflect fundamental differences in functional organization of phasic and tonic muscular systems. It was hypothesized that the increase in contraction force under the effect of ATP is a mechanism providing maitenance of the contracted state of tonic muscle without appreciable metabolic costs.

  4. Optogenetic stimulation of VTA dopamine neurons reveals that tonic but not phasic patterns of dopamine transmission reduce ethanol self-administration

    Directory of Open Access Journals (Sweden)

    Caroline E Bass

    2013-11-01

    Full Text Available There is compelling evidence that acute ethanol exposure stimulates ventral tegmental area (VTA dopamine cell activity and that VTA-dependent dopamine release in terminal fields within the nucleus accumbens plays an integral role in the regulation of ethanol drinking behaviors. Unfortunately, due to technical limitations, the specific temporal dynamics linking VTA dopamine cell activation and ethanol self-administration are not known. In fact, establishing a causal link between specific patterns of dopamine transmission and ethanol drinking behaviors has proven elusive. Here, we sought to address these gaps in our knowledge using a newly developed viral-mediated gene delivery strategy to selectively express Channelrhodopsin-2 (ChR2 on dopamine cells in the VTA of wild-type rats. We then used this approach to precisely control VTA dopamine transmission during voluntary ethanol drinking sessions. The results confirmed that ChR2 was selectively expressed on VTA dopamine cells and delivery of blue light pulses to the VTA induced dopamine release in accumbal terminal fields with very high temporal and spatial precision. Brief high frequency VTA stimulation induced phasic patterns of dopamine release in the nucleus accumbens. Lower frequency stimulation, applied for longer periods mimicked tonic increases in accumbal dopamine. Notably, using this optogenetic approach in rats engaged in an intermittent ethanol drinking procedure, we found that tonic, but not phasic, stimulation of VTA dopamine cells selectively attenuated ethanol drinking behaviors. Collectively, these data demonstrate the effectiveness of a novel viral targeting strategy that can be used to restrict opsin expression to dopamine cells in standard outbred animals and provide the first causal evidence demonstrating that tonic activation of VTA dopamine neurons selectively decreases ethanol self-administration behaviors.

  5. Design, Simulation and Experimental Evaluation of Tri-Phasic Piezoelectric Composite Transducers

    Science.gov (United States)

    Tamez, Juan Pedro

    Piezoelectric ceramics exhibit excellent piezoelectric and dielectric properties that is the basis of practically all transducers and piezoelectric devices, but their inherent properties, such as brittleness, non-ductility and poor shapeability may limit their applications in areas such as vibration sensing, impact detection, structural health monitoring and other reinforced structures and energy harvesting. To compensate for such limitations, the 1-3 piezoelectric composites transducers have become the material of choice for many high performance ultrasound transducers since it was invented in the late 1970's [ref. Newnham/Cross]. Extensive studies on 1-3 composites have been performed since then to improve the performance of a transducer by modifying their electromechanical coupling, bandwidth, quality factor, and flexibility and by reducing or eliminating the cross talk, i.e., induced noise between the active piezoelectric elements, especially in high power and low frequency applications. These fundamental issues, their possible solutions and their wide impact underline the motivation of the current work in this dissertation report. The motivation for this dissertation was to study and provide a foundation to designing multiphasic piezoelectric transducers that could be useful for multitude of applications. The goal was to improve the 1-3 diphasic composite transducer by eliminating the cross talk between the active piezoelectric elements while maintaining and improving the figures of merit of the design. To achieve the ultimate goal, the steps outlined below were followed: i. Understanding the theoretical and mathematical modeling for tri-phasic piezoelectric composite. ii. Implement Finite Element Analysis (FEA) and simulations of tri-phasic piezoelectric composites where the different active piezoelectric material PZT-5H and PMN-30%PT is surrounded by a vacuum phase that is enclosed by a hexagonal polymer walls. iii. Propose a redesign of the tri-phasic

  6. Immediate early gene activity-regulated cytoskeletal-associated protein regulates estradiol-induced lordosis behavior in female rats.

    Science.gov (United States)

    Christensen, Amy; Dewing, Phoebe; Micevych, Pavel

    2015-01-01

    Sensory feedback is an important component of any behavior, with each instance influencing subsequent activity. Female sexual receptivity is mediated both by the steroid hormone milieu and interaction with the male. We tested the influence of repeated mating on the level of sexual receptivity in ovariectomized rats treated with estradiol benzoate (EB) once every fourth day to mimic the normal phasic changes of circulating estradiol. Females were divided into two groups: naïve, which were tested for lordosis behavior once, and experienced rats, which were tested for lordosis after each EB injection. To monitor the effect of mating, the number of neurons expressing the immediate early gene activity-regulated cytoskeleton-associated protein (Arc) were counted in the mediobasal hypothalamus. Females were unreceptive following the first EB treatment, but the mating induced Arc expression. In naïve rats, each subsequent EB injection increased the levels of sexual receptivity. This ramping was not observed in experienced rats, which achieved only a moderate level of sexual receptivity. However, experienced females treated with EB and progesterone were maximally receptive and did not have Arc expression. To test whether the expression of Arc attenuated lordosis, Arc antisense oligodeoxynucleotides (asODN) were microinjected into experienced females' arcuate nuclei. Arc expression was attenuated, and the experienced EB-treated females achieved maximal sexual receptivity. These results demonstrate that Arc expression in the hypothalamus might influence future sexual receptivity and provides evidence of learning in the arcuate nucleus. The loss of Arc results in unrestrained sexual receptivity. © 2014 Wiley Periodicals, Inc.

  7. Regulation of p21ras activity

    DEFF Research Database (Denmark)

    Lowy, D R; Zhang, K; DeClue, J E

    1992-01-01

    The ras genes encode GTP/GDP-binding proteins that participate in mediating mitogenic signals from membrane tyrosine kinases to downstream targets. The activity of p21ras is determined by the concentration of GTP-p21ras, which is tightly regulated by a complex array of positive and negative control...... mechanisms. GAP and NF1 can negatively regulate p21ras activity by stimulating hydrolysis of GTP bound to p21ras. Other cellular factors can positively regulate p21ras by stimulating GDP/GTP exchange....

  8. Regulation of ROCK Activity in Cancer

    DEFF Research Database (Denmark)

    Morgan-Fisher, Marie; Wewer, Ulla M; Yoneda, Atsuko

    2013-01-01

    , these findings demonstrate additional modes to regulate ROCK activity. This review describes the molecular mechanisms of ROCK activity regulation in cancer, with emphasis on ROCK isoform-specific regulation and interaction partners, and discusses the potential of ROCKs as therapeutic targets in cancer.......Cancer-associated changes in cellular behavior, such as modified cell-cell contact, increased migratory potential, and generation of cellular force, all require alteration of the cytoskeleton. Two homologous mammalian serine/threonine kinases, Rho-associated protein kinases (ROCK I and II), are key...... regulators of the actin cytoskeleton acting downstream of the small GTPase Rho. ROCK is associated with cancer progression, and ROCK protein expression is elevated in several types of cancer. ROCKs exist in a closed, inactive conformation under quiescent conditions, which is changed to an open, active...

  9. Tamping Ramping: Algorithmic, Implementational, and Computational Explanations of Phasic Dopamine Signals in the Accumbens.

    Directory of Open Access Journals (Sweden)

    Kevin Lloyd

    2015-12-01

    Full Text Available Substantial evidence suggests that the phasic activity of dopamine neurons represents reinforcement learning's temporal difference prediction error. However, recent reports of ramp-like increases in dopamine concentration in the striatum when animals are about to act, or are about to reach rewards, appear to pose a challenge to established thinking. This is because the implied activity is persistently predictable by preceding stimuli, and so cannot arise as this sort of prediction error. Here, we explore three possible accounts of such ramping signals: (a the resolution of uncertainty about the timing of action; (b the direct influence of dopamine over mechanisms associated with making choices; and (c a new model of discounted vigour. Collectively, these suggest that dopamine ramps may be explained, with only minor disturbance, by standard theoretical ideas, though urgent questions remain regarding their proximal cause. We suggest experimental approaches to disentangling which of the proposed mechanisms are responsible for dopamine ramps.

  10. Regulation of ROCK Activity in Cancer

    Science.gov (United States)

    Morgan-Fisher, Marie; Wewer, Ulla M.

    2013-01-01

    Cancer-associated changes in cellular behavior, such as modified cell-cell contact, increased migratory potential, and generation of cellular force, all require alteration of the cytoskeleton. Two homologous mammalian serine/threonine kinases, Rho-associated protein kinases (ROCK I and II), are key regulators of the actin cytoskeleton acting downstream of the small GTPase Rho. ROCK is associated with cancer progression, and ROCK protein expression is elevated in several types of cancer. ROCKs exist in a closed, inactive conformation under quiescent conditions, which is changed to an open, active conformation by the direct binding of guanosine triphosphate (GTP)–loaded Rho. In recent years, a number of ROCK isoform-specific binding partners have been found to modulate the kinase activity through direct interactions with the catalytic domain or via altered cellular localization of the kinases. Thus, these findings demonstrate additional modes to regulate ROCK activity. This review describes the molecular mechanisms of ROCK activity regulation in cancer, with emphasis on ROCK isoform-specific regulation and interaction partners, and discusses the potential of ROCKs as therapeutic targets in cancer. PMID:23204112

  11. Vagally mediated effects of brain stem dopamine on gastric tone and phasic contractions of the rat.

    Science.gov (United States)

    Anselmi, L; Toti, L; Bove, C; Travagli, R A

    2017-11-01

    Dopamine (DA)-containing fibers and neurons are embedded within the brain stem dorsal vagal complex (DVC); we have shown previously that DA modulates the membrane properties of neurons of the dorsal motor nucleus of the vagus (DMV) via DA1 and DA2 receptors. The vagally dependent modulation of gastric tone and phasic contractions, i.e., motility, by DA, however, has not been characterized. With the use of microinjections of DA in the DVC while recording gastric tone and motility, the aims of the present study were 1 ) assess the gastric effects of brain stem DA application, 2 ) identify the DA receptor subtype, and, 3 ) identify the postganglionic pathway(s) activated. Dopamine microinjection in the DVC decreased gastric tone and motility in both corpus and antrum in 29 of 34 rats, and the effects were abolished by ipsilateral vagotomy and fourth ventricular treatment with the selective DA2 receptor antagonist L741,626 but not by application of the selective DA1 receptor antagonist SCH 23390. Systemic administration of the cholinergic antagonist atropine attenuated the inhibition of corpus and antrum tone in response to DA microinjection in the DVC. Conversely, systemic administration of the nitric oxide synthase inhibitor nitro-l-arginine methyl ester did not alter the DA-induced decrease in gastric tone and motility. Our data provide evidence of a dopaminergic modulation of a brain stem vagal neurocircuit that controls gastric tone and motility. NEW & NOTEWORTHY Dopamine administration in the brain stem decreases gastric tone and phasic contractions. The gastric effects of dopamine are mediated via dopamine 2 receptors on neurons of the dorsal motor nucleus of the vagus. The inhibitory effects of dopamine are mediated via inhibition of the postganglionic cholinergic pathway. Copyright © 2017 the American Physiological Society.

  12. Regulation of brain aromatase activity in rats

    International Nuclear Information System (INIS)

    Roselli, C.E.; Ellinwood, W.E.; Resko, J.A.

    1984-01-01

    The distribution and regulation of aromatase activity in the adult rat brain with a sensitive in vitro assay that measures the amount of 3 H 2 O formed during the conversion of [1 beta- 3 H]androstenedione to estrone. The rate of aromatase activity in the hypothalamus-preoptic area (HPOA) was linear with time up to 1 h, and with tissue concentrations up to 5 mgeq/200 microliters incubation mixture. The enzyme demonstrated a pH optimum of 7.4 and an apparent Michaelis-Menten constant (Km) of 0.04 microns. The greatest amount of aromatase activity was found in amygdala and HPOA from intact male rats. The hippocampus, midbrain tegmentum, cerebral cortex, cerebellum, and anterior pituitary all contained negligible enzymatic activity. Castration produced a significant decrease in aromatase activity in the HPOA, but not in the amygdala or cerebral cortex. The HPOAs of male rats contained significantly greater aromatase activity than the HPOAs of female rats. In females, this enzyme activity did not change during the estrous cycle or after ovariectomy. Administration of testosterone to gonadectomized male and female rats significantly enhanced HPOA aromatase activities to levels approximating those found in HPOA from intact males. Therefore, the results suggest that testosterone, or one of its metabolites, is a major steroidal regulator of HPOA aromatase activity in rats

  13. Commission of energy regulation. 2004 activity report

    International Nuclear Information System (INIS)

    2004-01-01

    The commission of energy regulation (CRE) is an independent administrative authority in charge of the control of the operation of gas and electricity markets. This document is the fifth activity report of CRE and covers the July 1, 2003 - June 30, 2004 period, which corresponds to the era of opening of energy markets as a consequence of the enforcement of the June 26, 2003 European directive. In the framework of the stakes made by energy markets liberalization, this document presents the situation of the gas and electricity markets during this period (European framework, regulation of both markets, public utility mission..) and describes CRE's means for the monitoring of these markets. (J.S.)

  14. Mast cell activators as novel immune regulators.

    Science.gov (United States)

    Johnson-Weaver, Brandi; Choi, Hae Woong; Abraham, Soman N; Staats, Herman F

    2018-05-26

    Mast cells are an important cell type of the innate immune system that when activated, play a crucial role in generating protective innate host responses after bacterial and viral infection. Additionally, activated mast cells influence lymph node composition to regulate the induction of adaptive immune responses. The recognition that mast cells play a beneficial role in host responses to microbial infection and induction of adaptive immunity has provided the rationale to evaluate mast cell activators for use as antimicrobials or vaccine adjuvants. This review summarizes the role of mast cell activators in antimicrobial responses while also discussing the use of different classes of mast cell activators as potent vaccine adjuvants that enhance the induction of protective immune responses. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Src regulates the activity of SIRT2

    International Nuclear Information System (INIS)

    Choi, You Hee; Kim, Hangun; Lee, Sung Ho; Jin, Yun-Hye; Lee, Kwang Youl

    2014-01-01

    Highlights: • Src decreases the protein levels of Sirt2. • Src inhibitor and knockdown of Src increase the protein levels of Sirt2. • Src interacts with and phosphorylates Sirt2. • Src regulate the activity of Sirt2. - Abstract: SIRT2 is a mammalian member of the Sirtuin family of NAD + -dependent protein deacetylases. The tyrosine kinase Src is involved in a variety of cellular signaling pathways, leading to the induction of DNA synthesis, cell proliferation, and cytoskeletal reorganization. The function of SIRT2 is modulated by post-translational modifications; however, the precise molecular signaling mechanism of SIRT2 through interactions with c-Src has not yet been established. In this study, we investigated the potential regulation of SIRT2 function by c-Src. We found that the protein levels of SIRT2 were decreased by c-Src, and subsequently rescued by the addition of a Src specific inhibitor, SU6656, or by siRNA-mediated knockdown of c-Src. The c-Src interacts with and phosphorylates SIRT2 at Tyr104. c-Src also showed the ability to regulate the deacetylation activity of SIRT2. Investigation on the phosphorylation of SIRT2 suggested that this was the method of c-Src-mediated SIRT2 regulation

  16. Markets, prices and regulation in energetic activities

    International Nuclear Information System (INIS)

    Percebois, Jacques

    2015-09-01

    The author first outlines some fundamental characteristics of the different energy world markets (oil, natural gas, coal, electricity). He outlines their availability, locations, and different main geographical areas. Then, he discusses the relationships between costs and prices in which intervene external costs, taxes, feed-in tariffs, national regulations, incentives for consumers. He discusses the issue of regulation of some energy activities, i.e. how State may or may not intervene on the markets, how competition may influence the market, how activities can thus be divided (production, transport, distribution) with implications and consequences for prices. He finally outlines concerns about the future financing of investments required to face tomorrow's needs

  17. Context-dependent modulation of alphabetagamma and alphabetadelta GABA A receptors by penicillin: implications for phasic and tonic inhibition.

    Science.gov (United States)

    Feng, Hua-Jun; Botzolakis, Emmanuel J; Macdonald, Robert L

    2009-01-01

    Penicillin, an open-channel blocker of GABA(A) receptors, was recently reported to inhibit phasic, but not tonic, currents in hippocampal neurons. To distinguish between isoform-specific and context-dependent modulation as possible explanations for this selectivity, the effects of penicillin were evaluated on recombinant GABA(A) receptors expressed in HEK293T cells. When co-applied with saturating GABA, penicillin decreased peak amplitude, induced rebound, and prolonged deactivation of currents evoked from both synaptic and extrasynaptic receptor isoforms. However, penicillin had isoform-specific effects on the extent of desensitization, reflecting its ability to differentially modulate peak (non-equilibrium) and residual (near-equilibrium) currents. This suggested that the context of activation could determine the apparent sensitivity of a given receptor isoform to penicillin. To test this hypothesis, we explored the ability of penicillin to modulate synaptic and extrasynaptic isoform currents that were activated under more physiologically relevant conditions. Interestingly, while currents evoked from synaptic isoforms under phasic conditions (transient activation by a saturating concentration of GABA) were substantially inhibited by penicillin, currents evoked from extrasynaptic isoforms under tonic conditions (prolonged application by a sub-saturating concentration of GABA) were minimally affected. We therefore concluded that the reported inability of penicillin to modulate tonic currents could not simply be attributed to insensitivity of extrasynaptic receptors, but rather, reflected an inability to modulate these receptors in their native context of activation.

  18. Regulators of Slc4 bicarbonate transporter activity

    Directory of Open Access Journals (Sweden)

    Ian M. Thornell

    2015-06-01

    Full Text Available The Slc4 family of transporters is comprised of anion exchangers (AE1-4, Na-coupled bicarbonate transporters (NCBTs including electrogenic Na/bicarbonate cotransporters (NBCe1 and NBCe2, electroneutral Na/bicarbonate cotransporters (NBCn1 and NBCn2, and the electroneutral Na-driven Cl-bicarbonate exchanger (NDCBE, as well as a borate transporter (BTR1. These transporters regulate intracellular pH (pHi and contribute to steady-state pHi, but are also involved in other physiological processes including CO2 carriage by red blood cells and solute secretion/reabsorption across epithelia. Acid-base transporters function as either acid extruders or acid loaders, with the Slc4 proteins moving HCO3– either into or out of cells. According to results from both molecular and functional studies, multiple Slc4 proteins and/or associated splice variants with similar expected effects on pHi are often found in the same tissue or cell. Such apparent redundancy is likely to be physiologically important. In addition to regulating pHi, a HCO3– transporter contributes to a cell’s ability to fine tune the intracellular regulation of the cotransported/exchanged ion(s (e.g., Na+ or Cl–. In addition, functionally similar transporters or splice variants with different regulatory profiles will optimize pH physiology and solute transport under various conditions or within subcellular domains. Such optimization will depend on activated signaling pathways and transporter expression profiles. In this review, we will summarize and discuss both classical and more recently identified regulators of the Slc4 proteins. Some of these regulators include traditional second messengers, lipids, binding proteins, autoregulatory domains, and less conventional regulators. The material presented will provide insight into the diversity and physiological significance of multiple members within the Slc4 gene family.

  19. Regulation of pokemon 1 activity by sumoylation.

    Science.gov (United States)

    Roh, Hee-Eun; Lee, Min-Nyung; Jeon, Bu-Nam; Choi, Won-Il; Kim, Yoo-Jin; Yu, Mi-Young; Hur, Man-Wook

    2007-01-01

    Pokemon 1 is a proto-oncogenic transcriptional regulator that contains a POZ domain at the N-terminus and four Kruppel-like zinc fingers at the C-terminus. Pokemon 1 plays an important role in adipogenesis, osteogenesis, oncogenesis, and transcription of NF-kB responsive genes. Recent reports have shown that biological activities of transcription factors are regulated by sumolylation. We investigated whether Pokemon 1 is post-translationally modified by sumoylation and whether the modification affects Pokemon 1's transcriptional properties. We found that Pokemon 1 is sumoylated in vitro and in vivo. Upon careful analysis of the amino acid sequence of Pokemon 1, we found ten potential sumoylation sites located at lysines 61, 354, 371, 379, 383, 396, 486, 487, 536 and 539. We mutated each of these amino acids into arginine and tested whether the mutation could affect the transcriptional properties of Pokemon 1 on the Pokemon 1 responsive genes, such as ADH5/FDH and pG5-FRE-Luc. Wild-type Pokemon 1 potently represses transcription of ADH5/FDH. Most of the mutants, however, were weaker transcription repressors and repressed transcription 1.3-3.3 fold less effective. Although potential sumoylation sites were located close to the DNA binding domain or the nuclear localization sequence, the mutations did not alter nuclear localization or DNA binding activity. In addition, on the pG5-FRE-Luc test promoter construct, ectopic SUMO-1 repressed transcription in the presence of Pokemon 1. The sumoylation target lysine residue at amino acid 61, which is located in the middle of the POZ-domain, is important because K61R mutation resulted in a much weaker molecular interaction with corepressors. Our data suggest that Pokemon 1's activity as a transcription factor may involve sumoylation, and that sumoylation might be important in the regulation of transcription by Pokemon 1.

  20. NEA activities in safety and regulation

    International Nuclear Information System (INIS)

    Stadie, K.B.

    1983-01-01

    The NEA programme on Safety and Regulations is briefly reviewed. It encompasses four main areas - nuclear safety technology; nuclear licensing; radiation protection; and waste management - with three principal objectives: to promote exchanges of technical information in order to enlarge the data base for national decision making; to improve co-ordination of national R and D activities with emphasis on international standard problem exercises, and to promote international projects; to develop common technical, administrative and legal approaches to improve compatibility of safety and regulatory practices

  1. Basic principles for regulating nuclear activities

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-03-01

    The AECB has developed as its mission statement: `To ensure that the use of nuclear energy in Canada does not pose undue risk to health, safety, security and the environment`. This report proposes eleven qualitative principles for regulating nuclear activities whose achievement would satisfy the broad policy enunciated in the statement. They would further provide a basis for the specific regulatory requirements expressed by the AECB in its Regulations and other documents. They would thus represent a connecting link between the policy enunciated in the mission statement and the requirements. The proposed principles are largely concerned with how the allowable risk should be set for members of the public, for industry workers, for society as a whole, and for the environment. In making these recommendations the risks from normal operation of the licensed facility and those from a possible serious accident are considered separately. The distribution of risk between geographic communities and between generations is also addressed in the proposed principles. These are listed in the final section of the report. 23 refs.

  2. Basic principles for regulating nuclear activities

    International Nuclear Information System (INIS)

    1996-03-01

    The AECB has developed as its mission statement: 'To ensure that the use of nuclear energy in Canada does not pose undue risk to health, safety, security and the environment'. This report proposes eleven qualitative principles for regulating nuclear activities whose achievement would satisfy the broad policy enunciated in the statement. They would further provide a basis for the specific regulatory requirements expressed by the AECB in its Regulations and other documents. They would thus represent a connecting link between the policy enunciated in the mission statement and the requirements. The proposed principles are largely concerned with how the allowable risk should be set for members of the public, for industry workers, for society as a whole, and for the environment. In making these recommendations the risks from normal operation of the licensed facility and those from a possible serious accident are considered separately. The distribution of risk between geographic communities and between generations is also addressed in the proposed principles. These are listed in the final section of the report. 23 refs

  3. Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target.

    Science.gov (United States)

    Hiu, Takeshi; Farzampour, Zoya; Paz, Jeanne T; Wang, Eric Hou Jen; Badgely, Corrine; Olson, Andrew; Micheva, Kristina D; Wang, Gordon; Lemmens, Robin; Tran, Kevin V; Nishiyama, Yasuhiro; Liang, Xibin; Hamilton, Scott A; O'Rourke, Nancy; Smith, Stephen J; Huguenard, John R; Bliss, Tonya M; Steinberg, Gary K

    2016-02-01

    Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem's potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

  4. The Roles of Phasic and Tonic Dopamine in Tic Learning and Expression.

    Science.gov (United States)

    Maia, Tiago V; Conceição, Vasco A

    2017-09-15

    Tourette syndrome (TS) prominently involves dopaminergic disturbances, but the precise nature of those disturbances has remained elusive. A substantial body of empirical work and recent computational models have characterized the specific roles of phasic and tonic dopamine (DA) in action learning and selection, respectively. Using insights from this work and models, we suggest that TS involves increases in both phasic and tonic DA, which produce increased propensities for tic learning and expression, respectively. We review the evidence from reinforcement-learning and habit-learning studies in TS, which supports the idea that TS involves increased phasic DA responses; we also review the evidence that tics engage the habit-learning circuitry. On the basis of these findings, we suggest that tics are exaggerated, maladaptive, and persistent motor habits reinforced by aberrant, increased phasic DA responses. Increased tonic DA amplifies the tendency to execute learned tics and also provides a fertile ground of motor hyperactivity for tic learning. We review evidence suggesting that antipsychotics may counter both the increased propensity for tic expression, by increasing excitability in the indirect pathway, and the increased propensity for tic learning, by shifting plasticity in the indirect pathway toward long-term potentiation (and possibly also through more complex mechanisms). Finally, we review evidence suggesting that low doses of DA agonists that effectively treat TS decrease both phasic and tonic DA, thereby also reducing the propensity for both tic learning and tic expression, respectively. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Basal activity of voltage-gated Ca(2+) channels controls the IP3-mediated contraction by α(1)-adrenoceptor stimulation of mouse aorta segments.

    Science.gov (United States)

    Leloup, Arthur J; Van Hove, Cor E; De Meyer, Guido R Y; Schrijvers, Dorien M; Fransen, Paul

    2015-08-05

    α1-Adrenoceptor stimulation of mouse aorta causes intracellular Ca(2+) release from sarcoplasmic reticulum Ca(2+) stores via stimulation of inositoltriphosphate (IP3) receptors. It is hypothesized that this Ca(2+) release from the contractile and IP3-sensitive Ca(2+) store is under the continuous dynamic control of time-independent basal Ca(2+) influx via L-type voltage-gated Ca(2+) channels (LCC) residing in their window voltage range. Mouse aortic segments were α1-adrenoceptor stimulated with phenylephrine in the absence of external Ca(2+) (0Ca) to measure phasic isometric contractions. They gradually decreased with time in 0Ca, were inhibited with 2-aminoethoxydiphenyl borate, and declined with previous membrane potential hyperpolarization (levcromakalim) or with previous inhibition of LCC (diltiazem). Former basal stimulation of LCC with depolarization (15 mM K(+)) or with BAY K8644 increased the subsequent phasic contractions by phenylephrine in 0Ca. Although exogenous NO (diethylamine NONOate) reduced the phasic contractions by phenylephrine, stimulation of endothelial cells with acetylcholine in 0Ca failed to attenuate these phasic contractions. Finally, inhibition of the basal release of NO with N(Ω)-nitro-L-arginine methyl ester also attenuated the phasic contractions by phenylephrine. Results indicated that α1-adrenoceptor stimulation with phenylephrine causes phasic contractions, which are controlled by basal LCC and endothelial NO synthase activity. Endothelial NO release by acetylcholine was absent in 0Ca. Given the growing interest in the active regulation of arterial compliance, the dependence of contractile SR Ca(2+) store-refilling in basal conditions on the activity of LCC and basal eNOS may contribute to a more thorough understanding of physiological mechanisms leading to arterial stiffness. Copyright © 2015. Published by Elsevier B.V.

  6. Behavioral and Brain Measures of Phasic Alerting Effects on Visual Attention

    DEFF Research Database (Denmark)

    Wiegand, Iris Michaela; Petersen, Anders; Finke, Kathrin

    2017-01-01

    In the present study, we investigated effects of phasic alerting on visual attention in a partial report task, in which half of the displays were preceded by an auditory warning cue. Based on the computational Theory of Visual Attention (TVA), we estimated parameters of spatial and non......-spatial aspects of visual attention and measured event-related lateralizations (ERLs) over visual processing areas. We found that the TVA parameter sensory effectiveness a, which is thought to reflect visual processing capacity, significantly increased with phasic alerting. By contrast, the distribution of visual....... These results suggest that phasic alerting facilitates visual processing in a general, unselective manner and that this effect originates in early stages of visual information processing....

  7. Phasic alerting increases visual attention capacity in younger but not in older individuals

    DEFF Research Database (Denmark)

    Wiegand, Iris Michaela; Petersen, Anders; Bundesen, Claus

    2017-01-01

    In the present study, we investigated effects of phasic alerting on visual attention in younger and older adults. We modelled parameters of visual attention based on the computational Theory of Visual Attention (TVA) and measured event-related lateralizations (ERLs) in a partial report task, in w...... and attention, which governs the responsiveness to external cues and is critical for general cognitive functioning in aging.......In the present study, we investigated effects of phasic alerting on visual attention in younger and older adults. We modelled parameters of visual attention based on the computational Theory of Visual Attention (TVA) and measured event-related lateralizations (ERLs) in a partial report task...

  8. Regulation of Metabolic Activity by p53

    Directory of Open Access Journals (Sweden)

    Jessica Flöter

    2017-05-01

    Full Text Available Metabolic reprogramming in cancer cells is controlled by the activation of multiple oncogenic signalling pathways in order to promote macromolecule biosynthesis during rapid proliferation. Cancer cells also need to adapt their metabolism to survive and multiply under the metabolically compromised conditions provided by the tumour microenvironment. The tumour suppressor p53 interacts with the metabolic network at multiple nodes, mostly to reduce anabolic metabolism and promote preservation of cellular energy under conditions of nutrient restriction. Inactivation of this tumour suppressor by deletion or mutation is a frequent event in human cancer. While loss of p53 function lifts an important barrier to cancer development by deleting cell cycle and apoptosis checkpoints, it also removes a crucial regulatory mechanism and can render cancer cells highly sensitive to metabolic perturbation. In this review, we will summarise the major concepts of metabolic regulation by p53 and explore how this knowledge can be used to selectively target p53 deficient cancer cells in the context of the tumour microenvironment.

  9. Legislation on and regulation of nuclear activities

    International Nuclear Information System (INIS)

    1984-05-01

    This work is a compilation of legislative texts and regulations published by the Atomic Energy Commission's Legal Affairs Department (CEA). It provides a comprehensive source of knowledge and information on nuclear energy law. Legislative texts published over the last forty years, are collected and analytically indexed. The publication covers both French regulations and regulations of international organisations such as the International Atomic Energy Agency and Euratom. It is divided into eight different chapters, dealing with regulations relevant to international and national institutions, nuclear installations, third party liability, protection of persons and the environment, etc. A chronological table of the texts of international and national laws is also included in this work. (NEA) [fr

  10. An open-source LabVIEW application toolkit for phasic heart rate analysis in psychophysiological research.

    Science.gov (United States)

    Duley, Aaron R; Janelle, Christopher M; Coombes, Stephen A

    2004-11-01

    The cardiovascular system has been extensively measured in a variety of research and clinical domains. Despite technological and methodological advances in cardiovascular science, the analysis and evaluation of phasic changes in heart rate persists as a way to assess numerous psychological concomitants. Some researchers, however, have pointed to constraints on data analysis when evaluating cardiac activity indexed by heart rate or heart period. Thus, an off-line application toolkit for heart rate analysis is presented. The program, written with National Instruments' LabVIEW, incorporates a variety of tools for off-line extraction and analysis of heart rate data. Current methods and issues concerning heart rate analysis are highlighted, and how the toolkit provides a flexible environment to ameliorate common problems that typically lead to trial rejection is discussed. Source code for this program may be downloaded from the Psychonomic Society Web archive at www.psychonomic.org/archive/.

  11. Behavioral and Brain Measures of Phasic Alerting Effects on Visual Attention.

    Science.gov (United States)

    Wiegand, Iris; Petersen, Anders; Finke, Kathrin; Bundesen, Claus; Lansner, Jon; Habekost, Thomas

    2017-01-01

    In the present study, we investigated effects of phasic alerting on visual attention in a partial report task, in which half of the displays were preceded by an auditory warning cue. Based on the computational Theory of Visual Attention (TVA), we estimated parameters of spatial and non-spatial aspects of visual attention and measured event-related lateralizations (ERLs) over visual processing areas. We found that the TVA parameter sensory effectiveness a , which is thought to reflect visual processing capacity, significantly increased with phasic alerting. By contrast, the distribution of visual processing resources according to task relevance and spatial position, as quantified in parameters top-down control α and spatial bias w index , was not modulated by phasic alerting. On the electrophysiological level, the latencies of ERLs in response to the task displays were reduced following the warning cue. These results suggest that phasic alerting facilitates visual processing in a general, unselective manner and that this effect originates in early stages of visual information processing.

  12. Activation and Regulation of Cellular Eicosanoid Biosynthesis

    Directory of Open Access Journals (Sweden)

    Thomas G. Brock

    2007-01-01

    Full Text Available There is a growing appreciation for the wide variety of physiological responses that are regulated by lipid messengers. One particular group of lipid messengers, the eicosanoids, plays a central role in regulating immune and inflammatory responses in a receptor-mediated fashion. These mediators are related in that they are all derived from one polyunsaturated fatty acid, arachidonic acid. However, the various eicosanoids are synthesized by a wide variety of cell types by distinct enzymatic pathways, and have diverse roles in immunity and inflammation. In this review, the major pathways involved in the synthesis of eicosanoids, as well as key points of regulation, are presented.

  13. Regulation of higher-activity NARM wastes by EPA

    International Nuclear Information System (INIS)

    Bandrowski, M.S.

    1988-01-01

    The US Environmental Protection Agency (EPA) is currently developing standards for the disposal of low-level radioactive waste (LLW). As part of this Standard, EPA is including regulations for the disposal of naturally occurring and accelerator-produced radioactive material (NARM) wastes not covered under the Atomic Energy Act (AEA). The regulations will cover only higher-activity NARM wastes, defined as NARM waste with specific activity exceeding two nanocuries per gram. The proposed regulations will specify that NARM wastes exceeding the above limits, except for specific exempted items, must be disposed of in regulated radioactive waste disposal facilities. The proposed EPA regulations for NARM wastes will be discussed, as well as the costs and benefits of the regulation, how it will be implemented by EPA, and the rationale for covering only higher-activity NARM wastes exceeding two nanocuries per gram

  14. Tonic 5nM DA stabilizes neuronal output by enabling bidirectional activity-dependent regulation of the hyperpolarization activated current via PKA and calcineurin.

    Science.gov (United States)

    Krenz, Wulf-Dieter C; Rodgers, Edmund W; Baro, Deborah J

    2015-01-01

    Volume transmission results in phasic and tonic modulatory signals. The actions of tonic dopamine (DA) at type 1 DA receptors (D1Rs) are largely undefined. Here we show that tonic 5nM DA acts at D1Rs to stabilize neuronal output over minutes by enabling activity-dependent regulation of the hyperpolarization activated current (I h). In the presence but not absence of 5nM DA, I h maximal conductance (G max) was adjusted according to changes in slow wave activity in order to maintain spike timing. Our study on the lateral pyloric neuron (LP), which undergoes rhythmic oscillations in membrane potential with depolarized plateaus, demonstrated that incremental, bi-directional changes in plateau duration produced corresponding alterations in LP I hG max when preparations were superfused with saline containing 5nM DA. However, when preparations were superfused with saline alone there was no linear correlation between LP I hGmax and duty cycle. Thus, tonic nM DA modulated the capacity for activity to modulate LP I h G max; this exemplifies metamodulation (modulation of modulation). Pretreatment with the Ca2+-chelator, BAPTA, or the specific PKA inhibitor, PKI, prevented all changes in LP I h in 5nM DA. Calcineurin inhibitors blocked activity-dependent changes enabled by DA and revealed a PKA-mediated, activity-independent enhancement of LP I hG max. These data suggested that tonic 5nM DA produced two simultaneous, PKA-dependent effects: a direct increase in LP I h G max and a priming event that permitted calcineurin regulation of LP I h. The latter produced graded reductions in LP I hG max with increasing duty cycles. We also demonstrated that this metamodulation preserved the timing of LP's first spike when network output was perturbed with bath-applied 4AP. In sum, 5nM DA permits slow wave activity to provide feedback that maintains spike timing, suggesting that one function of low-level, tonic modulation is to stabilize specific features of a dynamic output.

  15. Tonic 5nM DA stabilizes neuronal output by enabling bidirectional activity-dependent regulation of the hyperpolarization activated current via PKA and calcineurin.

    Directory of Open Access Journals (Sweden)

    Wulf-Dieter C Krenz

    Full Text Available Volume transmission results in phasic and tonic modulatory signals. The actions of tonic dopamine (DA at type 1 DA receptors (D1Rs are largely undefined. Here we show that tonic 5nM DA acts at D1Rs to stabilize neuronal output over minutes by enabling activity-dependent regulation of the hyperpolarization activated current (I h. In the presence but not absence of 5nM DA, I h maximal conductance (G max was adjusted according to changes in slow wave activity in order to maintain spike timing. Our study on the lateral pyloric neuron (LP, which undergoes rhythmic oscillations in membrane potential with depolarized plateaus, demonstrated that incremental, bi-directional changes in plateau duration produced corresponding alterations in LP I hG max when preparations were superfused with saline containing 5nM DA. However, when preparations were superfused with saline alone there was no linear correlation between LP I hGmax and duty cycle. Thus, tonic nM DA modulated the capacity for activity to modulate LP I h G max; this exemplifies metamodulation (modulation of modulation. Pretreatment with the Ca2+-chelator, BAPTA, or the specific PKA inhibitor, PKI, prevented all changes in LP I h in 5nM DA. Calcineurin inhibitors blocked activity-dependent changes enabled by DA and revealed a PKA-mediated, activity-independent enhancement of LP I hG max. These data suggested that tonic 5nM DA produced two simultaneous, PKA-dependent effects: a direct increase in LP I h G max and a priming event that permitted calcineurin regulation of LP I h. The latter produced graded reductions in LP I hG max with increasing duty cycles. We also demonstrated that this metamodulation preserved the timing of LP's first spike when network output was perturbed with bath-applied 4AP. In sum, 5nM DA permits slow wave activity to provide feedback that maintains spike timing, suggesting that one function of low-level, tonic modulation is to stabilize specific features of a dynamic output.

  16. Modern aspects of tax regulation of investment activity

    Directory of Open Access Journals (Sweden)

    E.S. Podakov

    2016-03-01

    Full Text Available The article investigates the tax regulation of investment activity in modern conditions. Scientists studied different views about the impact of tax regulations on the investment activity in the country. The author determines that the tax regulation of investment activity involves the use of state mechanisms taxation of certain measures to improve investment conditions. The subject is the state tax regulations, and the object is the investment activity of individual and institutional investors of any form of ownership including organizational and legal forms. Such regulation is performed by using complex special tools. The possible methods of tax stimulation of investment processes are described. The article deals with the current results of tax reform in Ukraine and predicts its possible consequences for agricultural producers. The rating positions of Ukraine according to international organizations are showed. The systematic analysis has been carried out and the impact of differential tax rates, tax exemption for a specified period, reducing the tax base, elimination of double taxation on investment activity in certain areas have been researched. The special instruments of investment activity tax regulation are considered. The options for improving investment activity by introducing effective tax regulation are determined.

  17. Commission for energy regulation - 2012 Activity Report

    International Nuclear Information System (INIS)

    2013-06-01

    After a presentation of the organisation, role and missions of the French Commission for Energy Regulation (CRE), and of its relationship with other institutional actors, this report describes and comments the action of the CRE in the fields of dialogue and transparency. It presents and comments key figures regarding the electricity and gas retail markets. It reports and comments the European reaction to the cold peak of February 2012 (historical peak for consumption and prices, inquiry on the causes of these price peaks, need of a European market). The next part addresses the relationship between electricity grids and territories (solidarity between electricity grids as the basis of the Europe of energy, evolution of French grids to face new needs and to take regional and local dimensions into account). Another part addresses gas infrastructures which are considered as the cornerstone of a good operation for the French market and for the integration of the European energy market (gas world market in 2012, definition of a target model for the gas market by European regulators, evolution of the French market in compliance with the European target model, new tariffs for the use of natural gas transport networks). The report then addresses the development of renewable energies: actions of CRE (bidding, opinion of tariffs), influence of renewable energy development on electricity prices on gross markets, needed evolution of electricity grids. A last part addresses the issues of energy cost, demand management, and struggle against energy poverty

  18. Phasic valence and arousal do not influence post-conflict adjustments in the Simon task.

    Science.gov (United States)

    Dignath, David; Janczyk, Markus; Eder, Andreas B

    2017-03-01

    According to theoretical accounts of cognitive control, conflict between competing responses is monitored and triggers post conflict behavioural adjustments. Some models proposed that conflict is detected as an affective signal. While the conflict monitoring theory assumed that conflict is registered as a negative valence signal, the adaptation by binding model hypothesized that conflict provides a high arousal signal. The present research induced phasic affect in a Simon task with presentations of pleasant and unpleasant pictures that were high or low in arousal. If conflict is registered as an affective signal, the presentation of a corresponding affective signal should potentiate post conflict adjustments. Results did not support the hypothesis, and Bayesian analyses corroborated the conclusion that phasic affects do not influence post conflict behavioural adjustments in the Simon task. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Synergism in regulation of nuclear and radiological activities

    International Nuclear Information System (INIS)

    Buzdugan, A.

    2009-01-01

    In 2006 the reform of nuclear activity regulation in Moldova was initiated. On May 11, 2006, the Parliament of the Republic of Moldova passed the law Nr 111-XVI 'About Safe Accomplishment of Nuclear and Radiological Activity'. On the 23rd of March, 2007 the National Agency for Regulation of Nuclear and Radiological Activities (NARNRA) was founded due to the decree of the Government under the Ministry of Ecology and Natural Resources. Its first objective was elaboration of necessary regulation documents in this field

  20. How is AMPK activity regulated in skeletal muscles during exercise?

    DEFF Research Database (Denmark)

    Jørgensen, Sebastian Beck; Rose, Adam John

    2008-01-01

    AMPK is a metabolic "master" controller activated in skeletal muscle by exercise in a time and intensity dependent manner, and has been implicated in regulating metabolic pathways in muscle during physical exercise. AMPK signaling in skeletal muscle is regulated by several systemic...... and intracellular factors and the regulation of skeletal muscle AMPK in response to exercise is the focus of this review. Specifically, the role of LKB1 and phosphatase PP2C in nucleotide-dependent activation of AMPK, and ionized calcium in CaMKK-dependent activation of AMPK in working muscle is discussed. We also...

  1. Context-Dependent Modulation of αβγ and αβγ GABAA Receptors by Penicillin: Implications for Phasic and Tonic Inhibition

    Science.gov (United States)

    Feng, Hua-Jun; Botzolakis, Emmanuel J.; Macdonald, Robert L.

    2009-01-01

    Summary Penicillin, an open-channel blocker of GABAA receptors, was recently reported to inhibit phasic, but not tonic, currents in hippocampal neurons. To distinguish between isoform-specific and context-dependent modulation as possible explanations for this selectivity, the effects of penicillin were evaluated on recombinant GABAA receptors expressed in HEK293T cells. When co-applied with saturating GABA, penicillin decreased peak amplitude, induced rebound, and prolonged deactivation of currents evoked from both synaptic and extrasynaptic receptor isoforms. However, penicillin had isoform-specific effects on the extent of desensitization, reflecting its ability to differentially modulate peak (non-equilibrium) and residual (near-equilibrium) currents. This suggested that the context of activation could determine the apparent sensitivity of a given receptor isoform to penicillin. To test this hypothesis, we explored the ability of penicillin to modulate synaptic and extrasynaptic isoforms that were activated under more physiologically relevant conditions. Interestingly, while currents evoked from synaptic isoforms under phasic conditions (transient activation by a saturating concentration of GABA) were substantially inhibited by penicillin, currents evoked from extrasynaptic isoforms under tonic conditions (prolonged application by a sub-saturating concentration of GABA) were minimally affected. We therefore concluded that the reported inability of penicillin to modulate tonic currents could not simply be attributed to insensitivity of extrasynaptic receptors, but rather, reflected an inability to modulate these receptors in their native context of activation. PMID:18775733

  2. Self-regulation as a type of managerial activity.

    Directory of Open Access Journals (Sweden)

    Anna Algazina

    2017-01-01

    Full Text Available УДК 342.9The subject. In the context of the ongoing administrative reform in the Russian Federation the issue of self-regulation is becoming increasingly important.Introduction of Institute of self-regulation is intended to reduce the degree of state intervention in private spheres of professional activity, to eliminate excessive administrative barriers, reduce government expenditures on regulation and control in their respective areas of operation, which is especially important in the current economic conditions.However, in Russian legal science is no recognized definition of "self-regulation", but a unity of views on the question of the relationship between self-regulation and state regulation of business relations.In this regard, the author attempts to examine the concept of "self-regulation" through the prism of knowledge about public administration.The purpose of the article is to identify the essential features and to articulate the concept of self-regulation by comparing it with other varieties of regulation.Methodology. The methodological basis for the study: general scientific methods (analysis, synthesis, comparison, description; private and academic (interpretation, formal-legal.Results, scope. Based on the analysis allocated in the science of administrative law approaches to the system of public administration justifies the conclusion that the notion "regulation" is specific in relation to the generic concept of "management" and is a kind of management, consisting in the drafting of rules of conduct and sanctions for non-compliance or inadequate performance.In addition, the article highlights the problem of the genesis of self-regulation, building a system of principles of self-regulation, comparison of varieties of self-regulatory organizations among themselves.Conclusions. The comparison of self-regulation other types of regulation (such as state regulation and co-regulation highlighted the essential features of this phenomenon

  3. Endogenous Methanol Regulates Mammalian Gene Activity

    Science.gov (United States)

    Komarova, Tatiana V.; Petrunia, Igor V.; Shindyapina, Anastasia V.; Silachev, Denis N.; Sheshukova, Ekaterina V.; Kiryanov, Gleb I.; Dorokhov, Yuri L.

    2014-01-01

    We recently showed that methanol emitted by wounded plants might function as a signaling molecule for plant-to-plant and plant-to-animal communications. In mammals, methanol is considered a poison because the enzyme alcohol dehydrogenase (ADH) converts methanol into toxic formaldehyde. However, the detection of methanol in the blood and exhaled air of healthy volunteers suggests that methanol may be a chemical with specific functions rather than a metabolic waste product. Using a genome-wide analysis of the mouse brain, we demonstrated that an increase in blood methanol concentration led to a change in the accumulation of mRNAs from genes primarily involved in detoxification processes and regulation of the alcohol/aldehyde dehydrogenases gene cluster. To test the role of ADH in the maintenance of low methanol concentration in the plasma, we used the specific ADH inhibitor 4-methylpyrazole (4-MP) and showed that intraperitoneal administration of 4-MP resulted in a significant increase in the plasma methanol, ethanol and formaldehyde concentrations. Removal of the intestine significantly decreased the rate of methanol addition to the plasma and suggested that the gut flora may be involved in the endogenous production of methanol. ADH in the liver was identified as the main enzyme for metabolizing methanol because an increase in the methanol and ethanol contents in the liver homogenate was observed after 4-MP administration into the portal vein. Liver mRNA quantification showed changes in the accumulation of mRNAs from genes involved in cell signalling and detoxification processes. We hypothesized that endogenous methanol acts as a regulator of homeostasis by controlling the mRNA synthesis. PMID:24587296

  4. Dietary methanol regulates human gene activity.

    Directory of Open Access Journals (Sweden)

    Anastasia V Shindyapina

    Full Text Available Methanol (MeOH is considered to be a poison in humans because of the alcohol dehydrogenase (ADH-mediated conversion of MeOH to formaldehyde (FA, which is toxic. Our recent genome-wide analysis of the mouse brain demonstrated that an increase in endogenous MeOH after ADH inhibition led to a significant increase in the plasma MeOH concentration and a modification of mRNA synthesis. These findings suggest endogenous MeOH involvement in homeostasis regulation by controlling mRNA levels. Here, we demonstrate directly that study volunteers displayed increasing concentrations of MeOH and FA in their blood plasma when consuming citrus pectin, ethanol and red wine. A microarray analysis of white blood cells (WBC from volunteers after pectin intake showed various responses for 30 significantly differentially regulated mRNAs, most of which were somehow involved in the pathogenesis of Alzheimer's disease (AD. There was also a decreased synthesis of hemoglobin mRNA, HBA and HBB, the presence of which in WBC RNA was not a result of red blood cells contamination because erythrocyte-specific marker genes were not significantly expressed. A qRT-PCR analysis of volunteer WBCs after pectin and red wine intake confirmed the complicated relationship between the plasma MeOH content and the mRNA accumulation of both genes that were previously identified, namely, GAPDH and SNX27, and genes revealed in this study, including MME, SORL1, DDIT4, HBA and HBB. We hypothesized that human plasma MeOH has an impact on the WBC mRNA levels of genes involved in cell signaling.

  5. Endogenous methanol regulates mammalian gene activity.

    Directory of Open Access Journals (Sweden)

    Tatiana V Komarova

    Full Text Available We recently showed that methanol emitted by wounded plants might function as a signaling molecule for plant-to-plant and plant-to-animal communications. In mammals, methanol is considered a poison because the enzyme alcohol dehydrogenase (ADH converts methanol into toxic formaldehyde. However, the detection of methanol in the blood and exhaled air of healthy volunteers suggests that methanol may be a chemical with specific functions rather than a metabolic waste product. Using a genome-wide analysis of the mouse brain, we demonstrated that an increase in blood methanol concentration led to a change in the accumulation of mRNAs from genes primarily involved in detoxification processes and regulation of the alcohol/aldehyde dehydrogenases gene cluster. To test the role of ADH in the maintenance of low methanol concentration in the plasma, we used the specific ADH inhibitor 4-methylpyrazole (4-MP and showed that intraperitoneal administration of 4-MP resulted in a significant increase in the plasma methanol, ethanol and formaldehyde concentrations. Removal of the intestine significantly decreased the rate of methanol addition to the plasma and suggested that the gut flora may be involved in the endogenous production of methanol. ADH in the liver was identified as the main enzyme for metabolizing methanol because an increase in the methanol and ethanol contents in the liver homogenate was observed after 4-MP administration into the portal vein. Liver mRNA quantification showed changes in the accumulation of mRNAs from genes involved in cell signalling and detoxification processes. We hypothesized that endogenous methanol acts as a regulator of homeostasis by controlling the mRNA synthesis.

  6. Norepinephrine release from Locus Ceruleus:a central regulator for the CNS spatio-temporal activation pattern?

    Directory of Open Access Journals (Sweden)

    Marco Atzori

    2016-08-01

    Full Text Available Norepinephrine (NE is synthesized in the Locus Coeruleus (LC of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework.Since three main families of NE receptors are represented – in decreasing order of affinity for the catecholamine – by: 2 adrenoceptors (2Rs, high affinity, 1 adrenoceptors (1Rs, intermediate affinity, and  adrenoceptors (Rs, low affinity, on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: 1 sleep: virtual absence of NE, 2 quiet wake: activation of 2Rs, 3 active wake/physiological stress: activation of 2- and 1Rs, 4 distress: activation of 2-, 1-, and Rs.We postulate that excess intensity and/or duration of states 3 and 4 may lead to maladaptive plasticity, causing – in turn – a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the central nervous system. While the model

  7. Early and phasic cortical metabolic changes in vestibular neuritis onset.

    Directory of Open Access Journals (Sweden)

    Marco Alessandrini

    Full Text Available Functional brain activation studies described the presence of separate cortical areas responsible for central processing of peripheral vestibular information and reported their activation and interactions with other sensory modalities and the changes of this network associated to strategic peripheral or central vestibular lesions. It is already known that cortical changes induced by acute unilateral vestibular failure (UVF are various and undergo variations over time, revealing different cortical involved areas at the onset and recovery from symptoms. The present study aimed at reporting the earliest change in cortical metabolic activity during a paradigmatic form of UVF such as vestibular neuritis (VN, that is, a purely peripheral lesion of the vestibular system, that offers the opportunity to study the cortical response to altered vestibular processing. This research reports [(18F]fluorodeoxyglucose positron emission tomography brain scan data concerning the early cortical metabolic activity associated to symptoms onset in a group of eight patients suffering from VN. VN patients' cortical metabolic activity during the first two days from symptoms onset was compared to that recorded one month later and to a control healthy group. Beside the known cortical response in the sensorimotor network associated to vestibular deafferentation, we show for the first time the involvement of Entorhinal (BAs 28, 34 and Temporal (BA 38 cortices in early phases of symptomatology onset. We interpret these findings as the cortical counterparts of the attempt to reorient oneself in space counteracting the vertigo symptom (Bas 28, 34 and of the emotional response to the new pathologic condition (BA 38 respectively. These interpretations were further supported by changes in patients' subjective ratings in balance, anxiety, and depersonalization/derealization scores when tested at illness onset and one month later. The present findings contribute in expanding

  8. Regulation of MDM2 Activity by Nucleolin

    Science.gov (United States)

    2007-06-01

    plicated in the binding of HIV particles to CD4 cells. J. Biol. Chem. 273:21988–21997. 8. Carty, M. P., M. Zernik -Kobak, S. McGrath, and K. Dixon. 1994...replication products and not due to repair synthesis (Fig. 3D ). RPARPA2D is therefore functionally active in supporting DNA replication in vitro...Further intermediate RPA2 mutants were designed to roughly follow the phosphor- ylation pathway, as suggested by the data of Zernik -Kobak and colleagues

  9. Effects of a phasic oral contraceptive containing desogestrel on facial seborrhea and acne.

    Science.gov (United States)

    Prilepskaya, V N; Serov, V N; Zharov, E V; Golousenko, I J; Mejevitinova, E A; Gogaeva, E V; Yaglov, V V; Golubeva, O N

    2003-10-01

    The combined oral contraceptive containing ethinylestradiol and the selective progestogen, desogestrel, in a phasic regimen (DSG-OC, Tri-merci) has been shown to reduce facial oiliness. This study was designed to evaluate further the effects of this OC on the skin of women with facial seborrhea and mild or moderate acne. This was an open, noncomparative, bicenter study in 60 healthy Russian women, aged 18-30 years, with facial seborrhea and mild or moderate facial acne, who wished to use oral contraception. All women received the OC containing desogestrel (50/100/150 microg) and ethinylestradiol (35/30/30 microg) for three phases of 7 days followed by a 7-day pill-free interval, for six cycles. Seborrhea was assessed using the Sebutape technique, in which strips of adhesive microporous polymeric film pressed onto facial sites are used to assess sebaceous activity. Acne was assessed by counting facial lesions. Subjective evaluations of skin and hair condition, patients' feelings to them and satisfaction with the OC were made using a visual analogue scale (VAS). Assessments were made at baseline, and after one, three and six treatment cycles. Sebutape assessments of seborrhea were significantly improved, on the right and left cheeks, after one treatment cycle, and on the forehead after three treatment cycles. These improvements increased steadily and were much larger at the end of Cycle 6. Acne grades were significantly improved after three and six treatment cycles. VAS scores in response to questions dealing with self-esteem and self-confidence were significantly improved after three cycles and in some cases after just one cycle. The women's views of their skin and hair (greasiness) were correspondingly significantly improved. Subjective assessments indicated that after one, three and six cycles, 69%, 93% and 98%, respectively, of women were satisfied or very satisfied with the DSG-OC. In women with facial seborrhea and mild or moderate acne, the use of DSG

  10. Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain.

    Science.gov (United States)

    Miranda, Hugo F; Noriega, Viviana; Zanetta, Pilar; Prieto, Juan Carlos; Prieto-Rayo, Juan Carlos; Aranda, Nicolás; Sierralta, Fernando

    2014-07-15

    Opioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated. The potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED50 was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes. These results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity.

  11. Active Power Regulation based on Droop for AC Microgrid

    DEFF Research Database (Denmark)

    Li, Chendan; Coelho, Ernane A. A.; Firoozabadi, Mehdi Savaghebi

    2015-01-01

    In this paper, two different control strategies are proposed to address the active power regulation issue in AC microgrids. The principle of power regulation in the droop controller is firstly introduced. Frequency scheduling and droop gain scheduling on top of droop control is proposed...... to successfully follow the active power command. The limitation of each method is discussed in term of small signal stability and light load sharing, respectively. Discussion on the effects of power command is also given. The simulation is carried out for both the strategies to verify the active power control...

  12. Developmental regulation of aromatase activity in the rat hypothalamus

    International Nuclear Information System (INIS)

    Lephart, E.D.

    1989-01-01

    The brain of all mammalian species studied thus far contain an enzymatic activity (aromatase) that catalyzes the conversion of androgens to estrogens. The activity is highest during prenatal development and contributes to the establishment of sex differences which determine adult gonadotropin secretion patterns and reproductive behavior. The studies presented in this dissertation represent a systematic effort to elucidate the mechanism(s) that control the initiation of and contribute to maintaining rat hypothalamic aromatase activity during pre- and postnatal development. Aromatase enzyme activity was measured by the 3 H 2 O release assay or by traditional estrogen product isolation. Brain aromatase mRNA was detected by hybridization to a cDNA encoding rat aromatase cytochrome P-450. In both males and females the time of puberty was associated with a decline in hypothalamic aromatase activity. This decline may represent a factor underlying the peri-pubertal decrease in the sensitivity to gonadal steroid feedback that accompanies completion of puberty. The results also indicate that androgens regulate brain aromatase levels during both the prepubertal and peri-pubertal stages of sexual development and that this regulation is transiently lost in young adults. Utilizing a hypothalamic organotypic culture system, aromatase activity in vitro was maintained for as long as two days. The results of studies of a variety of hormonal and metabolic regulators suggest that prenatal aromatase activity is regulated by factor(s) that function independently from the classical cyclic AMP and protein kinase C trans-membrane signaling pathways

  13. Activity-regulated genes as mediators of neural circuit plasticity.

    Science.gov (United States)

    Leslie, Jennifer H; Nedivi, Elly

    2011-08-01

    Modifications of neuronal circuits allow the brain to adapt and change with experience. This plasticity manifests during development and throughout life, and can be remarkably long lasting. Evidence has linked activity-regulated gene expression to the long-term structural and electrophysiological adaptations that take place during developmental critical periods, learning and memory, and alterations to sensory map representations in the adult. In all these cases, the cellular response to neuronal activity integrates multiple tightly coordinated mechanisms to precisely orchestrate long-lasting, functional and structural changes in brain circuits. Experience-dependent plasticity is triggered when neuronal excitation activates cellular signaling pathways from the synapse to the nucleus that initiate new programs of gene expression. The protein products of activity-regulated genes then work via a diverse array of cellular mechanisms to modify neuronal functional properties. Synaptic strengthening or weakening can reweight existing circuit connections, while structural changes including synapse addition and elimination create new connections. Posttranscriptional regulatory mechanisms, often also dependent on activity, further modulate activity-regulated gene transcript and protein function. Thus, activity-regulated genes implement varied forms of structural and functional plasticity to fine-tune brain circuit wiring. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Post-translational regulation of Oct4 transcriptional activity.

    Directory of Open Access Journals (Sweden)

    Jonathan P Saxe

    Full Text Available Oct4 is a key component of the molecular circuitry which regulates embryonic stem cell proliferation and differentiation. It is essential for maintenance of undifferentiated, pluripotent cell populations, and accomplishes these tasks by binding DNA in multiple heterodimer and homodimer configurations. Very little is known about how formation of these complexes is regulated, or the mechanisms through which Oct4 proteins respond to complex extracellular stimuli which regulate pluripotency. Here, we provide evidence for a phosphorylation-based mechanism which regulates specific Oct4 homodimer conformations. Point mutations of a putative phosphorylation site can specifically abrogate transcriptional activity of a specific homodimer assembly, with little effect on other configurations. Moreover, we performed bioinformatic predictions to identify a subset of Oct4 target genes which may be regulated by this specific assembly, and show that altering Oct4 protein levels affects transcription of Oct4 target genes which are regulated by this assembly but not others. Finally, we identified several signaling pathways which may mediate this phosphorylation and act in combination to regulate Oct4 transcriptional activity and protein stability. These results provide a mechanism for rapid and reversible alteration of Oct4 transactivation potential in response to extracellular signals.

  15. Contact heat-evoked temporal summation: tonic versus repetitive-phasic stimulation.

    Science.gov (United States)

    Granot, Michal; Granovsky, Yelena; Sprecher, Elliot; Nir, Rony-Reuven; Yarnitsky, David

    2006-06-01

    Temporal summation (TS) is usually evoked by repetitive mechanical or electrical stimuli, and less commonly by tonic heat pain. The present study aimed to examine the TS induction by repetitive-phasic versus tonic heat pain stimuli. Using 27 normal volunteers, we compared the extent of summation by three calculation methods: start-to-end pain rating difference, percent change, and double-logarithmic regression of successive ratings along the stimulation. Subjects were tested twice, and the reliability of each of the paradigms was obtained. In addition, personality factors related to pain catastrophizing and anxiety level were also correlated with the psychophysical results. Both paradigms induced significant TS, with similar increases for the repetitive-phasic and the tonic paradigms, as measured on 0-100 numerical pain scale (from 52.9+/-11.7 to 80.2+/-15.5, p<0.001; and from 38.5+/-13.3 to 75.8+/-18.3, p<0.001, respectively). The extent of summation was significantly correlated between the two paradigms, when calculated by absolute change (r=0.543, p=0.004) and by regression (r=0.438, p=0.025). Session-to-session variability was similar for both paradigms, relatively large, yet not biased. As with other psychophysical parameters, this poses some limitations on TS assessment in individual patients over time. The extent of TS induced by both paradigms was found to be associated with anxiety level and pain catastrophizing. Despite some dissimilarity between the repetitive-phasic and the tonic paradigms, the many similarities suggest that the two represent a similar physiological process, even if not precisely the same. Future clinical applications of these tests will determine the clinical relevance of the TS paradigms presented in this study.

