Revealing the Radial Effect on Orientation Discrimination by Manual Reaction Time

PubMed Central

Liang, Lixin; Zhou, Yang; Zhang, Mingsha; Pan, Yujun

2017-01-01

It has been shown that the sensitivity and accuracy of orientation perception in the periphery is significantly better when the orientations are radial with respect to the fixation point than when they are tangential. However, since perception and action may be dissociated, it is unclear whether the perceptual radial effect has a counterpart in reaction time (RT) of motor responses. Furthermore, it is unknown whether or how stimulus-response-compatibility (SRC) effect interacts with the radial effect to determine RT. To address these questions, we measured subjects' manual RT to grating stimuli that appeared across upper visual field (VF). We found that (1) RTs were significantly shorter when a grating was oriented closer to the radial direction than when it was oriented closer to the tangential direction even though the perceptual accuracies for the more radial and more tangential orientations were not significantly different under our experimental condition; (2) This RT version of the radial effect was larger in the left VF than in the right VF; (3) The radial effect and SRC effect interacted with each other to determine the overall RT. These results suggest that the RT radial effect reported here is not a passive reflection of the radial effect in perceptual accuracy, but instead, represents different processing time of radial and tangential orientations along the sensorimotor pathway. PMID:29225564

The Activation of Effect Codes in Response Preparation: New Evidence from an Indirect Priming Paradigm

PubMed Central

Ziessler, Michael; Nattkemper, Dieter; Vogt, Stefan

2012-01-01

Evidence for the anticipation of environmental effects as an integral part of response planning comes mainly from experiments in which the effects were physically presented. Thus, in these studies it cannot be excluded that effect codes were activated during response preparation only because the effects were displayed as external stimuli before response execution. In order to provide more clear-cut evidence for the anticipation of response effects in action planning, we performed a series of three experiments using a new paradigm, where displaying effect codes before the response was avoided. Participants first learned arbitrary effects of key-pressing responses. In the following test phase they were instructed to execute a response only if a Go stimulus was presented after a variable stimulus onset asynchrony (SOA). The Go stimulus was either compatible or incompatible with the effect, but independent of the response. In Experiment 1 we tested the paradigm with two responses and two effects. We found a significant compatibility effect: If the Go stimulus was compatible with the response effect, responses were initiated faster than in incompatible trials. In Experiment 2 response effects were only present in the acquisition phase, but not in the test phase. The compatibility effect disappeared, indicating that the results of Experiment 1 were indeed related to the anticipation of the forthcoming response effects. In Experiment 3 we extended this paradigm by using a larger number of stimuli and response alternatives. Again we found a robust compatibility effect, which can only be explained if the effect representations are active before response execution. The compatibility effects in Experiments 1 and 3 did not depend on the SOA. The fact that the Go stimulus affected response preparation at any time indicates that the role of effect anticipation is not limited to response selection. PMID:23293623

The impact of subliminal effect images in voluntary vs. stimulus-driven actions.

PubMed

Le Bars, Solène; Hsu, Yi-Fang; Waszak, Florian

2016-11-01

According to the ideomotor theory, actions are represented in terms of their sensory effects. In the current study we tested whether subliminal effect images influence action control (1) at early and/or late preparatory stages of (2) voluntary actions or stimulus-driven actions (3) with or without Stimulus-Response (S-R) compatibility. In Experiment 1, participants were presented at random with 50% of S-R compatible stimulus-driven action trials and 50% of voluntary action trials. The actions' effects (i.e. up- or down-pointing arrows) were presented subliminally before each action (i.e. a keypress). In voluntary actions, participants selected more often the action congruent with the prime when it was presented at long intervals before the action. Moreover they responded faster in prime-congruent than in prime-incongruent trials when primes were presented at short intervals before the action. In Experiment 2, participants were only presented with stimulus-driven action trials, with or without S-R compatibility. In stimulus-driven action trials with S-R compatibility (e.g., left-pointing arrow signaling a left keypress), subliminal action-effects did not generate any significant effect on RTs or error rates. On the other hand, in stimulus-driven action trials without S-R compatibility (e.g., letter "H" signaling a left keypress), participants were significantly faster in prime-congruent trials when primes were presented at the shortest time interval before the action. These results suggest that subliminal effect images facilitate voluntary action preparation on an early and a late level. Stimulus-driven action preparation is influenced on a late level only, and only if there is no compatibility between the stimulus and the motor response, that is when the response is not automatically triggered by the common properties existing between the stimulus and the required action. Copyright © 2016 Elsevier B.V. All rights reserved.

Effector identity and orthogonal stimulus-response compatibility in blindness to response-compatible stimuli.

PubMed

Nishimura, Akio; Yokosawa, Kazuhiko

2010-03-01

Perceiving a visual stimulus is hampered when the stimulus is compatible with simultaneously prepared or executed action (blindness effect). We explored the roles of the effector identity of the responding hand and of orthogonal compatibility (above-right/below-left correspondence) in the blindness effect. In Experiment 1, participants conducted bimanual key presses with vertically arranged responses while perceiving a brief presentation of rightward or leftward arrowheads. A blindness effect based on the effector identity did emerge, but only with the above-right/below-left key-hand arrangement. An orthogonal blindness effect was not found in Experiment 2 with a horizontal key-press action task and a vertical arrowhead perception task. We concluded that the anatomical identity of the responding hand was not integrated into the action plan with an orthogonally incompatible key-hand arrangement. The findings are discussed in terms of the generality and limits of the blindness effect, and hierarchical response coding.

Distinct cognitive control mechanisms as revealed by modality-specific conflict adaptation effects.

PubMed

Yang, Guochun; Nan, Weizhi; Zheng, Ya; Wu, Haiyan; Li, Qi; Liu, Xun

2017-04-01

Cognitive control is essential to resolve conflict in stimulus-response compatibility (SRC) tasks. The SRC effect in the current trial is reduced after an incongruent trial as compared with a congruent trial, a phenomenon being termed conflict adaptation (CA). The CA effect is found to be domain-specific , such that it occurs when adjacent trials contain the same type of conflict, but disappears when the conflicts are of different types. Similar patterns have been observed when tasks involve different modalities, but the modality-specific effect may have been confounded by task switching. In the current study, we investigated whether or not cognitive control could transfer across auditory and visual conflicts when task-switching was controlled. Participants were asked to respond to a visual or auditory (Experiments 1A/B) stimulus, with conflict coming from either the same or a different modality. CA effects showed modality-specific patterns. To account for potential confounding effects caused by differences in task-irrelevant properties, we specifically examined the influence of task-irrelevant properties on CA effects within the visual modality (Experiments 2A/B). Significant CA effects were observed across different conflicts from distinct task-irrelevant properties, ruling out that the lack of cross-modal CA effects in Experiments 1A/B resulted from differences in task-irrelevant information. Task-irrelevant properties were further matched in Experiments 3A/B to examine the pure effect of modality. Results replicated Experiments 1A/B showing robust modality-specific CA effects. Taken together, we provide supporting evidences that modality affects cognitive control in conflict resolution, which should be taken into account in theories of cognitive control. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Conflict-Specific Aging Effects Mainly Manifest in Early Information Processing Stages-An ERP Study with Different Conflict Types.

PubMed

Korsch, Margarethe; Frühholz, Sascha; Herrmann, Manfred

2016-01-01

Aging is usually accompanied by alterations of cognitive control functions such as conflict processing. Recent research suggests that aging effects on cognitive control seem to vary with degree and source of conflict, and conflict specific aging effects on performance measures as well as neural activation patterns have been shown. However, there is sparse information whether and how aging affects different stages of conflict processing as indicated by event related potentials (ERPs) such as the P2, N2 and P3 components. In the present study, 19 young and 23 elderly adults performed a combined Flanker conflict and stimulus-response-conflict (SRC) task. Analysis of the reaction times (RTs) revealed an increased SRC related conflict effect in elderly. ERP analysis furthermore demonstrated an age-related increase of the P2 amplitude in response to the SRC task. In addition, elderly adults exhibited an increased P3 amplitude modulation induced by incongruent SRC and Flanker conflict trials.

Mirror neuron activation as a function of explicit learning: changes in mu-event-related power after learning novel responses to ideomotor compatible, partially compatible, and non-compatible stimuli.

PubMed

Behmer, Lawrence P; Fournier, Lisa R

2016-11-01

Questions regarding the malleability of the mirror neuron system (MNS) continue to be debated. MNS activation has been reported when people observe another person performing biological goal-directed behaviors, such as grasping a cup. These findings support the importance of mapping goal-directed biological behavior onto one's motor repertoire as a means of understanding the actions of others. Still, other evidence supports the Associative Sequence Learning (ASL) model which predicts that the MNS responds to a variety of stimuli after sensorimotor learning, not simply biological behavior. MNS activity develops as a consequence of developing stimulus-response associations between a stimulus and its motor outcome. Findings from the ideomotor literature indicate that stimuli that are more ideomotor compatible with a response are accompanied by an increase in response activation compared to less compatible stimuli; however, non-compatible stimuli robustly activate a constituent response after sensorimotor learning. Here, we measured changes in the mu-rhythm, an EEG marker thought to index MNS activity, predicting that stimuli that differ along dimensions of ideomotor compatibility should show changes in mirror neuron activation as participants learn the respective stimulus-response associations. We observed robust mu-suppression for ideomotor-compatible hand actions and partially compatible dot animations prior to learning; however, compatible stimuli showed greater mu-suppression than partially or non-compatible stimuli after explicit learning. Additionally, non-compatible abstract stimuli exceeded baseline only after participants explicitly learned the motor responses associated with the stimuli. We conclude that the empirical differences between the biological and ASL accounts of the MNS can be explained by Ideomotor Theory. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The negative compatibility effect with relevant masks: a case for automatic motor inhibition

PubMed Central

Ocampo, Brenda; Finkbeiner, Matthew

2013-01-01

For many years controversy has surrounded the so-called “negative compatibility effect” (NCE), a surprising phenomenon whereby responses to a target stimulus are delayed when the target is preceded by an unconscious, response-compatible prime. According to proponents of the “self-inhibition” hypothesis, the NCE occurs when a low-level self-inhibitory mechanism supresses early motor activations that are no longer supported by perceptual evidence. This account has been debated, however, by those who regard the NCE to be a stimulus-specific phenomenon that can be explained without recourse to a self-inhibitory mechanism. The present study used a novel reach-to-touch paradigm to test whether unconscious response priming would manifest as motor activation of the opposite-to-prime response (supporting mask-induced priming accounts), or motor inhibition of the primed response (supporting the notion of low-level self-inhibition). This paper presents new findings that show the emergence of positive and negative compatibility effects as they occur in stimulus processing time. In addition, evidence is provided suggesting that the NCE is not driven by the activation of the incorrect, “opposite-to-prime” response, but rather might reflect automatic motor inhibition. PMID:24265623

How Do Children Deal With Conflict? A Developmental Study of Sequential Conflict Modulation

PubMed Central

Smulders, Silvan F. A.; Soetens, Eric L. L.; van der Molen, Maurits W.

2018-01-01

This study examined age-related differences in sequential conflict modulation (SCM), elicited in three tasks requiring the inhibition of pre-potent responses; a Simon task, an S-R compatibility (SRC) task and a hybrid Choice-reaction/NoGo task. The primary focus was on age-related changes in performance changes following a conflict trial. A secondary aim was to assess whether SCM follows different developmental trajectories depending on the type of conflict elicited by the tasks. The tasks were presented to three different groups of participants with an age range between 7- to 25-years—one group of participants for each task. For each task, the response-to-stimulus interval (RSI) was manipulated (50 vs. 500 ms) across trial blocks to assess time-dependent changes in conflict modulation. The results showed SCM for all three tasks, although the specific patterns differed between tasks and RSIs. Importantly, the magnitude of SCM decreased with advancing age, but this developmental trend did not survive when considering age-group differences in basic response speed. The current results contribute to the emerging evidence suggesting that patterns of SCM are task specific and were interpreted in terms of multiple bottom-up control mechanisms. PMID:29875718

Assessment of Tobacco-Related Approach and Attentional Biases in Smokers, Cravers, Ex-Smokers, and Non-Smokers

PubMed Central

Woud, Marcella L.; Maas, Joyce; Wiers, Reinout W.; Becker, Eni S.; Rinck, Mike

2016-01-01

According to theories of addictive behaviors, approach and attentional biases toward smoking-related cues play a crucial role in tobacco dependence. Several studies have investigated these biases by using various paradigms in different sample types. However, this heterogeneity makes it difficult to compare and evaluate the results. The present study aimed to address this problem, via (i) a structural comparison of different measures of approach-avoidance and a measure of smoking-related attentional biases, and (ii) using within one study different representative samples in the context of tobacco dependence. Three measures of approach-avoidance were employed: an Approach Avoidance Task (AAT), a Stimulus Response Compatibility Task (SRC), and a Single Target Implicit Association Test (ST-IAT). To assess attentional biases, a modified Stroop task including smoking-related words was administered. The study included four groups: n = 58 smokers, n = 57 non-smokers, n = 52 cravers, and n = 54 ex-smokers. We expected to find strong tobacco-related approach biases and attentional biases in smokers and cravers. However, the general pattern of results did not confirm these expectations. Approach responses assessed during the AAT and SRC did not differ between groups. Moreover, the Stroop did not show the expected interference effect. For the ST-IAT, cravers had stronger approach associations toward smoking-related cues, whereas non-smokers showed stronger avoidance associations. However, no such differences in approach-avoidance associations were found in smokers and ex-smokers. To conclude, these data do not provide evidence for a strong role of implicit approach and attentional biases toward smoking-related cues in tobacco dependency. PMID:26955359

The influence of the Japanese waving cat on the joint spatial compatibility effect: A replication and extension of Dolk, Hommel, Prinz, and Liepelt (2013).

PubMed

Puffe, Lydia; Dittrich, Kerstin; Klauer, Karl Christoph

2017-01-01

In a joint go/no-go Simon task, each of two participants is to respond to one of two non-spatial stimulus features by means of a spatially lateralized response. Stimulus position varies horizontally and responses are faster and more accurate when response side and stimulus position match (compatible trial) than when they mismatch (incompatible trial), defining the social Simon effect or joint spatial compatibility effect. This effect was originally explained in terms of action/task co-representation, assuming that the co-actor's action is automatically co-represented. Recent research by Dolk, Hommel, Prinz, and Liepelt (2013) challenged this account by demonstrating joint spatial compatibility effects in a task-setting in which non-social objects like a Japanese waving cat were present, but no real co-actor. They postulated that every sufficiently salient object induces joint spatial compatibility effects. However, what makes an object sufficiently salient is so far not well defined. To scrutinize this open question, the current study manipulated auditory and/or visual attention-attracting cues of a Japanese waving cat within an auditory (Experiment 1) and a visual joint go/no-go Simon task (Experiment 2). Results revealed that joint spatial compatibility effects only occurred in an auditory Simon task when the cat provided auditory cues while no joint spatial compatibility effects were found in a visual Simon task. This demonstrates that it is not the sufficiently salient object alone that leads to joint spatial compatibility effects but instead, a complex interaction between features of the object and the stimulus material of the joint go/no-go Simon task.

The influence of dimensional overlap on location-related priming in the Simon task.

PubMed

Lehle, Carola; Stürmer, Birgit; Sommer, Werner

2013-01-01

Choice reaction times are shorter when stimulus and response locations are compatible than when they are incompatible as in the Simon effect. Recent studies revealed that Simon effects are strongly attenuated when there is temporal overlap with a different high-priority task, accompanied by a decrease of early location-related response priming as reflected in the lateralized readiness potential (LRP). The latter result was obtained in a study excluding overlap of stimulus location with any other dimension in the tasks. Independent evidence suggests that location-related priming might be present in conditions with dimensional overlap. Here we tested this prediction in a dual-task experiment supplemented with recording LRPs. The secondary task was either a standard Simon task where irrelevant stimulus location overlapped with dimensions of the primary task or a Stroop-like Simon task including additional overlap of irrelevant and relevant stimulus attributes. At high temporal overlap, there was no Simon effect nor was there stimulus-related response priming in either condition. Therefore stimulus-triggered response priming seems to be abolished in conditions of limited capacity even if the likelihood of an S-R compatibility effect is maximized.

On the temporal dynamics of spatial stimulus-response transfer between spatial incompatibility and Simon tasks

PubMed Central

Ivanoff, Jason; Blagdon, Ryan; Feener, Stefanie; McNeil, Melanie; Muir, Paul H.

2014-01-01

The Simon effect refers to the performance (response time and accuracy) advantage for responses that spatially correspond to the task-irrelevant location of a stimulus. It has been attributed to a natural tendency to respond toward the source of stimulation. When location is task-relevant, however, and responses are intentionally directed away (incompatible) or toward (compatible) the source of the stimulation, there is also an advantage for spatially compatible responses over spatially incompatible responses. Interestingly, a number of studies have demonstrated a reversed, or reduced, Simon effect following practice with a spatial incompatibility task. One interpretation of this finding is that practicing a spatial incompatibility task disables the natural tendency to respond toward stimuli. Here, the temporal dynamics of this stimulus-response (S-R) transfer were explored with speed-accuracy trade-offs (SATs). All experiments used the mixed-task paradigm in which Simon and spatial compatibility/incompatibility tasks were interleaved across blocks of trials. In general, bidirectional S-R transfer was observed: while the spatial incompatibility task had an influence on the Simon effect, the task-relevant S-R mapping of the Simon task also had a small impact on congruency effects within the spatial compatibility and incompatibility tasks. These effects were generally greater when the task contexts were similar. Moreover, the SAT analysis of performance in the Simon task demonstrated that the tendency to respond to the location of the stimulus was not eliminated because of the spatial incompatibility task. Rather, S-R transfer from the spatial incompatibility task appeared to partially mask the natural tendency to respond to the source of stimulation with a conflicting inclination to respond away from it. These findings support the use of SAT methodology to quantitatively describe rapid response tendencies. PMID:25191217

Embodiment of abstract categories in space… grounding or mere compatibility effects? The case of politics.

PubMed

Farias, Ana Rita; Garrido, Margarida V; Semin, Gün R

2016-05-01

In two experiments, the role played by stimulus response compatibility in driving the spatial grounding of abstract concepts is examined. In Experiment 1, participants were asked to classify politics-related words appearing to the left or the right side of a computer monitor as socialist or conservative. Responses were given by pressing vertically aligned keys and thus orthogonal to the spatial information that may have been implied by the words. Responses given by left or right index finger were counterbalanced. In Experiment 2, a lexical decision task, participants categorized political words or non-words presented to the left or the right auditory channels, by pressing the top/bottom button of a response box. The response category labels (word or non-word) were also orthogonal to the spatial information that may have been implied by the stimulus words. In both experiments, responses were faster when socialism-related words were presented on the left and conservatism-related words were presented on the right, irrespective of the reference of the response keys or labels. Overall, our findings suggest that the spatial grounding of abstract concepts (or at least politics-related ones) is independent of experimentally driven stimulus-response compatibility effects. Copyright © 2016 Elsevier B.V. All rights reserved.

The Effects of Spatial Stimulus-Response Compatibility on Choice Time Production Accuracy and Variability

ERIC Educational Resources Information Center

Rakitin, Brian C.

2005-01-01

Five experiments examined the relations between timing and attention using a choice time production task in which the latency of a spatial choice response is matched to a target interval (3 or 5 s). Experiments 1 and 2 indicated that spatial stimulus-response incompatibility increased nonscalar timing variability without affecting timing accuracy…

Longitudinal Brain Magnetic Resonance Imaging CO2 Stress Testing in Individual Adolescent Sports-Related Concussion Patients: A Pilot Study.

PubMed

Mutch, W Alan C; Ellis, Michael J; Ryner, Lawrence N; Morissette, Marc P; Pries, Philip J; Dufault, Brenden; Essig, Marco; Mikulis, David J; Duffin, James; Fisher, Joseph A

2016-01-01

Advanced neuroimaging studies in concussion have been limited to detecting group differences between concussion patients and healthy controls. In this small pilot study, we used brain magnetic resonance imaging (MRI) CO2 stress testing to longitudinally assess cerebrovascular responsiveness (CVR) in individual sports-related concussion (SRC) patients. Six SRC patients (three males and three females; mean age = 15.7, range = 15-17 years) underwent longitudinal brain MRI CO2 stress testing using blood oxygen level-dependent (BOLD) MRI and model-based prospective end-tidal CO2 targeting under isoxic conditions. First-level and second-level comparisons were undertaken using statistical parametric mapping (SPM) to score the scans and compare them to an atlas of 24 healthy control subjects. All tests were well tolerated and without any serious adverse events. Anatomical MRI was normal in all study participants. The CO2 stimulus was consistent between the SRC patients and control subjects and within SRC patients across the longitudinal study. Individual SRC patients demonstrated both quantitative and qualitative patient-specific alterations in CVR (p < 0.005) that correlated strongly with clinical findings, and that persisted beyond clinical recovery. Standardized brain MRI CO2 stress testing is capable of providing a longitudinal assessment of CVR in individual SRC patients. Consequently, larger prospective studies are needed to examine the utility of brain MRI CO2 stress testing as a clinical tool to help guide the evaluation, classification, and longitudinal management of SRC patients.

Central Cross-Talk in Task Switching : Evidence from Manipulating Input-Output Modality Compatibility

ERIC Educational Resources Information Center

Stephan, Denise Nadine; Koch, Iring

2010-01-01

Two experiments examined the role of compatibility of input and output (I-O) modality mappings in task switching. We define I-O modality compatibility in terms of similarity of stimulus modality and modality of response-related sensory consequences. Experiment 1 included switching between 2 compatible tasks (auditory-vocal vs. visual-manual) and…

Holding a manual response sequence in memory can disrupt vocal responses that share semantic features with the manual response.

PubMed

Fournier, Lisa Renee; Wiediger, Matthew D; McMeans, Ryan; Mattson, Paul S; Kirkwood, Joy; Herzog, Theibot

2010-07-01

Holding an action plan in memory for later execution can delay execution of another action if the actions share a similar (compatible) feature. This compatibility interference (CI) occurs for actions that share the same response modality (e.g., manual response). We investigated whether CI can generalize to actions that utilize different response modalities (manual and vocal). In three experiments, participants planned and withheld a sequence of key-presses with the left- or right-hand based on the visual identity of the first stimulus, and then immediately executed a speeded, vocal response ('left' or 'right') to a second visual stimulus. The vocal response was based on discriminating stimulus color (Experiment 1), reading a written word (Experiment 2), or reporting the antonym of a written word (Experiment 3). Results showed that CI occurred when the manual response hand (e.g., left) was compatible with the identity of the vocal response (e.g., 'left') in Experiment 1 and 3, but not in Experiment 2. This suggests that partial overlap of semantic codes is sufficient to obtain CI unless the intervening action can be accessed automatically (Experiment 2). These findings are consistent with the code occupation hypothesis and the general framework of the theory of event coding (Behav Brain Sci 24:849-878, 2001a; Behav Brain Sci 24:910-937, 2001b).

Conflict Adaptation and Cue Competition during Learning in an Eriksen Flanker Task

PubMed Central

Ghinescu, Rodica; Ramsey, Ashley K.; Gratton, Gabriele; Fabiani, Monica

2016-01-01

Two experiments investigated competition between cues that predicted the correct target response to a target stimulus in a response conflict procedure using a flanker task. Subjects received trials with five-character arrays with a central target character and distractor flanker characters that matched (compatible) or did not match (incompatible) the central target. Subjects’ expectancies for compatible and incompatible trials were manipulated by presenting pre-trial cues that signaled the occurrence of compatible or incompatible trials. On some trials, a single cue predicted the target stimulus and the required target response. On other trials, a second redundant, predictive cue was also present on such trials. The results showed an effect of competition between cues for control over strategic responding to the target stimuli, a finding that is predicted by associative learning theories. The finding of competition between pre-trial cues that predict incompatible trials, but not cues that predict compatible trials, suggests that different strategic processes may occur during adaptation to conflict when different kinds of trials are expected. PMID:27941977

Transfer of an implied incompatible spatial mapping to a Simon task.

PubMed

Luo, Chunming; Proctor, Robert W

2016-02-01

When location words left and right are presented in left and right locations and mapped to left and right keypress responses in the Hedge and Marsh (1975) task (Arend & Wandmacher, 1987), a compatible mapping of words to responses yields a benefit for stimulus-response location correspondence (sometimes called the Simon effect), whereas an incompatible mapping yields a benefit for noncorrespondence (called the Hedge and Marsh reversal). Experiment 1 replicated the correspondence benefit and its reversal by using Chinese location words [symbol: see text] (left) and [symbol: see text] (right) in the Hedge and Marsh task. Experiments 2 and 3 examined whether the tendency to respond with the noncorresponding response when the mapping is incompatible transfers to the task version in which the mapping is compatible, and Experiment 4 examined whether transfer similarly occurs from the compatible mapping to the task version with incompatible mapping. Transfer of the incompatible relation was apparent in a lack of correspondence benefit when the mapping was changed to compatible, but transfer of the compatible relation to the incompatible mapping did not occur. The results suggest that an association between noncorresponding stimulus-response locations is acquired when the word-response mapping is incompatible, even though this relation is only implicit, regardless of whether through misapplication of a logical recoding rule or spatial representations shared by the locations and words. These associations then continue to affect processing of location when the mapping is compatible. Copyright © 2015 Elsevier B.V. All rights reserved.

Automatic Approach Tendencies toward High and Low Caloric Food in Restrained Eaters: Influence of Task-Relevance and Mood

PubMed Central

Neimeijer, Renate A. M.; Roefs, Anne; Ostafin, Brian D.; de Jong, Peter J.

2017-01-01

Objective: Although restrained eaters are motivated to control their weight by dieting, they are often unsuccessful in these attempts. Dual process models emphasize the importance of differentiating between controlled and automatic tendencies to approach food. This study investigated the hypothesis that heightened automatic approach tendencies in restrained eaters would be especially prominent in contexts where food is irrelevant for their current tasks. Additionally, we examined the influence of mood on the automatic tendency to approach food as a function of dietary restraint. Methods: An Affective Simon Task-manikin was administered to measure automatic approach tendencies where food is task-irrelevant, and a Stimulus Response Compatibility task (SRC) to measure automatic approach in contexts where food is task-relevant, in 92 female participants varying in dietary restraint. Prior to the task, sad, stressed, neutral, or positive mood was induced. Food intake was measured during a bogus taste task after the computer tasks. Results: Consistent with their diet goals, participants with a strong tendency to restrain their food intake showed a relatively weak approach bias toward food when food was task-relevant (SRC) and this effect was independent of mood. Restrained eaters showed a relatively strong approach bias toward food when food was task-irrelevant in the positive condition and a relatively weak approach in the sad mood. Conclusion: The weak approach bias in contexts where food is task-relevant may help high-restrained eaters to comply with their diet goal. However, the strong approach bias in contexts where food is task-irrelevant and when being in a positive mood may interfere with restrained eaters’ goal of restricting food-intake. PMID:28443045

Modality-specific effects on crosstalk in task switching: evidence from modality compatibility using bimodal stimulation.

PubMed

Stephan, Denise Nadine; Koch, Iring

2016-11-01

The present study was aimed at examining modality-specific influences in task switching. To this end, participants switched either between modality compatible tasks (auditory-vocal and visual-manual) or incompatible spatial discrimination tasks (auditory-manual and visual-vocal). In addition, auditory and visual stimuli were presented simultaneously (i.e., bimodally) in each trial, so that selective attention was required to process the task-relevant stimulus. The inclusion of bimodal stimuli enabled us to assess congruence effects as a converging measure of increased between-task interference. The tasks followed a pre-instructed sequence of double alternations (AABB), so that no explicit task cues were required. The results show that switching between two modality incompatible tasks increases both switch costs and congruence effects compared to switching between two modality compatible tasks. The finding of increased congruence effects in modality incompatible tasks supports our explanation in terms of ideomotor "backward" linkages between anticipated response effects and the stimuli that called for this response in the first place. According to this generalized ideomotor idea, the modality match between response effects and stimuli would prime selection of a response in the compatible modality. This priming would cause increased difficulties to ignore the competing stimulus and hence increases the congruence effect. Moreover, performance would be hindered when switching between modality incompatible tasks and facilitated when switching between modality compatible tasks.

Comparing Angular and Curved Shapes in Terms of Implicit Associations and Approach/Avoidance Responses.

PubMed

Palumbo, Letizia; Ruta, Nicole; Bertamini, Marco

2015-01-01

Most people prefer smoothly curved shapes over more angular shapes. We investigated the origin of this effect using abstract shapes and implicit measures of semantic association and preference. In Experiment 1 we used a multidimensional Implicit Association Test (IAT) to verify the strength of the association of curved and angular polygons with danger (safe vs. danger words), valence (positive vs. negative words) and gender (female vs. male names). Results showed that curved polygons were associated with safe and positive concepts and with female names, whereas angular polygons were associated with danger and negative concepts and with male names. Experiment 2 used a different implicit measure, which avoided any need to categorise the stimuli. Using a revised version of the Stimulus Response Compatibility (SRC) task we tested with a stick figure (i.e., the manikin) approach and avoidance reactions to curved and angular polygons. We found that RTs for approaching vs. avoiding angular polygons did not differ, even in the condition where the angles were more pronounced. By contrast participants were faster and more accurate when moving the manikin towards curved shapes. Experiment 2 suggests that preference for curvature cannot derive entirely from an association of angles with threat. We conclude that smoothly curved contours make these abstract shapes more pleasant. Further studies are needed to clarify the nature of such a preference.

Comparing Angular and Curved Shapes in Terms of Implicit Associations and Approach/Avoidance Responses

PubMed Central

Palumbo, Letizia; Ruta, Nicole; Bertamini, Marco

2015-01-01

Most people prefer smoothly curved shapes over more angular shapes. We investigated the origin of this effect using abstract shapes and implicit measures of semantic association and preference. In Experiment 1 we used a multidimensional Implicit Association Test (IAT) to verify the strength of the association of curved and angular polygons with danger (safe vs. danger words), valence (positive vs. negative words) and gender (female vs. male names). Results showed that curved polygons were associated with safe and positive concepts and with female names, whereas angular polygons were associated with danger and negative concepts and with male names. Experiment 2 used a different implicit measure, which avoided any need to categorise the stimuli. Using a revised version of the Stimulus Response Compatibility (SRC) task we tested with a stick figure (i.e., the manikin) approach and avoidance reactions to curved and angular polygons. We found that RTs for approaching vs. avoiding angular polygons did not differ, even in the condition where the angles were more pronounced. By contrast participants were faster and more accurate when moving the manikin towards curved shapes. Experiment 2 suggests that preference for curvature cannot derive entirely from an association of angles with threat. We conclude that smoothly curved contours make these abstract shapes more pleasant. Further studies are needed to clarify the nature of such a preference. PMID:26460610

Keys and seats: Spatial response coding underlying the joint spatial compatibility effect.

PubMed

Dittrich, Kerstin; Dolk, Thomas; Rothe-Wulf, Annelie; Klauer, Karl Christoph; Prinz, Wolfgang

2013-11-01

Spatial compatibility effects (SCEs) are typically observed when participants have to execute spatially defined responses to nonspatial stimulus features (e.g., the color red or green) that randomly appear to the left and the right. Whereas a spatial correspondence of stimulus and response features facilitates response execution, a noncorrespondence impairs task performance. Interestingly, the SCE is drastically reduced when a single participant responds to one stimulus feature (e.g., green) by operating only one response key (individual go/no-go task), whereas a full-blown SCE is observed when the task is distributed between two participants (joint go/no-go task). This joint SCE (a.k.a. the social Simon effect) has previously been explained by action/task co-representation, whereas alternative accounts ascribe joint SCEs to spatial components inherent in joint go/no-go tasks that allow participants to code their responses spatially. Although increasing evidence supports the idea that spatial rather than social aspects are responsible for joint SCEs emerging, it is still unclear to which component(s) the spatial coding refers to: the spatial orientation of response keys, the spatial orientation of responding agents, or both. By varying the spatial orientation of the responding agents (Exp. 1) and of the response keys (Exp. 2), independent of the spatial orientation of the stimuli, in the present study we found joint SCEs only when both the seating and the response key alignment matched the stimulus alignment. These results provide evidence that spatial response coding refers not only to the response key arrangement, but also to the-often neglected-spatial orientation of the responding agents.

Compatibility and consistency in display-control systems - Implications for aircraft decision aid design

NASA Technical Reports Server (NTRS)

Andre, Anthony D.; Wickens, Christopher D.

1992-01-01

In this study we contrast display-control movement relations defined in terms of stimulus-response (physical) compatibility with those defined by stimulus-cognitive compatibility, and we relate these findings to the issue of command versus status levels of decision aid support. A second issue addressed is the cost of inconsistency across multiple display-control mappings. Subjects performed a flight control task while responding to one to four analog indicators, formatted as either command or status displays. The results suggest that there is an advantage for the status format when subjects are required to verbally report the state of the indicator(s), but no advantage was found for either format when subjects were required to manually correct the indicated state. The data point to the importance of display-control consistency and suggest that it may even outweigh that of compatibility.

Stimulus-Response Compatibility in Spatial Precuing and Symbolic Identification: Effects of Coding Practice, Retention and Transfer

DTIC Science & Technology

1989-05-31

for the effects. Most of the pqychophysiological research has examined event-related potentials (ERPs). Bashore (Chapter 7 ), Ragot (Chapter 8), and...flanking noise letters I signaled a response that was incongruent with the resTcnse i:.dicated b., a target letter. Bashore (Chapter 7 ) describes a...forms. First, compatibility effects have been used as estimates of interhemispheric transmission time (Bashore, I Chapter 7 ). The logic, articulated

Contrasting motivational orientation and evaluative coding accounts: on the need to differentiate the effectors of approach/avoidance responses.

PubMed

Kozlik, Julia; Neumann, Roland; Lozo, Ljubica

2015-01-01

Several emotion theorists suggest that valenced stimuli automatically trigger motivational orientations and thereby facilitate corresponding behavior. Positive stimuli were thought to activate approach motivational circuits which in turn primed approach-related behavioral tendencies whereas negative stimuli were supposed to activate avoidance motivational circuits so that avoidance-related behavioral tendencies were primed (motivational orientation account). However, recent research suggests that typically observed affective stimulus-response compatibility phenomena might be entirely explained in terms of theories accounting for mechanisms of general action control instead of assuming motivational orientations to mediate the effects (evaluative coding account). In what follows, we explore to what extent this notion is applicable. We present literature suggesting that evaluative coding mechanisms indeed influence a wide variety of affective stimulus-response compatibility phenomena. However, the evaluative coding account does not seem to be sufficient to explain affective S-R compatibility effects. Instead, several studies provide clear evidence in favor of the motivational orientation account that seems to operate independently of evaluative coding mechanisms. Implications for theoretical developments and future research designs are discussed.

Congruency sequence effect without feature integration and contingency learning.

PubMed

Kim, Sanga; Cho, Yang Seok

2014-06-01

The magnitude of congruency effects, such as the flanker-compatibility effects, has been found to vary as a function of the congruency of the previous trial. Some studies have suggested that this congruency sequence effect is attributable to stimulus and/or response priming, and/or contingency learning, whereas other studies have suggested that the control process triggered by conflict modulates the congruency effect. The present study examined whether sequential modulation can occur without stimulus and response repetitions and contingency learning. Participants were asked to perform two color flanker-compatibility tasks alternately in a trial-by-trial manner, with four fingers of one hand in Experiment 1 and with the index and middle fingers of two hands in Experiment 2, to avoid stimulus and response repetitions and contingency learning. A significant congruency sequence effect was obtained between the congruencies of the two tasks in Experiment 1 but not in Experiment 2. These results provide evidence for the idea that the sequential modulation is, at least in part, an outcome of the top-down control process triggered by conflict, which is specific to response mode. Copyright © 2014 Elsevier B.V. All rights reserved.

Automatic Imitation

ERIC Educational Resources Information Center

Heyes, Cecilia

2011-01-01

"Automatic imitation" is a type of stimulus-response compatibility effect in which the topographical features of task-irrelevant action stimuli facilitate similar, and interfere with dissimilar, responses. This article reviews behavioral, neurophysiological, and neuroimaging research on automatic imitation, asking in what sense it is "automatic"…

Dual-task interference with equal task emphasis: graded capacity sharing or central postponement?

NASA Technical Reports Server (NTRS)

Ruthruff, Eric; Pashler, Harold E.; Hazeltine, Eliot

2003-01-01

Most studies using the psychological refractory period (PRP) design suggest that dual-task performance is limited by a central bottleneck. Because subjects are usually told to emphasize Task 1, however, the bottleneck might reflect a strategic choice rather than a structural limitation. To evaluate the possibility that central operations can proceed in parallel, albeit with capacity limitations, we conducted two dual-task experiments with equal task emphasis. In both experiments, subjects tended to either group responses together or respond to one task well before the other. In addition, stimulus-response compatibility effects were roughly constant across stimulus onset asynchronies (SOAs). At the short SOA, compatibility effects also carried over onto response times for the other task. This pattern of results is difficult to reconcile with the possibility that subjects share capacity roughly equally between simultaneous central operations. However, this pattern is consistent with the existence of a structural central bottleneck.

Effects of in-vehicle warning information displays with or without spatial compatibility on driving behaviors and response performance.

PubMed

Liu, Yung-Ching; Jhuang, Jing-Wun

2012-07-01

A driving simulator study was conducted to evaluate the effects of five in-vehicle warning information displays upon drivers' emergent response and decision performance. These displays include visual display, auditory displays with and without spatial compatibility, hybrid displays in both visual and auditory format with and without spatial compatibility. Thirty volunteer drivers were recruited to perform various tasks that involved driving, stimulus-response, divided attention and stress rating. Results show that for displays of single-modality, drivers benefited more when coping with visual display of warning information than auditory display with or without spatial compatibility. However, auditory display with spatial compatibility significantly improved drivers' performance in reacting to the divided attention task and making accurate S-R task decision. Drivers' best performance results were obtained for hybrid display with spatial compatibility. Hybrid displays enabled drivers to respond the fastest and achieve the best accuracy in both S-R and divided attention tasks. Copyright © 2011 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Influence of auditory and audiovisual stimuli on the right-left prevalence effect.

PubMed

Vu, Kim-Phuong L; Minakata, Katsumi; Ngo, Mary Kim

2014-01-01

When auditory stimuli are used in two-dimensional spatial compatibility tasks, where the stimulus and response configurations vary along the horizontal and vertical dimensions simultaneously, a right-left prevalence effect occurs in which horizontal compatibility dominates over vertical compatibility. The right-left prevalence effects obtained with auditory stimuli are typically larger than that obtained with visual stimuli even though less attention should be demanded from the horizontal dimension in auditory processing. In the present study, we examined whether auditory or visual dominance occurs when the two-dimensional stimuli are audiovisual, as well as whether there will be cross-modal facilitation of response selection for the horizontal and vertical dimensions. We also examined whether there is an additional benefit of adding a pitch dimension to the auditory stimulus to facilitate vertical coding through use of the spatial-musical association of response codes (SMARC) effect, where pitch is coded in terms of height in space. In Experiment 1, we found a larger right-left prevalence effect for unimodal auditory than visual stimuli. Neutral, non-pitch coded, audiovisual stimuli did not result in cross-modal facilitation, but did show evidence of visual dominance. The right-left prevalence effect was eliminated in the presence of SMARC audiovisual stimuli, but the effect influenced horizontal rather than vertical coding. Experiment 2 showed that the influence of the pitch dimension was not in terms of influencing response selection on a trial-to-trial basis, but in terms of altering the salience of the task environment. Taken together, these findings indicate that in the absence of salient vertical cues, auditory and audiovisual stimuli tend to be coded along the horizontal dimension and vision tends to dominate audition in this two-dimensional spatial stimulus-response task.

Ideomotor compatibility in the psychological refractory period effect: 29 years of oversimplification

NASA Technical Reports Server (NTRS)

Lien, Mei-Ching; Proctor, Robert W.; Allen, Philip A.

2002-01-01

Four experiments examined whether the psychological refractory period (PRP) effect can be eliminated with ideomotor compatible (IM) but not stimulus-response compatible (SR) tasks, as reported by A. G. Greenwald and H. G. Shulman (1973). Their tasks were used: a left or right movement to a left- or right-pointing arrow (IM) or to the word left or right (SR) for Task 1; saying "A" or "B" (IM) or "1" or "2" (SR) to an auditory A or B for Task 2. The stimulus onset asynchronies were 0, 100, 200, 300, 500, and 1,000 ms in Experiment 1, and only 0, 100, 200, and 1,000 ms in Experiments 2-4. The arrow was in the center of the screen in Experiments 1-3 and to the left or right in Experiment 4. As in Greenwald and Shulman's Experiment 2, the instructions stated that most often the 2 stimuli would be presented simultaneously. A PRP effect was obtained in all conditions, most likely because response-selection decisions are required even for IM tasks.

Ideomotor compatibility in the psychological refractory period effect: 29 years of oversimplification.

PubMed

Lien, Mei-Ching; Proctor, Robert W; Allen, Philip A

2002-04-01

Four experiments examined whether the psychological refractory period (PRP) effect can be eliminated with ideomotor compatible (IM) but not stimulus-response compatible (SR) tasks, as reported by A. G. Greenwald and H. G. Shulman (1973). Their tasks were used: a left or right movement to a left- or right-pointing arrow (IM) or to the word left or right (SR) for Task 1; saying "A" or "B" (IM) or "1" or "2" (SR) to an auditory A or B for Task 2. The stimulus onset asynchronies were 0, 100, 200, 300, 500, and 1,000 ms in Experiment 1, and only 0, 100, 200, and 1,000 ms in Experiments 2-4. The arrow was in the center of the screen in Experiments 1-3 and to the left or right in Experiment 4. As in Greenwald and Shulman's Experiment 2, the instructions stated that most often the 2 stimuli would be presented simultaneously. A PRP effect was obtained in all conditions, most likely because response-selection decisions are required even for IM tasks.

When congruence breeds preference: the influence of selective attention processes on evaluative conditioning.

PubMed

Blask, Katarina; Walther, Eva; Frings, Christian

2017-09-01

We investigated in two experiments whether selective attention processes modulate evaluative conditioning (EC). Based on the fact that the typical stimuli in an EC paradigm involve an affect-laden unconditioned stimulus (US) and a neutral conditioned stimulus (CS), we started from the assumption that learning might depend in part upon selective attention to the US. Attention to the US was manipulated by including a variant of the Eriksen flanker task in the EC paradigm. Similarly to the original Flanker paradigm, we implemented a target-distracter logic by introducing the CS as the task-relevant stimulus (i.e. the target) to which the participants had to respond and the US as a task-irrelevant distracter. Experiment 1 showed that CS-US congruence modulated EC if the CS had to be selected against the US. Specifically, EC was more pronounced for congruent CS-US pairs as compared to incongruent CS-US pairs. Experiment 2 disentangled CS-US congruence and CS-US compatibility and suggested that it is indeed CS-US stimulus congruence rather than CS-US response compatibility that modulates EC.

Negative Stimulus-Response Compatibility Observed with a Briefly Displayed Image of a Hand

ERIC Educational Resources Information Center

Vainio, Lari

2011-01-01

Manual responses can be primed by viewing an image of a hand. The left-right identity of the viewed hand reflexively facilitates responses of the hand that corresponds to the identity. Previous research also suggests that when the response activation is triggered by an arrow, which is backward-masked and presented briefly, the activation manifests…

Age-related changes in cognitive conflict processing: an event-related potential study.

PubMed

Mager, Ralph; Bullinger, Alex H; Brand, Serge; Schmidlin, Maria; Schärli, Heinz; Müller-Spahn, Franz; Störmer, Robert; Falkenstein, Michael

2007-12-01

Cognitive tasks involving conflicting stimuli and responses are associated with an early age-related decline in performance. Conflict and conflict-induced interference can be stimulus- or response-related. In classical stimulus-response compatibility tasks, such as the Stroop task, the event-related potential (ERP) usually reveals a greater negativity on incongruent versus congruent trials which has often been linked with conflict processing. However, it is unclear whether this negativity is related to stimulus- or response-related conflict, thus rendering the meaning of age-related changes inconclusive. In the present study, a modified Stroop task was used to focus on stimulus-related interference processes while excluding response-related interference. Since we intended to study work-relevant effects ERPs and performance were determined in young (about 30 years old) and middle-aged (about 50 years old) healthy subjects (total n=80). In the ERP, a broad negativity developed after incongruent versus congruent stimuli between 350 and 650 ms. An age-related increase of the latency and amplitude of this negativity was observed. These results indicate age-related alterations in the processing of conflicting stimuli already in middle age.

Intact Rapid Facial Mimicry as well as Generally Reduced Mimic Responses in Stable Schizophrenia Patients

PubMed Central

Chechko, Natalya; Pagel, Alena; Otte, Ellen; Koch, Iring; Habel, Ute

2016-01-01

Spontaneous emotional expressions (rapid facial mimicry) perform both emotional and social functions. In the current study, we sought to test whether there were deficits in automatic mimic responses to emotional facial expressions in patients (15 of them) with stable schizophrenia compared to 15 controls. In a perception-action interference paradigm (the Simon task; first experiment), and in the context of a dual-task paradigm (second experiment), the task-relevant stimulus feature was the gender of a face, which, however, displayed a smiling or frowning expression (task-irrelevant stimulus feature). We measured the electromyographical activity in the corrugator supercilii and zygomaticus major muscle regions in response to either compatible or incompatible stimuli (i.e., when the required response did or did not correspond to the depicted facial expression). The compatibility effect based on interactions between the implicit processing of a task-irrelevant emotional facial expression and the conscious production of an emotional facial expression did not differ between the groups. In stable patients (in spite of a reduced mimic reaction), we observed an intact capacity to respond spontaneously to facial emotional stimuli. PMID:27303335

Anticipatory Regulation of Action Control in a Simon Task: Behavioral, Electrophysiological, and fMRI Correlates

PubMed Central

Strack, Gamze; Kaufmann, Christian; Kehrer, Stefanie; Brandt, Stephan; Stürmer, Birgit

2013-01-01

With the present study we investigated cue-induced preparation in a Simon task and measured electroencephalogram and functional magnetic resonance imaging (fMRI) data in two within-subjects sessions. Cues informed either about the upcoming (1) spatial stimulus-response compatibility (rule cues), or (2) the stimulus location (position cues), or (3) were non-informative. Only rule cues allowed anticipating the upcoming compatibility condition. Position cues allowed anticipation of the upcoming location of the Simon stimulus but not its compatibility condition. Rule cues elicited fastest and most accurate performance for both compatible and incompatible trials. The contingent negative variation (CNV) in the event-related potential (ERP) of the cue-target interval is an index of anticipatory preparation and was magnified after rule cues. The N2 in the post-target ERP as a measure of online action control was reduced in Simon trials after rule cues. Although compatible trials were faster than incompatible trials in all cue conditions only non-informative cues revealed a compatibility effect in additional indicators of Simon task conflict like accuracy and the N2. We thus conclude that rule cues induced anticipatory re-coding of the Simon task that did not involve cognitive conflict anymore. fMRI revealed that rule cues yielded more activation of the left rostral, dorsal, and ventral prefrontal cortex as well as the pre-SMA as compared to POS and NON-cues. Pre-SMA and ventrolateral prefrontal activation after rule cues correlated with the effective use of rule cues in behavioral performance. Position cues induced a smaller CNV effect and exhibited less prefrontal and pre-SMA contributions in fMRI. Our data point to the importance to disentangle different anticipatory adjustments that might also include the prevention of upcoming conflict via task re-coding. PMID:23408377

Cognitive-behavioral therapy induces sensorimotor and specific electrocortical changes in chronic tic and Tourette's disorder.

PubMed

Morand-Beaulieu, Simon; O'Connor, Kieron P; Sauvé, Geneviève; Blanchet, Pierre J; Lavoie, Marc E

2015-12-01

Tic disorders, such as the Gilles de la Tourette syndrome and persistent tic disorder, are neurodevelopmental movement disorders involving impaired motor control. Hence, patients show repetitive unwanted muscular contractions in one or more parts of the body. A cognitive-behavioral therapy, with a particular emphasis on the psychophysiology of tic expression and sensorimotor activation, can reduce the frequency and intensity of tics. However, its impact on motor activation and inhibition is not fully understood. To study the effects of a cognitive-behavioral therapy on electrocortical activation, we recorded the event-related potentials (ERP) and lateralized readiness potentials (LRP), before and after treatment, of 20 patients with tic disorders and 20 healthy control participants (matched on age, sex and intelligence), during a stimulus-response compatibility inhibition task. The cognitive-behavioral therapy included informational, awareness training, relaxation, muscle discrimination, cognitive restructuration and relapse prevention strategies. Our results revealed that prior to treatment; tic patients had delayed stimulus-locked LRP onset latency, larger response-locked LRP peak amplitude, and a frontal overactivation during stimulus inhibition processing. Both stimulus-locked LRP onset latency and response-locked LRP peak amplitude normalized after the cognitive behavioral therapy completion. However, the frontal overactivation related to inhibition remained unchanged following therapy. Our results showed that P300 and reaction times are sensitive to stimulus-response compatibility, but are not related to tic symptoms. Secondly, overactivity of the frontal LPC and impulsivity in TD patients were not affected by treatment. Finally, CBT had normalizing effects on the activation of the pre-motor and motor cortex in TD patients. These results imply specific modifications of motor processes following therapy, while inhibition processes remained unchanged. Given that LRPs are partially generated within the sensorimotor and supplementary motor area, the reported reduction in tic frequency and improvements of LRPs components suggest that CBT induced a physiological change in patients' motor area. Copyright © 2015 Elsevier Ltd. All rights reserved.

Simultaneous dual-task performance reveals parallel response selection after practice

NASA Technical Reports Server (NTRS)

Hazeltine, Eliot; Teague, Donald; Ivry, Richard B.

2002-01-01

E. H. Schumacher, T. L. Seymour, J. M. Glass, D. E. Kieras, and D. E. Meyer (2001) reported that dual-task costs are minimal when participants are practiced and give the 2 tasks equal emphasis. The present research examined whether such findings are compatible with the operation of an efficient response selection bottleneck. Participants trained until they were able to perform both tasks simultaneously without interference. Novel stimulus pairs produced no reaction time costs, arguing against the development of compound stimulus-response associations (Experiment 1). Manipulating the relative onsets (Experiments 2 and 4) and durations (Experiments 3 and 4) of response selection processes did not lead to dual-task costs. The results indicate that the 2 tasks did not share a bottleneck after practice.

49 CFR Appendix F to Part 229 - Recommended Practices for Design and Safety Analysis

Code of Federal Regulations, 2014 CFR

2014-10-01

... expected order of use; (v) Group similar controls together; (vi) Design for high stimulus-response compatibility (geometric and conceptual); (vii) Design safety-critical controls to require more than one... description of all backup methods of operation; and (s) The configuration/revision control measures designed...

49 CFR Appendix F to Part 229 - Recommended Practices for Design and Safety Analysis

Code of Federal Regulations, 2012 CFR

2012-10-01

... expected order of use; (v) Group similar controls together; (vi) Design for high stimulus-response compatibility (geometric and conceptual); (vii) Design safety-critical controls to require more than one... description of all backup methods of operation; and (s) The configuration/revision control measures designed...

49 CFR Appendix F to Part 229 - Recommended Practices for Design and Safety Analysis

Code of Federal Regulations, 2013 CFR

2013-10-01

... expected order of use; (v) Group similar controls together; (vi) Design for high stimulus-response compatibility (geometric and conceptual); (vii) Design safety-critical controls to require more than one... description of all backup methods of operation; and (s) The configuration/revision control measures designed...

Cardiorespiratory Fitness and the Flexible Modulation of Cognitive Control in Preadolescent Children

ERIC Educational Resources Information Center

Pontifex, Matthew B.; Raine, Lauren B.; Johnson, Christopher R.; Chaddock, Laura; Voss, Michelle W.; Cohen, Neal J.; Kramer, Arthur F.; Hillman, Charles H.

2011-01-01

The influence of cardiorespiratory fitness on the modulation of cognitive control was assessed in preadolescent children separated into higher- and lower-fit groups. Participants completed compatible and incompatible stimulus-response conditions of a modified flanker task, consisting of congruent and incongruent arrays, while ERPs and task…

49 CFR Appendix E to Part 236 - Human-Machine Interface (HMI) Design

Code of Federal Regulations, 2013 CFR

2013-10-01

... operator to change position; (4) Arrange controls according to their expected order of use; (5) Group similar controls together; (6) Design for high stimulus-response compatibility (geometric and conceptual); (7) Design safety-critical controls to require more than one positive action to activate (e.g., auto...

49 CFR Appendix E to Part 236 - Human-Machine Interface (HMI) Design

Code of Federal Regulations, 2010 CFR

2010-10-01

... operator to change position; (4) Arrange controls according to their expected order of use; (5) Group similar controls together; (6) Design for high stimulus-response compatibility (geometric and conceptual); (7) Design safety-critical controls to require more than one positive action to activate (e.g., auto...

49 CFR Appendix E to Part 236 - Human-Machine Interface (HMI) Design

Code of Federal Regulations, 2014 CFR

2014-10-01

... operator to change position; (4) Arrange controls according to their expected order of use; (5) Group similar controls together; (6) Design for high stimulus-response compatibility (geometric and conceptual); (7) Design safety-critical controls to require more than one positive action to activate (e.g., auto...

49 CFR Appendix E to Part 236 - Human-Machine Interface (HMI) Design

Code of Federal Regulations, 2011 CFR

2011-10-01

... operator to change position; (4) Arrange controls according to their expected order of use; (5) Group similar controls together; (6) Design for high stimulus-response compatibility (geometric and conceptual); (7) Design safety-critical controls to require more than one positive action to activate (e.g., auto...

49 CFR Appendix E to Part 236 - Human-Machine Interface (HMI) Design

Code of Federal Regulations, 2012 CFR

2012-10-01

... operator to change position; (4) Arrange controls according to their expected order of use; (5) Group similar controls together; (6) Design for high stimulus-response compatibility (geometric and conceptual); (7) Design safety-critical controls to require more than one positive action to activate (e.g., auto...

Preparation for horizontal or vertical dimensions affects the right-left prevalence effect.

PubMed

Nishimura, Akio; Yokosawa, Kazuhiko

2007-10-01

When stimulus and response simultaneously vary in both horizontal and vertical dimensions, the stimulus-response compatibility effect is often larger for the horizontal dimension. We investigated the role of preparation for each dimension in this right-left prevalence. In Experiment 1, tasks based on horizontal and vertical dimensions were mixed in random order, and the relevant dimension in each trial was cued with a variable cue-target stimulus onset asynchrony (SOA). A right-left prevalence effect was observed only when participants prepared for the upcoming task. Experiment 2 replicated the absence of the prevalence effect for the simultaneous presentation of cue and target using a fixed SOA of 0 msec. In Experiment 3, the right-left prevalence emerged with a 0-msec SOA when participants prepared for e achdimension basedon its frequency. These resultssuggest that participants' internal set can be greater for the horizontal dimension, leading to the right-left prevalence effect.

Approach-bias predicts development of cannabis problem severity in heavy cannabis users: results from a prospective FMRI study.

PubMed

Cousijn, Janna; Goudriaan, Anna E; Ridderinkhof, K Richard; van den Brink, Wim; Veltman, Dick J; Wiers, Reinout W

2012-01-01

A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.

Approach-Bias Predicts Development of Cannabis Problem Severity in Heavy Cannabis Users: Results from a Prospective FMRI Study

PubMed Central

Cousijn, Janna; Goudriaan, Anna E.; Ridderinkhof, K. Richard; van den Brink, Wim; Veltman, Dick J.; Wiers, Reinout W.

2012-01-01

A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment. PMID:22957019

Horizontal and Vertical Pseudoneglect in Peri- and Extrapersonal Space

ERIC Educational Resources Information Center

Heber, Ines Ann; Siebertz, Sarah; Wolter, Marc; Kuhlen, Torsten; Fimm, Bruno

2010-01-01

The present study investigates the influence of depth on pseudoneglect in healthy young participants (n = 18) within three-dimensional virtual space, by presenting a variation of the greyscales task and a landmark task, which were specifically matched for stimulus-response compatibility, as well as perceptual factors within and across the tasks.…

Performance of Deaf Children on Memory Tasks: Some Considerations.

ERIC Educational Resources Information Center

Green, Bernard L.

1980-01-01

This paper makes a start in the search for a fair test of prelingually deaf children's short-term visual memory ability by exploring the coding problems presented to them by the traditional digit-span test. It suggests that more research be devoted to the problem of stimulus-response compatibility. (Suthor/SJL)

Visual context modulates potentiation of grasp types during semantic object categorization.

PubMed

Kalénine, Solène; Shapiro, Allison D; Flumini, Andrea; Borghi, Anna M; Buxbaum, Laurel J

2014-06-01

Substantial evidence suggests that conceptual processing of manipulable objects is associated with potentiation of action. Such data have been viewed as evidence that objects are recognized via access to action features. Many objects, however, are associated with multiple actions. For example, a kitchen timer may be clenched with a power grip to move it but pinched with a precision grip to use it. The present study tested the hypothesis that action evocation during conceptual object processing is responsive to the visual scene in which objects are presented. Twenty-five healthy adults were asked to categorize object pictures presented in different naturalistic visual contexts that evoke either move- or use-related actions. Categorization judgments (natural vs. artifact) were performed by executing a move- or use-related action (clench vs. pinch) on a response device, and response times were assessed as a function of contextual congruence. Although the actions performed were irrelevant to the categorization judgment, responses were significantly faster when actions were compatible with the visual context. This compatibility effect was largely driven by faster pinch responses when objects were presented in use-compatible, as compared with move-compatible, contexts. The present study is the first to highlight the influence of visual scene on stimulus-response compatibility effects during semantic object processing. These data support the hypothesis that action evocation during conceptual object processing is biased toward context-relevant actions.

Divergent modulation of Rho‐kinase and Ca2+ influx pathways by Src family kinases and focal adhesion kinase in airway smooth muscle

PubMed Central

Shaifta, Yasin; Irechukwu, Nneka; Prieto‐Lloret, Jesus; MacKay, Charles E; Marchon, Keisha A; Ward, Jeremy P T

2015-01-01

Background and Purpose The importance of tyrosine kinases in airway smooth muscle (ASM) contraction is not fully understood. The aim of this study was to investigate the role of Src‐family kinases (SrcFK) and focal adhesion kinase (FAK) in GPCR‐mediated ASM contraction and associated signalling events. Experimental Approach Contraction was recorded in intact or α‐toxin permeabilized rat bronchioles. Phosphorylation of SrcFK, FAK, myosin light‐chain‐20 (MLC20) and myosin phosphatase targeting subunit‐1 (MYPT‐1) was evaluated in cultured human ASM cells (hASMC). [Ca2+]i was evaluated in Fura‐2 loaded hASMC. Responses to carbachol (CCh) and bradykinin (BK) and the contribution of SrcFK and FAK to these responses were determined. Key Results Contractile responses in intact bronchioles were inhibited by antagonists of SrcFK, FAK and Rho‐kinase, while after α‐toxin permeabilization, they were sensitive to inhibition of SrcFK and Rho‐kinase, but not FAK. CCh and BK increased phosphorylation of MYPT‐1 and MLC20 and auto‐phosphorylation of SrcFK and FAK. MYPT‐1 phosphorylation was sensitive to inhibition of Rho‐kinase and SrcFK, but not FAK. Contraction induced by SR Ca2+ depletion and equivalent [Ca2+]i responses in hASMC were sensitive to inhibition of both SrcFK and FAK, while depolarization‐induced contraction was sensitive to FAK inhibition only. SrcFK auto‐phosphorylation was partially FAK‐dependent, while FAK auto‐phosphorylation was SrcFK‐independent. Conclusions and Implications SrcFK mediates Ca2+‐sensitization in ASM, while SrcFK and FAK together and individually influence multiple Ca2+ influx pathways. Tyrosine phosphorylation is therefore a key upstream signalling event in ASM contraction and may be a viable target for modulating ASM tone in respiratory disease. PMID:26294392

The power of instructions: Proactive configuration of stimulus-response translation.

PubMed

Meiran, Nachshon; Pereg, Maayan; Kessler, Yoav; Cole, Michael W; Braver, Todd S

2015-05-01

Humans are characterized by an especially highly developed ability to use instructions to prepare toward upcoming events; yet, it is unclear just how powerful instructions can be. Although prior work provides evidence that instructions can be sufficiently powerful to proactively program working memory to execute stimulus-response (S-R) translations, in a reflexlike fashion (intention-based reflexivity [IBR]), the results to date have been equivocal. To overcome this shortcoming, we developed, and tested in 4 studies, a novel paradigm (the NEXT paradigm) that isolates IBR effects even prior to first task execution. In each miniblock, participants received S-R mapping instructions for a new task. Prior to implementing this mapping, responses were required to advance through screens during a preparatory (NEXT) phase. When the NEXT response was incompatible with the instructed S-R mapping, interference (IBR effect) was observed. This NEXT compatibility effect and performance in the implementation (GO) trials barely changed when prior practice of a few trials was provided. Finally, a manipulation that encouraged preparation resulted in relatively durable NEXT compatibility effects (indicating durable preparatory efforts) coupled with improved GO performance (indicating the success of these efforts). Together, these findings establish IBR as a marker of instructed proactive control. (c) 2015 APA, all rights reserved).

Stimulus-response incompatibility activates cortex proximate to three eye fields

NASA Technical Reports Server (NTRS)

Merriam, E. P.; Colby, C. L.; Thulborn, K. R.; Luna, B.; Olson, C. R.; Sweeney, J. A.

2001-01-01

We used functional magnetic resonance imaging (fMRI) to investigate cortical activation during the performance of three oculomotor tasks that impose increasing levels of cognitive demand. (1) In a visually guided saccade (VGS) task, subjects made saccades to flashed targets. (2) In a compatible task, subjects made leftward and rightward saccades in response to foveal presentation of the uppercase words "LEFT" or "RIGHT." (3) In a mixed task, subjects made rightward saccades in response to the lowercase word "left" and leftward saccades in response to the lowercase word "right" on incompatible trials (60%). The remaining 40% of trials required compatible responses to uppercase words. The VGS and compatible tasks, when compared to fixation, activated the three cortical eye fields: the supplementary eye field (SEF), the frontal eye field (FEF), and the parietal eye field (PEF). The mixed task, when compared to the compatible task, activated three additional cortical regions proximate to the three eye fields: (1) rostral to the SEF in medial frontal cortex; (2) rostral to the FEF in dorsolateral prefrontal cortex (DLPFC); (3) rostral and lateral to the PEF in posterior parietal cortex. These areas may contribute to the suppression of prepotent responses and in holding novel visuomotor associations in working memory. Copyright 2001 Academic Press.

Information processing. [in human performance

NASA Technical Reports Server (NTRS)

Wickens, Christopher D.; Flach, John M.

1988-01-01

Theoretical models of sensory-information processing by the human brain are reviewed from a human-factors perspective, with a focus on their implications for aircraft and avionics design. The topics addressed include perception (signal detection and selection), linguistic factors in perception (context provision, logical reversals, absence of cues, and order reversals), mental models, and working and long-term memory. Particular attention is given to decision-making problems such as situation assessment, decision formulation, decision quality, selection of action, the speed-accuracy tradeoff, stimulus-response compatibility, stimulus sequencing, dual-task performance, task difficulty and structure, and factors affecting multiple task performance (processing modalities, codes, and stages).

Sequential Effects on Speeded Information Processing: A Developmental Study

ERIC Educational Resources Information Center

Smulders, S.F.A.; Notebaert, W.; Meijer, M.; Crone, E.A.; van der Molen, M.W.; Soetens, E.

2005-01-01

Two experiments were performed to assess age-related changes in sequential effects on choice reaction time (RT). Sequential effects portray the influence of previous trials on the RT to the current stimulus. In Experiment 1, three age groups (7-9, 10-12, and 18-25 years) performed a spatially compatible choice task, with response-to-stimulus…

Decomposing Sources of Response Slowing in the PRP Paradigm

ERIC Educational Resources Information Center

Jentzsch, Ines; Leuthold, Hartmut; Ulrich, Rolf

2007-01-01

The mechanism underlying the reaction time (RT2) slowing to the 2nd of 2 successively presented stimuli (S1 and S2) in the psychological refractory period paradigm was investigated. Stimulus onset synchrony (SOA) between S1 and S2, contrast of S2, and Task 2 set-level compatibility was manipulated. Specifically, the authors used a…

Steroid Receptor Coactivator 3 Contributes to Host Defense against Enteric Bacteria by Recruiting Neutrophils via Upregulation of CXCL2 Expression.