  16. Acute phenylalanine/tyrosine depletion of phasic dopamine in the rat brain.

    Science.gov (United States)

    Shnitko, Tatiana A; Taylor, Sarah C; Stringfield, Sierra J; Zandy, Shannon L; Cofresí, Roberto U; Doherty, James M; Lynch, William B; Boettiger, Charlotte A; Gonzales, Rueben A; Robinson, Donita L

    2016-06-01

    Dopamine plays a critical role in striatal and cortical function, and depletion of the dopamine precursors phenylalanine and tyrosine is used in humans to temporarily reduce dopamine and probe the role of dopamine in behavior. This method has been shown to alter addiction-related behaviors and cognitive functioning presumably by reducing dopamine transmission, but it is unclear what specific aspects of dopamine transmission are altered. We performed this study to confirm that administration of an amino acid mixture omitting phenylalanine and tyrosine (Phe/Tyr[-]) reduces tyrosine tissue content in the prefrontal cortex (PFC) and nucleus accumbens (NAc), and to test the hypothesis that Phe/Tyr[-] administration reduces phasic dopamine release in the NAc. Rats were injected with a Phe/Tyr[-] amino acid mixture, a control amino acid mixture, or saline. High-performance liquid chromatography was used to determine the concentration of tyrosine, dopamine, or norepinephrine in tissue punches from the PFC and ventral striatum. In a separate group of rats, phasic dopamine release was measured with fast-scan cyclic voltammetry in the NAc core after injection with either the Phe/Tyr[-] mixture or the control amino acid solution. Phe/Tyr[-] reduced tyrosine content in the PFC and NAc, but dopamine and norepinephrine tissue content were not reduced. Moreover, Phe/Tyr[-] decreased the frequency of dopamine transients, but not their amplitude, in freely moving rats. These results indicate that depletion of tyrosine via Phe/Tyr[-] decreases phasic dopamine transmission, providing insight into the mechanism by which this method modifies dopamine-dependent behaviors in human imaging studies.

  17. Activation of ion transport systems during cell volume regulation

    International Nuclear Information System (INIS)

    Eveloff, J.L.; Warnock, D.G.

    1987-01-01

    This review discusses the activation of transport pathways during volume regulation, including their characteristics, the possible biochemical pathways that may mediate the activation of transport pathways, and the relations between volume regulation and transepithelial transport in renal cells. Many cells regulate their volume when exposed to an anisotonic medium. The changes in cell volume are caused by activation of ion transport pathways, plus the accompanying osmotically driven water movement such that cell volume returns toward normal levels. The swelling of hypertonically shrunken cells is termed regulatory volume increase (RVI) and involves an influx of NaCl into the cell via either activation of Na-Cl, Na-K-2Cl cotransport systems, or Na + -H + and Cl - -HCO 3 - exchangers. The reshrinking of hypotonically swollen cells is termed regulatory volume decrease (RVD) and involves an efflux of KCl and water from the cell by activation of either separate K + and Cl - conductances, a K-Cl cotransport system, or parallel K + -H + and Cl - -HCO 3 - exchangers. The biochemical mechanisms involved in the activation of transport systems are largely unknown, however, the phosphoinositide pathway may be implicated in RVI; phorbol esters, cGMP, and Ca 2+ affect the process of volume regulation. Renal tubular cells, as well as the blood cells that transverse the medulla, are subjected to increasing osmotic gradients from the corticomedullary junction to the papillary tip, as well as changing interstitial and tubule fluid osmolarity, depending on the diuretic state of the animal. Medullary cells from the loop of Henle and the papilla can volume regulate by activating Na-K-2Cl cotransport or Na + -H + and Cl - -HCO 3 - exchange systems

  18. Energy Regulation Commission. Activity report. 1 July - 31 December 2008

    International Nuclear Information System (INIS)

    2009-01-01

    After a description of the scope of activities, organisation and operation of the CRE (Commission de Regulation de l'Energie, Energy regulation commission) and of the CorDIS (Comite de reglement des differents et des sanctions de la CRE, CRE's Committee for settlements of controversies and sanctions), this report outlines the importance of the grid manager independence and of the regulation reinforcement for the building up of a domestic energy market. It discusses the role of the regulation authority in the interconnection of European grids, their operation security and supply security, but also in pricing and in investments. It highlights the relationship between the reduction of carbon emission, energy demand management, strengthening of electric grids, financial incentives, and advanced metering systems. It describes how the CRE ensures a good operation of electricity and natural gas markets

  19. Active Inference, homeostatic regulation and adaptive behavioural control.

    Science.gov (United States)

    Pezzulo, Giovanni; Rigoli, Francesco; Friston, Karl

    2015-11-01

    We review a theory of homeostatic regulation and adaptive behavioural control within the Active Inference framework. Our aim is to connect two research streams that are usually considered independently; namely, Active Inference and associative learning theories of animal behaviour. The former uses a probabilistic (Bayesian) formulation of perception and action, while the latter calls on multiple (Pavlovian, habitual, goal-directed) processes for homeostatic and behavioural control. We offer a synthesis these classical processes and cast them as successive hierarchical contextualisations of sensorimotor constructs, using the generative models that underpin Active Inference. This dissolves any apparent mechanistic distinction between the optimization processes that mediate classical control or learning. Furthermore, we generalize the scope of Active Inference by emphasizing interoceptive inference and homeostatic regulation. The ensuing homeostatic (or allostatic) perspective provides an intuitive explanation for how priors act as drives or goals to enslave action, and emphasises the embodied nature of inference. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. THE EUROPEAN MODEL OF STATE REGULATION OF TOURISM ACTIVITIES

    Directory of Open Access Journals (Sweden)

    О. Davydova

    2013-11-01

    Full Text Available In the article the existing model of state regulation of the development of tourism. Expediency of the European model of state regulation of tourism development in Ukraine. It is noted that the European model of state regulation of tourism activities based on the coordination of marketing activities and the development of cooperation between the public and private sectors. The basic forms of public-private partnerships and the advantages of using cluster model of development of tourism, namely, contracts, production sharing agreement, lease, joint venture. Promising areas of application of the PPP identified the transport sector, housing and utilities, energy and tourism sector. The features of cluster formations in the country and the prospects for tourism clusters.

  1. Commission for Energy regulation (CRE) - Activity report June 2004

    International Nuclear Information System (INIS)

    2004-01-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2004 activity report of CRE. Content: A - Opening of the gas and electricity markets for professional customers on 1 July 2004; B - Regulation of the gas market: Gas markets and players (The European environment, The French gas market); Regulation of the gas market (Implementing regulation, Works planned for the coming year; C - Regulation of the electricity market: The electricity markets and players (The European electricity markets, The French electricity market, Monitoring the electricity market); Regulation of the French electricity market (Access to public grid, Cross-border exchanges, Un-bundled accounting principles); The public electricity service in the regulated market (Content of the public service, Public service charges, Electricity production public service financing, Electricity sales tariffs) D - The working of CRE: How CRE exercises its jurisdiction, Tools; E - Appendices: Glossary, Units and conversions, Council of European Energy Regulators, Index of tables and figures

  2. Commission for Energy regulation (CRE) - Activity report June 2004

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2004-07-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2004 activity report of CRE. Content: A - Opening of the gas and electricity markets for professional customers on 1 July 2004; B - Regulation of the gas market: Gas markets and players (The European environment, The French gas market); Regulation of the gas market (Implementing regulation, Works planned for the coming year; C - Regulation of the electricity market: The electricity markets and players (The European electricity markets, The French electricity market, Monitoring the electricity market); Regulation of the French electricity market (Access to public grid, Cross-border exchanges, Un-bundled accounting principles); The public electricity service in the regulated market (Content of the public service, Public service charges, Electricity production public service financing, Electricity sales tariffs) D - The working of CRE: How CRE exercises its jurisdiction, Tools; E - Appendices: Glossary, Units and conversions, Council of European Energy Regulators, Index of tables and figures.

  3. Regulations on environmental data for the petroleum activity

    International Nuclear Information System (INIS)

    1990-01-01

    The publication deals with the regulations on environmental data for the petroleum activity, stipulated by the Norwegian Petroleum Directorate on 1 December 1989 pursuant to Royal Decree of 28 June 1985, cf. Sections 7 and 33, cf. delegation of authority by the Ministry of Local Government and Labour of 28 June 1985. 1 tab

  4. [Immune regulation activity and mechanism of Tibetan Kefir exopolysaccharide fractions].

    Science.gov (United States)

    Meng, Li; Zhang, Lanwei

    2009-12-01

    To investigate the effects and mechanism on immune regulation activity in mice of two Tibetan Kefir exoploysaccharides (EPS) with different molecular weight of 0.1 x 10(5) - 3 x 10(5) (fraction 1) and 1.8 x 10(3) (fraction 2). The immune regulation activity experiment was carried out in vitro based on the Functional Assessment Procedure and Test Methods of Health Food, which was issued by Ministry of Health of China. First, we treated mice subjects with EPS at doses of 40 mg/kg, 80 mg/kg, 120 mg/kg through ig. Then we detected the index of immune organs, the ability of antibody production (tested by HC50), activity of NK cell, delayed type hypersensitivity (DTH) and phagocytosis of macrophage in mice. Finally, we examined the expression of Erk protein in Macrophages by Western Blot assay. Fraction 1 could promote HC50, activity of NK cell and DTH in mice which low dose showed better. Fraction 2 could promote DTH, phagocytosis of macrophage which high dose showed better. The expression of Erk and COX-2 had the same trend with Phagocytic index. We verified the two fractions of Tibetan Kefir EPS could enhance immune functions in mice. Fraction 1 regulated immune function through NK cell and B cell while fraction 2 through macrophage cell and T cell. The effects to macrophage of Tibetan Kefir EPS in mice may realize through extra cellular signal-regulated kinase Erk pathway.

  5. MDCT urography: experience with a bi-phasic excretory phase examination protocol

    International Nuclear Information System (INIS)

    Meindl, Thomas; Coppenrath, Eva; Degenhart, Christoph; Reiser, Maximilian F.; Mueller-Lisse, Ullrich G.; Mueller-Lisse, Ulrike L.

    2007-01-01

    The benefit of multidetector computed tomographic urography (MDCTU) for visualising early and late excretory phase (EP) upper urinary tract (UUT) opacification has been studied. UUT opacification was retrospectively evaluated in 45 bi-phasic four-row MDCTU examinations. The UUT was divided into intrarenal collecting system (IRCS), proximal, middle and distal ureter. Two independent readers rated opacification: 1, none; 2, partial; 3, complete. Numbers of segments and percentages of UUTs at each score were calculated for each EP and two EPs combined. Results of a single EP and of combined EPs were compared by Wilcoxon matched-pairs signed-ranks. IRCS and proximal ureter were at least partially opacified in each EP in >95%. The middle ureter was at least partially opacified in the early and late EP in 85% and 93%, respectively. The distal ureter was opacified in 65% (49/75) in the early EP and in 78% (59/75) in the late EP. Combining two EPs, non-opacified distal segments decreased to 9% (7/75). Significant improvement between a single EP and combining two EPs were found for the middle and distal ureter (P < 0.03). Bi-phasic MDCTU substantially improved opacification of the middle and distal ureter. IRCS and proximal ureter are reliably opacified with one EP. (orig.)

  6. Commission for Energy regulation (CRE) - Activity report june 2008

    International Nuclear Information System (INIS)

    2008-01-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2008 activity report of CRE. Content: A - How CRE works: CRE regulatory authority and organisation: Powers, Organisation; Budget resources; Personnel; B - The Standing Committee for Dispute Settlement and Sanctions (CoRDiS) activity: Admissibility, Authority; C - Building a single European energy market: Overview; Organisation and coordination of the main European regulators (Work carried out collectively by European regulators, Regulator organisation and development, CRE's relations with European Community institutions, Development of CEER activities outside the European Union); CRE's European activities (The contribution of European regulators to the Third Energy Package, Integration of gas markets, Integration of electricity markets, Operation of the European interconnected electricity grid and security of supply, Opening up markets to benefit consumers); European Community activities (The European Commission's proposals for the internal energy market: the Third Energy Package, The European Commission's proposals for fighting climate change: the Climate Package, Infringement

  7. Tetraspanin CD9 regulates osteoclastogenesis via regulation of p44/42 MAPK activity

    International Nuclear Information System (INIS)

    Yi, TacGhee; Kim, Hye-Jin; Cho, Je-Yoel; Woo, Kyung Mi; Ryoo, Hyun-Mo; Kim, Gwan-Shik; Baek, Jeong-Hwa

    2006-01-01

    Tetraspanin CD9 has been shown to regulate cell-cell fusion in sperm-egg fusion and myotube formation. However, the role of CD9 in osteoclast, another multinucleated cell type, is not still clear. Therefore, we investigated the role of CD9 in osteoclast differentiation. CD9 was expressed in osteoclast lineage cells and its expression level increased during the progression of RANKL-induced osteoclastogenesis. KMC8, a neutralizing antibody specific to CD9, significantly suppressed RANKL-induced multinucleated osteoclast formation and the mRNA expression of osteoclast differentiation marker genes. To define CD9-regulated osteoclastogenic signaling pathway, MAPK pathways were examined. KMC8 induced long-term phosphorylation of p44/42 MAPK, but not of p38 MAPK. Constitutive activation of p44/42 MAPK by overexpressing constitutive-active mutant of MEK1 almost completely blocked osteoclast differentiation. Taken together, these results suggest that CD9 expressed on osteoclast lineage cells might positively regulate osteoclastogenesis via the regulation of p44/42 MAPK activity

  8. Validation of a closed bi-phasic extraction system and of the pancake probe as instruments to radiopharmaceutical quality control procedures

    International Nuclear Information System (INIS)

    Marques, F.L.N.; Okamoto, M.R.Y.; Sapienza, M.T.; Ferraro, G.C.

    2002-01-01

    Aim: Quality control of radiopharmaceuticals is not a common practice in Nuclear Medicine Services in Brazil. One frequent limitation is that the well counter, used to radioactivity measurement of chromatographic strips, is not available in most services. On the other hand, it's mandatory that all services have a pancake probe to control contaminations. The purpose of this study was to evaluate the accuracy of the quality control (QC) of technetium-99m labeled radiopharmaceuticals using a pancake probe, including chromatography of 99m Tc-MDP, 99m Tc-DMSA, 99m Tc-DMSA-V, 99m Tc-Pyp, 99m Tc-ECD, 99m Tc-Dextran, 99m Tc-colloid. Also, we had available a solvent extraction methods using a multi-use closed bi-phasic system to 99m Tc-ECD and 99m Tc-MIBI, to replace the classical single-use open bi-phasic system. Material and Methods: Classical chromatographic well counter reading and solvent extraction radiochemical controls were used as standards. To variant radiation reading method, pancake probe was covered with a lead disk 3 mm thick, with a 40x10 mm slit; the activity on chromatographic strips (80x10 mm) was read over the slit. The multi-use closed bi-phasic system was done closing the extremities of a 5 or 10 mL glass pipette using flame in the point side, and rubber septa in the other side. The pipette was filled with 2.5 or 3 mL, both organic solvent and aqueous NaCl 0.9 %; then two or three drops of the sample were applied and the tube shook during 30 seconds. Two minutes after, the activity was measured over each phase using the pancake detector. The same solvent mixture was used 3 times, with 48 h interval to allow radioactivity decay. Results: Radiochemical purity determined by the classical or the modified procedures showed Pearson's correlation of 0.973 (n=17) to chromatography; 0.993 to ECD (n=14) extraction and 0.919 to MIBI (n=21) extraction. Conclusion: Our findings suggest that the pancake can be used as a detection instrument in 99m Tc

  9. Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics

    Science.gov (United States)

    Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen; Christensen, Sune M.; Abel, Steven M.; Iwig, Jeff; Wu, Hung-Jen; Gureasko, Jodi; Rhodes, Christopher; Petit, Rebecca S.; Hansen, Scott D.; Thill, Peter; Yu, Cheng-Han; Stamou, Dimitrios; Chakraborty, Arup K.; Kuriyan, John; Groves, Jay T.

    2014-01-01

    Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras–guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average. PMID:24994643

  10. Commission for Energy regulation (CRE) - Activity report June 2007

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2007-07-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2007 activity report of CRE. Content: A - Towards a single European energy market: Birth of a single European energy market (Origins of Europe of Energy, Emergence of a European energy policy); Main European Community guiding lines (European governance as regards energy, Guiding principles for the internal energy market); European Community activities (European Commission reports, Electricity and gas Regional Initiatives); Organisation and coordination of European regulators (Joint organisation of European regulators, CRE's relations with European Community institutions); CRE's European activities (Regional integration of gas markets, Regional integration of electricity markets, Operation of the European interconnected electricity grid and security of supply, CRE's other European activities); B - CRE action at national level: Grids/networks and infrastructures (General information, Electricity grids, Regulation of gas networks and infrastructures); Markets (Changes in the regulatory and legislative contexts of electricity and natural gas markets, Electricity markets

  11. Commission for Energy regulation (CRE) - Activity report June 2007

    International Nuclear Information System (INIS)

    2007-01-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2007 activity report of CRE. Content: A - Towards a single European energy market: Birth of a single European energy market (Origins of Europe of Energy, Emergence of a European energy policy); Main European Community guiding lines (European governance as regards energy, Guiding principles for the internal energy market); European Community activities (European Commission reports, Electricity and gas Regional Initiatives); Organisation and coordination of European regulators (Joint organisation of European regulators, CRE's relations with European Community institutions); CRE's European activities (Regional integration of gas markets, Regional integration of electricity markets, Operation of the European interconnected electricity grid and security of supply, CRE's other European activities); B - CRE action at national level: Grids/networks and infrastructures (General information, Electricity grids, Regulation of gas networks and infrastructures); Markets (Changes in the regulatory and legislative contexts of electricity and natural gas markets, Electricity markets, Natural gas

  12. Commission for Energy regulation (CRE) - Activity report June 2005

    International Nuclear Information System (INIS)

    2005-01-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2005 activity report of CRE. Content: A - The opening of the markets in France and in Europe: The opening of the markets one year after 1 July 2004 (An especially important step, Electricity and gas: a common framework with structural differences, The coexistence of market prices and regulated tariffs); The European texts of 26 June 2003 (Texts to give new impetus, Texts to harmonize the role and powers of national regulators, Texts to guarantee the independence of system operators, Texts to ensure transparent and non-discriminatory access to networks, Texts providing for strengthening of interconnections); The outlook for 2007, a fully open market (1 July 2007: a date set by the directives, Priority given to informing and protecting consumers); B - Regulation of the natural gas market: The gas market in the European context (Europe's dependency on imports is increasing, Gas prices increased considerably across the whole of Europe in 2004, The European gas scene continues to be dominated by a small number of players, Gas infrastructures need to be developed in Europe, The new European

  13. Summary of regulation applicable to the gamma-graphy activities

    International Nuclear Information System (INIS)

    2004-04-01

    The regulations relative to the gamma radiography activities concerns in one hand the radioactive sources, and on the other hand the radiation protection of the workers. The necessity of having a person competent in radiation protection and the tasks he or she has to do are described. The training of operators, the medical surveillance, the dosimetry are such obligations. The maintenance of equipment is an other obligation. The last point concerns the transport of radioactive materials. (N.C.)

  14. Sphingosine-1-Phosphate Is a Novel Regulator of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR Activity.

    Directory of Open Access Journals (Sweden)

    Firhan A Malik

    Full Text Available The cystic fibrosis transmembrane conductance regulator (CFTR attenuates sphingosine-1-phosphate (S1P signaling in resistance arteries and has emerged as a prominent regulator of myogenic vasoconstriction. This investigation demonstrates that S1P inhibits CFTR activity via adenosine monophosphate-activated kinase (AMPK, establishing a potential feedback link. In Baby Hamster Kidney (BHK cells expressing wild-type human CFTR, S1P (1μmol/L attenuates forskolin-stimulated, CFTR-dependent iodide efflux. S1P's inhibitory effect is rapid (within 30 seconds, transient and correlates with CFTR serine residue 737 (S737 phosphorylation. Both S1P receptor antagonism (4μmol/L VPC 23019 and AMPK inhibition (80μmol/L Compound C or AMPK siRNA attenuate S1P-stimluated (i AMPK phosphorylation, (ii CFTR S737 phosphorylation and (iii CFTR activity inhibition. In BHK cells expressing the ΔF508 CFTR mutant (CFTRΔF508, the most common mutation causing cystic fibrosis, both S1P receptor antagonism and AMPK inhibition enhance CFTR activity, without instigating discernable correction. In summary, we demonstrate that S1P/AMPK signaling transiently attenuates CFTR activity. Since our previous work positions CFTR as a negative S1P signaling regulator, this signaling link may positively reinforce S1P signals. This discovery has clinical ramifications for the treatment of disease states associated with enhanced S1P signaling and/or deficient CFTR activity (e.g. cystic fibrosis, heart failure. S1P receptor/AMPK inhibition could synergistically enhance the efficacy of therapeutic strategies aiming to correct aberrant CFTR trafficking.

  15. After the Slippery Slope: Dutch Experiences on Regulating Active Euthanasia

    OpenAIRE

    Boer, Th.A.

    2003-01-01

    “When a country legalizes active euthanasia, it puts itself on a slippery slope from where it may well go further downward.” If true, this is a forceful argument in the battle of those who try to prevent euthanasia from becoming legal. The force of any slippery-slope argument, however, is by definition limited by its reference to future developments which cannot empirically be sustained. Experience in the Netherlands—where a law regulating active euthanasia was accepted in April 2001—may shed...

  16. The GABAA Antagonist DPP-4-PIOL Selectively Antagonises Tonic over Phasic GABAergic Currents in Dentate Gyrus Granule Cells

    DEFF Research Database (Denmark)

    Boddum, Kim; Frølund, Bente; Kristiansen, Uffe

    2014-01-01

    that phasic and tonic GABAA receptor currents can be selectively inhibited by the antagonists SR 95531 and the 4-PIOL derivative, 4-(3,3-diphenylpropyl)-5-(4-piperidyl)-3-isoxazolol hydrobromide (DPP-4-PIOL), respectively. In dentate gyrus granule cells, SR 95531 was found approximately 4 times as potent...

  17. Development of Tropical Lowland Peat Forest Phasic Community Zonations in the Kota Samarahan-Asajaya area, West Sarawak, Malaysia

    Directory of Open Access Journals (Sweden)

    Mohamad Tarmizi Mohamad

    2016-01-01

    Full Text Available Logging observations of auger profiles (Tarmizi, 2014 indicate a vertical, downwards, general decrease of peat humification levels with depth in a tropical lowland peat forest in the Kota Samarahan-Asajaya area in the region of West Sarawak (Malaysia. Based on pollen analyses and field observations, the studied peat profiles can be interpreted as part of a progradation deltaic succession. Continued regression of sea levels, gave rise to the development of peat in a transitional mangrove to floodplain/floodbasin environment, followed by a shallow, topogenic peat depositional environment with riparian influence at approximately 2420 ± 30 years B.P. (until present time. The inferred peat vegetational succession reached Phasic Community I at approximately 2380 ± 30 years B.P. and followed by Phasic Community II at approximately 1780 ± 30 years B.P., towards the upper part of the present, ombrogenic, peat profile. Observations of the presence of large, hollow, Shorea type trees, supports that successive vegetational zonation of the tropical lowland peat dome may have reached Phasic Community II. Some pollen types were found that are also known to occur in the inferred vegetational zonation of Phasic Community III and IV or higher. Pollen analyses indicate that estuarine and deltaic, brackish to saline water influence may have gradually ceased at approximately 0.5 m below the lithological boundary between peat and underlying soil (floodplain deposit in the tropical lowland peat basin.

  18. Low amplitude rhythmic contraction frequency in human detrusor strips correlates with phasic intravesical pressure waves.

    Science.gov (United States)

    Colhoun, Andrew F; Speich, John E; Cooley, Lauren F; Bell, Eugene D; Barbee, R Wayne; Guruli, Georgi; Ratz, Paul H; Klausner, Adam P

    2017-08-01

    Low amplitude rhythmic contractions (LARC) occur in detrusor smooth muscle and may play a role in storage disorders such as overactive bladder and detrusor overactivity. The purpose of this study was to determine whether LARC frequencies identified in vitro from strips of human urinary bladder tissue correlate with in vivo LARC frequencies, visualized as phasic intravesical pressure (p ves ) waves during urodynamics (UD). After IRB approval, fresh strips of human urinary bladder were obtained from patients. LARC was recorded with tissue strips at low tension (rhythmic frequency similar to the in vitro LARC frequency quantified in human urinary bladder tissue strips. Further refinements of this technique may help identify subsets of individuals with LARC-mediated storage disorders.

  19. Effects of dietary tryptophan and phenylalanine–tyrosine depletion on phasic alertness in healthy adults – A pilot study

    Directory of Open Access Journals (Sweden)

    Patricia Hildebrand

    2015-04-01

    Full Text Available Background: The synthesis of the neurotransmitters serotonin (5-HT and dopamine (DA in the brain can be directly altered by dietary manipulation of their relevant precursor amino acids (AA. There is evidence that altered serotonergic and dopaminergic neurotransmission are both associated with impaired attentional control. Specifically, phasic alertness is one specific aspect of attention that has been linked to changes in 5-HT and DA availability in different neurocircuitries related to attentional processes. The present study investigated the impact of short-term reductions in central nervous system 5-HT and DA synthesis, which was achieved by dietary depletion of the relevant precursor AA, on phasic alertness in healthy adult volunteers; body weight–adapted dietary tryptophan and phenylalanine–tyrosine depletion (PTD techniques were used. Methods: The study employed a double-blind between-subject design. Fifty healthy male and female subjects were allocated to three groups in a randomized and counterbalanced manner and received three different dietary challenge conditions: acute tryptophan depletion (ATD, for the depletion of 5-HT; N=16, PTD (for the depletion of DA; N=17, and a balanced AA load (BAL; N=17, which served as a control condition. Three hours after challenge intake (ATD/PTD/BAL, phasic alertness was assessed using a standardized test battery for attentional performance (TAP. Blood samples for AA level analyses were obtained at baseline and 360 min after the challenge intake. Results: Overall, there were no significant differences in phasic alertness for the different challenge conditions. Regarding PTD administration, a positive correlation between the reaction times and the DA-related depletion magnitude was detected via the lower plasma tyrosine levels and the slow reaction times of the first run of the task. In contrast, higher tryptophan concentrations were associated with slower reaction times in the fourth run of the

  20. Echocardiographic and hemodynamic determinants of right coronary artery flow reserve and phasic flow pattern in advanced non-ischemic cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Mady Charles

    2007-09-01

    Full Text Available Abstract Background In patients with advanced non-ischemic cardiomyopathy (NIC, right-sided cardiac disturbances has prognostic implications. Right coronary artery (RCA flow pattern and flow reserve (CFR are not well known in this setting. The purpose of this study was to assess, in human advanced NIC, the RCA phasic flow pattern and CFR, also under right-sided cardiac disturbances, and compare with left coronary circulation. As well as to investigate any correlation between the cardiac structural, mechanical and hemodynamic parameters with RCA phasic flow pattern or CFR. Methods Twenty four patients with dilated severe NIC were evaluated non-invasively, even by echocardiography, and also by cardiac catheterization, inclusive with Swan-Ganz catheter. Intracoronary Doppler (Flowire data was obtained in RCA and left anterior descendent coronary artery (LAD before and after adenosine. Resting RCA phasic pattern (diastolic/systolic was compared between subgroups with and without pulmonary hypertension, and with and without right ventricular (RV dysfunction; and also with LAD. RCA-CFR was compared with LAD, as well as in those subgroups. Pearson's correlation analysis was accomplished among echocardiographic (including LV fractional shortening, mass index, end systolic wall stress more hemodynamic parameters with RCA phasic flow pattern or RCA-CFR. Results LV fractional shortening and end diastolic diameter were 15.3 ± 3.5 % and 69.4 ± 12.2 mm. Resting RCA phasic pattern had no difference comparing subgroups with vs. without pulmonary hypertension (1.45 vs. 1.29, p = NS either with vs. without RV dysfunction (1.47 vs. 1.23, p = NS; RCA vs. LAD was 1.35 vs. 2.85 (p Conclusion In patients with chronic advanced NIC, RCA phasic flow pattern has a mild diastolic predominance, less marked than in LAD, with no effects from pulmonary artery hypertension or RV dysfunction. There is no significant correlation between any cardiac mechanical-structural or

  1. Cooperative activation of transcription by autoimmune regulator AIRE and CBP

    International Nuclear Information System (INIS)

    Pitkaenen, J.; Rebane, A.; Rowell, J.; Murumaegi, A.; Stroebel, P.; Moell, K.; Saare, M.; Heikkilae, J.; Doucas, V.; Marx, A.; Peterson, P.

    2005-01-01

    Autoimmune regulator (AIRE) is a transcriptional regulator that is believed to control the expression of tissue-specific genes in the thymus. Mutated AIRE is responsible for onset of the hereditary autoimmune disease APECED. AIRE is able to form nuclear bodies (NBs) and interacts with the ubiquitous transcriptional coactivator CBP. In this paper, we show that CBP and AIRE synergistically activate transcription on different promoter reporters whereas AIRE gene mutation R257X, found in APECED patients, interferes with this coactivation effect. Furthermore, the overexpression of AIRE and CBP collaboratively enhance endogenous IFNβ mRNA expression. The immunohistochemical studies suggest that CBP, depending on the balance of nuclear proteins, is a component of AIRE NBs. We also show that AIRE NBs are devoid of active chromatin and, therefore, not sites of transcription. In addition, we demonstrate by 3D analyses that AIRE and CBP, when colocalizing, are located spatially differently within AIRE NBs. In conclusion, our data suggest that AIRE activates transcription of the target genes, i.e., autoantigens in collaboration with CBP and that this activation occurs outside of AIRE NBs

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Commission for Energy regulation (CRE) - Activity report june 2006

    International Nuclear Information System (INIS)

    2006-01-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2006 activity report of CRE. Content: A - Opening of the electricity and natural gas markets to household consumers on 1 July 2007: CRE at the service of eligible customers (Information for eligible customers, Improved knowledge of non-household customers); Monitoring of the non-discrimination, transparency and independence of system operators (Drafting and distribution of codes of good conduct for system operators, The necessary improvement of system operator independence); Preparing the practical methods of opening: GTE 2007 and GTG 2007 (The necessary simplification of relations between operators and customers, Achieving a greater level of consumer information and protection, The clearly defined stages of the 'customer pathway', Profiling and settlement mechanisms: turning experience feedback from 2004 to good account); Persisting uncertainties and hurdles (The need for a suitable regulatory and legislative platform, Hurdles to the opening of the household market); B - Regulation of the natural gas market: The gas market in the European context (Increasing weight of imports in gas

  4. Commission for Energy regulation (CRE) - Activity report june 2006

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2006-07-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2006 activity report of CRE. Content: A - Opening of the electricity and natural gas markets to household consumers on 1 July 2007: CRE at the service of eligible customers (Information for eligible customers, Improved knowledge of non-household customers); Monitoring of the non-discrimination, transparency and independence of system operators (Drafting and distribution of codes of good conduct for system operators, The necessary improvement of system operator independence); Preparing the practical methods of opening: GTE 2007 and GTG 2007 (The necessary simplification of relations between operators and customers, Achieving a greater level of consumer information and protection, The clearly defined stages of the 'customer pathway', Profiling and settlement mechanisms: turning experience feedback from 2004 to good account); Persisting uncertainties and hurdles (The need for a suitable regulatory and legislative platform, Hurdles to the opening of the household market); B - Regulation of the natural gas market: The gas market in the European context (Increasing weight of

  5. Active pre-filters for dc/dc Boost regulators

    Directory of Open Access Journals (Sweden)

    Carlos Andrés Ramos-Paja

    2014-05-01

    Full Text Available This paper proposes an active pre-filter to mitigate the current harmonics generated by classical dc/dc Boost regulators, which generate current ripples proportional to the duty cycle. Therefore, high output voltage conditions, i.e., high voltage conversion ratios, produce high current harmonics that must be filtered to avoid damage or source losses. Traditionally, these current components are filtered using electrolytic capacitors, which introduce reliability problems because of their high failure rate. The solution introduced in this paper instead uses a dc/dc converter based on the parallel connection of the Boost canonical cells to filter the current ripples generated by the Boost regulator, improving the system reliability. This solution provides the additional benefits of improving the overall efficiency and the voltage conversion ratio. Finally, the solution is validated with simulations and experimental results.

  6. Calcium and cargoes as regulators of myosin 5a activity

    International Nuclear Information System (INIS)

    Sellers, James R.; Thirumurugan, Kavitha; Sakamoto, Takeshi; Hammer, John A.; Knight, Peter J.

    2008-01-01

    Myosin 5a is a two-headed actin-dependent motor that transports various cargoes in cells. Its enzymology and mechanochemistry have been extensively studied in vitro. It is a processive motor that takes multiple 36 nm steps on actin. The enzymatic activity of myosin 5 is regulated by an intramolecular folding mechanism whereby its lever arms fold back against the coiled-coil tail such that the motor domains directly bind the globular tail domains. We show that the structure seen in individual folded molecules is consistent with electron density map of two-dimensional crystals of the molecule. In this compact state, the actin-activated MgATPase activity of the molecule is markedly inhibited and the molecule cannot move processively on surface bound actin filaments. The actin-activated MgATPase activity of myosin 5a is activated by increasing the calcium concentration or by binding of a cargo-receptor molecule, melanophilin, in vitro. However, calcium binding to the calmodulin light chains results in dissociation of some of the calmodulin which disrupts the ability of myosin 5a to move on actin filaments in vitro. Thus we propose that the physiologically relevant activation pathway in vivo involves binding of cargo-receptor proteins

  7. DUB3 Deubiquitylating Enzymes Regulate Hippo Pathway Activity by Regulating the Stability of ITCH, LATS and AMOT Proteins

    DEFF Research Database (Denmark)

    Nguyen, Thanh Hung; Kugler, Jan-Michael; Cohen, Stephen Michael

    2017-01-01

    /TAZ, is regulated by ubiquitin mediated protein turnover and several ubiquitin ligase complexes have been implicated in human cancer. However, little is known about the deubiquitylating enzymes that counteract these ubiquitin ligases in regulation of the Hippo pathway. Here we identify the DUB3 family...... deubiquitylating enzymes as regulators of Hippo pathway activity. We provide evidence that DUB3 proteins regulate YAP/TAZ activity by controlling the stability of the E3 ligase ITCH, the LATS kinases and the AMOT family proteins. As a novel Hippo pathway regulator, DUB3 has the potential to act a tumor suppressor...

  8. Recent development in safety regulation of nuclear fuel cycle activities

    International Nuclear Information System (INIS)

    Kato, S.

    2001-01-01

    Through the effort of deliberation and legislation over five years, Japanese government structure was reformed this January, with the aim of realizing simple, efficient and transparent administration. Under the reform, the Agency for Nuclear and Industrial Safety (ANIS) was founded in the Ministry of Economy, Trade and Industry (METI) to be responsible for safety regulation of energy-related nuclear activities, including nuclear fuel cycle activities, and industrial activities, including explosives, high-pressure gasses and mining. As one of the lessons learned from the JCO criticality accident of September 1999, it was pointed out that the government's inspection function was not enough for fuel fabrication facilities. Accordingly, new statutory regulatory activities were introduced, namely, inspection of observance of safety rules and procedures for all kinds of nuclear operators and periodic inspection of fuel fabrication facilities. In addition, in order to cope with insufficient safety education and training of workers in nuclear facilities, licensees of nuclear facilities are required by law to specify safety education and training for their workers. ANIS is committed to enforce these new regulatory activities effectively and efficiently. In addition, it is going to be prepared, in its capacity as safety regulatory authority, for future development of Japanese fuel cycle activities, including commissioning of JNFL Rokkasho reprocessing plant and possible application for licenses for JNFL MOX fabrication plant and for spent fuel interim storage facilities. (author)

  9. Regulation by magnesium of potato tuber mitochondrial respiratory activities.

    Science.gov (United States)

    Vicente, Joaquim A F; Madeira, Vítor M C; Vercesi, Anibal E

    2004-12-01

    Dehydrogenase activities of potato tuber mitochondria and corresponding phosphorylation rates were measured for the dependence on external and mitochondrial matrix Mg2+. Magnesium stimulated state 3 and state 4 respiration, with significantly different concentrations of matrix Mg2+ required for optimal activities of the several substrates. Maximal stimulation of respiration with all substrates was obtained at 2-mM external Mg2+. However, respiration of malate, citrate, and alpha-ketoglutarate requires at least 4-mM Mg2+ inside mitochondria for maximization of dehydrogenase activities. The phosphorylation system, requires a low level of internal Mg2+ (0.25 mM) to reach high activity, as judged by succinate-dependent respiration. However, mitochondria respiring on citrate or alpha-ketoglutarate only sustain high levels of phosphorylation with at least 4-mM matrix Mg2+. Respiration of succinate is active without external and matrix Mg2+, although stimulated by the cation. Respiration of alpha-ketoglutarate was strictly dependent on external Mg2+ required for substrate transport into mitochondria, and internal Mg2+ is required for dehydrogenase activity. Respiration of citrate and malate also depend on internal Mg2+ but, unlike alpha-ketoglutarate, some activity still remains without external Mg2+. All the substrates revealed insensitive to external and internal mitochondrial Ca2+, except the exogenous NADH dehydrogenase, which requires either external Ca2+ or Mg2+ for detectable activity. Calcium is more efficient than Mg2+, both having cumulative stimulation. Unlike Ca2+, Mn2+ could substitute for Mg2+, before and after addition of A23, showing its ability to regulate phosphorylation and succinate dehydrogenase activities, with almost the same efficiency as Mg2+.

  10. Dynamic regulation of Drosophila nuclear receptor activity in vivo.

    Science.gov (United States)

    Palanker, Laura; Necakov, Aleksandar S; Sampson, Heidi M; Ni, Ruoyu; Hu, Chun; Thummel, Carl S; Krause, Henry M

    2006-09-01

    Nuclear receptors are a large family of transcription factors that play major roles in development, metamorphosis, metabolism and disease. To determine how, where and when nuclear receptors are regulated by small chemical ligands and/or protein partners, we have used a 'ligand sensor' system to visualize spatial activity patterns for each of the 18 Drosophila nuclear receptors in live developing animals. Transgenic lines were established that express the ligand binding domain of each nuclear receptor fused to the DNA-binding domain of yeast GAL4. When combined with a GAL4-responsive reporter gene, the fusion proteins show tissue- and stage-specific patterns of activation. We show that these responses accurately reflect the presence of endogenous and exogenously added hormone, and that they can be modulated by nuclear receptor partner proteins. The amnioserosa, yolk, midgut and fat body, which play major roles in lipid storage, metabolism and developmental timing, were identified as frequent sites of nuclear receptor activity. We also see dynamic changes in activation that are indicative of sweeping changes in ligand and/or co-factor production. The screening of a small compound library using this system identified the angular psoralen angelicin and the insect growth regulator fenoxycarb as activators of the Ultraspiracle (USP) ligand-binding domain. These results demonstrate the utility of this system for the functional dissection of nuclear receptor pathways and for the development of new receptor agonists and antagonists that can be used to modulate metabolism and disease and to develop more effective means of insect control.

  11. Erk1 positively regulates osteoclast differentiation and bone resorptive activity.

    Directory of Open Access Journals (Sweden)

    Yongzheng He

    Full Text Available The extracellular signal-regulated kinases (ERK1 and 2 are widely-expressed and they modulate proliferation, survival, differentiation, and protein synthesis in multiple cell lineages. Altered ERK1/2 signaling is found in several genetic diseases with skeletal phenotypes, including Noonan syndrome, Neurofibromatosis type 1, and Cardio-facio-cutaneous syndrome, suggesting that MEK-ERK signals regulate human skeletal development. Here, we examine the consequence of Erk1 and Erk2 disruption in multiple functions of osteoclasts, specialized macrophage/monocyte lineage-derived cells that resorb bone. We demonstrate that Erk1 positively regulates osteoclast development and bone resorptive activity, as genetic disruption of Erk1 reduced osteoclast progenitor cell numbers, compromised pit formation, and diminished M-CSF-mediated adhesion and migration. Moreover, WT mice reconstituted long-term with Erk1(-/- bone marrow mononuclear cells (BMMNCs demonstrated increased bone mineral density as compared to recipients transplanted with WT and Erk2(-/- BMMNCs, implicating marrow autonomous, Erk1-dependent osteoclast function. These data demonstrate Erk1 plays an important role in osteoclast functions while providing rationale for the development of Erk1-specific inhibitors for experimental investigation and/or therapeutic modulation of aberrant osteoclast function.

  12. Regulation of dopamine transporter activity by carboxypeptidase E

    Directory of Open Access Journals (Sweden)

    Zhang Heping

    2009-05-01

    Full Text Available Abstract Background The dopamine transporter (DAT plays a critical role in terminating the action of dopamine by rapid reuptake into the presynaptic neuron. Previous studies have revealed that the DAT carboxyl terminus (DAT-CT can directly interact with other cellular proteins and regulate DAT function and trafficking. Results Here, we have identified that carboxypeptidase E (CPE, a prohormone processing exopeptidase and sorting receptor for the regulated secretory pathway, interacts with the DAT-CT and affects DAT function. Mammalian cell lines coexpressing CPE and DAT exhibited increased DAT-mediated dopamine uptake activity compared to cells expressing DAT alone. Moreover, coexpression of an interfering DAT-CT minigene inhibited the effects of CPE on DAT. Functional changes caused by CPE could be attributed to enhanced DAT expression and subsequent increase in DAT cell surface localization, due to decreased DAT degradation. In addition, CPE association could reduce the phosphorylation state of DAT on serine residues, potentially leading to reduced internalization, thus stabilizing plasmalemmal DAT localization. Conclusion Taken together, our results reveal a novel role for CPE in the regulation of DAT trafficking and DAT-mediated DA uptake, which may provide a novel target in the treatment of dopamine-governed diseases such as drug addiction and obesity.

  13. Pacing and awareness: brain regulation of physical activity.

    Science.gov (United States)

    Edwards, A M; Polman, R C J

    2013-11-01

    The aim of this current opinion article is to provide a contemporary perspective on the role of brain regulatory control of paced performances in response to exercise challenges. There has been considerable recent conjecture as to the role of the brain during exercise, and it is now broadly accepted that fatigue does not occur without brain involvement and that all voluntary activity is likely to be paced at some level by the brain according to individualised priorities and knowledge of personal capabilities. This article examines the role of pacing in managing and distributing effort to successfully accomplish physical tasks, while extending existing theories on the role of the brain as a central controller of performance. The opinion proposed in this article is that a central regulator operates to control exercise performance but achieves this without the requirement of an intelligent central governor located in the subconscious brain. It seems likely that brain regulation operates at different levels of awareness, such that minor homeostatic challenges are addressed automatically without conscious awareness, while larger metabolic disturbances attract conscious awareness and evoke a behavioural response. This supports the view that the brain regulates exercise performance but that the interpretation of the mechanisms underlying this effect have not yet been fully elucidated.

  14. The regulation of ant colony foraging activity without spatial information.

    Directory of Open Access Journals (Sweden)

    Balaji Prabhakar

    Full Text Available Many dynamical networks, such as the ones that produce the collective behavior of social insects, operate without any central control, instead arising from local interactions among individuals. A well-studied example is the formation of recruitment trails in ant colonies, but many ant species do not use pheromone trails. We present a model of the regulation of foraging by harvester ant (Pogonomyrmex barbatus colonies. This species forages for scattered seeds that one ant can retrieve on its own, so there is no need for spatial information such as pheromone trails that lead ants to specific locations. Previous work shows that colony foraging activity, the rate at which ants go out to search individually for seeds, is regulated in response to current food availability throughout the colony's foraging area. Ants use the rate of brief antennal contacts inside the nest between foragers returning with food and outgoing foragers available to leave the nest on the next foraging trip. Here we present a feedback-based algorithm that captures the main features of data from field experiments in which the rate of returning foragers was manipulated. The algorithm draws on our finding that the distribution of intervals between successive ants returning to the nest is a Poisson process. We fitted the parameter that estimates the effect of each returning forager on the rate at which outgoing foragers leave the nest. We found that correlations between observed rates of returning foragers and simulated rates of outgoing foragers, using our model, were similar to those in the data. Our simple stochastic model shows how the regulation of ant colony foraging can operate without spatial information, describing a process at the level of individual ants that predicts the overall foraging activity of the colony.

  15. Rac1 activity regulates proliferation of aggressive metastatic melanoma

    International Nuclear Information System (INIS)

    Bauer, Natalie N.; Chen Yihwen; Samant, Rajeev S.; Shevde, Lalita A.; Fodstad, Oystein

    2007-01-01

    Molecular mechanisms underlying the different capacity of two in vivo selected human melanoma cell variants to form experimental metastases were studied. The doubling times of the FEMX-I and FEMX-V cell sublines in vitro were 15 and 25 h, respectively. The invasive capacity of FEMX-I cells was 8-fold higher than FEMX-V cells, and the time to form approximately 10 mm s.c. tumors in nude mice was 21 versus 35 days. FEMX-I displayed a spindle-like formation in vitro, whereas FEMX-V cells had a rounded shape. Hence, we examined known determinants of cell shape and proliferation, the small GTPases. The four studied showed equal expression in both cell types, but Rac1 activity was significantly decreased in FEMX-V cells. Rac1 stimulates NFκB, and we found that endogenous NFκB activity of FEMX-V cells was 2% of that of FEMX-I cells. Inhibition of Rac1 resulted in blocked NFκB activity. Specific inhibition of either Rac1 or NFκB significantly reduced proliferation and invasion of FEMX-I cells, the more pronounced effects observed with Rac1 inhibition. These data indicate that Rac1 activity in FEMX cells regulates cell proliferation and invasion, in part via its effect on NFκB, signifying Rac1 as a key molecule in melanoma progression and metastasis

  16. Physical Activity Plays an Important Role in Body Weight Regulation

    Directory of Open Access Journals (Sweden)

    Jean-Philippe Chaput

    2011-01-01

    Full Text Available Emerging literature highlights the need to incorporate physical activity into every strategy intended to prevent weight gain as well as to maintain weight loss over time. Furthermore, physical activity should be part of any plan to lose weight. The stimulus of exercise provides valuable metabolic adaptations that improve energy and macronutrient balance regulation. A tight coupling between energy intake and energy expenditure has been documented at high levels of physical exercise, suggesting that exercise may improve appetite control. The regular practice of physical activity has also been reported to reduce the risk of stress-induced weight gain. A more personalized approach is recommended when planning exercise programs in a clinical weight loss setting in order to limit the compensatory changes associated to exercise-induced weight loss. With modern environment promoting overeating and sedentary behavior, there is an urgent need for a concerted action including legislative measures to promote healthy active living in order to curb the current epidemic of chronic diseases.

  17. First calorimetric determination of heat of extraction of 248Cm in a bi-phasic system

    International Nuclear Information System (INIS)

    Martin, Leigh R.; Zalupski, Peter R.

    2011-01-01

    This report presents a summary of the work performed to meet FCR and D level 2 milestone M21SW050201, 'Complete the first calorimetric determination of heat of extraction of 248Cm in a bi-phasic system'. This work was carried out under the auspices of the Thermodynamics and Kinetics FCR and D work package. To complement previous work undertaken under this work package we have extended out heat of extraction studies by di-2-ethyl-hexyl-phosphoric acid to curium. This report also details the heat of extraction of samarium in the same system. This work was performed to not only test the methodology but also to check for consistency with the heats of extraction obtained with those in the prior literature. The heat of extraction for samarium that was obtained in this study was -9.6 kJ mol-1, which is in reasonable agreement with the previously obtained value of -10.9 kJ mol-1. The curium heat of extraction was performed under two sets of conditions and the obtained heats of extraction were in reasonable agreement with each other at -16.0 ± 1.1 and -16.8 ± 1.5 kJ mol-1.

  18. Glucose metabolism regulates T cell activation, differentiation and functions

    Directory of Open Access Journals (Sweden)

    Clovis Steve Palmer

    2015-01-01

    Full Text Available The adaptive immune system is equipped to eliminate both tumors and pathogenic microorganisms. It requires a series of complex and coordinated signals to drive the activation, proliferation and differentiation of appropriate T cell subsets. It is now established that changes in cellular activation are coupled to profound changes in cellular metabolism. In addition, emerging evidence now suggest that specific metabolic alterations associated with distinct T cell subsets may be ancillary to their differentiation and influential in their immune functions. The Warburg effect originally used to describe a phenomenon in which most cancer cells relied on aerobic glycolysis for their growth is a key process that sustain T cell activation and differentiation. Here we review how different aspects of metabolism in T cells influence their functions, focusing on the emerging role of key regulators of glucose metabolism such as HIF-1α. A thorough understanding of the role of metabolism in T cell function could provide insights into mechanisms involved in inflammatory-mediated conditions, with the potential for developing novel therapeutic approaches to treat these diseases.

  19. Thyroid states regulate subcellular glucose phosphorylation activity in male mice

    Directory of Open Access Journals (Sweden)

    Flavia Letícia Martins Peçanha

    2017-07-01

    Full Text Available The thyroid hormones (THs, triiodothyronine (T3 and thyroxine (T4, are very important in organism metabolism and regulate glucose utilization. Hexokinase (HK is responsible for the first step of glycolysis, catalyzing the conversion of glucose to glucose 6-phosphate. HK has been found in different cellular compartments, and new functions have been attributed to this enzyme. The effects of hyperthyroidism on subcellular glucose phosphorylation in mouse tissues were examined. Tissues were removed, subcellular fractions were isolated from eu- and hyperthyroid (T3, 0.25 μg/g, i.p. during 21 days mice and HK activity was assayed. Glucose phosphorylation was increased in the particulate fraction in soleus (312.4% ± 67.1, n = 10, gastrocnemius (369.2% ± 112.4, n = 10 and heart (142.2% ± 13.6, n = 10 muscle in the hyperthyroid group compared to the control group. Hexokinase activity was not affected in brain or liver. No relevant changes were observed in HK activity in the soluble fraction for all tissues investigated. Acute T3 administration (single dose of T3, 1.25 μg/g, i.p. did not modulate HK activity. Interestingly, HK mRNA levels remained unchanged and HK bound to mitochondria was increased by T3 treatment, suggesting a posttranscriptional mechanism. Analysis of the AKT pathway showed a 2.5-fold increase in AKT and GSK3B phosphorylation in the gastrocnemius muscle in the hyperthyroid group compared to the euthyroid group. Taken together, we show for the first time that THs modulate HK activity specifically in particulate fractions and that this action seems to be under the control of the AKT and GSK3B pathways.

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

    Czech Academy of Sciences Publication Activity Database

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

    2016-01-01

    Roč. 36, č. 7 (2016), s. 2161-2175 ISSN 0270-6474 R&D Projects: GA ČR(CZ) GAP303/12/1464; GA ČR(CZ) GBP304/12/G069; GA TA ČR(CZ) TE01020028; GA ČR(CZ) GBP208/12/G016; GA MŠk(CZ) EE2.3.30.0025; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 ; RVO:61388963 Keywords : memantine * neuroprotection * neurosteroid * NMDA receptor * pregnanolone sulfate * synaptic transmission Subject RIV: ED - Physiology Impact factor: 5.988, year: 2016

  1. Regulation of sucrose metabolism in higher plants: localization and regulation of activity of key enzymes

    Science.gov (United States)

    Winter, H.; Huber, S. C.; Brown, C. S. (Principal Investigator)

    2000-01-01

    Sucrose (Suc) plays a central role in plant growth and development. It is a major end product of photosynthesis and functions as a primary transport sugar and in some cases as a direct or indirect regulator of gene expression. Research during the last 2 decades has identified the pathways involved and which enzymes contribute to the control of flux. Availability of metabolites for Suc synthesis and 'demand' for products of sucrose degradation are important factors, but this review specifically focuses on the biosynthetic enzyme sucrose-phosphate synthase (SPS), and the degradative enzymes, sucrose synthase (SuSy), and the invertases. Recent progress has included the cloning of genes encoding these enzymes and the elucidation of posttranslational regulatory mechanisms. Protein phosphorylation is emerging as an important mechanism controlling SPS activity in response to various environmental and endogenous signals. In terms of Suc degradation, invertase-catalyzed hydrolysis generally has been associated with cell expansion, whereas SuSy-catalyzed metabolism has been linked with biosynthetic processes (e.g., cell wall or storage products). Recent results indicate that SuSy may be localized in multiple cellular compartments: (1) as a soluble enzyme in the cytosol (as traditionally assumed); (2) associated with the plasma membrane; and (3) associated with the actin cytoskeleton. Phosphorylation of SuSy has been shown to occur and may be one of the factors controlling localization of the enzyme. The purpose of this review is to summarize some of the recent developments relating to regulation of activity and localization of key enzymes involved in sucrose metabolism in plants.

  2. Regulation of ALF promoter activity in Xenopus oocytes.

    Directory of Open Access Journals (Sweden)

    Dan Li

    Full Text Available BACKGROUND: In this report we evaluate the use of Xenopus laevis oocytes as a matched germ cell system for characterizing the organization and transcriptional activity of a germ cell-specific X. laevis promoter. PRINCIPAL FINDINGS: The promoter from the ALF transcription factor gene was cloned from X. laevis genomic DNA using a PCR-based genomic walking approach. The endogenous ALF gene was characterized by RACE and RT-PCR for transcription start site usage, and by sodium bisulfite sequencing to determine its methylation status in somatic and oocyte tissues. Homology between the X. laevis ALF promoter sequence and those from human, chimpanzee, macaque, mouse, rat, cow, pig, horse, dog, chicken and X. tropicalis was relatively low, making it difficult to use such comparisons to identify putative regulatory elements. However, microinjected promoter constructs were very active in oocytes and the minimal promoter could be narrowed by PCR-mediated deletion to a region as short as 63 base pairs. Additional experiments using a series of site-specific promoter mutants identified two cis-elements within the 63 base pair minimal promoter that were critical for activity. Both elements (A and B were specifically recognized by proteins present in crude oocyte extracts based on oligonucleotide competition assays. The activity of promoter constructs in oocytes and in transfected somatic Xenopus XLK-WG kidney epithelial cells was quite different, indicating that the two cell types are not functionally equivalent and are not interchangeable as assay systems. CONCLUSIONS: Overall the results provide the first detailed characterization of the organization of a germ cell-specific Xenopus promoter and demonstrate the feasibility of using immature frog oocytes as an assay system for dissecting the biochemistry of germ cell gene regulation.

  3. After the slippery slope: Dutch experiences on regulating active euthanasia.

    Science.gov (United States)

    Boer, Theo A

    2003-01-01

    "When a country legalizes active euthanasia, it puts itself on a slippery slope from where it may well go further downward." If true, this is a forceful argument in the battle of those who try to prevent euthanasia from becoming legal. The force of any slippery slope argument, however, is by definition limited by its reference to future developments which cannot empirically be sustained. Experience in the Netherlands--where a law regulating active euthanasia was accepted in April 2001--may shed light on the strengths as well as the weaknesses of the slippery slope argument in the context of the euthanasia debate. This paper consists of three parts. First, it clarifies the Dutch legislation on euthanasia and explains the cultural context in which it originated. Second, it looks at the argument of the slippery slope. A logical and an empirical version are distinguished, and the latter, though philosophically less interesting, proves to be most relevant in the discussion on euthanasia. Thirdly, it addresses the question whether Dutch experiences in the process of legalizing euthanasia justify the fear of the slippery slope. The conclusion is that Dutch experiences justify some caution.

  4. Regulation of invadopodia formation and activity by CD147

    Science.gov (United States)

    Grass, G. Daniel; Bratoeva, Momka; Toole, Bryan P.

    2012-01-01

    A defining feature of malignant tumor progression is cellular penetration through the basement membrane and interstitial matrices that separate various cellular compartments. Accumulating evidence supports the notion that invasive cells employ specialized structures termed invadopodia to breach these structural barriers. Invadopodia are actin-based, lipid-raft-enriched membrane protrusions containing membrane-type-1 matrix metalloproteinase (MT1-MMP; also known as matrix metalloproteinase 14; MMP14) and several signaling proteins. CD147 (emmprin, basigin), an immunoglobulin superfamily protein that is associated with tumor invasion and metastasis, induces the synthesis of various matrix metalloproteinases in many systems. In this study we show that upregulation of CD147 is sufficient to induce MT1-MMP expression, invasiveness and formation of invadopodia-like structures in non-transformed, non-invasive, breast epithelial cells. We also demonstrate that CD147 and MT1-MMP are in close proximity within these invadopodia-like structures and co-fractionate in membrane compartments with the properties of lipid rafts. Moreover, manipulation of CD147 levels in invasive breast carcinoma cells causes corresponding changes in MT1-MMP expression, invasiveness and invadopodia formation and activity. These findings indicate that CD147 regulates invadopodia formation and activity, probably through assembly of MT1-MMP-containing complexes within lipid-raft domains of the invadopodia. PMID:22389410

  5. Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity

    Directory of Open Access Journals (Sweden)

    Jeon Hyejin

    2012-06-01

    Full Text Available Abstract Background Plasminogen activator inhibitor type 1 (PAI-1 is the primary inhibitor of urokinase type plasminogen activators (uPA and tissue type plasminogen activators (tPA, which mediate fibrinolysis. PAI-1 is also involved in the innate immunity by regulating cell migration and phagocytosis. However, little is known about the role of PAI-1 in the central nervous system. Methods In this study, we identified PAI-1 in the culture medium of mouse mixed glial cells by liquid chromatography and tandem mass spectrometry. Secretion of PAI-1 from glial cultures was detected by ELISA and western blotting analysis. Cell migration was evaluated by in vitro scratch-wound healing assay or Boyden chamber assay and an in vivo stab wound injury model. Phagocytic activity was measured by uptake of zymosan particles. Results The levels of PAI-1 mRNA and protein expression were increased by lipopolysaccharide and interferon-γ stimulation in both microglia and astrocytes. PAI-1 promoted the migration of microglial cells in culture via the low-density lipoprotein receptor-related protein (LRP 1/Janus kinase (JAK/signal transducer and activator of transcription (STAT1 axis. PAI-1 also increased microglial migration in vivo when injected into mouse brain. PAI-1-mediated microglial migration was independent of protease inhibition, because an R346A mutant of PAI-1 with impaired PA inhibitory activity also promoted microglial migration. Moreover, PAI-1 was able to modulate microglial phagocytic activity. PAI-1 inhibited microglial engulfment of zymosan particles in a vitronectin- and Toll-like receptor 2/6-dependent manner. Conclusion Our results indicate that glia-derived PAI-1 may regulate microglial migration and phagocytosis in an autocrine or paracrine manner. This may have important implications in the regulation of brain microglial activities in health and disease.

  6. Gonadotropin Regulation of Retinoic Acid Activity in the Testis

    Directory of Open Access Journals (Sweden)

    Seyedmehdi Nourashrafeddin

    2018-02-01

    Full Text Available Initiation of spermatogenesis in primates is triggered at puberty by an increase in gonadotropins; i.e., follicle-stimulating hormone (FSH and luteinizing hormone (LH. Prior to puberty, testis of the monkey contains only undifferentiated germ cells. However, sermatogonial differentiation and spermatogenesis may be initiated prior to puberty after stimulation with exogenous LH and FSH. Retinoic acid (RA signaling is considered to be a major component that drives spermatogonial differentiation. We were interested in evaluating the relative role of LH and FSH, either alone or in combination, in regulating the retinoic acid signaling in monkey testis. Sixteen juvenile male rhesus monkeys (Macaca mulatta were infused with intermittent recombinant single chain human LH (schLH or recombinant human FSH (rhFSH or a combination of both for 11 days. We then analyzed the expression of the several putative RA signaling pathway related genes; i.e. RDH10, RDH11, ALDH1A1, ALDH1A2, CYP26B1, CRABP1, CRABP2, STRA6, STRA8 in the testis after 11 days of stimulation with vehicle, LH, FSH and combination LH/FSH using quantitative real-time PCR (qPCR. The qPCR results analysis showed that administration of gonadotropins affected a significant change in expression of some RA signaling related genes in the monkey testis. The gonadotropins, either alone or in combination dramatically increased expression of CRABP2 (p≤0.001, whereas there was a decrease in ALDH1A2 expression (p≤0.001. Moreover, combined gonadotropin treatment led to the significant decrease in CRABP1 expression (p≤0.05. These findings are the first evidence that the activity of retinoic acid signaling in the monkey testis is regulated through gonadotropins (LH/FSH levels.