PubMed

Chen, Wenbo; Lu, Xuqiang; Chen, Yuan; Li, Ming; Mo, Pingli; Tong, Zhangwei; Wang, Wei; Wan, Wei; Su, Guoqiang; Xu, Jianming; Yu, Chundong

2017-02-15

Steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator that interacts with nuclear receptors and some other transcription factors to enhance their effects on target gene transcription. We reported previously that SRC-3-deficient (SRC-3 -/- ) mice are extremely susceptible to Escherichia coli-induced septic peritonitis as a result of uncontrolled inflammation and a defect in bacterial clearance. In this study, we observed significant upregulation of SRC-3 in colonic epithelial cells in response to Citrobacter rodentium infection. Based on these findings, we hypothesized that SRC-3 is involved in host defense against attaching and effacing bacterial infection. We compared the responses of SRC-3 -/- and wild-type mice to intestinal C. rodentium infection. We found that SRC-3 -/- mice exhibited delayed clearance of C. rodentium and more severe tissue pathology after oral infection with C. rodentium compared with wild-type mice. SRC-3 -/- mice expressed normal antimicrobial peptides in the colons but exhibited delayed recruitment of neutrophils into the colonic mucosa. Accordingly, SRC-3 -/- mice showed a delayed induction of CXCL2 and CXCL5 in colonic epithelial cells, which are responsible for neutrophil recruitment. At the molecular level, we found that SRC-3 can activate the NF-κB signaling pathway to promote CXCL2 expression at the transcriptional level. Collectively, we show that SRC-3 contributes to host defense against enteric bacteria, at least in part via upregulating CXCL2 expression to recruit neutrophils. Copyright © 2017 by The American Association of Immunologists, Inc.

SGT1 is required in PcINF1/SRC2-1 induced pepper defense response by interacting with SRC2-1

PubMed Central

Liu, Zhi-qin; Liu, Yan-yan; Shi, Lan-ping; Yang, Sheng; Shen, Lei; Yu, Huan-xin; Wang, Rong-zhang; Wen, Jia-yu; Tang, Qian; Hussain, Ansar; Khan, Muhammad Ifnan; Hu, Jiong; Liu, Cai-ling; Zhang, Yang-wen; Cheng, Wei; He, Shui-lin

2016-01-01

PcINF1 was previously found to induce pepper defense response by interacting with SRC2-1, but the underlying mechanism remains uninvestigated. Herein, we describe the involvement of SGT1 in the PcINF1/SRC2-1-induced immunity. SGT1 was observed to be up-regulated by Phytophthora capsici inoculation and synergistically transient overexpression of PcINF1/SRC2-1 in pepper plants. SGT1-silencing compromised HR cell death, blocked H2O2 accumulation, and downregulated HR-associated and hormones-dependent marker genes’ expression triggered by PcINF1/SRC2-1 co-overexpression. The interaction between SRC2-1 and SGT1 was found by the yeast two hybrid system and was further confirmed by bimolecular fluorescence complementation and co-immunoprecipitation analyses. The SGT1/SRC2-1 interaction was enhanced by transient overexpression of PcINF1 and Phytophthora capsici inoculation, and SGT1-silencing attenuated PcINF1/SRC2-1 interaction. Additionally, by modulating subcellular localizations of SRC2-1, SGT1, and the interacting complex of SGT1/SRC2-1, it was revealed that exclusive nuclear targeting of the SGT1/SRC2-1 complex blocks immunity triggered by formation of SGT1/SRC2-1, and a translocation of the SGT1/SRC2-1 complex from the plasma membrane and cytoplasm to the nuclei upon the inoculation of P. capsici. Our data demonstrate that the SGT1/SRC2-1 interaction, and its nucleocytoplasmic partitioning, is involved in pepper’s immunity against P. capsici, thus providing a molecular link between Ca2+ signaling associated SRC2-1 and SGT1-mediated defense signaling. PMID:26898479

Endothelial Barrier Protection by Local Anesthetics: Ropivacaine and Lidocaine Block Tumor Necrosis Factor-α–induced Endothelial Cell Src Activation

PubMed Central

Piegeler, Tobias; Votta-Velis, E. Gina; Bakhshi, Farnaz R.; Mao, Mao; Carnegie, Graeme; Bonini, Marcelo G.; Schwartz, David E.; Borgeat, Alain; Beck-Schimmer, Beatrice; Minshall, Richard D.

2014-01-01

Background Pulmonary endothelial barrier dysfunction mediated in part by Src-kinase activation plays a crucial role in acute inflammatory disease. Proinflammatory cytokines, such as tumor necrosis factor-α (TNFα), activate Src via phosphatidylinositide 3-kinase/Akt-dependent nitric oxide generation, a process initiated by recruitment of phosphatidylinositide 3-kinase regulatory subunit p85 to TNF-receptor-1. Because amide-linked local anesthetics have well-established anti-inflammatory effects, the authors hypothesized that ropivacaine and lidocaine attenuate inflammatory Src signaling by disrupting the phosphatidylinositide 3-kinase–Akt–nitric oxide pathway, thus blocking Src-dependent neutrophil adhesion and endothelial hyperpermeability. Methods Human lung microvascular endothelial cells, incubated with TNFα in the absence or presence of clinically relevant concentrations of ropivacaine and lidocaine, were analyzed by Western blot, probing for phosphorylated/activated Src, endothelial nitric oxide synthase, Akt, intercellular adhesion molecule-1, and caveolin-1. The effect of ropivacaine on TNFα-induced nitric oxide generation, co-immunoprecipitation of TNF-receptor-1 with p85, neutrophil adhesion, and endothelial barrier disruption were assessed. Results Ropivacaine and lidocaine attenuated TNFα-induced Src activation (half-maximal inhibitory concentration [IC50] = 8.611 × 10−10 M for ropivacaine; IC50 = 5.864 × 10−10 M for lidocaine) and endothelial nitric oxide synthase phosphorylation (IC50 = 7.572 × 10−10 M for ropivacaine; IC50 = 6.377 × 10−10 M for lidocaine). Akt activation (n = 7; P = 0.006) and stimulus-dependent binding of TNF-receptor-1 and p85 (n = 6; P = 0.043) were blocked by 1 nM of ropivacaine. TNFα-induced neutrophil adhesion and disruption of endothelial monolayers via Src-dependent intercellular adhesion molecule-1- and caveolin-1-phosphorylation, respectively, were also attenuated. Conclusions Ropivacaine and lidocaine effectively blocked inflammatory TNFα signaling in endothelial cells by attenuating p85 recruitment to TNF-receptor-1. The resultant decrease in Akt, endothelial nitric oxide synthase, and Src phosphorylation reduced neutrophil adhesion and endothelial hyperpermeability. This novel anti-inflammatory “side-effect” of ropivacaine and lidocaine may provide therapeutic benefit in acute inflammatory disease. PMID:24525631

Endothelial barrier protection by local anesthetics: ropivacaine and lidocaine block tumor necrosis factor-α-induced endothelial cell Src activation.

PubMed

Piegeler, Tobias; Votta-Velis, E Gina; Bakhshi, Farnaz R; Mao, Mao; Carnegie, Graeme; Bonini, Marcelo G; Schwartz, David E; Borgeat, Alain; Beck-Schimmer, Beatrice; Minshall, Richard D

2014-06-01

Pulmonary endothelial barrier dysfunction mediated in part by Src-kinase activation plays a crucial role in acute inflammatory disease. Proinflammatory cytokines, such as tumor necrosis factor-α (TNFα), activate Src via phosphatidylinositide 3-kinase/Akt-dependent nitric oxide generation, a process initiated by recruitment of phosphatidylinositide 3-kinase regulatory subunit p85 to TNF-receptor-1. Because amide-linked local anesthetics have well-established anti-inflammatory effects, the authors hypothesized that ropivacaine and lidocaine attenuate inflammatory Src signaling by disrupting the phosphatidylinositide 3-kinase-Akt-nitric oxide pathway, thus blocking Src-dependent neutrophil adhesion and endothelial hyperpermeability. Human lung microvascular endothelial cells, incubated with TNFα in the absence or presence of clinically relevant concentrations of ropivacaine and lidocaine, were analyzed by Western blot, probing for phosphorylated/activated Src, endothelial nitric oxide synthase, Akt, intercellular adhesion molecule-1, and caveolin-1. The effect of ropivacaine on TNFα-induced nitric oxide generation, co-immunoprecipitation of TNF-receptor-1 with p85, neutrophil adhesion, and endothelial barrier disruption were assessed. Ropivacaine and lidocaine attenuated TNFα-induced Src activation (half-maximal inhibitory concentration [IC50] = 8.611 × 10 M for ropivacaine; IC50 = 5.864 × 10 M for lidocaine) and endothelial nitric oxide synthase phosphorylation (IC50 = 7.572 × 10 M for ropivacaine; IC50 = 6.377 × 10 M for lidocaine). Akt activation (n = 7; P = 0.006) and stimulus-dependent binding of TNF-receptor-1 and p85 (n = 6; P = 0.043) were blocked by 1 nM of ropivacaine. TNFα-induced neutrophil adhesion and disruption of endothelial monolayers via Src-dependent intercellular adhesion molecule-1- and caveolin-1-phosphorylation, respectively, were also attenuated. Ropivacaine and lidocaine effectively blocked inflammatory TNFα signaling in endothelial cells by attenuating p85 recruitment to TNF-receptor-1. The resultant decrease in Akt, endothelial nitric oxide synthase, and Src phosphorylation reduced neutrophil adhesion and endothelial hyperpermeability. This novel anti-inflammatory "side-effect" of ropivacaine and lidocaine may provide therapeutic benefit in acute inflammatory disease.

Variant estrogen receptor-c-Src molecular interdependence and c-Src structural requirements for endothelial NO synthase activation.

PubMed

Li, Lei; Hisamoto, Koji; Kim, Kyung Hee; Haynes, M Page; Bauer, Philip M; Sanjay, Archana; Collinge, Mark; Baron, Roland; Sessa, William C; Bender, Jeffrey R

2007-10-16

Little is known about the tyrosine kinase c-Src's function in the systemic circulation, in particular its role in arterial responses to hormonal stimuli. In human aortic and venous endothelial cells, c-Src is indispensable for 17beta-estradiol (E2)-stimulated phosphatidylinositol 3-kinase/Akt/endothelial NO synthase (eNOS) pathway activation, a possible mechanism in E2-mediated vascular protection. Here we show that c-Src supports basal and E2-stimulated NO production and is required for E2-induced vasorelaxation in murine aortas. Only membrane c-Src is structurally and functionally involved in E2-induced eNOS activation. Independent of c-Src kinase activity, c-Src is associated with an N-terminally truncated estrogen receptor alpha variant (ER46) and eNOS in the plasma membrane through its "open" (substrate-accessible) conformation. In the presence of E2, c-Src kinase is activated by membrane ER46 and in turn phosphorylates ER46 for subsequent ER46 and c-Src membrane recruitment, the assembly of an eNOS-centered membrane macrocomplex, and membrane-initiated eNOS activation. Overall, these results provide insights into a critical role for the tyrosine kinase c-Src in estrogen-stimulated arterial responses, and in membrane-initiated rapid signal transduction, for which obligate complex assembly and localization require the c-Src substrate-accessible structure.

Inverse target- and cue-priming effects of masked stimuli.

PubMed

Mattler, Uwe

2007-02-01

The processing of a visual target that follows a briefly presented prime stimulus can be facilitated if prime and target stimuli are similar. In contrast to these positive priming effects, inverse priming effects (or negative compatibility effects) have been found when a mask follows prime stimuli before the target stimulus is presented: Responses are facilitated after dissimilar primes. Previous studies on inverse priming effects examined target-priming effects, which arise when the prime and the target stimuli share features that are critical for the response decision. In contrast, 3 experiments of the present study demonstrate inverse priming effects in a nonmotor cue-priming paradigm. Inverse cue-priming effects exhibited time courses comparable to inverse target-priming effects. Results suggest that inverse priming effects do not arise from specific processes of the response system but follow from operations that are more general.

Gene expression profiles analysis identifies key genes for acute lung injury in patients with sepsis.

PubMed

Guo, Zhiqiang; Zhao, Chuncheng; Wang, Zheng

2014-09-26

To identify critical genes and biological pathways in acute lung injury (ALI), a comparative analysis of gene expression profiles of patients with ALI + sepsis compared with patients with sepsis alone were performed with bioinformatic tools. GSE10474 was downloaded from Gene Expression Omnibus, including a collective of 13 whole blood samples with ALI + sepsis and 21 whole blood samples with sepsis alone. After pre-treatment with robust multichip averaging (RMA) method, differential analysis was conducted using simpleaffy package based upon t-test and fold change. Hierarchical clustering was also performed using function hclust from package stats. Beisides, functional enrichment analysis was conducted using iGepros. Moreover, the gene regulatory network was constructed with information from Kyoto Encyclopedia of Genes and Genomes (KEGG) and then visualized by Cytoscape. A total of 128 differentially expressed genes (DEGs) were identified, including 47 up- and 81 down-regulated genes. The significantly enriched functions included negative regulation of cell proliferation, regulation of response to stimulus and cellular component morphogenesis. A total of 27 DEGs were significantly enriched in 16 KEGG pathways, such as protein digestion and absorption, fatty acid metabolism, amoebiasis, etc. Furthermore, the regulatory network of these 27 DEGs was constructed, which involved several key genes, including protein tyrosine kinase 2 (PTK2), v-src avian sarcoma (SRC) and Caveolin 2 (CAV2). PTK2, SRC and CAV2 may be potential markers for diagnosis and treatment of ALI. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5865162912987143.

Exploring Modality Compatibility in the Response-Effect Compatibility Paradigm.

PubMed

Földes, Noémi; Philipp, Andrea M; Badets, Arnaud; Koch, Iring

2017-01-01

According to ideomotor theory , action planning is based on anticipatory perceptual representations of action-effects. This aspect of action control has been investigated in studies using the response-effect compatibility (REC) paradigm, in which responses have been shown to be facilitated if ensuing perceptual effects share codes with the response based on dimensional overlap (i.e., REC). Additionally, according to the notion of ideomotor compatibility, certain response-effect (R-E) mappings will be stronger than others because some response features resemble the anticipated sensory response effects more strongly than others (e.g., since vocal responses usually produce auditory effects, an auditory stimulus should be anticipated in a stronger manner following vocal responses rather than following manual responses). Yet, systematic research on this matter is lacking. In the present study, two REC experiments aimed to explore the influence of R-E modality mappings. In Experiment 1, vocal number word responses produced visual effects on the screen (digits vs. number words; i.e., visual-symbolic vs. visual-verbal effect codes). The REC effect was only marginally larger for visual-verbal than for visual-symbolic effects. Using verbal effect codes in Experiment 2, we found that the REC effect was larger with auditory-verbal R-E mapping than with visual-verbal R-E mapping. Overall, the findings support the hypothesis of a role of R-E modality mappings in REC effects, suggesting both further evidence for ideomotor accounts as well as code-specific and modality-specific contributions to effect anticipation.

Are Automatic Imitation and Spatial Compatibility Mediated by Different Processes?

ERIC Educational Resources Information Center

Cooper, Richard P.; Catmur, Caroline; Heyes, Cecilia

2013-01-01

Automatic imitation or "imitative compatibility" is thought to be mediated by the mirror neuron system and to be a laboratory model of the motor mimicry that occurs spontaneously in naturalistic social interaction. Imitative compatibility and spatial compatibility effects are known to depend on different stimulus dimensions--body…

Visual context modulates potentiation of grasp types during semantic object categorization

PubMed Central

Kalénine, Solène; Shapiro, Allison D.; Flumini, Andrea; Borghi, Anna M.; Buxbaum, Laurel J.

2013-01-01

Substantial evidence suggests that conceptual processing of manipulable objects is associated with potentiation of action. Such data have been viewed as evidence that objects are recognized via access to action features. Many objects, however, are associated with multiple actions. For example, a kitchen timer may be clenched with a power grip to move it, but pinched with a precision grip to use it. The present study tested the hypothesis that action evocation during conceptual object processing is responsive to the visual scene in which objects are presented. Twenty-five healthy adults were asked to categorize object pictures presented in different naturalistic visual contexts that evoke either move- or use-related actions. Categorization judgments (natural vs. artifact) were performed by executing a move- or use-related action (clench vs. pinch) on a response device, and response times were assessed as a function of contextual congruence. Although the actions performed were irrelevant to the categorization judgment, responses were significantly faster when actions were compatible with the visual context. This compatibility effect was largely driven by faster pinch responses when objects were presented in use- compared to move-compatible contexts. The present study is the first to highlight the influence of visual scene on stimulus-response compatibility effects during semantic object processing. These data support the hypothesis that action evocation during conceptual object processing is biased toward context-relevant actions. PMID:24186270

Accuracy of Monte Carlo photon transport simulation in characterizing brachytherapy dosimeter energy-response artefacts

NASA Astrophysics Data System (ADS)

Das, R. K.; Li, Z.; Perera, H.; Williamson, J. F.

1996-06-01

Practical dosimeters in brachytherapy, such as thermoluminescent dosimeters (TLD) and diodes, are usually calibrated against low-energy megavoltage beams. To measure absolute dose rate near a brachytherapy source, it is necessary to establish the energy response of the detector relative to that of the calibration energy. The purpose of this paper is to assess the accuracy of Monte Carlo photon transport (MCPT) simulation in modelling the absolute detector response as a function of detector geometry and photon energy. We have exposed two different sizes of TLD-100 (LiF chips) and p-type silicon diode detectors to calibrated , HDR source and superficial x-ray beams. For the Scanditronix electron-field diode, the relative detector response, defined as the measured detector readings per measured unit of air kerma, varied from (40 kVp beam) to ( beam). Similarly for the large and small chips the same quantity varied from and , respectively. Monte Carlo simulation was used to calculate the absorbed dose to the active volume of the detector per unit air kerma. If the Monte Carlo simulation is accurate, then the absolute detector response, which is defined as the measured detector reading per unit dose absorbed by the active detector volume, and is calculated by Monte Carlo simulation, should be a constant. For the diode, the absolute response is . For TLDs of size the absolute response is and for TLDs of it is . From the above results we can conclude that the absolute response function of detectors (TLDs and diodes) is directly proportional to absorbed dose by the active volume of the detector and is independent of beam quality.

Three conceptual units for behavior

PubMed Central

Moxley, Roy

1987-01-01

Three generic units for behavior are examined in terms of their background: an if-then unit for stimulus and response (S-R), a holistic unit for Kantor's behavior segment, and an AB-because-of-C unit for Skinner's three-term contingency. The units are distinguished in terms of their respective historical backgrounds, causal modes, advantages, and disadvantages. The ways in which these units may be compatible are discussed. PMID:22477957

Mapping the Identity of a Viewed Hand in the Motor System: Evidence from Stimulus-Response Compatibility

ERIC Educational Resources Information Center

Vainio, Lari; Mustonen, Terhi

2011-01-01

Brain-imaging research has shown that a viewed acting hand is mapped to the observer's hand representation that corresponds with the identity of the hand. In contrast, behavioral research has suggested that rather than representing a seen hand in relation to one's own manual system, it is represented in relation to the midline of an imaginary…

Age-related slowing of response selection and production in a visual choice reaction time task

PubMed Central

Woods, David L.; Wyma, John M.; Yund, E. William; Herron, Timothy J.; Reed, Bruce

2015-01-01

Aging is associated with delayed processing in choice reaction time (CRT) tasks, but the processing stages most impacted by aging have not been clearly identified. Here, we analyzed CRT latencies in a computerized serial visual feature-conjunction task. Participants responded to a target letter (probability 40%) by pressing one mouse button, and responded to distractor letters differing either in color, shape, or both features from the target (probabilities 20% each) by pressing the other mouse button. Stimuli were presented randomly to the left and right visual fields and stimulus onset asynchronies (SOAs) were adaptively reduced following correct responses using a staircase procedure. In Experiment 1, we tested 1466 participants who ranged in age from 18 to 65 years. CRT latencies increased significantly with age (r = 0.47, 2.80 ms/year). Central processing time (CPT), isolated by subtracting simple reaction times (SRT) (obtained in a companion experiment performed on the same day) from CRT latencies, accounted for more than 80% of age-related CRT slowing, with most of the remaining increase in latency due to slowed motor responses. Participants were faster and more accurate when the stimulus location was spatially compatible with the mouse button used for responding, and this effect increased slightly with age. Participants took longer to respond to distractors with target color or shape than to distractors with no target features. However, the additional time needed to discriminate the more target-like distractors did not increase with age. In Experiment 2, we replicated the findings of Experiment 1 in a second population of 178 participants (ages 18–82 years). CRT latencies did not differ significantly in the two experiments, and similar effects of age, distractor similarity, and stimulus-response spatial compatibility were found. The results suggest that the age-related slowing in visual CRT latencies is largely due to delays in response selection and production. PMID:25954175

Testing sensory evidence against mnemonic templates

PubMed Central

Myers, Nicholas E; Rohenkohl, Gustavo; Wyart, Valentin; Woolrich, Mark W; Nobre, Anna C; Stokes, Mark G

2015-01-01

Most perceptual decisions require comparisons between current input and an internal template. Classic studies propose that templates are encoded in sustained activity of sensory neurons. However, stimulus encoding is itself dynamic, tracing a complex trajectory through activity space. Which part of this trajectory is pre-activated to reflect the template? Here we recorded magneto- and electroencephalography during a visual target-detection task, and used pattern analyses to decode template, stimulus, and decision-variable representation. Our findings ran counter to the dominant model of sustained pre-activation. Instead, template information emerged transiently around stimulus onset and quickly subsided. Cross-generalization between stimulus and template coding, indicating a shared neural representation, occurred only briefly. Our results are compatible with the proposal that template representation relies on a matched filter, transforming input into task-appropriate output. This proposal was consistent with a signed difference response at the perceptual decision stage, which can be explained by a simple neural model. DOI: http://dx.doi.org/10.7554/eLife.09000.001 PMID:26653854

Src is required for migration, phagocytosis, and interferon beta production in Toll-like receptor-engaged macrophages.

PubMed

Maa, Ming-Chei; Leu, Tzeng-Horng

2016-06-01

As an evolutionarily conserved mechanism, innate immunity controls self-nonself discrimination to protect a host from invasive pathogens. Macrophages are major participants of the innate immune system. Through the activation of diverse Toll-like receptors (TLRs), macrophages are triggered to initiate a variety of functions including locomotion, phagocytosis, and secretion of cytokines that requires the participation of tyrosine kinases. Fgr, Hck, and Lyn are myeloid-specific Src family kinases. Despite their constitutively high expression in macrophages, their absence does not impair LPS responsiveness. In contrast, Src, a barely detectable tyrosine kinase in resting macrophages, becomes greatly inducible in response to TLR engagement, implicating its role in macrophage activation. Indeed, silencing Src suppresses the activated TLR-mediated migration, phagocytosis, and interferon-beta (IFN-β) secretion in macrophages. And these physiological defects can be restored by the introduction of siRNA-resistant Src. Notably, the elevated expression and activity of Src is inducible nitric oxide synthase (iNOS)-dependent. Due to (1) iNOS being a NF-κB target, which can be induced by various TLR ligands, (2) Src can mediate NF-κB activation, therefore, there ought to exist a loop of signal amplification that regulates macrophage physiology in response to the engagement of TLRs.

v-src induction of the TIS10/PGS2 prostaglandin synthase gene is mediated by an ATF/CRE transcription response element.

PubMed

Xie, W; Fletcher, B S; Andersen, R D; Herschman, H R

1994-10-01

We recently reported the cloning of a mitogen-inducible prostaglandin synthase gene, TIS10/PGS2. In addition to growth factors and tumor promoters, the v-src oncogene induces TIS10/PGS2 expression in 3T3 cells. Deletion analysis, using luciferase reporters, identifies a region between -80 and -40 nucleotides 5' of the TIS10/PGS2 transcription start site that mediates pp60v-src induction in 3T3 cells. This region contains the sequence CGTCACGTG, which includes overlapping ATF/CRE (CGTCA) and E-box (CACGTG) sequences. Gel shift-oligonucleotide competition experiments with nuclear extracts from cells stably transfected with a temperature-sensitive v-src gene demonstrate that the CGTCACGTG sequence can bind proteins at both the ATF/CRE and E-box sequences. Dominant-negative CREB and Myc proteins that bind DNA, but do not transactivate, block v-src induction of a luciferase reporter driven by the first 80 nucleotides of the TIS10/PGS2 promoter. Mutational analysis distinguishes which TIS10/PGS2 cis-acting element mediates pp60v-src induction. E-box mutation has no effect on the fold induction in response to pp60v-src. In contrast, ATF/CRE mutation attenuates the pp60v-src response. Antibody supershift and methylation interference experiments demonstrate that CREB and at least one other ATF transcription factor in these extracts bind to the TIS10/PGS2 ATF/CRE element. Expression of a dominant-negative ras gene also blocks TIS10/PGS2 induction by v-src. Our data suggest that Ras mediates pp60v-src activation of an ATF transcription factor, leading to induced TIS10/PGS2 expression via the ATF/CRE element of the TIS10/PGS2 promoter. This is the first description of v-src activation of gene expression via an ATF/CRE element.

Cigarette Smoke Activates the Proto-Oncogene c-Src to Promote Airway Inflammation and Lung Tissue Destruction

PubMed Central

Geraghty, Patrick; Hardigan, Andrew

2014-01-01

The diagnosis of chronic obstructive pulmonary disease (COPD) confers a 2-fold increased lung cancer risk even after adjusting for cigarette smoking, suggesting that common pathways are operative in both diseases. Although the role of the tyrosine kinase c-Src is established in lung cancer, less is known about its impact in other lung diseases, such as COPD. This study examined whether c-Src activation by cigarette smoke contributes to the pathogenesis of COPD. Cigarette smoke increased c-Src activity in human small airway epithelial (SAE) cells from healthy donors and in the lungs of exposed mice. Similarly, higher c-Src activation was measured in SAE cells from patients with COPD compared with healthy control subjects. In SAE cells, c-Src silencing or chemical inhibition prevented epidermal growth factor (EGF) receptor signaling in response to cigarette smoke but not EGF stimulation. Further studies showed that cigarette smoke acted through protein kinase C α to trigger c-Src to phosphorylate EGF receptor and thereby to induce mitogen-activated protein kinase responses in these cells. To further investigate the role of c-Src, A/J mice were orally administered the specific Src inhibitor AZD-0530 while they were exposed to cigarette smoke for 2 months. AZD-0530 treatment blocked c-Src activation, decreased macrophage influx, and prevented airspace enlargement in the lungs of cigarette smoke–exposed mice. Moreover, inhibiting Src deterred the cigarette smoke–mediated induction of matrix metalloproteinase-9 and -12 in alveolar macrophages and lung expression of cathepsin K, IL-17, TNF-α, MCP-1, and KC, all key factors in the pathogenesis of COPD. These results indicate that activation of the proto-oncogene c-Src by cigarette smoke promotes processes linked to the development of COPD. PMID:24111605

Brain-robot interface driven plasticity: Distributed modulation of corticospinal excitability.

PubMed

Kraus, Dominic; Naros, Georgios; Bauer, Robert; Leão, Maria Teresa; Ziemann, Ulf; Gharabaghi, Alireza

2016-01-15

Brain-robot interfaces (BRI) are studied as novel interventions to facilitate functional restoration in patients with severe and persistent motor deficits following stroke. They bridge the impaired connection in the sensorimotor loop by providing brain-state dependent proprioceptive feedback with orthotic devices attached to the hand or arm of the patients. The underlying neurophysiology of this BRI neuromodulation is still largely unknown. We investigated changes of corticospinal excitability with transcranial magnetic stimulation in thirteen right-handed healthy subjects who performed 40min of kinesthetic motor imagery receiving proprioceptive feedback with a robotic orthosis attached to the left hand contingent to event-related desynchronization of the right sensorimotor cortex in the β-band (16-22Hz). Neural correlates of this BRI intervention were probed by acquiring the stimulus-response curve (SRC) of both motor evoked potential (MEP) peak-to-peak amplitudes and areas under the curve. In addition, a motor mapping was obtained. The specificity of the effects was studied by comparing two neighboring hand muscles, one BRI-trained and one control muscle. Robust changes of MEP amplitude but not MEP area occurred following the BRI intervention, but only in the BRI-trained muscle. The steep part of the SRC showed an MEP increase, while the plateau of the SRC showed an MEP decrease. MEP mapping revealed a distributed pattern with a decrease of excitability in the hand area of the primary motor cortex, which controlled the BRI, but an increase of excitability in the surrounding somatosensory and premotor cortex. In conclusion, the BRI intervention induced a complex pattern of modulated corticospinal excitability, which may boost subsequent motor learning during physiotherapy. Copyright © 2015 Elsevier Inc. All rights reserved.

Novel Bioluminescent Activatable Reporter for Src Tyrosine Kinase Activity in Living Mice

PubMed Central

Leng, Weibing; Li, Dezhi; Chen, Liang; Xia, Hongwei; Tang, Qiulin; Chen, Baoqin; Gong, Qiyong; Gao, Fabao; Bi, Feng

2016-01-01

Aberrant activation of the Src kinase is implicated in the development of a variety of human malignancies. However, it is almost impossible to monitor Src activity in an in vivo setting with current biochemical techniques. To facilitate the noninvasive investigation of the activity of Src kinase both in vitro and in vivo, we developed a genetically engineered, activatable bioluminescent reporter using split-luciferase complementation. The bioluminescence of this reporter can be used as a surrogate for Src activity in real time. This hybrid luciferase reporter was constructed by sandwiching a Src-dependent conformationally responsive unit (SH2 domain-Srcpep) between the split luciferase fragments. The complementation bioluminescence of this reporter was dependent on the Src activity status. In our study, Src kinase activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to clinical small-molecular kinase inhibitors, dasatinib and saracatinib. This system was also applied for high-throughput screening of Src inhibitors against a kinase inhibitor library in living cells. These results provide unique insights into drug development and pharmacokinetics/phoarmocodynamics of therapeutic drugs targeting Src signaling pathway enabling the optimization of drug administration schedules for maximum benefit. Using both Firefly and Renilla luciferase imaging, we have successfully monitored Src tyrosine kinase activity and Akt serine/threonine kinase activity concurrently in one tumor xenograft. This dual luciferase reporter imaging system will be helpful in exploring the complex signaling networks in vivo. The strategies reported here can also be extended to study and image other important kinases and the cross-talks among them. PMID:26941850

Best not to bet on the horserace: A comment on Forrin and MacLeod (2017) and a relevant stimulus-response compatibility view of colour-word contingency learning asymmetries.

PubMed

Schmidt, James R

2018-02-01

One powerfully robust method for the study of human contingency learning is the colour-word contingency learning paradigm. In this task, participants respond to the print colour of neutral words, each of which is presented most often in one colour. The contingencies between words and colours are learned, as indicated by faster and more accurate responses when words are presented in their expected colour relative to an unexpected colour. In a recent report, Forrin and MacLeod (2017b, Memory & Cognition) asked to what extent this performance (i.e., response time) measure of learning might depend on the relative speed of processing of the word and the colour. With keypress responses, learning effects were comparable when responding to the word and to the colour (contrary to predictions). However, an asymmetry appeared in a second experiment with vocal responses, with a contingency effect only present for colour identification. In a third experiment, the colour was preexposed, and contingency effects were again roughly symmetrical. In their report, they suggested that a simple speed-of-processing (or "horserace") model might explain when contingency effects are observed in colour and word identification. In the present report, an alternative view is presented. In particular, it is argued that the results are best explained by appealing to the notion of relevant stimulus-response compatibility, which also resolves discrepancies between horserace model predictions and participant results. The article presents simulations with the Parallel Episodic Processing model to demonstrate this case.

Modulation-Frequency-Specific Adaptation in Awake Auditory Cortex

PubMed Central

Beitel, Ralph E.; Vollmer, Maike; Heiser, Marc A.; Schreiner, Christoph E.

2015-01-01

Amplitude modulations are fundamental features of natural signals, including human speech and nonhuman primate vocalizations. Because natural signals frequently occur in the context of other competing signals, we used a forward-masking paradigm to investigate how the modulation context of a prior signal affects cortical responses to subsequent modulated sounds. Psychophysical “modulation masking,” in which the presentation of a modulated “masker” signal elevates the threshold for detecting the modulation of a subsequent stimulus, has been interpreted as evidence of a central modulation filterbank and modeled accordingly. Whether cortical modulation tuning is compatible with such models remains unknown. By recording responses to pairs of sinusoidally amplitude modulated (SAM) tones in the auditory cortex of awake squirrel monkeys, we show that the prior presentation of the SAM masker elicited persistent and tuned suppression of the firing rate to subsequent SAM signals. Population averages of these effects are compatible with adaptation in broadly tuned modulation channels. In contrast, modulation context had little effect on the synchrony of the cortical representation of the second SAM stimuli and the tuning of such effects did not match that observed for firing rate. Our results suggest that, although the temporal representation of modulated signals is more robust to changes in stimulus context than representations based on average firing rate, this representation is not fully exploited and psychophysical modulation masking more closely mirrors physiological rate suppression and that rate tuning for a given stimulus feature in a given neuron's signal pathway appears sufficient to engender context-sensitive cortical adaptation. PMID:25878263

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer.

PubMed

Bauman, Julie E; Duvvuri, Umamaheswar; Gooding, William E; Rath, Tanya J; Gross, Neil D; Song, John; Jimeno, Antonio; Yarbrough, Wendell G; Johnson, Faye M; Wang, Lin; Chiosea, Simion; Sen, Malabika; Kass, Jason; Johnson, Jonas T; Ferris, Robert L; Kim, Seungwon; Hirsch, Fred R; Ellison, Kimberly; Flaherty, John T; Mills, Gordon B; Grandis, Jennifer R

2017-03-23

BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms ( P = 0.0014); however, no effect was seen with dasatinib alone ( P = 0.24). High baseline pMAPK expression was associated with response to erlotinib ( P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib ( P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

PubMed Central

Bauman, Julie E.; Duvvuri, Umamaheswar; Gooding, William E.; Rath, Tanya J.; Gross, Neil D.; Song, John; Jimeno, Antonio; Yarbrough, Wendell G.; Johnson, Faye M.; Wang, Lin; Chiosea, Simion; Sen, Malabika; Kass, Jason; Johnson, Jonas T.; Ferris, Robert L.; Kim, Seungwon; Hirsch, Fred R.; Ellison, Kimberly; Flaherty, John T.; Mills, Gordon B.

2017-01-01

BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II–IVa HNSCC were randomized to 7–21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma. PMID:28352657

Role of src-family kinases in hypoxic vasoconstriction of rat pulmonary artery

PubMed Central

Knock, Greg A.; Snetkov, Vladimir A.; Shaifta, Yasin; Drndarski, Svetlana; Ward, Jeremy P.T.; Aaronson, Philip I.

2008-01-01

Aims We investigated the role of src-family kinases (srcFKs) in hypoxic pulmonary vasoconstriction (HPV) and how this relates to Rho-kinase-mediated Ca2+ sensitization and changes in intracellular Ca2+ concentration ([Ca2+]i). Methods and results Intra-pulmonary arteries (IPAs) were obtained from male Wistar rats. HPV was induced in myograph-mounted IPAs. Auto-phosphorylation of srcFKs and phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and myosin light-chain (MLC20) in response to hypoxia were determined by western blotting. Translocation of Rho-kinase and effects of siRNA knockdown of src and fyn were examined in cultured pulmonary artery smooth muscle cells (PASMCs). [Ca2+]i was estimated in Fura-PE3-loaded IPA. HPV was inhibited by two blockers of srcFKs, SU6656 and PP2. Hypoxia enhanced phosphorylation of three srcFK proteins at Tyr-416 (60, 59, and 54 kDa, corresponding to src, fyn, and yes, respectively) and enhanced srcFK-dependent tyrosine phosphorylation of multiple target proteins. Hypoxia caused a complex, time-dependent enhancement of MYPT-1 and MLC20 phosphorylation, both in the absence and presence of pre-constriction. The sustained component of this enhancement was blocked by SU6656 and the Rho-kinase inhibitor Y27632. In PASMCs, hypoxia caused translocation of Rho-kinase from the nucleus to the cytoplasm, and this was prevented by anti-src siRNA and to a lesser extent by anti-fyn siRNA. The biphasic increases in [Ca2+]i that accompany HPV were also inhibited by PP2. Conclusion Hypoxia activates srcFKs and triggers protein tyrosine phosphorylation in IPA. Hypoxia-mediated Rho-kinase activation, Ca2+ sensitization, and [Ca2+]i responses are depressed by srcFK inhibitors and/or siRNA knockdown, suggesting a central role of srcFKs in HPV. PMID:18682436

NEPRILYSIN REGULATES PULMONARY ARTERY SMOOTH MUSCLE CELL PHENOTYPE THROUGH A PDGF RECEPTOR DEPENDENT MECHANISM

PubMed Central

Karoor, Vijaya; Oka, Masahiko; Walchak, Sandra J.; Hersh, Louis B.; Miller, York E.; Dempsey, Edward C.

2013-01-01

Reduced neprilysin (NEP), a cell surface metallopeptidase, which cleaves and inactivates pro-inflammatory and vasoactive peptides, predisposes the lung vasculature to exaggerated remodeling in response to hypoxia. We hypothesize that loss of NEP in pulmonary artery smooth muscle cells (PASMCs) results in increased migration and proliferation. PASMCs isolated from NEP−/− mice exhibited enhanced migration and proliferation in response to serum and PDGF, which was attenuated by NEP replacement. Inhibition of NEP by overexpression of a peptidase dead mutant or knockdown by siRNA in NEP+/+ cells increased migration and proliferation. Loss of NEP led to an increase in Src kinase activity and phosphorylation of PTEN resulting in activation of the PDGF receptor (PDGFR). Knockdown of Src kinase with siRNA or inhibition with PP2 a src kinase inhibitor decreased PDGFRY751 phosphorylation and attenuated migration and proliferation in NEP−/− SMCs. NEP substrates, endothelin-1(ET-1) or fibroblast growth factor-2 (FGF2), increased activation of Src and PDGFR in NEP+/+ cells, which was decreased by an ETAR antagonist, neutralizing antibody to FGF2 and Src inhibitor. Similar to the observations in PASMCs levels of p-PDGFR, p-Src and p-PTEN were elevated in NEP−/− lungs. ETAR antagonist also attenuated the enhanced responses in NEP−/−PASMCs and lungs. Taken together our results suggest a novel mechanism for regulation of PDGFR signaling by NEP substrates involving Src and PTEN. Strategies that increase lung NEP activity/expression or target key downstream effectors, like Src, PTEN or PDGFR, may be of therapeutic benefit in pulmonary vascular disease. PMID:23381789

On Why Targets Evoke P3 Components in Prediction Tasks: Drawing an Analogy between Prediction and Matching Tasks

PubMed Central

Verleger, Rolf; Cäsar, Stephanie; Siller, Bastian; Śmigasiewicz, Kamila

2017-01-01

P3 is the most conspicuous component in recordings of stimulus-evoked EEG potentials from the human scalp, occurring whenever some task has to be performed with the stimuli. The process underlying P3 has been assumed to be the updating of expectancies. More recently, P3 has been related to decision processing and to activation of established stimulus-response associations (S/R-link hypothesis). However, so far this latter approach has not provided a conception about how to explain the occurrence of P3 with predicted stimuli, although P3 was originally discovered in a prediction task. The present article proposes such a conception. We assume that the internal responses right or wrong both become associatively linked to each predicted target and that one of these two response alternatives gets activated as a function of match or mismatch of the target to the preceding prediction. This seems similar to comparison tasks where responses depend on the matching of the target stimulus with a preceding first stimulus (S1). Based on this idea, this study compared the effects of frequencies of first events (predictions or S1) on target-evoked P3s in prediction and comparison tasks. Indeed, frequencies not only of targets but also of first events had similar effects across tasks on target-evoked P3s. These results support the notion that P3 evoked by predicted stimuli reflects activation of appropriate internal “match” or “mismatch” responses, which is compatible with S/R-link hypothesis. PMID:29066965

CHARACTERIZATION of SEX-BASED DIFFERENCES IN THE MECHANICAL PROPERTIES OF HUMAN FINGER GLABROUS TISSUE USING A FIBEROPTIC SENSOR

PubMed Central

Venkatesan, Lalit; Barlow, Steven M.

2014-01-01

TAC-Cell is a custom-built somatosensory stimulator that delivers pneumatic cutaneous tactile inputs to virtually any skin target on the body and by virtue of its non-ferrous materials is compatible with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) brain scanners. In this study, we describe the method to measure apparent skin displacement induced by TAC-Cell stimulation of the glabrous surface of the distal phalanx of the index finger. Specifically, we studied the effect of four servo controller input voltages (0.4V to 1.0V) on resultant skin displacement among eighteen, neurotypical adult male and female participants. A fiberoptic displacement sensor, commonly used in industrial applications, was coupled to the TAC-Cell to measure the glabrous skin’s kinematic response to different stimulus amplitudes. Skin displacement was significantly dependent on stimulus amplitudes and sex (p< 0.0001). Power spectrum and kinematic analysis of skin displacement showed that the pneumatic TAC-Cell stimulus consists of a spectrally rich, high velocity signal. In related work, we have shown that this dynamic pneumocutaneous stimulus is highly effective in evoking a cortical brain response for neurodiagnostic applications and somatosensory pathway analysis in health and disease. PMID:24856834

Characterization of sex-based differences in the mechanical properties of human finger glabrous tissue using a fiberoptic sensor.

PubMed

Venkatesan, Lalit; Barlow, Steven M

2014-07-18

TAC-Cell is a custom-built somatosensory stimulator that delivers pneumatic cutaneous tactile inputs to virtually any skin target on the body and by virtue of its non-ferrous materials is compatible with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) brain scanners. In this study, we describe the method to measure apparent skin displacement induced by TAC-Cell stimulation of the glabrous surface of the distal phalanx of the index finger. Specifically, we studied the effect of four servo controller input voltages (0.4V-1.0 V) on resultant skin displacement among eighteen, neurotypical adult male and female participants. A fiberoptic displacement sensor, commonly used in industrial applications, was coupled to the TAC-Cell to measure the glabrous skin׳s kinematic response to different stimulus amplitudes. Skin displacement was significantly dependent on stimulus amplitudes and sex (p<0.0001). Power spectrum and kinematic analysis of skin displacement showed that the pneumatic TAC-Cell stimulus consists of a spectrally rich, high velocity signal. In related work, we have shown that this dynamic pneumocutaneous stimulus is highly effective in evoking a cortical brain response for neurodiagnostic applications and somatosensory pathway analysis in health and disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

Brief flight to a familiar enclosure in response to a conditional stimulus in rats.

PubMed

de Oca, Beatrice M; Minor, Thomas R; Fanselow, Michael S

2007-04-01

The authors observed brief, directed movement to a familiar enclosure in rats to determine whether this behavior is part of a rat's defensive repertoire when exposed to a conditional-fear stimulus. In Experiment 1, upon exposure to the compound conditional-fear stimulus of tone and light, only rats that received paired presentations of the conditional stimuli and shock fled into a small, familiar enclosure where they then froze. Rats that had received unpaired presentations did not enter the enclosure in significant amounts when later tested. In Experiment 2, the authors observed rats' freezing and use of either a familiar or an unfamiliar enclosure when tested with a conditional-fear stimulus. Rats tested with a familiar enclosure entered it more quickly than did rats without prior exposure to the enclosure. Freezing was greatest when both training and testing environments were similar with respect to access to the enclosure. The results of these 2 experiments support the idea that brief, directed flight in rats is a component of the postencounter stage of predatory imminence (M. S. Fanselow & L. S. Lester, 1988) and is compatible with freezing.

Molecular signaling in live cells studied by FRET

NASA Astrophysics Data System (ADS)

Chien, Shu; Wang, Yingxiao

2011-11-01

Genetically encoded biosensors based on fluorescence resonance energy transfer (FRET) enables visualization of signaling events in live cells with high spatiotemporal resolution. We have used FRET to assess temporal and spatial characteristics for signaling molecules, including tyrosine kinases Src and FAK, small GTPase Rac, calcium, and a membrane-bound matrix metalloproteinase MT1-MMP. Activations of Src and Rac by platelet derived growth factor (PDGF) led to distinct subcellular patterns during cell migration on micropatterned surface, and these two enzymes interact with each other to form a feedback loop with differential regulations at different subcellular locations. We have developed FRET biosensors to monitor FAK activities at rafts vs. non-raft regions of plasma membrane in live cells. In response to cell adhesion on matrix proteins or stimulation by PDGF, the raft-targeting FAK biosensor showed a stronger FRET response than that at non-rafts. The FAK activation at rafts induced by PDGF is mediated by Src. In contrast, the FAK activation at rafts induced by adhesion is independent of Src activity, but rather is essential for Src activation. Thus, Src is upstream to FAK in response to chemical stimulation (PDGF), but FAK is upstream to Src in response to mechanical stimulation (adhesion). A novel biosensor has been developed to dynamically visualize the activity of membrane type-1-matrix metalloproteinase (MT1-MMP), which proteolytically remodels the extracellular matrix. Epidermal growth factor (EGF) directed active MT1-MMP to the leading edge of migrating live cancer cells with local accumulation of EGF receptor via a process dependent on an intact cytoskeletal network. In summary, FRET-based biosensors enable the elucidation of molecular processes and hierarchies underlying spatiotemporal regulation of biological and pathological processes, thus advancing our knowledge on how cells perceive mechanical/chemical cues in space and time to coordinate molecular/cellular functions.

Molecular signaling in live cells studied by FRET

NASA Astrophysics Data System (ADS)

Chien, Shu; Wang, Yingxiao

2012-03-01

Genetically encoded biosensors based on fluorescence resonance energy transfer (FRET) enables visualization of signaling events in live cells with high spatiotemporal resolution. We have used FRET to assess temporal and spatial characteristics for signaling molecules, including tyrosine kinases Src and FAK, small GTPase Rac, calcium, and a membrane-bound matrix metalloproteinase MT1-MMP. Activations of Src and Rac by platelet derived growth factor (PDGF) led to distinct subcellular patterns during cell migration on micropatterned surface, and these two enzymes interact with each other to form a feedback loop with differential regulations at different subcellular locations. We have developed FRET biosensors to monitor FAK activities at rafts vs. non-raft regions of plasma membrane in live cells. In response to cell adhesion on matrix proteins or stimulation by PDGF, the raft-targeting FAK biosensor showed a stronger FRET response than that at non-rafts. The FAK activation at rafts induced by PDGF is mediated by Src. In contrast, the FAK activation at rafts induced by adhesion is independent of Src activity, but rather is essential for Src activation. Thus, Src is upstream to FAK in response to chemical stimulation (PDGF), but FAK is upstream to Src in response to mechanical stimulation (adhesion). A novel biosensor has been developed to dynamically visualize the activity of membrane type-1-matrix metalloproteinase (MT1-MMP), which proteolytically remodels the extracellular matrix. Epidermal growth factor (EGF) directed active MT1-MMP to the leading edge of migrating live cancer cells with local accumulation of EGF receptor via a process dependent on an intact cytoskeletal network. In summary, FRET-based biosensors enable the elucidation of molecular processes and hierarchies underlying spatiotemporal regulation of biological and pathological processes, thus advancing our knowledge on how cells perceive mechanical/chemical cues in space and time to coordinate molecular/cellular functions.

Plan for radionuclide tracer studies of the residence time distribution in the Wilsonville dissolver and preheater

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jolley, R.L.; Begovich, J.M.; Brashear, H.R.

1983-12-01

Stimulus-response measurements using radiotracers to measure residence time distribution (RTD) and hydrodynamic parameters for the preheaters and dissolvers at the Ft. Lewis Solvent Refined Coal (SRC) and the Exxon Donor Solvent (EDS) coal conversion pilot plants are reviewed. A plan is also presented for a series of radioactive tracer studies proposed for the Advanced Coal Liquefaction Facility at Wilsonville, Alabama, to measure the RTD for the preheater and dissolvers in the SRC-I mode. The tracer for the gas phase will be /sup 133/Xe, and /sup 198/Au (on carbonized resin or as an aqueous colloidal suspension) will be used as themore » slurry tracer. Four experimental phases are recommended for the RTD tracer studies: (1) preheater; (2) dissolver with 100% takeoff; (3) dissolver with 100% takeoff and solids withdrawal; and (4) dissolver with 50% takeoff. Eighteen gas-tracer and 22 liquid-tracer injections are projected to accomplish the four experimental phases. Two to four tracer injections are projected for preliminary tests to ensure the capability of safe injection of the radiotracers and the collection of statistically significant data. A complete projected cost and time schedule is provided, including procurement of necessary components, preparation of the radiotracers, assembly and testing of tracer injection apparatus and detection systems, onsite work and tracer injections, laboratory experimentation, data analysis, and report writing.« less

Nanometer Scale Titanium Surface Texturing Are Detected by Signaling Pathways Involving Transient FAK and Src Activations

PubMed Central

Zambuzzi, Willian F.; Bonfante, Estevam A.; Jimbo, Ryo; Hayashi, Mariko; Andersson, Martin; Alves, Gutemberg; Takamori, Esther R.; Beltrão, Paulo J.; Coelho, Paulo G.; Granjeiro, José M.

2014-01-01

Background It is known that physico/chemical alterations on biomaterial surfaces have the capability to modulate cellular behavior, affecting early tissue repair. Such surface modifications are aimed to improve early healing response and, clinically, offer the possibility to shorten the time from implant placement to functional loading. Since FAK and Src are intracellular proteins able to predict the quality of osteoblast adhesion, this study evaluated the osteoblast behavior in response to nanometer scale titanium surface texturing by monitoring FAK and Src phosphorylations. Methodology Four engineered titanium surfaces were used for the study: machined (M), dual acid-etched (DAA), resorbable media microblasted and acid-etched (MBAA), and acid-etch microblasted (AAMB). Surfaces were characterized by scanning electron microscopy, interferometry, atomic force microscopy, x-ray photoelectron spectroscopy and energy dispersive X-ray spectroscopy. Thereafter, those 4 samples were used to evaluate their cytotoxicity and interference on FAK and Src phosphorylations. Both Src and FAK were investigated by using specific antibody against specific phosphorylation sites. Principal Findings The results showed that both FAK and Src activations were differently modulated as a function of titanium surfaces physico/chemical configuration and protein adsorption. Conclusions It can be suggested that signaling pathways involving both FAK and Src could provide biomarkers to predict osteoblast adhesion onto different surfaces. PMID:24999733

A Protein Scaffold Coordinates SRC-Mediated JNK Activation in Response to Metabolic Stress.

PubMed

Kant, Shashi; Standen, Claire L; Morel, Caroline; Jung, Dae Young; Kim, Jason K; Swat, Wojciech; Flavell, Richard A; Davis, Roger J

2017-09-19

Obesity is a major risk factor for the development of metabolic syndrome and type 2 diabetes. How obesity contributes to metabolic syndrome is unclear. Free fatty acid (FFA) activation of a non-receptor tyrosine kinase (SRC)-dependent cJun NH 2 -terminal kinase (JNK) signaling pathway is implicated in this process. However, the mechanism that mediates SRC-dependent JNK activation is unclear. Here, we identify a role for the scaffold protein JIP1 in SRC-dependent JNK activation. SRC phosphorylation of JIP1 creates phosphotyrosine interaction motifs that bind the SH2 domains of SRC and the guanine nucleotide exchange factor VAV. These interactions are required for SRC-induced activation of VAV and the subsequent engagement of a JIP1-tethered JNK signaling module. The JIP1 scaffold protein, therefore, plays a dual role in FFA signaling by coordinating upstream SRC functions together with downstream effector signaling by the JNK pathway. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

p68 Sam is a substrate of the insulin receptor and associates with the SH2 domains of p85 PI3K.

PubMed

Sánchez-Margalet, V; Najib, S

1999-07-23

The 68 kDa Src substrate associated during mitosis is an RNA binding protein with Src homology 2 and 3 domain binding sites. A role for Src associated in mitosis 68 as an adaptor protein in signaling transduction has been proposed in different systems such as T-cell receptors. In the present work, we have sought to assess the possible role of Src associated in mitosis 68 in insulin receptor signaling. We performed in vivo studies in HTC-IR cells and in vitro studies using recombinant Src associated in mitosis 68, purified insulin receptor and fusion proteins containing either the N-terminal or the C-terminal Src homology 2 domain of p85 phosphatidylinositol-3-kinase. We have found that Src associated in mitosis 68 is a substrate of the insulin receptor both in vivo and in vitro. Moreover, tyrosine-phosphorylated Src associated in mitosis 68 was found to associate with p85 phosphatidylinositol-3-kinase in response to insulin, as assessed by co-immunoprecipitation studies. Therefore, Src associated in mitosis 68 may be part of the signaling complexes of insulin receptor along with p85. In vitro studies demonstrate that Src associated in mitosis 68 associates with the Src homology 2 domains of p85 after tyrosine phosphorylation by the activated insulin receptor. Moreover, tyr-phosphorylated Src associated in mitosis 68 binds with a higher affinity to the N-terminal Src homology 2 domain of p85 compared to the C-terminal Src homology 2 domain of p85, suggesting a preferential association of Src associated in mitosis 68 with the N-terminal Src homology 2 domain of p85. This association may be important for the link of the signaling with RNA metabolism.

When irrelevance matters: Stimulus-response binding in decision making under uncertainty.

PubMed

Nett, Nadine; Bröder, Arndt; Frings, Christian

2015-11-01

According to distractor-based response retrieval (Frings, Rothermund, & Wentura, 2007), irrelevant information will be integrated with the response to the relevant stimuli and further, the immediate repetition of irrelevant information can retrieve the previously executed response thereby influencing responding to the current target (leading either to benefits or costs if the retrieved response is compatible or incompatible, respectively, to the currently demanded response). We analyzed whether this effect also holds for decisions rather than simple motoric reactions. The hypothesis was tested in 4 experiments in which participants had to decide as fast as possible which disease an imagined patient suffered from. The decisions were based on 2 cues; 1 did not give any hint for a disease (the irrelevant cue), whereas the other did (the relevant cue). We found a significant influence of repeating the irrelevant cue on decision behavior. That is, participants tended to repeat their decision if the irrelevant cue was repeated in the following decision situation. Thus, stimulus-response binding which typically is discussed in basic processes of perception and action has also implications for arguably more deliberative cognitive processes in decision making under uncertainty. (c) 2015 APA, all rights reserved).

Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model.

PubMed

El-Hashim, Ahmed Z; Khajah, Maitham A; Renno, Waleed M; Babyson, Rhema S; Uddin, Mohib; Benter, Ibrahim F; Ezeamuzie, Charles; Akhtar, Saghir

2017-08-30

The molecular mechanisms underlying asthma pathogenesis are poorly characterized. In this study, we investigated (1) whether Src mediates epidermal growth factor receptor (EGFR) transactivation; (2) if ERK1/2, PI3Kδ/Akt and NF-κB are signaling effectors downstream of Src/EGFR activation; and (3) if upstream inhibition of Src/EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways. Allergic inflammation resulted in increased phosphorylation of EGFR, Akt, ERK1/2 and IκB in the lung tissues from ovalbumin (OVA)-challenged BALB/c mice. Treatment with inhibitors of Src (SU6656) or EGFR (AG1478) reduced EGFR phosphorylation and downstream signaling which resulted in the inhibition of the OVA-induced inflammatory cell influx in bronchoalveolar lavage fluid (BALF), perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyper-responsiveness. Treatment with pathway-selective inhibitors for ERK1/2 (PD89059) and PI3Kδ/Akt (IC-87114) respectively, or an inhibitor of NF-κB (BAY11-7085) also reduced the OVA-induced asthmatic phenotype but to a lesser extent compared to Src/EGFR inhibition. Thus, Src via EGFR transactivation and subsequent downstream activation of multiple pathways regulates the allergic airway inflammatory response. Furthermore, a broader upstream inhibition of Src/EGFR offers an attractive therapeutic alternative in the treatment of asthma relative to selectively targeting the individual downstream signaling effectors.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Soeda, Shuhei; Nakayama, Yuji, E-mail: nakayama@mb.kyoto-phu.ac.jp; Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414

Src-family tyrosine kinases are aberrantly activated in cancers, and this activation is associated with malignant tumor progression. v-Src, encoded by the v-src transforming gene of the Rous sarcoma virus, is a mutant variant of the cellular proto-oncogene c-Src. Although investigations with temperature sensitive mutants of v-Src have shown that v-Src induces many oncogenic processes, the effects on cell division are unknown. Here, we show that v-Src inhibits cellular proliferation of HCT116, HeLa S3 and NIH3T3 cells. Flow cytometry analysis indicated that inducible expression of v-Src results in an accumulation of 4N cells. Time-lapse analysis revealed that binucleation is induced throughmore » the inhibition of cytokinesis, a final step of cell division. The localization of Mklp1, which is essential for cytokinesis, to the spindle midzone is inhibited in v-Src-expressing cells. Intriguingly, Aurora B, which regulates Mklp1 localization at the midzone, is delocalized from the spindle midzone and the midbody but not from the metaphase chromosomes upon v-Src expression. Mklp2, which is responsible for the relocation of Aurora B from the metaphase chromosomes to the spindle midzone, is also lost from the spindle midzone. These results suggest that v-Src inhibits cytokinesis through the delocalization of Mklp1 and Aurora B from the spindle midzone, resulting in binucleation. -- Highlights: • v-Src inhibits cell proliferation of HCT116, HeLa S3 and NIH3T3 cells. • v-Src induces binucleation together with cytokinesis failure. • v-Src causes delocalization of Mklp1, Aurora B and INCENP from the spindle midzone.« less

Src binds cortactin through an SH2 domain cystine-mediated linkage.

PubMed

Evans, Jason V; Ammer, Amanda G; Jett, John E; Bolcato, Chris A; Breaux, Jason C; Martin, Karen H; Culp, Mark V; Gannett, Peter M; Weed, Scott A

2012-12-15

Tyrosine-kinase-based signal transduction mediated by modular protein domains is critical for cellular function. The Src homology (SH)2 domain is an important conductor of intracellular signaling that binds to phosphorylated tyrosines on acceptor proteins, producing molecular complexes responsible for signal relay. Cortactin is a cytoskeletal protein and tyrosine kinase substrate that regulates actin-based motility through interactions with SH2-domain-containing proteins. The Src kinase SH2 domain mediates cortactin binding and tyrosine phosphorylation, but how Src interacts with cortactin is unknown. Here we demonstrate that Src binds cortactin through cystine bonding between Src C185 in the SH2 domain within the phosphotyrosine binding pocket and cortactin C112/246 in the cortactin repeats domain, independent of tyrosine phosphorylation. Interaction studies show that the presence of reducing agents ablates Src-cortactin binding, eliminates cortactin phosphorylation by Src, and prevents Src SH2 domain binding to cortactin. Tandem MS/MS sequencing demonstrates cystine bond formation between Src C185 and cortactin C112/246. Mutational studies indicate that an intact cystine binding interface is required for Src-mediated cortactin phosphorylation, cell migration, and pre-invadopodia formation. Our results identify a novel phosphotyrosine-independent binding mode between the Src SH2 domain and cortactin. Besides Src, one quarter of all SH2 domains contain cysteines at or near the analogous Src C185 position. This provides a potential alternative mechanism to tyrosine phosphorylation for cysteine-containing SH2 domains to bind cognate ligands that may be widespread in propagating signals regulating diverse cellular functions.

Src binds cortactin through an SH2 domain cystine-mediated linkage

PubMed Central

Evans, Jason V.; Ammer, Amanda G.; Jett, John E.; Bolcato, Chris A.; Breaux, Jason C.; Martin, Karen H.; Culp, Mark V.; Gannett, Peter M.; Weed, Scott A.

2012-01-01

Summary Tyrosine-kinase-based signal transduction mediated by modular protein domains is critical for cellular function. The Src homology (SH)2 domain is an important conductor of intracellular signaling that binds to phosphorylated tyrosines on acceptor proteins, producing molecular complexes responsible for signal relay. Cortactin is a cytoskeletal protein and tyrosine kinase substrate that regulates actin-based motility through interactions with SH2-domain-containing proteins. The Src kinase SH2 domain mediates cortactin binding and tyrosine phosphorylation, but how Src interacts with cortactin is unknown. Here we demonstrate that Src binds cortactin through cystine bonding between Src C185 in the SH2 domain within the phosphotyrosine binding pocket and cortactin C112/246 in the cortactin repeats domain, independent of tyrosine phosphorylation. Interaction studies show that the presence of reducing agents ablates Src-cortactin binding, eliminates cortactin phosphorylation by Src, and prevents Src SH2 domain binding to cortactin. Tandem MS/MS sequencing demonstrates cystine bond formation between Src C185 and cortactin C112/246. Mutational studies indicate that an intact cystine binding interface is required for Src-mediated cortactin phosphorylation, cell migration, and pre-invadopodia formation. Our results identify a novel phosphotyrosine-independent binding mode between the Src SH2 domain and cortactin. Besides Src, one quarter of all SH2 domains contain cysteines at or near the analogous Src C185 position. This provides a potential alternative mechanism to tyrosine phosphorylation for cysteine-containing SH2 domains to bind cognate ligands that may be widespread in propagating signals regulating diverse cellular functions. PMID:23097045

Bimanual cross-talk during reaching movements is primarily related to response selection, not the specification of motor parameters

NASA Technical Reports Server (NTRS)

Hazeltine, Eliot; Diedrichsen, Joern; Kennerley, Steven W.; Ivry, Richard B.

2003-01-01

Simultaneous reaching movements made with the two hands can show a considerable increase in reaction time (RT) when they differ in terms of direction or extent, compared to when the movements involve the same direction and extent. This cost has been attributed to cross-talk in the specification of the motor parameters for the two hands. However, a recent study [Diedrichsen, Hazeltine, Kennerley, & Ivry, (2001). Psychological Science, 12, 493-498] indicates that when reaching movements are cued by the onset of the target endpoint, no compatibility effects are observed. To determine why directly cued movements are immune from interference, we varied the stimulus onset asynchrony for the two movements and used different combinations of directly cued and symbolically cued movements. In two experiments, compatibility effects were only observed when both movements were symbolically cued. No difference was found between compatible and incompatible movements when both movements were directly cued or when one was directly cued and the other was symbolically cued. These results indicate that interference is not related to the specification of movement parameters but instead emerges from processes associated with response selection. Moreover, the data suggest that cross-talk, when present, primarily shortens the RT of the second movement on compatible trials rather than lengthening this RT on incompatible trials.

Detection of back-to-back proton pairs in charged-current neutrino interactions with the ArgoNeuT detector in the NuMI low energy beam line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Acciarri, R.; Adams, C.; Asaadi, J.

2014-07-01

Short range nucleon-nucleon correlations in nuclei (NN SRC) carry important information on nuclear structure and dynamics. NN SRC have been extensively probed through two-nucleon knock- out reactions in both pion and electron scattering experiments. We report here on the detection of two-nucleon knock-out events from neutrino interactions and discuss their topological features as possibly involving NN SRC content in the target argon nuclei. The ArgoNeuT detector in the Main Injector neutrino beam at Fermilab has recorded a sample of 30 fully reconstructed charged current events where the leading muon is accompanied by a pair of protons at the interaction vertex,more » 19 of which have both protons above the Fermi momentum of the Ar nucleus. Out of these 19 events, four are found with the two protons in a strictly back-to-back high momenta configuration directly observed in the final state and can be associated to nucleon Resonance pionless mechanisms involving a pre-existing short range correlated np pair in the nucleus. Another fraction (four events) of the remaining 15 events have a reconstructed back-to-back configuration of a np pair in the initial state, a signature compatible with one-body Quasi Elastic interaction on a neutron in a SRC pair. The detection of these two subsamples of the collected (mu- + 2p) events suggests that mechanisms directly involving nucleon-nucleon SRC pairs in the nucleus are active and can be efficiently explored in neutrino-argon interactions with the LAr TPC technology.« less

Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I1,2

PubMed Central

Ivakine, Evgueni A.; Lam, Emily; Deurloo, Marielle; Dida, Joana; Zirngibl, Ralph A.