  7. Characteristic phasic evolution of convulsive seizure in PCDH19-related epilepsy.

    Science.gov (United States)

    Ikeda, Hiroko; Imai, Katsumi; Ikeda, Hitoshi; Shigematsu, Hideo; Takahashi, Yukitoshi; Inoue, Yushi; Higurashi, Norimichi; Hirose, Shinichi

    2016-03-01

    PCDH19-related epilepsy is a genetic disorder that was first described in 1971, then referred to as "epilepsy and mental retardation limited to females". PCDH19 has recently been identified as the responsible gene, but a detailed characterization of the seizure manifestation based on video-EEG recording is still limited. The purpose of this study was to elucidate features of the seizure semiology in children with PCDH19-related epilepsy. To do this, ictal video-EEG recordings of 26 convulsive seizures in three girls with PCDH19-related epilepsy were analysed. All seizures occurred in clusters, mainly during sleep accompanied by fever. The motor manifestations consisted of six sequential phases: "jerk", "reactive", "mild tonic", "fluttering", "mild clonic", and "postictal". Some phases were brief or lacking in some seizures, whereas others were long or pronounced. In the reactive phase, the patients looked fearful or startled with sudden jerks and turned over reactively. The tonic and clonic components were less intense compared with those of typical tonic-clonic seizures in other types of epilepsy. The fluttering phase was characterised initially by asymmetric, less rhythmic, and less synchronous tremulous movement and was then followed by the subtle clonic phase. Subtle oral automatism was observed in the postictal phase. The reactive, mild tonic, fluttering and mild clonic phases were most characteristic of seizures of PCDH19-related epilepsy. Ictal EEG started bilaterally and was symmetric in some patients but asymmetric in others. It showed asymmetric rhythmic discharges in some seizures at later phases. The electroclinical pattern of the phasic evolution of convulsive seizure suggests a focal onset seizure with secondary generalisation. Based on our findings, we propose that the six unique sequential phases in convulsive seizures suggest the diagnosis of PCDH19-related epilepsy when occurring in clusters with or without high fever in girls. [Published with

  8. Phasic or terminal detrusor overactivity in women: age, urodynamic findings and sphincter behavior relationships

    Directory of Open Access Journals (Sweden)

    Françoise A. Valentini

    2011-12-01

    Full Text Available OBJECTIVES: To search for relationships between phasic (P and terminal (T DO with age, urodynamic findings and sphincter behavior during involuntary detrusor contraction in woman. MATERIALS AND METHODS: Urodynamic studies (triple lumen catheter 7F, seated position of 164 successive women referred for LUTS with diagnosis of DO were reviewed. Patients were stratified in 4 sub-groups: pre- (18-44y, peri- (45-54 y, post-menopause (55-74 y and oldest old (≥ 75 y. The urethral sensor was positioned at the level of the maximum urethral closure pressure for sphincter behavior analysis. A variation of at least 5 cmH2O in pressure (detrusor or urethra was chosen to assert DO or sphincter response. Sphincter response was classified as relaxation (re before or during DO, or steady (st. RESULTS: Occurrence of P and TDO was similar: 77 P and 87 T. The PDO group was significantly younger (p = 0.0003. TDO was more frequent in patients with a history of neurological disease. The percentage of PDO remained almost constant in age groups, while that of TDO increased with age from 6.7% to 23.2% (p = 0.0013. Uninhibited contraction occurred at a smaller bladder volume in the P group: 149 ± 95 vs. 221 ± 113 mL (p < 0.0001. Steady sphincter predominated in the TDO subgroup: 45.9% vs. 32.1% and increased significantly in each DO sub-group of ³ 75y. CONCLUSION: Steady sphincter during both P and TDO, and occurrence of TDO appear as specific of aging. The last result could be related to structural changes in the detrusor muscle with aging.

  9. Regulation of AMP-activated protein kinase by natural and synthetic activators

    Directory of Open Access Journals (Sweden)

    David Grahame Hardie

    2016-01-01

    Full Text Available The AMP-activated protein kinase (AMPK is a sensor of cellular energy status that is almost universally expressed in eukaryotic cells. While it appears to have evolved in single-celled eukaryotes to regulate energy balance in a cell-autonomous manner, during the evolution of multicellular animals its role has become adapted so that it also regulates energy balance at the whole body level, by responding to hormones that act primarily on the hypothalamus. AMPK monitors energy balance at the cellular level by sensing the ratios of AMP/ATP and ADP/ATP, and recent structural analyses of the AMPK heterotrimer that have provided insight into the complex mechanisms for these effects will be discussed. Given the central importance of energy balance in diseases that are major causes of morbidity or death in humans, such as type 2 diabetes, cancer and inflammatory disorders, there has been a major drive to develop pharmacological activators of AMPK. Many such activators have been described, and the various mechanisms by which these activate AMPK will be discussed. A particularly large class of AMPK activators are natural products of plants derived from traditional herbal medicines. While the mechanism by which most of these activate AMPK has not yet been addressed, I will argue that many of them may be defensive compounds produced by plants to deter infection by pathogens or grazing by insects or herbivores, and that many of them will turn out to be inhibitors of mitochondrial function.

  10. Harmonisation of regulations on back-end activities - WENRA

    International Nuclear Information System (INIS)

    Hedberg, B.; Theis, S.

    2014-01-01

    The Western European Nuclear Regulators Association (WENRA) was established in 1999. The main objectives at that time were to develop a common approach to nuclear safety in Europe and to provide an independent capability to examine nuclear safety in applicant countries. Two working groups were launched to harmonise safety approaches between countries in Europe, the Reactor Harmonisation Working Group (RHWG) and the Working Group on Waste and Decommissioning (WGWD). In response to the events in Japanese reactors following the tsunami in 2011 WENRA established the contents of the 'NPP stress test'. Recent WENRA activities are concerned with inspection practices and research reactors. The WGWD has to date developed Safety Reference Levels (SRL) reports for decommissioning and storage according to its original mandate (WENRA, 2011, 2012a). WENRA members have experienced a benchmarking process and established national action plans for the modification of their national legal systems and practices according to benchmarking results. WGWD is currently working on developing a SRL report for disposal facilities for radioactive waste. A first draft version with SRLs for disposal was published in November 2012 on WENRA's web page, for comments from stakeholders. This paper presents the current status of development and elaborates on the role of WENRA WGWD work in harmonising approaches in Europe regarding development of the safety case for disposal of spent fuel and radioactive waste. (authors)

  11. Distinct mechanisms regulate Lck spatial organization in activated T cells

    Directory of Open Access Journals (Sweden)

    Natasha eKapoor-Kaushik

    2016-03-01

    Full Text Available Phosphorylation of the T cell receptor (TCR by the kinase Lck is the first detectable signaling event upon antigen engagement. The distribution of Lck within the plasma membrane, its conformational state, kinase activity and protein interactions all contribute to determine how efficiently Lck phosphorylates the engaged TCR. Here we used cross-correlation raster image spectroscopy (ccRICS and photoactivated localization microscopy (PALM to identify two mechanisms of Lck clustering: an intrinsic mechanism of Lck clustering induced by locking Lck in its open conformation, and an extrinsic mechanism of clustering controlled by the phosphorylation of tyrosine 192, which regulates the affinity of Lck SH2 domain. Both mechanisms of clustering were differently affected by the absence of the kinase Zap70 or the adaptor Lat. We further observed that the adaptor TSAd bound to and promoted the diffusion of Lck when it is phosphorylated on tyrosine 192. Our data suggest that while Lck open conformation drives aggregation and clustering, the spatial organization of Lck is further controlled by signaling events downstream of TCR phosphorylation.

  12. Synaptic activity regulates AMPA receptor trafficking through different recycling pathways

    Science.gov (United States)

    Zheng, Ning; Jeyifous, Okunola; Munro, Charlotte; Montgomery, Johanna M; Green, William N

    2015-01-01

    Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. In this study, we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites. DOI: http://dx.doi.org/10.7554/eLife.06878.001 PMID:25970033

  13. AMP-activated protein kinase phosphorylates CtBP1 and down-regulates its activity

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae-Hwan; Choi, Soo-Youn; Kang, Byung-Hee; Lee, Soon-Min [National Creative Research Center for Epigenome Reprogramming Network, Departments of Biomedical Sciences and Biochemistry and Molecular Biology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Park, Hyung Soon; Kang, Gum-Yong; Bang, Joo Young [Center for Biomedical Mass Spectrometry, Diatech Korea Co., Ltd., Seoul (Korea, Republic of); Cho, Eun-Jung [National Research Laboratory for Chromatin Dynamics, College of Pharmacy, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Youn, Hong-Duk, E-mail: hdyoun@snu.ac.kr [National Creative Research Center for Epigenome Reprogramming Network, Departments of Biomedical Sciences and Biochemistry and Molecular Biology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence and Technology, Seoul National University, Seoul (Korea, Republic of)

    2013-02-01

    Highlights: ► AMPK phosphorylates CtBP1 on serine 158. ► AMPK-mediated phosphorylation of CtBP1 causes the ubiquitination and nuclear export of CtBP1. ► AMPK downregulates the CtBP1-mediated repression of Bax transcription. -- Abstract: CtBP is a transcriptional repressor which plays a significant role in the regulation of cell proliferation and tumor progression. It was reported that glucose withdrawal causes induction of Bax due to the dissociation of CtBP from the Bax promoter. However, the precise mechanism involved in the regulation of CtBP still remains unclear. In this study, we found that an activated AMP-activated protein kinase (AMPK) phosphorylates CtBP1 on Ser-158 upon metabolic stresses. Moreover, AMPK-mediated phosphorylation of CtBP1 (S158) attenuates the repressive function of CtBP1. We also confirmed that triggering activation of AMPK by various factors resulted in an increase of Bax gene expression. These findings provide connections of AMPK with CtBP1-mediated regulation of Bax expression for cell death under metabolic stresses.

  14. A Rewriting Framework and Logic for Activities Subject to Regulations

    Science.gov (United States)

    2015-02-28

    Regulations may be imposed by multiple governmental agencies as well as by institutional policies and protocols. Due to the complexity of both regulations and...positive number and decrements it; (3) A 0-test ri instruction is a branching instruction leading to one state if ri contains zero and to another state... insurance scenario discussed in (LMS09). De Young et al. describe in (DGJ+10) the challenges of formally specifying the temporal properties of regulations

  15. Abscisic acid-dependent multisite phosphorylation regulates the activity of a transcription activator AREB1.

    Science.gov (United States)

    Furihata, Takashi; Maruyama, Kyonoshin; Fujita, Yasunari; Umezawa, Taishi; Yoshida, Riichiro; Shinozaki, Kazuo; Yamaguchi-Shinozaki, Kazuko

    2006-02-07

    bZIP-type transcription factors AREBs/ABFs bind an abscisic acid (ABA)-responsive cis-acting element named ABRE and transactivate downstream gene expression in Arabidopsis. Because AREB1 overexpression could not induce downstream gene expression, activation of AREB1 requires ABA-dependent posttranscriptional modification. We confirmed that ABA activated 42-kDa kinase activity, which, in turn, phosphorylated Ser/Thr residues of R-X-X-S/T sites in the conserved regions of AREB1. Amino acid substitutions of R-X-X-S/T sites to Ala suppressed transactivation activity, and multiple substitution of these sites resulted in almost complete suppression of transactivation activity in transient assays. In contrast, substitution of the Ser/Thr residues to Asp resulted in high transactivation activity without exogenous ABA application. A phosphorylated, transcriptionally active form was achieved by substitution of Ser/Thr in all conserved R-X-X-S/T sites to Asp. Transgenic plants overexpressing the phosphorylated active form of AREB1 expressed many ABA-inducible genes, such as RD29B, without ABA treatment. These results indicate that the ABA-dependent multisite phosphorylation of AREB1 regulates its own activation in plants.

  16. Regulation of platelet activating factor receptor coupled phosphoinositide-specific phospholipase C activity

    International Nuclear Information System (INIS)

    Morrison, W.J.

    1988-01-01

    The major objectives of this study were two-fold. The first was to establish whether binding of platelet activating factor (PAF) to its receptor was integral to the stimulation of polyphosphoinositide-specific phospholipase C (PLC) in rabbit platelets. The second was to determine regulatory features of this receptor-coupled mechanism. [ 3 H]PAF binding demonstrated two binding sites, a high affinity site with a inhibitory constant (Ki) of 2.65 nM and a low affinity site with a Ki of 0.80 μM. PAF receptor coupled activation of phosphoinositide-specific PLC was studied in platelets which were made refractory, by short term pretreatments, to either PAF or thrombin. Saponin-permeabilized rabbit platelets continue to regulate the mechanism(s) coupling PAF receptors to PLC stimulation. However, TRPγS and GDPβS, which affect guanine nucleotide regulatory protein functions, were unable to modulate the PLC activity to any appreciable extent as compared to PAF. The possible involvement of protein kinase C (PKC) activation in regulating PAF-stimulated PLC activity was studied in rabbit platelets pretreated with staurosporine followed by pretreatments with PAF or phorbol 12-myristate 13-acetate (PMA)

  17. 30 CFR 285.1000 - What activities does this subpart regulate?

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 2 2010-07-01 2010-07-01 false What activities does this subpart regulate? 285.1000 Section 285.1000 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR... Activities § 285.1000 What activities does this subpart regulate? (a) This subpart provides the general...

  18. Vinculin contributes to Cell Invasion by Regulating Contractile Activation

    Science.gov (United States)

    Mierke, Claudia Tanja

    2008-07-01

    Vinculin is a component of the focal adhesion complex and is described as a mechano-coupling protein connecting the integrin receptor and the actin cytoskeleton. Vinculin knock-out (k.o.) cells (vin-/-) displayed increased migration on a 2-D collagen- or fibronectin-coated substrate compared to wildtype cells, but the role of vinculin in cell migration through a 3-D connective tissue is unknown. We determined the invasiveness of established tumor cell lines using a 3-D collagen invasion assay. Gene expression analysis of 4 invasive and 4 non-invasive tumor cell lines revealed that vinculin expression was significantly increased in invasive tumor cell lines. To analyze the mechanisms by which vinculin increased cell invasion in a 3-D gel, we studied mouse embryonic fibroblasts wildtype and vin-/- cells. Wildtype cells were 3-fold more invasive compared vin-/- cells. We hypothesized that the ability to generate sufficient traction forces is a prerequisite for tumor cell migration in a 3-D connective tissue matrix. Using traction microscopy, we found that wildtype exerted 3-fold higher tractions on fibronectin-coated polyacrylamide gels compared to vin-/- cells. These results show that vinculin controls two fundamental functions that lead to opposite effects on cell migration in a 2-D vs. a 3-D environment: On the one hand, vinculin stabilizes the focal adhesions (mechano-coupling function) and thereby reduces motility in 2-D. On the other hand, vinculin is also a potent activator of traction generation (mechano-regulating function) that is important for cell invasion in a 3-D environment.

  19. Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons.

    Science.gov (United States)

    Yapo, Cedric; Nair, Anu G; Clement, Lorna; Castro, Liliana R; Hellgren Kotaleski, Jeanette; Vincent, Pierre

    2017-12-15

    Brief dopamine events are critical actors of reward-mediated learning in the striatum; the intracellular cAMP-protein kinase A (PKA) response of striatal medium spiny neurons to such events was studied dynamically using a combination of biosensor imaging in mouse brain slices and in silico simulations. Both D1 and D2 medium spiny neurons can sense brief dopamine transients in the sub-micromolar range. While dopamine transients profoundly change cAMP levels in both types of medium spiny neurons, the PKA-dependent phosphorylation level remains unaffected in D2 neurons. At the level of PKA-dependent phosphorylation, D2 unresponsiveness depends on protein phosphatase-1 (PP1) inhibition by DARPP-32. Simulations suggest that D2 medium spiny neurons could detect transient dips in dopamine level. The phasic release of dopamine in the striatum determines various aspects of reward and action selection, but the dynamics of the dopamine effect on intracellular signalling remains poorly understood. We used genetically encoded FRET biosensors in striatal brain slices to quantify the effect of transient dopamine on cAMP or PKA-dependent phosphorylation levels, and computational modelling to further explore the dynamics of this signalling pathway. Medium-sized spiny neurons (MSNs), which express either D 1 or D 2 dopamine receptors, responded to dopamine by an increase or a decrease in cAMP, respectively. Transient dopamine showed similar sub-micromolar efficacies on cAMP in both D1 and D2 MSNs, thus challenging the commonly accepted notion that dopamine efficacy is much higher on D 2 than on D 1 receptors. However, in D2 MSNs, the large decrease in cAMP level triggered by transient dopamine did not translate to a decrease in PKA-dependent phosphorylation level, owing to the efficient inhibition of protein phosphatase 1 by DARPP-32. Simulations further suggested that D2 MSNs can also operate in a 'tone-sensing' mode, allowing them to detect transient dips in basal dopamine

  20. Cognitive emotion regulation enhances aversive prediction error activity while reducing emotional responses.

    Science.gov (United States)

    Mulej Bratec, Satja; Xie, Xiyao; Schmid, Gabriele; Doll, Anselm; Schilbach, Leonhard; Zimmer, Claus; Wohlschläger, Afra; Riedl, Valentin; Sorg, Christian

    2015-12-01

    Cognitive emotion regulation is a powerful way of modulating emotional responses. However, despite the vital role of emotions in learning, it is unknown whether the effect of cognitive emotion regulation also extends to the modulation of learning. Computational models indicate prediction error activity, typically observed in the striatum and ventral tegmental area, as a critical neural mechanism involved in associative learning. We used model-based fMRI during aversive conditioning with and without cognitive emotion regulation to test the hypothesis that emotion regulation would affect prediction error-related neural activity in the striatum and ventral tegmental area, reflecting an emotion regulation-related modulation of learning. Our results show that cognitive emotion regulation reduced emotion-related brain activity, but increased prediction error-related activity in a network involving ventral tegmental area, hippocampus, insula and ventral striatum. While the reduction of response activity was related to behavioral measures of emotion regulation success, the enhancement of prediction error-related neural activity was related to learning performance. Furthermore, functional connectivity between the ventral tegmental area and ventrolateral prefrontal cortex, an area involved in regulation, was specifically increased during emotion regulation and likewise related to learning performance. Our data, therefore, provide first-time evidence that beyond reducing emotional responses, cognitive emotion regulation affects learning by enhancing prediction error-related activity, potentially via tegmental dopaminergic pathways. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Hepatitis C virus core protein regulates p300/CBP co-activation function. Possible role in the regulation of NF-AT1 transcriptional activity

    International Nuclear Information System (INIS)

    Gomez-Gonzalo, Marta; Benedicto, Ignacio; Carretero, Marta; Lara-Pezzi, Enrique; Maldonado-Rodriguez, Alejandra; Moreno-Otero, Ricardo; Lai, Michael M.C.; Lopez-Cabrera, Manuel

    2004-01-01

    Hepatitis C virus (HCV) core is a viral structural protein; it also participates in some cellular processes, including transcriptional regulation. However, the mechanisms of core-mediated transcriptional regulation remain poorly understood. Oncogenic virus proteins often target p300/CBP, a known co-activator of a wide variety of transcription factors, to regulate the expression of cellular and viral genes. Here we demonstrate, for the first time, that HCV core protein interacts with p300/CBP and enhances both its acetyl-transferase and transcriptional activities. In addition, we demonstrate that nuclear core protein activates the NH 2 -terminal transcription activation domain (TAD) of NF-AT1 in a p300/CBP-dependent manner. We propose a model in which core protein regulates the co-activation function of p300/CBP and activates NF-AT1, and probably other p300/CBP-regulated transcription factors, by a novel mechanism involving the regulation of the acetylation state of histones and/or components of the transcriptional machinery

  2. Flipped Classroom with Problem Based Activities: Exploring Self-Regulated Learning in a Programming Language Course

    Science.gov (United States)

    Çakiroglu, Ünal; Öztürk, Mücahit

    2017-01-01

    This study intended to explore the development of self-regulation in a flipped classroom setting. Problem based learning activities were carried out in flipped classrooms to promote self-regulation. A total of 30 undergraduate students from Mechatronic department participated in the study. Self-regulation skills were discussed through students'…

  3. 15 CFR 922.72 - Prohibited or otherwise regulated activities-Sanctuary-wide.

    Science.gov (United States)

    2010-01-01

    ... activities-Sanctuary-wide. 922.72 Section 922.72 Commerce and Foreign Trade Regulations Relating to Commerce... OCEAN AND COASTAL RESOURCE MANAGEMENT NATIONAL MARINE SANCTUARY PROGRAM REGULATIONS Channel Islands National Marine Sanctuary § 922.72 Prohibited or otherwise regulated activities—Sanctuary-wide. (a) Except...

  4. Calcium-Oxidant Signaling Network Regulates AMP-activated Protein Kinase (AMPK) Activation upon Matrix Deprivation*

    Science.gov (United States)

    Sundararaman, Ananthalakshmy; Amirtham, Usha; Rangarajan, Annapoorni

    2016-01-01

    The AMP-activated protein kinase (AMPK) has recently been implicated in anoikis resistance. However, the molecular mechanisms that activate AMPK upon matrix detachment remain unexplored. In this study, we show that AMPK activation is a rapid and sustained phenomenon upon matrix deprivation, whereas re-attachment to the matrix leads to its dephosphorylation and inactivation. Because matrix detachment leads to loss of integrin signaling, we investigated whether integrin signaling negatively regulates AMPK activation. However, modulation of focal adhesion kinase or Src, the major downstream components of integrin signaling, failed to cause a corresponding change in AMPK signaling. Further investigations revealed that the upstream AMPK kinases liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) contribute to AMPK activation upon detachment. In LKB1-deficient cells, we found AMPK activation to be predominantly dependent on CaMKKβ. We observed no change in ATP levels under detached conditions at early time points suggesting that rapid AMPK activation upon detachment was not triggered by energy stress. We demonstrate that matrix deprivation leads to a spike in intracellular calcium as well as oxidant signaling, and both these intracellular messengers contribute to rapid AMPK activation upon detachment. We further show that endoplasmic reticulum calcium release-induced store-operated calcium entry contributes to intracellular calcium increase, leading to reactive oxygen species production, and AMPK activation. We additionally show that the LKB1/CaMKK-AMPK axis and intracellular calcium levels play a critical role in anchorage-independent cancer sphere formation. Thus, the Ca2+/reactive oxygen species-triggered LKB1/CaMKK-AMPK signaling cascade may provide a quick, adaptable switch to promote survival of metastasizing cancer cells. PMID:27226623

  5. Regulation of nuclear and radiological activities; Reglementarea activitatilor nucleare si radiologice

    Energy Technology Data Exchange (ETDEWEB)

    Sidorencu, Angela; Vasilieva, Natalia; Buzdugan, Artur; Balan, Ionel [Agentia Nationala de Reglementare a Activitatilor Nucleare si Radiologice, Alecu Russo, 1, MD 2068, Chisinau (Moldova, Republic of)

    2012-08-15

    The paper presents a review of the Moldovan regulatory framework regarding nuclear and radiological activities and of the competence of state regulatory authority - the National Agency for the Regulation of Nuclear and Radiological Activities.

  6. The transcriptional activator GAL4-VP16 regulates the intra ...

    Indian Academy of Sciences (India)

    Activator also reduced the TBP dimer levels both in vitro and in vivo, suggesting the dimer may be a direct target of transcriptional activators. The transcriptional activator facilitated the dimer to monomer transition and activated monomers further to help TBP bind even the weaker TATA boxes stably. The overall stimulatory ...

  7. A decentralized control scheme for an effective coordination of phasic and tonic control in a snake-like robot

    International Nuclear Information System (INIS)

    Sato, Takahide; Kano, Takeshi; Ishiguro, Akio

    2012-01-01

    Autonomous decentralized control has attracted considerable attention because it enables us to understand the adaptive and versatile locomotion of animals and facilitates the construction of truly intelligent artificial agents. Thus far, we have developed a snake-like robot (HAUBOT I) that is driven by a decentralized control scheme based on a discrepancy function, which incorporates phasic control. In this paper, we investigate a decentralized control scheme in which phasic and tonic control are well coordinated, as an extension of our previous study. To verify the validity of the proposed control scheme, we apply it to a snake-like robot (HAUBOT II) that can adjust both the phase relationship between its body segments and the stiffness at each joint. The results indicate that the proposed control scheme enables the robot to exhibit remarkable real-time adaptability over various frictional and inclined terrains. These findings can potentially enable us to gain a deeper insight into the autonomous decentralized control mechanism underlying the adaptive and resilient locomotion of animals.

  8. Trophic Ecology of Benthic Marine Invertebrates with Bi-Phasic Life Cycles: What Are We Still Missing?

    Science.gov (United States)

    Calado, Ricardo; Leal, Miguel Costa

    2015-01-01

    The study of trophic ecology of benthic marine invertebrates with bi-phasic life cycles is critical to understand the mechanisms shaping population dynamics. Moreover, global climate change is impacting the marine environment at an unprecedented level, which promotes trophic mismatches that affect the phenology of these species and, ultimately, act as drivers of ecological and evolutionary change. Assessing the trophic ecology of marine invertebrates is critical to understanding maternal investment, larval survival to metamorphosis, post-metamorphic performance, resource partitioning and trophic cascades. Tools already available to assess the trophic ecology of marine invertebrates, including visual observation, gut content analysis, food concentration, trophic markers, stable isotopes and molecular genetics, are reviewed and their main advantages and disadvantages for qualitative and quantitative approaches are discussed. The challenges to perform the partitioning of ingestion, digestion and assimilation are discussed together with different approaches to address each of these processes for short- and long-term fingerprinting. Future directions for research on the trophic ecology of benthic marine invertebrates with bi-phasic life cycles are discussed with emphasis on five guidelines that will allow for systematic study and comparative meta-analysis to address important unresolved questions. © 2015 Elsevier Ltd. All rights reserved.

  9. Robust, synergistic regulation of human gene expression using TALE activators.

    Science.gov (United States)

    Maeder, Morgan L; Linder, Samantha J; Reyon, Deepak; Angstman, James F; Fu, Yanfang; Sander, Jeffry D; Joung, J Keith

    2013-03-01

    Artificial activators designed using transcription activator-like effector (TALE) technology have broad utility, but previous studies suggest that these monomeric proteins often exhibit low activities. Here we demonstrate that TALE activators can robustly function individually or in synergistic combinations to increase expression of endogenous human genes over wide dynamic ranges. These findings will encourage applications of TALE activators for research and therapy, and guide design of monomeric TALE-based fusion proteins.

  10. The State Regulation of Innovation Activity at the Present Stage

    Directory of Open Access Journals (Sweden)

    Qoqiauri Lamara G.

    2017-06-01

    Full Text Available The article discusses the necessity of state regulation in the field of development of innovations and technologies at the present stage. The main directions of the state innovation policies in developed countries of the world are studied and analyzed. Special attention is paid to the objectives of the national strategy for development of science and innovations and to searching the ways for fulfilling this strategy. Apart from these specific problems, the work considers the issue of the state regulation and support of further introduction of innovations and increase of the so called “entrepreneurial” role of the state.

  11. Self-Regulated Learning and Perceived Health among University Students Participating in Physical Activity Classes

    Science.gov (United States)

    McBride, Ron E.; Altunsöz, Irmak Hürmeriç; Su, Xiaoxia; Xiang, Ping; Demirhan, Giyasettin

    2016-01-01

    The purpose of this study was to explore motivational indicators of self-regulated learning (SRL) and the relationship between self-regulation (SR) and perceived health among university students enrolled in physical activity (PA) classes. One hundred thirty-one Turkish students participating in physical education activity classes at two…

  12. 78 FR 19632 - Special Local Regulations; St. Thomas Carnival Watersport Activities, Charlotte Amalie Harbor; St...

    Science.gov (United States)

    2013-04-02

    ...-AA08 Special Local Regulations; St. Thomas Carnival Watersport Activities, Charlotte Amalie Harbor; St... proposes to establish a special local regulation on the waters of Charlotte Amalie Harbor in St Thomas, USVI during the St. Thomas Carnival Watersport Activities, a high speed boat race. The event is...

  13. DMPD: Receptor tyrosine kinases and the regulation of macrophage activation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14726496 Receptor tyrosine kinases and the regulation of macrophage activation. Cor...osine kinases and the regulation of macrophage activation. PubmedID 14726496 Title Receptor tyrosine...rell PH, Morrison AC, Lutz MA. J Leukoc Biol. 2004 May;75(5):731-7. Epub 2004 Jan 14. (.png) (.svg) (.html) (.csml) Show Receptor tyr

  14. Physical Activity, Self-Regulation, and Early Academic Achievement in Preschool Children

    Science.gov (United States)

    Becker, Derek R.; McClelland, Megan M.; Loprinzi, Paul; Trost, Stewart G.

    2014-01-01

    Research Findings: The present study investigated whether active play during recess was associated with self-regulation and academic achievement in a prekindergarten sample. A total of 51 children in classes containing approximately half Head Start children were assessed on self-regulation, active play, and early academic achievement. Path…

  15. Active Learning and Self-Regulation Enhance Student Teachers' Professional Competences

    Science.gov (United States)

    Virtanen, Päivi; Niemi, Hannele M.; Nevgi, Anne

    2017-01-01

    The study identifies the relationships between active learning, student teachers' self-regulated learning and professional competences. Further, the aim is to investigate how active learning promotes professional competences of student teachers with different self-regulation profiles. Responses from 422 student teachers to an electronic survey…

  16. In vitro production of growth regulators and phosphatase activity by ...

    African Journals Online (AJOL)

    The result showed that the population levels of phosphobacteria were higher in the rhizosphere soil of groundnut plant. Further, all the strains of phosphobacteria were able to produce phytohormones and phosphatase enzyme under in vitro conditions. Keywords: In vitro, phosphobacteria, growth regulators ...

  17. Dynamics of study strategies and teacher regulation in virtual patient learning activities: a cross sectional survey.

    Science.gov (United States)

    Edelbring, Samuel; Wahlström, Rolf

    2016-04-23

    Students' self-regulated learning becomes essential with increased use of exploratory web-based activities such as virtual patients (VPs). The purpose was to investigate the interplay between students' self-regulated learning strategies and perceived benefit in VP learning activities. A cross-sectional study (n = 150) comparing students' study strategies and perceived benefit of a virtual patient learning activity in a clinical clerkship preparatory course. Teacher regulation varied among three settings and was classified from shared to strong. These settings were compared regarding their respective relations between regulation strategies and perceived benefit of the virtual patient activity. Self-regulation learning strategy was generally associated with perceived benefit of the VP activities (rho 0.27, p strategies can increase the value of flexible web-based learning resources to students.

  18. Commission of energy regulation. 2004 activity report; Commission de regulation de l'energie. Rapport d'activite 2004

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2004-07-01

    The commission of energy regulation (CRE) is an independent administrative authority in charge of the control of the operation of gas and electricity markets. This document is the fifth activity report of CRE and covers the July 1, 2003 - June 30, 2004 period, which corresponds to the era of opening of energy markets as a consequence of the enforcement of the June 26, 2003 European directive. In the framework of the stakes made by energy markets liberalization, this document presents the situation of the gas and electricity markets during this period (European framework, regulation of both markets, public utility mission..) and describes CRE's means for the monitoring of these markets. (J.S.)

  19. Exocytosis of ATP From Astrocytes Modulates Phasic and Tonic Inhibition in the Neocortex

    Science.gov (United States)

    Rasooli-Nejad, Seyed; Andrew, Jemma; Haydon, Philip G.; Pankratov, Yuriy

    2014-01-01

    Communication between neuronal and glial cells is important for many brain functions. Astrocytes can modulate synaptic strength via Ca2+-stimulated release of various gliotransmitters, including glutamate and ATP. A physiological role of ATP release from astrocytes was suggested by its contribution to glial Ca2+-waves and purinergic modulation of neuronal activity and sleep homeostasis. The mechanisms underlying release of gliotransmitters remain uncertain, and exocytosis is the most intriguing and debated pathway. We investigated release of ATP from acutely dissociated cortical astrocytes using “sniff-cell” approach and demonstrated that release is vesicular in nature and can be triggered by elevation of intracellular Ca2+ via metabotropic and ionotropic receptors or direct UV-uncaging. The exocytosis of ATP from neocortical astrocytes occurred in the millisecond time scale contrasting with much slower nonvesicular release of gliotransmitters via Best1 and TREK-1 channels, reported recently in hippocampus. Furthermore, we discovered that elevation of cytosolic Ca2+ in cortical astrocytes triggered the release of ATP that directly activated quantal purinergic currents in the pyramidal neurons. The glia-driven burst of purinergic currents in neurons was followed by significant attenuation of both synaptic and tonic inhibition. The Ca2+-entry through the neuronal P2X purinoreceptors led to phosphorylation-dependent down-regulation of GABAA receptors. The negative purinergic modulation of postsynaptic GABA receptors was accompanied by small presynaptic enhancement of GABA release. Glia-driven purinergic modulation of inhibitory transmission was not observed in neurons when astrocytes expressed dn-SNARE to impair exocytosis. The astrocyte-driven purinergic currents and glia-driven modulation of GABA receptors were significantly reduced in the P2X4 KO mice. Our data provide a key evidence to support the physiological importance of exocytosis of ATP from astrocytes

  20. Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex.

    Directory of Open Access Journals (Sweden)

    Ulyana Lalo

    2014-01-01

    Full Text Available Communication between neuronal and glial cells is important for many brain functions. Astrocytes can modulate synaptic strength via Ca(2+-stimulated release of various gliotransmitters, including glutamate and ATP. A physiological role of ATP release from astrocytes was suggested by its contribution to glial Ca(2+-waves and purinergic modulation of neuronal activity and sleep homeostasis. The mechanisms underlying release of gliotransmitters remain uncertain, and exocytosis is the most intriguing and debated pathway. We investigated release of ATP from acutely dissociated cortical astrocytes using "sniff-cell" approach and demonstrated that release is vesicular in nature and can be triggered by elevation of intracellular Ca(2+ via metabotropic and ionotropic receptors or direct UV-uncaging. The exocytosis of ATP from neocortical astrocytes occurred in the millisecond time scale contrasting with much slower nonvesicular release of gliotransmitters via Best1 and TREK-1 channels, reported recently in hippocampus. Furthermore, we discovered that elevation of cytosolic Ca(2+ in cortical astrocytes triggered the release of ATP that directly activated quantal purinergic currents in the pyramidal neurons. The glia-driven burst of purinergic currents in neurons was followed by significant attenuation of both synaptic and tonic inhibition. The Ca(2+-entry through the neuronal P2X purinoreceptors led to phosphorylation-dependent down-regulation of GABAA receptors. The negative purinergic modulation of postsynaptic GABA receptors was accompanied by small presynaptic enhancement of GABA release. Glia-driven purinergic modulation of inhibitory transmission was not observed in neurons when astrocytes expressed dn-SNARE to impair exocytosis. The astrocyte-driven purinergic currents and glia-driven modulation of GABA receptors were significantly reduced in the P2X4 KO mice. Our data provide a key evidence to support the physiological importance of exocytosis of

  1. Activity-Dependent Regulation of Surface Glucose Transporter-3

    OpenAIRE

    Ferreira, Jainne M.; Burnett, Arthur L.; Rameau, Gerald A.

    2011-01-01

    Glucose transporter 3 (GLUT3) is the main facilitative glucose transporter in neurons. Glucose provides neurons with a critical energy source for neuronal activity. However, the mechanism by which neuronal activity controls glucose influx via GLUT3 is unknown. We investigated the influence of synaptic stimulation on GLUT3 surface expression and glucose import in primary cultured cortical and hippocampal neurons. Synaptic activity increased surface expression of GLUT3 leading to an elevation o...

  2. Active Learning and Self-Regulation Enhance Student Teachers’ Professional Competences

    OpenAIRE

    Virtanen, Päivi; Niemi, Hannele M.; Nevgi, Anne

    2017-01-01

    The study identifies the relationships between active learning, student teachers’ self-regulated learning and professional competences. Further, the aim is to investigate how active learning promotes professional competences of student teachers with different self-regulation profiles. Responses from 422 student teachers to an electronic survey were analysed using statistical methods. It was found that the use of active learning methods, such as goal-oriented and intentional learning as well a...

  3. Insulin signaling regulates fatty acid catabolism at the level of CoA activation.

    Directory of Open Access Journals (Sweden)

    Xiaojun Xu

    2012-01-01

    Full Text Available The insulin/IGF signaling pathway is a highly conserved regulator of metabolism in flies and mammals, regulating multiple physiological functions including lipid metabolism. Although insulin signaling is known to regulate the activity of a number of enzymes in metabolic pathways, a comprehensive understanding of how the insulin signaling pathway regulates metabolic pathways is still lacking. Accepted knowledge suggests the key regulated step in triglyceride (TAG catabolism is the release of fatty acids from TAG via the action of lipases. We show here that an additional, important regulated step is the activation of fatty acids for beta-oxidation via Acyl Co-A synthetases (ACS. We identify pudgy as an ACS that is transcriptionally regulated by direct FOXO action in Drosophila. Increasing or reducing pudgy expression in vivo causes a decrease or increase in organismal TAG levels respectively, indicating that pudgy expression levels are important for proper lipid homeostasis. We show that multiple ACSs are also transcriptionally regulated by insulin signaling in mammalian cells. In sum, we identify fatty acid activation onto CoA as an important, regulated step in triglyceride catabolism, and we identify a mechanistic link through which insulin regulates lipid homeostasis.

  4. Regulation of calcium homeostasis in activated human neutrophils ...

    African Journals Online (AJOL)

    Objectives. The objectives of the current study were to: (i) present an integrated model for the restoration of calcium homeostasis in activated human neutrophils based on current knowledge and recent research; and (ii) identify potential targets for the modulation of calcium fluxes in activated neutrophils based on this model ...

  5. Examining "Active" Procrastination from a Self-Regulated Learning Perspective

    Science.gov (United States)

    Cao, Li

    2012-01-01

    This study examined the notion that active procrastinators are a positive type of procrastinators who possess desirable characteristics similar to non-procrastinators, but different from the traditional passive procrastinators. A two-step procedure was followed to categorise university students (N = 125) as active procrastinators, passive…

  6. Recent achievements in regulating nuclear power activities in taiwan

    International Nuclear Information System (INIS)

    Ouyang, M.S.

    2006-01-01

    Full text: The energy resources in Taiwan are very scarce with more than 98% of the fuel sources imported from foreign countries. The nuclear power became essential because of its stability and economy in price. There are six operating nuclear power units in Taiwan, and two more advanced boiling water reactor units under construction. As the country's nuclear power still plays an important role, the Atomic Energy Council (AEC) devotes its great efforts working on reactor safety regulation, radiation protection, nuclear security, nuclear emergency preparedness, nuclear waste management and environmental monitoring. Recent achievements of AEC on the above mentioned topics will be covered in this presentation

  7. Simulated shift work in rats perturbs multiscale regulation of locomotor activity

    Science.gov (United States)

    Hsieh, Wan-Hsin; Escobar, Carolina; Yugay, Tatiana; Lo, Men-Tzung; Pittman-Polletta, Benjamin; Salgado-Delgado, Roberto; Scheer, Frank A. J. L.; Shea, Steven A.; Buijs, Ruud M.; Hu, Kun

    2014-01-01

    Motor activity possesses a multiscale regulation that is characterized by fractal activity fluctuations with similar structure across a wide range of timescales spanning minutes to hours. Fractal activity patterns are disturbed in animals after ablating the master circadian pacemaker (suprachiasmatic nucleus, SCN) and in humans with SCN dysfunction as occurs with aging and in dementia, suggesting the crucial role of the circadian system in the multiscale activity regulation. We hypothesized that the normal synchronization between behavioural cycles and the SCN-generated circadian rhythms is required for multiscale activity regulation. To test the hypothesis, we studied activity fluctuations of rats in a simulated shift work protocol that was designed to force animals to be active during the habitual resting phase of the circadian/daily cycle. We found that these animals had gradually decreased mean activity level and reduced 24-h activity rhythm amplitude, indicating disturbed circadian and behavioural cycles. Moreover, these animals had disrupted fractal activity patterns as characterized by more random activity fluctuations at multiple timescales from 4 to 12 h. Intriguingly, these activity disturbances exacerbated when the shift work schedule lasted longer and persisted even in the normal days (without forced activity) following the shift work. The disrupted circadian and fractal patterns resemble those of SCN-lesioned animals and of human patients with dementia, suggesting a detrimental impact of shift work on multiscale activity regulation. PMID:24829282

  8. Light-regulation of enzyme activity in anacystis nidulans (Richt.).

    Science.gov (United States)

    Duggan, J X; Anderson, L E

    1975-01-01

    The effect of light on the levels of activity of six enzymes which are light-modulated in higher plants was examined in the photosynthetic procaryot Anacystis nidulans. Ribulose-5-phosphate kinase (EC 2.7.1.19) was found to be light-activated in vivo and dithiothreitol-activated in vitro while glucose-6-phosphate dehydrogenase (EC 1.1.1.49) was light-inactivated and dithiothreitol-inactivated. The enzymes fructose-1,6-diphosphate phosphatase (EC 3.1.3.11), sedoheptulose-1,7-diphosphate phosphatase, NAD- and NADP-linked glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12; EC 1.2.1.13) were not affected by light treatment of the intact algae, but sedoheptulose-diphosphate phosphatase and the glyceraldehyde-3-phosphate dehydrogenases were dithiothreitol-activated in crude extracts. Light apparently controls the activity of the reductive and oxidative pentose phosphate pathway in this photosynthetic procaryot as in higher plants, through a process which probably involves reductive modulation of enzyme activity.

  9. Phasic dopamine as a prediction error of intrinsic and extrinsic reinforcements driving both action acquisition and reward maximization: a simulated robotic study.

    Science.gov (United States)

    Mirolli, Marco; Santucci, Vieri G; Baldassarre, Gianluca

    2013-03-01

    An important issue of recent neuroscientific research is to understand the functional role of the phasic release of dopamine in the striatum, and in particular its relation to reinforcement learning. The literature is split between two alternative hypotheses: one considers phasic dopamine as a reward prediction error similar to the computational TD-error, whose function is to guide an animal to maximize future rewards; the other holds that phasic dopamine is a sensory prediction error signal that lets the animal discover and acquire novel actions. In this paper we propose an original hypothesis that integrates these two contrasting positions: according to our view phasic dopamine represents a TD-like reinforcement prediction error learning signal determined by both unexpected changes in the environment (temporary, intrinsic reinforcements) and biological rewards (permanent, extrinsic reinforcements). Accordingly, dopamine plays the functional role of driving both the discovery and acquisition of novel actions and the maximization of future rewards. To validate our hypothesis we perform a series of experiments with a simulated robotic system that has to learn different skills in order to get rewards. We compare different versions of the system in which we vary the composition of the learning signal. The results show that only the system reinforced by both extrinsic and intrinsic reinforcements is able to reach high performance in sufficiently complex conditions. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Emotion regulation strategies: procedure modeling of J. Gross and cultural activity approach

    Directory of Open Access Journals (Sweden)

    Elena I. Pervichko

    2015-03-01

    Full Text Available The first part of this paper argued the desirability of structural-dynamic model of emotion regulation in the theoretical and methodological framework of cultural activity paradigm with the construction of a psychologically-based typology of emotion regulation strategies in norm and pathology, and also psychological mechanisms enabling the regulation of emotions. This conclusion was based on the analysis of the basic concepts and paradigms in which the issue of emotion regulation is studied: cognitive and psychoanalytic approaches, concept and emotional development of emotional intelligence, cultural activity approach. The paper considers the procedure model of emotion regulation by J. Gross, identifies emotion regulation strategies and evaluates their effectiveness. The possibilities and limitations of the model. Based on the review of the today research the conclusion is arrived at that the existing labels on a wide range of regulatory strategies remain an open issue.The author’s definition of emotion regulation is drawn. Emotion regulation is deemed as a set of mental processes, psychological mechanisms and regulatory strategies that people use to preserve the capacity for productive activities in a situation of emotional stress; to ensure optimal impulse control and emotions; to maintain the excitement at the optimum level. The second part of this paper provides the general description of emotion regulation strategies, the approach to their typology, the psychological mechanisms of emotion regulation that lie in the basis of this typology, i.e. the main elements of the structural-dynamic model of emotion regulation. The work shows theoretical and methodological efficacy of empirical significance of signs and symbols and also personal reflection. The diagnostic system to allow empirically identify a wide range of emotion regulation strategies is suggested. The psychological mechanisms used by the subject to solve the problem of emotional

  11. Biological/Genetic Regulation of Physical Activity Level: Consensus from GenBioPAC.

    Science.gov (United States)

    Lightfoot, J Timothy; DE Geus, Eco J C; Booth, Frank W; Bray, Molly S; DEN Hoed, Marcel; Kaprio, Jaakko; Kelly, Scott A; Pomp, Daniel; Saul, Michael C; Thomis, Martine A; Garland, Theodore; Bouchard, Claude

    2018-04-01

    Physical activity unquestionably maintains and improves health; however, physical activity levels globally are low and not rising despite all the resources devoted to this goal. Attention in both the research literature and the public policy domain has focused on social-behavioral factors; however, a growing body of literature suggests that biological determinants play a significant role in regulating physical activity levels. For instance, physical activity level, measured in various manners, has a genetic component in both humans and nonhuman animal models. This consensus article, developed as a result of an American College of Sports Medicine-sponsored round table, provides a brief review of the theoretical concepts and existing literature that supports a significant role of genetic and other biological factors in the regulation of physical activity. Future research on physical activity regulation should incorporate genetics and other biological determinants of physical activity instead of a sole reliance on social and other environmental determinants.

  12. Nuclear translocation contributes to regulation of DNA excision repair activities

    DEFF Research Database (Denmark)

    Knudsen, Nina Østergaard; Andersen, Sofie Dabros; Lützen, Anne

    2009-01-01

    for regulation of nuclear import that is necessary for proper localization of the repair proteins. This review summarizes the current knowledge on nuclear import mechanisms of DNA excision repair proteins and provides a model that categorizes the import by different mechanisms, including classical nuclear import......DNA mutations are circumvented by dedicated specialized excision repair systems, such as the base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR) pathways. Although the individual repair pathways have distinct roles in suppressing changes in the nuclear DNA......, it is evident that proteins from the different DNA repair pathways interact [Y. Wang, D. Cortez, P. Yazdi, N. Neff, S.J. Elledge, J. Qin, BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures, Genes Dev. 14 (2000) 927-939; M. Christmann, M...

  13. REGULATION AND SUPERVISION OF BANKING ACTIVITY IN ROMANIA

    Directory of Open Access Journals (Sweden)

    Anisoara Niculina APETRI

    2015-04-01

    Full Text Available The main challenges currently faced by most central banks are generated by the effects of the economic and financial crisis. Thus, at the national, European and international level there is a trend of changing the economic governance structures and improving the regulatory and supervisory policies, focusing on macro-prudential oversight. In the context of changes at the European Union level, the central banks of the Member States become also subject to changes in their carried out actions. The objectives of this research aim mainly at: highlighting the role of the National Bank of Romania in regulating and supervising the banking system in Romania and analyzing the measures implemented by the National Bank of Romania after the crisis so far; identifying the challenges of the National Bank of Romania on the basis of changes operated by European Union at the supervisory framework level.

  14. Assessing brain activations associated with emotional regulation during virtual reality mood induction procedures

    NARCIS (Netherlands)

    Rodriguez, A.; Rey, B.; Clemente, M.; Wrzesien, M.; Alcañiz, M.

    2015-01-01

    Emotional regulation strategies are used by people to influence their emotional responses to external or internal emotional stimuli. The aim of this study is to evaluate the brain activations that are associated with the application of two different emotional regulation strategies (cognitive

  15. Design for mood : Twenty activity-based opportunities to design for mood regulation

    NARCIS (Netherlands)

    Desmet, P.M.A.

    2015-01-01

    This paper introduces a theory-based approach to design for mood regulation. The main proposition is that design can best influence mood by enabling and stimulating people to engage in a broad range of mood-regulating activities. The first part of the manuscript reviews state-of-the art mood-focused

  16. Methodical approaches to development of classification state methods of regulation business activity in fishery

    OpenAIRE

    She Son Gun

    2014-01-01

    Approaches to development of classification of the state methods of regulation of economy are considered. On the basis of the provided review the complex method of state regulation of business activity is reasonable. The offered principles allow improving public administration and can be used in industry concepts and state programs on support of small business in fishery.

  17. USP21 regulates Hippo pathway activity by mediating MARK protein turnover

    DEFF Research Database (Denmark)

    Nguyen, Thanh Hung; Kugler, Jan-Michael; Loya, Anand Chainsukh

    2017-01-01

    observed in cancer and often correlates with worse survival. The activity and stability of Hippo pathway components, including YAP/TAZ, AMOT and LATS1/2, are regulated by ubiquitin-mediated protein degradation. Aberrant expression of ubiquitin ligase complexes that regulate the turnover of Hippo components...

  18. Relationship Between Self-Regulation and Balance-Confidence in Active and Inactive Elderly Men

    Directory of Open Access Journals (Sweden)

    Fatemeh Sadat Hosseini

    2018-01-01

    Conclusion This study confirms that lack of self-regulation in the elderly can lead to decreased physical activity and restrictions. It is suggested that self-regulation should be emphasized in the elderly so that they can overcome their environmental issues and enhance their balance confidence.

  19. Hypothalamic-Pituitary-Adrenal and Sympathetic Nervous System Activity and Children's Behavioral Regulation

    Science.gov (United States)

    Lisonbee, Jared A.; Pendry, Patricia; Mize, Jacquelyn; Gwynn, Eugenia Parrett

    2010-01-01

    Self-regulation ability is an important component of children's academic success. Physiological reactivity may relate to brain activity governing attention and behavioral regulation. Saliva samples collected from 186 preschool children (101 boys, mean age = 53 months, 34% minority) before and after a series of mildly challenging games and again 30…

  20. Interaction Analysis for Supporting Students' Self-Regulation during Blog-Based CSCL Activities

    Science.gov (United States)

    Michailidis, Nikolaos; Kapravelos, Efstathios; Tsiatsos, Thrasyvoulos

    2018-01-01

    Self-regulated learning is an important means of supporting students' self-awareness and self-regulation level so as to enhance their motivation and engagement. Interaction Analysis (IA) contributes to this end, and its use in studying learning dynamics involved in asynchronous Computer-Supported Collaborative Learning (CSCL) activities has…

  1. 75 FR 67094 - Agency Information Collection Activities: CBP Regulations Pertaining to Customs Brokers

    Science.gov (United States)

    2010-11-01

    ... Activities: CBP Regulations Pertaining to Customs Brokers AGENCY: U.S. Customs and Border Protection... collection requirement concerning the: CBP Regulations Pertaining to Customs Brokers (19 CFR Part 111). This... Pertaining to Customs Brokers (19 CFR Part 111). OMB Number: 1651-0034. Form Numbers: CBP Forms 3124 and...

  2. Proposal for regulation of logging activities in oil wells using ionizing radiation sources

    International Nuclear Information System (INIS)

    Hidrowoh, Jacob R.

    2000-01-01

    It covers general aspects of nuclear energy and the suitable legal frame for its application related to oil industry. Besides, a regulation proposal to control logging activities in Ecuador using ionizing radiation sources in oil wells. It was prepared taking into account the Ecuadorian Atomic Energy Commission criteria and international regulations

  3. Gene program-specific regulation of PGC-1{alpha} activity

    DEFF Research Database (Denmark)

    Schmidt, Søren F; Mandrup, Susanne

    2011-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 α (PGC-1α) activation coordinates induction of the hepatic fasting response through coactivation of numerous transcription factors and gene programs. In the June 15, 2011, issue of Genes & Development, Lustig and colleagues (pp....... 1232-1244) demonstrated that phosphorylation of PGC-1α by the p70 ribosomal protein S6 kinase 1 (S6K1) specifically interfered with the interaction between PGC-1α and HNF4α in liver and blocked the coactivation of the gluconeogenic target genes. This demonstrates how independent fine-tuning of gene...

  4. Young Children's Interest-Oriented Activity and Later Academic Self-Regulation Strategies in Kindergarten

    Science.gov (United States)

    Neitzel, Carin; Alexander, Joyce M.; Johnson, Kathy E.

    2016-01-01

    This study investigated children's interest-based activities in the home during the preschool years and their subsequent academic self-regulation behaviors in school. Children's home activities were tracked for 1 year prior to kindergarten entry. Based on their profiles of activities, children (109) were assigned to one of four interest groups:…

  5. Regulation of AMP-activated protein kinase by LKB1 and CaMKK in adipocytes

    DEFF Research Database (Denmark)

    Gormand, Amélie; Henriksson, Emma; Ström, Kristoffer

    2011-01-01

    AMP-activated protein kinase (AMPK) is a serine/threonine kinase that regulates cellular and whole body energy homeostasis. In adipose tissue, activation of AMPK has been demonstrated in response to a variety of extracellular stimuli. However, the upstream kinase that activates AMPK in adipocytes...

  6. After the Slippery Slope: Dutch Experiences on Regulating Active Euthanasia

    NARCIS (Netherlands)

    Boer, Th.A.

    2003-01-01

    “When a country legalizes active euthanasia, it puts itself on a slippery slope from where it may well go further downward.” If true, this is a forceful argument in the battle of those who try to prevent euthanasia from becoming legal. The force of any slippery-slope argument, however, is by

  7. Regulation of the branchial ciliary activity in the mussel

    NARCIS (Netherlands)

    Dral, A.D.G.

    1977-01-01

    In mussels the movement of the cilia on the gill are basically autonomous and influenced by environmental factors. The branchial nerve has an inhibitory as well as a stimulating effect on the activity of the lateral cilia. The reactions of these cilia to changing temperature and chlorinity in

  8. Active Compound of Zingiber Cassumunar Roxb. Down-Regulates ...

    African Journals Online (AJOL)

    MMPs activities in the culture media were analyzed by zymographic techniques. Dexamethasone was used as the positive control. It was found that compound D at the concentration of 10 - 100 µM significantly decreased the mRNA expressions of MMP-1, -2, -3, and -13 which was induced by IL-1ß (P<0.05) concomitantly ...

  9. BAD and KATP channels regulate neuron excitability and epileptiform activity.

    Science.gov (United States)

    Martínez-François, Juan Ramón; Fernández-Agüera, María Carmen; Nathwani, Nidhi; Lahmann, Carolina; Burnham, Veronica L; Danial, Nika N; Yellen, Gary

    2018-01-25

    Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad ( B CL-2 a gonist of cell d eath) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (K ATP ) channels. Here we investigated the effect of BAD manipulation on K ATP channel activity and excitability in acute brain slices. We found that BAD's influence on neuronal K ATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal K ATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of K ATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a 'dentate gate' function that is reinforced by increased K ATP channel activity. © 2018, Martínez-François et al.

  10. Regulation of hepatic lipase activity by sphingomyelin in plasma lipoproteins.

    Science.gov (United States)

    Yang, Peng; Subbaiah, Papasani V

    2015-10-01

    Hepatic lipase (HL) is an important enzyme in the clearance of triacylglycerol (TAG) from the circulation, and has been proposed to have pro-atherogenic as well as anti-atherogenic properties. It hydrolyzes both phospholipids and TAG of lipoproteins, and its activity is negatively correlated with HDL levels. Although it is known that HL acts preferentially on HDL lipids, the basis for this specificity is not known, since it does not require any specific apoprotein for activity. In this study, we tested the hypothesis that sphingomyelin (SM), whose concentration is much higher in VLDL and LDL compared to HDL, is an inhibitor of HL, and that this could explain the lipoprotein specificity of the enzyme. The results presented show that the depletion of SM from normal lipoproteins activated the HL roughly in proportion to their SM content. SM depletion stimulated the hydrolysis of both phosphatidylcholine (PC) and TAG, although the PC hydrolysis was stimulated more. In the native lipoproteins, HL showed specificity for PC species containing polyunsaturated fatty acids at sn-2 position, and produced more unsaturated lyso PC species. The enzyme also showed preferential hydrolysis of certain TAG species over others. SM depletion affected the specificity of the enzyme towards PC and TAG species modestly. These results show that SM is a physiological inhibitor of HL activity in lipoproteins and that the specificity of the enzyme towards HDL is at least partly due to its low SM content. Published by Elsevier B.V.

  11. Redox regulation of the AMP-activated protein kinase.

    Directory of Open Access Journals (Sweden)

    Yingying Han

    2010-11-01

    Full Text Available Redox state is a critical determinant of cell function, and any major imbalances can cause severe damage or death.The aim of this study is to determine if AMP-activated protein kinase (AMPK, a cellular energy sensor, is activated by oxidants generated by Berberine in endothelial cells (EC.Bovine aortic endothelial cells (BAEC were exposed to Berberine. AMPK activity and reactive oxygen species were monitored after the incubation.In BAEC, Berberine caused a dose- and time-dependent increase in the phosphorylation of AMPK at Thr172 and acetyl CoA carboxylase (ACC at Ser79, a well characterized downstream target of AMPK. Concomitantly, Berberine increased peroxynitrite, a potent oxidant formed by simultaneous generation of superoxide and nitric oxide. Pre-incubation of BAEC with anti-oxidants markedly attenuated Berberine-enhanced phosphorylation of both AMPK and ACC. Consistently, adenoviral expression of superoxide dismutase and pretreatment of L-N(G-Nitroarginine methyl ester (L-NAME; a non-selective NOS inhibitor blunted Berberine-induced phosphorylation of AMPK. Furthermore, mitochondria-targeted tempol (mito-tempol pretreatment or expression of uncoupling protein attenuated AMPK activation caused by Berberine. Depletion of mitochondria abolished the effects of Berberine on AMPK in EC. Finally, Berberine significantly increased the phosphorylation of LKB1 at Ser307 and gene silencing of LKB1 attenuated Berberine-enhanced AMPK Thr172 phosphorylation in BAEC.Our results suggest that mitochondria-derived superoxide anions and peroxynitrite are required for Berberine-induced AMPK activation in endothelial cells.

  12. Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1.

    Science.gov (United States)

    Gaude, H; Aznar, N; Delay, A; Bres, A; Buchet-Poyau, K; Caillat, C; Vigouroux, A; Rogon, C; Woods, A; Vanacker, J-M; Höhfeld, J; Perret, C; Meyer, P; Billaud, M; Forcet, C

    2012-03-22

    LKB1 is a tumor suppressor that is constitutionally mutated in a cancer-prone condition, called Peutz-Jeghers syndrome, as well as somatically inactivated in a sizeable fraction of lung and cervical neoplasms. The LKB1 gene encodes a serine/threonine kinase that associates with the pseudokinase STRAD (STE-20-related pseudokinase) and the scaffolding protein MO25, the formation of this heterotrimeric complex promotes allosteric activation of LKB1. We have previously reported that the molecular chaperone heat shock protein 90 (Hsp90) binds to and stabilizes LKB1. Combining pharmacological studies and RNA interference approaches, we now provide evidence that the co-chaperone Cdc37 participates to the regulation of LKB1 stability. It is known that the Hsp90-Cdc37 complex recognizes a surface within the N-terminal catalytic lobe of client protein kinases. In agreement with this finding, we found that the chaperones Hsp90 and Cdc37 interact with an LKB1 isoform that differs in the C-terminal region, but not with a novel LKB1 variant that lacks a portion of the kinase N-terminal lobe domain. Reconstitution of the two complexes LKB1-STRAD and LKB1-Hsp90-Cdc37 with recombinant proteins revealed that the former is catalytically active whereas the latter is inactive. Furthermore, consistent with a documented repressor function of Hsp90, LKB1 kinase activity was transiently stimulated upon dissociation of Hsp90. Finally, disruption of the LKB1-Hsp90 complex favors the recruitment of both Hsp/Hsc70 and the U-box dependent E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein) that triggers LKB1 degradation. Taken together, our results establish that the Hsp90-Cdc37 complex controls both the stability and activity of the LKB1 kinase. This study further shows that two chaperone complexes with antagonizing activities, Hsp90-Cdc37 and Hsp/Hsc70-CHIP, finely control the cellular level of LKB1 protein.

  13. Niacin and its metabolites as master regulators of macrophage activation.

    Science.gov (United States)

    Montserrat-de la Paz, Sergio; Naranjo, M Carmen; Lopez, Sergio; Abia, Rocio; Muriana, Francisco J Garcia; Bermudez, Beatriz

    2017-01-01

    Niacin is a broad-spectrum lipid-regulating drug used for clinical therapy of chronic high-grade inflammatory diseases. However, the mechanisms by which either niacin or the byproducts of its catabolism ameliorate these inflammatory diseases are not clear yet. Human circulating monocytes and mature macrophages were used to analyze the effects of niacin and its metabolites (NAM, NUA and 2-Pyr) on oxidative stress, plasticity and inflammatory response by using biochemical, flow cytometry, quantitative real-time PCR and Western blot technologies. Niacin, NAM and 2-Pyr significantly decreased ROS, NO and NOS2 expression in LPS-treated human mature macrophages. Niacin and NAM skewed macrophage polarization toward antiinflammatory M2 macrophage whereas a trend toward proinflammatory M1 macrophage was noted following treatment with NUA. Niacin and NAM also reduced the inflammatory competence of LPS-treated human mature macrophages and promoted bias toward antiinflammatory CD14 + CD16 ++ nonclassical human primary monocytes. This study reveals for the first time that niacin and its metabolites possess antioxidant, reprogramming and antiinflammatory properties on human primary monocytes and monocyte-derived macrophages. Our findings imply a new understanding of the mechanisms by which niacin and its metabolites favor a continuous and gradual plasticity process in the human monocyte/macrophage system. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Substrate Specificity, Membrane Topology, and Activity Regulation of Human Alkaline Ceramidase 2 (ACER2)*

    OpenAIRE

    Sun, Wei; Jin, Junfei; Xu, Ruijuan; Hu, Wei; Szulc, Zdzislaw M.; Bielawski, Jacek; Obeid, Lina M.; Mao, Cungui

    2010-01-01

    Human alkaline ceramidase 2 (ACER2) plays an important role in cellular responses by regulating the hydrolysis of ceramides in cells. Here we report its biochemical characterization, membrane topology, and activity regulation. Recombinant ACER2 was expressed in yeast mutant cells (Δypc1Δydc1) that lack endogenous ceramidase activity, and microsomes from ACER2-expressiong yeast cells were used to biochemically characterize ACER2. ACER2 catalyzed the hydrolysis of various ceramides and followed...

  15. Regulation of drugs affecting striatal cholinergic activity by corticostriatal projections

    International Nuclear Information System (INIS)

    Ladinsky, H.

    1986-01-01

    Research demonstrates that the chronic degeneration of the corticostriatal excitatory pathway makes the cholinergic neurons of the striatum insensitive to the neuropharmacological action of a number of different drugs. Female rats were used; they were killed and after the i.v. infusion of tritium-choline precursor, choline acetyltransferase activity was measured. Striatal noradrenaline, dopamine and serotonin content was measured by electrochemical detection coupled with high pressure liquid chromatography. Uptake of tritium-glutamic acid was estimated. The data were analyzed statistically. It is shown that there is evidence that the effects of a number of drugs capable of depressing cholinergic activity through receptor-mediated responses are operative only if the corticostriatal pathway is integral. Neuropharmacological responses in the brain appear to be the result of an interaction between several major neurotransmitter systems

  16. Cis-regulatory RNA elements that regulate specialized ribosome activity.

    Science.gov (United States)

    Xue, Shifeng; Barna, Maria

    2015-01-01

    Recent evidence has shown that the ribosome itself can play a highly regulatory role in the specialized translation of specific subpools of mRNAs, in particular at the level of ribosomal proteins (RP). However, the mechanism(s) by which this selection takes place has remained poorly understood. In our recent study, we discovered a combination of unique RNA elements in the 5'UTRs of mRNAs that allows for such control by the ribosome. These mRNAs contain a Translation Inhibitory Element (TIE) that inhibits general cap-dependent translation, and an Internal Ribosome Entry Site (IRES) that relies on a specific RP for activation. The unique combination of an inhibitor of general translation and an activator of specialized translation is key to ribosome-mediated control of gene expression. Here we discuss how these RNA regulatory elements provide a new level of control to protein expression and their implications for gene expression, organismal development and evolution.