2015-01-01

Abstract Src is a nonreceptor protein tyrosine kinase that is expressed widely throughout the central nervous system and is involved in diverse biological functions. Mice homozygous for a spontaneous mutation in Src (Src thl/thl) exhibited hypersociability and hyperactivity along with impairments in visuospatial, amygdala-dependent, and motor learning as well as an increased startle response to loud tones. The phenotype of Src thl/thl mice showed significant overlap with Williams-Beuren syndrome (WBS), a disorder caused by the deletion of several genes, including General Transcription Factor 2-I (GTF2I). Src phosphorylation regulates the movement of GTF2I protein (TFII-I) between the nucleus, where it is a transcriptional activator, and the cytoplasm, where it regulates trafficking of transient receptor potential cation channel, subfamily C, member 3 (TRPC3) subunits to the plasma membrane. Here, we demonstrate altered cellular localization of both TFII-I and TRPC3 in the Src mutants, suggesting that disruption of Src can phenocopy behavioral phenotypes observed in WBS through its regulation of TFII-I. PMID:26464974

Calcium-permeable α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors Trigger Neuronal Nitric-oxide Synthase Activation to Promote Nerve Cell Death in an Src Kinase-dependent Fashion*

PubMed Central

Socodato, Renato; Santiago, Felipe N.; Portugal, Camila C.; Domingues, Ana F.; Santiago, Ana R.; Relvas, João B.; Ambrósio, António F.; Paes-de-Carvalho, Roberto

2012-01-01

In the retina information decoding is dependent on excitatory neurotransmission and is critically modulated by AMPA glutamate receptors. The Src-tyrosine kinase has been implicated in modulating neurotransmission in CNS. Thus, our main goal was to correlate AMPA-mediated excitatory neurotransmission with the modulation of Src activity in retinal neurons. Cultured retinal cells were used to access the effects of AMPA stimulation on nitric oxide (NO) production and Src phosphorylation. 4-Amino-5-methylamino-2′,7′-difluorofluorescein diacetate fluorescence mainly determined NO production, and immunocytochemistry and Western blotting evaluated Src activation. AMPA receptors activation rapidly up-regulated Src phosphorylation at tyrosine 416 (stimulatory site) and down-regulated phosphotyrosine 527 (inhibitory site) in retinal cells, an effect mainly mediated by calcium-permeable AMPA receptors. Interestingly, experiments confirmed that neuronal NOS was activated in response to calcium-permeable AMPA receptor stimulation. Moreover, data suggest NO pathway as a key regulatory signaling in AMPA-induced Src activation in neurons but not in glial cells. The NO donor SNAP (S-nitroso-N-acetyl-dl-penicillamine) and a soluble guanylyl cyclase agonist (YC-1) mimicked AMPA effect in Src Tyr-416 phosphorylation, reinforcing that Src activation is indeed modulated by the NO pathway. Gain and loss-of-function data demonstrated that ERK is a downstream target of AMPA-induced Src activation and NO signaling. Furthermore, AMPA stimulated NO production in organotypic retinal cultures and increased Src activity in the in vivo retina. Additionally, AMPA-induced apoptotic retinal cell death was regulated by both NOS and Src activity. Because Src activity is pivotal in several CNS regions, the data presented herein highlight that Src modulation is a critical step in excitatory retinal cell death. PMID:22992730

Calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors trigger neuronal nitric-oxide synthase activation to promote nerve cell death in an Src kinase-dependent fashion.

PubMed

Socodato, Renato; Santiago, Felipe N; Portugal, Camila C; Domingues, Ana F; Santiago, Ana R; Relvas, João B; Ambrósio, António F; Paes-de-Carvalho, Roberto

2012-11-09

In the retina information decoding is dependent on excitatory neurotransmission and is critically modulated by AMPA glutamate receptors. The Src-tyrosine kinase has been implicated in modulating neurotransmission in CNS. Thus, our main goal was to correlate AMPA-mediated excitatory neurotransmission with the modulation of Src activity in retinal neurons. Cultured retinal cells were used to access the effects of AMPA stimulation on nitric oxide (NO) production and Src phosphorylation. 4-Amino-5-methylamino-2',7'-difluorofluorescein diacetate fluorescence mainly determined NO production, and immunocytochemistry and Western blotting evaluated Src activation. AMPA receptors activation rapidly up-regulated Src phosphorylation at tyrosine 416 (stimulatory site) and down-regulated phosphotyrosine 527 (inhibitory site) in retinal cells, an effect mainly mediated by calcium-permeable AMPA receptors. Interestingly, experiments confirmed that neuronal NOS was activated in response to calcium-permeable AMPA receptor stimulation. Moreover, data suggest NO pathway as a key regulatory signaling in AMPA-induced Src activation in neurons but not in glial cells. The NO donor SNAP (S-nitroso-N-acetyl-DL-penicillamine) and a soluble guanylyl cyclase agonist (YC-1) mimicked AMPA effect in Src Tyr-416 phosphorylation, reinforcing that Src activation is indeed modulated by the NO pathway. Gain and loss-of-function data demonstrated that ERK is a downstream target of AMPA-induced Src activation and NO signaling. Furthermore, AMPA stimulated NO production in organotypic retinal cultures and increased Src activity in the in vivo retina. Additionally, AMPA-induced apoptotic retinal cell death was regulated by both NOS and Src activity. Because Src activity is pivotal in several CNS regions, the data presented herein highlight that Src modulation is a critical step in excitatory retinal cell death.

Extinction of aversive classically conditioned human sexual response.

PubMed

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Both, Stephanie

2015-04-01

Research has shown that acquired subjective likes and dislikes are quite resistant to extinction. Moreover, studies on female sexual response demonstrated that diminished genital arousal and positive affect toward erotic stimuli due to aversive classical conditioning did not extinguish during an extinction phase. Possible resistance to extinction of aversive conditioned sexual responses may have important clinical implications. However, resistance to extinction of aversive conditioned human sexual response has not been studied using extensive extinction trials. This article aims to study resistance to extinction of aversive conditioned sexual responses in sexually functional men and women. A differential conditioning experiment was conducted, with two erotic pictures as conditioned stimulus (CSs) and a painful stimulus as unconditioned stimuli (USs). Only one CS (the CS+) was followed by the US during the acquisition phase. Conditioned responses were assessed during the extinction phase. Penile circumference and vaginal pulse amplitude were assessed, and ratings of affective value and subjective sexual arousal were obtained. Also, a stimulus response compatibility task was included to assess automatic approach and avoidance tendencies. Men and women rated the CS+ more negative as compared with the CS-. During the first trials of the extinction phase, vaginal pulse amplitude was lower in response to the CS+ than in response to the CS-, and on the first extinction trial women rated the CS+ as less sexually arousing. Intriguingly, men did not demonstrate attenuated genital and subjective sexual response. Aversive conditioning, by means of painful stimuli, only affects sexual responses in women, whereas it does not in men. Although conditioned sexual likes and dislikes are relatively persistent, conditioned affect eventually does extinguish. © 2014 International Society for Sexual Medicine.

Transfer effects of manipulating temporal constraints on learning a two-choice reaction time task with low stimulus-response compatibility.

PubMed

Chen, David D; Pei, Laura; Chan, John S Y; Yan, Jin H

2012-10-01

Recent research using deliberate amplification of spatial errors to increase motor learning leads to the question of whether amplifying temporal errors may also facilitate learning. We investigated transfer effects caused by manipulating temporal constraints on learning a two-choice reaction time (CRT) task with varying degrees of stimulus-response compatibility. Thirty-four participants were randomly assigned to one of the three groups and completed 120 trials during acquisition. For every fourth trial, one group was instructed to decrease CRT by 50 msec. relative to the previous trial and a second group was instructed to increase CRT by 50 msec. The third group (the control) was told not to change their responses. After a 5-min. break, participants completed a 40-trial no-feedback transfer test. A 40-trial delayed transfer test was administered 24 hours later. During acquisition, the Decreased Reaction Time group responded faster than the two other groups, but this group also made more errors than the other two groups. In the 5-min. delayed test (immediate transfer), the Decreased Reaction Time group had faster reaction times than the other two groups, while for the 24-hr. delayed test (delayed transfer), both the Decreased Reaction Time group and Increased Reaction Time group had significantly faster reaction times than the control. For delayed transfer, both Decreased and Increased Reaction Time groups reacted significantly faster than the control group. Analyses of error scores in the transfer tests indicated revealed no significant group differences. Results were discussed with regard to the notion of practice variability and goal-setting benefits.

Stimuli-responsive chitosan-based nanocarriers for cancer therapy

PubMed Central

Fathi, Marziyeh; Sahandi Zangabad, Parham; Majidi, Sima; Barar, Jaleh; Erfan-Niya, Hamid

2017-01-01

Introduction: Stimuli-responsive nanocarriers offer unique advantages over the traditional drug delivery systems (DDSs) in terms of targeted drug delivery and on-demand release of cargo drug molecules. Of these, chitosan (CS)-based DDSs offer several advantages such as high compatibility with biological settings. Methods: In this study, we surveyed the literature in terms of the stimuli-responsive nanocarriers and discussed the most recent advancements in terms of CS-based nanosystems and their applications in cancer therapy and diagnosis. Results: These advanced DDSs are able to release the entrapped drugs in response to a specific endogenous stimulus (e.g., pH, glutathione concentration or certain enzymes) or exogenous stimulus (e.g., temperature, light, ultrasound, and magnetic field) at the desired time and target site. Dual-responsive nanocarriers by the combination of different stimuli have also been developed as efficient and improved DDSs. Among the stimuli-responsive nanocarriers, CS-based DDSs offer several advantages, including biocompatibility and biodegradability, antibacterial activity, ease of modification and functionalization, and non-immunogenicity. They are as one of the most ideal smart multifunction DDSs. Conclusion: The CS-based stimuli-responsive multifunctional nanosystems (NSs) offer unique potential for the targeted delivery of anticancer agents and provide great potential for on-demand and controlled-release of anticancer agents in response to diverse external/internal stimuli. PMID:29435435

Stimuli-responsive chitosan-based nanocarriers for cancer therapy.

PubMed

Fathi, Marziyeh; Sahandi Zangabad, Parham; Majidi, Sima; Barar, Jaleh; Erfan-Niya, Hamid; Omidi, Yadollah

2017-01-01

Introduction: Stimuli-responsive nanocarriers offer unique advantages over the traditional drug delivery systems (DDSs) in terms of targeted drug delivery and on-demand release of cargo drug molecules. Of these, chitosan (CS)-based DDSs offer several advantages such as high compatibility with biological settings. Methods: In this study, we surveyed the literature in terms of the stimuli-responsive nanocarriers and discussed the most recent advancements in terms of CS-based nanosystems and their applications in cancer therapy and diagnosis. Results: These advanced DDSs are able to release the entrapped drugs in response to a specific endogenous stimulus (e.g., pH, glutathione concentration or certain enzymes) or exogenous stimulus (e.g., temperature, light, ultrasound, and magnetic field) at the desired time and target site. Dual-responsive nanocarriers by the combination of different stimuli have also been developed as efficient and improved DDSs. Among the stimuli-responsive nanocarriers, CS-based DDSs offer several advantages, including biocompatibility and biodegradability, antibacterial activity, ease of modification and functionalization, and non-immunogenicity. They are as one of the most ideal smart multifunction DDSs. Conclusion: The CS-based stimuli-responsive multifunctional nanosystems (NSs) offer unique potential for the targeted delivery of anticancer agents and provide great potential for on-demand and controlled-release of anticancer agents in response to diverse external/internal stimuli.

Functional diversity of Csk, Chk, and Src SH2 domains due to a single residue variation.

PubMed

Ayrapetov, Marina K; Nam, Nguyen Hai; Ye, Guofeng; Kumar, Anil; Parang, Keykavous; Sun, Gongqin

2005-07-08

The C-terminal Src kinase (Csk) family of protein tyrosine kinases contains two members: Csk and Csk homologous kinase (Chk). Both phosphorylate and inactivate Src family kinases. Recent reports suggest that the Src homology (SH) 2 domains of Csk and Chk may bind to different phosphoproteins, which provides a basis for different cellular functions for Csk and Chk. To verify and characterize such a functional divergence, we compared the binding properties of the Csk, Chk, and Src SH2 domains and investigated the structural basis for the functional divergence. First, the study demonstrated striking functional differences between the Csk and Chk SH2 domains and revealed functional similarities between the Chk and Src SH2 domains. Second, structural analysis and mutagenic studies revealed that the functional differences among the three SH2 domains were largely controlled by one residue, Glu127 in Csk, Ile167 in Chk, and Lys200 in Src. Mutating these residues in the Csk or Chk SH2 domain to the Src counterpart resulted in dramatic gain of function similar to Src SH2 domain, whereas mutating Lys200 in Src SH2 domain to Glu (the Csk counterpart) resulted in loss of Src SH2 function. Third, a single point mutation of E127K rendered Csk responsive to activation by a Src SH2 domain ligand. Finally, the optimal phosphopeptide sequence for the Chk SH2 domain was determined. These results provide a compelling explanation for the functional differences between two homologous protein tyrosine kinases and reveal a new structure-function relationship for the SH2 domains.

Simultaneous inhibition of aryl hydrocarbon receptor (AhR) and Src abolishes androgen receptor signaling.

PubMed

Ghotbaddini, Maryam; Cisse, Keyana; Carey, Alexis; Powell, Joann B

2017-01-01

Altered c-Src activity has been strongly implicated in the development, growth, progression, and metastasis of human cancers including prostate cancer. Src is known to regulate several biological functions of tumor cells, including proliferation. There are several Src inhibitors under evaluation for clinical effectiveness but have shown little activity in monotherapy trials of solid tumors. Combination studies are being explored by in vitro analysis and in clinical trials. Here we investigate the effect of simultaneous inhibition of the aryl hydrocarbon receptor (AhR) and Src on androgen receptor (AR) signaling in prostate cancer cells. AhR has also been reported to interact with the Src signaling pathway during prostate development. c-Src protein kinase is associated with the AhR complex in the cytosol and upon ligand binding to AhR, c-Src is activated and released from the complex. AhR has also been shown to regulate AR signaling which remains functionally important in the development and progression of prostate cancer. We provide evidence that co-inhibition of AhR and Src abolish AR activity. Evaluation of total protein and cellular fractions revealed decreased pAR expression and AR nuclear localization. Assays utilizing an androgen responsive element (ARE) and qRT-PCR analysis of AR genes revealed decreased AR promoter activity and transcriptional activity in the presence of both AhR and Src inhibitors. Furthermore, co-inhibition of AhR and Src reduced the growth of prostate cancer cells compared to individual treatments. Several studies have revealed that AhR and Src individually inhibit cellular proliferation. However, this study is the first to suggest simultaneous inhibition of AhR and Src to inhibit AR signaling and prostate cancer cell growth.

Differential effects of phosphotyrosine phosphatase expression on hormone-dependent and independent pp60c-src activity.

PubMed

Way, B A; Mooney, R A

1994-10-26

pp60c-src kinase activity can be increased by phosphotyrosine dephosphorylation or growth factor-dependent phosphorylation reactions. Expression of the transmembrane phosphotyrosine phosphatase (PTPase) CD45 has been shown to inhibit growth factor receptor signal transduction (Mooney, RA, Freund, GG, Way, BA and Bordwell, KL (1992) J Biol Chem 267, 23443-23446). Here it is shown that PTPase expression decreased platelet-derived growth factor (PDGF)-dependent activation of pp60c-src but failed to increase hormone independent (basal) pp60c-src activity. PDGF-dependent tyrosine phosphorylation of its receptor was reduced by approximately 60% in cells expressing the PTPase. In contrast, a change in phosphotyrosine content of pp60c-src was not detected in response to PDGF or in PTPase+ cells. PDGF increased the intrinsic tyrosine kinase activity of pp60c-src in both control and PTPase+ cells, but the effect was smaller in PTPase+ cells. In an in vitro assay, hormone-stimulated pp60c-src autophosphorylation from PTPase+ cells was decreased 64 +/- 22%, and substrate phosphorylation by pp60c-src was reduced 54 +/- 16% compared to controls. Hormone-independent pp60c-src kinase activity was unchanged by expression of the PTPase. pp60c-src was, however, an in vitro substrate for CD45, being dephosphorylated at both the regulatory (Tyr527) and kinase domain (Tyr416) residues. In addition, in vitro dephosphorylation by CD45 increased pp60c-src activity. These findings suggest that the PDGF receptor was an in vivo substrate of CD45 but pp60c-src was not. The lack of activation of pp60c-src in the presence of expressed PTPase may demonstrate the importance of compartmentalization and/or accessory proteins to PTPase-substrate interactions.

Inverse Target- and Cue-Priming Effects of Masked Stimuli

ERIC Educational Resources Information Center

Mattler, Uwe

2007-01-01

The processing of a visual target that follows a briefly presented prime stimulus can be facilitated if prime and target stimuli are similar. In contrast to these positive priming effects, inverse priming effects (or negative compatibility effects) have been found when a mask follows prime stimuli before the target stimulus is presented: Responses…

Task-set inertia and memory-consolidation bottleneck in dual tasks.

PubMed

Koch, Iring; Rumiati, Raffaella I

2006-11-01

Three dual-task experiments examined the influence of processing a briefly presented visual object for deferred verbal report on performance in an unrelated auditory-manual reaction time (RT) task. RT was increased at short stimulus-onset asynchronies (SOAs) relative to long SOAs, showing that memory consolidation processes can produce a functional processing bottleneck in dual-task performance. In addition, the experiments manipulated the spatial compatibility of the orientation of the visual object and the side of the speeded manual response. This cross-task compatibility produced relative RT benefits only when the instruction for the visual task emphasized overlap at the level of response codes across the task sets (Experiment 1). However, once the effective task set was in place, it continued to produce cross-task compatibility effects even in single-task situations ("ignore" trials in Experiment 2) and when instructions for the visual task did not explicitly require spatial coding of object orientation (Experiment 3). Taken together, the data suggest a considerable degree of task-set inertia in dual-task performance, which is also reinforced by finding costs of switching task sequences (e.g., AC --> BC vs. BC --> BC) in Experiment 3.

Automatized smoking-related action schemata are reflected by reduced fMRI activity in sensorimotor brain regions of smokers.

PubMed

Isik, Ayse Ilkay; Naumer, Marcus J; Kaiser, Jochen; Buschenlange, Christian; Wiesmann, Sandro; Czoschke, Stefan; Yalachkov, Yavor

2017-01-01

In the later stages of addiction, automatized processes play a prominent role in guiding drug-seeking and drug-taking behavior. However, little is known about the neural correlates of automatized drug-taking skills and drug-related action knowledge in humans. We employed functional magnetic resonance imaging (fMRI) while smokers and non-smokers performed an orientation affordance task, where compatibility between the hand used for a behavioral response and the spatial orientation of a priming stimulus leads to shorter reaction times resulting from activation of the corresponding motor representations. While non-smokers exhibited this behavioral effect only for control objects, smokers showed the affordance effect for both control and smoking-related objects. Furthermore, smokers exhibited reduced fMRI activation for smoking-related as compared to control objects for compatible stimulus-response pairings in a sensorimotor brain network consisting of the right primary motor cortex, supplementary motor area, middle occipital gyrus, left fusiform gyrus and bilateral cingulate gyrus. In the incompatible condition, we found higher fMRI activation in smokers for smoking-related as compared to control objects in the right primary motor cortex, cingulate gyrus, and left fusiform gyrus. This suggests that the activation and performance of deeply embedded, automatized drug-taking schemata employ less brain resources. This might reduce the threshold for relapsing in individuals trying to abstain from smoking. In contrast, the interruption or modification of already triggered automatized action representations require increased neural resources.

Controlling automatic imitative tendencies: interactions between mirror neuron and cognitive control systems.

PubMed

Cross, Katy A; Torrisi, Salvatore; Reynolds Losin, Elizabeth A; Iacoboni, Marco

2013-12-01

Humans have an automatic tendency to imitate others. Although several regions commonly observed in social tasks have been shown to be involved in imitation control, there is little work exploring how these regions interact with one another. We used fMRI and dynamic causal modeling to identify imitation-specific control mechanisms and examine functional interactions between regions. Participants performed a pre-specified action (lifting their index or middle finger) in response to videos depicting the same two actions (biological cues) or dots moving with similar trajectories (non-biological cues). On congruent trials, the stimulus and response were similar (e.g. index finger response to index finger or left side dot stimulus), while on incongruent trials the stimulus and response were dissimilar (e.g. index finger response to middle finger or right side dot stimulus). Reaction times were slower on incongruent compared to congruent trials for both biological and non-biological stimuli, replicating previous findings that suggest the automatic imitative or spatially compatible (congruent) response must be controlled on incongruent trials. Neural correlates of the congruency effects were different depending on the cue type. The medial prefrontal cortex, anterior cingulate, inferior frontal gyrus pars opercularis (IFGpo) and the left anterior insula were involved specifically in controlling imitation. In addition, the IFGpo was also more active for biological compared to non-biological stimuli, suggesting that the region represents the frontal node of the human mirror neuron system (MNS). Effective connectivity analysis exploring the interactions between these regions, suggests a role for the mPFC and ACC in imitative conflict detection and the anterior insula in conflict resolution processes, which may occur through interactions with the frontal node of the MNS. We suggest an extension of the previous models of imitation control involving interactions between imitation-specific and general cognitive control mechanisms. © 2013.

c-Src, Insulin-Like Growth Factor I Receptor, G-Protein-Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes.

PubMed

DeRita, Rachel M; Zerlanko, Brad; Singh, Amrita; Lu, Huimin; Iozzo, Renato V; Benovic, Jeffrey L; Languino, Lucia R

2017-01-01

It is well known that Src tyrosine kinase, insulin-like growth factor 1 receptor (IGF-IR), and focal adhesion kinase (FAK) play important roles in prostate cancer (PrCa) development and progression. Src, which signals through FAK in response to integrin activation, has been implicated in many aspects of tumor biology, such as cell proliferation, metastasis, and angiogenesis. Furthermore, Src signaling is known to crosstalk with IGF-IR, which also promotes angiogenesis. In this study, we demonstrate that c-Src, IGF-IR, and FAK are packaged into exosomes (Exo), c-Src in particular being highly enriched in Exo from the androgen receptor (AR)-positive cell line C4-2B and AR-negative cell lines PC3 and DU145. Furthermore, we show that the active phosphorylated form of Src (Src pY416 ) is co-expressed in Exo with phosphorylated FAK (FAK pY861 ), a known target site of Src, which enhances proliferation and migration. We further demonstrate for the first time exosomal enrichment of G-protein-coupled receptor kinase (GRK) 5 and GRK6, both of which regulate Src and IGF-IR signaling and have been implicated in cancer. Finally, Src pY416 and c-Src are both expressed in Exo isolated from the plasma of prostate tumor-bearing TRAMP mice, and those same mice have higher levels of exosomal c-Src than their wild-type counterparts. In summary, we provide new evidence that active signaling molecules relevant to PrCa are enriched in Exo, and this suggests that the Src signaling network may provide useful biomarkers detectable by liquid biopsy, and may contribute to PrCa progression via Exo. J. Cell. Biochem. 118: 66-73, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Src kinases and ERK activate distinct responses to Stitcher receptor tyrosine kinase signaling during wound healing in Drosophila.

PubMed

Tsarouhas, Vasilios; Yao, Liqun; Samakovlis, Christos

2014-04-15

Metazoans have evolved efficient mechanisms for epidermal repair and survival following injury. Several cellular responses and key signaling molecules that are involved in wound healing have been identified in Drosophila, but the coordination of cytoskeletal rearrangements and the activation of gene expression during barrier repair are poorly understood. The Ret-like receptor tyrosine kinase (RTK) Stitcher (Stit, also known as Cad96Ca) regulates both re-epithelialization and transcriptional activation by Grainy head (Grh) to induce restoration of the extracellular barrier. Here, we describe the immediate downstream effectors of Stit signaling in vivo. Drk (Downstream of receptor kinase) and Src family tyrosine kinases bind to the same docking site in the Stit intracellular domain. Drk is required for the full activation of transcriptional responses but is dispensable for re-epithelialization. By contrast, Src family kinases (SFKs) control both the assembly of a contractile actin ring at the wound periphery and Grh-dependent activation of barrier-repair genes. Our analysis identifies distinct pathways mediating injury responses and reveals an RTK-dependent activation mode for Src kinases and their central functions during epidermal wound healing in vivo.

Transfer of dimensional associability in human contingency learning.

PubMed

Kattner, Florian; Green, C Shawn

2016-01-01

Several studies have demonstrated processing advantages for stimuli that were experienced to be reliable predictors of an outcome relative to other stimuli. The present study tested whether such increases in associability apply at the level of entire stimulus dimensions (as suggested by Sutherland & Mackintosh, 1971). In 4 experiments, participants had to learn associations between Gabor gratings and particular responses. In a first experiment, some gratings were more predictive of the response than other gratings, whereas in 3 subsequent experiments, one stimulus dimension (i.e., either the orientation or spatial frequency of the grating) was more predictive than the other dimension. In contrast to the learned predictiveness of individual gratings (Experiment 1), dimensional predictiveness did not affect the subsequent rate of learning (Experiments 2 and 3), suggesting changes in the associability of specific stimuli, but not of stimulus dimensions. Moreover, greater transfer of predictiveness was found in all experiments when particular stimulus values of the test discrimination did not lie between the previously relevant stimuli. In Experiment 4, an increased learning rate was found for discriminations along the previously predictive dimension compared with a dimension that was indicative of uncertainty, but again the transfer was more pronounced for specific stimuli that were compatible with the previously learned discrimination. Taken together, the results imply that a transfer of associability typically applies to individual stimuli and depends on how the transfer stimuli relate to those stimuli that individuals previously learned to attend. (c) 2016 APA, all rights reserved).

Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis

PubMed Central

Dasgupta, Subhamoy; Putluri, Nagireddy; Long, Weiwen; Zhang, Bin; Wang, Jianghua; Kaushik, Akash K.; Arnold, James M.; Bhowmik, Salil K.; Stashi, Erin; Brennan, Christine A.; Rajapakshe, Kimal; Coarfa, Cristian; Mitsiades, Nicholas; Ittmann, Michael M.; Chinnaiyan, Arul M.; Sreekumar, Arun; O’Malley, Bert W.

2015-01-01

Metabolic pathway reprogramming is a hallmark of cancer cell growth and survival and supports the anabolic and energetic demands of these rapidly dividing cells. The underlying regulators of the tumor metabolic program are not completely understood; however, these factors have potential as cancer therapy targets. Here, we determined that upregulation of the oncogenic transcriptional coregulator steroid receptor coactivator 2 (SRC-2), also known as NCOA2, drives glutamine-dependent de novo lipogenesis, which supports tumor cell survival and eventual metastasis. SRC-2 was highly elevated in a variety of tumors, especially in prostate cancer, in which SRC-2 was amplified and overexpressed in 37% of the metastatic tumors evaluated. In prostate cancer cells, SRC-2 stimulated reductive carboxylation of α-ketoglutarate to generate citrate via retrograde TCA cycling, promoting lipogenesis and reprogramming of glutamine metabolism. Glutamine-mediated nutrient signaling activated SRC-2 via mTORC1-dependent phosphorylation, which then triggered downstream transcriptional responses by coactivating SREBP-1, which subsequently enhanced lipogenic enzyme expression. Metabolic profiling of human prostate tumors identified a massive increase in the SRC-2–driven metabolic signature in metastatic tumors compared with that seen in localized tumors, further implicating SRC-2 as a prominent metabolic coordinator of cancer metastasis. Moreover, SRC-2 inhibition in murine models severely attenuated the survival, growth, and metastasis of prostate cancer. Together, these results suggest that the SRC-2 pathway has potential as a therapeutic target for prostate cancer. PMID:25664849

Attention-shift vs. response-priming explanations for the spatial cueing effect in cross-modal tasks.

PubMed

Paavilainen, Petri; Illi, Janne; Moisseinen, Nella; Niinisalo, Maija; Ojala, Karita; Reinikainen, Johanna; Vainio, Lari

2016-06-01

The task-irrelevant spatial location of a cue stimulus affects the processing of a subsequent target. This "Posner effect" has been explained by an exogenous attention shift to the spatial location of the cue, improving perceptual processing of the target. We studied whether the left/right location of task-irrelevant and uninformative tones produces cueing effects on the processing of visual targets. Tones were presented randomly from left or right. In the first condition, the subsequent visual target, requiring response either with the left or right hand, was presented peripherally to left or right. In the second condition, the target was a centrally presented left/right-pointing arrow, indicating the response hand. In the third condition, the tone and the central arrow were presented simultaneously. Data were recorded on compatible (the tone location and the response hand were the same) and incompatible trials. Reaction times were longer on incompatible than on compatible trials. The results of the second and third conditions are difficult to explain with the attention-shift model emphasizing improved perceptual processing in the cued location, as the central target did not require any location-based processing. Consequently, as an alternative explanation they suggest response priming in the hand corresponding to the spatial location of the tone. Simultaneous lateralized readiness potential (LRP) recordings were consistent with the behavioral data, the tone cues eliciting on incompatible trials a fast preparation for the incorrect response and on compatible trials preparation for the correct response. © 2016 Scandinavian Psychological Associations and John Wiley & Sons Ltd.

Action video game training reduces the Simon Effect.

PubMed

Hutchinson, Claire V; Barrett, Doug J K; Nitka, Aleksander; Raynes, Kerry

2016-04-01

A number of studies have shown that training on action video games improves various aspects of visual cognition including selective attention and inhibitory control. Here, we demonstrate that action video game play can also reduce the Simon Effect, and, hence, may have the potential to improve response selection during the planning and execution of goal-directed action. Non-game-players were randomly assigned to one of four groups; two trained on a first-person-shooter game (Call of Duty) on either Microsoft Xbox or Nintendo DS, one trained on a visual training game for Nintendo DS, and a control group who received no training. Response times were used to contrast performance before and after training on a behavioral assay designed to manipulate stimulus-response compatibility (the Simon Task). The results revealed significantly faster response times and a reduced cost of stimulus-response incompatibility in the groups trained on the first-person-shooter game. No benefit of training was observed in the control group or the group trained on the visual training game. These findings are consistent with previous evidence that action game play elicits plastic changes in the neural circuits that serve attentional control, and suggest training may facilitate goal-directed action by improving players' ability to resolve conflict during response selection and execution.

The Simon effect in action: planning and/or on-line control effects?

PubMed

Scorolli, Claudia; Pellicano, Antonello; Nicoletti, Roberto; Rubichi, Sandro; Castiello, Umberto

2015-07-01

Choice reaction tasks are performed faster when stimulus location corresponds to response location (Simon effect). This spatial stimulus-response compatibility effect affects performance at the level of action planning and execution. However, when response selection is completed before movement initiation, the Simon effect arises only at the planning level. The aim of this study was to ascertain whether when a precocious response selection is requested, the Simon effect can be detected on the kinematics characterizing the online control phase of a non-ballistic movement. Participants were presented with red or green colored squares, which could appear on the right, left, above, or below a central cross. Depending on the square's color, participants had to release one of two buttons (right/left), then reach toward and press a corresponding lateral pad. We found evidence of the Simon effect on both action planning and on-line control. Moreover, the investigation of response conflict at the level of previous trials (i.e., n-1), a factor that might determine interference at the level of the current response, revealed a conflict adaptation process across trials. Results are discussed in terms of current theories concerned with the Simon effect and the distinction between action planning and control. Copyright © 2014 Cognitive Science Society, Inc.

Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukumoto, Yasunori, E-mail: fukumoto@faculty.chiba-u.jp; Kuki, Kazumasa; Morii, Mariko

2014-09-26

Highlights: • Inhibition of Src family kinases decreased γ-H2AX signal. • Inhibition of Src family increased ATM-dependent phosphorylation of Chk2 and Kap1. • shRNA-mediated knockdown of Lyn increased phosphorylation of Kap1 by ATM. • Ectopic expression of Src family kinase suppressed ATM-mediated Kap1 phosphorylation. • Src is involved in upstream signaling for inactivation of ATM signaling. - Abstract: DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the processmore » by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks. Inhibition of Src activity increased ATM-dependent phosphorylation of Chk2 and Kap1. Src inhibition increased ATM signaling both in G2 phase and during asynchronous growth. shRNA knockdown of Lyn increased ATM signaling. Src-dependent nuclear tyrosine phosphorylation suppressed ATM-mediated Kap1 phosphorylation. These results suggest that Src family kinases are involved in upstream signaling that leads to inactivation of the ATM-dependent DNA damage checkpoint.« less

Transfer of location-specific control to untrained locations.

PubMed

Weidler, Blaire J; Bugg, Julie M

2016-11-01

Recent research highlights a seemingly flexible and automatic form of cognitive control that is triggered by potent contextual cues, as exemplified by the location-specific proportion congruence effect--reduced compatibility effects in locations associated with a high as compared to low likelihood of conflict. We investigated just how flexible location-specific control is by examining whether novel locations effectively cue control for congruency-unbiased stimuli. In two experiments, biased (mostly compatible or mostly incompatible) training stimuli appeared in distinct locations. During a final block, unbiased (50% compatible) stimuli appeared in novel untrained locations spatially linked to biased locations. The flanker compatibly effect was reduced for unbiased stimuli in novel locations linked to a mostly incompatible compared to a mostly compatible location, indicating transfer. Transfer was observed when stimuli appeared along a linear function (Experiment 1) or in rings of a bullseye (Experiment 2). The novel transfer effects imply that location-specific control is more flexible than previously reported and further counter the complex stimulus-response learning account of location-specific proportion congruence effects. We propose that the representation and retrieval of control settings in untrained locations may depend on environmental support and the presentation of stimuli in novel locations that fall within the same categories of space as trained locations.

Suppression and Contrast Normalization in Motion Processing

PubMed Central

2017-01-01

Sensory neurons are activated by a range of stimuli to which they are said to be tuned. Usually, they are also suppressed by another set of stimuli that have little effect when presented in isolation. The interactions between preferred and suppressive stimuli are often quite complex and vary across neurons, even within a single area, making it difficult to infer their collective effect on behavioral responses mediated by activity across populations of neurons. Here, we investigated this issue by measuring, in human subjects (three males), the suppressive effect of static masks on the ocular following responses induced by moving stimuli. We found a wide range of effects, which depend in a nonlinear and nonseparable manner on the spatial frequency, contrast, and spatial location of both stimulus and mask. Under some conditions, the presence of the mask can be seen as scaling the contrast of the driving stimulus. Under other conditions, the effect is more complex, involving also a direct scaling of the behavioral response. All of this complexity at the behavioral level can be captured by a simple model in which stimulus and mask interact nonlinearly at two stages, one monocular and one binocular. The nature of the interactions is compatible with those observed at the level of single neurons in primates, usually broadly described as divisive normalization, without having to invoke any scaling mechanism. SIGNIFICANCE STATEMENT The response of sensory neurons to their preferred stimulus is often modulated by stimuli that are not effective when presented alone. Individual neurons can exhibit multiple modulatory effects, with considerable variability across neurons even in a single area. Such diversity has made it difficult to infer the impact of these modulatory mechanisms on behavioral responses. Here, we report the effects of a stationary mask on the reflexive eye movements induced by a moving stimulus. A model with two stages, each incorporating a divisive modulatory mechanism, reproduces our experimental results and suggests that qualitative variability of masking effects in cortical neurons might arise from differences in the extent to which such effects are inherited from earlier stages. PMID:29018158

Activity-dependent extracellular K+ accumulation in rat optic nerve: the role of glial and axonal Na+ pumps

PubMed Central

Ransom, Christopher B; Ransom, Bruce R; Sontheimer, Harald

2000-01-01

We measured activity-dependent changes in [K+]o with K+-selective microelectrodes in adult rat optic nerve, a CNS white matter tract, to investigate the factors responsible for post-stimulus recovery of [K+]o.Post-stimulus recovery of [K+]o followed a double-exponential time course with an initial, fast time constant, τfast, of 0.9 ± 0.2 s (mean ±s.d.) and a later, slow time constant, τslow, of 4.2 ± 1 s following a 1 s, 100 Hz stimulus. τfast, but not τslow, decreased with increasing activity-dependent rises in [K+]o. τslow, but not τfast, increased with increasing stimulus duration.Post-stimulus recovery of [K+]o was temperature sensitive. The apparent temperature coefficients (Q10, 27–37°C) for the fast and slow components following a 1 s, 100 Hz stimulus were 1.7 and 2.6, respectively.Post-stimulus recovery of [K+]o was sensitive to Na+ pump inhibition with 50 μM strophanthidin. Following a 1 s, 100 Hz stimulus, 50 μM strophanthidin increased τfast and τslow by 81 and 464%, respectively. Strophanthidin reduced the temperature sensitivity of post-stimulus recovery of [K+]o.Post-stimulus recovery of [K+]o was minimally affected by the K+ channel blocker Ba2+ (0.2 mm). Following a 10 s, 100 Hz stimulus, 0.2 mm Ba2+ increased τfast and τslow by 24 and 18%, respectively.Stimulated increases in [K+]o were followed by undershoots of [K+]o. Post-stimulus undershoot amplitude increased with stimulus duration but was independent of the peak preceding [K+]o increase.These observations imply that two distinct processes contribute to post-stimulus recovery of [K+]o in central white matter. The results are compatible with a model of K+ removal that attributes the fast, initial phase of K+ removal to K+ uptake by glial Na+ pumps and the slower, sustained decline to K+ uptake via axonal Na+ pumps. PMID:10713967

Activated d16HER2 homodimers and SRC kinase mediate optimal efficacy for trastuzumab.

PubMed

Castagnoli, Lorenzo; Iezzi, Manuela; Ghedini, Gaia C; Ciravolo, Valentina; Marzano, Giulia; Lamolinara, Alessia; Zappasodi, Roberta; Gasparini, Patrizia; Campiglio, Manuela; Amici, Augusto; Chiodoni, Claudia; Palladini, Arianna; Lollini, Pier Luigi; Triulzi, Tiziana; Menard, Sylvie; Nanni, Patrizia; Tagliabue, Elda; Pupa, Serenella M

2014-11-01

A splice isoform of the HER2 receptor that lacks exon 16 (d16HER2) is expressed in many HER2-positive breast tumors, where it has been linked with resistance to the HER2-targeting antibody trastuzumab, but the impact of d16HER2 on tumor pathobiology and therapeutic response remains uncertain. Here, we provide genetic evidence in transgenic mice that expression of d16HER2 is sufficient to accelerate mammary tumorigenesis and improve the response to trastuzumab. A comparative analysis of effector signaling pathways activated by d16HER2 and wild-type HER2 revealed that d16HER2 was optimally functional through a link to SRC activation (pSRC). Clinically, HER2-positive breast cancers from patients who received trastuzumab exhibited a positive correlation in d16HER2 and pSRC abundance, consistent with the mouse genetic results. Moreover, patients expressing high pSRC or an activated "d16HER2 metagene" were found to derive the greatest benefit from trastuzumab treatment. Overall, our results establish the d16HER2 signaling axis as a signature for decreased risk of relapse after trastuzumab treatment. ©2014 American Association for Cancer Research.

A Kinase-Independent Function of c-Src Mediates p130Cas Phosphorylation at the Serine-639 Site in Pressure Overloaded Myocardium.

PubMed

Palanisamy, Arun P; Suryakumar, Geetha; Panneerselvam, Kavin; Willey, Christopher D; Kuppuswamy, Dhandapani

2015-12-01

Early work in pressure overloaded (PO) myocardium shows that integrins mediate focal adhesion complex formation by recruiting the adaptor protein p130Cas (Cas) and nonreceptor tyrosine kinase c-Src. To explore c-Src role in Cas-associated changes during PO, we used a feline right ventricular in vivo PO model and a three-dimensional (3D) collagen-embedded adult cardiomyocyte in vitro model that utilizes a Gly-Arg-Gly-Asp-Ser (RGD) peptide for integrin stimulation. Cas showed slow electrophoretic mobility (band-shifting), recruitment to the cytoskeleton, and tyrosine phosphorylation at 165, 249, and 410 sites in both 48 h PO myocardium and 1 h RGD-stimulated cardiomyocytes. Adenoviral mediated expression of kinase inactive (negative) c-Src mutant with intact scaffold domains (KN-Src) in cardiomyocytes did not block the RGD stimulated changes in Cas. Furthermore, expression of KN-Src or kinase active c-Src mutant with intact scaffold function (A-Src) in two-dimensionally (2D) cultured cardiomyocytes was sufficient to cause Cas band-shifting, although tyrosine phosphorylation required A-Src. These data indicate that c-Src's adaptor function, but not its kinase function, is required for a serine/threonine specific phosphorylation(s) responsible for Cas band-shifting. To explore this possibility, Chinese hamster ovary cells that stably express Cas were infected with either β-gal or KN-Src adenoviruses and used for Cas immunoprecipitation combined with mass spectrometry analysis. In the KN-Src expressing cells, Cas showed phosphorylation at the serine-639 (human numbering) site. A polyclonal antibody raised against phospho-serine-639 detected Cas phosphorylation in 24-48 h PO myocardium. Our studies indicate that c-Src's adaptor function mediates serine-639 phosphorylation of Cas during integrin activation in PO myocardium. © 2015 Wiley Periodicals, Inc.

Mitochondrial events responsible for morphine's cardioprotection against ischemia/reperfusion injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Haiyan; Department of Pharmacology, Tianjin Medical University, Tianjin 300070; Huh, Jin

Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate morphine's protection. We aimed to address the role of the mitochondrial Src tyrosine kinase in morphine's protection. Isolated rat hearts were subjected to 30 min ischemia and 2 h of reperfusion. Morphine was given before the onset of ischemia. Infarct size and troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated ischemia/reperfusion and LDH release and mitochondrial membrane potential (ΔΨm) were measured. Morphinemore » reduced infarct size as well as cardiac troponin I release which were aborted by the selective Src tyrosine kinase inhibitors PP2 and Src-I1. Morphine also attenuated LDH release and prevented a loss of ΔΨm at reperfusion in a Src tyrosine kinase dependent manner in HL-1 cells. However, morphine failed to reduce LDH release in HL-1 cells transfected with Src siRNA. Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2. Morphine attenuated mitochondrial protein carbonylation and mitochondrial superoxide generation at reperfusion through Src tyrosine kinase. The inhibitory effect of morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by morphine. - Highlights: • Morphine induced mito-Src phosphorylation and reduced infarct size in rat hearts. • Morphine failed to reduce I/R-induced LDH release in Src-silencing HL-1 cells. • Morphine prevented mitochondria damage caused by I/R through Src. • Morphine reduced mitochondrial ROS generation by inhibiting complex I via Src.« less

The effects of display-control I/O, compatibility, and integrality on dual-task performance and subjective workload

NASA Technical Reports Server (NTRS)

Tsang, Pamela S.; Hart, Sandra G.; Vidulich, Michael A.

1987-01-01

The utility of speech technology was evaluated in terms of three dual task principles: resource competition between the time shared tasks, stimulus central processing response compatibility, and task integrality. Empirical support for these principles was reviewed. Two studies investigating the interactive effects of the three principles were described. Objective performance and subjective workload ratings for both single and dual tasks were examined. It was found that the single task measures were not necessarily good predictors for the dual task measures. It was shown that all three principles played an important role in determining an optimal task configuration. This was reflected in both the performance measures and the subjective measures. Therefore, consideration of all three principles is required to insure proper use of speech technology in a complex environment.

A Kinase-Independent Function of c-Src Mediates p130Cas Phosphorylation at the Serine-639 Site in Pressure Overloaded Myocardium

PubMed Central

Palanisamy, Arun P.; Suryakumar, Geetha; Panneerselvam, Kavin; Willey, Christopher D.; Kuppuswamy, Dhandapani

2017-01-01

Early work in pressure overloaded (PO) myocardium shows that integrins mediate focal adhesion complex formation by recruiting the adaptor protein p130Cas (Cas) and nonreceptor tyrosine kinase c-Src. To explore c-Src role in Cas-associated changes during PO, we used a feline right ventricular in vivo PO model and a three-dimensional (3D) collagen-embedded adult cardiomyocyte in vitro model that utilizes a Gly-Arg-Gly-Asp-Ser (RGD) peptide for integrin stimulation. Cas showed slow electrophoretic mobility (band-shifting), recruitment to the cytoskeleton, and tyrosine phosphorylation at 165, 249, and 410 sites in both 48 h PO myocardium and 1 h RGD-stimulated cardiomyocytes. Adenoviral mediated expression of kinase inactive (negative) c-Src mutant with intact scaffold domains (KN-Src) in cardiomyocytes did not block the RGD stimulated changes in Cas. Furthermore, expression of KN-Src or kinase active c-Src mutant with intact scaffold function (A-Src) in two-dimensionally (2D) cultured cardiomyocytes was sufficient to cause Cas band-shifting, although tyrosine phosphorylation required A-Src. These data indicate that c-Src’s adaptor function, but not its kinase function, is required for a serine/threonine specific phosphorylation(s) responsible for Cas band-shifting. To explore this possibility, Chinese hamster ovary cells that stably express Cas were infected with either β-gal or KN-Src adenoviruses and used for Cas immunoprecipitation combined with mass spectrometry analysis. In the KN-Src expressing cells, Cas showed phosphorylation at the serine-639 (human numbering) site. A polyclonal antibody raised against phospho-serine-639 detected Cas phosphorylation in 24–48 h PO myocardium. Our studies indicate that c-Src’s adaptor function mediates serine-639 phosphorylation of Cas during integrin activation in PO myocardium. PMID:25976166

Are Canadian clinicians providing consistent sport-related concussion management advice?

PubMed

Carson, James D; Rendely, Alexandra; Garel, Alisha; Meaney, Christopher; Stoller, Jacqueline; Kaicker, Jatin; Hayden, Leigh; Moineddin, Rahim; Frémont, Pierre

2016-06-01

To compare the knowledge and use of recommendations for the management of sport-related concussion (SRC) among sport and exercise medicine physicians (SEMPs) and emergency department physicians (EDPs) to assess the success of SRC knowledge transfer across Canada. A self-administered, multiple-choice survey accessed via e-mail by SEMPs and EDPs. The survey had been assessed for content validity. Canada. The survey was completed between May and July 2012 by SEMPs who had passed the diploma examination of the Canadian Academy of Sport and Exercise Medicine and by EDPs who did not hold this diploma. Knowledge and identification of sources of concussion management information, use of concussion diagnosis strategies, and whether physicians use common and consistent terminology when explaining cognitive rest strategies to patients after an SRC. There was a response rate of 28% (305 of 1085). The SEMP and EDP response rates were 41% (147 of 360) and 22% (158 of 725), respectively. Of the responses, 41% of EDPs and 3% of SEMPs were unaware of any consensus statements on concussion in sport; 74% of SEMPs used the Sport Concussion Assessment Tool, version 2 (SCAT2), "usually or always," whereas 88% of EDPs never used the SCAT2. When queried about how cognitive rest could best be achieved after an SRC, no consistent answer was documented. Differences and a lack of consistency in the implementation of recommendations for SRC patients were identified for SEMPs and EDPs. It appears that the SCAT2 is used more in the SEMP setting than in the emergency context. Further knowledge transfer efforts and research should address the barriers to achieving more consistent advice given by physicians who attend SRC patients. Copyright© the College of Family Physicians of Canada.

Investigating Perfect Timesharing: The Relationship between IM-Compatible Tasks and Dual-Task Performance

ERIC Educational Resources Information Center

Halvorson, Kimberly M.; Ebner, Herschel; Hazeltine, Eliot

2013-01-01

Why are dual-task costs reduced with ideomotor (IM) compatible tasks (Greenwald & Shulman, 1973; Lien, Proctor & Allen, 2002)? In the present experiments, we first examine three different measures of single-task performance (pure single-task blocks, mixed blocks, and long stimulus onset asynchrony [SOA] trials in dual-task blocks) and two…

The Endoplasmic Reticulum Is a Reservoir for WAVE/SCAR Regulatory Complex Signaling in the Arabidopsis Leaf1[W][OA

PubMed Central

Zhang, Chunhua; Mallery, Eileen; Reagan, Sara; Boyko, Vitaly P.; Kotchoni, Simeon O.; Szymanski, Daniel B.

2013-01-01

During plant cell morphogenesis, signal transduction and cytoskeletal dynamics interact to locally organize the cytoplasm and define the geometry of cell expansion. The WAVE/SCAR (for WASP family verprolin homologous/suppressor of cyclic AMP receptor) regulatory complex (W/SRC) is an evolutionarily conserved heteromeric protein complex. Within the plant kingdom W/SRC is a broadly used effector that converts Rho-of-Plants (ROP)/Rac small GTPase signals into Actin-Related Protein2/3 and actin-dependent growth responses. Although the components and biochemistry of the W/SRC pathway are well understood, a basic understanding of how cells partition W/SRC into active and inactive pools is lacking. In this paper, we report that the endoplasmic reticulum (ER) is an important organelle for W/SRC regulation. We determined that a large intracellular pool of the core W/SRC subunit NAP1, like the known positive regulator of W/SRC, the DOCK family guanine nucleotide-exchange factor SPIKE1 (SPK1), localizes to the surface of the ER. The ER-associated NAP1 is inactive because it displays little colocalization with the actin network, and ER localization requires neither activating signals from SPK1 nor a physical association with its W/SRC-binding partner, SRA1. Our results indicate that in Arabidopsis (Arabidopsis thaliana) leaf pavement cells and trichomes, the ER is a reservoir for W/SRC signaling and may have a key role in the early steps of W/SRC assembly and/or activation. PMID:23613272

Response surface methodology to simplify calculation of wood energy potency from tropical short rotation coppice species

NASA Astrophysics Data System (ADS)

Haqiqi, M. T.; Yuliansyah; Suwinarti, W.; Amirta, R.

2018-04-01

Short Rotation Coppice (SRC) system is an option to provide renewable and sustainable feedstock in generating electricity for rural area. Here in this study, we focussed on application of Response Surface Methodology (RSM) to simplify calculation protocols to point out wood chip production and energy potency from some tropical SRC species identified as Bauhinia purpurea, Bridelia tomentosa, Calliandra calothyrsus, Fagraea racemosa, Gliricidia sepium, Melastoma malabathricum, Piper aduncum, Vernonia amygdalina, Vernonia arborea and Vitex pinnata. The result showed that the highest calorific value was obtained from V. pinnata wood (19.97 MJ kg-1) due to its high lignin content (29.84 %, w/w). Our findings also indicated that the use of RSM for estimating energy-electricity of SRC wood had significant term regarding to the quadratic model (R2 = 0.953), whereas the solid-chip ratio prediction was accurate (R2 = 1.000). In the near future, the simple formula will be promising to calculate energy production easily from woody biomass, especially from SRC species.

Population activity statistics dissect subthreshold and spiking variability in V1.

PubMed

Bányai, Mihály; Koman, Zsombor; Orbán, Gergő

2017-07-01

Response variability, as measured by fluctuating responses upon repeated performance of trials, is a major component of neural responses, and its characterization is key to interpret high dimensional population recordings. Response variability and covariability display predictable changes upon changes in stimulus and cognitive or behavioral state, providing an opportunity to test the predictive power of models of neural variability. Still, there is little agreement on which model to use as a building block for population-level analyses, and models of variability are often treated as a subject of choice. We investigate two competing models, the doubly stochastic Poisson (DSP) model assuming stochasticity at spike generation, and the rectified Gaussian (RG) model tracing variability back to membrane potential variance, to analyze stimulus-dependent modulation of both single-neuron and pairwise response statistics. Using a pair of model neurons, we demonstrate that the two models predict similar single-cell statistics. However, DSP and RG models have contradicting predictions on the joint statistics of spiking responses. To test the models against data, we build a population model to simulate stimulus change-related modulations in pairwise response statistics. We use single-unit data from the primary visual cortex (V1) of monkeys to show that while model predictions for variance are qualitatively similar to experimental data, only the RG model's predictions are compatible with joint statistics. These results suggest that models using Poisson-like variability might fail to capture important properties of response statistics. We argue that membrane potential-level modeling of stochasticity provides an efficient strategy to model correlations. NEW & NOTEWORTHY Neural variability and covariability are puzzling aspects of cortical computations. For efficient decoding and prediction, models of information encoding in neural populations hinge on an appropriate model of variability. Our work shows that stimulus-dependent changes in pairwise but not in single-cell statistics can differentiate between two widely used models of neuronal variability. Contrasting model predictions with neuronal data provides hints on the noise sources in spiking and provides constraints on statistical models of population activity. Copyright © 2017 the American Physiological Society.

Short-term residential care for dementia patients: predictors for utilization and expected quality from a family caregiver's point of view.

PubMed

Donath, Carolin; Winkler, Angelika; Grässel, Elmar

2009-08-01

Short-term residential care (SRC) has proved to be effective in reducing the burden on family caregivers of dementia patients. Nevertheless, little is known about the factors which influence its usage or the expectations of family caregivers regarding quality. In this paper we address the following questions: (i) which variables of the care situation, the caregivers and their attitudes act as predictors for the utilization of SRC facilities? (ii) What are the views of caregivers about the quality of SRC? The cross-sectional study was carried out as an anonymous written survey of family caregivers of dementia patients in four regions of Germany. With a 20% response it was possible to analyze the quantitative and qualitative data from 404 and 254 family caregivers respectively. Predictors for utilization were evaluated using binary logistic regression analysis. The answers to questions of quality were evaluated using qualitative content analysis. Significant predictors for the utilization of SRC are the assessment of the helpfulness of SRC and the caregiver's knowledge of the accessibility of SRC facilities. Family caregivers who had already used SRC most frequently expressed the wish for "good care" in SRC facilities, followed by a program of suitable activities for dementia patients. In order to increase the rate of utilization, family caregivers must be convinced of the relevant advantages of using SRC facilities. The staff should be trained in caring for dementia patients and appropriate activities should be available.

Rhynchophylline Ameliorates Endothelial Dysfunction via Src-PI3K/Akt-eNOS Cascade in the Cultured Intrarenal Arteries of Spontaneous Hypertensive Rats

PubMed Central

Hao, Hui-Feng; Liu, Li-Mei; Pan, Chun-Shui; Wang, Chuan-She; Gao, Yuan-Sheng; Fan, Jing-Yu; Han, Jing-Yan

2017-01-01

Objectives: To examine the protective effect of Rhynchophylline (Rhy) on vascular endothelial function in spontaneous hypertensive rats (SHRs) and the underlying mechanism. Methods: Intrarenal arteries of SHRs and Wistar rats were suspended in myograph for force measurement. Expression and phosphorylation of endothelial nitric oxide (NO) synthase (eNOS), Akt, and Src kinase (Src) were examined by Western blotting. NO production was assayed by ELISA. Results: Rhy time- and concentration-dependently improved endothelium-dependent relaxation in the renal arteries from SHRs, but had no effect on endothelium-independent relaxation in SHR renal arteries. Wortmannin (an inhibitor of phosphatidylinositol 3-kinase) or PP2 (an inhibitor of Src) inhibited the improvement of relaxation in response to acetylcholine by 12 h-incubation with 300 μM Rhy. Western blot analysis revealed that Rhy elevated phosphorylations of eNOS, Akt, and Src in SHR renal arteries. Moreover, wortmannin reversed the increased phosphorylations of Akt and eNOS induced by Rhy, but did not affect the phosphorylation of Src. Furthermore, the enhanced phosphorylations of eNOS, Akt, and Src were blunted by PP2. Importantly, Rhy increased NO production and this effect was blocked by inhibition of Src or PI3K/Akt. Conclusion: The present study provides evidences for the first time that Rhy ameliorates endothelial dysfunction in SHRs through the activation of Src-PI3K/Akt-eNOS signaling pathway. PMID:29187825

HSP27 phosphorylation modulates TRAIL-induced activation of Src-Akt/ERK signaling through interaction with β-arrestin2.

PubMed

Qi, Shimei; Xin, Yinqiang; Qi, Zhilin; Xu, Yimiao; Diao, Ying; Lan, Lei; Luo, Lan; Yin, Zhimin

2014-03-01

Heat shock protein 27 (HSP27) regulates critical cellular functions such as development, differentiation, cell growth and apoptosis. A variety of stimuli induce the phosphorylation of HSP27, which affects its cellular functions. However, most previous studies focused on the role of HSP27 protein itself in apoptosis, the particular role of its phosphorylation state in signaling transduction remains largely unclear. In the present study, we reported that HSP27 phosphorylation modulated TRAIL-triggered pro-survival signaling transduction. In HeLa cells, suppression of HSP27 phosphorylation by specific inhibitor KRIBB3 or MAPKAPK2 (MK2) knockdown and by overexpression of non-phosphorylatable HSP27(3A) mutant demonstrated that hindered HSP27 phosphorylation enhanced the TRAIL-induced apoptosis. In addition, reduced HSP27 phosphorylation by KRIBB3 treatment or MK2 knockdown attenuated the TRAIL-induced activation of Akt and ERK survival signaling through suppressing the phosphorylation of Src. By overexpression of HSP27(15A) or HSP27(78/82A) phosphorylation mutant, we further showed that phosphorylation of HSP27 at serine 78/82 residues was essential to TRAIL-triggered Src-Akt/ERK signaling transduction. Co-immunoprecipitation and confocal microscopy showed that HSP27 interacted with Src and scaffolding protein β-arrestin2 in response of TRAIL stimulation and suppression of HSP27 phosphorylation apparently disrupted the TRAIL-induced interaction of HSP27 and Src or interaction of HSP27 and β-arrestin2. We further demonstrated that β-arrestin2 mediated HSP27 action on TRAIL-induced Src activation, which was achieved by recruiting signaling complex of HSP27/β-arrestin2/Src in response to TRAIL. Taken together, our study revealed that HSP27 phosphorylation modulates TRAIL-triggered activation of Src-Akt/ERK pro-survival signaling via interacting with β-arrestin2 in HeLa cells. Copyright © 2013 Elsevier Inc. All rights reserved.

Wireless simultaneous stimulation-and-recording device to train cortical circuits in somatosensory cortex.

PubMed

Ramshur, John T; de Jongh Curry, Amy L; Waters, Robert S

2014-01-01

We describe for the first time the design, implementation, and testing of a telemetry controlled simultaneous stimulation and recording device (SRD) to deliver chronic intercortical microstimulation (ICMS) to physiologically identified sites in rat somatosensory cortex (SI) and test hypotheses that chronic ICMS strengthens interhemispheric pathways and leads to functional reorganization in the enhanced cortex. The SRD is a custom embedded device that uses the Cypress Semiconductor's programmable system on a chip (PSoC) that is remotely controlled via Bluetooth. The SRC can record single or multiunit responses from any two of 12 available inputs at 1-15 ksps per channel and simultaneously deliver stimulus pulses (0-255 μA; 10 V compliance) to two user selectable electrodes using monophasic, biphasic, or pseudophasic stimulation waveforms (duration: 0-5 ms, inter-phase interval: 0-5 ms, frequency: 0.1-5 s, delay: 0-10 ms). The SRD was bench tested and validated in vivo in a rat animal model.

Express path analysis identifies a tyrosine kinase Src-centric network regulating divergent host responses to Mycobacterium tuberculosis infection.

PubMed

Karim, Ahmad Faisal; Chandra, Pallavi; Chopra, Aanchal; Siddiqui, Zaved; Bhaskar, Ashima; Singh, Amit; Kumar, Dhiraj

2011-11-18

Global gene expression profiling has emerged as a major tool in understanding complex response patterns of biological systems to perturbations. However, a lack of unbiased analytical approaches has restricted the utility of complex microarray data to gain novel system level insights. Here we report a strategy, express path analysis (EPA), that helps to establish various pathways differentially recruited to achieve specific cellular responses under contrasting environmental conditions in an unbiased manner. The analysis superimposes differentially regulated genes between contrasting environments onto the network of functional protein associations followed by a series of iterative enrichments and network analysis. To test the utility of the approach, we infected THP1 macrophage cells with a virulent Mycobacterium tuberculosis strain (H37Rv) or the attenuated non-virulent strain H37Ra as contrasting perturbations and generated the temporal global expression profiles. EPA of the results provided details of response-specific and time-dependent host molecular network perturbations. Further analysis identified tyrosine kinase Src as the major regulatory hub discriminating the responses between wild-type and attenuated Mtb infection. We were then able to verify this novel role of Src experimentally and show that Src executes its role through regulating two vital antimicrobial processes of the host cells (i.e. autophagy and acidification of phagolysosome). These results bear significant potential for developing novel anti-tuberculosis therapy. We propose that EPA could prove extremely useful in understanding complex cellular responses for a variety of perturbations, including pathogenic infections.

C-terminal Src kinase (Csk) regulates the tricellular junction protein Gliotactin independent of Src

PubMed Central

Samarasekera, G. D. N. Gayathri; Auld, Vanessa Jane

2018-01-01

Tricellular junctions (TCJs) are uniquely placed permeability barriers formed at the corners of polarized epithelia where tight junctions in vertebrates or septate junctions (SJ) in invertebrates from three cells converge. Gliotactin is a Drosophila TCJ protein, and loss of Gliotactin results in SJ and TCJ breakdown and permeability barrier loss. When overexpressed, Gliotactin spreads away from the TCJs, resulting in disrupted epithelial architecture, including overproliferation, cell delamination, and migration. Gliotactin levels are tightly controlled at the mRNA level and at the protein level through endocytosis and degradation triggered by tyrosine phosphorylation. We identified C-terminal Src kinase (Csk) as a tyrosine kinase responsible for regulating Gliotactin endocytosis. Increased Csk suppresses the Gliotactin overexpression phenotypes by increasing endocytosis. Loss of Csk causes Gliotactin to spread away from the TCJ. Although Csk is known as a negative regulator of Src kinases, the effects of Csk on Gliotactin are independent of Src and likely occur through an adherens junction associated complex. Overall, we identified a new Src-independent role for Csk in the control of Gliotactin, a key tricellular junction protein. PMID:29167383

Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer.

PubMed

Moi, Line L Haugan; Flågeng, Marianne Hauglid; Gjerde, Jennifer; Madsen, Andre; Røst, Therese Halvorsen; Gudbrandsen, Oddrun Anita; Lien, Ernst A; Mellgren, Gunnar

2012-06-15

Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0.001). The expression of SRCs and HER-2 and -3 is stimulated by tamoxifen treatment in DMBA-induced breast cancer. Stimulation and positive correlation of coactivators and HERs may represent an early response to endocrine treatment. The role of SRCs and HER-2 and -3 should be further studied in order to evaluate their effects on response to long-term tamoxifen treatment.

Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer

PubMed Central

2012-01-01

Background Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Methods Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Results Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0.001). Conclusions The expression of SRCs and HER-2 and -3 is stimulated by tamoxifen treatment in DMBA-induced breast cancer. Stimulation and positive correlation of coactivators and HERs may represent an early response to endocrine treatment. The role of SRCs and HER-2 and -3 should be further studied in order to evaluate their effects on response to long-term tamoxifen treatment. PMID:22703232

Behavioral and TMS Markers of Action Observation Might Reflect Distinct Neuronal Processes.

PubMed

Hétu, Sébastien; Taschereau-Dumouchel, Vincent; Meziane, Hadj Boumediene; Jackson, Philip L; Mercier, Catherine

2016-01-01

Transcranial magnetic stimulation (TMS) studies have shown that observing an action induces muscle-specific changes in corticospinal excitability. From a signal detection theory standpoint, this pattern can be related to sensitivity, which here would measure the capacity to distinguish between two action observation conditions. In parallel to these TMS studies, action observation has also been linked to behavioral effects such as motor priming and interference. It has been hypothesized that behavioral markers of action observation could be related to TMS markers and thus represent a potentially cost-effective mean of assessing the functioning of the action-perception system. However, very few studies have looked at possible relationships between these two measures. The aim of this study was to investigate if individual differences in sensitivity to action observation could be related to the behavioral motor priming and interference effects produced by action observation. To this end, 14 healthy participants observed index and little finger movements during a TMS task and a stimulus-response compatibility task. Index muscle displayed sensitivity to action observation, and action observation resulted in significant motor priming+interference, while no significant effect was observed for the little finger in both task. Nevertheless, our results indicate that the sensitivity measured in TMS was not related to the behavioral changes measured in the stimulus-response compatibility task. Contrary to a widespread assumption, the current results indicate that individual differences in physiological and behavioral markers of action observation may be unrelated. This could have important impacts on the potential use of behavioral markers in place of more costly physiological markers of action observation in clinical settings.

Activation of Src kinase by protein-tyrosine phosphatase-PEST in osteoclasts: comparative analysis of the effects of bisphosphonate and protein-tyrosine phosphatase inhibitor on Src activation in vitro.