  17. DMPD: Nuclear factor-kappaB: activation and regulation during toll-like receptorsignaling. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17349209 Nuclear factor-kappaB: activation and regulation during toll-like receptorsignaling. Carmody...uclear factor-kappaB: activation and regulation during toll-like receptorsignaling. Authors Carmody

  18. Self-regulation resources and physical activity participation among adults with type 2 diabetes.

    Science.gov (United States)

    Castonguay, Alexandre; Miquelon, Paule; Boudreau, François

    2018-01-01

    Physical activity plays a crucial role in the prevention and treatment of type 2 diabetes. Therefore, it is important to understand why so few adults with type 2 diabetes regularly engage in physical activity. The role of self-regulation in the context of health-related behavior adherence, especially in terms of physical activity engagement and adherence, has largely been reviewed based on the strength energy model. Building on this line of research, the aim of this theoretical work was to highlight how self-regulation and ego depletion can influence the lower rate of physical activity participation among adults with type 2 diabetes, compared to adults from the general population.

  19. Commission de regulation de l'energie. Activity Report June 2003

    International Nuclear Information System (INIS)

    2003-06-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the June 2003 activity report of CRE. Content: A - Energy markets regulation: a new step; B - Gas market regulation: gas markets and actors, gas market regulation (legal and institutional framework, networks access, methane terminals and modulation services, freedom spaces, European market regulation, gas utility, CRE gas activities and priorities in 2003); C - Electricity market regulation: electricity markets (European markets, operators activity on the French market), French electricity market regulation (public networks access, trans-border power exchanges, EDF's un-bundled accounts audit, market operation), electric utility in the regulated market (public utility content, public utility charges, power generation public utility financing, electricity pre-tax sale tariffs for non-eligible customers); D - CRE operation (means and resources, exercise of its implementing powers, European and international activities); E - Appendixes: Glossary; Units and conversions; Council of European Energy Regulators, Index of figures and tables

  20. Glutathionylation regulates cytosolic NADP+-dependent isocitrate dehydrogenase activity.

    Science.gov (United States)

    Shin, Seoung Woo; Oh, Chang Joo; Kil, In Sup; Park, Jeen-Woo

    2009-04-01

    Cytosolic NADP+-dependent isocitrate dehydrogenase (IDPc) is susceptible to inactivation by numerous thiol-modifying reagents. This study now reports that Cys269 of IDPc is a target for S-glutathionylation and that this modification is reversed by dithiothreitol as well as enzymatically by cytosolic glutaredoxin in the presence of GSH. Glutathionylated IDPc was significantly less susceptible than native protein to peptide fragmentation by reactive oxygen species and proteolytic digestion. Glutathionylation may play a protective role in the degradation of protein through the structural alterations of IDPc. HEK293 cells treated with diamide displayed decreased IDPc activity and accumulated glutathionylated enzyme. Using immunoprecipitation with an anti-IDPc IgG and immunoblotting with an anti-GSH IgG, we purified and positively identified glutathionylated IDPc from the kidneys of mice subjected to ischemia/reperfusion injury and from the livers of ethanol-administered rats. These results suggest that IDPc activity is modulated through enzymatic glutathionylation and deglutathionylation during oxidative stress.

  1. Xanthine oxidase activity regulates human embryonic brain cells growth

    Directory of Open Access Journals (Sweden)

    Kevorkian G. A.

    2011-10-01

    Full Text Available Aim. Involvement of Xanthine Oxidase (XO; EC1.1.3.22 in cellular proliferation and differentiation has been suggested by the numerous investigations. We have proposed that XO might have undoubtedly important role during the development, maturation as well as the death of human embryos brain cells. Methods. Human abortion material was utilized for the cultivation of brain cells (E90. XO activity was measured by the formation of uric acid in tissue. Cell death was detected by the utility of Trypan Blue dye. Results. Allopurinol suppressed the XO activity in the brain tissue (0.12 ± 0.02; 0.20 ± 0.03 resp., p < 0.05. On day 12th the number of cells in the culture treated with the Allopurinol at the early stage of development was higher in comparison with the Control (2350.1 ± 199.0 vs 2123 ± 96 and higher in comparison with the late period of treatment (1479.6 ± 103.8, p < < 0.05. In all groups, the number of the dead cells was less than in Control, indicating the protective nature of Allopurinol as an inhibitor of XO. Conclusions. Allopurinol initiates cells proliferation in case of the early treatment of the human brain derived cell culture whereas at the late stages it has an opposite effect.

  2. DMPD: Genetic regulation of macrophage priming/activation: the Lsh gene story. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 1757110 Genetic regulation of macrophage priming/activation: the Lsh gene story. Bl... (.svg) (.html) (.csml) Show Genetic regulation of macrophage priming/activation: the Lsh gene story. Pubmed...ID 1757110 Title Genetic regulation of macrophage priming/activation: the Lsh gen

  3. GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters.

    Science.gov (United States)

    Ramesh, Sunita A; Tyerman, Stephen D; Xu, Bo; Bose, Jayakumar; Kaur, Satwinder; Conn, Vanessa; Domingos, Patricia; Ullah, Sana; Wege, Stefanie; Shabala, Sergey; Feijó, José A; Ryan, Peter R; Gilliham, Matthew; Gillham, Matthew

    2015-07-29

    The non-protein amino acid, gamma-aminobutyric acid (GABA) rapidly accumulates in plant tissues in response to biotic and abiotic stress, and regulates plant growth. Until now it was not known whether GABA exerts its effects in plants through the regulation of carbon metabolism or via an unidentified signalling pathway. Here, we demonstrate that anion flux through plant aluminium-activated malate transporter (ALMT) proteins is activated by anions and negatively regulated by GABA. Site-directed mutagenesis of selected amino acids within ALMT proteins abolishes GABA efficacy but does not alter other transport properties. GABA modulation of ALMT activity results in altered root growth and altered root tolerance to alkaline pH, acid pH and aluminium ions. We propose that GABA exerts its multiple physiological effects in plants via ALMT, including the regulation of pollen tube and root growth, and that GABA can finally be considered a legitimate signalling molecule in both the plant and animal kingdoms.

  4. Legal Instruments of Regulation of Development of Banking Activity in Ukraine

    Directory of Open Access Journals (Sweden)

    Senyshch Pavlo M.

    2014-03-01

    Full Text Available The article considers main approaches to identification of essence of legal instruments of regulation of development of the banking activity, identifies the mechanism of legal regulation of the banking activity and its elements and justifies the system and form of legal regulation of the banking activity in Ukraine. It describes subjects of legal regulation of the banking activity at the international level, which are the Basel Committee on Banking Supervision, European Central Bank, IMF, International Financial Reporting Standards Foundation and others. The article considers specific features of the regulatory requirements of Basel II and Basel III and specific features of their introduction into the banking activity. It describes anti-cyclic measures offered by the Basel Committee, which should facilitate formation of such conditions, under which the banking sector could have a lower level of leverage and stability with respect to influence of system risks. Significant attention is paid to international instruments of regulation of the banking activity, which include the following legal acts: Uniform Rules for Collections, Uniform Customs and Practice for Documentary Credits, and Unified Rules for Loan Guarantees. The article shows that the share of subordinate legal acts is significant in the Ukrainian system of banking regulatory and legal acts since the state cannot operatively react to the changing processes in banking at the legislative level and, that is why, basic provisions on carrying out banking activity should be fixed in law.

  5. Activating transcription factor 3 regulates immune and metabolic homeostasis.

    Science.gov (United States)

    Rynes, Jan; Donohoe, Colin D; Frommolt, Peter; Brodesser, Susanne; Jindra, Marek; Uhlirova, Mirka

    2012-10-01

    Integration of metabolic and immune responses during animal development ensures energy balance, permitting both growth and defense. Disturbed homeostasis causes organ failure, growth retardation, and metabolic disorders. Here, we show that the Drosophila melanogaster activating transcription factor 3 (Atf3) safeguards metabolic and immune system homeostasis. Loss of Atf3 results in chronic inflammation and starvation responses mounted primarily by the larval gut epithelium, while the fat body suffers lipid overload, causing energy imbalance and death. Hyperactive proinflammatory and stress signaling through NF-κB/Relish, Jun N-terminal kinase, and FOXO in atf3 mutants deregulates genes important for immune defense, digestion, and lipid metabolism. Reducing the dose of either FOXO or Relish normalizes both lipid metabolism and gene expression in atf3 mutants. The function of Atf3 is conserved, as human ATF3 averts some of the Drosophila mutant phenotypes, improving their survival. The single Drosophila Atf3 may incorporate the diversified roles of two related mammalian proteins.

  6. Therapeutic potential of carbohydrates as regulators of macrophage activation.

    Science.gov (United States)

    Lundahl, Mimmi L E; Scanlan, Eoin M; Lavelle, Ed C

    2017-12-15

    It is well established for a broad range of disease states, including cancer and Mycobacterium tuberculosis infection, that pathogenesis is bolstered by polarisation of macrophages towards an anti-inflammatory phenotype, known as M2. As these innate immune cells are relatively long-lived, their re-polarisation to pro-inflammatory, phagocytic and bactericidal "classically activated" M1 macrophages is an attractive therapeutic approach. On the other hand, there are scenarios where the resolving inflammation, wound healing and tissue remodelling properties of M2 macrophages are beneficial - for example the successful introduction of biomedical implants. Although there are numerous endogenous and exogenous factors that have an impact on the macrophage polarisation spectrum, this review will focus specifically on prominent macrophage-modulating carbohydrate motifs with a view towards highlighting structure-function relationships and therapeutic potential. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Reciprocal regulation of LXRα activity by ASXL1 and ASXL2 in lipogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Park, Ui-Hyun; Seong, Mi-ran [Department of Bioscience and Biotechnology, Institute of Bioscience, BK21 Graduate Program, Sejong University, Seoul 143-747 (Korea, Republic of); Kim, Eun-Joo; Hur, Wonhee; Kim, Sung Woo [Department of Molecular Biology, BK21 Graduate Program, Dankook University, Gyeonggi-do 448-701 (Korea, Republic of); Yoon, Seung Kew [The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, The Catholic University, College of Medicine, Seoul 137-701 (Korea, Republic of); Um, Soo-Jong, E-mail: umsj@sejong.ac.kr [Department of Bioscience and Biotechnology, Institute of Bioscience, BK21 Graduate Program, Sejong University, Seoul 143-747 (Korea, Republic of)

    2014-01-10

    Highlights: •ASXL1 and ASXL2 directly interact with ligand-bound LXRα. •Ligand-induced LXRα activity is repressed by ASXL1 and activated by ASXL2. •ASXL1 and ASXL2 bind to the LXRE of the LXRα target promoter. •ASXL1 and ASXL2 reciprocally regulate lipogenesis in liver cells. -- Abstract: Liver X receptor alpha (LXRα), a member of the nuclear receptor superfamily, plays a pivotal role in hepatic cholesterol and lipid metabolism, regulating the expression of genes associated with hepatic lipogenesis. The additional sex comb-like (ASXL) family was postulated to regulate chromatin function. Here, we investigate the roles of ASXL1 and ASXL2 in regulating LXRα activity. We found that ASXL1 suppressed ligand-induced LXRα transcriptional activity, whereas ASXL2 increased LXRα activity through direct interaction in the presence of the ligand. Chromatin immunoprecipitation (ChIP) assays showed ligand-dependent recruitment of ASXLs to ABCA1 promoters, like LXRα. Knockdown studies indicated that ASXL1 inhibits, while ASXL2 increases, lipid accumulation in H4IIE cells, similar to their roles in transcriptional regulation. We also found that ASXL1 expression increases under fasting conditions, and decreases in insulin-treated H4IIE cells and the livers of high-fat diet-fed mice. Overall, these results support the reciprocal role of the ASXL family in lipid homeostasis through the opposite regulation of LXRα.

  8. Activating Transcription Factor 3 Regulates Immune and Metabolic Homeostasis

    Science.gov (United States)

    Rynes, Jan; Donohoe, Colin D.; Frommolt, Peter; Brodesser, Susanne; Jindra, Marek

    2012-01-01

    Integration of metabolic and immune responses during animal development ensures energy balance, permitting both growth and defense. Disturbed homeostasis causes organ failure, growth retardation, and metabolic disorders. Here, we show that the Drosophila melanogaster activating transcription factor 3 (Atf3) safeguards metabolic and immune system homeostasis. Loss of Atf3 results in chronic inflammation and starvation responses mounted primarily by the larval gut epithelium, while the fat body suffers lipid overload, causing energy imbalance and death. Hyperactive proinflammatory and stress signaling through NF-κB/Relish, Jun N-terminal kinase, and FOXO in atf3 mutants deregulates genes important for immune defense, digestion, and lipid metabolism. Reducing the dose of either FOXO or Relish normalizes both lipid metabolism and gene expression in atf3 mutants. The function of Atf3 is conserved, as human ATF3 averts some of the Drosophila mutant phenotypes, improving their survival. The single Drosophila Atf3 may incorporate the diversified roles of two related mammalian proteins. PMID:22851689

  9. Transposable element activity, genome regulation and human health.

    Science.gov (United States)

    Wang, Lu; Jordan, I King

    2018-03-02

    A convergence of novel genome analysis technologies is enabling population genomic studies of human transposable elements (TEs). Population surveys of human genome sequences have uncovered thousands of individual TE insertions that segregate as common genetic variants, i.e. TE polymorphisms. These recent TE insertions provide an important source of naturally occurring human genetic variation. Investigators are beginning to leverage population genomic data sets to execute genome-scale association studies for assessing the phenotypic impact of human TE polymorphisms. For example, the expression quantitative trait loci (eQTL) analytical paradigm has recently been used to uncover hundreds of associations between human TE insertion variants and gene expression levels. These include population-specific gene regulatory effects as well as coordinated changes to gene regulatory networks. In addition, analyses of linkage disequilibrium patterns with previously characterized genome-wide association study (GWAS) trait variants have uncovered TE insertion polymorphisms that are likely causal variants for a variety of common complex diseases. Gene regulatory mechanisms that underlie specific disease phenotypes have been proposed for a number of these trait associated TE polymorphisms. These new population genomic approaches hold great promise for understanding how ongoing TE activity contributes to functionally relevant genetic variation within and between human populations. Copyright © 2018 Elsevier Ltd. All rights reserved.

  10. Nutritive, Post-ingestive Signals Are the Primary Regulators of AgRP Neuron Activity

    Directory of Open Access Journals (Sweden)

    Zhenwei Su

    2017-12-01

    Full Text Available Summary: The brain regulates food intake by processing sensory cues and peripheral physiological signals, but the neural basis of this integration remains unclear. Hypothalamic, agouti-related protein (AgRP-expressing neurons are critical regulators of food intake. AgRP neuron activity is high during hunger and is rapidly reduced by the sight and smell of food. Here, we reveal two distinct components of AgRP neuron activity regulation: a rapid but transient sensory-driven signal and a slower, sustained calorie-dependent signal. We discovered that nutrients are necessary and sufficient for sustained reductions in AgRP neuron activity and that activity reductions are proportional to the calories obtained. This change in activity is recapitulated by exogenous administration of gut-derived satiation signals. Furthermore, we showed that the nutritive value of food trains sensory systems—in a single trial—to drive rapid, anticipatory AgRP neuron activity inhibition. Together, these data demonstrate that nutrients are the primary regulators of AgRP neuron activity. : Su et al. demonstrate that nutrient content in the GI tract is rapidly signaled to hypothalamic neurons activated by hunger. This rapid effect is mediated by three satiation signals that synergistically reduce the activity of AgRP neurons. These findings uncover how hunger circuits in the brain are regulated and raise the possibility that hunger can be pharmacologically controlled. Keywords: calcium imaging, AgRP neurons, calories, satiation signals, sensory regulation, single trial learning, cholecystokinin, CCK, peptide tyrosine tyrosine, PYY, amylin, homeostasis

  11. Analyzing the Impact of Using Optional Activities in Self-Regulated Learning

    Science.gov (United States)

    Ruipérez-Valiente, Jose A.; Muñoz-Merino, Pedro J.; Kloos, Carlos Delgado; Niemann, Katja; Scheffel, Maren; Wolpers, Martin

    2016-01-01

    Self-regulated learning (SRL) environments provide students with activities to improve their learning (e.g., by solving exercises), but they might also provide optional activities (e.g., changing an avatar image or setting goals) where students can decide whether they would like to use or do them and how. Few works have dealt with the use of…

  12. Regulation of antioxidant enzyme activities in male and female rat macrophages by sex steroids

    Directory of Open Access Journals (Sweden)

    Azevedo R.B.

    2001-01-01

    Full Text Available Human and animal immune functions present sex dimorphism that seems to be mainly regulated by sex hormones. In the present study, the activities of the antioxidant enzymes total superoxide dismutase (SOD, catalase (CAT, and glutathione peroxidase (GSH-Px were measured in intraperitoneal resident macrophages from adult male and female rats. In addition to comparing males and females, we also examined the regulation of these enzyme activities in macrophages by sex steroids. GSH-Px activity did not differ between male and female macrophages. However, both total SOD and CAT activities were markedly higher in females than in males (83 and 180%. Removal of the gonads in both males and females (comparison between castrated groups increased the difference in SOD activity from 83 to 138% and reduced the difference in CAT activity from 180 to 86%. Castration and testosterone administration did not significantly modify the activities of the antioxidant enzymes in male macrophages. Ovariectomy did not affect SOD or GSH-Px activity but markedly reduced (48% CAT activity. This latter change was fully reversed by estrogen administration, whereas progesterone had a smaller effect. These results led us to conclude that differences in the SOD and CAT activities may partially explain some of the differences in immune function reported for males and females. Also, estrogen is a potent regulator of CAT in macrophages and therefore this enzyme activity in macrophages may vary considerably during the menstrual cycle.

  13. Successful emotion regulation is predicted by amygdala activity and aspects of personality: A latent variable approach.

    Science.gov (United States)

    Morawetz, Carmen; Alexandrowicz, Rainer W; Heekeren, Hauke R

    2017-04-01

    The experience of emotions and their cognitive control are based upon neural responses in prefrontal and subcortical regions and could be affected by personality and temperamental traits. Previous studies established an association between activity in reappraisal-related brain regions (e.g., inferior frontal gyrus and amygdala) and emotion regulation success. Given these relationships, we aimed to further elucidate how individual differences in emotion regulation skills relate to brain activity within the emotion regulation network on the one hand, and personality/temperamental traits on the other. We directly examined the relationship between personality and temperamental traits, emotion regulation success and its underlying neuronal network in a large sample (N = 82) using an explicit emotion regulation task and functional MRI (fMRI). We applied a multimethodological analysis approach, combing standard activation-based analyses with structural equation modeling. First, we found that successful downregulation is predicted by activity in key regions related to emotion processing. Second, the individual ability to successfully upregulate emotions is strongly associated with the ability to identify feelings, conscientiousness, and neuroticism. Third, the successful downregulation of emotion is modulated by openness to experience and habitual use of reappraisal. Fourth, the ability to regulate emotions is best predicted by a combination of brain activity and personality as well temperamental traits. Using a multimethodological analysis approach, we provide a first step toward a causal model of individual differences in emotion regulation ability by linking biological systems underlying emotion regulation with descriptive constructs. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  14. Neuronal activity rapidly induces transcription of the CREB-regulated microRNA-132, in vivo

    DEFF Research Database (Denmark)

    Nudelman, Aaron Samuel; DiRocco, Derek P; Lambert, Talley J

    2010-01-01

    Activity-dependent changes in gene-expression are believed to underlie the molecular representation of memory. In this study, we report that in vivo activation of neurons rapidly induces the CREB-regulated microRNA miR-132. To determine if production of miR-132 is regulated by neuronal activity its......, olfactory bulb, and striatum by contextual fear conditioning, odor-exposure, and cocaine-injection, respectively, also increased pri-miR-132. Induction kinetics of pri-miR-132 were monitored and found to parallel those of immediate early genes, peaking at 45 min and returning to basal levels within 2 h...

  15. RhoGDI: multiple functions in the regulation of Rho family GTPase activities

    DEFF Research Database (Denmark)

    Dovas, Athanassios; Couchman, John R

    2005-01-01

    necessary for the correct targeting and regulation of Rho activities by conferring cues for spatial restriction, guidance and availability to effectors. These potential functions are discussed in the context of RhoGDI-associated multimolecular complexes, the newly emerged shuttling capability...... insight as to how RhoGDI exerts its effects on nucleotide binding, the membrane association-dissociation cycling of the GTPase and how these activities are controlled. Despite the initial negative roles attributed to RhoGDI, recent evidence has come to suggest that it may also act as a positive regulator...... of activities....

  16. Resveratrol inhibits Cdk5 activity through regulation of p35 expression

    Directory of Open Access Journals (Sweden)

    Kulkarni Ashok B

    2011-07-01

    Full Text Available Abstract Background We have previously reported that cyclin-dependent kinase 5 (Cdk5 participates in the regulation of nociceptive signaling. Through activation of the ERK1/2 pathway, Tumor Necrosis Factor-α (TNF-α induces expression of Egr-1. This results in the sustained and robust expression of p35, a coactivator of Cdk5, in PC12 cells, thereby increasing Cdk5 kinase activity. The aim of our present study was to test whether resveratrol, a polyphenolic compound with known analgesic activity, can regulate Cdk5/p35 activity. Results Here we used a cell-based assay in which a p35 promoter-luciferase construct was stably transfected in PC12 cells. Our studies demonstrate that resveratrol inhibits p35 promoter activity and also blocks the TNF-α mediated increase in Cdk5 activity in PC12 cells. Resveratrol also inhibits p35 expression and blocks the TNF-α mediated increase in Cdk5 activity in DRG neurons. In the presence of resveratrol, the MEK inhibitor decreased p35 promoter activity, whereas the inhibitors of p38 MAPK, JNK and NF-κB increased p35 promoter activity, indicating that these pathways regulate p35 expression differently. The TNF-α-mediated increase in Egr-1 expression was decreased by resveratrol treatment with a concomitant reduction in p35 expression and protein levels, resulting in reduced Cdk5 kinase activity. Conclusions We demonstrate here that resveratrol regulates p35 promoter activity in PC12 cells and DRG neurons. Most importantly, resveratrol blocks the TNF-α-mediated increase in p35 promoter activity, thereby reducing p35 expression and subsequent Cdk5 kinase activity. This new molecular mechanism adds to the known analgesic effects of resveratrol and confirms the need for identifying new analgesics based on their ability to inhibit Cdk5 activity for effective treatment of pain.

  17. Synergistic Effect of Auto-Activation and Small RNA Regulation on Gene Expression

    Science.gov (United States)

    Xiong, Li-Ping; Ma, Yu-Qiang; Tang, Lei-Han

    2010-09-01

    Auto-activation and small ribonucleic acid (RNA)-mediated regulation are two important mechanisms in controlling gene expression. We study the synergistic effect of these two regulations on gene expression. It is found that under this combinatorial regulation, gene expression exhibits bistable behaviors at the transition regime, while each of these two regulations, if working solely, only leads to monostability. Within the stochastic framework, the base pairing strength between sRNA and mRNA plays an important role in controlling the transition time between on and off states. The noise strength of protein number in the off state approaches 1 and is smaller than that in the on state. The noise strength also depends on which parameters, the feedback strength or the synthesis rate of small RNA, are tuned in switching the gene expression on and off. Our findings may provide a new insight into gene-regulation mechanism and can be applied in synthetic biology.

  18. Synergistic Effect of Auto-Activation and Small RNA Regulation on Gene Expression

    International Nuclear Information System (INIS)

    Li-Ping, Xiong; Yu-Qiang, Ma; Lei-Han, Tang

    2010-01-01

    Auto-activation and small ribonucleic acid (RNA)-mediated regulation are two important mechanisms in controlling gene expression. We study the synergistic effect of these two regulations on gene expression. It is found that under this combinatorial regulation, gene expression exhibits bistable behaviors at the transition regime, while each of these two regulations, if working solely, only leads to monostability. Within the stochastic framework, the base pairing strength between sRNA and mRNA plays an important role in controlling the transition time between on and off states. The noise strength of protein number in the off state approaches 1 and is smaller than that in the on state. The noise strength also depends on which parameters, the feedback strength or the synthesis rate of small RNA, are tuned in switching the gene expression on and off. Our findings may provide a new insight into gene-regulation mechanism and can be applied in synthetic biology

  19. Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

    Science.gov (United States)

    Wang, Xuefei; Sugam, Jonathan A.; Carelli, Regina M.

    2016-01-01

    Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. SIGNIFICANCE STATEMENT Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence

  20. Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats.

    Science.gov (United States)

    Saddoris, Michael P; Wang, Xuefei; Sugam, Jonathan A; Carelli, Regina M

    2016-01-06

    Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence, particularly its role in

  1. Neuronal MHC Class I Expression Is Regulated by Activity Driven Calcium Signaling.

    Directory of Open Access Journals (Sweden)

    Dan Lv

    Full Text Available MHC class I (MHC-I molecules are important components of the immune system. Recently MHC-I have been reported to also play important roles in brain development and synaptic plasticity. In this study, we examine the molecular mechanism(s underlying activity-dependent MHC-I expression using hippocampal neurons. Here we report that neuronal expression level of MHC-I is dynamically regulated during hippocampal development after birth in vivo. Kainic acid (KA treatment significantly increases the expression of MHC-I in cultured hippocampal neurons in vitro, suggesting that MHC-I expression is regulated by neuronal activity. In addition, KA stimulation decreased the expression of pre- and post-synaptic proteins. This down-regulation is prevented by addition of an MHC-I antibody to KA treated neurons. Further studies demonstrate that calcium-dependent protein kinase C (PKC is important in relaying KA simulation activation signals to up-regulated MHC-I expression. This signaling cascade relies on activation of the MAPK pathway, which leads to increased phosphorylation of CREB and NF-κB p65 while also enhancing the expression of IRF-1. Together, these results suggest that expression of MHC-I in hippocampal neurons is driven by Ca2+ regulated activation of the MAPK signaling transduction cascade.

  2. The Brakeless co-regulator can directly activate and repress transcription in early Drosophila embryos.

    Science.gov (United States)

    Crona, Filip; Holmqvist, Per-Henrik; Tang, Min; Singla, Bhumica; Vakifahmetoglu-Norberg, Helin; Fantur, Katrin; Mannervik, Mattias

    2015-11-01

    The Brakeless protein performs many important functions during Drosophila development, but how it controls gene expression is poorly understood. We previously showed that Brakeless can function as a transcriptional co-repressor. In this work, we perform transcriptional profiling of brakeless mutant embryos. Unexpectedly, the majority of affected genes are down-regulated in brakeless mutants. We demonstrate that genomic regions in close proximity to some of these genes are occupied by Brakeless, that over-expression of Brakeless causes a reciprocal effect on expression of these genes, and that Brakeless remains an activator of the genes upon fusion to an activation domain. Together, our results show that Brakeless can both repress and activate gene expression. A yeast two-hybrid screen identified the Mediator complex subunit Med19 as interacting with an evolutionarily conserved part of Brakeless. Both down- and up-regulated Brakeless target genes are also affected in Med19-depleted embryos, but only down-regulated targets are influenced in embryos depleted of both Brakeless and Med19. Our data provide support for a Brakeless activator function that regulates transcription by interacting with Med19. We conclude that the transcriptional co-regulator Brakeless can either activate or repress transcription depending on context. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Correlation set analysis: detecting active regulators in disease populations using prior causal knowledge

    Directory of Open Access Journals (Sweden)

    Huang Chia-Ling

    2012-03-01

    Full Text Available Abstract Background Identification of active causal regulators is a crucial problem in understanding mechanism of diseases or finding drug targets. Methods that infer causal regulators directly from primary data have been proposed and successfully validated in some cases. These methods necessarily require very large sample sizes or a mix of different data types. Recent studies have shown that prior biological knowledge can successfully boost a method's ability to find regulators. Results We present a simple data-driven method, Correlation Set Analysis (CSA, for comprehensively detecting active regulators in disease populations by integrating co-expression analysis and a specific type of literature-derived causal relationships. Instead of investigating the co-expression level between regulators and their regulatees, we focus on coherence of regulatees of a regulator. Using simulated datasets we show that our method performs very well at recovering even weak regulatory relationships with a low false discovery rate. Using three separate real biological datasets we were able to recover well known and as yet undescribed, active regulators for each disease population. The results are represented as a rank-ordered list of regulators, and reveals both single and higher-order regulatory relationships. Conclusions CSA is an intuitive data-driven way of selecting directed perturbation experiments that are relevant to a disease population of interest and represent a starting point for further investigation. Our findings demonstrate that combining co-expression analysis on regulatee sets with a literature-derived network can successfully identify causal regulators and help develop possible hypothesis to explain disease progression.

  4. Characterization of DNA binding, transcriptional activation, and regulated nuclear association of recombinant human NFATp

    Directory of Open Access Journals (Sweden)

    Seto Anita G

    2000-11-01

    Full Text Available Abstract Background NFATp is one member of a family of transcriptional activators whose nuclear accumulation and hence transcriptional activity is regulated in mammalian cells. Human NFATp exists as a phosphoprotein in the cytoplasm of naive T cells. Upon antigen stimulation, NFATp is dephosphorylated, accumulates in nuclei, and functions to regulate transcription of genes including those encoding cytokines. While the properties of the DNA binding domain of NFATp have been investigated in detail, biochemical studies of the transcriptional activation and regulated association with nuclei have remained unexplored because of a lack of full length, purified recombinant NFATp. Results We developed methods for expressing and purifying full length recombinant human NFATp that has all of the properties known to be associated with native NFATp. The recombinant NFATp binds DNA on its own and cooperatively with AP-1 proteins, activates transcription in vitro, is phosphorylated, can be dephosphorylated by calcineurin, and exhibits regulated association with nuclei in vitro. Importantly, activation by recombinant NFATp in a reconstituted transcription system required regions of the protein outside of the central DNA binding domain. Conclusions We conclude that NFATp is a bona fide transcriptional activator. Moreover, the reagents and methods that we developed will facilitate future studies on the mechanisms of transcriptional activation and nuclear accumulation by NFATp, a member of an important family of transcriptional regulatory proteins.

  5. Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes

    Science.gov (United States)

    Das, Hiranmoy; Kumar, Ajay; Lin, Zhiyong; Patino, Willmar D.; Hwang, Paul M.; Feinberg, Mark W.; Majumder, Pradip K.; Jain, Mukesh K.

    2006-01-01

    The mechanisms regulating activation of monocytes remain incompletely understood. Herein we provide evidence that Kruppel-like factor 2 (KLF2) inhibits proinflammatory activation of monocytes. In vitro, KLF2 expression in monocytes is reduced by cytokine activation or differentiation. Consistent with this observation, KLF2 expression in circulating monocytes is reduced in patients with chronic inflammatory conditions such as coronary artery disease. Adenoviral overexpression of KLF2 inhibits the LPS-mediated induction of proinflammatory factors, cytokines, and chemokines and reduces phagocytosis. Conversely, short interfering RNA-mediated reduction in KLF2 increased inflammatory gene expression. Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation. Mechanistically, KLF2 inhibits the transcriptional activity of both NF-κB and activator protein 1, in part by means of recruitment of transcriptional coactivator p300/CBP-associated factor. These observations identify KLF2 as a novel negative regulator of monocytic activation. PMID:16617118

  6. Activity-dependent self-regulation of viscous length scales in biological systems

    Science.gov (United States)

    Nandi, Saroj Kumar

    2018-05-01

    The cellular cortex, which is a highly viscous thin cytoplasmic layer just below the cell membrane, controls the cell's mechanical properties, which can be characterized by a hydrodynamic length scale ℓ . Cells actively regulate ℓ via the activity of force-generating molecules, such as myosin II. Here we develop a general theory for such systems through a coarse-grained hydrodynamic approach including activity in the static description of the system providing an experimentally accessible parameter and elucidate the detailed mechanism of how a living system can actively self-regulate its hydrodynamic length scale, controlling the rigidity of the system. Remarkably, we find that ℓ , as a function of activity, behaves universally and roughly inversely proportional to the activity of the system. Our theory rationalizes a number of experimental findings on diverse systems, and comparison of our theory with existing experimental data shows good agreement.

  7. Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

    KAUST Repository

    Lissanu Deribe, Yonathan

    2016-03-01

    PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2E824*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57KIP2). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.

  8. Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma.

    Science.gov (United States)

    Lissanu Deribe, Yonathan; Shi, Yanxia; Rai, Kunal; Nezi, Luigi; Amin, Samir B; Wu, Chia-Chin; Akdemir, Kadir C; Mahdavi, Mozhdeh; Peng, Qian; Chang, Qing Edward; Hornigold, Kirsti; Arold, Stefan T; Welch, Heidi C E; Garraway, Levi A; Chin, Lynda

    2016-03-01

    PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2(E824)*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57(KIP2)). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.

  9. Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

    KAUST Repository

    Lissanu Deribe, Yonathan; Shi, Yanxia; Rai, Kunal; Nezi, Luigi; Amin, Samir B.; Wu, Chia-Chin; Akdemir, Kadir C.; Mahdavi, Mozhdeh; Peng, Qian; Chang, Qing Edward; Hornigold, Kirsti; Arold, Stefan T.; Welch, Heidi C. E.; Garraway, Levi A.; Chin, Lynda

    2016-01-01

    PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2E824*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57KIP2). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.

  10. Relationship between child care centers' compliance with physical activity regulations and children's physical activity, New York City, 2010.

    Science.gov (United States)

    Stephens, Robert L; Xu, Ye; Lesesne, Catherine A; Dunn, Lillian; Kakietek, Jakub; Jernigan, Jan; Khan, Laura Kettel

    2014-10-16

    Physical activity may protect against overweight and obesity among preschoolers, and the policies and characteristics of group child care centers influence the physical activity levels of children who attend them. We examined whether children in New York City group child care centers that are compliant with the city's regulations on child physical activity engage in more activity than children in centers who do not comply. A sample of 1,352 children (mean age, 3.39 years) served by 110 group child care centers in low-income neighborhoods participated. Children's anthropometric data were collected and accelerometers were used to measure duration and intensity of physical activity. Multilevel generalized linear regression modeling techniques were used to assess the effect of center- and child-level factors on child-level physical activity. Centers' compliance with the regulation of obtaining at least 60 minutes of total physical activity per day was positively associated with children's levels of moderate to vigorous physical activity (MVPA); compliance with the regulation of obtaining at least 30 minutes of structured activity was not associated with increased levels of MVPA. Children in centers with a dedicated outdoor play space available also spent more time in MVPA. Boys spent more time in MVPA than girls, and non-Hispanic black children spent more time in MVPA than Hispanic children. To increase children's level of MVPA in child care, both time and type of activity should be considered. Further examination of the role of play space availability and its effect on opportunities for engaging in physical activity is needed.

  11. Activated H-Ras regulates hematopoietic cell survival by modulating Survivin

    International Nuclear Information System (INIS)

    Fukuda, Seiji; Pelus, Louis M.

    2004-01-01

    Survivin expression and Ras activation are regulated by hematopoietic growth factors. We investigated whether activated Ras could circumvent growth factor-regulated Survivin expression and if a Ras/Survivin axis mediates growth factor independent survival and proliferation in hematopoietic cells. Survivin expression is up-regulated by IL-3 in Ba/F3 and CD34 + cells and inhibited by the Ras inhibitor, farnesylthiosalicylic acid. Over-expression of constitutively activated H-Ras (CA-Ras) in Ba/F3 cells blocked down-modulation of Survivin expression, G 0 /G 1 arrest, and apoptosis induced by IL-3 withdrawal, while dominant-negative (DN) H-Ras down-regulated Survivin. Survivin disruption by DN T34A Survivin blocked CA-Ras-induced IL-3-independent cell survival and proliferation; however, it did not affect CA-Ras-mediated enhancement of S-phase, indicating that the anti-apoptotic activity of CA-Ras is Survivin dependent while its S-phase enhancing effect is not. These results indicate that CA-Ras modulates Survivin expression independent of hematopoietic growth factors and that a CA-Ras/Survivin axis regulates survival and proliferation of transformed hematopoietic cells

  12. Regulation of mitogen-activated protein kinase pathways by the plasma membrane Na+/H+ exchanger, NHE1

    DEFF Research Database (Denmark)

    Pedersen, Stine Helene Falsig; Darborg, Barbara Vasek; Rentsch, Maria Louise

    2006-01-01

    activity is regulated by a three-tiered phosphorelay system, which is in turn regulated by a complex network of signaling events and scaffolding proteins. The ubiquitous plasma membrane Na(+)/H(+) exchanger NHE1 is activated by, and implicated in, the physiological/pathophysiological responses to many...... of the same stimuli that modulate MAPK activity. While under some conditions, NHE1 is regulated by MAPKs, a number of studies have, conversely, implicated NHE1 in the regulation of MAPK activity. Here, we discuss the current evidence indicating the involvement of NHE1 in MAPK regulation, the mechanisms...

  13. Context-Dependent Modulation of αβγ and αβγ GABAA Receptors by Penicillin: Implications for Phasic and Tonic Inhibition

    OpenAIRE

    Feng, Hua-Jun; Botzolakis, Emmanuel J.; Macdonald, Robert L.

    2008-01-01

    Penicillin, an open-channel blocker of GABAA receptors, was recently reported to inhibit phasic, but not tonic, currents in hippocampal neurons. To distinguish between isoform-specific and context-dependent modulation as possible explanations for this selectivity, the effects of penicillin were evaluated on recombinant GABAA receptors expressed in HEK293T cells. When co-applied with saturating GABA, penicillin decreased peak amplitude, induced rebound, and prolonged deactivation of currents e...

  14. Reduction of the pace polarization artefact for capture detection applications by a tri-phasic stimulation pulse.

    Science.gov (United States)

    Sutton, R; Fröhlig, G; de Voogt, W G; Goethals, M; Hintringer, F; Kennergren, C; Scanu, P; Guilleman, D; Treese, N; Hartung, W M; Stammwitz, E; Muetstege, A

    2004-11-01

    This study investigated the ability to minimize pace polarization artefacts (PPA) by adjusting the post-stimulus pulse duration of a tri-phasic stimulation pulse. Adjustment of the stimulation pulse was enabled by downloading special study software into an already implanted pacemaker. Tests were performed in a total of 296 atrial leads and 311 ventricular leads. Both chronic and acute leads were included in the study. Statistically significant differences were found in the initial PPA (without any adjustment of the stimulus pulse) between atrial and ventricular leads. In addition, significant differences were observed among various lead models with respect to changes over time in the initial ventricular PPA. Successful PPA reduction was defined as a reduction of the PPA below 0.5 mV for atrial leads and below 1 mV for ventricular leads. Results show a success rate for ventricular and atrial PPA reduction of 97.8% and 98.7%, respectively. Threshold tests showed that after reduction of the PPA loss of ventricular capture can be reliably detected. However, atrial threshold tests showed many false positive evoked response detections. In addition, unexpectedly high evoked response amplitudes were observed in the atrium after reduction of the PPA. Results from additional measurements suggest that these high atrial evoked response amplitudes come from the influence of the input filter of the pacemaker.

  15. Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder.

    Science.gov (United States)

    Goodman, Marianne; Carpenter, David; Tang, Cheuk Y; Goldstein, Kim E; Avedon, Jennifer; Fernandez, Nicolas; Mascitelli, Kathryn A; Blair, Nicholas J; New, Antonia S; Triebwasser, Joseph; Siever, Larry J; Hazlett, Erin A

    2014-10-01

    Siever and Davis' (1991) psychobiological framework of borderline personality disorder (BPD) identifies affective instability (AI) as a core dimension characterized by prolonged and intense emotional reactivity. Recently, deficient amygdala habituation, defined as a change in response to repeated relative to novel unpleasant pictures within a session, has emerged as a biological correlate of AI in BPD. Dialectical behavior therapy (DBT), an evidence-based treatment, targets AI by teaching emotion-regulation skills. This study tested the hypothesis that BPD patients would exhibit decreased amygdala activation and improved habituation, as well as improved emotion regulation with standard 12-month DBT. Event-related fMRI was obtained pre- and post-12-months of standard-DBT in unmedicated BPD patients. Healthy controls (HCs) were studied as a benchmark for normal amygdala activity and change over time (n = 11 per diagnostic-group). During each scan, participants viewed an intermixed series of unpleasant, neutral and pleasant pictures presented twice (novel, repeat). Change in emotion regulation was measured with the Difficulty in Emotion Regulation (DERS) scale. fMRI results showed the predicted Group × Time interaction: compared with HCs, BPD patients exhibited decreased amygdala activation with treatment. This post-treatment amygdala reduction in BPD was observed for all three pictures types, but particularly marked in the left hemisphere and during repeated-emotional pictures. Emotion regulation measured with the DERS significantly improved with DBT in BPD patients. Improved amygdala habituation to repeated-unpleasant pictures in patients was associated with improved overall emotional regulation measured by the DERS (total score and emotion regulation strategy use subscale). These findings have promising treatment implications and support the notion that DBT targets amygdala hyperactivity-part of the disturbed neural circuitry underlying emotional dysregulation

  16. Regulation of hepatitis B virus ENI enhancer activity by hepatocyte-enriched transcription factor HNF3.

    Science.gov (United States)

    Chen, M; Hieng, S; Qian, X; Costa, R; Ou, J H

    1994-11-15

    Hepatitis B virus (HBV) ENI enhancer can activate the expression of HBV and non-HBV genes in a liver-specific manner. By performing the electrophoretic mobility-shift assays, we demonstrated that the three related, liver-enriched, transcription factors, HNF3 alpha, HNF3 beta, and HNF3 gamma could all bind to the 2c site of HBV ENI enhancer. Mutations introduced in the 2c site to abolish the binding by HNF3 reduced the enhancer activity approximately 15-fold. Moreover, expression of HNF3 antisense sequences to suppress the expression of HNF3 in Huh-7 hepatoma cells led to reduction of the ENI enhancer activity. These results indicate that HNF3 positively regulates the ENI enhancer activity and this regulation is most likely mediated through the 2c site. The requirement of HNF3 for the ENI enhancer activity could explain the liver specificity of this enhancer element.

  17. Down-regulation of telomerase activity in DLD-1 human colorectal adenocarcinoma cells by tocotrienol

    International Nuclear Information System (INIS)

    Eitsuka, Takahiro; Nakagawa, Kiyotaka; Miyazawa, Teruo

    2006-01-01

    As high telomerase activity is detected in most cancer cells, inhibition of telomerase by drug or dietary food components is a new strategy for cancer prevention. Here, we investigated the inhibitory effect of vitamin E, with particular emphasis on tocotrienol (unsaturated vitamin E), on human telomerase in cell-culture study. As results, tocotrienol inhibited telomerase activity of DLD-1 human colorectal adenocarcinoma cells in time- and dose-dependent manner, interestingly, with δ-tocotrienol exhibiting the highest inhibitory activity. Tocotrienol inhibited protein kinase C activity, resulting in down-regulation of c-myc and human telomerase reverse transcriptase (hTERT) expression, thereby reducing telomerase activity. In contrast to tocotrienol, tocopherol showed very weak telomerase inhibition. These results provide novel evidence for First time indicating that tocotrienol acts as a potent candidate regulator of telomerase and supporting the anti-proliferative function of tocotrienol

  18. Regulation of pH in human skeletal muscle: adaptations to physical activity

    DEFF Research Database (Denmark)

    Juel, C

    2008-01-01

    -transport) and describes the contribution of each transport system in pH regulation at rest and during muscle activity. It is reported that the mechanisms involved in pH regulation can undergo adaptational changes in association with physical activity and that these changes are of functional importance....... resonance technique to exercise experiments including blood sampling and muscle biopsies. The present review characterizes the cellular buffering system as well as the most important membrane transport systems involved (Na(+)/H(+) exchange, Na-bicarbonate co-transport and lactate/H(+) co...

  19. Motivation and Behavioral Regulation of Physical Activity in Middle School Students.

    Science.gov (United States)

    Dishman, Rod K; McIver, Kerry L; Dowda, Marsha; Saunders, Ruth P; Pate, Russell R

    2015-09-01

    This study aimed to examine whether intrinsic motivation and behavioral self-regulation are related to physical activity during middle school. Structural equation modeling was applied in cross-sectional and longitudinal tests of self-determination theory. Consistent with theory, hypothesized relations among variables were supported. Integrated regulation and intrinsic motivation were most strongly correlated with moderate-to-vigorous physical activity measured by an accelerometer. Results were independent of a measure of biological maturity. Construct validity and equivalence of measures were confirmed longitudinally between the sixth and seventh grades and between boys and girls, non-Hispanic Black and White children and overweight and normal-weight students. Measures of autonomous motivation (identified, integrated, and intrinsic) were more strongly related to physical activity in the seventh grade than measures of controlled motivation (external and introjected), implying that physical activity became more intrinsically motivating for some girls and boys as they moved through middle school. Nonetheless, change in introjected regulation was related to change in physical activity in the seventh grade, suggesting that internalized social pressures, which can be detrimental to sustained activity and well-being, also became motivating. These results encourage longer prospective studies during childhood and adolescence to clarify how controlled and autonomous motivations for physical activity develop and whether they respond to interventions designed to increase physical activity.

  20. Motivation and Behavioral Regulation of Physical Activity in Middle-School Students

    Science.gov (United States)

    Dishman, Rod K.; McIver, Kerry L; Dowda, Marsha; Saunders, Ruth P.; Pate, Russell R.

    2015-01-01

    Purpose To examine whether intrinsic motivation and behavioral self-regulation are related to physical activity during middle school. Method Structural equation modeling was applied in cross-sectional and longitudinal tests of self-determination theory. Results Consistent with theory, hypothesized relationships among variables were supported. Integrated regulation and intrinsic motivation were most strongly correlated with moderate-to-vigorous physical activity measured by an accelerometer. Results were independent of a measure of biological maturity. Construct validity and equivalence of measures was confirmed longitudinally between 6th and 7th grades and between boys and girls, non-Hispanic black and white children and overweight and normal weight students. Conclusions Measures of autonomous motivation (identified, integrated, and intrinsic) were more strongly related to physical activity in the 7th grade than measures of controlled motivation (external and introjected), implying that physical activity became more intrinsically motivating for some girls and boys as they moved through middle school. Nonetheless, introjected regulation was related to physical activity in 7th grade, suggesting that internalized social pressures, which can be detrimental to sustained activity and well-being, also became motivating. These results encourage longer prospective studies during childhood and adolescence to clarify how controlled and autonomous motivations for physical activity develop and whether they respond to interventions designed to increase physical activity. PMID:25628178

  1. Regulation

    International Nuclear Information System (INIS)

    Ballereau, P.

    1999-01-01

    The different regulations relative to nuclear energy since the first of January 1999 are given here. Two points deserve to be noticed: the decree of the third august 1999 authorizing the national Agency for the radioactive waste management to install and exploit on the commune of Bures (Meuse) an underground laboratory destined to study the deep geological formations where could be stored the radioactive waste. The second point is about the uranium residues and the waste notion. The judgment of the administrative tribunal of Limoges ( 9. july 1998) forbidding the exploitation of a storage installation of depleted uranium considered as final waste and qualifying it as an industrial waste storage facility has been annulled bu the Court of Appeal. It stipulated that, according to the law number 75663 of the 15. july 1965, no criteria below can be applied to depleted uranium: production residue (possibility of an ulterior enrichment), abandonment of a personal property or simple intention to do it ( future use aimed in the authorization request made in the Prefecture). This judgment has devoted the primacy of the waste notion on this one of final waste. (N.C.)

  2. All-trans retinoic acid negatively regulates cytotoxic activities of nature killer cell line 92

    International Nuclear Information System (INIS)

    Li Ang; He Meilan; Wang Hui; Qiao Bin; Chen Ping; Gu Hua; Zhang Mengjie; He Shengxiang

    2007-01-01

    NK cells are key components of innate immune systems and their activities are regulated by cytokines and hormones. All-trans retinoic acid (ATRA), as a metabolite of vitamin A and an immunomodulatory hormone, plays an important role in regulating immune responses. In the present study, we investigated the effect of ATRA on human NK cell line NK92. We found that ATRA dose-dependently suppressed cytotoxic activities of NK92 cells without affecting their proliferation. To explore the mechanisms underlying the ATRA influence on NK92 cells, we examined the production of cytokines (TNF-α, IFN-γ), gene expression of cytotoxic-associated molecules (perforin, granzyme B, nature killer receptors (NCRs), and NKG2D), and the activation of NF-κB pathways related with immune response. Our results demonstrated that ATRA suppressed NF-κB activity and prevented IκBα degradation in a dose-dependent way, inhibited IFN-γ production and gene expression of granzyme B and NKp46. Our findings suggest that ATRA is a negative regulator of NK92 cell activation and may act as a potential regulator of anti-inflammatory functions in vivo

  3. Neural activity to a partner's facial expression predicts self-regulation after conflict

    Science.gov (United States)

    Hooker, Christine I.; Gyurak, Anett; Verosky, Sara; Miyakawa, Asako; Ayduk, Özlem

    2009-01-01

    Introduction Failure to self-regulate after an interpersonal conflict can result in persistent negative mood and maladaptive behaviors. Research indicates that lateral prefrontal cortex (LPFC) activity is related to the regulation of emotional experience in response to lab-based affective challenges, such as viewing emotional pictures. This suggests that compromised LPFC function may be a risk-factor for mood and behavior problems after an interpersonal stressor. However, it remains unclear whether LPFC activity to a lab-based affective challenge predicts self-regulation in real-life. Method We investigated whether LPFC activity to a lab-based affective challenge (negative facial expressions of a partner) predicts self-regulation after a real-life affective challenge (interpersonal conflict). During an fMRI scan, healthy, adult participants in committed, dating relationships (N = 27) viewed positive, negative, and neutral facial expressions of their partners. In an online daily-diary, participants reported conflict occurrence, level of negative mood, rumination, and substance-use. Results LPFC activity in response to the lab-based affective challenge predicted self-regulation after an interpersonal conflict in daily life. When there was no interpersonal conflict, LPFC activity was not related to the change in mood or behavior the next day. However, when an interpersonal conflict did occur, ventral LPFC (VLPFC) activity predicted the change in mood and behavior the next day, such that lower VLPFC activity was related to higher levels of negative mood, rumination, and substance-use. Conclusions Low LPFC function may be a vulnerability and high LPFC function may be a protective factor for the development of mood and behavior problems after an interpersonal stressor. PMID:20004365

  4. Neural activity to a partner's facial expression predicts self-regulation after conflict.

    Science.gov (United States)

    Hooker, Christine I; Gyurak, Anett; Verosky, Sara C; Miyakawa, Asako; Ayduk, Ozlem

    2010-03-01

    Failure to self-regulate after an interpersonal conflict can result in persistent negative mood and maladaptive behaviors. Research indicates that lateral prefrontal cortex (LPFC) activity is related to emotion regulation in response to laboratory-based affective challenges, such as viewing emotional pictures. This suggests that compromised LPFC function may be a risk factor for mood and behavior problems after an interpersonal conflict. However, it remains unclear whether LPFC activity to a laboratory-based affective challenge predicts self-regulation in real life. We investigated whether LPFC activity to a laboratory-based affective challenge (negative facial expressions of a partner) predicts self-regulation after a real-life affective challenge (interpersonal conflict). During a functional magnetic resonance imaging scan, healthy, adult participants in committed relationships (n = 27) viewed positive, negative, and neutral facial expressions of their partners. In a three-week online daily diary, participants reported conflict occurrence, level of negative mood, rumination, and substance use. LPFC activity in response to the laboratory-based affective challenge predicted self-regulation after an interpersonal conflict in daily life. When there was no interpersonal conflict, LPFC activity was not related to mood or behavior the next day. However, when an interpersonal conflict did occur, ventral LPFC (VLPFC) activity predicted mood and behavior the next day, such that lower VLPFC activity was related to higher levels of negative mood, rumination, and substance use. Low LPFC function may be a vulnerability and high LPFC function may be a protective factor for the development of mood and behavior problems after an interpersonal stressor. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Institutional preconditions of socio-ecological-economic regulation of environmental management activities

    Directory of Open Access Journals (Sweden)

    T. A. Plaksunova

    2017-01-01

    Full Text Available The need to regulate environmental management activities of institutional entities arises when it affects the interests of third-party entities or threatened by the ongoing entity manufacturing practices its own resilience, to achieve the main goal. The complexity and diversity of the forms of socio-ecological and ecological-economic issues at different levels of the economic system leads to the development of many directions and views on the expansion of the management process of these levels (global, national, regional, local and techniques from rigid-deklorative state before combination with the market. In this respect, the neoclassical economic theory actively generated new analytical ideas and concept that enables to respond adequately to emerging economic realities. So we can distinguish the following approaches to regulate environmental management activities: T. Malthus and D. Ricardo, revealing issues of social, ecological and economic implications of limited natural resources in the context of the law of diminishing effectiveness and the need to regulate environmental management activities. John. St. Mill and George proved to be ineffective in addressing environmental problems in the industrial economy of the type of the imperfection of the institutions of society, justifying the occurrence of crises protohistoric speculation nature's benefits. A. Pigou developed the theory of externalities, which revealed the need for state regulation of the environmental management activities of economic entities, harmonization of individual and social interests. Research I. Kula, F. Khan and P. Samuelson identified a pattern about the formation of the system of regulation nature-safety activities, not only within individual States but also on a global level. R. Crows have shown that the methods of direct state regulation of nature economic activity is not as good as it seems at first glance and so you should not underestimate the role and potential

  6. Mechanisms and pathways of innate immune activation and regulation in health and cancer.

    Science.gov (United States)

    Cui, Jun; Chen, Yongjun; Wang, Helen Y; Wang, Rong-Fu

    2014-01-01

    Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer.

  7. Activization of the Industrial Development on the Platform of Partnership: Measures of State Regulation

    Directory of Open Access Journals (Sweden)

    Anastasia Y. Nikitaeva

    2016-12-01

    Full Text Available Various forms of partnership and interaction of economic actors play an important role in activization of an industrial development, achieving a critical mass, necessary for generation of essential positive results, due to special measures of state regulation. According to this, the factors influencing the choice of measures of state regulation of partner interactions and formation of their complex structure are defined and analysed. On the example of clusters possible roles of the state in formation and development of partner associations of the appropriate type are presented. The potential risks arising in the course of development and implementation of measures of state regulation of integration structures are shown. The sequence of steps for determination of measures of state regulation of development of partnership in the industrial sphere taking into account local specifics is offered in the paper.

  8. GABA regulates synaptic integration of newly generated neurons in the adult brain

    Science.gov (United States)

    Ge, Shaoyu; Goh, Eyleen L. K.; Sailor, Kurt A.; Kitabatake, Yasuji; Ming, Guo-Li; Song, Hongjun

    2006-02-01

    Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (γ-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

  9. Catecholaminergic Regulation of Learning Rate in a Dynamic Environment.

    Directory of Open Access Journals (Sweden)

    Marieke Jepma

    2016-10-01

    Full Text Available Adaptive behavior in a changing world requires flexibly adapting one's rate of learning to the rate of environmental change. Recent studies have examined the computational mechanisms by which various environmental factors determine the impact of new outcomes on existing beliefs (i.e., the 'learning rate'. However, the brain mechanisms, and in particular the neuromodulators, involved in this process are still largely unknown. The brain-wide neurophysiological effects of the catecholamines norepinephrine and dopamine on stimulus-evoked cortical responses suggest that the catecholamine systems are well positioned to regulate learning about environmental change, but more direct evidence for a role of this system is scant. Here, we report evidence from a study employing pharmacology, scalp electrophysiology and computational modeling (N = 32 that suggests an important role for catecholamines in learning rate regulation. We found that the P3 component of the EEG-an electrophysiological index of outcome-evoked phasic catecholamine release in the cortex-predicted learning rate, and formally mediated the effect of prediction-error magnitude on learning rate. P3 amplitude also mediated the effects of two computational variables-capturing the unexpectedness of an outcome and the uncertainty of a preexisting belief-on learning rate. Furthermore, a pharmacological manipulation of catecholamine activity affected learning rate following unanticipated task changes, in a way that depended on participants' baseline learning rate. Our findings provide converging evidence for a causal role of the human catecholamine systems in learning-rate regulation as a function of environmental change.

  10. Catecholaminergic Regulation of Learning Rate in a Dynamic Environment.

    Science.gov (United States)

    Jepma, Marieke; Murphy, Peter R; Nassar, Matthew R; Rangel-Gomez, Mauricio; Meeter, Martijn; Nieuwenhuis, Sander

    2016-10-01

    Adaptive behavior in a changing world requires flexibly adapting one's rate of learning to the rate of environmental change. Recent studies have examined the computational mechanisms by which various environmental factors determine the impact of new outcomes on existing beliefs (i.e., the 'learning rate'). However, the brain mechanisms, and in particular the neuromodulators, involved in this process are still largely unknown. The brain-wide neurophysiological effects of the catecholamines norepinephrine and dopamine on stimulus-evoked cortical responses suggest that the catecholamine systems are well positioned to regulate learning about environmental change, but more direct evidence for a role of this system is scant. Here, we report evidence from a study employing pharmacology, scalp electrophysiology and computational modeling (N = 32) that suggests an important role for catecholamines in learning rate regulation. We found that the P3 component of the EEG-an electrophysiological index of outcome-evoked phasic catecholamine release in the cortex-predicted learning rate, and formally mediated the effect of prediction-error magnitude on learning rate. P3 amplitude also mediated the effects of two computational variables-capturing the unexpectedness of an outcome and the uncertainty of a preexisting belief-on learning rate. Furthermore, a pharmacological manipulation of catecholamine activity affected learning rate following unanticipated task changes, in a way that depended on participants' baseline learning rate. Our findings provide converging evidence for a causal role of the human catecholamine systems in learning-rate regulation as a function of environmental change.

  11. Modeling post-transcriptional regulation activity of small non-coding RNAs in Escherichia coli.

    Science.gov (United States)

    Wang, Rui-Sheng; Jin, Guangxu; Zhang, Xiang-Sun; Chen, Luonan

    2009-04-29

    Transcriptional regulation is a fundamental process in biological systems, where transcription factors (TFs) have been revealed to play crucial roles. In recent years, in addition to TFs, an increasing number of non-coding RNAs (ncRNAs) have been shown to mediate post-transcriptional processes and regulate many critical pathways in both prokaryotes and eukaryotes. On the other hand, with more and more high-throughput biological data becoming available, it is possible and imperative to quantitatively study gene regulation in a systematic and detailed manner. Most existing studies for inferring transcriptional regulatory interactions and the activity of TFs ignore the possible post-transcriptional effects of ncRNAs. In this work, we propose a novel framework to infer the activity of regulators including both TFs and ncRNAs by exploring the expression profiles of target genes and (post)transcriptional regulatory relationships. We model the integrated regulatory system by a set of biochemical reactions which lead to a log-bilinear problem. The inference process is achieved by an iterative algorithm, in which two linear programming models are efficiently solved. In contrast to available related studies, the effects of ncRNAs on transcription process are considered in this work, and thus more reasonable and accurate reconstruction can be expected. In addition, the approach is suitable for large-scale problems from the viewpoint of computation. Experiments on two synthesized data sets and a model system of Escherichia coli (E. coli) carbon source transition from glucose to acetate illustrate the effectiveness of our model and algorithm. Our results show that incorporating the post-transcriptional regulation of ncRNAs into system model can mine the hidden effects from the regulation activity of TFs in transcription processes and thus can uncover the biological mechanisms in gene regulation in a more accurate manner. The software for the algorithm in this paper is available

  12. Commission de regulation de l'energie. activity report 2015 - Reference document, 15 years of regulation

    International Nuclear Information System (INIS)

    2016-06-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the June 2015 activity report of CRE. The report comes in two volumes. The first provides comprehensive details of the CRE's activities in 2015, while the second highlights just how far the CRE has come since it was established in 2000. Content: A - Message from the Board; B - The Energy Regulatory Commission: The organisation and missions of CRE (organisation of CRE, missions of CRE, CRE and other institutional actors, CRE consultation and transparency, Human resources and budgetary means; CRE playing a role at the heart of Europe (CRE within ACER and CEER, Cooperation with other regulators; C - CRE and the markets: As part of its monitoring task, CRE assesses the wholesale market (The wholesale energy market has been affected by the significant fall in prices, The European regulation (REMIT) is a legal tool for monitoring the markets at European level, The capacity mechanism has been defined to promote the security of supply at national level); The retail market was growing fast in 2015 (The implementation of the NOME law provides a new legal framework for regulated tariffs

  13. Self-Regulation and Implicit Attitudes Toward Physical Activity Influence Exercise Behavior.

    Science.gov (United States)

    Padin, Avelina C; Emery, Charles F; Vasey, Michael; Kiecolt-Glaser, Janice K

    2017-08-01

    Dual-process models of health behavior posit that implicit and explicit attitudes independently drive healthy behaviors. Prior evidence indicates that implicit attitudes may be related to weekly physical activity (PA) levels, but the extent to which self-regulation attenuates this link remains unknown. This study examined the associations between implicit attitudes and self-reported PA during leisure time among 150 highly active young adults and evaluated the extent to which effortful control (one aspect of self-regulation) moderated this relationship. Results indicated that implicit attitudes toward exercise were unrelated to average workout length among individuals with higher effortful control. However, those with lower effortful control and more negative implicit attitudes reported shorter average exercise sessions compared with those with more positive attitudes. Implicit and explicit attitudes were unrelated to total weekly PA. A combination of poorer self-regulation and negative implicit attitudes may leave individuals vulnerable to mental and physical health consequences of low PA.