PubMed

Chellaiah, Meenakshi A; Schaller, Michael D

2009-08-01

PTP-PEST is involved in the regulation of sealing ring formation in osteoclasts. In this article, we have shown a regulatory role for PTP-PEST on dephosphorylation of c-Src at Y527 and phosphorylation at Y418 in the catalytic site. Activation of Src in osteoclasts by over-expression of PTP-PEST resulted in the phosphorylation of cortactin at Y421 and WASP at Y294. Also enhanced as a result, is the interaction of Src, cortactin, and Arp2 with WASP. Moreover, the number of osteoclasts displaying sealing ring and bone resorbing activity was increased in response to PTP-PEST over-expression as compared with control osteoclasts. Cells expressing constitutively active-Src (527YDeltaF) simulate the effects mediated by PTP-PEST. Treatment of osteoclasts with a bisphosphonate alendronate or a potent PTP inhibitor PAO decreased the activity and phosphorylation of Src at Y418 due to reduced dephosphorylation state at Y527. Therefore, Src-mediated phosphorylation of cortactin and WASP as well as the formation of WASP.cortactin.Arp2 complex and sealing ring were reduced in these osteoclasts. Similar effects were observed in osteoclasts treated with an Src inhibitor PP2. We have shown that bisphosphonates could modulate the function of osteoclasts by inhibiting downstream signaling mediated by PTP-PEST/Src, in addition to its effect on the inhibition of the post-translational modification of small GTP-binding proteins such as Rab, Rho, and Rac as shown by others. The promising effects of the inhibitors PP2 and PAO on osteoclast function suggest a therapeutic approach for patients with bone metastases and osteoporosis as an alternative to bisphosphonates.

Scavenger Receptor C Mediates Phagocytosis of White Spot Syndrome Virus and Restricts Virus Proliferation in Shrimp

PubMed Central

Yang, Ming-Chong; Shi, Xiu-Zhen; Yang, Hui-Ting; Sun, Jie-Jie; Xu, Ling; Wang, Xian-Wei; Zhao, Xiao-Fan

2016-01-01

Scavenger receptors are an important class of pattern recognition receptors that play several important roles in host defense against pathogens. The class C scavenger receptors (SRCs) have only been identified in a few invertebrates, and their role in the immune response against viruses is seldom studied. In this study, we firstly identified an SRC from kuruma shrimp, Marsupenaeus japonicus, designated MjSRC, which was significantly upregulated after white spot syndrome virus (WSSV) challenge at the mRNA and protein levels in hemocytes. The quantity of WSSV increased in shrimp after knockdown of MjSRC, compared with the controls. Furthermore, overexpression of MjSRC led to enhanced WSSV elimination via phagocytosis by hemocytes. Pull-down and co-immunoprecipitation assays demonstrated the interaction between MjSRC and the WSSV envelope protein. Electron microscopy observation indicated that the colloidal gold-labeled extracellular domain of MjSRC was located on the outer surface of WSSV. MjSRC formed a trimer and was internalized into the cytoplasm after WSSV challenge, and the internalization was strongly inhibited after knockdown of Mjβ-arrestin2. Further studies found that Mjβ-arrestin2 interacted with the intracellular domain of MjSRC and induced the internalization of WSSV in a clathrin-dependent manner. WSSV were co-localized with lysosomes in hemocytes and the WSSV quantity in shrimp increased after injection of lysosome inhibitor, chloroquine. Collectively, this study demonstrated that MjSRC recognized WSSV via its extracellular domain and invoked hemocyte phagocytosis to restrict WSSV systemic infection. This is the first study to report an SRC as a pattern recognition receptor promoting phagocytosis of a virus. PMID:28027319

The Role of C-SRC Activation in Prostate Tumor Progression

DTIC Science & Technology

2006-07-01

cancer cell line PANC -1 and prostrate cancer cell line PC-3 (B2-fold increase relative to control in both cell lines), while the Src inhibitory PP2 blocks...at normoxia in PANC -1 and PC-3 cells, its levels significantly increase in response to hypoxia (B4.5–8-fold induction). Inhibition of endo- genous c...Src activation in PANC -1 and PC-3 cells by PP2 drastically reduced HIF-1a levels to below those levels observed at normoxia (Figure 1a). STAT3 has

Focal complex formation in adult cardiomyocytes is accompanied by the activation of beta3 integrin and c-Src.

PubMed

Willey, Christopher D; Balasubramanian, Sundaravadivel; Rodríguez Rosas, María C; Ross, Robert S; Kuppuswamy, Dhandapani

2003-06-01

In pressure-overloaded myocardium, our recent study demonstrated cytoskeletal assembly of c-Src and other signaling proteins which was partially mimicked in vitro using adult feline cardiomyocytes embedded in three-dimensional (3D) collagen matrix and stimulated with an integrin-binding Arg-Gly-Asp (RGD) peptide. In the present study, we improved this model further to activate c-Src and obtain a full assembly of the focal adhesion complex (FAC), and characterized c-Src localization and integrin subtype(s) involved. RGD dose response experiments revealed that c-Src activation occurs subsequent to its cytoskeletal recruitment and is accompanied by p130Cas cytoskeletal binding and focal adhesion kinase (FAK) Tyr925 phosphorylation. When cardiomyocytes expressing hexahistidine-tagged c-Src via adenoviral gene delivery were used for RGD stimulation, the expressed c-Src exhibited relocation: (i) biochemical analysis revealed c-Src movement from the detergent-soluble to the -insoluble cytoskeletal fraction and (ii) confocal microscopic analysis showed c-Src movement from a nuclear/perinuclear to a sarcolemmal region. RGD treatment also caused sarcolemmal co-localization of FAK and vinculin. Characterization of integrin subtypes revealed that beta3, but not beta1, integrin plays a predominant role: (i) expression of cytoplasmic domain of beta1A integrin did not affect the RGD-stimulated FAC formation and (ii) both pressure-overloaded myocardium and RGD-stimulated cardiomyocytes exhibited phosphorylation of beta3 integrin at Tyr773/785 sites but not beta1 integrin at Thr788/789 sites. Together these data indicate that RGD treatment in cardiomyocytes causes beta3 integrin activation and c-Src sarcolemmal localization, that subsequent c-Src activation is accompanied by p130Cas binding and FAK Tyr925 phosphorylation, and that these events might be crucial for growth and remodeling of hypertrophying adult cardiomyocytes.

Effects of working memory contents and perceptual load on distractor processing: When a response-related distractor is held in working memory.

PubMed

Koshino, Hideya

2017-01-01

Working memory and attention are closely related. Recent research has shown that working memory can be viewed as internally directed attention. Working memory can affect attention in at least two ways. One is the effect of working memory load on attention, and the other is the effect of working memory contents on attention. In the present study, an interaction between working memory contents and perceptual load in distractor processing was investigated. Participants performed a perceptual load task in a standard form in one condition (Single task). In the other condition, a response-related distractor was maintained in working memory, rather than presented in the same stimulus display as a target (Dual task). For the Dual task condition, a significant compatibility effect was found under high perceptual load; however, there was no compatibility effect under low perceptual load. These results suggest that the way the contents of working memory affect visual search depends on perceptual load. Copyright © 2016 Elsevier B.V. All rights reserved.

Src-dependent Tyrosine Phosphorylation of Non-muscle Myosin Heavy Chain-IIA Restricts Listeria monocytogenes Cellular Infection*

PubMed Central

Almeida, Maria Teresa; Mesquita, Francisco S.; Cruz, Rui; Osório, Hugo; Custódio, Rafael; Brito, Cláudia; Vingadassalom, Didier; Martins, Mariana; Leong, John M.; Holden, David W.; Cabanes, Didier; Sousa, Sandra

2015-01-01

Bacterial pathogens often interfere with host tyrosine phosphorylation cascades to control host responses and cause infection. Given the role of tyrosine phosphorylation events in different human infections and our previous results showing the activation of the tyrosine kinase Src upon incubation of cells with Listeria monocytogenes, we searched for novel host proteins undergoing tyrosine phosphorylation upon L. monocytogenes infection. We identify the heavy chain of the non-muscle myosin IIA (NMHC-IIA) as being phosphorylated in a specific tyrosine residue in response to L. monocytogenes infection. We characterize this novel post-translational modification event and show that, upon L. monocytogenes infection, Src phosphorylates NMHC-IIA in a previously uncharacterized tyrosine residue (Tyr-158) located in its motor domain near the ATP-binding site. In addition, we found that other intracellular and extracellular bacterial pathogens trigger NMHC-IIA tyrosine phosphorylation. We demonstrate that NMHC-IIA limits intracellular levels of L. monocytogenes, and this is dependent on the phosphorylation of Tyr-158. Our data suggest a novel mechanism of regulation of NMHC-IIA activity relying on the phosphorylation of Tyr-158 by Src. PMID:25635050

Coal Technology Program progress report for April 1976

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

In the Hydrocarbonization Research program, two successful experiments were completed in the bench-scale hydrocarbonizer. A settling test at a lower temperature (390/sup 0/F) using 20 percent toluene in Solvent Refined Coal (SRC) Unfiltered Oil (UFO) produced a 30 percent clarified product in 2 hr. Characterization tests include distillation curves for Wilsonville's SRC-UFO and a particle size distribution of Pittsburg and Midway Coal Mining Company's (PAMCO) SRC-UFO. Studies of intermediate-temperature pyrolysis of large blocks have been maintained with char samples continuing to demonstrate pyrophoricity, even after heating to 700/sup 0/C. Simulated distillation analysis of tars produced by the last eight experimentsmore » are being compared with those performed at Laramie upon tars produced by the Hanna No. 2 experiment. In Coal-Fueled MIUS, stainless steel tubing to be used in one of the furnace tube bundles was ordered and the bid package for the furnace completed. Tests continued on the coal feed system and with the cold flow fluidized bed model. For the Synthoil process, flow diagrams, material balances, and utilities requirements were completed for the entire facility. For the Hydrocarbonization process, flowsheets were reviewed for compatibility; equipment lists were brought up to date; and utilities requirements were compiled from the individual flowsheets. The char recovery and storage subsystem flowsheet was completed. (auth)« less

Hormonal regulation of steroid receptor coactivator-1 mRNA in the male and female green anole brain.

PubMed

Kerver, H N; Wade, J

2015-03-01

Green anole lizards are seasonal breeders, with male sexual behaviour primarily regulated by an annual increase in testosterone. Morphological, biochemical and behavioural changes associated with reproduction are activated by testosterone, generally with a greater effect in the breeding season (BS) than in the nonbreeding season (NBS). The present study investigates the possibility that differences in a steroid receptor coactivator may regulate this seasonal difference in responsiveness to testosterone. In situ hybridisation was used to examine the expression of steroid receptor coactivator-1 (SRC-1) in the brains of gonadally intact male and female green anoles across breeding states. A second experiment examined gonadectomised animals with and without testosterone treatment. Gonadally intact males had more SRC-1 expressing cells in the preoptic area and larger volumes of this region as defined by these cells than females. Main effects of both sex and season (males > females and BS > NBS) were present in cell number and volume of the ventromedial hypothalamus. An interaction between sex and season suggested that high expression in BS males was driving these effects. In hormone-manipulated animals, testosterone treatment increased both the number of SRC-1 expressing cells in and volumes of the preoptic area and amygdala. These results suggest that testosterone selectively regulates SRC-1, and that this coactivator may play a role in facilitating reproductive behaviours across both sexes. However, changes in SRC-1 expression are not likely responsible for the seasonal change in responsiveness to testosterone. © 2014 British Society for Neuroendocrinology.

Atypical protein kinase C activity is required for extracellular matrix degradation and invasion by Src-transformed cells.

PubMed

Rodriguez, Elena M; Dunham, Elizabeth E; Martin, G Steven

2009-10-01

Atypical protein kinase C (aPKC) isoforms have been shown to mediate Src-dependent signaling in response to growth factor stimulation. To determine if aPKC activity contributes to the transformed phenotype of cells expressing oncogenic Src, we have examined the activity and function of aPKCs in 3T3 cells expressing viral Src (v-Src). aPKC activity and tyrosine phosphorylation were found to be elevated in some but not all clones of mouse fibroblasts expressing v-Src. aPKC activity was inhibited either by addition of a membrane-permeable pseudosubstrate, by expression of a dominant-negative aPKC, or by RNAi-mediated knockdown of specific aPKC isoforms. aPKC activity contributes to morphological transformation and stress fiber disruption, and is required for migration of Src-transformed cells and for their ability to polarize at the edge of a monolayer. The lambda isoform of aPKC is specifically required for invasion through extracellular matrix in Boyden chamber assays and for degradation of the extracellular matrix in in situ zymography assays. Tyrosine phosphorylation of aPKClambda is required for its ability to promote cell invasion. The defect in invasion upon aPKC inhibition appears to result from a defect in the assembly and/or function of podosomes, invasive adhesions on the ventral surface of the cell that are sites of protease secretion. aPKC was also found to localize to podosomes of v-Src transformed cells, suggesting a direct role for aPKC in podosome assembly and/or function. We conclude that basal or elevated aPKC activity is required for the ability of Src-transformed cells to degrade and invade the extracellular matrix. Copyright 2009 Wiley-Liss, Inc.

1α,25(OH)2-Vitamin D3 Inhibits C2C12 Cell Differentiation by Activating c-Src and ERK1/2.

PubMed

Wang, Zhonghua; Jiang, Aijun; Mei, Jingwei; Zhang, Xinyan

2018-05-01

The steroid hormone 1α,25(OH)2-vitamin D3 (1,25-D3) induced some biological responses through activation of MAPK cascades in various cell types. It seems that 1,25-D3 plays different roles at different stages of proliferating, differentiating, and differentiated C2C12 cells. We wanted to detect the effect of 1,25-D3 on myogenic differentiation and the role of ERK1/2 in differentiating stage induced by 2% horse serum with 1,25-D3. In this study, cells were induced to differentiate with 2% horse serum until the 7th day (with addition of 1,25-D3 every two days). The protein level of MHC (myosin heavy chain) and phosphorylation level of Src and ERK1/2 were determined with western blot. U0126 (MEK inhibitor) and PP2 (Src specific inhibitor) were used to confirm the relationship between 1,25-D3, MHC, Src, and ERK1/2. 1,25-D3 inhibited differentiation of C2C12 cells and fusion of myotubes by phosphorylating and activating Src and ERK1/2. Phosphorylation of ERK1/2 was inhibited, not only by U0126 but also by PP2 (a Src specific inhibitor) which led to the promotion of differentiation of C2C12 cells; however, U0126 did not inhibit Src phosphorylation. These results suggested that 1,25-D3 possibly inhibited C2C12 differentiation through Src and ERK1/2, and Src played an upstream role in this signaling pathway.

Control of vascular smooth muscle function by Src-family kinases and reactive oxygen species in health and disease

PubMed Central

MacKay, Charles E; Knock, Greg A

2015-01-01

Abstract Reactive oxygen species (ROS) are now recognised as second messenger molecules that regulate cellular function by reversibly oxidising specific amino acid residues of key target proteins. Amongst these are the Src-family kinases (SrcFKs), a multi-functional group of non-receptor tyrosine kinases highly expressed in vascular smooth muscle (VSM). In this review we examine the evidence supporting a role for ROS-induced SrcFK activity in normal VSM contractile function and in vascular remodelling in cardiovascular disease. VSM contractile responses to G-protein-coupled receptor stimulation, as well as hypoxia in pulmonary artery, are shown to be dependent on both ROS and SrcFK activity. Specific phosphorylation targets are identified amongst those that alter intracellular Ca2+ concentration, including transient receptor potential channels, voltage-gated Ca2+ channels and various types of K+ channels, as well as amongst those that regulate actin cytoskeleton dynamics and myosin phosphatase activity, including focal adhesion kinase, protein tyrosine kinase-2, Janus kinase, other focal adhesion-associated proteins, and Rho guanine nucleotide exchange factors. We also examine a growing weight of evidence in favour of a key role for SrcFKs in multiple pro-proliferative and anti-apoptotic signalling pathways relating to oxidative stress and vascular remodelling, with a particular focus on pulmonary hypertension, including growth-factor receptor transactivation and downstream signalling, hypoxia-inducible factors, positive feedback between SrcFK and STAT3 signalling and positive feedback between SrcFK and NADPH oxidase dependent ROS production. We also discuss evidence for and against the potential therapeutic targeting of SrcFKs in the treatment of pulmonary hypertension. PMID:25384773

Priming Gestures with Sounds

PubMed Central

Lemaitre, Guillaume; Heller, Laurie M.; Navolio, Nicole; Zúñiga-Peñaranda, Nicolas

2015-01-01

We report a series of experiments about a little-studied type of compatibility effect between a stimulus and a response: the priming of manual gestures via sounds associated with these gestures. The goal was to investigate the plasticity of the gesture-sound associations mediating this type of priming. Five experiments used a primed choice-reaction task. Participants were cued by a stimulus to perform response gestures that produced response sounds; those sounds were also used as primes before the response cues. We compared arbitrary associations between gestures and sounds (key lifts and pure tones) created during the experiment (i.e. no pre-existing knowledge) with ecological associations corresponding to the structure of the world (tapping gestures and sounds, scraping gestures and sounds) learned through the entire life of the participant (thus existing prior to the experiment). Two results were found. First, the priming effect exists for ecological as well as arbitrary associations between gestures and sounds. Second, the priming effect is greatly reduced for ecologically existing associations and is eliminated for arbitrary associations when the response gesture stops producing the associated sounds. These results provide evidence that auditory-motor priming is mainly created by rapid learning of the association between sounds and the gestures that produce them. Auditory-motor priming is therefore mediated by short-term associations between gestures and sounds that can be readily reconfigured regardless of prior knowledge. PMID:26544884

JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells.

PubMed

Maślikowski, Bart M; Wang, Lizhen; Wu, Ying; Fielding, Ben; Bédard, Pierre-André

2017-01-01

The increase in AP-1 activity is a hallmark of cell transformation by tyrosine kinases. Previously, we reported that blocking AP-1 using the c-Jun dominant negative mutant TAM67 induced senescence, adipogenesis, or apoptosis in v-Src-transformed chicken embryo fibroblasts (CEFs) whereas inhibition of JunD by short hairpin RNA (shRNA) specifically induced apoptosis. To investigate the role of AP-1 in Src-mediated transformation, we undertook a gene profiling study to characterize the transcriptomes of v-Src-transformed CEFs expressing either TAM67 or the JunD shRNA. Our study revealed a cluster of 18 probe sets upregulated exclusively in response to AP-1/JunD impairment and v-Src transformation. Four of these probe sets correspond to genes involved in the interferon pathway. One gene in particular, death-associated protein kinase 1 (DAPK1), is a C/EBPβ-regulated mediator of apoptosis in gamma interferon (IFN-γ)-induced cell death. Here, we show that inhibition of DAPK1 abrogates cell death in v-Src-transformed cells expressing the JunD shRNA. Chromatin immunoprecipitation data indicated that C/EBPβ was recruited to the DAPK1 promoter while the expression of a dominant negative mutant of C/EBPβ abrogated the induction of DAPK1 in response to the inhibition of AP-1. In contrast, as determined by chromatin immunoprecipitation (ChIP) assays, JunD was not detected on the DAPK1 promoter under any conditions, suggesting that JunD promotes survival by indirectly antagonizing the expression of DAPK1 in v-Src transformed cells. Transformation by the v-Src oncoprotein causes extensive changes in gene expression in primary cells such as chicken embryo fibroblasts. These changes, determining the properties of transformed cells, are controlled in part at the transcriptional level. Much attention has been devoted to transcription factors such as AP-1 and NF-κB and the control of genes associated with a more aggressive phenotype. In this report, we describe a novel mechanism of action determined by the JunD component of AP-1, a factor enhancing cell survival in v-Src-transformed cells. We show that the loss of JunD results in the aberrant activation of a genetic program leading to cell death. This program requires the activation of the tumor suppressor death-associated protein kinase 1 (DAPK1). Since DAPK1 is phosphorylated and inhibited by v-Src, these results highlight the importance of this kinase and the multiple mechanisms controlled by v-Src to antagonize the tumor suppressor function of DAPK1. Copyright © 2016 American Society for Microbiology.

Combining Src inhibitors and aromatase inhibitors: a novel strategy for overcoming endocrine resistance and bone loss.

PubMed

Hiscox, Stephen; Barrett-Lee, Peter; Borley, Annabel C; Nicholson, Robert I

2010-08-01

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes. Copyright 2010 Elsevier Ltd. All rights reserved.

A RNA Interference Screen Identifies the Protein Phosphatase 2A Subunit PR55γ as a Stress-Sensitive Inhibitor of c-SRC

PubMed Central

Eichhorn, Pieter J. A; Creyghton, Menno P; Wilhelmsen, Kevin; van Dam, Hans; Bernards, René

2007-01-01

Protein Phosphatase type 2A (PP2A) represents a family of holoenzyme complexes with diverse biological activities. Specific holoenzyme complexes are thought to be deregulated during oncogenic transformation and oncogene-induced signaling. Since most studies on the role of this phosphatase family have relied on the use of generic PP2A inhibitors, the contribution of individual PP2A holoenzyme complexes in PP2A-controlled signaling pathways is largely unclear. To gain insight into this, we have constructed a set of shRNA vectors targeting the individual PP2A regulatory subunits for suppression by RNA interference. Here, we identify PR55γ and PR55δ as inhibitors of c-Jun NH2-terminal kinase (JNK) activation by UV irradiation. We show that PR55γ binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC. We also find that the physical interaction between PR55γ and c-SRC is sensitive to UV irradiation. Our data reveal a novel mechanism of c-SRC regulation whereby in response to stress c-SRC activity is regulated, at least in part, through loss of the interaction with its inhibitor, PR55γ. PMID:18069897

Selecting cockpit functions for speech I/O technology

NASA Technical Reports Server (NTRS)

Simpson, C. A.

1985-01-01

A general methodology for the initial selection of functions for speech generation and speech recognition technology is discussed. The SCR (Stimulus/Central-Processing/Response) compatibility model of Wickens et al. (1983) is examined, and its application is demonstrated for a particular cockpit display problem. Some limits of the applicability of that model are illustrated in the context of predicting overall pilot-aircraft system performance. A program of system performance measurement is recommended for the evaluation of candidate systems. It is suggested that no one measure of system performance can necessarily be depended upon to the exclusion of others. Systems response time, system accuracy, and pilot ratings are all important measures. Finally, these measures must be collected in the context of the total flight task environment.

Post-traumatic stress avoidance is attenuated by corticosterone and associated with brain levels of steroid receptor co-activator-1 in rats.

PubMed

Whitaker, Annie M; Farooq, Muhammad A; Edwards, Scott; Gilpin, Nicholas W

2016-01-01

Individuals with post-traumatic stress disorder (PTSD) avoid trauma-related stimuli and exhibit blunted hypothalamic-pituitary-adrenal (HPA) axis activation at the time of stress. Our rodent model of stress mimics the avoidance symptom cluster of PTSD. Rats are classified as "Avoiders" or "Non-Avoiders" post-stress based on the avoidance of a predator-odor paired context. Previously, we found Avoiders exhibit an attenuated HPA stress response to predator odor. We hypothesized that corticosterone administration before stress would reduce the magnitude and incidence of stress-paired context avoidance. Furthermore, we also predicted that Avoiders would exhibit altered expression of glucocorticoid receptor (GR) signaling machinery elements, including steroid receptor co-activator (SRC)-1. Male Wistar rats (n = 16) were pretreated with corticosterone (25 mg/kg) or saline and exposed to predator-odor stress paired with a context and tested for avoidance 24 h later. A second group of corticosterone-naïve rats (n = 24) were stressed (or not), indexed for avoidance 24 h later, and killed 48 h post-odor exposure to measure phosphorylated GR, FKBP51 and SRC-1 levels in the paraventricular nucleus (PVN), central amygdala (CeA) and ventral hippocampus (VH), all brain sites that highly express GRs and regulate HPA function. Corticosterone pretreatment reduced the magnitude and incidence of avoidance. In Avoiders, predator-odor exposure led to lower SRC-1 expression in the PVN and CeA, and higher SRC-1 expression in the VH. SRC-1 expression in PVN, CeA and VH was predicted by prior avoidance behavior. Hence, a blunted HPA stress response may contribute to stress-induced neuroadaptations in central SRC-1 levels and behavioral dysfunction in Avoider rats.

Advancing bioluminescence imaging technology for the evaluation of anticancer agents in the MDA-MB-435-HAL-Luc mammary fat pad and subrenal capsule tumor models.

PubMed

Zhang, Cathy; Yan, Zhengming; Arango, Maria E; Painter, Cory L; Anderes, Kenna

2009-01-01

Tumors grafted s.c. or under the mammary fat pad (MFP) rarely develop efficient metastasis. By applying bioluminescence imaging (BLI) technology, the MDA-MB-435-HAL-Luc subrenal capsule (SRC) model was compared with the MFP model for disease progression, metastatic potential, and response to therapy. The luciferase-expressing MDA-MB-435-HAL-Luc cell line was used in both MFP and SRC models. BLI technology allowed longitudinal assessment of disease progression and the therapeutic response to PD-0332991, Avastin, and docetaxel. Immunohistochemical analysis of Ki67 and CD31 staining in the primary tumors was compared in these models. Caliper measurement was used in the MFP model to validate the BLI quantification of primary tumors. The primary tumors in MDA-MB-435-HAL-Luc MFP and SRC models displayed comparable growth rates and vascularity. However, tumor-bearing mice in the SRC model developed lung metastases much earlier (4 weeks) than in the MFP model (>7 weeks), and the metastatic progression contributed significantly to the survival time. In the MFP model, BLI and caliper measurements were comparable for quantifying palpable tumors, but BLI offered an advantage for detecting the primary tumors that fell below a palpable threshold and for visualizing metastases. In the SRC model, BLI allowed longitudinal assessment of the antitumor and antimetastatic effects of PD-0332991, Avastin, and docetaxel, and the results correlated with the survival benefits of these agents. The MDA-MB-435-HAL-Luc SRC model and the MFP model displayed differences in disease progression. BLI is an innovative approach for developing animal models and creates opportunities for improving preclinical evaluations of anticancer agents.

Optimization study for Pb(II) and COD sequestration by consortium of sulphate-reducing bacteria

NASA Astrophysics Data System (ADS)

Verma, Anamika; Bishnoi, Narsi R.; Gupta, Asha

2017-09-01

In this study, initial minimum inhibitory concentration (MIC) of Pb(II) ions was analysed to check optimum concentration of Pb(II) ions at which the growth of sulphate-reducing consortium (SRC) was found to be maximum. 80 ppm of Pb(II) ions was investigated as minimum inhibitory concentration for SRC. Influence of electron donors such as lactose, sucrose, glucose and sodium lactate was examined to investigate best carbon source for growth and activity of sulphate-reducing bacteria. Sodium lactate was found to be the prime carbon source for SRC. Later optimization of various parameters was executed using Box-Behnken design model of response surface methodology to explore the effectiveness of three independent operating variables, namely, pH (5.0-9.0), temperature (32-42 °C) and time (5.0-9.0 days), on dependent variables, i.e. protein content, precipitation of Pb(II) ions, and removal of COD by SRC biomass. Maximum removal of COD and Pb(II) was observed to be 91 and 98 %, respectively, at pH 7.0 and temperature 37 °C and incubation time 7 days. According to response surface analysis and analysis of variance, the experimental data were perfectly fitted to the quadratic model, and the interactive influence of pH, temperature and time on Pb(II) and COD removal was highly significant. A high regression coefficient between the variables and response ( r 2 = 0.9974) corroborate eminent evaluation of experimental data by second-order polynomial regression model. SEM and Fourier transform infrared analysis was performed to investigate morphology of PbS precipitates, sorption mechanism and involved functional groups in metal-free and metal-loaded biomass of SRC for Pb(II) binding.

Abnormally reduced primary motor cortex output is related to impaired hand function in chronic stroke.

PubMed

Buetefisch, Cathrin M; Pirog Revill, Kathleen; Haut, Marc W; Kowalski, Greg M; Wischnewski, Miles; Pifer, Marissa; Belagaje, Samir R; Nahab, Fadi; Cobia, Derin J; Hu, Xiaoping; Drake, Daniel; Hobbs, Gerald

2018-06-20

Stroke often involves primary motor cortex (M1) and its corticospinal projections (CST). As hand function is critically dependent on these structures, its recovery is often incomplete. The neuronal substrate supporting affected hand function is not well understood but likely involves reorganized M1 and CST of the lesioned hemisphere (M1 IL and CST IL ). We hypothesized that affected hand function in chronic stroke is related to structural and functional reorganization of M1 IL and CST IL . We tested 18 patients with chronic ischemic stroke involving M1 or CST. Their hand function was compared to 18 age matched healthy subjects. M1 IL thickness and CST IL fractional anisotropy (FA) were determined with MRI and compared to measures of the other hemisphere. Transcranial magnetic stimulation (TMS) was applied to M1 IL to determine its input output function (stimulus response curve, SRC). The plateau of the SRC (MEPmax), inflection point and slope parameters of the curve were extracted. Results were compared to measures in 12 age matched healthy controls. MEPmax of M1 IL was significantly smaller (p=0.02) in the patients, indicating reduced CST IL motor output, and was correlated with impaired hand function (p=0.02). M1 IL thickness (p<0.01) and CST IL -FA (p<0.01) were reduced but did not correlate with hand function. The results indicate that employed M1 IL or CST IL structural measures do not explain the extent of impairment in hand function once M1 and CST are sufficiently functional for TMS to evoke a motor potential. Instead, impairment of hand function is best explained by the abnormally low output from M1 IL .

The Influence of Emotion Upregulation on the Expectation of Sexual Reward.

PubMed

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Trimbos, Baptist; Both, Stephanie

2016-01-01

Emotion regulation research has shown successful altering of unwanted aversive emotional reactions. Cognitive strategies can also downregulate expectations of reward arising from conditioned stimuli, including sexual stimuli. However, little is known about whether such strategies can also efficiently upregulate expectations of sexual reward arising from conditioned stimuli, and possible gender differences therein. The present study examined whether a cognitive upregulatory strategy could successfully upregulate sexual arousal elicited by sexual reward-conditioned cues in men and women. Men (n = 40) and women (n = 53) participated in a study using a differential conditioning paradigm, with genital vibrostimulation as unconditioned stimulus (US) and sexually relevant pictures as conditional stimuli. Penile circumference and vaginal pulse amplitude were assessed and ratings of US expectancy, affective value, and sexual arousal value were obtained. Also a stimulus response compatibility task was included to assess automatic approach and avoidance tendencies. Evidence was found for emotion upregulation to increase genital arousal response in the acquisition phase in both sexes, and to enhance resistance to extinction of conditioned genital responding in women. In men, the emotion upregulatory strategy resulted in increased conditioned positive affect. The findings support that top-down modulation may indeed influence conditioned sexual responses. This knowledge may have implications for treating disturbances in sexual appetitive responses, such as low sexual arousal and desire. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

A cell-penetrating peptide based on the interaction between c-Src and connexin43 reverses glioma stem cell phenotype

PubMed Central

Gangoso, E; Thirant, C; Chneiweiss, H; Medina, J M; Tabernero, A

2014-01-01

Connexin43 (Cx43), the main gap junction channel-forming protein in astrocytes, is downregulated in malignant gliomas. These tumors are composed of a heterogeneous population of cells that include many with stem-cell-like properties, called glioma stem cells (GSCs), which are highly tumorigenic and lack Cx43 expression. Interestingly, restoring Cx43 reverses GSC phenotype and consequently reduces their tumorigenicity. In this study, we investigated the mechanism by which Cx43 exerts its antitumorigenic effects on GSCs. We have focused on the tyrosine kinase c-Src, which interacts with the intracellular carboxy tail of Cx43. We found that Cx43 regulates c-Src activity and proliferation in human GSCs expanded in adherent culture. Thus, restoring Cx43 in GSCs inhibited c-Src activity, which in turn promoted the downregulation of the inhibitor of differentiation Id1. Id1 sustains stem cell phenotype as it controls the expression of Sox2, responsible for stem cell self-renewal, and promotes cadherin switching, which has been associated to epithelial–mesenchymal transition. Our results show that both the ectopic expression of Cx43 and the inhibition of c-Src reduced Id1, Sox2 expression and promoted the switch from N- to E-cadherin, suggesting that Cx43, by inhibiting c-Src, downregulates Id1 with the subsequent changes in stem cell phenotype. On the basis of this mechanism, we found that a cell-penetrating peptide, containing the region of Cx43 that interacts with c-Src, mimics the effect of Cx43 on GSC phenotype, confirming the relevance of the interaction between Cx43 and c-Src in the regulation of the malignant phenotype and pinpointing this interaction as a promising therapeutic target. PMID:24457967

Verbal and numerical consumer recommendations: switching between recommendation formats leads to preference inconsistencies.