  14. Reducing Conservatism in Aircraft Engine Response Using Conditionally Active Min-Max Limit Regulators

    Science.gov (United States)

    May, Ryan D.; Garg, Sanjay

    2012-01-01

    Current aircraft engine control logic uses a Min-Max control selection structure to prevent the engine from exceeding any safety or operational limits during transients due to throttle commands. This structure is inherently conservative and produces transient responses that are slower than necessary. In order to utilize the existing safety margins more effectively, a modification to this architecture is proposed, referred to as a Conditionally Active (CA) limit regulator. This concept uses the existing Min-Max architecture with the modification that limit regulators are active only when the operating point is close to a particular limit. This paper explores the use of CA limit regulators using a publicly available commercial aircraft engine simulation. The improvement in thrust response while maintaining all necessary safety limits is demonstrated in a number of cases.

  15. Mitochondrial activity in the regulation of stem cell self-renewal and differentiation.

    Science.gov (United States)

    Khacho, Mireille; Slack, Ruth S

    2017-12-01

    Mitochondria are classically known as the essential energy producers in cells. As such, the activation of mitochondrial metabolism upon cellular differentiation was deemed a necessity to fuel the high metabolic needs of differentiated cells. However, recent studies have revealed a direct role for mitochondrial activity in the regulation of stem cell fate and differentiation. Several components of mitochondrial metabolism and respiration have now been shown to regulate different aspects of stem cell differentiation through signaling, transcriptional, proteomic and epigenetic modulations. In light of these findings mitochondrial metabolism is no longer considered a consequence of cellular differentiation, but rather a key regulatory mechanism of this process. This review will focus on recent progress that defines mitochondria as the epicenters for the regulation of stem cell fate decisions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Glycogen synthase kinase 3 alpha phosphorylates and regulates the osteogenic activity of Osterix.

    Science.gov (United States)

    Li, Hongyan; Jeong, Hyung Min; Choi, You Hee; Lee, Sung Ho; Jeong, Hye Gwang; Jeong, Tae Cheon; Lee, Kwang Youl

    2013-05-10

    Osteoblast-specific transcription factor Osterix is a zinc-finger transcription factor that required for osteoblast differentiation and new bone formation. The function of Osterix can be modulated by post-translational modification. Glycogen synthase kinase 3 alpha (GSK3α) is a multifunctional serine/threonine protein kinase that plays a role in the Wnt signaling pathways and is implicated in the control of several regulatory proteins and transcription factors. In the present study, we investigated how GSK3α regulates Osterix during osteoblast differentiation. Wide type GSK3α up-regulated the protein level, protein stability and transcriptional activity of Osterix. These results suggest that GSK3α regulates osteogenic activity of Osterix. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Dual regulation of muscle glycogen synthase during exercise by activation and compartmentalization

    DEFF Research Database (Denmark)

    Prats, Clara; Helge, Jørn W; Nordby, Pernille

    2009-01-01

    Glycogen synthase (GS) is considered the rate-limiting enzyme in glycogenesis but still today there is a lack of understanding on its regulation. We have previously shown phosphorylation-dependent GS intracellular redistribution at the start of glycogen re-synthesis in rabbit skeletal muscle (Prats......, C., Cadefau, J. A., Cussó, R., Qvortrup, K., Nielsen, J. N., Wojtaszewki, J. F., Wojtaszewki, J. F., Hardie, D. G., Stewart, G., Hansen, B. F., and Ploug, T. (2005) J. Biol. Chem. 280, 23165-23172). In the present study we investigate the regulation of human muscle GS activity by glycogen, exercise......, and insulin. Using immunocytochemistry we investigate the existence and relevance of GS intracellular compartmentalization during exercise and during glycogen re-synthesis. The results show that GS intrinsic activity is strongly dependent on glycogen levels and that such regulation involves associated...

  18. Acetic acid activates the AMP-activated protein kinase signaling pathway to regulate lipid metabolism in bovine hepatocytes.

    Directory of Open Access Journals (Sweden)

    Xinwei Li

    Full Text Available The effect of acetic acid on hepatic lipid metabolism in ruminants differs significantly from that in monogastric animals. Therefore, the aim of this study was to investigate the regulation mechanism of acetic acid on the hepatic lipid metabolism in dairy cows. The AMP-activated protein kinase (AMPK signaling pathway plays a key role in regulating hepatic lipid metabolism. In vitro, bovine hepatocytes were cultured and treated with different concentrations of sodium acetate (neutralized acetic acid and BML-275 (an AMPKα inhibitor. Acetic acid consumed a large amount of ATP, resulting in an increase in AMPKα phosphorylation. The increase in AMPKα phosphorylation increased the expression and transcriptional activity of peroxisome proliferator-activated receptor α, which upregulated the expression of lipid oxidation genes, thereby increasing lipid oxidation in bovine hepatocytes. Furthermore, elevated AMPKα phosphorylation reduced the expression and transcriptional activity of the sterol regulatory element-binding protein 1c and the carbohydrate responsive element-binding protein, which reduced the expression of lipogenic genes, thereby decreasing lipid biosynthesis in bovine hepatocytes. In addition, activated AMPKα inhibited the activity of acetyl-CoA carboxylase. Consequently, the triglyceride content in the acetate-treated hepatocytes was significantly decreased. These results indicate that acetic acid activates the AMPKα signaling pathway to increase lipid oxidation and decrease lipid synthesis in bovine hepatocytes, thereby reducing liver fat accumulation in dairy cows.

  19. Roles of ADAM13-regulated Wnt activity in early Xenopus eye development

    OpenAIRE

    Wei, Shuo; Xu, Guofeng; Bridges, Lance C.; Williams, Phoebe; Nakayama, Takuya; Shah, Anoop; Grainger, Robert M.; White, Judith M.; DeSimone, Douglas W.

    2011-01-01

    Pericellular proteolysis by ADAM family metalloproteinases has been widely implicated in cell signaling and development. We recently found that Xenopus ADAM13, an ADAM metalloproteinase, is required for activation of canonical Wnt signaling during cranial neural crest (CNC) induction by regulating a novel crosstalk between Wnt and ephrin B (EfnB) signaling pathways (Wei et al., 2010b). In the present study we show that the metalloproteinase activity of ADAM13 also plays important roles in eye...

  20. Regulation of crp gene expression by the catabolite repressor/activator, Cra, in Escherichia coli.

    Science.gov (United States)

    Zhang, Zhongge; Aboulwafa, Mohammad; Saier, Milton H

    2014-01-01

    Growth of E. coli on several carbon sources is dependent on the catabolite repressor/activator (Cra) protein although a Cra consensus DNA-binding site is not present in the control regions of the relevant catabolic operons. We show that Cra regulates growth by activating expression of the crp gene. It thereby mediates catabolite repression of catabolic operons by an indirect mechanism. © 2014 S. Karger AG, Basel.

  1. 14 CFR 1204.1503 - Programs and activities subject to these regulations.

    Science.gov (United States)

    2010-01-01

    ... regulations. 1204.1503 Section 1204.1503 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION ADMINISTRATIVE AUTHORITY AND POLICY Intergovernmental Review of National Aeronautics and Space Administration... publishes in the Federal Register a description of the Agency's programs and activities that are subject to...

  2. 75 FR 28276 - Agency Information Collection Activities: NAFTA Regulations and Certificate of Origin

    Science.gov (United States)

    2010-05-20

    ... Review: Revision. Affected Public: Businesses. Form 434, NAFTA Certificate of Origin: Estimated Number of... Activities: NAFTA Regulations and Certificate of Origin AGENCY: U.S. Customs and Border Protection... Homeland Security has submitted the following information collection request to the Office of Management...

  3. Self-Regulated Learning and Perceived Health among Students Participating in University Physical Activity Classes

    Science.gov (United States)

    McBride, Ron E.; Xiang, Ping

    2013-01-01

    Three hundred and sixty-one students participating in university physical activity classes completed questionnaires assessing perceived health and self-regulated learning. In addition, 20 students (11 men; 9 women) were interviewed about their reasons for enrolling, participation and goals in the class. Results indicated the students endorsed…

  4. A Kinesthetic Activity Using LEGO Bricks and Buckets for Illustrating the Regulation of Blood Sugar

    Science.gov (United States)

    Urschler, Margaret; Meidl, Katherine; Browning, Samantha; Khan, Basima; Milanick, Mark

    2015-01-01

    This article describes how, when first faced with understanding blood sugar regulation, students often resort to simple memorization.Many students would like to get more involved with the conceptual framework but do not know how to start. The authors have developed an activity based on the Modell approach, a "view from the inside." This…

  5. Activity Regulation by Heteromerization of Arabidopsis Allene Oxide Cyclase Family Members

    Czech Academy of Sciences Publication Activity Database

    Otto, M.; Naumann, Ch.; Brandt, W.; Wasternack, Claus; Hause, B.

    2016-01-01

    Roč. 5, č. 1 (2016), č. článku 3. ISSN 2223-7747 R&D Projects: GA MŠk(CZ) LO1204 Institutional support: RVO:61389030 Keywords : Activity regulation * Arabidopsis allene oxide cyclase isoforms * Heteromerization Subject RIV: EB - Genetics ; Molecular Biology

  6. PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner

    NARCIS (Netherlands)

    Sjöqvist, M.; Antfolk, D.; Ferraris, S.; Rraklli, V.; Haga, C.; Antila, C.; Mutvei, A.; Imanishi, S.Y.; Holmberg, J.; Jin, S.; Eriksson, J.E.; Lendahl, U.; Sahlgren, C.M.

    Activation of Notch signaling requires intracellular routing of the receptor, but the mechanisms controlling the distinct steps in the routing process is poorly understood. We identify PKCζ as a key regulator of Notch receptor intracellular routing. When PKCζ was inhibited in the developing chick

  7. 15 CFR 20.2 - Programs or activities to which these regulations apply.

    Science.gov (United States)

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Programs or activities to which these regulations apply. 20.2 Section 20.2 Commerce and Foreign Trade Office of the Secretary of Commerce... adopted by an elected, general purpose legislative body which: (i) Provides benefits or assistance to...

  8. Running on Empty: Leptin Signaling in VTA Regulates Reward from Physical Activity.

    Science.gov (United States)

    Chen, Zuxin; Kenny, Paul J

    2015-10-06

    Hunger increases physical activity and stamina to support food-directed foraging behaviors, but underlying mechanisms are unclear. In this issue, Fernandes et al. (2015) show that disruption of leptin-regulated STAT3 signaling in midbrain dopamine neurons increases the rewarding effects of running in mice, which could explain the "high" experienced by endurance runners. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Regulation of activity of the yeast TATA-binding protein through intra ...

    Indian Academy of Sciences (India)

    Unknown

    Abbreviations used: BMH, Bismaleimidohexane; TBP, TATA-binding protein; yTBP, yeast TBP. J. Biosci. | Vol. ... Therefore for full-length TBP, intra-molecular interactions can regulate its activity via a similar ..... simulations (Miaskeiwicz and Ornstein 1996). .... box binding protein (TBP): A molecular dynamics computa-.

  10. 78 FR 78375 - Agency Information Collection Activities: CBP Regulations Pertaining to Customs Brokers

    Science.gov (United States)

    2013-12-26

    ... DEPARTMENT OF HOMELAND SECURITY U.S. Customs and Border Protection Agency Information Collection Activities: CBP Regulations Pertaining to Customs Brokers Correction In notice document 2013-30220 appearing on page 76851 of the issue of Thursday, December 19, 2013, make the following correction: In the...

  11. Resveratrol post-transcriptionally regulates pro-inflammatory gene expression via regulation of KSRP RNA binding activity

    Science.gov (United States)

    Bollmann, Franziska; Art, Julia; Henke, Jenny; Schrick, Katharina; Besche, Verena; Bros, Matthias; Li, Huige; Siuda, Daniel; Handler, Norbert; Bauer, Florian; Erker, Thomas; Behnke, Felix; Mönch, Bettina; Härdle, Lorena; Hoffmann, Markus; Chen, Ching-Yi; Förstermann, Ulrich; Dirsch, Verena M.; Werz, Oliver; Kleinert, Hartmut; Pautz, Andrea

    2014-01-01

    Resveratrol shows beneficial effects in inflammation-based diseases like cancer, cardiovascular and chronic inflammatory diseases. Therefore, the molecular mechanisms of the anti-inflammatory resveratrol effects deserve more attention. In human epithelial DLD-1 and monocytic Mono Mac 6 cells resveratrol decreased the expression of iNOS, IL-8 and TNF-α by reducing mRNA stability without inhibition of the promoter activity. Shown by pharmacological and siRNA-mediated inhibition, the observed effects are SIRT1-independent. Target-fishing and drug responsive target stability experiments showed selective binding of resveratrol to the RNA-binding protein KSRP, a central post-transcriptional regulator of pro-inflammatory gene expression. Knockdown of KSRP expression prevented resveratrol-induced mRNA destabilization in human and murine cells. Resveratrol did not change KSRP expression, but immunoprecipitation experiments indicated that resveratrol reduces the p38 MAPK-related inhibitory KSRP threonine phosphorylation, without blocking p38 MAPK activation or activity. Mutation of the p38 MAPK target site in KSRP blocked the resveratrol effect on pro-inflammatory gene expression. In addition, resveratrol incubation enhanced KSRP-exosome interaction, which is important for mRNA degradation. Finally, resveratrol incubation enhanced its intra-cellular binding to the IL-8, iNOS and TNF-α mRNA. Therefore, modulation of KSRP mRNA binding activity and, thereby, enhancement of mRNA degradation seems to be the common denominator of many anti-inflammatory effects of resveratrol. PMID:25352548

  12. Simultaneous Activation of Iron- and Thiol-Based Sensor-Regulator Systems by Redox-Active Compounds.

    Science.gov (United States)

    Lee, Kang-Lok; Yoo, Ji-Sun; Oh, Gyeong-Seok; Singh, Atul K; Roe, Jung-Hye

    2017-01-01

    Bacteria in natural habitats are exposed to myriad redox-active compounds (RACs), which include producers of reactive oxygen species (ROS) and reactive electrophile species (RES) that alkylate or oxidize thiols. RACs can induce oxidative stress in cells and activate response pathways by modulating the activity of sensitive regulators. However, the effect of a certain compound on the cell has been investigated primarily with respect to a specific regulatory pathway. Since a single compound can exert multiple chemical effects in the cell, its effect can be better understood by time-course monitoring of multiple sensitive regulatory pathways that the compound induces. We investigated the effect of representative RACs by monitoring the activity of three sensor-regulators in the model actinobacterium Streptomyces coelicolor ; SoxR that senses reactive compounds directly through oxidation of its [2Fe-2S] cluster, CatR/PerR that senses peroxides through bound iron, and an anti-sigma factor RsrA that senses RES via disulfide formation. The time course and magnitude of induction of their target transcripts were monitored to predict the chemical activities of each compound in S. coelicolor . Phenazine methosulfate (PMS) was found to be an effective RAC that directly activated SoxR and an effective ROS-producer that induced CatR/PerR with little thiol-perturbing activity. p -Benzoquinone was an effective RAC that directly activated SoxR, with slower ROS-producing activity, and an effective RES that induced the RsrA-SigR system. Plumbagin was an effective RAC that activated SoxR, an effective ROS-producer, and a less agile but effective RES. Diamide was an RES that effectively formed disulfides and a weak RAC that activated SoxR. Monobromobimane was a moderately effective RES and a slow producer of ROS. Interestingly, benzoquinone induced the SigR system by forming adducts on cysteine thiols in RsrA, revealing a new pathway to modulate RsrA activity. Overall, this study showed

  13. An Arabidopsis SUMO E3 Ligase, SIZ1, Negatively Regulates Photomorphogenesis by Promoting COP1 Activity

    KAUST Repository

    Lin, Xiao-Li

    2016-04-29

    COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1), a ubiquitin E3 ligase, is a central negative regulator of photomorphogenesis. However, how COP1 activity is regulated by post-translational modifications remains largely unknown. Here we show that SUMO (small ubiquitin-like modifier) modification enhances COP1 activity. Loss-of-function siz1 mutant seedlings exhibit a weak constitutive photomorphogenic phenotype. SIZ1 physically interacts with COP1 and mediates the sumoylation of COP1. A K193R substitution in COP1 blocks its SUMO modification and reduces COP1 activity in vitro and in planta. Consistently, COP1 activity is reduced in siz1 and the level of HY5, a COP1 target protein, is increased in siz1. Sumoylated COP1 may exhibits higher transubiquitination activity than does non-sumoylated COP1, but SIZ1-mediated SUMO modification does not affect COP1 dimerization, COP1-HY5 interaction, and nuclear accumulation of COP1. Interestingly, prolonged light exposure reduces the sumoylation level of COP1, and COP1 mediates the ubiquitination and degradation of SIZ1. These regulatory mechanisms may maintain the homeostasis of COP1 activity, ensuing proper photomorphogenic development in changing light environment. Our genetic and biochemical studies identify a function for SIZ1 in photomorphogenesis and reveal a novel SUMO-regulated ubiquitin ligase, COP1, in plants.

  14. An Arabidopsis SUMO E3 Ligase, SIZ1, Negatively Regulates Photomorphogenesis by Promoting COP1 Activity

    KAUST Repository

    Lin, Xiao-Li; Niu, De; Hu, Zi-Liang; Kim, Dae Heon; Jin, Yin Hua; Cai, Bin; Liu, Peng; Miura, Kenji; Yun, Dae-Jin; Kim, Woe-Yeon; Lin, Rongcheng; Jin, Jing Bo

    2016-01-01

    COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1), a ubiquitin E3 ligase, is a central negative regulator of photomorphogenesis. However, how COP1 activity is regulated by post-translational modifications remains largely unknown. Here we show that SUMO (small ubiquitin-like modifier) modification enhances COP1 activity. Loss-of-function siz1 mutant seedlings exhibit a weak constitutive photomorphogenic phenotype. SIZ1 physically interacts with COP1 and mediates the sumoylation of COP1. A K193R substitution in COP1 blocks its SUMO modification and reduces COP1 activity in vitro and in planta. Consistently, COP1 activity is reduced in siz1 and the level of HY5, a COP1 target protein, is increased in siz1. Sumoylated COP1 may exhibits higher transubiquitination activity than does non-sumoylated COP1, but SIZ1-mediated SUMO modification does not affect COP1 dimerization, COP1-HY5 interaction, and nuclear accumulation of COP1. Interestingly, prolonged light exposure reduces the sumoylation level of COP1, and COP1 mediates the ubiquitination and degradation of SIZ1. These regulatory mechanisms may maintain the homeostasis of COP1 activity, ensuing proper photomorphogenic development in changing light environment. Our genetic and biochemical studies identify a function for SIZ1 in photomorphogenesis and reveal a novel SUMO-regulated ubiquitin ligase, COP1, in plants.

  15. Antisense long noncoding RNAs regulate var gene activation in the malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    Amit-Avraham, Inbar; Pozner, Guy; Eshar, Shiri; Fastman, Yair; Kolevzon, Netanel; Yavin, Eylon; Dzikowski, Ron

    2015-03-03

    The virulence of Plasmodium falciparum, the causative agent of the deadliest form of human malaria, is attributed to its ability to evade human immunity through antigenic variation. These parasites alternate between expression of variable antigens, encoded by members of a multicopy gene family named var. Immune evasion through antigenic variation depends on tight regulation of var gene expression, ensuring that only a single var gene is expressed at a time while the rest of the family is maintained transcriptionally silent. Understanding how a single gene is chosen for activation is critical for understanding mutually exclusive expression but remains a mystery. Here, we show that antisense long noncoding RNAs (lncRNAs) initiating from var introns are associated with the single active var gene at the time in the cell cycle when the single var upstream promoter is active. We demonstrate that these antisense transcripts are incorporated into chromatin, and that expression of these antisense lncRNAs in trans triggers activation of a silent var gene in a sequence- and dose-dependent manner. On the other hand, interference with these lncRNAs using complement peptide nucleic acid molecules down-regulated the active var gene, erased the epigenetic memory, and induced expression switching. Altogether, our data provide evidence that these antisense lncRNAs play a key role in regulating var gene activation and mutually exclusive expression.

  16. Inhibition of calmodulin - regulated calcium pump activity in rat brain by toxaphene

    International Nuclear Information System (INIS)

    Trottman, C.H.; Moorthy, K.S.

    1986-01-01

    In vivo effects of toxaphene on calcium pump activity in rat brain synaptosomes was studied. Male Sprague-Dawley rats were dosed with toxaphene at 0,25,50, and 100 mg/kg/day for 3 days and sacrificed 24 h after last dose. Ca 2+ -ATPase activity and 45 Ca uptake were determined in brain P 2 fraction. Toxaphene inhibited both Ca 2+ -ATPase activity and 45 Ca 2+ uptake and the inhibition was dose dependent. Both substrate and Ca 2+ activation kinetics of Ca 2+ -ATPase indicated non-competitive type of inhibition as evidenced by decreased catalytic velocity but not enzyme-substrate affinity. The inhibited Ca 2+ -ATPase activity and Ca 2+ uptake were restored to normal level by exogenously added calmodulin which increased both velocity and affinity. The inhibition of Ca 2+ -ATPase activity and Ca 2+ uptake and restoration by calmodulin suggests that toxaphene may impair active calcium transport mechanisms by decreasing regulator protein calmodulin levels

  17. DMPD: Regulation of arachidonic acid release and cytosolic phospholipase A2activation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 10080535 Regulation of arachidonic acid release and cytosolic phospholipase A2activ...on of arachidonic acid release and cytosolic phospholipase A2activation. PubmedID 10080535 Title Regulation ...of arachidonic acid release and cytosolic phospholipase A2activation. Authors Gij

  18. Slow phasic changes in nucleus accumbens dopamine release during fixed ratio acquisition: a microdialysis study.

    Science.gov (United States)

    Segovia, K N; Correa, M; Salamone, J D

    2011-11-24

    Nucleus accumbens dopamine (DA) is a critical component of the brain circuitry regulating behavioral output during reinforcement-seeking behavior. Several studies have investigated the characteristics of accumbens DA release during the performance of well-learned operant behaviors, but relatively few have focused on the initial acquisition of particular instrumental behaviors or operant schedules. The present experiments focused on the initial acquisition of operant performance on a reinforcement schedule by studying the transition from a fixed ratio 1 (FR1) schedule to another operant schedule with a higher ratio requirement (i.e. fixed ratio 5 [FR5]). Microdialysis sessions were conducted in different groups of rats that were tested on either the FR1 schedule; the first, second, or third day of FR5 training; or after weeks of FR5 training. Consistent with previous studies, well-trained rats performing on the FR5 schedule after weeks of training showed significant increases in extracellular DA in both core and shell subregions of nucleus accumbens during the behavioral session. On the first day of FR5 training, there was a substantial increase in DA release in nucleus accumbens shell (i.e. approximately 300% of baseline). In contrast, accumbens core DA release was greatest on the second day of FR5 training. In parallel experiments, DA release in core and shell subregions did not significantly increase during free consumption of the same high carbohydrate food pellets that were used in the operant experiments, despite the very high levels of food intake in experienced rats. However, in rats exposed to the high-carbohydrate food for the first time, there was a tendency for extracellular DA to show a small increase. These results demonstrate that transient increases in accumbens DA release occur during the initial acquisition of ratio performance, and suggest that core and shell subregions show different temporal patterns during acquisition of instrumental behavior

  19. Phasic and tonic stress-strain data obtained in intact intestinal segment in vitro

    DEFF Research Database (Denmark)

    Zhao, Jingbo; Liao, Donghua; Gregersen, Hans

    2008-01-01

    segments were isolated from ten Wistar rats and put into an organ bath containing 37 degrees C aerated Krebs solution. Ramp distension was done on active and passive intestinal segments at longitudinal stretch ratios of 0, 10, and 20%. Ramp pressures from 0 to 7.5 cmH(2)O were applied to the intestinal...... was defined as the total stress minus the passive stress. The total and passive circumferential stresses increased exponentially as a function of the strain. The amplitude of both the total and passive stress was biggest in the jejunum. The total circumferential stress decreased whereas the passive...

  20. LIX1 regulates YAP1 activity and controls the proliferation and differentiation of stomach mesenchymal progenitors.

    Science.gov (United States)

    McKey, Jennifer; Martire, Delphine; de Santa Barbara, Pascal; Faure, Sandrine

    2016-04-28

    Smooth muscle cell (SMC) plasticity maintains the balance between differentiated SMCs and proliferative mesenchymal progenitors, crucial for muscular tissue homeostasis. Studies on the development of mesenchymal progenitors into SMCs have proven useful in identifying molecular mechanisms involved in digestive musculature plasticity in physiological and pathological conditions. Here, we show that Limb Expression 1 (LIX1) molecularly defines the population of mesenchymal progenitors in the developing stomach. Using in vivo functional approaches in the chick embryo, we demonstrate that LIX1 is a key regulator of stomach SMC development. We show that LIX1 is required for stomach SMC determination to regulate the expression of the pro-proliferative gene YAP1 and mesenchymal cell proliferation. However, as stomach development proceeds, sustained LIX1 expression has a negative impact on further SMC differentiation and this is associated with a decrease in YAP1 activity. We demonstrate that expression of LIX1 must be tightly regulated to allow fine-tuning of the transcript levels and state of activation of the pro-proliferative transcriptional coactivator YAP1 to regulate proliferation rates of stomach mesenchymal progenitors and their differentiation. Our data highlight dual roles for LIX1 and YAP1 and provide new insights into the regulation of cell density-dependent proliferation, which is essential for the development and homeostasis of organs.

  1. Endogenous Cholinergic Inputs and Local Circuit Mechanisms Govern the Phasic Mesolimbic Dopamine Response to Nicotine

    Science.gov (United States)

    Graupner, Michael; Maex, Reinoud; Gutkin, Boris

    2013-01-01

    Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement. PMID:23966848

  2. Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation

    Directory of Open Access Journals (Sweden)

    Raj Kumar

    2008-08-01

    Full Text Available Raj Kumar1, William J Calhoun21Division of Gastroenterology; 2Division of Allergy, Pulmonary, Immunology, Critical Care, and Sleep (APICS, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USAAbstract: Post-translational modifications such as phosphorylation are known to play an important role in the gene regulation by the transcription factors including the nuclear hormone receptor superfamily of which the glucocorticoid receptor (GR is a member. Protein phosphorylation often switches cellular activity from one state to another. Like many other transcription factors, the GR is a phosphoprotein, and phosphorylation plays an important role in the regulation of GR activity. Cell signaling pathways that regulate phosphorylation of the GR and its associated proteins are important determinants of GR function under various physiological conditions. While the role of many phosphorylation sites in the GR is still not fully understood, the role of others is clearer. Several aspects of transcription factor function, including DNA binding affinity, interaction of transactivation domains with the transcription initiation complex, and shuttling between the cytoplasmic compartments, have all been linked to site-specific phosphorylation. All major phosphorylation sites in the human GR are located in the N-terminal domain including the major transactivation domain, AF1. Available literature clearly indicates that many of these potential phosphorylation sites are substrates for multiple kinases, suggesting the potential for a very complex regulatory network. Phosphorylated GR interacts favorably with critical coregulatory proteins and subsequently enhances transcriptional activity. In addition, the activities and specificities of coregulators may be subject to similar regulation by phosphorylation. Regulation of the GR activity due to phosphorylation appears to be site-specific and dependent upon specific cell signaling cascade

  3. Cyclic nucleotides and mitogen-activated protein kinases: regulation of simvastatin in platelet activation

    Directory of Open Access Journals (Sweden)

    Hou Ssu-Yu

    2010-06-01

    Full Text Available Abstract Background 3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA reductase inhibitors (statins have been widely used to reduce cardiovascular risk. These statins (i.e., simvastatin may exert other effects besides from their cholesterol-lowering actions, including inhibition of platelet activation. Platelet activation is relevant to a variety of coronary heart diseases. Although the inhibitory effect of simvastatin in platelet activation has been studied; the detailed signal transductions by which simvastatin inhibit platelet activation has not yet been completely resolved. Methods The aim of this study was to systematically examine the detailed mechanisms of simvastatin in preventing platelet activation. Platelet aggregation, flow cytometric analysis, immunoblotting, and electron spin resonance studies were used to assess the antiplatelet activity of simvastatin. Results Simvastatin (20-50 μM exhibited more-potent activity of inhibiting platelet aggregation stimulated by collagen than other agonists (i.e., thrombin. Simvastatin inhibited collagen-stimulated platelet activation accompanied by [Ca2+]i mobilization, thromboxane A2 (TxA2 formation, and phospholipase C (PLCγ2, protein kinase C (PKC, and mitogen-activated protein kinases (i.e., p38 MAPK, JNKs phosphorylation in washed platelets. Simvastatin obviously increased both cyclic AMP and cyclic GMP levels. Simvastatin markedly increased NO release, vasodilator-stimulated phosphoprotein (VASP phosphorylation, and endothelial nitric oxide synthase (eNOS expression. SQ22536, an inhibitor of adenylate cyclase, markedly reversed the simvastatin-mediated inhibitory effects on platelet aggregation, PLCγ2 and p38 MAPK phosphorylation, and simvastatin-mediated stimulatory effects on VASP and eNOS phosphorylation. Conclusion The most important findings of this study demonstrate for the first time that inhibitory effect of simvastatin in platelet activation may involve activation of the cyclic AMP

  4. Network feedback regulates motor output across a range of modulatory neuron activity.

    Science.gov (United States)

    Spencer, Robert M; Blitz, Dawn M

    2016-06-01

    Modulatory projection neurons alter network neuron synaptic and intrinsic properties to elicit multiple different outputs. Sensory and other inputs elicit a range of modulatory neuron activity that is further shaped by network feedback, yet little is known regarding how the impact of network feedback on modulatory neurons regulates network output across a physiological range of modulatory neuron activity. Identified network neurons, a fully described connectome, and a well-characterized, identified modulatory projection neuron enabled us to address this issue in the crab (Cancer borealis) stomatogastric nervous system. The modulatory neuron modulatory commissural neuron 1 (MCN1) activates and modulates two networks that generate rhythms via different cellular mechanisms and at distinct frequencies. MCN1 is activated at rates of 5-35 Hz in vivo and in vitro. Additionally, network feedback elicits MCN1 activity time-locked to motor activity. We asked how network activation, rhythm speed, and neuron activity levels are regulated by the presence or absence of network feedback across a physiological range of MCN1 activity rates. There were both similarities and differences in responses of the two networks to MCN1 activity. Many parameters in both networks were sensitive to network feedback effects on MCN1 activity. However, for most parameters, MCN1 activity rate did not determine the extent to which network output was altered by the addition of network feedback. These data demonstrate that the influence of network feedback on modulatory neuron activity is an important determinant of network output and feedback can be effective in shaping network output regardless of the extent of network modulation. Copyright © 2016 the American Physiological Society.

  5. The zinc transporter ZIPT-7.1 regulates sperm activation in nematodes.

    Directory of Open Access Journals (Sweden)

    Yanmei Zhao

    2018-06-01

    Full Text Available Sperm activation is a fascinating example of cell differentiation, in which immotile spermatids undergo a rapid and dramatic transition to become mature, motile sperm. Because the sperm nucleus is transcriptionally silent, this transition does not involve transcriptional changes. Although Caenorhabditis elegans is a leading model for studies of sperm activation, the mechanisms by which signaling pathways induce this transformation remain poorly characterized. Here we show that a conserved transmembrane zinc transporter, ZIPT-7.1, regulates the induction of sperm activation in Caenorhabditis nematodes. The zipt-7.1 mutant hermaphrodites cannot self-fertilize, and males reproduce poorly, because mutant spermatids are defective in responding to activating signals. The zipt-7.1 gene is expressed in the germ line and functions in germ cells to promote sperm activation. When expressed in mammalian cells, ZIPT-7.1 mediates zinc transport with high specificity and is predominantly located on internal membranes. Finally, genetic epistasis places zipt-7.1 at the end of the spe-8 sperm activation pathway, and ZIPT-7.1 binds SPE-4, a presenilin that regulates sperm activation. Based on these results, we propose a new model for sperm activation. In spermatids, inactive ZIPT-7.1 is localized to the membranous organelles, which contain higher levels of zinc than the cytoplasm. When sperm activation is triggered, ZIPT-7.1 activity increases, releasing zinc from internal stores. The resulting increase in cytoplasmic zinc promotes the phenotypic changes characteristic of activation. Thus, zinc signaling is a key step in the signal transduction process that mediates sperm activation, and we have identified a zinc transporter that is central to this activation process.

  6. PPARβ/δ regulates glucocorticoid- and sepsis-induced FOXO1 activation and muscle wasting.

    Directory of Open Access Journals (Sweden)

    Estibaliz Castillero

    Full Text Available FOXO1 is involved in glucocorticoid- and sepsis-induced muscle wasting, in part reflecting regulation of atrogin-1 and MuRF1. Mechanisms influencing FOXO1 expression in muscle wasting are poorly understood. We hypothesized that the transcription factor peroxisome proliferator-activated receptor β/δ (PPARβ/δ upregulates muscle FOXO1 expression and activity with a downstream upregulation of atrogin-1 and MuRF1 expression during sepsis and glucocorticoid treatment and that inhibition of PPARβ/δ activity can prevent muscle wasting. We found that activation of PPARβ/δ in cultured myotubes increased FOXO1 activity, atrogin-1 and MuRF1 expression, protein degradation and myotube atrophy. Treatment of myotubes with dexamethasone increased PPARβ/δ expression and activity. Dexamethasone-induced FOXO1 activation and atrogin-1 and MuRF1 expression, protein degradation, and myotube atrophy were inhibited by PPARβ/δ blocker or siRNA. Importantly, muscle wasting induced in rats by dexamethasone or sepsis was prevented by treatment with a PPARβ/δ inhibitor. The present results suggest that PPARβ/δ regulates FOXO1 activation in glucocorticoid- and sepsis-induced muscle wasting and that treatment with a PPARβ/δ inhibitor may ameliorate loss of muscle mass in these conditions.

  7. TALE activators regulate gene expression in a position- and strand-dependent manner in mammalian cells.

    Science.gov (United States)

    Uhde-Stone, Claudia; Cheung, Edna; Lu, Biao

    2014-01-24

    Transcription activator-like effectors (TALEs) are a class of transcription factors that are readily programmable to regulate gene expression. Despite their growing popularity, little is known about binding site parameters that influence TALE-mediated gene activation in mammalian cells. We demonstrate that TALE activators modulate gene expression in mammalian cells in a position- and strand-dependent manner. To study the effects of binding site location, we engineered TALEs customized to recognize specific DNA sequences located in either the promoter or the transcribed region of reporter genes. We found that TALE activators robustly activated reporter genes when their binding sites were located within the promoter region. In contrast, TALE activators inhibited the expression of reporter genes when their binding sites were located on the sense strand of the transcribed region. Notably, this repression was independent of the effector domain utilized, suggesting a simple blockage mechanism. We conclude that TALE activators in mammalian cells regulate genes in a position- and strand-dependent manner that is substantially different from gene activation by native TALEs in plants. These findings have implications for optimizing the design of custom TALEs for genetic manipulation in mammalian cells. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility

    Science.gov (United States)

    Lamontanara, Allan Joaquim; Georgeon, Sandrine; Tria, Giancarlo; Svergun, Dmitri I.; Hantschel, Oliver

    2014-11-01

    The activity of protein kinases is regulated by multiple molecular mechanisms, and their disruption is a common driver of oncogenesis. A central and almost universal control element of protein kinase activity is the activation loop that utilizes both conformation and phosphorylation status to determine substrate access. In this study, we use recombinant Abl tyrosine kinases and conformation-specific kinase inhibitors to quantitatively analyse structural changes that occur after Abl activation. Allosteric SH2-kinase domain interactions were previously shown to be essential for the leukemogenesis caused by the Bcr-Abl oncoprotein. We find that these allosteric interactions switch the Abl activation loop from a closed to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker. Disruption of the SH2-kinase interaction abolishes activation loop phosphorylation. Our analysis provides a molecular mechanism for the SH2 domain-dependent activation of Abl that may also regulate other tyrosine kinases.

  9. Bi-directional astrocytic regulation of neuronal activity within a network

    Directory of Open Access Journals (Sweden)

    Susan Yu Gordleeva

    2012-11-01

    Full Text Available The concept of a tripartite synapse holds that astrocytes can affect both the pre- and postsynaptic compartments through the Ca2+-dependent release of gliotransmitters. Because astrocytic Ca2+ transients usually last for a few seconds, we assumed that astrocytic regulation of synaptic transmission may also occur on the scale of seconds. Here, we considered the basic physiological functions of tripartite synapses and investigated astrocytic regulation at the level of neural network activity. The firing dynamics of individual neurons in a spontaneous firing network was described by the Hodgkin-Huxley model. The neurons received excitatory synaptic input driven by the Poisson spike train with variable frequency. The mean field concentration of the released neurotransmitter was used to describe the presynaptic dynamics. The amplitudes of the excitatory postsynaptic currents (PSCs obeyed the gamma distribution law. In our model, astrocytes depressed the presynaptic release and enhanced the postsynaptic currents. As a result, low frequency synaptic input was suppressed while high frequency input was amplified. The analysis of the neuron spiking frequency as an indicator of network activity revealed that tripartite synaptic transmission dramatically changed the local network operation compared to bipartite synapses. Specifically, the astrocytes supported homeostatic regulation of the network activity by increasing or decreasing firing of the neurons. Thus, the astrocyte activation may modulate a transition of neural network into bistable regime of activity with two stable firing levels and spontaneous transitions between them.

  10. Environment-dependent regulation of spliceosome activity by the LSM2-8 complex in Arabidopsis.

    Science.gov (United States)

    Carrasco-López, Cristian; Hernández-Verdeja, Tamara; Perea-Resa, Carlos; Abia, David; Catalá, Rafael; Salinas, Julio

    2017-07-07

    Spliceosome activity is tightly regulated to ensure adequate splicing in response to internal and external cues. It has been suggested that core components of the spliceosome, such as the snRNPs, would participate in the control of its activity. The experimental indications supporting this proposition, however, remain scarce, and the operating mechanisms poorly understood. Here, we present genetic and molecular evidence demonstrating that the LSM2-8 complex, the protein moiety of the U6 snRNP, regulates the spliceosome activity in Arabidopsis, and that this regulation is controlled by the environmental conditions. Our results show that the complex ensures the efficiency and accuracy of constitutive and alternative splicing of selected pre-mRNAs, depending on the conditions. Moreover, miss-splicing of most targeted pre-mRNAs leads to the generation of nonsense mediated decay signatures, indicating that the LSM2-8 complex also guarantees adequate levels of the corresponding functional transcripts. Interestingly, the selective role of the complex has relevant physiological implications since it is required for adequate plant adaptation to abiotic stresses. These findings unveil an unanticipated function for the LSM2-8 complex that represents a new layer of posttranscriptional regulation in response to external stimuli in eukaryotes. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  11. Natural compounds regulate energy metabolism by the modulating the activity of lipid-sensing nuclear receptors.

    Science.gov (United States)

    Goto, Tsuyoshi; Kim, Young-Il; Takahashi, Nobuyuki; Kawada, Teruo

    2013-01-01

    Obesity causes excess fat accumulation in various tissues, most notoriously in the adipose tissue, along with other insulin-responsive organs such as skeletal muscle and the liver, which predisposes an individual to the development of metabolic abnormalities. The molecular mechanisms underlying obesity-induced metabolic abnormalities have not been completely elucidated; however, in recent years, the search for therapies to prevent the development of obesity and obesity-associated metabolic disorders has increased. It is known that several nuclear receptors, when activated by specific ligands, regulate carbohydrate and lipid metabolism at the transcriptional level. The expression of lipid metabolism-related enzymes is directly regulated by the activity of various nuclear receptors via their interaction with specific response elements in promoters of those genes. Many natural compounds act as ligands of nuclear receptors and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors. In this review, we describe our current knowledge of obesity, the role of lipid-sensing nuclear receptors in energy metabolism, and several examples of food factors that act as agonists or antagonists of nuclear receptors, which may be useful for the management of obesity and the accompanying energy metabolism abnormalities. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Safety research activities for Japanese regulations of spent fuel interim storage facilities

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-08-15

    Japan Nuclear Energy Safety Organization (JNES) carries out (a) preparation of technical documents, (b) technical evaluations of standards (prepared by academic societies), etc. and (c) other R and D activities, to support Nuclear Regulation Authority (NRA: which controls the regulations for Spent Fuel Interim Storage Facilities). In 2012 fiscal year, JNES carried out dynamic test of spent fuel to examine the integrity of spent fuel under cask drop accidents, and preparation for PWR spent fuel storage test to prove long term integrity of spent fuel and cask itself. Some of these tests will be also carried out in 2013 fiscal year and after. (author)

  13. Considerations on Law no. 78/2014 regarding the Regulation of the Volunteering Activity in Romania

    Directory of Open Access Journals (Sweden)

    Tache BOCĂNIALĂ

    2014-08-01

    Full Text Available In this paper we aim at highlighting the progress in the regulation of volunteering activity in Romania through the recent adoption by the Parliament of the Law no. 78/2014 on the regulation of volunteering in Romania. The new legislative act, which replaced Volunteering Law no. 195 / 2001 (republished tries and we believe that it actually succeeds in providing consistent and harmonized solutions at European level to problems of organizations working with volunteers and thus creating a modern legal framework, appropriately adapted to the national and European context in the field of volunteering.

  14. DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses.

    Science.gov (United States)

    Bruneau, Sarah; Nakayama, Hironao; Woda, Craig B; Flynn, Evelyn A; Briscoe, David M

    2013-09-05

    The maintenance of normal tissue homeostasis and the prevention of chronic inflammatory disease are dependent on the active process of inflammation resolution. In endothelial cells (ECs), proinflammation results from the activation of intracellular signaling responses and/or the inhibition of endogenous regulatory/pro-resolution signaling networks that, to date, are poorly defined. In this study, we find that DEP domain containing mTOR interacting protein (DEPTOR) is expressed in different microvascular ECs in vitro and in vivo, and using a small interfering RNA (siRNA) knockdown approach, we find that it regulates mammalian target of rapamycin complex 1 (mTORC1), extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription 1 activation in part through independent mechanisms. Moreover, using limited gene arrays, we observed that DEPTOR regulates EC activation including mRNA expression of the T-cell chemoattractant chemokines CXCL9, CXCL10, CXCL11, CX3CL1, CCL5, and CCL20 and the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (P < .05). DEPTOR siRNA-transfected ECs also bound increased numbers of peripheral blood mononuclear cells (P < .005) and CD3+ T cells (P < .005) in adhesion assays in vitro and had increased migration and angiogenic responses in spheroid sprouting (P < .01) and wound healing (P < .01) assays. Collectively, these findings define DEPTOR as a critical upstream regulator of EC activation responses and suggest that it plays an important role in endogenous mechanisms of anti-inflammation and pro-resolution.

  15. Light Controls Cytokinin Signaling via Transcriptional Regulation of Constitutively Active Sensor Histidine Kinase CKI1.

    Science.gov (United States)

    Dobisova, Tereza; Hrdinova, Vendula; Cuesta, Candela; Michlickova, Sarka; Urbankova, Ivana; Hejatkova, Romana; Zadnikova, Petra; Pernisova, Marketa; Benkova, Eva; Hejatko, Jan

    2017-05-01

    In plants, the multistep phosphorelay (MSP) pathway mediates a range of regulatory processes, including those activated by cytokinins. The cross talk between cytokinin response and light has been known for a long time. However, the molecular mechanism underlying the interaction between light and cytokinin signaling remains elusive. In the screen for upstream regulators we identified a LONG PALE HYPOCOTYL ( LPH ) gene whose activity is indispensable for spatiotemporally correct expression of CYTOKININ INDEPENDENT1 ( CKI1 ), encoding the constitutively active sensor His kinase that activates MSP signaling. lph is a new allele of HEME OXYGENASE1 ( HY1 ) that encodes the key protein in the biosynthesis of phytochromobilin, a cofactor of photoconvertible phytochromes. Our analysis confirmed the light-dependent regulation of the CKI1 expression pattern. We show that CKI1 expression is under the control of phytochrome A (phyA), functioning as a dual (both positive and negative) regulator of CKI1 expression, presumably via the phyA-regulated transcription factors (TF) PHYTOCHROME INTERACTING FACTOR3 and CIRCADIAN CLOCK ASSOCIATED1. Changes in CKI1 expression observed in lph / hy1 - 7 and phy mutants correlate with misregulation of MSP signaling, changed cytokinin sensitivity, and developmental aberrations that were previously shown to be associated with cytokinin and/or CKI1 action. Besides that, we demonstrate a novel role of phyA-dependent CKI1 expression in the hypocotyl elongation and hook development during skotomorphogenesis. Based on these results, we propose that the light-dependent regulation of CKI1 provides a plausible mechanistic link underlying the well-known interaction between light- and cytokinin-controlled plant development. © 2017 American Society of Plant Biologists. All Rights Reserved.

  16. Acoustic input and efferent activity regulate the expression of molecules involved in cochlear micromechanics

    Science.gov (United States)

    Lamas, Veronica; Arévalo, Juan C.; Juiz, José M.; Merchán, Miguel A.

    2015-01-01

    Electromotile activity in auditory outer hair cells (OHCs) is essential for sound amplification. It relies on the highly specialized membrane motor protein prestin, and its interactions with the cytoskeleton. It is believed that the expression of prestin and related molecules involved in OHC electromotility may be dynamically regulated by signals from the acoustic environment. However little is known about the nature of such signals and how they affect the expression of molecules involved in electromotility in OHCs. We show evidence that prestin oligomerization is regulated, both at short and relatively long term, by acoustic input and descending efferent activity originating in the cortex, likely acting in concert. Unilateral removal of the middle ear ossicular chain reduces levels of trimeric prestin, particularly in the cochlea from the side of the lesion, whereas monomeric and dimeric forms are maintained or even increased in particular in the contralateral side, as shown in Western blots. Unilateral removal of the auditory cortex (AC), which likely causes an imbalance in descending efferent activity on the cochlea, also reduces levels of trimeric and tetrameric forms of prestin in the side ipsilateral to the lesion, whereas in the contralateral side prestin remains unaffected, or even increased in the case of trimeric and tetrameric forms. As far as efferent inputs are concerned, unilateral ablation of the AC up-regulates the expression of α10 nicotinic Ach receptor (nAChR) transcripts in the cochlea, as shown by RT-Quantitative real-time PCR (qPCR). This suggests that homeostatic synaptic scaling mechanisms may be involved in dynamically regulating OHC electromotility by medial olivocochlear efferents. Limited, unbalanced efferent activity after unilateral AC removal, also affects prestin and β-actin mRNA levels. These findings support that the concerted action of acoustic and efferent inputs to the cochlea is needed to regulate the expression of major

  17. Abscisic acid-dependent multisite phosphorylation regulates the activity of a transcription activator AREB1

    OpenAIRE

    Furihata, Takashi; Maruyama, Kyonoshin; Fujita, Yasunari; Umezawa, Taishi; Yoshida, Riichiro; Shinozaki, Kazuo; Yamaguchi-Shinozaki, Kazuko

    2006-01-01

    bZIP-type transcription factors AREBs/ABFs bind an abscisic acid (ABA)-responsive cis-acting element named ABRE and transactivate downstream gene expression in Arabidopsis. Because AREB1 overexpression could not induce downstream gene expression, activation of AREB1 requires ABA-dependent posttranscriptional modification. We confirmed that ABA activated 42-kDa kinase activity, which, in turn, phosphorylated Ser/Thr residues of R-X-X-S/T sites in the conserved regions of AREB1. Amino acid subs...

  18. Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase.

    Directory of Open Access Journals (Sweden)

    Kara R Barber

    2017-02-01

    Full Text Available Disruption of synapses underlies a plethora of neurodevelopmental and neurodegenerative disease. Presynaptic specialization called the active zone plays a critical role in the communication with postsynaptic neuron. While the role of many proteins at the active zones in synaptic communication is relatively well studied, very little is known about how these proteins are transported to the synapses. For example, are there distinct mechanisms for the transport of active zone components or are they all transported in the same transport vesicle? Is active zone protein transport regulated? In this report we show that overexpression of Par-1/MARK kinase, a protein whose misregulation has been implicated in Autism spectrum disorders (ASDs and neurodegenerative disorders, lead to a specific block in the transport of an active zone protein component- Bruchpilot at Drosophila neuromuscular junctions. Consistent with a block in axonal transport, we find a decrease in number of active zones and reduced neurotransmission in flies overexpressing Par-1 kinase. Interestingly, we find that Par-1 acts independently of Tau-one of the most well studied substrates of Par-1, revealing a presynaptic function for Par-1 that is independent of Tau. Thus, our study strongly suggests that there are distinct mechanisms that transport components of active zones and that they are tightly regulated.

  19. Atrial natriuretic peptide regulates lipid mobilization and oxygen consumption in human adipocytes by activating AMPK

    Energy Technology Data Exchange (ETDEWEB)

    Souza, Sandra C. [Translational Sciences - Translational Medicine, Novartis Institutes for Biomedical Research, Inc., 220 Massachusetts Avenue, Cambridge, MA 02139 (United States); Chau, Mary D.L.; Yang, Qing [Cardiovascular and Metabolism Disease Area, Novartis Institutes for Biomedical Research, Inc., 100 Technology Square, Cambridge, MA 02139 (United States); Gauthier, Marie-Soleil [Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02140 (United States); Clairmont, Kevin B.; Wu, Zhidan; Gromada, Jesper [Cardiovascular and Metabolism Disease Area, Novartis Institutes for Biomedical Research, Inc., 100 Technology Square, Cambridge, MA 02139 (United States); Dole, William P., E-mail: bill.dole@novartis.com [Translational Sciences - Translational Medicine, Novartis Institutes for Biomedical Research, Inc., 220 Massachusetts Avenue, Cambridge, MA 02139 (United States)

    2011-07-08

    Highlights: {yields} Treatment of differentiated human adipocytes with atrial natriuretic peptide (ANP) increased lipolysis and oxygen consumption by activating AMP-activated protein kinase (AMPK). {yields} ANP stimulated lipid mobilization by selective activation of the alpha2 subunit of AMPK and increased energy utilization through activation of both the alpha1 and alpha2 subunits of AMPK. {yields} ANP enhanced adipocyte mitochondrial oxidative capacity as evidenced by induction of oxidative mitochondrial genes and increase in oxygen consumption. {yields} Exposure of human adipocytes to fatty acids and (TNF{alpha}) induced insulin resistance and decreased expression of mitochondrial genes which was restored to normal by ANP. -- Abstract: Atrial natriuretic peptide (ANP) has been shown to regulate lipid and carbohydrate metabolism providing a possible link between cardiovascular function and metabolism by mediating the switch from carbohydrate to lipid mobilization and oxidation. ANP exerts a potent lipolytic effect via cGMP-dependent protein kinase (cGK)-I mediated-stimulation of AMP-activated protein kinase (AMPK). Activation of the ANP/cGK signaling cascade also promotes muscle mitochondrial biogenesis and fat oxidation. Here we demonstrate that ANP regulates lipid metabolism and oxygen utilization in differentiated human adipocytes by activating the alpha2 subunit of AMPK. ANP treatment increased lipolysis by seven fold and oxygen consumption by two fold, both of which were attenuated by inhibition of AMPK activity. ANP-induced lipolysis was shown to be mediated by the alpha2 subunit of AMPK as introduction of dominant-negative alpha2 subunit of AMPK attenuated ANP effects on lipolysis. ANP-induced activation of AMPK enhanced mitochondrial oxidative capacity as evidenced by a two fold increase in oxygen consumption and induction of mitochondrial genes, including carnitine palmitoyltransferase 1A (CPT1a) by 1.4-fold, cytochrome C (CytC) by 1.3-fold, and

  20. Atrial natriuretic peptide regulates lipid mobilization and oxygen consumption in human adipocytes by activating AMPK

    International Nuclear Information System (INIS)

    Souza, Sandra C.; Chau, Mary D.L.; Yang, Qing; Gauthier, Marie-Soleil; Clairmont, Kevin B.; Wu, Zhidan; Gromada, Jesper; Dole, William P.

    2011-01-01

    Highlights: → Treatment of differentiated human adipocytes with atrial natriuretic peptide (ANP) increased lipolysis and oxygen consumption by activating AMP-activated protein kinase (AMPK). → ANP stimulated lipid mobilization by selective activation of the alpha2 subunit of AMPK and increased energy utilization through activation of both the alpha1 and alpha2 subunits of AMPK. → ANP enhanced adipocyte mitochondrial oxidative capacity as evidenced by induction of oxidative mitochondrial genes and increase in oxygen consumption. → Exposure of human adipocytes to fatty acids and (TNFα) induced insulin resistance and decreased expression of mitochondrial genes which was restored to normal by ANP. -- Abstract: Atrial natriuretic peptide (ANP) has been shown to regulate lipid and carbohydrate metabolism providing a possible link between cardiovascular function and metabolism by mediating the switch from carbohydrate to lipid mobilization and oxidation. ANP exerts a potent lipolytic effect via cGMP-dependent protein kinase (cGK)-I mediated-stimulation of AMP-activated protein kinase (AMPK). Activation of the ANP/cGK signaling cascade also promotes muscle mitochondrial biogenesis and fat oxidation. Here we demonstrate that ANP regulates lipid metabolism and oxygen utilization in differentiated human adipocytes by activating the alpha2 subunit of AMPK. ANP treatment increased lipolysis by seven fold and oxygen consumption by two fold, both of which were attenuated by inhibition of AMPK activity. ANP-induced lipolysis was shown to be mediated by the alpha2 subunit of AMPK as introduction of dominant-negative alpha2 subunit of AMPK attenuated ANP effects on lipolysis. ANP-induced activation of AMPK enhanced mitochondrial oxidative capacity as evidenced by a two fold increase in oxygen consumption and induction of mitochondrial genes, including carnitine palmitoyltransferase 1A (CPT1a) by 1.4-fold, cytochrome C (CytC) by 1.3-fold, and peroxisome proliferator-activated

  1. Active site loop conformation regulates promiscuous activity in a lactonase from Geobacillus kaustophilus HTA426.

    Directory of Open Access Journals (Sweden)

    Yu Zhang

    Full Text Available Enzyme promiscuity is a prerequisite for fast divergent evolution of biocatalysts. A phosphotriesterase-like lactonase (PLL from Geobacillus kaustophilus HTA426 (GkaP exhibits main lactonase and promiscuous phosphotriesterase activities. To understand its catalytic and evolutionary mechanisms, we investigated a "hot spot" in the active site by saturation mutagenesis as well as X-ray crystallographic analyses. We found that position 99 in the active site was involved in substrate discrimination. One mutant, Y99L, exhibited 11-fold improvement over wild-type in reactivity (kcat/Km toward the phosphotriesterase substrate ethyl-paraoxon, but showed 15-fold decrease toward the lactonase substrate δ-decanolactone, resulting in a 157-fold inversion of the substrate specificity. Structural analysis of Y99L revealed that the mutation causes a ∼6.6 Å outward shift of adjacent loop 7, which may cause increased flexibility of the active site and facilitate accommodation and/or catalysis of organophosphate substrate. This study provides for the PLL family an example of how the evolutionary route from promiscuity to specificity can derive from very few mutations, which promotes alteration in the conformational adjustment of the active site loops, in turn draws the capacity of substrate binding and activity.

  2. Regulation of the activity of the dual-function DnaA protein in Caulobacter crescentus.

    Directory of Open Access Journals (Sweden)

    Carmen Fernandez-Fernandez

    Full Text Available DnaA is a conserved essential bacterial protein that acts as the initiator of chromosomal replication as well as a master transcriptional regulator in Caulobacter crescentus. Thus, the intracellular levels of active DnaA need to be tightly regulated during the cell cycle. Our previous work suggested that DnaA may be regulated at the level of its activity by the replisome-associated protein HdaA. Here, we describe the construction of a mutant DnaA protein [DnaA(R357A]. The R357 residue in the AAA+ domain of the C. crescentus DnaA protein is equivalent to the R334 residue of the E. coli DnaA protein, which is required for the Regulatory Inactivation of DnaA (RIDA. We found that the expression of the DnaA(R357A mutant protein in C. crescentus, but not the expression of the wild-type DnaA protein at similar levels, causes a severe phenotype of over-initiation of chromosomal replication and that it blocks cell division. Thus, the mutant DnaA(R357A protein is hyper-active to promote the initiation of DNA replication, compared to the wild-type DnaA protein. DnaA(R357A could not replace DnaA in vivo, indicating that the switch in DnaA activity once chromosomal replication has started may be an essential process in C. crescentus. We propose that the inactivation of DnaA is the main mechanism ensuring that chromosomal replication starts only once per cell cycle. We further observed that the R357A substitution in DnaA does not promote the activity of DnaA as a direct transcriptional activator of four important genes, encoding HdaA, the GcrA master cell cycle regulator, the FtsZ cell division protein and the MipZ spatial regulator of cell division. Thus, the AAA+ domain of DnaA may play a role in temporally regulating the bifunctionality of DnaA by reallocating DnaA molecules from initiating DNA replication to transcribing genes within the unique DnaA regulon of C. crescentus.

  3. Age-dependent regulation of ERF-VII transcription factor activity in Arabidopsis thaliana.

    Science.gov (United States)

    Giuntoli, Beatrice; Shukla, Vinay; Maggiorelli, Federica; Giorgi, Federico M; Lombardi, Lara; Perata, Pierdomenico; Licausi, Francesco

    2017-10-01

    The Group VII Ethylene Responsive Factors (ERFs-VII) RAP2.2 and RAP2.12 have been mainly characterized with regard to their contribution as activators of fermentation in plants. However, transcriptional changes measured in conditions that stabilize these transcription factors exceed the mere activation of this biochemical pathway, implying additional roles performed by the ERF-VIIs in other processes. We evaluated gene expression in transgenic Arabidopsis lines expressing a stabilized form of RAP2.12, or hampered in ERF-VII activity, and identified genes affected by this transcriptional regulator and its homologs, including some involved in oxidative stress response, which are not universally induced under anaerobic conditions. The contribution of the ERF-VIIs in regulating this set of genes in response to chemically induced or submergence-stimulated mitochondria malfunctioning was found to depend on the plant developmental stage. A similar age-dependent mechanism also restrained ERF-VII activity upon the core-hypoxic genes, independently of the N-end rule pathway, which is accounted for the control of the anaerobic response. To conclude, this study shed new light on a dual role of ERF-VII proteins under submergence: as positive regulators of the hypoxic response and as repressors of oxidative-stress related genes, depending on the developmental stage at which plants are challenged by stress conditions. © 2017 John Wiley & Sons Ltd.

  4. Roles of ADAM13-regulated Wnt activity in early Xenopus eye development

    Science.gov (United States)

    Wei, Shuo; Xu, Guofeng; Bridges, Lance C.; Williams, Phoebe; Nakayama, Takuya; Shah, Anoop; Grainger, Robert M.; White, Judith M.; DeSimone, Douglas W.

    2012-01-01

    Pericellular proteolysis by ADAM family metalloproteinases has been widely implicated in cell signaling and development. We recently found that Xenopus ADAM13, an ADAM metalloproteinase, is required for activation of canonical Wnt signaling during cranial neural crest (CNC) induction by regulating a novel crosstalk between Wnt and ephrin B (EfnB) signaling pathways (Wei et al., 2010b). In the present study we show that the metalloproteinase activity of ADAM13 also plays important roles in eye development in X. tropicalis. Knockdown of ADAM13 results in reduced expression of eye field markers pax6 and rx1, as well as that of the pan-neural marker sox2. Activation of canonical Wnt signaling or inhibition of forward EfnB signaling rescues the eye defects caused by loss of ADAM13, suggesting that ADAM13 functions through regulation of the EfnB-Wnt pathway interaction. Downstream of Wnt, the head inducer Cerberus was identified as an effector that mediates ADAM13 function in early eye field formation. Furthermore, ectopic expression of the Wnt target gene snail2 restores cerberus expression and rescues the eye defects caused by ADAM13 knockdown. Together these data suggest an important role of ADAM13-regulated Wnt activity in eye development in Xenopus. PMID:22227340

  5. Regulation of gene expression by manipulating transcriptional repressor activity using a novel CoSRI technology.

    Science.gov (United States)

    Xu, Yue; Li, Song Feng; Parish, Roger W

    2017-07-01

    Targeted gene manipulation is a central strategy for studying gene function and identifying related biological processes. However, a methodology for manipulating the regulatory motifs of transcription factors is lacking as these factors commonly possess multiple motifs (e.g. repression and activation motifs) which collaborate with each other to regulate multiple biological processes. We describe a novel approach designated conserved sequence-guided repressor inhibition (CoSRI) that can specifically reduce or abolish the repressive activities of transcription factors in vivo. The technology was evaluated using the chimeric MYB80-EAR transcription factor and subsequently the endogenous WUS transcription factor. The technology was employed to develop a reversible male sterility system applicable to hybrid seed production. In order to determine the capacity of the technology to regulate the activity of endogenous transcription factors, the WUS repressor was chosen. The WUS repression motif could be inhibited in vivo and the transformed plants exhibited the wus-1 phenotype. Consequently, the technology can be used to manipulate the activities of transcriptional repressor motifs regulating beneficial traits in crop plants and other eukaryotic organisms. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  6. Regulation of myogenesis and skeletal muscle regeneration: effects of oxygen levels on satellite cell activity.

    Science.gov (United States)

    Chaillou, Thomas; Lanner, Johanna T

    2016-12-01

    Reduced oxygen (O 2 ) levels (hypoxia) are present during embryogenesis and exposure to altitude and in pathologic conditions. During embryogenesis, myogenic progenitor cells reside in a hypoxic microenvironment, which may regulate their activity. Satellite cells are myogenic progenitor cells localized in a local environment, suggesting that the O 2 level could affect their activity during muscle regeneration. In this review, we present the idea that O 2 levels regulate myogenesis and muscle regeneration, we elucidate the molecular mechanisms underlying myogenesis and muscle regeneration in hypoxia and depict therapeutic strategies using changes in O 2 levels to promote muscle regeneration. Severe hypoxia (≤1% O 2 ) appears detrimental for myogenic differentiation in vitro, whereas a 3-6% O 2 level could promote myogenesis. Hypoxia impairs the regenerative capacity of injured muscles. Although it remains to be explored, hypoxia may contribute to the muscle damage observed in patients with pathologies associated with hypoxia (chronic obstructive pulmonary disease, and peripheral arterial disease). Hypoxia affects satellite cell activity and myogenesis through mechanisms dependent and independent of hypoxia-inducible factor-1α. Finally, hyperbaric oxygen therapy and transplantation of hypoxia-conditioned myoblasts are beneficial procedures to enhance muscle regeneration in animals. These therapies may be clinically relevant to treatment of patients with severe muscle damage.-Chaillou, T. Lanner, J. T. Regulation of myogenesis and skeletal muscle regeneration: effects of oxygen levels on satellite cell activity. © FASEB.

  7. Developmental programming of energy balance regulation: is physical activity more 'programmable' than food intake?

    Science.gov (United States)

    Zhu, Shaoyu; Eclarinal, Jesse; Baker, Maria S; Li, Ge; Waterland, Robert A

    2016-02-01

    Extensive human and animal model data show that environmental influences during critical periods of prenatal and early postnatal development can cause persistent alterations in energy balance regulation. Although a potentially important factor in the worldwide obesity epidemic, the fundamental mechanisms underlying such developmental programming of energy balance are poorly understood, limiting our ability to intervene. Most studies of developmental programming of energy balance have focused on persistent alterations in the regulation of energy intake; energy expenditure has been relatively underemphasised. In particular, very few studies have evaluated developmental programming of physical activity. The aim of this review is to summarise recent evidence that early environment may have a profound impact on establishment of individual propensity for physical activity. Recently, we characterised two different mouse models of developmental programming of obesity; one models fetal growth restriction followed by catch-up growth, and the other models early postnatal overnutrition. In both studies, we observed alterations in body-weight regulation that persisted to adulthood, but no group differences in food intake. Rather, in both cases, programming of energy balance appeared to be due to persistent alterations in energy expenditure and spontaneous physical activity (SPA). These effects were stronger in female offspring. We are currently exploring the hypothesis that developmental programming of SPA occurs via induced sex-specific alterations in epigenetic regulation in the hypothalamus and other regions of the central nervous system. We will summarise the current progress towards testing this hypothesis. Early environmental influences on establishment of physical activity are likely an important factor in developmental programming of energy balance. Understanding the fundamental underlying mechanisms in appropriate animal models will help determine whether early life

  8. Catalase activity prevents exercise-induced up-regulation of vasoprotective proteins in venous tissue.

    Science.gov (United States)

    Dao, Vu Thao-Vi; Floeren, Melanie; Kumpf, Stephanie; Both, Charlotte; Peter, Bärbel; Balz, Vera; Suvorava, Tatsiana; Kojda, Georg

    2011-11-01

    Physical activity induces favourable changes of arterial gene expression and protein activity, although little is known about its effect in venous tissue. Although our understanding of the initiating molecular signals is still incomplete, increased expression of endothelial nitric oxide synthase (eNOS) is considered a key event. This study sought to investigate the effects of two different training protocols on the expression of eNOS and extracellular superoxide dismutase (ecSOD) in venous and lung tissue and to evaluate the underlying molecular mechanisms. C57Bl/6 mice underwent voluntary exercise or forced physical activity. Changes of vascular mRNA and protein levels and activity of eNOS, ecSOD and catalase were determined in aorta, heart, lung and vena cava. Both training protocols similarly increased relative heart weight and resulted in up-regulation of aortic and myocardial eNOS. In striking contrast, eNOS expression in vena cava and lung remained unchanged. Likewise, exercise up-regulated ecSOD in the aorta and in left ventricular tissue but remained unchanged in lung tissue. Catalase expression in lung tissue and vena cava of exercised mice exceeded that in aorta by 6.9- and 10-fold, respectively, suggesting a lack of stimulatory effects of hydrogen peroxide. In accordance, treatment of mice with the catalase inhibitor aminotriazole for 6 weeks resulted in significant up-regulation of eNOS and ecSOD in vena cava. These data suggest that physiological venous catalase activity prevents exercise-induced up-regulation of eNOS and ecSOD. Furthermore, therapeutic inhibition of vascular catalase might improve pulmonary rehabilitation. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  9. Commission de regulation de l'energie. Activity Report 2009

    International Nuclear Information System (INIS)

    2010-01-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2009 activity report of CRE. Content: A - How the CRE works and the activity of the CoRDiS; B - Implementation of the third energy package will strengthen regulation in this sector; C - The regulator contributes to the correct operation of the infrastructures, the interconnection of European grids and security of supplies; D - Regulation: serving investment and quality; E - Renewable energy, advanced metering systems and the grids of the future are all priority means of delivering sustainable development; F - The CRE is contributing to the smooth operation of electricity and gas markets to the benefit of consumers; G - Appendices: 1. Summary of the principal deliberations of the CRE; 2. European and international calendar for 2009; 3. Council of European Energy Regulators (CEER); 4. Glossary; 5. Acronyms; 6. Units and conversions; 7. Index; 8. List of boxes, figures and tables

  10. Iron-Regulated Phospholipase C Activity Contributes to the Cytolytic Activity and Virulence of Acinetobacter baumannii.

    Directory of Open Access Journals (Sweden)

    Steven E Fiester

    Full Text Available Acinetobacter baumannii is an opportunistic Gram-negative pathogen that causes a wide range of infections including pneumonia, septicemia, necrotizing fasciitis and severe wound and urinary tract infections. Analysis of A. baumannii representative strains grown in Chelex 100-treated medium for hemolytic activity demonstrated that this pathogen is increasingly hemolytic to sheep, human and horse erythrocytes, which interestingly contain increasing amounts of phosphatidylcholine in their membranes. Bioinformatic, genetic and functional analyses of 19 A. baumannii isolates showed that the genomes of each strain contained two phosphatidylcholine-specific phospholipase C (PC-PLC genes, which were named plc1 and plc2. Accordingly, all of these strains were significantly hemolytic to horse erythrocytes and their culture supernatants tested positive for PC-PLC activity. Further analyses showed that the transcriptional expression of plc1 and plc2 and the production of phospholipase and thus hemolytic activity increased when bacteria were cultured under iron-chelation as compared to iron-rich conditions. Testing of the A. baumannii ATCC 19606T plc1::aph-FRT and plc2::aph isogenic insertion derivatives showed that these mutants had a significantly reduced PC-PLC activity as compared to the parental strain, while testing of plc1::ermAM/plc2::aph demonstrated that this double PC-PLC isogenic mutant expressed significantly reduced cytolytic and hemolytic activity. Interestingly, only plc1 was shown to contribute significantly to A. baumannii virulence using the Galleria mellonella infection model. Taken together, our data demonstrate that both PLC1 and PLC2, which have diverged from a common ancestor, play a concerted role in hemolytic and cytolytic activities; although PLC1 seems to play a more critical role in the virulence of A. baumannii when tested in an invertebrate model. These activities would provide access to intracellular iron stores this pathogen

  11. Tetraspanin 7 regulates sealing zone formation and the bone-resorbing activity of osteoclasts

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Jun-Oh; Lee, Yong Deok; Kim, Haemin; Kim, Min Kyung; Song, Min-Kyoung; Lee, Zang Hee; Kim, Hong-Hee, E-mail: hhbkim@snu.ac.kr

    2016-09-02

    Tetraspanin family proteins regulate morphology, motility, fusion, and signaling in various cell types. We investigated the role of the tetraspanin 7 (Tspan7) isoform in the differentiation and function of osteoclasts. Tspan7 was up-regulated during osteoclastogenesis. When Tspan7 expression was reduced in primary precursor cells by siRNA-mediated gene knock-down, the generation of multinuclear osteoclasts was not affected. However, a striking cytoskeletal abnormality was observed: the formation of the podosome belt structure was inhibited and the microtubular network were disrupted by Tspan7 knock-down. Decreases in acetylated microtubules and levels of phosphorylated Src and Pyk2 in Tspan7 knock-down cells supported the involvement of Tspan7 in cytoskeletal rearrangement signaling in osteoclasts. This cytoskeletal defect interfered with sealing zone formation and subsequently the bone-resorbing activity of mature osteoclasts on dentin surfaces. Our results suggest that Tspan7 plays an important role in cytoskeletal organization required for the bone-resorbing function of osteoclasts by regulating signaling to Src, Pyk2, and microtubules. - Highlights: • Tspan7 expression is up-regulated during osteoclastogenesis. • Tspan7 regulates podosome belt organization in osteoclasts. • Tspan7 is crucial for sealing zone formation and bone-resorption by osteoclasts. • Src and Pyk2 phosphorylation and microtubule acetylation mediate Tspan7 function.

  12. Molecular kinetics. Ras activation by SOS: allosteric regulation by altered fluctuation dynamics.

    Science.gov (United States)

    Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen; Christensen, Sune M; Abel, Steven M; Iwig, Jeff; Wu, Hung-Jen; Gureasko, Jodi; Rhodes, Christopher; Petit, Rebecca S; Hansen, Scott D; Thill, Peter; Yu, Cheng-Han; Stamou, Dimitrios; Chakraborty, Arup K; Kuriyan, John; Groves, Jay T

    2014-07-04

    Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras-guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average. Copyright © 2014, American Association for the Advancement of Science.

  13. Epidermis-type lipoxygenase 3 regulates adipocyte differentiation and peroxisome proliferator-activated receptor gamma activity

    DEFF Research Database (Denmark)

    Hallenborg, Philip; Jørgensen, Claus; Petersen, Rasmus K

    2010-01-01

    preadipocytes. Here, we show that forced expression of eLOX3 or addition of eLOX3 products stimulated adipogenesis under conditions that normally require an exogenous PPAR gamma ligand for differentiation. Hepoxilins, a group of oxidized arachidonic acid derivatives produced by eLOX3, bound to and activated...... PPAR gamma. Production of hepoxilins was increased transiently during the initial stages of adipogenesis. Furthermore, small interfering RNA-mediated or retroviral short hairpin RNA-mediated knockdown of eLOX3 expression abolished differentiation of 3T3-L1 preadipocytes. Finally, we demonstrate...... differentiation has remained enigmatic. Previously, we showed that lipoxygenase (LOX) activity is involved in activation of PPAR gamma during the early stages of adipocyte differentiation. Of the seven known murine LOXs, only the unconventional LOX epidermis-type lipoxygenase 3 (eLOX3) is expressed in 3T3-L1...

  14. Angiotensin II regulation of neuromodulation: downstream signaling mechanism from activation of mitogen-activated protein kinase.

    Science.gov (United States)

    Lu, D; Yang, H; Raizada, M K

    1996-12-01

    Angiotensin II (Ang II) stimulates expression of tyrosine hydroxylase and norepinephrine transporter genes in brain neurons; however, the signal-transduction mechanism is not clearly defined. This study was conducted to determine the involvement of the mitogen-activated protein (MAP) kinase signaling pathway in Ang II stimulation of these genes. MAP kinase was localized in the perinuclear region of the neuronal soma. Ang II caused activation of MAP kinase and its subsequent translocation from the cytoplasmic to nuclear compartment, both effects being mediated by AT1 receptor subtype. Ang II also stimulated SRE- and AP1-binding activities and fos gene expression and its translocation in a MAP kinase-dependent process. These observations are the first demonstration of a downstream signaling pathway involving MAP kinase in Ang II-mediated neuromodulation in noradrenergic neurons.

  15. A biomolecular proportional integral controller based on feedback regulations of protein level and activity.

    Science.gov (United States)

    Mairet, Francis

    2018-02-01

    Homeostasis is the capacity of living organisms to keep internal conditions regulated at a constant level, despite environmental fluctuations. Integral feedback control is known to play a key role in this behaviour. Here, I show that a feedback system involving transcriptional and post-translational regulations of the same executor protein acts as a proportional integral (PI) controller, leading to enhanced transient performances in comparison with a classical integral loop. Such a biomolecular controller-which I call a level and activity-PI controller (LA-PI)-is involved in the regulation of ammonium uptake by Escherichia coli through the transporter AmtB. The P II molecules, which reflect the nitrogen status of the cell, inhibit both the production of AmtB and its activity (via the NtrB-NtrC system and the formation of a complex with GlnK, respectively). Other examples of LA-PI controller include copper and zinc transporters, and the redox regulation in photosynthesis. This scheme has thus emerged through evolution in many biological systems, surely because of the benefits it offers in terms of performances (rapid and perfect adaptation) and economy (protein production according to needs).

  16. Involvement of Histidine Residue His382 in pH Regulation of MCT4 Activity.

    Directory of Open Access Journals (Sweden)

    Shotaro Sasaki

    Full Text Available Monocarboxylate transporter 4 (MCT4 is a pH-dependent bi-directional lactate transporter. Transport of lactate via MCT4 is increased by extracellular acidification. We investigated the critical histidine residue involved in pH regulation of MCT4 function. Transport of lactate via MCT4 was measured by using a Xenopus laevis oocyte expression system. MCT4-mediated lactate transport was inhibited by Zn2+ in a pH physiological condition but not in an acidic condition. The histidine modifier DEPC (diethyl pyrocarbonate reduced MCT4 activity but did not completely inactivate MCT4. After treatment with DEPC, pH regulation of MCT4 function was completely knocked out. Inhibitory effects of DEPC were reversed by hydroxylamine and suppressed in the presence of excess lactate and Zn2+. Therefore, we performed an experiment in which the extracellular histidine residue was replaced with alanine. Consequently, the pH regulation of MCT4-H382A function was also knocked out. Our findings demonstrate that the histidine residue His382 in the extracellular loop of the transporter is essential for pH regulation of MCT4-mediated substrate transport activity.

  17. Cyclin D3 interacts with vitamin D receptor and regulates its transcription activity

    International Nuclear Information System (INIS)

    Jian Yongzhi; Yan Jun; Wang Hanzhou; Chen Chen; Sun Maoyun; Jiang Jianhai; Lu Jieqiong; Yang Yanzhong; Gu Jianxin

    2005-01-01

    D-type cyclins are essential for the progression through the G1 phase of the cell cycle. Besides serving as cell cycle regulators, D-type cyclins were recently reported to have transcription regulation functions. Here, we report that cyclin D3 is a new interacting partner of vitamin D receptor (VDR), a member of the superfamily of nuclear receptors for steroid hormones, thyroid hormone, and the fat-soluble vitamins A and D. The interaction was confirmed with methods of yeast two-hybrid system, in vitro binding analysis and in vivo co-immunoprecipitation. Cyclin D3 interacted with VDR in a ligand-independent manner, but treatment of the ligand, 1,25-dihydroxyvitamin D3, strengthened the interaction. Confocal microscopy analysis showed that ligand-activated VDR led to an accumulation of cyclin D3 in the nuclear region. Cyclin D3 up-regulated transcriptional activity of VDR and this effect was counteracted by overexpression of CDK4 and CDK6. These findings provide us a new clue to understand the transcription regulation functions of D-type cyclins

  18. Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway

    Directory of Open Access Journals (Sweden)

    Valentina Rapisarda

    2017-03-01

    Full Text Available Cellular senescence is an important in vivo mechanism that prevents the propagation of damaged cells. However, the precise mechanisms regulating senescence are not well characterized. Here, we find that ITGB3 (integrin beta 3 or β3 is regulated by the Polycomb protein CBX7. β3 expression accelerates the onset of senescence in human primary fibroblasts by activating the transforming growth factor β (TGF-β pathway in a cell-autonomous and non-cell-autonomous manner. β3 levels are dynamically increased during oncogene-induced senescence (OIS through CBX7 Polycomb regulation, and downregulation of β3 levels overrides OIS and therapy-induced senescence (TIS, independently of its ligand-binding activity. Moreover, cilengitide, an αvβ3 antagonist, has the ability to block the senescence-associated secretory phenotype (SASP without affecting proliferation. Finally, we show an increase in β3 levels in a subset of tissues during aging. Altogether, our data show that integrin β3 subunit is a marker and regulator of senescence.

  19. Activation scheme to use performance indicators for the graded regulation on Korean NPPs

    International Nuclear Information System (INIS)

    Hwang, M. J.; Kang, D. I.; Kim, G. R.; Sung, G. Y.

    2003-01-01

    In this paper, we will provide an activation scheme of using performance indicators for graded regulation on Korean Nuclear Power Plants (NPPs). The safe operation of NPPs is the basic objective of nuclear society. To achieve the object, the direction of the regulation is established to regulate the risk of public health and safety. Therefore, it's essential to keep the safety of plants. However, it's not easy to define the appropriate safety level. So, the requirement of performance indicator establishment and framework establishment for safety management has been increased. Performance indicators can provide quantified safety value numerically. Therefore, we can increase the acceptance and trust of the public for safety of NPPs. Also, it helps pridictive regulation through the objective comparison of safety. Moreover, according to the importance of safety, we can allocate the resources effectively and lead an effort for the improvement of safety by comparison among nations and plants. The safety of a plant is affected by not only design but also the quality of operators, appropriate operation, maintenance and test. So, in this paper, we reviewed the application of performance indicators in domestic and foreign countries, and groped for a method to activate the use of performance indicators

  20. Tissue transglutaminase (TG2 activity regulates osteoblast differentiation and mineralization in the SAOS-2 cell line

    Directory of Open Access Journals (Sweden)

    Xiaoxue Yin

    2012-08-01

    Full Text Available Tissue transglutaminase (type II, TG2 has long been postulated to directly promote skeletal matrix calcification and play an important role in ossification. However, limited information is available on the expression, function and modulating mechanism of TG2 during osteoblast differentiation and mineralization. To address these issues, we cultured the well-established human osteosarcoma cell line SAOS-2 with osteo-inductive conditioned medium and set up three time points (culture days 4, 7, and 14 to represent different stages of SAOS-2 differentiation. Osteoblast markers, mineralization, as well as TG2 expression and activity, were then assayed in each stage. Furthermore, we inhibited TG activity with cystamine and then checked SAOS-2 differentiation and mineralization in each stage. The results showed that during the progression of osteoblast differentiation SAOS-2 cells presented significantly high levels of osteocalcin (OC mRNA, bone morphogenetic protein-2 (BMP-2 and collagen I, significantly high alkaline phosphatase (ALP activity, and the increased formation of calcified matrix. With the same tendency, TG2 expression and activity were up-regulated. Furthermore, inhibition of TG activity resulted in a significant decrease of OC, collagen I, and BMP-2 mRNA and of ALP activity and mineralization. This study demonstrated that TG2 is involved in osteoblast differentiation and may play a role in the initiation and regulation of the mineralization processes. Moreover, the modulating effects of TG2 on osteoblasts may be related to BMP-2.

  1. Type 1 plaminogen activator inhibitor gene: Functional analysis and glucocorticoid regulation of its promoter

    International Nuclear Information System (INIS)

    Van Zonneveld, A.J.; Curriden, S.A.; Loskutoff, D.J.

    1988-01-01

    Plasminogen activator inhibitor type 1 is an important component of the fibrinolytic system and its biosynthesis is subject to complex regulation. To study this regulation at the level of transcription, the authors have identified and sequenced the promoter of the human plasminogen activator inhibitor type 1 gene. Nuclease protection experiments were performed by using endothelial cell mRNA and the transcription initiation (cap) site was established. Sequence analysis of the 5' flanking region of the gene revealed a perfect TATA box at position -28 to position -23, the conserved distance from the cap site. Comparative functional studies with the firefly luciferase gene as a reporter gene showed that fragments derived from this 5' flanking region exhibited high promoter activity when transfected into bovine aortic endothelial cells and mouse Ltk - fibroblasts but were inactive when introduced into HeLa cells. These studies indicate that the fragments contain the plasminogen activator inhibitor type 1 promoter and that it is expressed in a tissue-specific manner. Although the fragments were also silent in rat FTO2B hepatoma cells, their promoter activity could be induced up to 40-fold with the synthetic glucocorticoid dexamethasone. Promoter deletion mapping experiments and studies involving the fusion of promoter fragments to a heterologous gene indicated that dexamethasone induction is mediated by a glucocorticoid responsive element with enhancer-like properties located within the region between nucleotides -305 and +75 of the plasminogen activator inhibitor type 1 gene

  2. Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation.

    LENUS (Irish Health Repository)

    Ni Ainle, Fionnuala

    2009-08-20

    Protamine sulfate is a positively charged polypeptide widely used to reverse heparin-induced anticoagulation. Paradoxically, prospective randomized trials have shown that protamine administration for heparin neutralization is associated with increased bleeding, particularly after cardiothoracic surgery with cardiopulmonary bypass. The molecular mechanism(s) through which protamine mediates this anticoagulant effect has not been defined. In vivo administration of pharmacologic doses of protamine to BALB\\/c mice significantly reduced plasma thrombin generation and prolonged tail-bleeding time (from 120 to 199 seconds). Similarly, in pooled normal human plasma, protamine caused significant dose-dependent prolongations of both prothrombin time and activated partial thromboplastin time. Protamine also markedly attenuated tissue factor-initiated thrombin generation in human plasma, causing a significant decrease in endogenous thrombin potential (41% +\\/- 7%). As expected, low-dose protamine effectively reversed the anticoagulant activity of unfractionated heparin in plasma. However, elevated protamine concentrations were associated with progressive dose-dependent reduction in thrombin generation. To assess the mechanism by which protamine mediates down-regulation of thrombin generation, the effect of protamine on factor V activation was assessed. Protamine was found to significantly reduce the rate of factor V activation by both thrombin and factor Xa. Protamine mediates its anticoagulant activity in plasma by down-regulation of thrombin generation via a novel mechanism, specifically inhibition of factor V activation.

  3. Commission de regulation de l'energie. Activity report june 2007

    International Nuclear Information System (INIS)

    2007-06-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2007 activity report of CRE. Content: A - Towards a single European energy market: Birth of a single European energy market (Origins of Europe of Energy, Emergence of a European energy policy); Main European Community guiding lines (European governance as regards energy, Guiding principles for the internal energy market); European Community activities (European Commission reports, Electricity and gas Regional Initiatives); Organisation and coordination of European regulators (Joint organisation of European regulators, CRE's relations with European Community institutions); CRE's European activities (Regional integration of gas markets, Regional integration of electricity markets, Operation of the European interconnected electricity grid and security of supply, CRE's other European activities); B - CRE action at national level: Grids/networks and infrastructures (General information, Electricity grids, Regulation of gas networks and infrastructures); Markets (Changes in the regulatory and legislative contexts of electricity and natural gas markets, Electricity markets

  4. Centriole maturation requires regulated Plk1 activity during two consecutive cell cycles.

    Science.gov (United States)

    Kong, Dong; Farmer, Veronica; Shukla, Anil; James, Jana; Gruskin, Richard; Kiriyama, Shigeo; Loncarek, Jadranka

    2014-09-29

    Newly formed centrioles in cycling cells undergo a maturation process that is almost two cell cycles long before they become competent to function as microtubule-organizing centers and basal bodies. As a result, each cell contains three generations of centrioles, only one of which is able to form cilia. It is not known how this long and complex process is regulated. We show that controlled Plk1 activity is required for gradual biochemical and structural maturation of the centrioles and timely appendage assembly. Inhibition of Plk1 impeded accumulation of appendage proteins and appendage formation. Unscheduled Plk1 activity, either in cycling or interphase-arrested cells, accelerated centriole maturation and appendage and cilia formation on the nascent centrioles, erasing the age difference between centrioles in one cell. These findings provide a new understanding of how the centriole cycle is regulated and how proper cilia and centrosome numbers are maintained in the cells.

  5. A Critical SUMO1 Modification of LKB1 Regulates AMPK Activity during Energy Stress

    KAUST Repository

    Ritho, Joan

    2015-07-23

    SUMOylation has been implicated in cellular stress adaptation, but its role in regulating liver kinase B1 (LKB1), a major upstream kinase of the energy sensor AMP-activated protein kinase (AMPK), is unknown. Here, we show that energy stress triggers an increase in SUMO1 modification of LKB1, despite a global reduction in both SUMO1 and SUMO2/3 conjugates. During metabolic stress, SUMO1 modification of LKB1 lysine 178 is essential in promoting its interaction with AMPK via a SUMO-interacting motif (SIM) essential for AMPK activation. The LKB1 K178R SUMO mutant had defective AMPK signaling and mitochondrial function, inducing death in energy-deprived cells. These results provide additional insight into how LKB1-AMPK signaling is regulated during energy stress, and they highlight the critical role of SUMOylation in maintaining the cell’s energy equilibrium.

  6. A Critical SUMO1 Modification of LKB1 Regulates AMPK Activity during Energy Stress

    KAUST Repository

    Ritho, Joan; Arold, Stefan T.; Yeh, Edward  T.H.

    2015-01-01

    SUMOylation has been implicated in cellular stress adaptation, but its role in regulating liver kinase B1 (LKB1), a major upstream kinase of the energy sensor AMP-activated protein kinase (AMPK), is unknown. Here, we show that energy stress triggers an increase in SUMO1 modification of LKB1, despite a global reduction in both SUMO1 and SUMO2/3 conjugates. During metabolic stress, SUMO1 modification of LKB1 lysine 178 is essential in promoting its interaction with AMPK via a SUMO-interacting motif (SIM) essential for AMPK activation. The LKB1 K178R SUMO mutant had defective AMPK signaling and mitochondrial function, inducing death in energy-deprived cells. These results provide additional insight into how LKB1-AMPK signaling is regulated during energy stress, and they highlight the critical role of SUMOylation in maintaining the cell’s energy equilibrium.

  7. Regulation of mitogen-activated protein kinase 3/1 activity during meiosis resumption in mammals

    Czech Academy of Sciences Publication Activity Database

    Procházka, Radek; Blaha, Milan

    2015-01-01

    Roč. 61, č. 6 (2015), s. 495-502 ISSN 0916-8818 R&D Projects: GA MZe(CZ) QJ1510138 Institutional support: RVO:67985904 Keywords : cumulus oocyte complexes * meiosis resumption * mitogen-activated protein kinase 3/1 (MAPK3/1) Subject RIV: GI - Animal Husbandry ; Breeding Impact factor: 1.453, year: 2015

  8. Vitamin D Receptor Negatively Regulates Bacterial-Stimulated NF-κB Activity in Intestine

    OpenAIRE

    Wu, Shaoping; Liao, Anne P.; Xia, Yinglin; Li, Yan Chun; Li, Jian-Dong; Sartor, R. Balfour; Sun, Jun

    2010-01-01

    Vitamin D receptor (VDR) plays an essential role in gastrointestinal inflammation. Most investigations have focused on the immune response; however, how bacteria regulate VDR and how VDR modulates the nuclear factor (NF)-κB pathway in intestinal epithelial cells remain unexplored. This study investigated the effects of VDR ablation on NF-κB activation in intestinal epithelia and the role of enteric bacteria on VDR expression. We found that VDR−/− mice exhibited a pro-inflammatory bias. After ...

  9. Replicative Stress Induces Intragenic Transcription of the ASE1 Gene that Negatively Regulates Ase1 Activity

    OpenAIRE

    McKnight, Kelly; Liu, Hong; Wang, Yanchang

    2014-01-01

    Intragenic transcripts initiate within the coding region of a gene, thereby producing shorter mRNAs and proteins. Although intragenic transcripts are widely expressed [1], their role in the functional regulation of genes remains largely unknown. In budding yeast, DNA replication stress activates the S-phase checkpoint that stabilizes replication forks and arrests cells in S-phase with a short spindle [2-4]. When yeast cells were treated with hydroxyurea (HU) to block DNA synthesis and induce ...

  10. Expression, processing and transcriptional regulation of granulysin in short-term activated human lymphocytes

    Directory of Open Access Journals (Sweden)

    Groscurth Peter

    2007-06-01

    Full Text Available Abstract Background Granulysin, a cytotoxic protein expressed in human natural killer cells and activated T lymphocytes, exhibits cytolytic activity against a variety of intracellular microbes. Expression and transcription have been partially characterised in vitro and four transcripts (NKG5, 519, 520, and 522 were identified. However, only a single protein product of 15 kDa was found, which is subsequently processed to an active 9 kDa protein. Results In this study we investigated generation of granulysin in lymphokine activated killer (LAK cells and antigen (Listeria specific T-cells. Semiquantitative RT-PCR revealed NKG5 to be the most prominent transcript. It was found to be up-regulated in a time-dependent manner in LAK cells and antigen specific T-cells and their subsets. Two isoforms of 519 mRNA were up-regulated under IL-2 and antigen stimulation. Moreover, two novel transcripts, without any known function, comprising solely parts of the 5 prime region of the primary transcript, were detected. A significant increase of granulysin expressing LAK cells as well as antigen specific T-cells was shown by fluorescence microscopy. On the subset level, increase in CD4+ granulysin expressing cells was found only under antigen stimulation. Immunoblotting showed the 15 kDa form of granulysin to be present in the first week of stimulation either with IL-2 or with bacterial antigen. Substantial processing to the 9 kDa form was detected during the first week in LAK cells and in the second week in antigen specific T-cells. Conclusion This first comprehensive study of granulysin gene regulation in primary cultured human lymphocytes shows that the regulation of granulysin synthesis in response to IL-2 or bacterial antigen stimulation occurs at several levels: RNA expression, extensive alternative splicing and posttranslational processing.

  11. Direct Ionic Regulation of the Activity of Myo-Inositol Biosynthesis Enzymes in Mozambique Tilapia.

    Directory of Open Access Journals (Sweden)

    Fernando D Villarreal

    Full Text Available Myo-inositol (Ins is a major compatible osmolyte in many cells, including those of Mozambique tilapia (Oreochromis mossambicus. Ins biosynthesis is highly up-regulated in tilapia and other euryhaline fish exposed to hyperosmotic stress. In this study, enzymatic regulation of two enzymes of Ins biosynthesis, Ins phosphate synthase (MIPS and inositol monophosphatase (IMPase, by direct ionic effects is analyzed. Specific MIPS and IMPase isoforms from Mozambique tilapia (MIPS-160 and IMPase 1 were selected based on experimental, phylogenetic, and structural evidence supporting their role for Ins biosynthesis during hyperosmotic stress. Recombinant tilapia IMPase 1 and MIPS-160 activity was assayed in vitro at ionic conditions that mimic changes in the intracellular milieu during hyperosmotic stress. The in vitro activities of MIPS-160 and IMPase 1 are highest at alkaline pH of 8.8. IMPase 1 catalytic efficiency is strongly increased during hyperosmolality (particularly for the substrate D-Ins-3-phosphate, Ins-3P, mainly as a result of [Na+] elevation. Furthermore, the substrate-specificity of IMPase 1 towards D-Ins-1-phosphate (Ins-1P is lower than towards Ins-3P. Because MIPS catalysis results in Ins-3P this results represents additional evidence for IMPase 1 being the isoform that mediates Ins biosynthesis in tilapia. Our data collectively demonstrate that the Ins biosynthesis enzymes are activated under ionic conditions that cells are exposed to during hypertonicity, resulting in Ins accumulation, which, in turn, results in restoration of intracellular ion homeostasis. We propose that the unique and direct ionic regulation of the activities of Ins biosynthesis enzymes represents an efficient biochemical feedback loop for regulation of intracellular physiological ion homeostasis during hyperosmotic stress.

  12. The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation

    OpenAIRE

    Malik, Sohail; Roeder, Robert G.

    2010-01-01

    The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes. In metazoan cells, multiple pathways that are responsible for homeostasis, cell growth and differentiation converge on the Mediator through transcriptional activators and repressors that target one or more of the almost 30 subunits of this complex. Besides interacting directly with RNA polymerase II, Mediator has multiple functions and can interact with and coordinate the action ...

  13. Direct Ionic Regulation of the Activity of Myo-Inositol Biosynthesis Enzymes in Mozambique Tilapia.

    Science.gov (United States)

    Villarreal, Fernando D; Kültz, Dietmar

    2015-01-01

    Myo-inositol (Ins) is a major compatible osmolyte in many cells, including those of Mozambique tilapia (Oreochromis mossambicus). Ins biosynthesis is highly up-regulated in tilapia and other euryhaline fish exposed to hyperosmotic stress. In this study, enzymatic regulation of two enzymes of Ins biosynthesis, Ins phosphate synthase (MIPS) and inositol monophosphatase (IMPase), by direct ionic effects is analyzed. Specific MIPS and IMPase isoforms from Mozambique tilapia (MIPS-160 and IMPase 1) were selected based on experimental, phylogenetic, and structural evidence supporting their role for Ins biosynthesis during hyperosmotic stress. Recombinant tilapia IMPase 1 and MIPS-160 activity was assayed in vitro at ionic conditions that mimic changes in the intracellular milieu during hyperosmotic stress. The in vitro activities of MIPS-160 and IMPase 1 are highest at alkaline pH of 8.8. IMPase 1 catalytic efficiency is strongly increased during hyperosmolality (particularly for the substrate D-Ins-3-phosphate, Ins-3P), mainly as a result of [Na+] elevation. Furthermore, the substrate-specificity of IMPase 1 towards D-Ins-1-phosphate (Ins-1P) is lower than towards Ins-3P. Because MIPS catalysis results in Ins-3P this results represents additional evidence for IMPase 1 being the isoform that mediates Ins biosynthesis in tilapia. Our data collectively demonstrate that the Ins biosynthesis enzymes are activated under ionic conditions that cells are exposed to during hypertonicity, resulting in Ins accumulation, which, in turn, results in restoration of intracellular ion homeostasis. We propose that the unique and direct ionic regulation of the activities of Ins biosynthesis enzymes represents an efficient biochemical feedback loop for regulation of intracellular physiological ion homeostasis during hyperosmotic stress.

  14. Tyrosine phosphorylation in T cells is regulated by phosphatase activity: studies with phenylarsine oxide.

    OpenAIRE

    Garcia-Morales, P; Minami, Y; Luong, E; Klausner, R D; Samelson, L E

    1990-01-01

    Activation of T cells induces rapid tyrosine phosphorylation on the T-cell receptor zeta chain and other substrates. These phosphorylations can be regulated by a number of protein-tyrosine kinases (ATP: protein-tyrosine O-phosphotransferase, EC 2.7.1.112) and protein-tyrosine-phosphatases (protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48). In this study, we demonstrate that phenylarsine oxide can inhibit tyrosine phosphatases while leaving tyrosine kinase function intact. We use this ...

  15. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.

    Science.gov (United States)

    Plikus, Maksim V; Mayer, Julie Ann; de la Cruz, Damon; Baker, Ruth E; Maini, Philip K; Maxson, Robert; Chuong, Cheng-Ming

    2008-01-17

    In the age of stem cell engineering it is critical to understand how stem cell activity is regulated during regeneration. Hairs are mini-organs that undergo cyclic regeneration throughout adult life, and are an important model for organ regeneration. Hair stem cells located in the follicle bulge are regulated by the surrounding microenvironment, or niche. The activation of such stem cells is cyclic, involving periodic beta-catenin activity. In the adult mouse, regeneration occurs in waves in a follicle population, implying coordination among adjacent follicles and the extrafollicular environment. Here we show that unexpected periodic expression of bone morphogenetic protein 2 (Bmp2) and Bmp4 in the dermis regulates this process. This BMP cycle is out of phase with the WNT/beta-catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signalling, respectively. Overexpression of noggin, a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wild-type host showed that follicles in donor and host can affect their cycling behaviours mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. These results show that BMPs may be the long-sought 'chalone' inhibitors of hair growth postulated by classical experiments. Taken together, results presented in this study provide an example of hierarchical regulation of local organ stem cell homeostasis by the inter-organ macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiological integration between these two thermo-regulatory organs. Our findings have practical importance for studies using mouse skin as a model for carcinogenesis, intra-cutaneous drug

  16. Novelty-induced activity-regulated cytoskeletal-associated protein (Arc) expression in frontal cortex requires serotonin 2A receptor activation

    DEFF Research Database (Denmark)

    Santini, Martin; Klein, A B; El-Sayed, M

    2011-01-01

    environment. As an output of FC activation we measured expression of activity-regulated cytoskeletal-associated protein (Arc). Novelty-exposure (open-field arena) robustly up-regulated FC Arc mRNA expression (∼160%) in mice compared to home-cage controls. This response was inhibited with the 5-HT(2A...

  17. Novelty-induced activity-regulated cytoskeletal-associated protein (Arc) expression in frontal cortex requires serotonin 2A receptor activation

    DEFF Research Database (Denmark)

    Santini, Martin; Klein, A B; El-Sayed, M

    2011-01-01

    environment. As an output of FC activation we measured expression of activity-regulated cytoskeletal-associated protein (Arc). Novelty-exposure (open-field arena) robustly up-regulated FC Arc mRNA expression (~160%) in mice compared to home-cage controls. This response was inhibited with the 5-HT(2A...

  18. Regulation of Calcitriol Biosynthesis and Activity: Focus on Gestational Vitamin D Deficiency and Adverse Pregnancy Outcomes

    Directory of Open Access Journals (Sweden)

    Andrea Olmos-Ortiz

    2015-01-01

    Full Text Available Vitamin D has garnered a great deal of attention in recent years due to a global prevalence of vitamin D deficiency associated with an increased risk of a variety of human diseases. Specifically, hypovitaminosis D in pregnant women is highly common and has important implications for the mother and lifelong health of the child, since it has been linked to maternal and child infections, small-for-gestational age, preterm delivery, preeclampsia, gestational diabetes, as well as imprinting on the infant for life chronic diseases. Therefore, factors that regulate vitamin D metabolism are of main importance, especially during pregnancy. The hormonal form and most active metabolite of vitamin D is calcitriol. This hormone mediates its biological effects through a specific nuclear receptor, which is found in many tissues including the placenta. Calcitriol synthesis and degradation depend on the expression and activity of CYP27B1 and CYP24A1 cytochromes, respectively, for which regulation is tissue specific. Among the factors that modify these cytochromes expression and/or activity are calcitriol itself, parathyroid hormone, fibroblast growth factor 23, cytokines, calcium and phosphate. This review provides a current overview on the regulation of vitamin D metabolism, focusing on vitamin D deficiency during gestation and its impact on pregnancy outcomes.

  19. Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins.

    Science.gov (United States)

    Chen, Buxin; Siderovski, David P; Neubig, Richard R; Lawson, Mark A; Trejo, Joann

    2014-01-17

    The G protein-coupled protease-activated receptor 1 (PAR1) is irreversibly proteolytically activated by thrombin. Hence, the precise regulation of PAR1 signaling is important for proper cellular responses. In addition to desensitization, internalization and lysosomal sorting of activated PAR1 are critical for the termination of signaling. Unlike most G protein-coupled receptors, PAR1 internalization is mediated by the clathrin adaptor protein complex 2 (AP-2) and epsin-1, rather than β-arrestins. However, the function of AP-2 and epsin-1 in the regulation of PAR1 signaling is not known. Here, we report that AP-2, and not epsin-1, regulates activated PAR1-stimulated phosphoinositide hydrolysis via two different mechanisms that involve, in part, a subset of R4 subfamily of "regulator of G protein signaling" (RGS) proteins. A significantly greater increase in activated PAR1 signaling was observed in cells depleted of AP-2 using siRNA or in cells expressing a PAR1 (420)AKKAA(424) mutant with defective AP-2 binding. This effect was attributed to AP-2 modulation of PAR1 surface expression and efficiency of G protein coupling. We further found that ectopic expression of R4 subfamily members RGS2, RGS3, RGS4, and RGS5 reduced activated PAR1 wild-type signaling, whereas signaling by the PAR1 AKKAA mutant was minimally affected. Intriguingly, siRNA-mediated depletion analysis revealed a function for RGS5 in the regulation of signaling by the PAR1 wild type but not the AKKAA mutant. Moreover, activation of the PAR1 wild type, and not the AKKAA mutant, induced Gαq association with RGS3 via an AP-2-dependent mechanism. Thus, AP-2 regulates activated PAR1 signaling by altering receptor surface expression and through recruitment of RGS proteins.

  20. Regulation of the ligand-dependent activation of the epidermal growth factor receptor by calmodulin

    DEFF Research Database (Denmark)

    Li, Hongbing; Panina, Svetlana; Kaur, Amandeep

    2012-01-01

    Calmodulin (CaM) is the major component of calcium signaling pathways mediating the action of various effectors. Transient increases in the intracellular calcium level triggered by a variety of stimuli lead to the formation of Ca2+/CaM complexes, which interact with and activate target proteins....... In the present study the role of Ca2+/CaM in the regulation of the ligand-dependent activation of the epidermal growth factor receptor (EGFR) has been examined in living cells. We show that addition of different cell permeable CaM antagonists to cultured cells or loading cells with a Ca2+ chelator inhibited...

  1. Expression of novel rice gibberellin 2-oxidase gene is under homeostatic regulation by biologically active gibberellins.

    Science.gov (United States)

    Sakai, Miho; Sakamoto, Tomoaki; Saito, Tamio; Matsuoka, Makoto; Tanaka, Hiroshi; Kobayashi, Masatomo

    2003-04-01

    We have cloned two genes for gibberellin (GA) 2-oxidase from rice ( Oryza sativa L.). Expression of OsGA2ox2 was not observed. The other gene, OsGA2ox3, was expressed in every tissue examined and was enhanced by the application of biologically active GA. Recombinant OsGA2ox3 protein catalyzed the metabolism of GA(1) to GA(8) and GA(20) to GA(29)-catabolite. These results indicate that OsGA2ox3 is involved in the homeostatic regulation of the endogenous level of biologically active GA in rice.

  2. An overview of the AECB's strategy for regulating radioactive waste management activities

    International Nuclear Information System (INIS)

    Hamel, P.E.; Smythe, W.D.; Duncan, R.M.; Coady, J.R.

    1982-07-01

    The goal of the Canadian Atomic Energy Control Board in regulating the management of radioactive wastes is to ensure the protection of people and the environment. A program of cooperation with other agencies, identification and adoption of baselines for describing radioactive wastes, development of explicit criteria and requirements, publication of related regulatory documents, establishment of independent consultative processes with technical experts and the public, and maintenance of awareness and compatibility with international activities is underway. Activities related to high-level radioactive waste, uranium mine and mill tailings, low- and medium-level wastes, radioactive effluents from nuclear facilities, and decommissioning and decontamination are described

  3. Deubiquitylating enzyme USP9x regulates hippo pathway activity by controlling angiomotin protein turnover

    DEFF Research Database (Denmark)

    Nguyen, Thanh Hung; Andrejeva, Diana; Gupta, Rajat

    2016-01-01

    /TAZ activity. We demonstrate that USPx regulates ubiquitin-mediated turnover of the YAP inhibitor, Angiomotin. USP9x acts to deubiquitylate Angiomotin at lysine 496, resulting in stabilization of Angiomotin and lower YAP/TAZ activity. USP9x mRNA levels were reduced in several cancers. Clinically, USP9x m......RNA levels were reduced in several cancers with low USPx expression correlating with poor prognosis in renal clear cell carcinoma. Our data indicate that USP9x may be a useful biomarker for renal clear cell carcinoma....

  4. Active cell-matrix coupling regulates cellular force landscapes of cohesive epithelial monolayers

    Science.gov (United States)

    Zhao, Tiankai; Zhang, Yao; Wei, Qiong; Shi, Xuechen; Zhao, Peng; Chen, Long-Qing; Zhang, Sulin

    2018-03-01

    Epithelial cells can assemble into cohesive monolayers with rich morphologies on substrates due to competition between elastic, edge, and interfacial effects. Here we present a molecularly based thermodynamic model, integrating monolayer and substrate elasticity, and force-mediated focal adhesion formation, to elucidate the active biochemical regulation over the cellular force landscapes in cohesive epithelial monolayers, corroborated by microscopy and immunofluorescence studies. The predicted extracellular traction and intercellular tension are both monolayer size and substrate stiffness dependent, suggestive of cross-talks between intercellular and extracellular activities. Our model sets a firm ground toward a versatile computational framework to uncover the molecular origins of morphogenesis and disease in multicellular epithelia.

  5. Abscisic Acid Regulates Inflammation via Ligand-binding Domain-independent Activation of Peroxisome Proliferator-activated Receptor γ*

    Science.gov (United States)

    Bassaganya-Riera, Josep; Guri, Amir J.; Lu, Pinyi; Climent, Montse; Carbo, Adria; Sobral, Bruno W.; Horne, William T.; Lewis, Stephanie N.; Bevan, David R.; Hontecillas, Raquel

    2011-01-01

    Abscisic acid (ABA) has shown efficacy in the treatment of diabetes and inflammation; however, its molecular targets and the mechanisms of action underlying its immunomodulatory effects remain unclear. This study investigates the role of peroxisome proliferator-activated receptor γ (PPAR γ) and lanthionine synthetase C-like 2 (LANCL2) as molecular targets for ABA. We demonstrate that ABA increases PPAR γ reporter activity in RAW 264.7 macrophages and increases ppar γ expression in vivo, although it does not bind to the ligand-binding domain of PPAR γ. LANCL2 knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR γ is dependent on lancl2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced prostaglandin E2 and MCP-1 production via a PPAR γ-dependent mechanism possibly involving activation of PPAR γ and suppression of NF-κB and nuclear factor of activated T cells. LPS challenge studies in PPAR γ-expressing and immune cell-specific PPAR γ null mice demonstrate that ABA down-regulates toll-like receptor 4 expression in macrophages and T cells in vivo through a PPAR γ-dependent mechanism. Global transcriptomic profiling and confirmatory quantitative RT-PCR suggest novel candidate targets and demonstrate that ABA treatment mitigates the effect of LPS on the expression of genes involved in inflammation, metabolism, and cell signaling, in part, through PPAR γ. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, ligand-binding domain-independent mechanism of PPAR γ activation. PMID:21088297

  6. Abscisic acid regulates inflammation via ligand-binding domain-independent activation of peroxisome proliferator-activated receptor gamma.

    Science.gov (United States)

    Bassaganya-Riera, Josep; Guri, Amir J; Lu, Pinyi; Climent, Montse; Carbo, Adria; Sobral, Bruno W; Horne, William T; Lewis, Stephanie N; Bevan, David R; Hontecillas, Raquel

    2011-01-28

    Abscisic acid (ABA) has shown efficacy in the treatment of diabetes and inflammation; however, its molecular targets and the mechanisms of action underlying its immunomodulatory effects remain unclear. This study investigates the role of peroxisome proliferator-activated receptor γ (PPAR γ) and lanthionine synthetase C-like 2 (LANCL2) as molecular targets for ABA. We demonstrate that ABA increases PPAR γ reporter activity in RAW 264.7 macrophages and increases ppar γ expression in vivo, although it does not bind to the ligand-binding domain of PPAR γ. LANCL2 knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR γ is dependent on lancl2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced prostaglandin E(2) and MCP-1 production via a PPAR γ-dependent mechanism possibly involving activation of PPAR γ and suppression of NF-κB and nuclear factor of activated T cells. LPS challenge studies in PPAR γ-expressing and immune cell-specific PPAR γ null mice demonstrate that ABA down-regulates toll-like receptor 4 expression in macrophages and T cells in vivo through a PPAR γ-dependent mechanism. Global transcriptomic profiling and confirmatory quantitative RT-PCR suggest novel candidate targets and demonstrate that ABA treatment mitigates the effect of LPS on the expression of genes involved in inflammation, metabolism, and cell signaling, in part, through PPAR γ. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, ligand-binding domain-independent mechanism of PPAR γ activation.

  7. Active Erk Regulates Microtubule Stability in H-ras-Transformed Cells

    Directory of Open Access Journals (Sweden)

    Rene E. Harrison

    2001-01-01

    Full Text Available Increasing evidence suggests that activated erk regulates cell functions, at least in part, by mechanisms that do not require gene transcription. Here we show that the map kinase, erk, decorates microtubules (MTs and mitotic spindles in both parental and mutant active rastransfected 10T1 /2 fibroblasts and MCF10A breast epithelial cells. Approximately 20% of total cellular erk decorated MTs in both cell lines. A greater proportion of activated erk was associated with MTs in the presence of mutant active H-ras than in parental cells. Activation of erk by the ras pathway coincided with a decrease in the stability of MT, as detected by a stability marker. The MKK1 inhibitor, PD98059 and transfection of a dominant negative MKK1 blocked ras-induced instability of MTs but did not modify the association of erk with MTs or affect MT stability of the parental cells. These results indicate that the subset of active erk kinase that associates with MTs contributes to their instability in the presence of a mutant active ras. The MT-associated subset of active erk likely contributes to the enhanced invasive and proliferative abilities of cells containing mutant active H-ras.

  8. Dimer formation and transcription activation in the sporulation response regulator Spo0A.

    Science.gov (United States)

    Lewis, Richard J; Scott, David J; Brannigan, James A; Ladds, Joanne C; Cervin, Marguerite A; Spiegelman, George B; Hoggett, James G; Barák, Imrich; Wilkinson, Anthony J

    2002-02-15

    The response regulator Spo0A is the master control element in the initiation of sporulation in Bacillus subtilis. Like many other multi-domain response regulators, the latent activity of the effector, C-terminal domain is stimulated by phosphorylation on a conserved aspartic acid residue in the regulatory, N-terminal domain. If a threshold concentration of phosphorylated Spo0A is achieved, the transcription of genes required for sporulation is activated, whereas the genes encoding stationary phase sentinels are repressed, and sporulation proceeds. Despite detailed genetic, biochemical and structural characterisation, it is not understood how the phosphorylation signal in the receiver domain is transduced into DNA binding and transcription activation in the distal effector domain. An obstacle to our understanding of Spo0A function is the uncertainty concerning changes in quaternary structure that accompany phosphorylation. Here we have revisited this question and shown unequivocally that Spo0A forms dimers upon phosphorylation and that the subunit interactions in the dimer are mediated principally by the receiver domain. Purified dimers of two mutants of Spo0A, in which the phosphorylatable aspartic acid residue has been substituted, activate transcription from the spoIIG promoter in vitro, whereas monomers do not. This suggests that dimers represent the activated form of Spo0A. Copyright 2002 Elsevier Science Ltd.

  9. Ornithine decarboxylase regulates the activity and localization of rhoA via polyamination

    International Nuclear Information System (INIS)

    Maekitie, Laura T.; Kanerva, Kristiina; Andersson, Leif C.

    2009-01-01

    Ornithine decarboxylase (ODC) is the rate-limiting enzyme of polyamine synthesis. Polyamines and ODC are connected to cell proliferation and transformation. Resting cells display a low ODC activity while normal, proliferating cells display fluctuations in ODC activity that coincide with changes in the actin cytoskeleton during the cell cycle. Cancerous cells display constitutively elevated ODC activity. Overexpression of ODC in NIH 3T3 fibroblasts induces a transformed phenotype. The cytoskeletal rearrangements during cytokinesis and cell transformation are intimately coupled to the ODC activity but the molecular mechanisms have remained elusive. In this study we investigated how ODC and polyamines influence the organization of the cytoskeleton. Given that the small G-proteins of the rho family are key modulators of the actin cytoskeleton, we investigated the molecular interactions of rhoA with ODC and polyamines. Our results show that transglutaminase-catalyzed polyamination of rhoA regulates its activity. The polyamination status of rhoA crucially influences the progress of the cell cycle as well as the rate of transformation of rat fibroblasts infected with temperature-sensitive v-src. We also show that ODC influences the intracellular distribution of rhoA. These findings provide novel insights into the mechanisms by which ODC and polyamines regulate the dynamics of the cytoskeleton during cell proliferation and transformation

  10. Calcium/calmodulin-dependent protein kinase II activity regulates the proliferative potential of growth plate chondrocytes.

    Science.gov (United States)

    Li, Yuwei; Ahrens, Molly J; Wu, Amy; Liu, Jennifer; Dudley, Andrew T

    2011-01-01

    For tissues that develop throughout embryogenesis and into postnatal life, the generation of differentiated cells to promote tissue growth is at odds with the requirement to maintain the stem cell/progenitor cell population to preserve future growth potential. In the growth plate cartilage, this balance is achieved in part by establishing a proliferative phase that amplifies the number of progenitor cells prior to terminal differentiation into hypertrophic chondrocytes. Here, we show that endogenous calcium/calmodulin-dependent protein kinase II (CamkII, also known as Camk2) activity is upregulated prior to hypertrophy and that loss of CamkII function substantially blocks the transition from proliferation to hypertrophy. Wnt signaling and Pthrp-induced phosphatase activity negatively regulate CamkII activity. Release of this repression results in activation of multiple effector pathways, including Runx2- and β-catenin-dependent pathways. We present an integrated model for the regulation of proliferation potential by CamkII activity that has important implications for studies of growth control and adult progenitor/stem cell populations.

  11. Activation of the TOR Signalling Pathway by Glutamine Regulates Insect Fecundity.

    Science.gov (United States)

    Zhai, Yifan; Sun, Zhongxiang; Zhang, Jianqing; Kang, Kui; Chen, Jie; Zhang, Wenqing

    2015-05-29

    The target of rapamycin (TOR) positively controls cell growth in response to nutrients such as amino acids. However, research on the specific nutrients sensed by TOR is limited. Glutamine (Gln), a particularly important amino acid involved in metabolism in organisms, is synthesised and catalysed exclusively by glutamine synthetase (GS), and our previous studies have shown that Gln may regulate fecundity in vivo levels of the brown planthopper (BPH) Nilaparvata lugens. Until now, it has remained unclear whether Gln activates or inhibits the TOR signalling pathway. Here, we performed the combined analyses of iTRAQ (isobaric tags for relative and absolute quantification) and DGE (tag-based digital gene expression) data in N. lugens at the protein and transcript levels after GS RNAi, and we found that 52 pathways overlap, including the TOR pathway. We further experimentally demonstrate that Gln activates the TOR pathway by promoting the serine/threonine protein kinase AKT and inhibiting the 5'AMP-activated protein kinase AMPK phosphorylation activity in the pest. Furthermore, TOR regulates the fecundity of N. lugens probably by mediating vitellogenin (Vg) expression. This work is the first report that Gln activates the TOR pathway in vivo.

  12. Lens ion transport: from basic concepts to regulation of Na,K-ATPase activity

    Science.gov (United States)

    Delamere, Nicholas A.; Tamiya, Shigeo

    2009-01-01

    In the late 1960s, studies by George Duncan explained many of the basic principles that underlie lens ion homeostasis. The experiments pointed to a permeability barrier close to the surface of the lens and illustrated the requirement for continuous Na,K-ATPase-mediated active sodium extrusion. Without active sodium extrusion, lens sodium and calcium content increases resulting in lens swelling and deterioration of transparency. Later, Duncan's laboratory discovered functional muscarinic and purinergic receptors at the surface of the lens. Recent studies using intact lens suggest purinergic receptors might be involved in short-term regulation of Na,K-ATPase in the epithelium. Purinergic receptor agonists ATP and UTP selectively activate certain Src family tyrosine kinases and stimulate Na,K-ATPase activity. This might represent part of a control mechanism capable of adjusting, perhaps fine tuning, lens ion transport machinery. PMID:18614168

  13. Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival.

    Directory of Open Access Journals (Sweden)

    Daniel Thomas

    Full Text Available The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K, promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3 and granulocyte macrophage colony stimulating factor (GM-CSF receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting

  14. Sigma E regulators control hemolytic activity and virulence in a shrimp pathogenic Vibrio harveyi.

    Directory of Open Access Journals (Sweden)

    Pimonsri Rattanama

    Full Text Available Members of the genus Vibrio are important marine and aquaculture pathogens. Hemolytic activity has been identified as a virulence factor in many pathogenic vibrios including V. cholerae, V. parahaemolyticus, V. alginolyticus, V. harveyi and V. vulnificus. We have used transposon mutagenesis to identify genes involved in the hemolytic activity of shrimp-pathogenic V. harveyi strain PSU3316. Out of 1,764 mutants screened, five mutants showed reduced hemolytic activity on sheep blood agar and exhibited virulence attenuation in shrimp (Litopenaeus vannamei. Mutants were identified by comparing transposon junction sequences to a draft of assembly of the PSU3316 genome. Surprisingly none of the disrupted open reading frames or gene neighborhoods contained genes annotated as hemolysins. The gene encoding RseB, a negative regulator of the sigma factor (σ(E, was interrupted in 2 out of 5 transposon mutants, in addition, the transcription factor CytR, a threonine synthetase, and an efflux-associated cytoplasmic protein were also identified. Knockout mutations introduced into the rpoE operon at the rseB gene exhibited low hemolytic activity in sheep blood agar, and were 3-to 7-fold attenuated for colonization in shrimp. Comparison of whole cell extracted proteins in the rseB mutant (PSU4030 to the wild-type by 2-D gel electrophoresis revealed 6 differentially expressed proteins, including two down-regulated porins (OmpC-like and OmpN and an upregulated protease (DegQ which have been associated with σ(E in other organisms. Our study is the first report linking hemolytic activity to the σ(E regulators in pathogenic Vibrio species and suggests expression of this virulence-linked phenotype is governed by multiple regulatory pathways within the V. harveyi.

  15. PTSD Psychotherapy Outcome Predicted by Brain Activation During Emotional Reactivity and Regulation.

    Science.gov (United States)

    Fonzo, Gregory A; Goodkind, Madeleine S; Oathes, Desmond J; Zaiko, Yevgeniya V; Harvey, Meredith; Peng, Kathy K; Weiss, M Elizabeth; Thompson, Allison L; Zack, Sanno E; Lindley, Steven E; Arnow, Bruce A; Jo, Booil; Gross, James J; Rothbaum, Barbara O; Etkin, Amit

    2017-12-01

    Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but many patients do not respond. Brain functions governing treatment outcome are not well characterized. The authors examined brain systems relevant to emotional reactivity and regulation, constructs that are thought to be central to PTSD and exposure therapy effects, to identify the functional traits of individuals most likely to benefit from treatment. Individuals with PTSD underwent functional MRI (fMRI) while completing three tasks assessing emotional reactivity and regulation. Participants were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30). A random subset of the prolonged exposure group (N=17) underwent single-pulse transcranial magnetic stimulation (TMS) concurrent with fMRI to examine whether predictive activation patterns reflect causal influence within circuits. Linear mixed-effects modeling in line with the intent-to-treat principle was used to examine how baseline brain function moderated the effect of treatment on PTSD symptoms. At baseline, individuals with larger treatment-related symptom reductions (compared with the waiting list condition) demonstrated 1) greater dorsal prefrontal activation and 2) less left amygdala activation, both during emotion reactivity; 3) better inhibition of the left amygdala induced by single TMS pulses to the right dorsolateral prefrontal cortex; and 4) greater ventromedial prefrontal/ventral striatal activation during emotional conflict regulation. Reappraisal-related activation was not a significant moderator of the treatment effect. Capacity to benefit from prolonged exposure in PTSD is gated by the degree to which prefrontal resources are spontaneously engaged when superficially processing threat and adaptively mitigating emotional interference, but not when deliberately reducing negative emotionality.

  16. Proteolytic fragmentation of inositol 1,4,5-trisphosphate receptors: a novel mechanism regulating channel activity?

    Science.gov (United States)

    Wang, Liwei; Alzayady, Kamil J; Yule, David I

    2016-06-01

    Inositol 1,4,5-trisphosphate receptors (IP3 Rs) are a family of ubiquitously expressed intracellular Ca(2+) release channels. Regulation of channel activity by Ca(2+) , nucleotides, phosphorylation, protein binding partners and other cellular factors is thought to play a major role in defining the specific spatiotemporal characteristics of intracellular Ca(2+) signals. These properties are, in turn, believed pivotal for the selective and specific physiological activation of Ca(2+) -dependent effectors. IP3 Rs are also substrates for the intracellular cysteine proteases, calpain and caspase. Cleavage of the IP3 R has been proposed to play a role in apoptotic cell death by uncoupling regions important for IP3 binding from the channel domain, leaving an unregulated leaky Ca(2+) pore. Contrary to this hypothesis, we demonstrate following proteolysis that N- and C-termini of IP3 R1 remain associated, presumably through non-covalent interactions. Further, we show that complementary fragments of IP3 R1 assemble into tetrameric structures and retain their ability to be regulated robustly by IP3 . While peptide continuity is clearly not necessary for IP3 -gating of the channel, we propose that cleavage of the IP3 R peptide chain may alter other important regulatory events to modulate channel activity. In this scenario, stimulation of the cleaved IP3 R may support distinct spatiotemporal Ca(2+) signals and activation of specific effectors. Notably, in many adaptive physiological events, the non-apoptotic activities of caspase and calpain are demonstrated to be important, but the substrates of the proteases are poorly defined. We speculate that proteolytic fragmentation may represent a novel form of IP3 R regulation, which plays a role in varied adaptive physiological processes. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  17. CNS β3-adrenergic receptor activation regulates feeding behavior, white fat browning, and body weight.

    Science.gov (United States)

    Richard, Jennifer E; López-Ferreras, Lorena; Chanclón, Belén; Eerola, Kim; Micallef, Peter; Skibicka, Karolina P; Wernstedt Asterholm, Ingrid

    2017-09-01

    Pharmacological β 3 -adrenergic receptor (β 3 AR) activation leads to increased mitochondrial biogenesis and activity in white adipose tissue (WAT), a process commonly referred to as "browning", and transiently increased insulin release. These effects are associated with improved metabolic function and weight loss. It is assumed that this impact of β 3 AR agonists is mediated solely through activation of β 3 ARs in adipose tissue. However, β 3 ARs are also found in the brain, in areas such as the brain stem and the hypothalamus, which provide multisynaptic innervation to brown and white adipose depots. Thus, contrary to the current adipocentric view, the central nervous system (CNS) may also have the ability to regulate energy balance and metabolism through actions on central β 3 ARs. Therefore, this study aimed to elucidate whether CNS β 3 ARs can regulate browning of WAT and other aspects of metabolic regulation, such as food intake control and insulin release. We found that acute central injection of β 3 AR agonist potently reduced food intake, body weight, and increased hypothalamic neuronal activity in rats. Acute central β 3 AR stimulation was also accompanied by a transient increase in circulating insulin levels. Moreover, subchronic central β 3 AR agonist treatment led to a browning response in both inguinal (IWAT) and gonadal WAT (GWAT), along with reduced GWAT and increased BAT mass. In high-fat, high-sugar-fed rats, subchronic central β 3 AR stimulation reduced body weight, chow, lard, and sucrose water intake, in addition to increasing browning of IWAT and GWAT. Collectively, our results identify the brain as a new site of action for the anorexic and browning impact of β 3 AR activation. Copyright © 2017 the American Physiological Society.

  18. Skin barrier homeostasis in atopic dermatitis: feedback regulation of kallikrein activity.

    Directory of Open Access Journals (Sweden)

    Reiko J Tanaka

    Full Text Available Atopic dermatitis (AD is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs, whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external stimulus. The model analysis confirmed that the hypothesised core model mechanisms capture the essence of inflammation outbreak by a defective skin barrier. Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control. We also proposed a novel quantitative indicator for inflammation level by applying principal component analysis to microarray data. The model analysis reproduced qualitative AD characteristics revealed by this indicator. Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation. We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier

  19. Regulation of Energy Stores and Feeding by Neuronal and Peripheral CREB Activity in Drosophila

    Science.gov (United States)

    Iijima, Koichi; Zhao, LiJuan; Shenton, Christopher; Iijima-Ando, Kanae

    2009-01-01

    The cAMP-responsive transcription factor CREB functions in adipose tissue and liver to regulate glycogen and lipid metabolism in mammals. While Drosophila has a homolog of mammalian CREB, dCREB2, its role in energy metabolism is not fully understood. Using tissue-specific expression of a dominant-negative form of CREB (DN-CREB), we have examined the effect of blocking CREB activity in neurons and in the fat body, the primary energy storage depot with functions of adipose tissue and the liver in flies, on energy balance, stress resistance and feeding behavior. We found that disruption of CREB function in neurons reduced glycogen and lipid stores and increased sensitivity to starvation. Expression of DN-CREB in the fat body also reduced glycogen levels, while it did not affect starvation sensitivity, presumably due to increased lipid levels in these flies. Interestingly, blocking CREB activity in the fat body increased food intake. These flies did not show a significant change in overall body size, suggesting that disruption of CREB activity in the fat body caused an obese-like phenotype. Using a transgenic CRE-luciferase reporter, we further demonstrated that disruption of the adipokinetic hormone receptor, which is functionally related to mammalian glucagon and β-adrenergic signaling, in the fat body reduced CRE-mediated transcription in flies. This study demonstrates that CREB activity in either neuronal or peripheral tissues regulates energy balance in Drosophila, and that the key signaling pathway regulating CREB activity in peripheral tissue is evolutionarily conserved. PMID:20041126

  20. O-GlcNAc transferase regulates transcriptional activity of human Oct4.

    Science.gov (United States)

    Constable, Sandii; Lim, Jae-Min; Vaidyanathan, Krithika; Wells, Lance

    2017-10-01

    O-linked β-N-acetylglucosamine (O-GlcNAc) is a single sugar modification found on many different classes of nuclear and cytoplasmic proteins. Addition of this modification, by the enzyme O-linked N-acetylglucosamine transferase (OGT), is dynamic and inducible. One major class of proteins modified by O-GlcNAc is transcription factors. O-GlcNAc regulates transcription factor properties through a variety of different mechanisms including localization, stability and transcriptional activation. Maintenance of embryonic stem (ES) cell pluripotency requires tight regulation of several key transcription factors, many of which are modified by O-GlcNAc. Octamer-binding protein 4 (Oct4) is one of the key transcription factors required for pluripotency of ES cells and more recently, the generation of induced pluripotent stem (iPS) cells. The action of Oct4 is modulated by the addition of several post-translational modifications, including O-GlcNAc. Previous studies in mice found a single site of O-GlcNAc addition responsible for transcriptional regulation. This study was designed to determine if this mechanism is conserved in humans. We mapped 10 novel sites of O-GlcNAc attachment on human Oct4, and confirmed a role for OGT in transcriptional activation of Oct4 at a site distinct from that found in mouse that allows distinction between different Oct4 target promoters. Additionally, we uncovered a potential new role for OGT that does not include its catalytic function. These results confirm that human Oct4 activity is being regulated by OGT by a mechanism that is distinct from mouse Oct4. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. CSK negatively regulates nerve growth factor induced neural differentiation and augments AKT kinase activity

    International Nuclear Information System (INIS)

    Dey, Nandini; Howell, Brian W.; De, Pradip K.; Durden, Donald L.

    2005-01-01

    Src family kinases are involved in transducing growth factor signals for cellular differentiation and proliferation in a variety of cell types. The activity of all Src family kinases (SFKs) is controlled by phosphorylation at their C-terminal 527-tyrosine residue by C-terminal SRC kinase, CSK. There is a paucity of information regarding the role of CSK and/or specific Src family kinases in neuronal differentiation. Pretreatment of PC12 cells with the Src family kinase inhibitor, PP1, blocked NGF-induced activation of SFKs and obliterated neurite outgrowth. To confirm a role for CSK and specific isoforms of SFKs in neuronal differentiation, we overexpressed active and catalytically dead CSK in the rat pheochromocytoma cell line, PC12. CSK overexpression caused a profound inhibition of NGF-induced activation of FYN, YES, RAS, and ERK and inhibited neurite outgrowth, NGF-stimulated integrin-directed migration and blocked the NGF-induced conversion of GDP-RAC to its GTP-bound active state. CSK overexpression markedly augmented the activation state of AKT following NGF stimulation. In contrast, kinase-dead CSK augmented the activation of FYN, RAS, and ERK and increased neurite outgrowth. These data suggest a distinct requirement for CSK in the regulation of NGF/TrkA activation of RAS, RAC, ERK, and AKT via the differential control of SFKs in the orchestration of neuronal differentiation

  2. Aspects on Media Self Regulation Reflected in the Activity of Romanian Journalists

    Directory of Open Access Journals (Sweden)

    Daniela Aurelia Popa

    2011-05-01

    Full Text Available The media organizations in Romania, reticent to the idea to constraint the press freedom, manage to understand the importance of implementing a system of media responsibility. Therefore, the present study is a research in incipient stage that begins with the identification of the initiatives of media self regulation as an alternative to the efforts of enacting press in Romania. The identification of the self regulating system in Romania will be accomplished through the description of the context of development of the media responsibility system in the Romanian journalistic culture and by underlining the self regulation initiatives. For the delineation and establishment of such important self regulation initiatives, the activity of an ethical instance is necessary, for the defense and solving cases of norms contained by the new deontological code. The establishment of such an instance in Romania will represent a viable solution for the development of a more ethical professional environment that confirms the assumption of media responsibility for the adhesion to quality journalistic standards.

  3. Multiple layers of posttranslational regulation refine circadian clock activity in Arabidopsis.

    Science.gov (United States)

    Seo, Pil Joon; Mas, Paloma

    2014-01-01

    The circadian clock is a cellular time-keeper mechanism that regulates biological rhythms with a period of ~24 h. The circadian rhythms in metabolism, physiology, and development are synchronized by environmental cues such as light and temperature. In plants, proper matching of the internal circadian time with the external environment confers fitness advantages on plant survival and propagation. Accordingly, plants have evolved elaborated regulatory mechanisms that precisely control the circadian oscillations. Transcriptional feedback regulation of several clock components has been well characterized over the past years. However, the importance of additional regulatory mechanisms such as chromatin remodeling, protein complexes, protein phosphorylation, and stability is only starting to emerge. The multiple layers of circadian regulation enable plants to properly synchronize with the environmental cycles and to fine-tune the circadian oscillations. This review focuses on the diverse posttranslational events that regulate circadian clock function. We discuss the mechanistic insights explaining how plants articulate a high degree of complexity in their regulatory networks to maintain circadian homeostasis and to generate highly precise waveforms of circadian expression and activity.

  4. Commission de regulation de l'electricite. Activity Report 30 June 2000

    International Nuclear Information System (INIS)

    2000-01-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity market for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity sector, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the June 2000 activity report of CRE. Content: A - Opening of the European electricity market: transposition into French law of the European Directive, access to the European power transportation network, obstacles to market deregulation, segmentation of the European market, deregulation impact on electricity market: the German example, state of the French market openness; B - The first regulation projects: network access, account un-bundling, production opening to competition modalities, studies relative to the creation of an electricity stock-exchange in France; C - The Commission: means, operation. D - Appendixes: Glossary; Units; Council of European Energy Regulators

  5. Syndecan-2 regulates melanin synthesis via protein kinase C βII-mediated tyrosinase activation.

    Science.gov (United States)

    Jung, Hyejung; Chung, Heesung; Chang, Sung Eun; Choi, Sora; Han, Inn-Oc; Kang, Duk-Hee; Oh, Eok-Soo

    2014-05-01

    Syndecan-2, a transmembrane heparan sulfate proteoglycan that is highly expressed in melanoma cells, regulates melanoma cell functions (e.g. migration). Since melanoma is a malignant tumor of melanocytes, which largely function to synthesize melanin, we investigated the possible involvement of syndecan-2 in melanogenesis. Syndecan-2 expression was increased in human skin melanoma tissues compared with normal skin. In both mouse and human melanoma cells, siRNA-mediated knockdown of syndecan-2 was associated with reduced melanin synthesis, whereas overexpression of syndecan-2 increased melanin synthesis. Similar effects were also detected in human primary epidermal melanocytes. Syndecan-2 expression did not affect the expression of tyrosinase, a key enzyme in melanin synthesis, but instead enhanced the enzymatic activity of tyrosinase by increasing the membrane and melanosome localization of its regulator, protein kinase CβII. Furthermore, UVB caused increased syndecan-2 expression, and this up-regulation of syndecan-2 was required for UVB-induced melanin synthesis. Taken together, these data suggest that syndecan-2 regulates melanin synthesis and could be a potential therapeutic target for treating melanin-associated diseases. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Liver X Receptor (LXR) activation negatively regulates visfatin expression in macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Mayi, Therese Hervee; Rigamonti, Elena [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France); Pattou, Francois [Univ Lille Nord de France, F-59000 Lille (France); Department of Endocrine Surgery, University Hospital, Lille (France); U859 Biotherapies for Diabetes, INSERM, Lille (France); Staels, Bart, E-mail: bart.staels@pasteur-lille.fr [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France); Chinetti-Gbaguidi, Giulia [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France)

    2011-01-07

    Research highlights: {yields} Synthetic LXR ligands decreased visfatin expression in human macrophages. {yields} LXR activation leads to a modest and transient decrease of NAD{sup +} concentration. {yields} LXR activation decreased PPAR{gamma}-induced visfatin in human macrophages. -- Abstract: Adipose tissue macrophages (ATM) are the major source of visfatin, a visceral fat adipokine upregulated during obesity. Also known to play a role in B cell differentiation (pre-B cell colony-enhancing factor (PBEF)) and NAD biosynthesis (nicotinamide phosphoribosyl transferase (NAMPT)), visfatin has been suggested to play a role in inflammation. Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR){gamma} are nuclear receptors expressed in macrophages controlling the inflammatory response. Recently, we reported visfatin as a PPAR{gamma} target gene in human macrophages. In this study, we examined whether LXR regulates macrophage visfatin expression. Synthetic LXR ligands decreased visfatin gene expression in a LXR-dependent manner in human and murine macrophages. The decrease of visfatin mRNA was paralleled by a decrease of protein secretion. Consequently, a modest and transient decrease of NAD{sup +} concentration was observed. Interestingly, LXR activation decreased the PPAR{gamma}-induced visfatin gene and protein secretion in human macrophages. Our results identify visfatin as a gene oppositely regulated by the LXR and PPAR{gamma} pathways in human macrophages.

  7. FGFR2c-mediated ERK-MAPK activity regulates coronal suture development

    Science.gov (United States)

    Pfaff, Miles J.; Xue, Ke; Li, Li; Horowitz, Mark C.; Steinbacher, Derek M.; Eswarakumar, Jacob V.P.

    2017-01-01

    Fibroblast growth factor receptor 2 (FGFR2) signaling is critical for proper craniofacial development. A gain-of-function mutation in the 2c splice variant of the receptor’s gene is associated with Crouzon syndrome, which is characterized by craniosynostosis, the premature fusion of one or more of the cranial vault sutures, leading to craniofacial maldevelopment. Insight into the molecular mechanism of craniosynostosis has identified the ERK-MAPK signaling cascade as a critical regulator of suture patency. The aim of this study is to investigate the role of FGFR2c-induced ERK-MAPK activation in the regulation of coronal suture development. Loss-of-function and gain-of-function Fgfr2c mutant mice have overlapping phenotypes, including coronal synostosis and craniofacial dysmorphia. In vivo analysis of coronal sutures in loss-of-function and gain-of-function models demonstrated fundamentally different pathogenesis underlying coronal suture synostosis. Calvarial osteoblasts from gain-of-function mice demonstrated enhanced osteoblastic function and maturation with concomitant increase in ERK-MAPK activation. In vitro inhibition with the ERK protein inhibitor U0126 mitigated ERK protein activation levels with a concomitant reduction in alkaline phosphatase activity. This study identifies FGFR2c-mediated ERK-MAPK signaling as a key mediator of craniofacial growth and coronal suture development. Furthermore, our results solve the apparent paradox between loss-of-function and gain-of-function FGFR2c mutants with respect to coronal suture synostosis. PMID:27034231

  8. Zyxin regulates migration of renal epithelial cells through activation of hepatocyte nuclear factor-1β.

    Science.gov (United States)

    Choi, Yun-Hee; McNally, Brian T; Igarashi, Peter

    2013-07-01

    Hepatocyte nuclear factor-1β (HNF-1β) is an epithelial tissue-specific transcription factor that regulates gene expression in the kidney, liver, pancreas, intestine, and other organs. Mutations of HNF-1β in humans produce renal cysts and congenital kidney anomalies. Here, we identify the LIM-domain protein zyxin as a novel binding partner of HNF-1β in renal epithelial cells. Zyxin shuttles to the nucleus where it colocalizes with HNF-1β. Immunoprecipitation of zyxin in leptomycin B-treated cells results in coprecipitation of HNF-1β. The protein interaction requires the second LIM domain of zyxin and two distinct domains of HNF-1β. Overexpression of zyxin stimulates the transcriptional activity of HNF-1β, whereas small interfering RNA silencing of zyxin inhibits HNF-1β-dependent transcription. Epidermal growth factor (EGF) induces translocation of zyxin into the nucleus and stimulates HNF-1β-dependent promoter activity. The EGF-mediated nuclear translocation of zyxin requires activation of Akt. Expression of dominant-negative mutant HNF-1β, knockdown of zyxin, or inhibition of Akt inhibits EGF-stimulated cell migration. These findings reveal a novel pathway by which extracellular signals are transmitted to the nucleus to regulate the activity of a transcription factor that is essential for renal epithelial differentiation.

  9. Regulation of ex vivo tyrosine hydroxylase (TH) activity is not altered by chronic lead (Pb) exposure

    International Nuclear Information System (INIS)

    Lasley, S.M.; Green, M.C.

    1991-01-01

    Previous studies have suggested that chronic Pb exposure results in impaired regulation of CNS dopamine (DA) synthesis in rats. The present study was designed to directly assess TH activity in exposed animals compared to controls, employing a pharmacological model that assesses the functional status of dopaminergic synthesis-modulating autoreceptors. At birth dams received 0.2% Pb acetate in drinking water. Offspring were weaned to and maintained on the same solution until termination at 60 or 120 days. Rats were given saline or a DA agonist (EMD 23448 or CGS 15855A) 45 min before sacrifice followed 15 min later by gamma-butyrolactone (GBL). Regional TH activity was measured by a modification of the tritium release method. DA content was determined by liquid chromatography. The ability of EMD 23448 to prevent the GBL-induced increase in DA content was significantly diminished in caudate-putamen (C-P) of exposed rats compared to controls, similar to previous observations. However, an analogous effect of Pb on TH activity in this drug model was not observed using CGS 15855A in rats either 60 or 120 days of age. These findings suggest that chronic Pb exposure has no effect on autoreceptor-mediated regulation of TH in DA neurons when TH activity is measured ex vivo

  10. ERalpha and ERbeta expression and transcriptional activity are differentially regulated by HDAC inhibitors

    Science.gov (United States)

    Duong, Vanessa; Licznar, Anne; Margueron, Raphaël; Boulle, Nathalie; Busson, Muriel; Lacroix, Matthieu; Katzenellenbogen, Benita S.; Cavaillès, Vincent; Lazennec, Gwendal

    2006-01-01

    The proliferative action of ERα largely accounts for the carcinogenic activity of estrogens. By contrast, recent data show that ERβ displays tumor-suppressor properties, thus supporting the interest to identify compounds which could increase its activity. Here, we show that histone deacetylase inhibitors (HDI) up-regulated ERβ protein levels, whereas it decreased ERα expression. Part of this regulation took place at the mRNA level through a mechanism independent of de novo protein synthesis. In addition, we found that, in various cancer cells, the treatment with different HDI enhanced the ligand-dependent activity of ERβ more strongly than that of ERα. On the other hand, in MDA-MB231 and HeLa cells, the expression of ERs modified the transcriptional response to HDI. The use of deletion mutants of both receptors demonstrated that AF1 domain of the receptors was required. Finally, we show that ERβ expression led to a dramatic increased in the antiproliferative activity of HDI, which correlated with a modification of the transcription of genes involved in cell cycle control by HDI. Altogether, these data demonstrate that the interference of ERβ and HDAC on the control of transcription and cell proliferation constitute a promising approach for cancer therapy. PMID:16158045

  11. Neuronal activity-regulated gene transcription: how are distant synaptic signals conveyed to the nucleus?

    Science.gov (United States)

    Matamales, Miriam

    2012-12-19

    Synaptic activity can trigger gene expression programs that are required for the stable change of neuronal properties, a process that is essential for learning and memory. Currently, it is still unclear how the stimulation of dendritic synapses can be coupled to transcription in the nucleus in a timely way given that large distances can separate these two cellular compartments. Although several mechanisms have been proposed to explain long distance communication between synapses and the nucleus, the possible co-existence of these models and their relevance in physiological conditions remain elusive. One model suggests that synaptic activation triggers the translocation to the nucleus of certain transcription regulators localised at postsynaptic sites that function as synapto-nuclear messengers. Alternatively, it has been hypothesised that synaptic activity initiates propagating regenerative intracellular calcium waves that spread through dendrites into the nucleus where nuclear transcription machinery is thereby regulated. It has also been postulated that membrane depolarisation of voltage-gated calcium channels on the somatic membrane is sufficient to increase intracellular calcium concentration and activate transcription without the need for transported signals from distant synapses. Here I provide a critical overview of the suggested mechanisms for coupling synaptic stimulation to transcription, the underlying assumptions behind them and their plausible physiological significance.

  12. Assessment of brain activation regulation in first graders via RAN / RAS test

    Directory of Open Access Journals (Sweden)

    Tatiana V. Akhutina

    2015-03-01

    Full Text Available RAN / RAS test (Rapid Automatized Naming / Rapid Alternating Stimulus has been used successfully used by many psychologists, primarily to predict the risk of dyslexia, as it includes a language component and requires good visual-verbal connections. However, The research demonstrates that the low speed of naming is an effective indicator of neurocognitive problems of information processing as a whole (learning difficulties in general, not just reading difficulties. This can be explained in two ways: disturbance of executive mental control and the difficulties of automatization: the difficulties of the transition from a controlled energy-consuming assignment to a less energy-consuming one. The second interpretation describes the problems of energy resources of cognitive functioning. It is similar to weak maintenance of cortical structures activation. However, using the test mentioned herewith for assessing functions of activation regulation has not been described previously. In terms of the Luria’s three functional units of the brain theory the RAN / RAS test can be considered as sensitive to the weakness of the first unit, whose function is to maintain the activity of cortical structures. So the aim of the research is to prove the possibility of assessing the activation regulation using the RAN / RAS test. This issue is relevant because neuropsychological tools for determining the weakness of Unit I functions are not quite sufficient, while the problem of “energetic” unit ranks first in the frequency of occurrence in children with learning disabilities.

  13. Regulation of the muscle fiber microenvironment by activated satellite cells during hypertrophy

    Science.gov (United States)

    Fry, Christopher S.; Lee, Jonah D.; Jackson, Janna R.; Kirby, Tyler J.; Stasko, Shawn A.; Liu, Honglu; Dupont-Versteegden, Esther E.; McCarthy, John J.; Peterson, Charlotte A.

    2014-01-01

    Our aim in the current study was to determine the necessity of satellite cells for long-term muscle growth and maintenance. We utilized a transgenic Pax7-DTA mouse model, allowing for the conditional depletion of > 90% of satellite cells with tamoxifen treatment. Synergist ablation surgery, where removal of synergist muscles places functional overload on the plantaris, was used to stimulate robust hypertrophy. Following 8 wk of overload, satellite cell-depleted muscle demonstrated an accumulation of extracellular matrix (ECM) and fibroblast expansion that resulted in reduced specific force of the plantaris. Although the early growth response was normal, an attenuation of hypertrophy measured by both muscle wet weight and fiber cross-sectional area occurred in satellite cell-depleted muscle. Isolated primary myogenic progenitor cells (MPCs) negatively regulated fibroblast ECM mRNA expression in vitro, suggesting a novel role for activated satellite cells/MPCs in muscle adaptation. These results provide evidence that satellite cells regulate the muscle environment during growth.—Fry, C. S., Lee, J. D., Jackson, J. R., Kirby, T. J., Stasko, S. A., Liu, H., Dupont-Versteegden, E. E., McCarthy, J. J., Peterson, C. A. Regulation of the muscle fiber microenvironment by activated satellite cells during hypertrophy. PMID:24376025

  14. TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities

    Directory of Open Access Journals (Sweden)

    Sara Montagner

    2016-05-01

    Full Text Available Summary: Dioxygenases of the TET family impact genome functions by converting 5-methylcytosine (5mC in DNA to 5-hydroxymethylcytosine (5hmC. Here, we identified TET2 as a crucial regulator of mast cell differentiation and proliferation. In the absence of TET2, mast cells showed disrupted gene expression and altered genome-wide 5hmC deposition, especially at enhancers and in the proximity of downregulated genes. Impaired differentiation of Tet2-ablated cells could be relieved or further exacerbated by modulating the activity of other TET family members, and mechanistically it could be linked to the dysregulated expression of C/EBP family transcription factors. Conversely, the marked increase in proliferation induced by the loss of TET2 could be rescued exclusively by re-expression of wild-type or catalytically inactive TET2. Our data indicate that, in the absence of TET2, mast cell differentiation is under the control of compensatory mechanisms mediated by other TET family members, while proliferation is strictly dependent on TET2 expression. : The impact of TET enzymes on gene expression and cell function is incompletely understood. Montagner et al. investigate the TET-mediated regulation of mast cell differentiation and function, uncover transcriptional pathways regulated by TET2, and identify both enzymatic activity-dependent and -independent functions of TET2. Keywords: differentiation, DNA hydroxymethylation, epigenetics, mast cells, proliferation, TET

  15. Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

    Directory of Open Access Journals (Sweden)

    Abdullah Mayati

    2017-04-01

    Full Text Available Drug transporters are now recognized as major actors in pharmacokinetics, involved notably in drug–drug interactions and drug adverse effects. Factors that govern their activity, localization and expression are therefore important to consider. In the present review, the implications of protein kinases C (PKCs in transporter regulations are summarized and discussed. Both solute carrier (SLC and ATP-binding cassette (ABC drug transporters can be regulated by PKCs-related signaling pathways. PKCs thus target activity, membrane localization and/or expression level of major influx and efflux drug transporters, in various normal and pathological types of cells and tissues, often in a PKC isoform-specific manner. PKCs are notably implicated in membrane insertion of bile acid transporters in liver and, in this way, are thought to contribute to cholestatic or choleretic effects of endogenous compounds or drugs. The exact clinical relevance of PKCs-related regulation of drug transporters in terms of drug resistance, pharmacokinetics, drug–drug interactions and drug toxicity remains however to be precisely determined. This issue is likely important to consider in the context of the development of new drugs targeting PKCs-mediated signaling pathways, for treating notably cancers, diabetes or psychiatric disorders.

  16. Systematic Analysis of the Functions of Lysine Acetylation in the Regulation of Tat Activity.

    Directory of Open Access Journals (Sweden)

    Minghao He

    Full Text Available The Tat protein of HIV-1 has several well-known properties, such as nucleocytoplasmic trafficking, transactivation of transcription, interaction with tubulin, regulation of mitotic progression, and induction of apoptosis. Previous studies have identified a couple of lysine residues in Tat that are essential for its functions. In order to analyze the functions of all the lysine residues in Tat, we mutated them individually to alanine, glutamine, and arginine. Through systematic analysis of the lysine mutants, we discovered several previously unidentified characteristics of Tat. We found that lysine acetylation could modulate the subcellular localization of Tat, in addition to the regulation of its transactivation activity. Our data also revealed that lysine mutations had distinct effects on microtubule assembly and Tat binding to bromodomain proteins. By correlation analysis, we further found that the effects of Tat on apoptosis and mitotic progression were not entirely attributed to its effect on microtubule assembly. Our findings suggest that Tat may regulate diverse cellular activities through binding to different proteins and that the acetylation of distinct lysine residues in Tat may modulate its interaction with various partners.

  17. The regulation of visitors conduction activity in the State System os Brazilian Conservation Units

    Directory of Open Access Journals (Sweden)

    Cristina Alves Nascimento

    2016-08-01

    Full Text Available Beyond to conserving biodiversity, conservation units must promote public use in contact with nature, assisting in increasing the economic resource of the area, approximating the society to nature and promoting their sustainable use. In Brazil, there are rules of the Ministry of Environment and Chico Mendes Institute for Biodiversity Conservation that regulate the conduction of visitors in federal conservation units. Remains to know how the activity is regulated in other spheres of the National Conservation Units System. Therefore, this article purpose to identify the legal basis for the conduction of visitors in the state conservation units and their adherence to guidelines of the Ministry of Environment. The methodology consisted in documentary research and data survey of the legal basis, done through visits to websites and sending e-mails to state management agencies. Adherence to the guidelines of the regulations was done through the evaluation to fulfillment or not from them. Legal basis were found in 18.5% of federal units of Brazil, being that only Espírito Santo and Rio de Janeiro meet almost all of the guideline. The conclusion was that there is a long way to go forward as the creation of rules and procedures that simultaneously encourage visitation accompanied to qualified conductors and biodiversity conservation. It is recommended greater efforts of state management agencies for the development of these legal basis, promoting improvements in desenvolviment of the activity and awareness of society.

  18. An autocrine ATP release mechanism regulates basal ciliary activity in airway epithelium.

    Science.gov (United States)

    Droguett, Karla; Rios, Mariana; Carreño, Daniela V; Navarrete, Camilo; Fuentes, Christian; Villalón, Manuel; Barrera, Nelson P

    2017-07-15

    Extracellular ATP, in association with [Ca 2+ ] i regulation, is required to maintain basal ciliary beat frequency. Increasing extracellular ATP levels increases ciliary beating in airway epithelial cells, maintaining a sustained response by inducing the release of additional ATP. Extracellular ATP levels in the millimolar range, previously associated with pathophysiological conditions of the airway epithelium, produce a transient arrest of ciliary activity. The regulation of ciliary beat frequency is dependent on ATP release by hemichannels (connexin/pannexin) and P2X receptor activation, the blockage of which may even stop ciliary movement. The force exerted by cilia, measured by atomic force microscopy, is reduced following extracellular ATP hydrolysis. This result complements the current understanding of the ciliary beating regulatory mechanism, with special relevance to inflammatory diseases of the airway epithelium that affect mucociliary clearance. Extracellular nucleotides, including ATP, are locally released by the airway epithelium and stimulate ciliary activity in a [Ca 2+ ] i -dependent manner after mechanical stimulation of ciliated cells. However, it is unclear whether the ATP released is involved in regulating basal ciliary activity and mediating changes in ciliary activity in response to chemical stimulation. In the present study, we evaluated ciliary beat frequency (CBF) and ciliary beating forces in primary cultures from mouse tracheal epithelium, using videomicroscopy and atomic force microscopy (AFM), respectively. Extracellular ATP levels and [Ca 2+ ] i were measured by luminometric and fluorimetric assays, respectively. Uptake of ethidium bromide was measured to evaluate hemichannel functionality. We show that hydrolysis of constitutive extracellular ATP levels with apyrase (50 U ml -1 ) reduced basal CBF by 45% and ciliary force by 67%. The apyrase effect on CBF was potentiated by carbenoxolone, a hemichannel inhibitor, and oxidized ATP, an

  19. Regulation of phase I and phase II steroid metabolism enzymes by PPARα activators

    International Nuclear Information System (INIS)

    Fan Liqun; You Li; Brown-Borg, Holly; Brown, Sherri; Edwards, Robert J.; Corton, J. Christopher

    2004-01-01

    Peroxisome proliferators (PP) are a large class of structurally diverse chemicals that mediate their effects in the liver mainly through the peroxisome proliferator-activated receptor α (PPARα). Exposure to some PP results in alterations of steroid levels that may be mechanistically linked to adverse effects in reproductive organs. We hypothesized that changes in steroid levels after PP exposure are due to alterations in the levels of P450 enzymes that hydroxylate testosterone and estrogen. In testosterone hydroxylase assays, exposure to the PP, WY-14,643 (WY), gemfibrozil or di-n-butyl phthalate (DBP) led to compound-specific increases in 6β and 16β-testosterone and androstenedione hydroxylase activities and decreases in 16α, 2α-hydroxylase activities by all three PP. The decreases in 16α and 2α-testosterone hydroxylase activity can be attributed to a 2α and 16α- testosterone hydroxylase, CYP2C11, which we previously showed was dramatically down-regulated in these same tissues (Corton et al., 1998; Mol. Pharmacol. 54, 463-473). To explain the increases in 6β- and 16β-testosterone hydroxylase activities, we examined the expression of P450 family members known to carry out these functions. Alterations in the 6β-testosterone hydroxylases CYP3A1, CYP3A2 and the 16β-testosterone hydroxylase, CYP2B1 were observed after exposure to some PP. The male-specific estrogen sulfotransferase was down-regulated in rat liver after exposure to all PP. The mouse 6β-testosterone hydroxylase, Cyp3a11 was down-regulated by WY in wild-type but not PPARα-null mice. In contrast, DEHP increased Cyp3a11 in both wild-type and PPARα-null mice. These studies demonstrate that PP alter the expression and activity of a number of enzymes which regulate levels of sex steroids. The changes in these enzymes may help explain why exposure to some PP leads to adverse effects in endocrine tissues that produce or are the targets of sex hormones

  20. The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury.

    Science.gov (United States)

    McDaniel, Kelly; Huang, Li; Sato, Keisaku; Wu, Nan; Annable, Tami; Zhou, Tianhao; Ramos-Lorenzo, Sugeily; Wan, Ying; Huang, Qiaobing; Francis, Heather; Glaser, Shannon; Tsukamoto, Hidekazu; Alpini, Gianfranco; Meng, Fanyin

    2017-07-07

    The let-7/Lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs in various human disorders and cancer development. This study evaluated the role of the let-7/Lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly down-regulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (HSCs) with lipopolysaccharide (LPS) and transforming growth factor-β (TGF-β) significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibroblastic activation of cultured human HSCs induced by LPS and TGF-β, as evidenced by repressed ACTA2 (α-actin 2), COL1A1 (collagen 1A1), TIMP1 (TIMP metallopeptidase inhibitor 1), and FN1 (fibronectin 1); this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that Lin28B and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, Lin28B deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by Lin28B is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/Lin28 axis as an important regulator of HSC activation as well as its upstream modulators and down-stream targets will provide insights into the involvement of altered microRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Plexin-B2 negatively regulates macrophage motility, Rac, and Cdc42 activation.

    Directory of Open Access Journals (Sweden)

    Kelly E Roney

    Full Text Available Plexins are cell surface receptors widely studied in the nervous system, where they mediate migration and morphogenesis though the Rho family of small GTPases. More recently, plexins have been implicated in immune processes including cell-cell interaction, immune activation, migration, and cytokine production. Plexin-B2 facilitates ligand induced cell guidance and migration in the nervous system, and induces cytoskeletal changes in overexpression assays through RhoGTPase. The function of Plexin-B2 in the immune system is unknown. This report shows that Plexin-B2 is highly expressed on cells of the innate immune system in the mouse, including macrophages, conventional dendritic cells, and plasmacytoid dendritic cells. However, Plexin-B2 does not appear to regulate the production of proinflammatory cytokines, phagocytosis of a variety of targets, or directional migration towards chemoattractants or extracellular matrix in mouse macrophages. Instead, Plxnb2(-/- macrophages have greater cellular motility than wild type in the unstimulated state that is accompanied by more active, GTP-bound Rac and Cdc42. Additionally, Plxnb2(-/- macrophages demonstrate faster in vitro wound closure activity. Studies have shown that a closely related family member, Plexin-B1, binds to active Rac and sequesters it from downstream signaling. The interaction of Plexin-B2 with Rac has only been previously confirmed in yeast and bacterial overexpression assays. The data presented here show that Plexin-B2 functions in mouse macrophages as a negative regulator of the GTPases Rac and Cdc42 and as a negative regulator of basal cell motility and wound healing.

  2. Activated Fps/Fes tyrosine kinase regulates erythroid differentiation and survival.

    Science.gov (United States)

    Sangrar, Waheed; Gao, Yan; Bates, Barbara; Zirngibl, Ralph; Greer, Peter A

    2004-10-01

    A substantial body of evidence implicates the cytoplasmic protein tyrosine kinase Fps/Fes in regulation of myeloid differentiation and survival. In this study we wished to determine if Fps/Fes also plays a role in the regulation of erythropoiesis. Mice tissue-specifically expressing a "gain-of-function" mutant fps/fes transgene (fps(MF)) encoding an activated variant of Fps/Fes (MFps), were used to explore the in vivo biological role of Fps/Fes. Erythropoiesis in these mice was assessed by hematological analysis, lineage marker analysis, bone-marrow colony assays, and biochemical approaches. fps(MF) mice displayed reductions in peripheral red cell counts. However, there was an accumulation of immature erythroid precursors, which displayed increased survival. Fps/Fes and the related Fer kinase were both detected in early erythroid progenitors/blasts and in mature red cells. Fps/Fes was also activated in response to erythropoietin (EPO) and stem cell factor (SCF), two critical factors in erythroid development. In addition, increased Stat5A/B activation and reduced Erk1/2 phosphorylation was observed in fps(MF) primary erythroid cells in response to EPO or SCF, respectively. These data support a role for Fps/Fes in regulating the survival and differentiation of erythroid cells through modulation of Stat5A/B and Erk kinase pathways induced by EPO and SCF. The increased numbers and survival of erythroid progenitors from fps(MF) mice, and their differential responsiveness to SCF and EPO, implicates Fps/Fes in the commitment of multilineage progenitors to the erythroid lineage. The anemic phenotype in fps(MF) mice suggests that downregulation of Fps/Fes activity might be required for terminal erythroid differentiation.

  3. Commission de regulation de l'energie. Activity report june 2006

    International Nuclear Information System (INIS)

    2006-06-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2006 activity report of CRE. Content: A - Opening of the electricity and natural gas markets to household consumers on 1 July 2007: CRE at the service of eligible customers (Information for eligible customers, Improved knowledge of non-household customers); Monitoring of the non-discrimination, transparency and independence of system operators (Drafting and distribution of codes of good conduct for system operators, The necessary improvement of system operator independence); Preparing the practical methods of opening: GTE 2007 and GTG 2007 (The necessary simplification of relations between operators and customers, Achieving a greater level of consumer information and protection, The clearly defined stages of the 'customer pathway', Profiling and settlement mechanisms: turning experience feedback from 2004 to good account); Persisting uncertainties and hurdles (The need for a suitable regulatory and legislative platform, Hurdles to the opening of the household market); B - Regulation of the natural gas market: The gas market in the European context (Increasing weight of

  4. Effect of Phosphodiesterase in Regulating the Activity of Lysosomes in the HeLa Cell Line.

    Science.gov (United States)

    Hong, Eun-Seon; Kim, Bit-Na; Kim, Yang-Hoon; Min, Jiho

    2017-02-28

    The transport of lysosomal enzymes into the lysosomes depends on the phosphorylation of their chains and the binding of the phosphorylated residues to mannose-6-phosphate receptors. The efficiency of separation depends more on the phosphodiesterases (PDEs) than on the activity of the phosphorylation of mannose residues and can be determined in vitro. PDEs play important roles in regulation of the activation of lysosomes. The expression of proteins was confirmed by western blotting. All PDE4 series protein expression was reduced in high concentrations of rolipram. As a result of observing the fluorescence intensity after rolipram treatment, the lysosomal enzyme was activated at low concentrations and suppressed at high concentrations. High concentrations of rolipram recovered the original function. Antimicrobial activity was not shown in either 10 or 100 µ concentrations of rolipram in treated HeLa cells in vitro. However, the higher anticancer activity at lower rolipram concentration was shown in lysosomal enzyme treated with 10 µ of rolipram. The anticancer activity was confirmed through cathepsin B and D assay. Tranfection allowed examination of the relationship between PDE4 and lysosomal activity in more detail. Protein expression was confirmed to be reduced. Fluorescence intensity showed decreased activity of lysosomes and ROS in cells transfected with the antisense sequences of PDE4 A, B, C, and D. PDE4A showed anticancer activity, whereas lysosome from cells transfected with the antisense sequences of PDE4 B, C, and D had decreased anticancer activity. These results showed the PDE4 A, B, C, and D are conjunctly related with lysosomal activity.

  5. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

    International Nuclear Information System (INIS)

    Heizmann, Beate; Sellars, MacLean; Macias-Garcia, Alejandra; Chan, Susan; Kastner, Philippe

    2016-01-01

    The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

  6. GCN5 Regulates FGF Signaling and Activates Selective MYC Target Genes during Early Embryoid Body Differentiation

    Directory of Open Access Journals (Sweden)

    Li Wang

    2018-01-01

    Full Text Available Precise control of gene expression during development is orchestrated by transcription factors and co-regulators including chromatin modifiers. How particular chromatin-modifying enzymes affect specific developmental processes is not well defined. Here, we report that GCN5, a histone acetyltransferase essential for embryonic development, is required for proper expression of multiple genes encoding components of the fibroblast growth factor (FGF signaling pathway in early embryoid bodies (EBs. Gcn5−/− EBs display deficient activation of ERK and p38, mislocalization of cytoskeletal components, and compromised capacity to differentiate toward mesodermal lineage. Genomic analyses identified seven genes as putative direct targets of GCN5 during early differentiation, four of which are cMYC targets. These findings established a link between GCN5 and the FGF signaling pathway and highlighted specific GCN5-MYC partnerships in gene regulation during early differentiation.

  7. Diacylglycerol Kinases: Regulated Controllers of T Cell Activation, Function, and Development

    Directory of Open Access Journals (Sweden)

    Gary A. Koretzky

    2013-03-01

    Full Text Available Diacylglycerol kinases (DGKs are a diverse family of enzymes that catalyze the conversion of diacylglycerol (DAG, a crucial second messenger of receptor-mediated signaling, to phosphatidic acid (PA. Both DAG and PA are bioactive molecules that regulate a wide set of intracellular signaling proteins involved in innate and adaptive immunity. Clear evidence points to a critical role for DGKs in modulating T cell activation, function, and development. More recently, studies have elucidated factors that control DGK function, suggesting an added complexity to how DGKs act during signaling. This review summarizes the available knowledge of the function and regulation of DGK isoforms in signal transduction with a particular focus on T lymphocytes.

  8. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Heizmann, Beate [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Sellars, MacLean [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Macias-Garcia, Alejandra [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Institute for Medical Engineering and Science at MIT, Cambridge, MA 02139 (United States); Chan, Susan, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Kastner, Philippe, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Faculté de Médecine, Université de Strasbourg, Strasbourg (France)

    2016-02-12

    The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

  9. Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors

    Energy Technology Data Exchange (ETDEWEB)

    Song, Xiaoling [Iowa State Univ., Ames, IA (United States)

    2010-01-01

    My research is on the synergistic regulation of PAI-1 by EGF and TGF-β. The mechanism of synergistic regulation of PAI-1 by EGF and TGF-β are addressed. Methods are described for effective identification of RNA accessible sites for antisense oligodexoxynucleotides (ODNs) and siRNA. In this study effective AS-ODN sequences for both Lcn2 and Bcl2 were identified by in vitro tiled microarray studies. Our results suggest that hybridization of ODN arrays to a target mRNA under physiological conditions might be used as a rapid and reliable in vitro method to accurately identify targets on mRNA molecules for effective antisense and potential siRNA activity in vivo.

  10. The regulation of transactivator of transcription on the activity of DNA-PKcs promoter

    International Nuclear Information System (INIS)

    Yang Tianyi; Zhang Shimeng; Qin Xia; Li Bing; Liu Xiaodan; Zhou Pingkun

    2012-01-01

    Objective: To explore the influence of human immunodeficiency virus transactivator of transcription (TAT) on the promoter activity of DNA dependent protein kinase catalytic subunit (DNA-PKcs). Methods: The truncated promoters of DNA-PKcs were cloned by PCR from the template DNA from HeLa genomic DNA, and the pGL3-basic-DNA-PKcs promoter reporter plasmids were constructed. The activity of DNA-PKcs promoters was detected by dual-luciferase reporter assay system. A Lac-repressor and Lacoperator based green fluorescent protein imaging system was used to assay the chromatin remodeling activity. Results: A series of reporter plasmids harboring the truncated promoters of DNA-PKcs from -939 bp to -1 bp were constructed. The sequence of -64 bp to-1 bp was identified as a critical element for the activity of DNA-PKes promoter. TAT can suppress the activity of DNA-PKcs promoter. TAT participates in the regulation of the large scale chromatin relaxation. Ionizing radiation attenuates the activity of TAT played in the chromatin remodeling. Conclusion: TAT represses the promoter activity of DNA repair protein DNA-PKcs, and also play a role of large scale chromatin remodeling which can te attenuated by ionizing radiation. (authors)

  11. Abscisic acid induction of vacuolar H+-ATPase activity in mesembryanthemum crystallinum is developmentally regulated

    Science.gov (United States)

    Barkla; Vera-Estrella; Maldonado-Gama; Pantoja

    1999-07-01

    Abscisic acid (ABA) has been implicated as a key component in water-deficit-induced responses, including those triggered by drought, NaCl, and low- temperature stress. In this study a role for ABA in mediating the NaCl-stress-induced increases in tonoplast H+-translocating ATPase (V-ATPase) and Na+/H+ antiport activity in Mesembryanthemum crystallinum, leading to vacuolar Na+ sequestration, were investigated. NaCl or ABA treatment of adult M. crystallinum plants induced V-ATPase H+ transport activity, and when applied in combination, an additive effect on V-ATPase stimulation was observed. In contrast, treatment of juvenile plants with ABA did not induce V-ATPase activity, whereas NaCl treatment resulted in a similar response to that observed in adult plants. Na+/H+ antiport activity was induced in both juvenile and adult plants by NaCl, but ABA had no effect at either developmental stage. Results indicate that ABA-induced changes in V-ATPase activity are dependent on the plant reaching its adult phase, whereas NaCl-induced increases in V-ATPase and Na+/H+ antiport activity are independent of plant age. This suggests that ABA-induced V-ATPase activity may be linked to the stress-induced, developmentally programmed switch from C3 metabolism to Crassulacean acid metabolism in adult plants, whereas, vacuolar Na+ sequestration, mediated by the V-ATPase and Na+/H+ antiport, is regulated through ABA-independent pathways.

  12. An activator of transcription regulates phage TP901-1 late gene expression

    DEFF Research Database (Denmark)

    Brøndsted, Lone; Pedersen, Margit; Hammer, Karin

    2001-01-01

    bp contains both the promoter and the region necessary for activation by ORF29. The transcriptional start site of the promoter was identified by primer extension to position 13073 on the TP901-1 genome, thus located 87 bp downstream of orf29 in a 580-bp intergenic region between orf29 and orf30....... Furthermore, the region located -85 to -61 bp upstream of the start site was shown to be necessary for promoter activity. During infection, the transcript arising from the late promoter is fully induced at 40 min postinfection, and our results suggest that a certain level of ORF29 must he reached in order...... to activate transcription of the promoter. Several lactococcal bacteriophages encode ORF29 homologous proteins, indicating that late transcription may be controlled by a similar mechanism in these phages. With the identification of this novel regulator, our results suggest that within the P335 group...

  13. The protease inhibitor HAI-2, but not HAI-1, regulates matriptase activation and shedding through prostasin

    DEFF Research Database (Denmark)

    Friis, Stine; Sales, Katiuchia Uzzun; Schafer, Jeffrey Martin

    2014-01-01

    cells. Whereas ablation of HAI-1 did not affect matriptase in epithelial cells of the small or large intestine, ablation of HAI-2 resulted in the loss of matriptase from both tissues. Gene silencing studies in intestinal Caco-2 cell monolayers revealed that this loss of cell-associated matriptase......The membrane-anchored serine proteases, matriptase and prostasin, and the membrane-anchored serine protease inhibitors, hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2, are critical effectors of epithelial development and postnatal epithelial homeostasis. Matriptase and prostasin...... form a reciprocal zymogen activation complex that results in the formation of active matriptase and prostasin that are targets for inhibition by HAI-1 and HAI-2. Conflicting data, however, have accumulated as to the existence of auxiliary functions for both HAI-1 and HAI-2 in regulating...

  14. Classroom Activities to Engage Students and Promote Critical Thinking about Genetic Regulation of Bacterial Quorum Sensing

    Directory of Open Access Journals (Sweden)

    Kimberly Aebli

    2016-05-01

    Full Text Available We developed an interactive activity to mimic bacterial quorum sensing, and a classroom worksheet to promote critical thinking about genetic regulation of the lux operon. The interactive quorum sensing activity engages students and provides a direct visualization of how population density functions to influence light production in bacteria. The worksheet activity consists of practice problems that require students to apply basic knowledge of the lux operon in order to make predictions about genetic complementation experiments, and students must evaluate how genetic mutations in the lux operon affect gene expression and overall phenotype. The worksheet promotes critical thinking and problem solving skills, and emphasizes the roles of diffusible signaling molecules, regulatory proteins, and structural proteins in quorum sensing.

  15. Regulation of myelin genes implicated in psychiatric disorders by functional activity in axons

    Directory of Open Access Journals (Sweden)

    Philip R Lee

    2009-06-01

    Full Text Available Myelination is a highly dynamic process that continues well into adulthood in humans. Several recent gene expression studies have found abnormal expression of genes involved in myelination in the prefrontal cortex of brains from patients with schizophrenia and other psychiatric illnesses. Defects in myelination could contribute to the pathophysiology of psychiatric illness by impairing information processing as a consequence of altered impulse conduction velocity and synchrony between cortical regions carrying out higher level cognitive functions. Myelination can be altered by impulse activity in axons and by environmental experience. Psychiatric illness is treated by psychotherapy, behavioral modification, and drugs affecting neurotransmission, raising the possibility that myelinating glia may not only contribute to such disorders, but that activity-dependent effects on myelinating glia could provide one of the cellular mechanisms contributing to the therapeutic effects of these treatments. This review examines evidence showing that genes and gene networks important for myelination can be regulated by functional activity in axons.

  16. Regulation of lipolytic activity by long-chain acyl-coenzyme A in islets and adipocytes

    DEFF Research Database (Denmark)

    Hu, Liping; Deeney, Jude T; Nolan, Christopher J

    2005-01-01

    -cells. The mechanisms by which lipolysis is regulated in different tissues is, therefore, of considerable interest. Here, the effects of long-chain acyl-CoA esters (LC-CoA) on lipase activity in islets and adipocytes were compared. Palmitoyl-CoA (Pal-CoA, 1-10 microM) stimulated lipase activity in islets from both....... The inhibitory effect of LC-CoA on adipocyte HSL was dependent on phosphorylation and enhanced by acyl-CoA-binding protein (ACBP). In contrast, the stimulatory effect on islet lipase activity was blocked by ACBP, presumably due to binding and sequestration of LC-CoA. These data suggest the following intertissue...

  17. The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation.

    Science.gov (United States)

    Malik, Sohail; Roeder, Robert G

    2010-11-01

    The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes. In metazoan cells, multiple pathways that are responsible for homeostasis, cell growth and differentiation converge on the Mediator through transcriptional activators and repressors that target one or more of the almost 30 subunits of this complex. Besides interacting directly with RNA polymerase II, Mediator has multiple functions and can interact with and coordinate the action of numerous other co-activators and co-repressors, including those acting at the level of chromatin. These interactions ultimately allow the Mediator to deliver outputs that range from maximal activation of genes to modulation of basal transcription to long-term epigenetic silencing.

  18. Identification and screening of active components from Ziziphora clinopodioides Lam. in regulating autophagy.

    Science.gov (United States)

    Zhang, Xuan-Ming; An, Dong-Qing; Guo, Long-Long; Yang, Ning-Hui; Zhang, Hua

    2018-04-03

    This study investigated the flavonoid constituents of a traditional Chinese medical plant Ziziphora clinopodioides Lam. by using ultra-performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry and screened the active components in regulating autophagy.Normal rat kidney (NRK) cells transfected with green fluorescent protein- microtubule-associated protein 1 light Chain 3(GFP-LC3) were treated with Z. clinopodioides flavonoids and its chemical compositions. After 4 h of treatment, the auto-phagy spot aggregation in NRK cells was photographed and observed by laser scanning confocal microscopy. The following 10 flavonoid components of Z. clinopodioides were identified: baicalein(1), quercetin(2), hyperoside(3), quercetin3-O-β-d-glucopyranoside(4), apigenin(5), kaempferol(6), chrysin(7), diosimin(8), linarin(9) and rutin(10). Among these flavonoids, chrysin, apigenin and quercetin were identified as the active principles in activating autophagy. This research may provide a reference for further developing and utilizing Z. clinopodioides.

  19. Differential Regulation of Telomerase Reverse Transcriptase Promoter Activation and Protein Degradation by Histone Deacetylase Inhibition.

    Science.gov (United States)

    Qing, Hua; Aono, Jun; Findeisen, Hannes M; Jones, Karrie L; Heywood, Elizabeth B; Bruemmer, Dennis

    2016-06-01

    Telomerase reverse transcriptase (TERT) maintains telomeres and is rate limiting for replicative life span. While most somatic tissues silence TERT transcription resulting in telomere shortening, cells derived from cancer or cardiovascular diseases express TERT and activate telomerase. In the present study, we demonstrate that histone deacetylase (HDAC) inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Finally, we demonstrate that HDAC inhibition decreases TERT expression during vascular remodeling in vivo. These data illustrate a differential regulation of TERT transcription and protein stability by HDAC inhibition and suggest that TERT may constitute an important target for the anti-proliferative efficacy of HDAC inhibitors. © 2015 Wiley Periodicals, Inc.

  20. COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity.

    Directory of Open Access Journals (Sweden)

    Isao Kurihara

    2007-06-01

    Full Text Available Progesterone and estrogen are critical regulators of uterine receptivity. To facilitate uterine remodeling for embryo attachment, estrogen activity in the uterine epithelia is attenuated by progesterone; however, the molecular mechanism by which this occurs is poorly defined. COUP-TFII (chicken ovalbumin upstream promoter transcription factor II; also known as NR2F2, a member of the nuclear receptor superfamily, is highly expressed in the uterine stroma and its expression is regulated by the progesterone-Indian hedgehog-Patched signaling axis that emanates from the epithelium. To further assess COUP-TFII uterine function, a conditional COUP-TFII knockout mouse was generated. This mutant mouse is infertile due to implantation failure, in which both embryo attachment and uterine decidualization are impaired. Using this animal model, we have identified a novel genetic pathway in which BMP2 lies downstream of COUP-TFII. Epithelial progesterone-induced Indian hedgehog regulates stromal COUP-TFII, which in turn controls BMP2 to allow decidualization to manifest in vivo. Interestingly, enhanced epithelial estrogen activity, which impedes maturation of the receptive uterus, was clearly observed in the absence of stromal-derived COUP-TFII. This finding is consistent with the notion that progesterone exerts its control of implantation through uterine epithelial-stromal cross-talk and reveals that stromal-derived COUP-TFII is an essential mediator of this complex cross-communication pathway. This finding also provides a new signaling paradigm for steroid hormone regulation in female reproductive biology, with attendant implications for furthering our understanding of the molecular mechanisms that underlie dysregulation of hormonal signaling in such human reproductive disorders as endometriosis and endometrial cancer.

  1. Leptin differentially regulate STAT3 activation in ob/ob mouse adipose mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Zhou Zhou

    2012-12-01

    Full Text Available Abstract Background Leptin-deficient ob/ob mice exhibit adipocyte hypertrophy and hyperplasia as well as elevated adipose tissue and systemic inflammation. Multipotent stem cells isolated from adult adipose tissue can differentiate into adipocytes ex vivo and thereby contribute toward increased adipocyte cell numbers, obesity, and inflamm ation. Currently, information is lacking regarding regulation of adipose stem cell numbers as well as leptin-induced inflammation and its signaling pathway in ob/ob mice. Methods Using leptin deficient ob/ob mice, we investigated whether leptin injection into ob/ob mice increases adipose stem cell numbers and adipose tissue inflammatory marker MCP-1 mRNA and secretion levels. We also determined leptin mediated signaling pathways in the adipose stem cells. Results We report here that adipose stem cell number is significantly increased following leptin injection in ob/ob mice and with treatment of isolated stem cells with leptin in vitro. Leptin also up-regulated MCP-1 secretion in a dose- and time-dependent manner. We further showed that increased MCP-1 mRNA levels were due to increased phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3 Ser727 but not STAT3 Tyr705 phosphorylation, suggesting differential regulation of MCP-1 gene expression under basal and leptin-stimulated conditions in adipose stem cells. Conclusions Taken together, these studies demonstrate that leptin increases adipose stem cell number and differentially activates STAT3 protein resulting in up-regulation of MCP-1 gene expression. Further studies of mechanisms mediating adipose stem cell hyperplasia and leptin signaling in obesity are warranted and may help identify novel anti-obesity target strategies.

  2. Carbonic anhydrase III regulates peroxisome proliferator-activated receptor-{gamma}2

    Energy Technology Data Exchange (ETDEWEB)

    Mitterberger, Maria C. [Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, 6020 Innsbruck (Austria); Kim, Geumsoo [Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-8012 (United States); Rostek, Ursula [Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, 6020 Innsbruck (Austria); Levine, Rodney L. [Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-8012 (United States); Zwerschke, Werner, E-mail: werner.zwerschke@oeaw.ac.at [Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, 6020 Innsbruck (Austria)

    2012-05-01

    Carbonic anhydrase III (CAIII) is an isoenzyme of the CA family. Because of its low specific anhydrase activity, physiological functions in addition to hydrating CO{sub 2} have been proposed. CAIII expression is highly induced in adipogenesis and CAIII is the most abundant protein in adipose tissues. The function of CAIII in both preadipocytes and adipocytes is however unknown. In the present study we demonstrate that adipogenesis is greatly increased in mouse embryonic fibroblasts (MEFs) from CAIII knockout (KO) mice, as demonstrated by a greater than 10-fold increase in the induction of fatty acid-binding protein-4 (FABP4) and increased triglyceride formation in CAIII{sup -/-} MEFs compared with CAIII{sup +/+} cells. To address the underlying mechanism, we investigated the expression of the two adipogenic key regulators, peroxisome proliferator-activated receptor-{gamma}2 (PPAR{gamma}2) and CCAAT/enhancer binding protein-{alpha}. We found a considerable (approximately 1000-fold) increase in the PPAR{gamma}2 expression in the CAIII{sup -/-} MEFs. Furthermore, RNAi-mediated knockdown of endogenous CAIII in NIH 3T3-L1 preadipocytes resulted in a significant increase in the induction of PPAR{gamma}2 and FABP4. When both CAIII and PPAR{gamma}2 were knocked down, FABP4 was not induced. We conclude that down-regulation of CAIII in preadipocytes enhances adipogenesis and that CAIII is a regulator of adipogenic differentiation which acts at the level of PPAR{gamma}2 gene expression. -- Highlights: Black-Right-Pointing-Pointer We discover a novel function of Carbonic anhydrase III (CAIII). Black-Right-Pointing-Pointer We show that CAIII is a regulator of adipogenesis. Black-Right-Pointing-Pointer We demonstrate that CAIII acts at the level of PPAR{gamma}2 gene expression. Black-Right-Pointing-Pointer Our data contribute to a better understanding of the role of CAIII in fat tissue.

  3. Electrophysiological evidence of increased glycine receptor-mediated phasic and tonic inhibition by blockade of glycine transporters in spinal superficial dorsal horn neurons of adult mice

    Directory of Open Access Journals (Sweden)

    Misa Oyama

    2017-03-01

    Full Text Available To understand the synaptic and/or extrasynaptic mechanisms underlying pain relief by blockade of glycine transporter subtypes GlyT1 and GlyT2, whole-cell recordings were made from dorsal horn neurons in spinal slices from adult mice, and the effects of NFPS and ALX-1393, selective GlyT1 and GlyT2 inhibitors, respectively, on phasic evoked or miniature glycinergic inhibitory postsynaptic currents (eIPSCs or mIPSCs were examined. NFPS and ALX-1393 prolonged the decay phase of eIPSCs without affecting their amplitude. In the presence of tetrodotoxin to record mIPSCs, NFPS and ALX-1393 induced a tonic inward current that was reversed by strychnine. Although NFPS had no statistically significant influences on mIPSCs, ALX-1393 significantly increased their frequency. We then further explored the role of GlyTs in the maintenance of glycinergic IPSCs. To facilitate vesicular release of glycine, repetitive high-frequency stimulation (HFS was applied at 10 Hz for 3 min during continuous recordings of eIPSCs at 0.1 Hz. Prominent suppression of eIPSCs was evident after HFS in the presence of ALX-1393, but not NFPS. Thus, it appears that phasic and tonic inhibition may contribute to the analgesic effects of GlyT inhibitors. However, reduced glycinergic inhibition due to impaired vesicular refilling could hamper the analgesic efficacy of GlyT2 inhibitors.

  4. Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism.

    Science.gov (United States)

    Dienel, Gerald A; Cruz, Nancy F

    2016-07-01

    Aerobic glycolysis occurs during brain activation and is characterized by preferential up-regulation of glucose utilization compared with oxygen consumption even though oxygen level and delivery are adequate. Aerobic glycolysis is a widespread phenomenon that underlies energetics of diverse brain activities, such as alerting, sensory processing, cognition, memory, and pathophysiological conditions, but specific cellular functions fulfilled by aerobic glycolysis are poorly understood. Evaluation of evidence derived from different disciplines reveals that aerobic glycolysis is a complex, regulated phenomenon that is prevented by propranolol, a non-specific β-adrenoceptor antagonist. The metabolic pathways that contribute to excess utilization of glucose compared with oxygen include glycolysis, the pentose phosphate shunt pathway, the malate-aspartate shuttle, and astrocytic glycogen turnover. Increased lactate production by unidentified cells, and lactate dispersal from activated cells and lactate release from the brain, both facilitated by astrocytes, are major factors underlying aerobic glycolysis in subjects with low blood lactate levels. Astrocyte-neuron lactate shuttling with local oxidation is minor. Blockade of aerobic glycolysis by propranolol implicates adrenergic regulatory processes including adrenal release of epinephrine, signaling to brain via the vagus nerve, and increased norepinephrine release from the locus coeruleus. Norepinephrine has a powerful influence on astrocytic metabolism and glycogen turnover that can stimulate carbohydrate utilization more than oxygen consumption, whereas β-receptor blockade 're-balances' the stoichiometry of oxygen-glucose or -carbohydrate metabolism by suppressing glucose and glycogen utilization more than oxygen consumption. This conceptual framework may be helpful for design of future studies to elucidate functional roles of preferential non-oxidative glucose utilization and glycogen turnover during brain

  5. MCPIP1 Regulates Alveolar Macrophage Apoptosis and Pulmonary Fibroblast Activation After in vitro Exposure to Silica.

    Science.gov (United States)

    Wang, Xingang; Zhang, Yuxia; Zhang, Wei; Liu, Haijun; Zhou, Zewei; Dai, Xiaoniu; Cheng, Yusi; Fang, Shencun; Zhang, Yingming; Yao, Honghong; Chao, Jie

    2016-05-01

    Silicosis is a fatal and fibrotic pulmonary disease caused by the inhalation of silica. After arriving at the alveoli, silica is ingested by alveolar macrophages (AMOs), in which monocyte chemotactic protein-induced protein 1 (MCPIP1) plays an essential role in controlling macrophage-mediated inflammatory responses. However, the mechanism of action of MCPIP1 in silicosis is poorly understood. Primary rat AMOs were isolated and treated with SiO2 (50 µg/cm(2)). MCPIP1 and AMO activation/apoptosis markers were detected by immunoblotting. MCPIP1 was down-regulated using siRNA in AMOs. The effects of AMOs on fibroblast activation and migration were evaluated using a gel contraction assay, a scratch assay, and a nested collagen matrix migration model. After exposure to SiO2, MCPIP1 was significantly increased in rat AMOs. Activation and apoptosis markers in AMOs were up-regulated after exposure to SiO2 Following siRNA-mediated silencing of MCPIP1 mRNA, the markers of AMO activation and apoptosis were significantly decreased. Rat pulmonary fibroblasts (PFBs) cultured in conditional medium from AMOs treated with MCPIP1 siRNA and SiO2 showed significantly less activation and migration compared with those cultured in conditional medium from AMOs treated with control siRNA and SiO2 CONCLUSION: Our data suggest a vital role for MCPIP1 in AMO apoptosis and PFB activation/migration induced by SiO2. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Palmitoylation regulates 17β-estradiol-induced estrogen receptor-α degradation and transcriptional activity.

    Science.gov (United States)

    La Rosa, Piergiorgio; Pesiri, Valeria; Leclercq, Guy; Marino, Maria; Acconcia, Filippo

    2012-05-01

    The estrogen receptor-α (ERα) is a transcription factor that regulates gene expression through the binding to its cognate hormone 17β-estradiol (E2). ERα transcriptional activity is regulated by E2-evoked 26S proteasome-mediated ERα degradation and ERα serine (S) residue 118 phosphorylation. Furthermore, ERα mediates fast cell responses to E2 through the activation of signaling cascades such as the MAPK/ERK and phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog 1 pathways. These E2 rapid effects require a population of the ERα located at the cell plasma membrane through palmitoylation, a dynamic enzymatic modification mediated by palmitoyl-acyl-transferases. However, whether membrane-initiated and transcriptional ERα activities integrate in a unique picture or represent parallel pathways still remains to be firmly clarified. Hence, we evaluated here the impact of ERα palmitoylation on E2-induced ERα degradation and S118 phosphorylation. The lack of palmitoylation renders ERα more susceptible to E2-dependent degradation, blocks ERα S118 phosphorylation and prevents E2-induced ERα estrogen-responsive element-containing promoter occupancy. Consequently, ERα transcriptional activity is prevented and the receptor addressed to the nuclear matrix subnuclear compartment. These data uncover a circuitry in which receptor palmitoylation links E2-dependent ERα degradation, S118 phosphorylation, and transcriptional activity in a unique molecular mechanism. We propose that rapid E2-dependent signaling could be considered as a prerequisite for ERα transcriptional activity and suggest an integrated model of ERα intracellular signaling where E2-dependent early extranuclear effects control late receptor-dependent nuclear actions.

  7. Imp2 regulates GBM progression by activating IGF2/PI3K/Akt pathway.

    Science.gov (United States)

    Mu, Qingchun; Wang, Lijun; Yu, Fengbo; Gao, Haijun; Lei, Ting; Li, Peiwen; Liu, Pengfei; Zheng, Xu; Hu, Xitong; Chen, Yong; Jiang, Zhenfeng; Sayari, Arash J; Shen, Jia; Huang, Haiyan

    2015-01-01

    Glioblastomas multiforme (GBM) are the most frequently occurring malignant brain cancers. Treatment for GBM consists of surgical resection and subsequent adjuvant radiation therapy and chemotherapy. Despite this, GBM patient survival is limited to 12-15 months, and researchers are continually trying to develop improved therapy options. Insulin-like growth factor 2 mRNA-binding protein 2 (Imp2) is known to be upregulated in many cancers and is known to regulate the signaling activity of insulin-like growth factor 2 (IGF2). However, relatively little is known about its role in malignant development of GBM. In this study, we first found Imp2 is upregulated in GBM tissues by using clinical samples and public database search. Studies with loss and gain of Imp2 expression in in vitro GBM cell culture system demonstrated the role of Imp2 in promoting GBM cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT). Additionally, our results show that Imp2 regulates the activity of IGF2, which further activates PI3K/Akt signaling, thereby to promote GBM malignancy. Inhibition of Imp2 was also found to sensitize GBM to temozolomide treatment. These observations add to the current knowledge of GBM biology, and may prove useful in development of more effective GBM therapy.

  8. CISH is induced during DC development and regulates DC-mediated CTL activation.

    Science.gov (United States)

    Miah, Mohammad Alam; Yoon, Cheol-Hee; Kim, Joonoh; Jang, Jinah; Seong, Young-Rim; Bae, Yong-Soo

    2012-01-01

    The cytokine inducible SH2-domain protein (CISH) is a well-known STAT5 target gene, but its role in the immune system remains uncertain. In this study, we found that CISH is predominantly induced during dendritic cell (DC) development from mouse bone marrow (BM) cells and plays a crucial role in type 1 DC development and DC-mediated CTL activation. CISH knockdown reduced the expression of MHC class I, co-stimulatory molecules and pro-inflammatory cytokines in BMDCs. Meanwhile, the DC yield was markedly enhanced by CISH knockdown via cell-cycle activation and reduction of cell apoptosis. Down-regulation of cell proliferation at the later stage of DC development was found to be associated with CISH-mediated negative feedback regulation of STAT5 activation. In T-cell immunity, OT-1 T-cell proliferation was significantly reduced by CISH knockdown in DCs, whereas OT-2 T-cell proliferation was not affected by CISH knockdown. CTLs generated by DC vaccination were also markedly reduced by CISH knockdown, followed by significant impairment of DC-based tumor immunotherapy. Taken together, our data suggest that CISH expression at the later stage of DC development triggers the shutdown of DC progenitor cell proliferation and facilitates DC differentiation into a potent stimulator of CTLs. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. PDK1 Is a Regulator of Epidermal Differentiation that Activates and Organizes Asymmetric Cell Division

    Directory of Open Access Journals (Sweden)

    Teruki Dainichi

    2016-05-01

    Full Text Available Asymmetric cell division (ACD in a perpendicular orientation promotes cell differentiation and organizes the stratified epithelium. However, the upstream cues regulating ACD have not been identified. Here, we report that phosphoinositide-dependent kinase 1 (PDK1 plays a critical role in establishing ACD in the epithelium. Production of phosphatidyl inositol triphosphate (PIP3 is localized to the apical side of basal cells. Asymmetric recruitment of atypical protein kinase C (aPKC and partitioning defective (PAR 3 is impaired in PDK1 conditional knockout (CKO epidermis. PDK1CKO keratinocytes do not undergo calcium-induced activation of aPKC or IGF1-induced activation of AKT and fail to differentiate. PDK1CKO epidermis shows decreased expression of Notch, a downstream effector of ACD, and restoration of Notch rescues defective expression of differentiation-induced Notch targets in vitro. We therefore propose that PDK1 signaling regulates the basal-to-suprabasal switch in developing epidermis by acting as both an activator and organizer of ACD and the Notch-dependent differentiation program.

  10. Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel.

    Science.gov (United States)

    He, Li; Si, Guangwei; Huang, Jiuhong; Samuel, Aravinthan D T; Perrimon, Norbert

    2018-03-01

    Somatic stem cells constantly adjust their self-renewal and lineage commitment by integrating various environmental cues to maintain tissue homeostasis. Although numerous chemical and biological signals have been identified that regulate stem-cell behaviour, whether stem cells can directly sense mechanical signals in vivo remains unclear. Here we show that mechanical stress regulates stem-cell differentiation in the adult Drosophila midgut through the stretch-activated ion channel Piezo. We find that Piezo is specifically expressed in previously unidentified enteroendocrine precursor cells, which have reduced proliferation ability and are destined to become enteroendocrine cells. Loss of Piezo activity reduces the generation of enteroendocrine cells in the adult midgut. In addition, ectopic expression of Piezo in all stem cells triggers both cell proliferation and enteroendocrine cell differentiation. Both the Piezo mutant and overexpression phenotypes can be rescued by manipulation of cytosolic Ca 2+ levels, and increases in cytosolic Ca 2+ resemble the Piezo overexpression phenotype, suggesting that Piezo functions through Ca 2+ signalling. Further studies suggest that Ca 2+ signalling promotes stem-cell proliferation and differentiation through separate pathways. Finally, Piezo is required for both mechanical activation of stem cells in a gut expansion assay and the increase of cytosolic Ca 2+ in response to direct mechanical stimulus in a gut compression assay. Thus, our study demonstrates the existence of a specific group of stem cells in the fly midgut that can directly sense mechanical signals through Piezo.

  11. Energy Conservation Analysis and Control of Hybrid Active Semiactive Suspension with Three Regulating Damping Levels

    Directory of Open Access Journals (Sweden)

    Long Chen

    2016-01-01

    Full Text Available Active suspension has not been popularized for high energy consumption. To address this issue, this paper introduces the concept of a new kind of suspension. The linear motor is considered to be integrated into an adjustable shock absorber to form the hybrid active semiactive suspension (HASAS. To realize the superiority of HASAS, its energy consumption and regeneration mechanisms are revealed. And the system controller which is composed of linear quadratic regulator (LQR controller, mode decision and switch controller, and the sliding mode control based thrust controller is developed. LQR controller is designed to maintain the suspension control objectives, while mode decision and switch controller decides the optimal damping level to tune motor thrust. The thrust controller ensures motor thrust tracking. An adjustable shock absorber with three regulating levels to be used in HASAS is trial produced and tested to obtain its working characteristics. Finally, simulation analysis is made with the experimental three damping characteristics. The impacts of adjustable damping on the motor force and energy consumption are investigated. Simulation results demonstrate the advantages of HASAS in energy conservation with various suspension control objectives. Even self-powered active control and energy regenerated to the power source can be realized.

  12. Challenges in safety regulation of R and D activities for advanced technologies in DAE units

    International Nuclear Information System (INIS)

    Shukla, Dinesh Kumar

    2016-01-01

    DAE is engaged in intensive research and developmental activities, especially for advanced technologies such as accelerators, lasers, supercomputers, advanced materials and instrumentation. The starting point of an R and D project might be a hypothesis to be tested, problem to be solved, or the performance of an item to be improved, and there may be many possible solutions and technologies that could be used. R and D is quite different from designing, constructing, operating a plant. In these, precisely described result can be defined from the beginning and can be described in design specifications, process descriptions and procedures. However, while established procedures may be available to begin an R and D project, deviation from these procedures may occur often as a legitimate component of the conduct of R and D. Nevertheless, the R and D activities have to be performed in a manner which provides assurance that safety requirements are adequately addressed. Hence, the regulatory approach for enforcing the safety regulation in such facilities is also not as rigid as those for an operating industry. This paper is aimed to discuss some of the key challenges in regulating such R and D activities and also attempts to suggest a way forward. (author)

  13. Regulation of the activity of the promoter of RNA-induced silencing, C3PO.

    Science.gov (United States)

    Sahu, Shriya; Williams, Leo; Perez, Alberto; Philip, Finly; Caso, Giuseppe; Zurawsky, Walter; Scarlata, Suzanne

    2017-09-01

    RNA-induced silencing is a process which allows cells to regulate the synthesis of specific proteins. RNA silencing is promoted by the protein C3PO (component 3 of RISC). We have previously found that phospholipase Cβ, which increases intracellular calcium levels in response to specific G protein signals, inhibits C3PO activity towards certain genes. Understanding the parameters that control C3PO activity and which genes are impacted by G protein activation would help predict which genes are more vulnerable to downregulation. Here, using a library of 10 18 oligonucleotides, we show that C3PO binds oligonucleotides with structural specificity but little sequence specificity. Alternately, C3PO hydrolyzes oligonucleotides with a rate that is sensitive to substrate stability. Importantly, we find that oligonucleotides with higher Tm values are inhibited by bound PLCβ. This finding is supported by microarray analysis in cells over-expressing PLCβ1. Taken together, this study allows predictions of the genes whose post-transcriptional regulation is responsive to the G protein/phospholipase Cβ/calcium signaling pathway. © 2017 The Protein Society.

  14. CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects

    Science.gov (United States)

    Bilbao, Ainhoa; Rieker, Claus; Cannella, Nazzareno; Parlato, Rosanna; Golda, Slawomir; Piechota, Marcin; Korostynski, Michal; Engblom, David; Przewlocki, Ryszard; Schütz, Günther; Spanagel, Rainer; Parkitna, Jan R.

    2014-01-01

    It is suggested that striatal cAMP responsive element binding protein (CREB) regulates sensitivity to psychostimulants. To test the cell-specificity of this hypothesis we examined the effects of a dominant-negative CREB protein variant expressed in dopamine receptor D1 (D1R) neurons on cocaine-induced behaviors. A transgenic mouse strain was generated by pronuclear injection of a BAC-derived transgene harboring the A-CREB sequence under the control of the D1R gene promoter. Compared to wild-type, drug-naïve mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. The behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB. PMID:24966820

  15. A ROLE FOR INTERLEUKIN 8 IN DIRECT REGULATION OF T CELL FUNCTIONAL ACTIVITY

    Directory of Open Access Journals (Sweden)

    M. E. Meniailo

    2017-01-01

    Full Text Available CD3+T lymphocytes were isolated from normal donors by positive magnetic separation. Activation of the T cells with particles conjugated with antibodies to CD3, СD28 and СD2 molecules led to substantial increase in T cell production of interleukin-8 (IL-8. An interleukin-8 receptor (CXCR1, CD181 was initially expressed in 13.3% of T lymphocytes. Activation of T lymphocytes resulted into a detectable increase of CD181+ cell number among CD4+ naïve cells and CD4+ terminally-differentiated effector cells, and, conversely, into decrease of their number among CD4+ effector memory cells. Activation of T lymphocytes was assessed by membrane expression of CD25 molecule (receptor for IL-2. IL-8 (0.01-10.0 ng/ml was shown to markedly reduce activation of both CD4- and CD4+ effector memory T cells, as well as terminallydifferentiated T effectors, without significantly affecting activation of naive T lymphocytes and central memory T cells. IL-8 noticeably increased IL-2 production by activated Т cells, caused a reduced IL-10 production, and did not significantly affect the secretion of IFNγ and IL-4. The data obtained suggest a significance of IL-8 for direct regulation of adaptive T cell responses.

  16. Locked and proteolysis-based transcription activator-like effector (TALE) regulation.

    Science.gov (United States)

    Lonzarić, Jan; Lebar, Tina; Majerle, Andreja; Manček-Keber, Mateja; Jerala, Roman

    2016-02-18

    Development of orthogonal, designable and adjustable transcriptional regulators is an important goal of synthetic biology. Their activity has been typically modulated through stimulus-induced oligomerization or interaction between the DNA-binding and activation/repression domain. We exploited a feature of the designable Transcription activator-like effector (TALE) DNA-binding domain that it winds around the DNA which allows to topologically prevent it from binding by intramolecular cyclization. This new approach was investigated through noncovalent ligand-induced cyclization or through a covalent split intein cyclization strategy, where the topological inhibition of DNA binding by cyclization and its restoration by a proteolytic release of the topologic constraint was expected. We show that locked TALEs indeed have diminished DNA binding and regain full transcriptional activity by stimulation with the rapamycin ligand or site-specific proteolysis of the peptide linker, with much higher level of activation than rapamycin-induced heterodimerization. Additionally, we demonstrated reversibility, activation of genomic targets and implemented logic gates based on combinations of protein cyclization, proteolytic cleavage and ligand-induced dimerization, where the strongest fold induction was achieved by the proteolytic cleavage of a repression domain from a linear TALE. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  17. Adiponectin activates the AMPK signaling pathway to regulate lipid metabolism in bovine hepatocytes.

    Science.gov (United States)

    Chen, Hui; Zhang, Liang; Li, Xinwei; Li, Xiaobing; Sun, Guoquan; Yuan, Xue; Lei, Liancheng; Liu, Juxiong; Yin, Liheng; Deng, Qinghua; Wang, Jianguo; Liu, Zhaoxi; Yang, Wentao; Wang, Zhe; Zhang, Hui; Liu, Guowen

    2013-11-01

    Adiponectin (Ad) plays a crucial role in hepatic lipid metabolism. However, the regulating mechanism of hepatic lipid metabolism by Ad in dairy cows is unclear. Hepatocytes from a newborn female calf were cultured in vitro and treated with different concentrations of Ad and BML-275 (an AMPKα inhibitor). The results showed that Ad significantly increased the expression of two Ad receptors. Furthermore, the phosphorylation and activity of AMPKα, as well as the expression levels and transcriptional activity of peroxisome proliferator activated receptor-α (PPARα) and its target genes involved in lipid oxidation, showed a corresponding trend of upregulation. However, the expression levels and transcriptional activity of sterol regulatory element binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP) decreased in a similar manner. When BML-275 was added, the p-AMPKα level as well as the expression and activity of PPARα and its target genes were significantly decreased. However, the expression levels of SREBP-1c, ChREBP and their target genes showed a trend of upregulation. Furthermore, the triglyceride (TG) content was significantly decreased in the Ad-treated groups. These results indicate that Ad activates the AMPK signaling pathway and mediates lipid metabolism in bovine hepatocytes cultured in vitro by promoting lipid oxidation, suppressing lipid synthesis and reducing hepatic lipid accumulation. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Gene expression analyses of immune responses in Atlantic salmon during early stages of infection by salmon louse (Lepeophtheirus salmonis revealed bi-phasic responses coinciding with the copepod-chalimus transition

    Directory of Open Access Journals (Sweden)

    Afanasyev Sergey

    2011-03-01

    Full Text Available Abstract Background The salmon louse (Lepeophtheirus salmonis Krøyer, an ectoparasitic copepod with a complex life cycle causes significant losses in salmon aquaculture. Pesticide treatments against the parasite raise environmental concerns and their efficacy is gradually decreasing. Improvement of fish resistance to lice, through biological control methods, needs better understanding of the protective mechanisms. We used a 21 k oligonucleotide microarray and RT-qPCR to examine the time-course of immune gene expression changes in salmon skin, spleen, and head kidney during the first 15 days after challenge, which encompassed the copepod and chalimus stages of lice development. Results Large scale and highly complex transcriptome responses were found already one day after infection (dpi. Many genes showed bi-phasic expression profiles with abrupt changes between 5 and 10 dpi (the copepod-chalimus transitions; the greatest fluctuations (up- and down-regulation were seen in a large group of secretory splenic proteases with unknown roles. Rapid sensing was witnessed with induction of genes involved in innate immunity including lectins and enzymes of eicosanoid metabolism in skin and acute phase proteins in spleen. Transient (1-5 dpi increase of T-cell receptor alpha, CD4-1, and possible regulators of lymphocyte differentiation suggested recruitment of T-cells of unidentified lineage to the skin. After 5 dpi the magnitude of transcriptomic responses decreased markedly in skin. Up-regulation of matrix metalloproteinases in all studied organs suggested establishment of a chronic inflammatory status. Up-regulation of putative lymphocyte G0/G1 switch proteins in spleen at 5 dpi, immunoglobulins at 15 dpi; and increase of IgM and IgT transcripts in skin indicated an onset of adaptive humoral immune responses, whereas MHCI appeared to be down-regulated. Conclusions Atlantic salmon develops rapid local and systemic reactions to L. salmonis, which, however

  19. PPARα gene expression is up-regulated by LXR and PXR activators in the small intestine

    International Nuclear Information System (INIS)

    Inoue, Jun; Satoh, Shin-ichi; Kita, Mariko; Nakahara, Mayuko; Hachimura, Satoshi; Miyata, Masaaki; Nishimaki-Mogami, Tomoko; Sato, Ryuichiro

    2008-01-01

    LXR, PXR, and PPARα are members of a nuclear receptor family which regulate the expression of genes involved in lipid metabolism. Here, we show the administration of T0901317 stimulates PPARα gene expression in the small intestine but not in the liver of both normal and FXR-null mice. The administration of LXR specific ligand GW3965, or PXR specific ligand PCN has the same effect, indicating that ligand-dependent activation of LXR and PXR, but not FXR, is responsible for the increased gene expression of PPARα in the mouse small intestine

  20. Proteomics analysis of dendritic cell activation by contact allergens reveals possible biomarkers regulated by Nrf2

    Energy Technology Data Exchange (ETDEWEB)

    Mussotter, Franz, E-mail: franz.mussotter@bfr.bund.de [German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Berlin (Germany); Tomm, Janina Melanie [Helmholtz Centre for Environmental Research (UFZ), Department of Molecular Systems Biology, Leipzig (Germany); El Ali, Zeina; Pallardy, Marc; Kerdine-Römer, Saadia [INSERM UMR 996, Univ Paris-Sud, Université Paris-Saclay, Chátenay-Malabry (France); Götz, Mario [German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Berlin (Germany); Bergen, Martin von [Helmholtz Centre for Environmental Research (UFZ), Department of Molecular Systems Biology, Leipzig (Germany); University of Leipzig, Institute of Biochemistry, Leipzig (Germany); Aalborg University, Department of Chemistry and Bioscience, Aalborg (Denmark); Haase, Andrea; Luch, Andreas [German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Berlin (Germany)

    2016-12-15

    Allergic contact dermatitis is a widespread disease with high clinical relevance affecting approximately 20% of the general population. Typically, contact allergens are low molecular weight electrophilic compounds which can activate the Keap1/Nrf2 pathway. We performed a proteomics study to reveal possible biomarkers for dendritic cell (DC) activation by contact allergens and to further elucidate the role of Keap1/Nrf2 signaling in this process. We used bone marrow derived dendritic cells (BMDCs) of wild-type (nrf2{sup +/+}) and Nrf2 knockout (nrf2{sup −/−}) mice and studied their response against the model contact sensitizers 2,4-dinitrochlorobenzene (DNCB), cinnamaldehyde (CA) and nickel(II) sulfate by 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) in combination with electrospray ionization tandem mass spectrometry (ESI-MS/MS). Sodium dodecyl sulfate (SDS, 100 μM) served as irritant control. While treatment with nickel(II) sulfate and SDS had only little effects, CA and DNCB led to significant changes in protein expression. We found 18 and 30 protein spots up-regulated in wild-type cells treated with 50 and 100 μM CA, respectively. For 5 and 10 μM DNCB, 32 and 37 spots were up-regulated, respectively. Almost all of these proteins were not differentially expressed in nrf2{sup −/−} BMDCs, indicating an Nrf2-dependent regulation. Among them proteins were detected which are involved in oxidative stress and heat shock responses, as well as in signal transduction or basic cellular pathways. The applied approach allowed us to differentiate between Nrf2-dependent and Nrf2-independent cellular biomarkers differentially regulated upon allergen-induced DC activation. The data presented might contribute to the further development of suitable in vitro testing methods for chemical-mediated sensitization. - Highlights: • Contact allergens induce proteins involved in DC maturation Nrf2-dependently. • Induction of these proteins points to a functional

  1. Zonulin as prehaptoglobin2 regulates lung permeability and activates the complement system

    OpenAIRE

    Rittirsch, Daniel; Flierl, Michael A.; Nadeau, Brian A.; Day, Danielle E.; Huber-Lang, Markus S.; Grailer, Jamison J.; Zetoune, Firas S.; Andjelkovic, Anuska V.; Fasano, Alessio; Ward, Peter A.

    2013-01-01

    Zonulin is a protein involved in the regulation of tight junctions (TJ) in epithelial or endothelial cells. Zonulin is known to affect TJ in gut epithelial cells, but little is known about its influences in other organs. Prehaptoglobin2 has been identified as zonulin and is related to serine proteases (MASPs, C1qrs) that activate the complement system. The current study focused on the role of zonulin in development of acute lung injury (ALI) in C57BL/6 male mice following intrapulmonary depos...

  2. Regulation of proximal tubule vacuolar H+-ATPase by PKA and AMP-activated protein kinase

    Science.gov (United States)

    Al-bataineh, Mohammad M.; Gong, Fan; Marciszyn, Allison L.; Myerburg, Michael M.

    2014-01-01

    The vacuolar H+-ATPase (V-ATPase) mediates ATP-driven H+ transport across membranes. This pump is present at the apical membrane of kidney proximal tubule cells and intercalated cells. Defects in the V-ATPase and in proximal tubule function can cause renal tubular acidosis. We examined the role of protein kinase A (PKA) and AMP-activated protein kinase (AMPK) in the regulation of the V-ATPase in the proximal tubule as these two kinases coregulate the V-ATPase in the collecting duct. As the proximal tubule V-ATPases have different subunit compositions from other nephron segments, we postulated that V-ATPase regulation in the proximal tubule could differ from other kidney tubule segments. Immunofluorescence labeling of rat ex vivo kidney slices revealed that the V-ATPase was present in the proximal tubule both at the apical pole, colocalizing with the brush-border marker wheat germ agglutinin, and in the cytosol when slices were incubated in buffer alone. When slices were incubated with a cAMP analog and a phosphodiesterase inhibitor, the V-ATPase accumulated at the apical pole of S3 segment cells. These PKA activators also increased V-ATPase apical membrane expression as well as the rate of V-ATPase-dependent extracellular acidification in S3 cell monolayers relative to untreated cells. However, the AMPK activator AICAR decreased PKA-induced V-ATPase apical accumulation in proximal tubules of kidney slices and decreased V-ATPase activity in S3 cell monolayers. Our results suggest that in proximal tubule the V-ATPase subcellular localization and activity are acutely coregulated via PKA downstream of hormonal signals and via AMPK downstream of metabolic stress. PMID:24553431

  3. Active and passive fatigue in simulated driving: discriminating styles of workload regulation and their safety impacts.

    Science.gov (United States)

    Saxby, Dyani J; Matthews, Gerald; Warm, Joel S; Hitchcock, Edward M; Neubauer, Catherine

    2013-12-01

    Despite the known dangers of driver fatigue, it is a difficult construct to study empirically. Different forms of task-induced fatigue may differ in their effects on driver performance and safety. Desmond and Hancock (2001) defined active and passive fatigue states that reflect different styles of workload regulation. In 2 driving simulator studies we investigated the multidimensional subjective states and safety outcomes associated with active and passive fatigue. Wind gusts were used to induce active fatigue, and full vehicle automation to induce passive fatigue. Drive duration was independently manipulated to track the development of fatigue states over time. Participants were undergraduate students. Study 1 (N = 108) focused on subjective response and associated cognitive stress processes, while Study 2 (N = 168) tested fatigue effects on vehicle control and alertness. In both studies the 2 fatigue manipulations produced different patterns of subjective response reflecting different styles of workload regulation, appraisal, and coping. Active fatigue was associated with distress, overload, and heightened coping efforts, whereas passive fatigue corresponded to large-magnitude declines in task engagement, cognitive underload, and reduced challenge appraisal. Study 2 showed that only passive fatigue reduced alertness, operationalized as speed of braking and steering responses to an emergency event. Passive fatigue also increased crash probability, but did not affect a measure of vehicle control. Findings support theories that see fatigue as an outcome of strategies for managing workload. The distinction between active and passive fatigue is important for assessment of fatigue and for evaluating automated driving systems which may induce dangerous levels of passive fatigue. PsycINFO Database Record (c) 2013 APA, all rights reserved.

  4. Unfolded protein response and activated degradative pathways regulation in GNE myopathy.

    Directory of Open Access Journals (Sweden)

    Honghao Li

    Full Text Available Although intracellular beta amyloid (Aβ accumulation is known as an early upstream event in the degenerative course of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE myopathy, the process by which Aβdeposits initiate various degradative pathways, and their relationship have not been fully clarified. We studied the possible secondary responses after amyloid beta precursor protein (AβPP deposition including unfolded protein response (UPR, ubiquitin proteasome system (UPS activation and its correlation with autophagy system. Eight GNE myopathy patients and five individuals with normal muscle morphology were included in this study. We performed immunofluorescence and immunoblotting to investigate the expression of AβPP, phosphorylated tau (p-tau and endoplasmic reticulum molecular chaperones. Proteasome activities were measured by cleavage of fluorogenic substrates. The expression of proteasome subunits and linkers between proteasomal and autophagy systems were also evaluated by immunoblotting and relative quantitative real-time RT-PCR. Four molecular chaperones, glucose-regulated protein 94 (GRP94, glucose-regulated protein 78 (GRP78, calreticulin and calnexin and valosin containing protein (VCP were highly expressed in GNE myopathy. 20S proteasome subunits, three main proteasome proteolytic activities, and the factors linking UPS and autophagy system were also increased. Our study suggests that AβPP deposition results in endoplasmic reticulum stress (ERS and highly expressed VCP deliver unfolded proteins from endoplasmic reticulum to proteosomal system which is activated in endoplasmic reticulum associated degradation (ERAD in GNE myopathy. Excessive ubiquitinated unfolded proteins are exported by proteins that connect UPS and autophagy to autophagy system, which is activated as an alternative pathway for degradation.

  5. Effects of activated fibroblasts on phenotype modulation, EGFR signalling and cell cycle regulation in OSCC cells

    Energy Technology Data Exchange (ETDEWEB)

    Berndt, Alexander, E-mail: alexander.berndt@med.uni-jena.de [Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena (Germany); Büttner, Robert, E-mail: Robert-Buettner@gmx.net [Institute of Biochemistry and Biophysics, Friedrich Schiller University Jena, 07740 Jena (Germany); Gühne, Stefanie, E-mail: stefanie_guehne@gmx.net [Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena (Germany); Gleinig, Anna, E-mail: annagleinig@yahoo.com [Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena (Germany); Richter, Petra, E-mail: P.Richter@med.uni-jena.de [Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena (Germany); Chen, Yuan, E-mail: Yuan.Chen@med.uni-jena.de [Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena (Germany); Franz, Marcus, E-mail: Marcus.Franz@med.uni-jena.de [Clinic of Internal Medicine I, Jena University Hospital, 07740 Jena (Germany); Liebmann, Claus, E-mail: Claus.Liebmann@uni-jena.de [Institute of Biochemistry and Biophysics, Friedrich Schiller University Jena, 07740 Jena (Germany)

    2014-04-01

    Crosstalk between carcinoma associated fibroblasts (CAFs) and oral squamous cell carcinoma (OSCC) cells is suggested to mediate phenotype transition of cancer cells as a prerequisite for tumour progression, to predict patients’ outcome, and to influence the efficacy of EGFR inhibitor therapies. Here we investigate the influence of activated fibroblasts as a model for CAFs on phenotype and EGFR signalling in OSCC cells in vitro. For this, immortalised hTERT-BJ1 fibroblasts were activated with TGFβ1 and PDGFAB to generate a myofibroblast or proliferative phenotype, respectively. Conditioned media (FCM{sub TGF}, FCM{sub PDGF}) were used to stimulate PE/CA-PJ15 OSCC cells. Results were compared to the effect of conditioned media of non-stimulated fibroblasts (FCM{sub B}). FCM{sub TGF} stimulation leads to an up-regulation of vimentin in the OSCC cells and an enhancement of invasive behaviour, indicating EMT-like effects. Similarly, FCM{sub TGF}≫FCM{sub PDGF} induced up-regulation of EGFR, but not of ErbB2/ErbB3. In addition, we detected an increase in basal activities of ERK, PI3K/Akt and Stat3 (FCM{sub TGF}>FCM{sub PDGF}) accompanied by protein interaction of vimentin with pERK. These effects are correlated with an increased proliferation. In summary, our results suggest that the activated myofibroblast phenotype provides soluble factors which are able to induce EMT-like phenomena and to increase EGFR signalling as well as cell proliferation in OSCC cells. Our results indicate a possible influence of activated myofibroblasts on EGFR-inhibitor therapy. Therefore, CAFs may serve as promising novel targets for combined therapy strategies. - Highlights: • A cell culture model for cancer associated fibroblasts is described. • The mutual interaction with OSCC cells leads to up-regulation of EGFR in tumour cells. • mCAF induces EGFR downstream signalling with increased proliferation in OSCC. • Erk activation is associated with protein interaction with vimentin

  6. Effects of activated fibroblasts on phenotype modulation, EGFR signalling and cell cycle regulation in OSCC cells

    International Nuclear Information System (INIS)

    Berndt, Alexander; Büttner, Robert; Gühne, Stefanie; Gleinig, Anna; Richter, Petra; Chen, Yuan; Franz, Marcus; Liebmann, Claus

    2014-01-01

    Crosstalk between carcinoma associated fibroblasts (CAFs) and oral squamous cell carcinoma (OSCC) cells is suggested to mediate phenotype transition of cancer cells as a prerequisite for tumour progression, to predict patients’ outcome, and to influence the efficacy of EGFR inhibitor therapies. Here we investigate the influence of activated fibroblasts as a model for CAFs on phenotype and EGFR signalling in OSCC cells in vitro. For this, immortalised hTERT-BJ1 fibroblasts were activated with TGFβ1 and PDGFAB to generate a myofibroblast or proliferative phenotype, respectively. Conditioned media (FCM TGF , FCM PDGF ) were used to stimulate PE/CA-PJ15 OSCC cells. Results were compared to the effect of conditioned media of non-stimulated fibroblasts (FCM B ). FCM TGF stimulation leads to an up-regulation of vimentin in the OSCC cells and an enhancement of invasive behaviour, indicating EMT-like effects. Similarly, FCM TGF ≫FCM PDGF induced up-regulation of EGFR, but not of ErbB2/ErbB3. In addition, we detected an increase in basal activities of ERK, PI3K/Akt and Stat3 (FCM TGF >FCM PDGF ) accompanied by protein interaction of vimentin with pERK. These effects are correlated with an increased proliferation. In summary, our results suggest that the activated myofibroblast phenotype provides soluble factors which are able to induce EMT-like phenomena and to increase EGFR signalling as well as cell proliferation in OSCC cells. Our results indicate a possible influence of activated myofibroblasts on EGFR-inhibitor therapy. Therefore, CAFs may serve as promising novel targets for combined therapy strategies. - Highlights: • A cell culture model for cancer associated fibroblasts is described. • The mutual interaction with OSCC cells leads to up-regulation of EGFR in tumour cells. • mCAF induces EGFR downstream signalling with increased proliferation in OSCC. • Erk activation is associated with protein interaction with vimentin as sign of EMT. • Results qualify

  7. Thalamic involvement in the regulation of alpha EEG activity in psychiatric patients

    International Nuclear Information System (INIS)

    Shirazi, S.P.; Pakula, J.; Young, I.J.; Crayton, J.W.; Konopka, L.M.; Rybak, M.

    2002-01-01

    1. This correlation involved: right thalamus and FP2 (r=0.587, p=0.021); F8 (r=0.777, p=0.001) electrode positions (right frontal lobe). No significant correlations were identified in the analysis of Gr 2. Conclusions: The current study provides evidence of a relationship between decreased right thalamic activity as in Gr 1, and right anterior quadrant alpha power activity. Frontal alpha activity is associated with a clinical presentation of depressive symptoms, ADHD, or an amotivational syndrome. This data support a role for thalamic activity in the regulating of frontal lobe electrical activity. It is not clear why such a relationship does not exist in Gr 2

  8. Commission de regulation de l'energie. Activity report 2013

    International Nuclear Information System (INIS)

    2014-01-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2013 activity report of CRE. Contents: 1 - Message from the board; 2 - The Energy Regulatory Commission; 3 - 2013: the energy market/S; 4 - The action of the regulator under the control of the judge; 5 - The usage tariff for public electricity networks; 6 - Smart grids; 7 - Consumers; 8 - Annex; 9 - Acronyms

  9. Maintaining activity engagement: individual differences in the process of self-regulating motivation.

    Science.gov (United States)

    Sansone, Carol; Thoman, Dustin B

    2006-12-01

    Typically, models of self-regulation include motivation in terms of goals. Motivation is proposed to differ among individuals as a consequence of the goals they hold as well as how much they value those goals and expect to attain them. We suggest that goal-defined motivation is only one source of motivation critical for sustained engagement. A second source is the motivation that arises from the degree of interest experienced in the process of goal pursuit. Our model integrates both sources of motivation within the goal-striving process and suggests that individuals may actively monitor and regulate them. Conceptualizing motivation in terms of a self-regulatory process provides an organizing framework for understanding how individuals might differ in whether they experience interest while working toward goals, whether they persist without interest, and whether and how they try to create interest. We first present the self-regulation of motivation model and then review research illustrating how the consideration of individual differences at different points in the process allows a better understanding of variability in people's choices, efforts, and persistence over time.

  10. TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.

    Science.gov (United States)

    Ji, Rui; Tian, Shifu; Lu, Helen J; Lu, Qingjun; Zheng, Yan; Wang, Xiaomin; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

    2013-12-15

    TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.

  11. 28 CFR 30.3 - What programs and activities of the Department are subject to these regulations?

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false What programs and activities of the Department are subject to these regulations? 30.3 Section 30.3 Judicial Administration DEPARTMENT OF JUSTICE... Department are subject to these regulations? The Attorney General publishes in the Federal Register a list of...

  12. 41 CFR 101-6.2103 - What programs and activities of GSA are subject to these regulations?

    Science.gov (United States)

    2010-07-01

    ... 41 Public Contracts and Property Management 2 2010-07-01 2010-07-01 true What programs and... Property Management Federal Property Management Regulations System FEDERAL PROPERTY MANAGEMENT REGULATIONS...? The Administrator publishes in the Federal Register a list of GSA's programs and activities that are...

  13. Wedelolactone Regulates Lipid Metabolism and Improves Hepatic Steatosis Partly by AMPK Activation and Up-Regulation of Expression of PPARα/LPL and LDLR.

    Directory of Open Access Journals (Sweden)

    Yun Zhao

    Full Text Available Hyperlipidemia is considered one of the greatest risk factors of cardiovascular diseases. We investigated the anti-hyperlipidemic effect and the underlying mechanism of wedelolactone, a plant-derived coumestan, in HepG2 cells and high-fat diet (HFD-induced hyperlipidemic hamsters. We showed that in cultured HepG2 cells, wedelolactone up-regulated protein levels of adenosine monophosphate activated protein kinase (AMPK and peroxisome proliferator-activated receptor-alpha (PPARα as well as the gene expression of AMPK, PPARα, lipoprotein lipase (LPL, and the low-density lipoprotein receptor (LDLR. Meanwhile, administration of wedelolactone for 4 weeks decreased the lipid profiles of plasma and liver in HFD-induced hyperlipidemic hamsters, including total cholesterol (TC, triglycerides (TG, and low-density lipoprotein-cholesterol (LDL-C. The activation of AMPK and up-regulation of PPARα was also observed with wedelolactone treatment. Furthermore, wedelolactone also increased the activities of superoxidase dismutase (SOD and glutathione peroxidase (GSH-Px and decreased the level of the lipid peroxidation product malondialdehyde (MDA in the liver, therefore decreasing the activity of alanine aminotransferase (ALT. In conclusion, we provide novel experimental evidence that wedelolactone possesses lipid-lowering and steatosis-improving effects, and the underlying mechanism is, at least in part, mediated by the activation of AMPK and the up-regulation of PPARα/LPL and LDLR.

  14. Cognitive emotion regulation in children: Reappraisal of emotional faces modulates neural source activity in a frontoparietal network.

    Science.gov (United States)

    Wessing, Ida; Rehbein, Maimu A; Romer, Georg; Achtergarde, Sandra; Dobel, Christian; Zwitserlood, Pienie; Fürniss, Tilman; Junghöfer, Markus

    2015-06-01

    Emotion regulation has an important role in child development and psychopathology. Reappraisal as cognitive regulation technique can be used effectively by children. Moreover, an ERP component known to reflect emotional processing called late positive potential (LPP) can be modulated by children using reappraisal and this modulation is also related to children's emotional adjustment. The present study seeks to elucidate the neural generators of such LPP effects. To this end, children aged 8-14 years reappraised emotional faces, while neural activity in an LPP time window was estimated using magnetoencephalography-based source localization. Additionally, neural activity was correlated with two indexes of emotional adjustment and age. Reappraisal reduced activity in the left dorsolateral prefrontal cortex during down-regulation and enhanced activity in the right parietal cortex during up-regulation. Activity in the visual cortex decreased with increasing age, more adaptive emotion regulation and less anxiety. Results demonstrate that reappraisal changed activity within a frontoparietal network in children. Decreasing activity in the visual cortex with increasing age is suggested to reflect neural maturation. A similar decrease with adaptive emotion regulation and less anxiety implies that better emotional adjustment may be associated with an advance in neural maturation. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. 40 CFR 260.41 - Procedures for case-by-case regulation of hazardous waste recycling activities.

    Science.gov (United States)

    2010-07-01

    ... of hazardous waste recycling activities. 260.41 Section 260.41 Protection of Environment... Rulemaking Petitions § 260.41 Procedures for case-by-case regulation of hazardous waste recycling activities... hazardous waste recycling activities described in § 261.6(a)(2)(iii) under the provisions of § 261.6 (b) and...

  16. 45 CFR 660.3 - What programs and activities of the Foundation are subject to these regulations?

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false What programs and activities of the Foundation are... (Continued) NATIONAL SCIENCE FOUNDATION INTERGOVERNMENTAL REVIEW OF THE NATIONAL SCIENCE FOUNDATION PROGRAMS AND ACTIVITIES § 660.3 What programs and activities of the Foundation are subject to these regulations...

  17. 49 CFR 17.3 - What programs and activities of the Department are subject to these regulations?

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false What programs and activities of the Department are subject to these regulations? 17.3 Section 17.3 Transportation Office of the Secretary of Transportation INTERGOVERNMENTAL REVIEW OF DEPARTMENT OF TRANSPORTATION PROGRAMS AND ACTIVITIES § 17.3 What programs and activities...

  18. Hormonal regulation of Na+/K+-dependent ATPase activity and pump function in corneal endothelial cells.

    Science.gov (United States)

    Hatou, Shin

    2011-10-01

    Na- and K-dependent ATPase (Na,K-ATPase) in the basolateral membrane of corneal endothelial cells plays an important role in the pump function of the corneal endothelium. We investigated the role of dexamethasone in the regulation of Na,K-ATPase activity and pump function in these cells. Mouse corneal endothelial cells were exposed to dexamethasone or insulin. ATPase activity was evaluated by spectrophotometric measurement, and pump function was measured using an Ussing chamber. Western blotting and immunocytochemistry were performed to measure the expression of the Na,K-ATPase α1-subunit. Dexamethasone increased Na,K-ATPase activity and the pump function of endothelial cells. Western blot analysis indicated that dexamethasone increased the expression of the Na,K-ATPase α1-subunit but decreased the ratio of active to inactive Na,K-ATPase α1-subunit. Insulin increased Na,K-ATPase activity and pump function of cultured corneal endothelial cells. These effects were transient and blocked by protein kinase C inhibitors and inhibitors of protein phosphatases 1 (PP1) and 2A (PP2A). Western blot analysis indicated that insulin decreased the amount of inactive Na,K-ATPase α1-subunit, but the expression of total Na,K-ATPase α1-subunit was unchanged. Immunocytochemistry showed that insulin increased cell surface expression of the Na,K-ATPase α1-subunit. Our results suggest that dexamethasone and insulin stimulate Na,K-ATPase activity in mouse corneal endothelial cells. The effect of dexamethasone activation in these cells was mediated by Na,K-ATPase synthesis and an increased enzymatic activity because of dephosphorylation of Na,K-ATPase α1-subunits. The effect of insulin is mediated by the protein kinase C, PP1, and/or PP2A pathways.

  19. Cirtical role for Salmonella effector SopB in regulating inflammasome activation.

    Science.gov (United States)

    Hu, Gui-Qiu; Song, Pei-Xuan; Chen, Wei; Qi, Shuai; Yu, Shui-Xing; Du, Chong-Tao; Deng, Xu-Ming; Ouyang, Hong-Sheng; Yang, Yong-Jun

    2017-10-01

    Salmonella is known to evolve many mechanisms to avoid or delay inflammasome activation which remain largely unknown. In this study, we investigated whether the SopB protein critical to bacteria virulence capacity was an effector that involved in the regulation of inflammasome activation. BMDMs from NLRC4-, NLRP3-, caspase-1/-11-, IFI16- and AIM2-deficient mice were pretreated with LPS, and subsequently stimulated with a series of SopB-related strains of Salmonella, inflammasome induced cell death, IL-1β secretion, cleaved caspase-1 production and ASC speckle formation were detected. We found that SopB could inhibit host IL-1β secretion, caspase-1 activation and inflammasome induced cell death using a series of SopB-related strains of Salmonella; however the reduction of IL-1β secretion was not dependent on sensor that contain PYD domain, such as NLRP3, AIM2 or IFI16, but dependent on NLRC4. Notably, SopB specifically prevented ASC oligomerization and the enzymatic activity of SopB was responsible for the inflammasome inhibition. Furthermore, inhibition of Akt signaling induced enhanced inflammasome activation. These results revealed a novel role in inhibition of NLRC4 inflammasome for Salmonella effector SopB. Copyright © 2017. Published by Elsevier Ltd.

  20. Active and Inactive Enhancers Cooperate to Exert Localized and Long-Range Control of Gene Regulation.

    Science.gov (United States)

    Proudhon, Charlotte; Snetkova, Valentina; Raviram, Ramya; Lobry, Camille; Badri, Sana; Jiang, Tingting; Hao, Bingtao; Trimarchi, Thomas; Kluger, Yuval; Aifantis, Iannis; Bonneau, Richard; Skok, Jane A

    2016-06-07

    V(D)J recombination relies on the presence of proximal enhancers that activate the antigen receptor (AgR) loci in a lineage- and stage-specific manner. Unexpectedly, we find that both active and inactive AgR enhancers cooperate to disseminate their effects in a localized and long-range manner. Here, we demonstrate the importance of short-range contacts between active enhancers that constitute an Igk super-enhancer in B cells. Deletion of one element reduces the interaction frequency between other enhancers in the hub, which compromises the transcriptional output of each component. Furthermore, we establish that, in T cells, long-range contact and cooperation between the inactive Igk enhancer MiEκ and the active Tcrb enhancer Eβ alters enrichment of CBFβ binding in a manner that impacts Tcrb recombination. These findings underline the complexities of enhancer regulation and point to a role for localized and long-range enhancer-sharing between active and inactive elements in lineage- and stage-specific control. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. Active and Inactive Enhancers Cooperate to Exert Localized and Long-Range Control of Gene Regulation

    Directory of Open Access Journals (Sweden)

    Charlotte Proudhon

    2016-06-01

    Full Text Available V(DJ recombination relies on the presence of proximal enhancers that activate the antigen receptor (AgR loci in a lineage- and stage-specific manner. Unexpectedly, we find that both active and inactive AgR enhancers cooperate to disseminate their effects in a localized and long-range manner. Here, we demonstrate the importance of short-range contacts between active enhancers that constitute an Igk super-enhancer in B cells. Deletion of one element reduces the interaction frequency between other enhancers in the hub, which compromises the transcriptional output of each component. Furthermore, we establish that, in T cells, long-range contact and cooperation between the inactive Igk enhancer MiEκ and the active Tcrb enhancer Eβ alters enrichment of CBFβ binding in a manner that impacts Tcrb recombination. These findings underline the complexities of enhancer regulation and point to a role for localized and long-range enhancer-sharing between active and inactive elements in lineage- and stage-specific control.

  2. Plant growth regulators induced urease activity in Cucurbita pepo L. cotyledons.

    Science.gov (United States)

    El Shora, Hamed M; Ali, Awatif S

    2016-03-01

    This study is aimed to investigate the activity of urease (EC 3.5.1.5, urea amidohydrolase) that catalyzes the hydrolysis of urea in 5-day-old Cucurbita pepo cotyledons subjected to various concentrations of different growth regulators. The treatment of C. pepo cotyledons with different concentrations (100-600 μmol) of different auxins [indole-3-acetic acid (IAA), indole butyric acid (IBA), indole propionic acid (IPA) and naphthalene acetic acid (NAA)]; or with different concentrations (100-300 μmol) of different cytokinins [kinetin, zeatin and benzyladenine (6-BA)] resulted in a significant increase of urease activity, compared to control. The optimal effects were recorded for each of 500 μmol of IAA and 300 μmol of zeatin treatments. A gradual increase in urease activity was detected in cotyledons treated with various concentrations (0.2-1.0 mM) of 28-homobrassinolide (HBL), in relative to control. A substantial increase in urease activity was observed in cotyledons subjected to different concentrations of triazole (10-60 mg L(-1)), containing either triadimefon (TDM) or hexaconazole (HEX), compared to control. The combination of 300 μmol zeatin with any of protein inhibitors, namely 5-fluorouridine (FUrd), cordycepin and α-amanitin, resulted in the alleviation of their inhibitory effect on the urease activity.

  3. Changes in self-regulation-related prefrontal activities in eating disorders: a near infrared spectroscopy study.

    Directory of Open Access Journals (Sweden)

    Chihiro Sutoh

    Full Text Available OBJECTIVE: The aim of this study is to clarify the symptomatology of the eating disorders examining the prefrontal function and activity associated with self-regulation among participants with or without eating disorders. METHODS: Ten patients with anorexia nervosa, fourteen with bulimia nervosa, and fourteen healthy control participants performed two cognitive tasks assessing self-regulatory functions, an auditorily distracted word fluency task and a rock-paper-scissors task under the measurements on prefrontal oxyhemoglobin concentration with near infrared spectroscopy. The psychiatric symptoms of patient groups were assessed with several questionnaires. RESULTS: Patients with bulimia nervosa showed decreased performances and prefrontal hyper activation patterns. Prefrontal activities showed a moderate negative correlation with task performances not in the patient groups but only in the healthy participants. The prefrontal activities of the patient groups showed positive correlations with some symptom scale aspects. CONCLUSIONS: The decreased cognitive abilities and characteristic prefrontal activation patterns associated with self-regulatory functions were shown in patients with bulimia nervosa, which correlated with their symptoms. These findings suggest inefficient prefrontal self-regulatory function of bulimia nervosa that associate with its symptoms.

  4. Desmoglein 2 regulates the intestinal epithelial barrier via p38 mitogen-activated protein kinase.

    Science.gov (United States)

    Ungewiß, Hanna; Vielmuth, Franziska; Suzuki, Shintaro T; Maiser, Andreas; Harz, Hartmann; Leonhardt, Heinrich; Kugelmann, Daniela; Schlegel, Nicolas; Waschke, Jens

    2017-07-24

    Intestinal epithelial barrier properties are maintained by a junctional complex consisting of tight junctions (TJ), adherens junctions (AJ) and desmosomes. Desmoglein 2 (Dsg2), an adhesion molecule of desmosomes and the only Dsg isoform expressed in enterocytes, is required for epithelial barrier properties and may contribute to barrier defects in Crohn's disease. Here, we identified extradesmosomal Dsg2 on the surface of polarized enterocytes by Triton extraction, confocal microscopy, SIM and STED. Atomic force microscopy (AFM) revealed Dsg2-specific binding events along the cell border on the surface of enterocytes with a mean unbinding force of around 30pN. Binding events were blocked by an inhibitory antibody targeting Dsg2 which under same conditions activated p38MAPK but did not reduce cell cohesion. In enterocytes deficient for Dsg2, p38MAPK activity was reduced and both barrier integrity and reformation were impaired. Dsc2 rescue did not restore p38MAPK activity indicating that Dsg2 is required. Accordingly, direct activation of p38MAPK in Dsg2-deficient cells enhanced barrier reformation demonstrating that Dsg2-mediated activation of p38MAPK is crucial for barrier function. Collectively, our data show that Dsg2, beside its adhesion function, regulates intestinal barrier function via p38MAPK signalling. This is in contrast to keratinocytes and points towards tissue-specific signalling functions of desmosomal cadherins.

  5. Iro/IRX transcription factors negatively regulate Dpp/TGF-β pathway activity during intestinal tumorigenesis.

    Science.gov (United States)

    Martorell, Òscar; Barriga, Francisco M; Merlos-Suárez, Anna; Stephan-Otto Attolini, Camille; Casanova, Jordi; Batlle, Eduard; Sancho, Elena; Casali, Andreu

    2014-11-01

    Activating mutations in Wnt and EGFR/Ras signaling pathways are common in colorectal cancer (CRC). Remarkably, clonal co-activation of these pathways in the adult Drosophila midgut induces "tumor-like" overgrowths. Here, we show that, in these clones and in CRC cell lines, Dpp/TGF-β acts as a tumor suppressor. Moreover, we discover that the Iroquois/IRX-family-protein Mirror downregulates the transcription of core components of the Dpp pathway, reducing its tumor suppressor activity. We also show that this genetic interaction is conserved in human CRC cells, where the Iro/IRX proteins IRX3 and IRX5 diminish the response to TGF-β. IRX3 and IRX5 are upregulated in human adenomas, and their levels correlate inversely with the gene expression signature of response to TGF-β. In addition, Irx5 expression confers a growth advantage in the presence of TGF-β, but is selected against in its absence. Together, our results identify a set of Iro/IRX proteins as conserved negative regulators of Dpp/TGF-β activity. We propose that during the characteristic adenoma-to-carcinoma transition of human CRC, the activity of IRX proteins could reduce the sensitivity to the cytostatic effect of TGF-β, conferring a growth advantage to tumor cells prior to the acquisition of mutations in TGF-β pathway components. © 2014 The Authors.

  6. Activity-Dependent Exocytosis of Lysosomes Regulates the Structural Plasticity of Dendritic Spines.

    Science.gov (United States)

    Padamsey, Zahid; McGuinness, Lindsay; Bardo, Scott J; Reinhart, Marcia; Tong, Rudi; Hedegaard, Anne; Hart, Michael L; Emptage, Nigel J

    2017-01-04

    Lysosomes have traditionally been viewed as degradative organelles, although a growing body of evidence suggests that they can function as Ca 2+ stores. Here we examined the function of these stores in hippocampal pyramidal neurons. We found that back-propagating action potentials (bpAPs) could elicit Ca 2+ release from lysosomes in the dendrites. This Ca 2+ release triggered the fusion of lysosomes with the plasma membrane, resulting in the release of Cathepsin B. Cathepsin B increased the activity of matrix metalloproteinase 9 (MMP-9), an enzyme involved in extracellular matrix (ECM) remodelling and synaptic plasticity. Inhibition of either lysosomal Ca 2+ signaling or Cathepsin B release prevented the maintenance of dendritic spine growth induced by Hebbian activity. This impairment could be rescued by exogenous application of active MMP-9. Our findings suggest that activity-dependent exocytosis of Cathepsin B from lysosomes regulates the long-term structural plasticity of dendritic spines by triggering MMP-9 activation and ECM remodelling. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  7. P21-activated kinase 2 (PAK2) regulates glucose uptake and insulin sensitivity in neuronal cells.

    Science.gov (United States)

    Varshney, Pallavi; Dey, Chinmoy Sankar

    2016-07-05

    P21-activated kinases (PAKs) are recently reported as important players of insulin signaling and glucose homeostasis in tissues like muscle, pancreas and liver. However, their role in neuronal insulin signaling is still unknown. Present study reports the involvement of PAK2 in neuronal insulin signaling, glucose uptake and insulin resistance. Irrespective of insulin sensitivity, insulin stimulation decreased PAK2 activity. PAK2 downregulation displayed marked enhancement of GLUT4 translocation with increase in glucose uptake whereas PAK2 over-expression showed its reduction. Treatment with Akti-1/2 and wortmannin suggested that Akt and PI3K are mediators of insulin effect on PAK2 and glucose uptake. Rac1 inhibition demonstrated decreased PAK2 activity while inhibition of PP2A resulted in increased PAK2 activity, with corresponding changes in glucose uptake. Taken together, present study demonstrates an inhibitory role of insulin signaling (via PI3K-Akt) and PP2A on PAK2 activity and establishes PAK2 as a Rac1-dependent negative regulator of neuronal glucose uptake and insulin sensitivity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. THE WAYS OF IMPROVING THE GOVERNMENTAL REGULATION OF TOURISM ACTIVITY IN UKRAINE

    Directory of Open Access Journals (Sweden)

    О. Davydova

    2014-09-01

    Full Text Available The areas of state regulation of tourism activity in Ukraine, such as legal, economic, social and information areas are highlighted. Each of these areas are analyzed and the implementation of the concession agreement as well as the investment tax credit are proposed in order to stimulate the development of tourism activity in the country. It is mentioned, that one of the main tools of development of the territories is to promote the tourism brand through creating a positive tourism image via information. It was suggested to update the web page of the The State Agency of Ukraine for Tourism and Resorts and to create a online rating of local tour operators. It is found out that promising types of national tourism are children, family, green and business types of tourism.

  9. Effects of stress and adrenalectomy on activity-regulated cytoskeleton protein (Arc) gene expression

    DEFF Research Database (Denmark)

    Mikkelsen, Jens D; Larsen, Marianne Hald

    2006-01-01

    Activity-regulated cytoskeletal-associated protein (Arc) is an effector immediate early gene induced by novelty and involved in consolidation of long-term memory. Since activation of glucocorticoid receptors is a prerequisite for memory consolidation, we therefore aimed to study the effect of acute...... restraint stress on Arc gene expression in adrenalectomized rats. Acute stress produced a significant increase in Arc gene expression in the medial prefrontal cortex, but not in the parietal cortex or in the pyramidal cell layer of the hippocampus. The basal level of Arc mRNA in adrenalectomized animals...... was high in the medial prefrontal cortex and unaffected by acute stress in these animals. These data are consistent with the role of Arc as an integrative modulator of synaptic plasticity by emphasizing the potential role of stress and glucocorticoids in the control of Arc gene expression....

  10. Hormonal and metabolic regulation of tomato fruit sink activity and yield under salinity

    DEFF Research Database (Denmark)

    Albacete, Alfonso; Cantero-Navarro, Elena; Balibrea, María E.

    2014-01-01

    Salinization of water and soil has a negative impact on tomato (Solanum lycopersicum L.) productivity by reducing growth of sink organs and by inducing senescence in source leaves. It has been hypothesized that yield stability implies the maintenance or increase of sink activity in the reproductive...... structures, thus contributing to the transport of assimilates from the source leaves through changes in sucrolytic enzymes and their regulation by phytohormones. In this study, classical and functional physiological approaches have been integrated to study the influence of metabolic and hormonal factors...... sucrolytic activities (mainly cwInv and sucrose synthase), sink strength, and fruit weight, whereas the ethylene-releasing compound ethephon had a negative effect in equivalent non-stressed fruits. Fruit yield was increased by both the constitutive expression of CIN1 in the fruits (up to 4-fold) or IPT...

  11. Regulating inflammation through the anti-inflammatory enzyme platelet-activating factor-acetylhydrolase

    Directory of Open Access Journals (Sweden)

    Hugo C Castro Faria Neto

    2005-03-01

    Full Text Available Platelet-activating factor (PAF is one of the most potent lipid mediators involved in inflammatory events. The acetyl group at the sn-2 position of its glycerol backbone is essential for its biological activity. Deacetylation induces the formation of the inactive metabolite lyso-PAF. This deacetylation reaction is catalyzed by PAF-acetylhydrolase (PAF-AH, a calcium independent phospholipase A2 that also degrades a family of PAF-like oxidized phospholipids with short sn-2 residues. Biochemical and enzymological evaluations revealed that at least three types of PAF-AH exist in mammals, namely the intracellular types I and II and a plasma type. Many observations indicate that plasma PAF AH terminates signals by PAF and oxidized PAF-like lipids and thereby regulates inflammatory responses. In this review, we will focus on the potential of PAF-AH as a modulator of diseases of dysregulated inflammation.

  12. Liberating and regulating of active effect reserves in the Norwegian power system

    International Nuclear Information System (INIS)

    Bakken, Bjoern H.

    2000-01-01

    This report is a summary of the work done in the project ''Active reserves and current control of the effect situation'' in the period 1997 - 99. The project is one of the 7 partial projects in the project '' Operational safety planning and control'' in the Norges forskningsraad's (The Research Council of Norway) EFFEKT program. The aim of the project has been to study and test methods for liberating and regulating active reserves in the Norwegian power system. Traditionally Norway has been rich in effect reserves but in the present deregulated system it will no longer obvious that these reserves are available as the micro economy is more focussed upon in an increasingly pressured operational situation. In the recent years the margins between the available generator effects and the systems maximum load have become increasingly smaller. With the various problems discussed in this report in mind, recommendations may be given with respect to specific measures in order to improve the systems operator possibilities for current control of the effect situation as well as recommendations regarding interesting concepts that ought to be continued in new research projects. The systems operators have implemented some of the proposed measures while others are being studied further. The following specific measures are proposed to the systems operators: 1) To implements graphical survey of the production and the reported reserves in the systems operator EMS tool. 2) To implement tools of the type ''gradual load flow'' in order to prepare possible regulations in critical periods. 3) Reserved instantaneous reserves are introduced as a systems service. 4) The systems operator can reserve effect up to the operational time. 5) Introduce incentives in order to activate the end user more strongly in the ''RK'' market. 5) To modify the methodology corresponding to ''Simultaneous load'' for forecasting bottlenecks in future operation weeks. 6) The systems service ''ramping'' is

  13. Commission for Energy regulation (CRE) - Activity report june 2008; Commission de regulation de l'energie (CRE) - Rapport d'activite juin 2008

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2008-07-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2008 activity report of CRE. Content: A - How CRE works: CRE regulatory authority and organisation: Powers, Organisation; Budget resources; Personnel; B - The Standing Committee for Dispute Settlement and Sanctions (CoRDiS) activity: Admissibility, Authority; C - Building a single European energy market: Overview; Organisation and coordination of the main European regulators (Work carried out collectively by European regulators, Regulator organisation and development, CRE's relations with European Community institutions, Development of CEER activities outside the European Union); CRE's European activities (The contribution of European regulators to the Third Energy Package, Integration of gas markets, Integration of electricity markets, Operation of the European interconnected electricity grid and security of supply, Opening up markets to benefit consumers); European Community activities (The European Commission's proposals for the internal energy market: the Third Energy Package, The European Commission's proposals for fighting climate change: the Climate Package, Infringement

  14. Commission for Energy regulation (CRE) - Activity report june 2008; Commission de regulation de l'energie (CRE) - Rapport d'activite juin 2008

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2008-07-01

    CRE is the French commission for energy regulation. CRE's remit is to assist in ensuring the proper operation of the electricity and natural gas markets for the benefit of the end-user. In particular, CRE ensures that the conditions of access to electricity and natural gas transmission and distribution systems do not hinder the development of competition. It monitors, for the electricity and natural gas sectors, all transactions made between suppliers, traders and producers, all transactions made on the organised markets and cross-border trading. It ensures that suppliers, traders and producers propose offers that are consistent with their financial and technical constraints. It monitors the implementation of and compliance with regulations giving consumers the right to choose their supplier in a competitive market, and allowing new suppliers to enter the market. This document is the 2008 activity report of CRE. Content: A - How CRE works: CRE regulatory authority and organisation: Powers, Organisation; Budget resources; Personnel; B - The Standing Committee for Dispute Settlement and Sanctions (CoRDiS) activity: Admissibility, Authority; C - Building a single European energy market: Overview; Organisation and coordination of the main European regulators (Work carried out collectively by European regulators, Regulator organisation and development, CRE's relations with European Community institutions, Development of CEER activities outside the European Union); CRE's European activities (The contribution of European regulators to the Third Energy Package, Integration of gas markets, Integration of electricity markets, Operation of the European interconnected electricity grid and security of supply, Opening up markets to benefit consumers); European Community