PubMed

Maciejovsky, Boris; Budescu, David V

2013-06-01

Many Web sites provide consumers with product recommendations, which are typically presented by a sequence of verbal reviews and numerical ratings. In three experiments, we demonstrate that when participants switch between formats (e.g., from verbal to numerical), they are more prone to preference inconsistencies than when they aggregate the recommendations within the same format (e.g., verbal). When evaluating recommendations, participants rely primarily on central-location measures (e.g., mean) and less on other distribution characteristics (e.g., variance). We explain our findings within the theoretical framework of stimulus-response compatibility and we make practical recommendations for the design of recommendation systems and Web portals.

Association of Dasatinib With Progression-Free Survival Among Patients With Advanced Gastrointestinal Stromal Tumors Resistant to Imatinib.

PubMed

Schuetze, Scott M; Bolejack, Vanessa; Thomas, Dafydd G; von Mehren, Margaret; Patel, Shreyaskumar; Samuels, Brian; Choy, Edwin; D'Amato, Gina; Staddon, Arthur P; Ganjoo, Kristen N; Chow, Warren A; Rushing, Daniel A; Forscher, Charles A; Priebat, Dennis A; Loeb, David M; Chugh, Rashmi; Okuno, Scott; Reinke, Denise K; Baker, Laurence H

2018-04-26

Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor α (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. Dasatinib, 70 mg orally twice daily. The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

Interaction between src family kinases and rho-kinase in agonist-induced Ca2+-sensitization of rat pulmonary artery.

PubMed

Knock, Greg A; Shaifta, Yasin; Snetkov, Vladimir A; Vowles, Benjamin; Drndarski, Svetlana; Ward, Jeremy P T; Aaronson, Philip I

2008-02-01

We investigated the role of src family kinases (srcFK) in agonist-mediated Ca2+-sensitization in pulmonary artery and whether this involves interaction with the rho/rho-kinase pathway. Intra-pulmonary arteries (IPAs) and cultured pulmonary artery smooth muscle cells (PASMC) were obtained from rat. Expression of srcFK was determined at the mRNA and protein levels. Ca2+-sensitization was induced by prostaglandin F(2 alpha) (PGF(2 alpha)) in alpha-toxin-permeabilized IPAs. Phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and of myosin light-chain-20 (MLC20) and translocation of rho-kinase in response to PGF(2 alpha) were also determined. Nine srcFK were expressed at the mRNA level, including src, fyn, and yes, and PGF(2 alpha) enhanced phosphorylation of three srcFK proteins at tyr-416. In alpha-toxin-permeabilized IPAs, PGF(2 alpha) enhanced the Ca2+-induced contraction (pCa 6.9) approximately three-fold. This enhancement was inhibited by the srcFK blockers SU6656 and PP2 and by the rho-kinase inhibitor Y27632. Y27632, but not SU6656 or PP2, also inhibited the underlying pCa 6.9 contraction. PGF(2 alpha) enhanced phosphorylation of MYPT-1 at thr-697 and thr-855 and of MLC20 at ser-19. This enhancement, but not the underlying basal phosphorylation, was inhibited by SU6656. Y27632 suppressed both basal and PGF(2 alpha)-mediated phosphorylation. The effects of SU6656 and Y27632, on both contraction and MYPT-1 and MLC20 phosphorylation, were not additive. PGF(2 alpha) triggered translocation of rho-kinase in PASMC, and this was inhibited by SU6656. srcFK are activated by PGF(2 alpha) in the rat pulmonary artery and may contribute to Ca2+-sensitization and contraction via rho-kinase translocation and phosphorylation of MYPT-1.

Src Drives Growth of Antiestrogen Resistant Breast Cancer Cell Lines and Is a Marker for Reduced Benefit of Tamoxifen Treatment

PubMed Central

Larsen, Sarah L.; Laenkholm, Anne-Vibeke; Duun-Henriksen, Anne Katrine; Bak, Martin; Lykkesfeldt, Anne E.; Kirkegaard, Tove

2015-01-01

The underlying mechanisms leading to antiestrogen resistance in estrogen-receptor α (ER)-positive breast cancer is still poorly understood. The aim of this study was therefore to identify biomarkers and novel treatments for antiestrogen resistant breast cancer. We performed a kinase inhibitor screen on antiestrogen responsive T47D breast cancer cells and T47D-derived tamoxifen and fulvestrant resistant cell lines. We found that dasatinib, a broad-spectrum kinase inhibitor, inhibited growth of the antiestrogen resistant cells compared to parental T47D cells. Furthermore western blot analysis showed increased expression and phosphorylation of Src in the resistant cells and that dasatinib inhibited phosphorylation of Src and also signaling via Akt and Erk in all cell lines. Immunoprecipitation revealed Src: ER complexes only in the parental T47D cells. In fulvestrant resistant cells, Src formed complexes with the Human Epidermal growth factor Receptor (HER)1 and HER2. Neither HER receptors nor ER were co-precipitated with Src in the tamoxifen resistant cell lines. Compared to treatment with dasatinib alone, combined treatment with dasatinib and fulvestrant had a stronger inhibitory effect on tamoxifen resistant cell growth, whereas dasatinib in combination with tamoxifen had no additive inhibitory effect on fulvestrant resistant growth. When performing immunohistochemical staining on 268 primary tumors from breast cancer patients who had received tamoxifen as first line endocrine treatment, we found that membrane expression of Src in the tumor cells was significant associated with reduced disease-free and overall survival. In conclusion, Src was identified as target for treatment of antiestrogen resistant T47D breast cancer cells. For tamoxifen resistant T47D cells, combined treatment with dasatinib and fulvestrant was superior to treatment with dasatinib alone. Src located at the membrane has potential as a new biomarker for reduced benefit of tamoxifen. PMID:25706943

Interaction between src family kinases and rho-kinase in agonist-induced Ca2+-sensitization of rat pulmonary artery

PubMed Central

Knock, Greg A.; Shaifta, Yasin; Snetkov, Vladimir A.; Vowles, Benjamin; Drndarski, Svetlana; Ward, Jeremy P.T.; Aaronson, Philip I.

2008-01-01

Abstract Aims We investigated the role of src family kinases (srcFK) in agonist-mediated Ca2+-sensitization in pulmonary artery and whether this involves interaction with the rho/rho-kinase pathway. Methods and results Intra-pulmonary arteries (IPAs) and cultured pulmonary artery smooth muscle cells (PASMC) were obtained from rat. Expression of srcFK was determined at the mRNA and protein levels. Ca2+-sensitization was induced by prostaglandin F2α (PGF2α) in α-toxin-permeabilized IPAs. Phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and of myosin light-chain-20 (MLC20) and translocation of rho-kinase in response to PGF2α were also determined. Nine srcFK were expressed at the mRNA level, including src, fyn, and yes, and PGF2α enhanced phosphorylation of three srcFK proteins at tyr-416. In α-toxin-permeabilized IPAs, PGF2α enhanced the Ca2+-induced contraction (pCa 6.9) approximately three-fold. This enhancement was inhibited by the srcFK blockers SU6656 and PP2 and by the rho-kinase inhibitor Y27632. Y27632, but not SU6656 or PP2, also inhibited the underlying pCa 6.9 contraction. PGF2α enhanced phosphorylation of MYPT-1 at thr-697 and thr-855 and of MLC20 at ser-19. This enhancement, but not the underlying basal phosphorylation, was inhibited by SU6656. Y27632 suppressed both basal and PGF2α-mediated phosphorylation. The effects of SU6656 and Y27632, on both contraction and MYPT-1 and MLC20 phosphorylation, were not additive. PGF2α triggered translocation of rho-kinase in PASMC, and this was inhibited by SU6656. Conclusions srcFK are activated by PGF2α in the rat pulmonary artery and may contribute to Ca2+-sensitization and contraction via rho-kinase translocation and phosphorylation of MYPT-1. PMID:18032393

ACTOG - AUTOCAD TO GIFTS TRANSLATOR

NASA Technical Reports Server (NTRS)

Jones, A.

1994-01-01

The AutoCad TO Gifts Translator program, ACTOG, was developed to facilitate quick generation of small finite element models using the CASA/Gifts finite element modeling program. ACTOG reads the geometric data of a drawing from the Data Exchange File (DXF) used in AutoCAD and other PC based drafting programs. The geometric entities recognized by ACTOG include POINTs, LINEs, ARCs, SOLIDs, 3DLINEs and 3DFACEs. From this information ACTOG creates a GIFTS SRC file which can then be read into the GIFTS preprocessor BULKM or can be modified and read into EDITM to create a finite element model. The GIFTS commands created include KPOINTs, SLINEs, CARCs, GRID3s and GRID4s. The SRC file can be used as is (using the default parameters) or edited for any number of uses. It is assumed that the user has at least a working knowledge of AutoCAD and GIFTS. ACTOG was written in Microsoft QuickBasic (Version 2.0). The program was developed for the IBM PC and has been implemented on an IBM PC compatible under DOS 3.21. ACTOG was developed in 1988.

Subliminal action priming modulates the perceived intensity of sensory action consequences.

PubMed

Stenner, Max-Philipp; Bauer, Markus; Sidarus, Nura; Heinze, Hans-Jochen; Haggard, Patrick; Dolan, Raymond J

2014-02-01

The sense of control over the consequences of one's actions depends on predictions about these consequences. According to an influential computational model, consistency between predicted and observed action consequences attenuates perceived stimulus intensity, which might provide a marker of agentic control. An important assumption of this model is that these predictions are generated within the motor system. However, previous studies of sensory attenuation have typically confounded motor-specific perceptual modulation with perceptual effects of stimulus predictability that are not specific to motor action. As a result, these studies cannot unambiguously attribute sensory attenuation to a motor locus. We present a psychophysical experiment on auditory attenuation that avoids this pitfall. Subliminal masked priming of motor actions with compatible prime-target pairs has previously been shown to modulate both reaction times and the explicit feeling of control over action consequences. Here, we demonstrate reduced perceived loudness of tones caused by compatibly primed actions. Importantly, this modulation results from a manipulation of motor processing and is not confounded by stimulus predictability. We discuss our results with respect to theoretical models of the mechanisms underlying sensory attenuation and subliminal motor priming. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Subliminal action priming modulates the perceived intensity of sensory action consequences☆

PubMed Central

Stenner, Max-Philipp; Bauer, Markus; Sidarus, Nura; Heinze, Hans-Jochen; Haggard, Patrick; Dolan, Raymond J.

2014-01-01

The sense of control over the consequences of one’s actions depends on predictions about these consequences. According to an influential computational model, consistency between predicted and observed action consequences attenuates perceived stimulus intensity, which might provide a marker of agentic control. An important assumption of this model is that these predictions are generated within the motor system. However, previous studies of sensory attenuation have typically confounded motor-specific perceptual modulation with perceptual effects of stimulus predictability that are not specific to motor action. As a result, these studies cannot unambiguously attribute sensory attenuation to a motor locus. We present a psychophysical experiment on auditory attenuation that avoids this pitfall. Subliminal masked priming of motor actions with compatible prime–target pairs has previously been shown to modulate both reaction times and the explicit feeling of control over action consequences. Here, we demonstrate reduced perceived loudness of tones caused by compatibly primed actions. Importantly, this modulation results from a manipulation of motor processing and is not confounded by stimulus predictability. We discuss our results with respect to theoretical models of the mechanisms underlying sensory attenuation and subliminal motor priming. PMID:24333539

Source-reconstruction of event-related fields reveals hyperfunction and hypofunction of cortical circuits in antipsychotic-naive, first-episode schizophrenia patients during Mooney face processing.

PubMed

Rivolta, Davide; Castellanos, Nazareth P; Stawowsky, Cerisa; Helbling, Saskia; Wibral, Michael; Grützner, Christine; Koethe, Dagmar; Birkner, Katharina; Kranaster, Laura; Enning, Frank; Singer, Wolf; Leweke, F Markus; Uhlhaas, Peter J

2014-04-23

Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with electrophysiological methods, such as EEG and MEG. In the present human study, we examined event-related fields (ERFs), in a sample of medication-naive, first-episode schizophrenia (FE-ScZ) patients (n = 14) and healthy control participants (n = 17) during perception of Mooney faces to investigate the integrity of neuromagnetic responses and their experience-dependent modification. ERF responses were analyzed for M100, M170, and M250 components at the sensor and source levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A'). At the sensor level, M100 and M170 responses in FE-ScZ were within the normal range, whereas the M250 response was impaired. However, source localization revealed widespread elevated activity for M100 and M170 in FE-ScZ and delayed peak latencies for the M100 and M250 responses. In addition, M170 source activity in FE-ScZ was not modulated by stimulus repetitions. The present findings suggest that neural circuits in FE-ScZ may be characterized by a disturbed balance between excitation and inhibition that could lead to a failure to gate information flow and abnormal spreading of activity, which is compatible with dysfunctional glutamatergic neurotransmission.

Influence of short incompatible practice on the Simon effect: transfer along the vertical dimension and across vertical and horizontal dimensions.

PubMed

Conde, Erick F Q; Fraga-Filho, Roberto Sena; Lameira, Allan Pablo; Mograbi, Daniel C; Riggio, Lucia; Gawryszewski, Luiz G

2015-11-01

In spatial compatibility and Simon tasks, the response is faster when stimulus and response locations are on the same side than when they are on opposite sides. It has been shown that a spatial incompatible practice leads to a subsequent modulation of the Simon effect along the horizontal dimension. It has also been reported that this modulation occurs both along and across vertical and horizontal dimensions, but only after intensive incompatible training (600 trials). In this work, we show that this modulatory effect can be obtained with a smaller number of incompatible trials, changing the spatial arrangement of the vertical response keys to obtain a stronger dimensional overlap between the spatial codes of stimuli and response keys. The results of Experiment 1 showed that 80 incompatible vertical trials abolished the Simon effect in the same dimension. Experiment 2 showed that a modulation of the vertical Simon effect could be obtained after 80 horizontal incompatible trials. Experiment 3 explored whether the transfer effect can also occur in a horizontal Simon task after a brief vertical spatial incompatibility task, and results were similar to the previous experiments. In conclusion, we suggest that the spatial arrangement between response key and stimulus locations may be critical to establish the short-term memory links that enable the transfer of learning between brief incompatible practices and the Simon effects, both along the vertical dimension and across vertical and horizontal dimensions.

Switching between univalent task-sets in schizophrenia: ERP evidence of an anticipatory task-set reconfiguration deficit.

PubMed

Karayanidis, Frini; Nicholson, Rebecca; Schall, Ulrich; Meem, Lydia; Fulham, Ross; Michie, Patricia T

2006-10-01

The present study used behavioral and event-related potential (ERP) indices of task-switching to examine whether schizophrenia patients have a specific deficit in anticipatory task-set reconfiguration. Participants switched between univalent tasks in an alternating runs paradigms with blocked response-stimulus interval (RSI) manipulation (150, 300, 600, and 1200ms). Nineteen high functioning people with schizophrenia were compared to controls that were matched for age, gender, education and premorbid IQ estimate. Schizophrenia patients had overall increased RT, but no increase in corrected RT switch cost. In the schizophrenia group, ERPs showed reduced activation of the differential positivity in anticipation of switch trial at the optimal 600ms RSI and reduced activation of the frontal post-stimulus switch negativity at both 600 and 1200ms RSI compared to the control group. Despite no behavioral differences in task switching performance, anticipatory and stimulus-triggered ERP indices of task-switching suggest group differences in processing of switch and repeat trials, especially at longer RSI conditions that for control participants provide opportunity for anticipatory activation of task-set reconfiguration processes. These results are compatible with impaired implementation of endogenously driven processes in schizophrenia and greater reliance on external task cues, especially at long preparation intervals.

Grasping the concept of personal property.

PubMed

Constable, Merryn D; Kritikos, Ada; Bayliss, Andrew P

2011-06-01

The concept of property is integral to personal and societal development, yet understanding of the cognitive basis of ownership is limited. Objects are the most basic form of property, so our physical interactions with owned objects may elucidate nuanced aspects of ownership. We gave participants a coffee mug to decorate, use and keep. The experimenter also designed a mug of her own. In Experiment 1, participants performed natural lifting actions with each mug. Participants lifted the Experimenter's mug with greater care, and moved it slightly more towards the Experimenter, while they lifted their own mug more forcefully and drew it closer to their own body. In Experiment 2, participants responded to stimuli presented on the mug handles in a computer-based stimulus-response compatibility task. Overall, participants were faster to respond in trials in which the handles were facing in the same direction as the response location compared to when the handles were facing away. The compatibility effect was abolished, however, for the Experimenter's mug--as if the action system is blind to the potential for action towards another person's property. These findings demonstrate that knowledge of the ownership status of objects influences visuomotor processing in subtle and revealing ways. Copyright © 2011 Elsevier B.V. All rights reserved.

SRC-induced disintegration of adherens junctions of madin-darby canine kidney cells is dependent on endocytosis of cadherin and antagonized by Tiam-1.

PubMed

Palovuori, Riitta; Sormunen, Raija; Eskelinen, Sinikka

2003-12-01

The effects of Src tyrosine kinase activation in subconfluent temperature sensitive (ts)-Src-transformed Madin-Darby canine kidney (MDCK) cells were analyzed by shifting them from nonpermissive (40.5 degrees C) to permissive (35 degrees C) temperature. Already, in 15 minutes, adherens junction components were released from the lateral walls and accumulated to basal surfaces. Simultaneously, membranous actin staining vanished, actin bundles appeared at the basal surface, and the cells flattened. The only component phosphorylated and translocated after the shift to 35 degrees C was p120ctn. The epithelial-mesenchymal transition could be inhibited by a specific inhibitor of Src kinase, PP2, or by inhibiting endocytosis. Therefore, Src activation was responsible for the transition, but not because of phosphorylation of adherens junction components but by way of activation of endocytic machinery and RhoGTPase. Expression of an RacGEF, Tiam-1 (T-lymphoma invasion and metastasis gene 1), prevented flattening of Src-transformed MDCK cells at 35 degrees C and resulted in accumulation of cadherin to lateral membranes. In the case where the Src-MDCK cells were cultivated at 35 degrees C and shifted for short time periods to 40.5 degrees C, cadherin rapidly returned to lateral membranes, whereas actin and p120ctn followed hours afterward. This further supports the view that cadherin internalization is the primary target of Src kinase. We also looked at the cell morphology and distribution of cadherin and Tiam-1 in cells grown in three-dimensional gels composed of collagen and laminin or in Matrigel. At nonpermissive temperature, both Src-MDCK and Tiam-1-transfected Src-MDCK cells exhibited nonpolarized morphology in collagen I, a loose cluster in the mixture of collagen I and laminin, and a differentiated cyst in Matrigel. In growth factor-depleted Matrigel, the Src-MDCK cells grew in nondifferentiated clusters, whereas Tiam-1-transfected cells went to apoptosis. The differentiated phenotype of both cell lines could be rescued by Matrigel-conditioned medium, platelet-derived growth factor, or cholera toxin. Concomitantly, both cadherin and Tiam-1 were recruited to lateral membranes. Therefore, cadherin and Tiam-1 seem to be the key players in the differentiation process of MDCK cells.

The Transmodulation of HER2 and EGFR by Substance P in Breast Cancer Cells Requires c-Src and Metalloproteinase Activation.

PubMed

Garcia-Recio, Susana; Pastor-Arroyo, Eva M; Marín-Aguilera, Mercedes; Almendro, Vanessa; Gascón, Pedro

2015-01-01

Substance P (SP) is a pleiotropic cytokine/neuropeptide that enhances breast cancer (BC) aggressiveness by transactivating tyrosine kinase receptors like EGFR and HER2. We previously showed that SP and its cognate receptor NK-1 (SP/NK1-R) signaling modulates the basal phosphorylation of HER2 and EGFR in BC, increasing aggressiveness and drug resistance. In order to elucidate the mechanisms responsible for NK-1R-mediated HER2 and EGFR transactivation, we investigated the involvement of c-Src (a ligand-independent mediator) and of metalloproteinases (ligand-dependent mediators) in HER2/EGFR activation. Overexpression of NK-1R in MDA-MB-231 and its chemical inhibition in SK-BR-3, BT-474 and MDA-MB-468 BC cells significantly modulated c-Src activation, suggesting that this protein is a mediator of NK-1R signaling. In addition, the c-Src inhibitor 4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline prevented SP-induced activation of HER2. On the other hand, SP-dependent phosphorylation of HER2 and EGFR decreased substantially in the presence of the MMP inhibitor 1-10, phenanthroline monohydrate, and the dual inhibition of both c-Src and MMP almost abolished the activation of HER2 and EGFR. Moreover, the use of these inhibitors demonstrated that this Src and MMP-dependent signaling is important to the cell viability and migration capacity of HER2+ and EGFR+ cell lines. Our results indicate that the transactivation of HER2 and EGFR by the pro-inflammatory cytokine/neuropeptide SP in BC cells is a c-Src and MMP-dependent process.

Src family kinase expression and subcellular localization in macrophages: implications for their role in CSF-1-induced macrophage migration.

PubMed

Dwyer, Amy R; Mouchemore, Kellie A; Steer, James H; Sunderland, Andrew J; Sampaio, Natalia G; Greenland, Eloise L; Joyce, David A; Pixley, Fiona J

2016-07-01

A major role of colony-stimulating factor-1 is to stimulate the differentiation of mononuclear phagocytic lineage cells into adherent, motile, mature macrophages. The colony-stimulating factor-1 receptor transduces colony-stimulating factor-1 signaling, and we have shown previously that phosphatidylinositol 3-kinase p110δ is a critical mediator of colony-stimulating factor-1-stimulated motility through the colony-stimulating factor-1 receptor pY721 motif. Src family kinases are also implicated in the regulation of macrophage motility and in colony-stimulating factor-1 receptor signaling, although functional redundancy of the multiple SFKs expressed in macrophages makes it challenging to delineate their specific functions. We report a comprehensive analysis of individual Src family kinase expression in macrophage cell lines and primary macrophages and demonstrate colony-stimulating factor-1-induced changes in Src family kinase subcellular localization, which provides clues to their distinct and redundant functions in macrophages. Moreover, expression of individual Src family kinases is both species specific and dependent on colony-stimulating factor-1-induced macrophage differentiation. Hck associated with the activated colony-stimulating factor-1 receptor, whereas Lyn associated with the receptor in a constitutive manner. Consistent with this, inhibitor studies revealed that Src family kinases were important for both colony-stimulating factor-1 receptor activation and colony-stimulating factor-1-induced macrophage spreading, motility, and invasion. Distinct colony-stimulating factor-1-induced changes in the subcellular localization of individual SFKs suggest specific roles for these Src family kinases in the macrophage response to colony-stimulating factor-1. © Society for Leukocyte Biology.

Steroid Receptor Coactivator-1 Knockdown Decreases Synaptic Plasticity and Impairs Spatial Memory in the Hippocampus of Mice.

PubMed

Bian, Chen; Huang, Yan; Zhu, Haitao; Zhao, Yangang; Zhao, Jikai; Zhang, Jiqiang

2018-05-01

Steroids have been demonstrated to play profound roles in the regulation of hippocampal function by acting on their receptors, which need coactivators for their transcriptional activities. Previous studies have shown that steroid receptor coactivator-1 (SRC-1) is the predominant coactivator in the hippocampus, but its exact role and the underlying mechanisms remain unclear. In this study, we constructed SRC-1 RNA interference (RNAi) lentiviruses, injected them into the hippocampus of male mice, and then examined the changes in the expression of selected synaptic proteins, CA1 synapse density, postsynaptic density (PSD) thickness, and in vivo long-term potentiation (LTP). Spatial learning and memory behavior changes were investigated using the Morris water maze. We then transfected the lentiviruses into cultured hippocampal cells and examined the changes in synaptic protein and phospho-cyclic AMP response element-binding protein (pCREB) expression. The in vivo results showed that SRC-1 knockdown significantly decreased the expression of synaptic proteins and CA1 synapse density as well as PSD thickness; SRC-1 knockdown also significantly impaired in vivo LTP and disrupted spatial learning and memory. The in vitro results showed that while the expression of synaptic proteins was significantly decreased by SRC-1 knockdown, pCREB expression was also significantly decreased. The above results suggest a pivotal role of SRC-1 in the regulation of hippocampal synaptic plasticity and spatial learning and memory, strongly indicating SRC-1 may serve as a novel therapeutic target for hippocampus-dependent memory disorders. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Duox, Flotillin-2, and Src42A Are Required to Activate or Delimit the Spread of the Transcriptional Response to Epidermal Wounds in Drosophila

PubMed Central

Juarez, Michelle T.; Patterson, Rachel A.; Sandoval-Guillen, Efren; McGinnis, William

2011-01-01

The epidermis is the largest organ of the body for most animals, and the first line of defense against invading pathogens. A breach in the epidermal cell layer triggers a variety of localized responses that in favorable circumstances result in the repair of the wound. Many cellular and genetic responses must be limited to epidermal cells that are close to wounds, but how this is regulated is still poorly understood. The order and hierarchy of epidermal wound signaling factors are also still obscure. The Drosophila embryonic epidermis provides an excellent system to study genes that regulate wound healing processes. We have developed a variety of fluorescent reporters that provide a visible readout of wound-dependent transcriptional activation near epidermal wound sites. A large screen for mutants that alter the activity of these wound reporters has identified seven new genes required to activate or delimit wound-induced transcriptional responses to a narrow zone of cells surrounding wound sites. Among the genes required to delimit the spread of wound responses are Drosophila Flotillin-2 and Src42A, both of which are transcriptionally activated around wound sites. Flotillin-2 and constitutively active Src42A are also sufficient, when overexpressed at high levels, to inhibit wound-induced transcription in epidermal cells. One gene required to activate epidermal wound reporters encodes Dual oxidase, an enzyme that produces hydrogen peroxide. We also find that four biochemical treatments (a serine protease, a Src kinase inhibitor, methyl-ß-cyclodextrin, and hydrogen peroxide) are sufficient to globally activate epidermal wound response genes in Drosophila embryos. We explore the epistatic relationships among the factors that induce or delimit the spread of epidermal wound signals. Our results define new genetic functions that interact to instruct only a limited number of cells around puncture wounds to mount a transcriptional response, mediating local repair and regeneration. PMID:22242003

Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis.

PubMed

Silva, Corinne M

2004-10-18

The signal transducers and activators of transcription (STATs) were originally identified in the signaling pathway activated by the nontyrosine kinase containing cytokine receptors. The role of these STATs in hematopoietic cell signaling has been well described. In the case of cytokine receptors, activation of STAT tyrosine phosphorylation occurs through ligand-induced recruitment, and activation of the intracellular JAK kinases. However, STATs can also be activated by growth factor receptors, particularly the EGFR; as well as by members of the Src Family of Kinases (SFKs), particularly c-Src. In many cases, there is a differential activation of the STATs by these tyrosine kinases as compared to activation by the cytokine receptors. This difference provides for the potential of unique actions of STATs in response to growth factor receptor and SFK activation. Since there are many cancers in which SFKs and c-Src in particular, are co-overexpressed with growth factor receptors, it is not surprising that STATs play an important role in the tumorigenesis process induced by c-Src. The activation paradigm and role of STATs in these cancers, with particular emphasis on breast cancer models, is discussed.

Solvent refined coal (SRC) process. Annual technical progress report, January 1979-December 1979

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1980-11-01

A set of statistically designed experiments was used to study the effects of several important operating variables on coal liquefaction product yield structures. These studies used a Continuous Stirred-Tank Reactor to provide a hydrodynamically well-defined system from which kinetic data could be extracted. An analysis of the data shows that product yield structures can be adequately represented by a correlative model. It was shown that second-order effects (interaction and squared terms) are necessary to provide a good model fit of the data throughout the range studied. Three reports were issued covering the SRC-II database and yields as functions of operatingmore » variables. The results agree well with the generally-held concepts of the SRC reaction process, i.e., liquid phase hydrogenolysis of liquid coal which is time-dependent, thermally activated, catalyzed by recycle ash, and reaction rate-controlled. Four reports were issued summarizing the comprehensive SRC reactor thermal response models and reporting the results of several studies made with the models. Analytical equipment for measuring SRC off-gas composition and simulated distillation of coal liquids and appropriate procedures have been established.« less

The targeted delivery of the c-Src peptide complexed with schizophyllan to macrophages inhibits polymicrobial sepsis and ulcerative colitis in mice.

PubMed

Kim, Ye-Ram; Hwang, Jangsun; Koh, Hyun-Jung; Jang, Kiseok; Lee, Jong-Dae; Choi, Jonghoon; Yang, Chul-Su

2016-05-01

Hyper-inflammatory responses triggered by intracellular reactive oxygen species (ROS) can lead to a variety of diseases, including sepsis and colitis. However, the regulators of this process remain poorly defined. In this study, we demonstrate that c-Src is a negative regulator of cellular ROS generation through its binding to p47phox. This molecule also competitively inhibits the NADPH oxidase complex (NOX) assembly. Furthermore, we developed the schizophyllan (SPG)-c-Src SH3 peptide, which is a β-1,3-glucan conjugated c-Src SH3-derived peptide composed of amino acids 91-108 and 121-140 of c-Src. The SPG-SH3 peptide has a significant therapeutic effect on mouse ROS-mediated inflammatory disease models, cecal-ligation-puncture-induced sepsis, and dextran sodium sulfate-induced colitis. It does so by inhibiting the NOX subunit assembly and proinflammatory mediator production. Therefore, the SPG-SH3 peptide is a potential therapeutic agent for ROS-associated lethal inflammatory diseases. Our findings provide clues for the development of new peptide-base drugs that will target p47phox. Copyright © 2016 Elsevier Ltd. All rights reserved.

Motivation and competence of participants in a learner-centered student-run clinic: an exploratory pilot study.

PubMed

Schutte, Tim; Tichelaar, Jelle; Dekker, Ramon S; Thijs, Abel; de Vries, Theo P G M; Kusurkar, Rashmi A; Richir, Milan C; van Agtmael, Michiel A

2017-01-25

The Learner-Centered Student-run Clinic (LC-SRC) was designed to teach and train prescribing skills grounded in a real-life context, to provide students with early clinical experience and responsibility. The current studies' theoretical framework was based on the Self-determination Theory. According to the Self-determination Theory, early involvement in clinical practice combined with a high level of responsibility makes the LC-SRC an environment that can stimulate intrinsic motivation. We investigated the different types of motivation and the proficiency in CanMEDS competencies of the participating students. Type of motivation was measured using the Academic Motivation Scale and Intrinsic Motivation Inventory. CanMEDS competencies were evaluated by faculty using a mini-clinical examination and by the students themselves using a post-participation questionnaire. The 29 participating students were highly intrinsic motivated for this project on all subscales of the Intrinsic Motivation Inventory. Motivation for medical school on the Academic Motivation Scale was high before and was not significantly changed after participation. Students considered that their CanMEDS competencies "Collaborator", "Communicator", "Academic", and "Medical expert" had improved. Their actual clinical team competence was judged by faculty to be at a junior doctor level. Students showed a high level of intrinsic motivation to participate in the LC-SRC and perceived an improvement in competence. Furthermore their actual clinical competence was at junior doctor level in all CanMEDS competencies. The stimulating characteristics of the LC-SRC, the high levels of intrinsic motivation and the qualitative comments of the students in this study makes the LC-SRC an attractive place for learning.

Microbial products activate monocytic cells through detergent-resistant membrane microdomains.

PubMed

Epelman, Slava; Berenger, Byron; Stack, Danuta; Neely, Graham G; Ma, Ling Ling; Mody, Christopher H

2008-12-01

Patients with cystic fibrosis suffer recurrent pulmonary infections that are characterized by an overactive yet ineffective and destructive inflammatory response that is associated with respiratory infections by Pseudomonas aeruginosa, a pathogen that produces a number of phlogistic molecules. To better understand this process, we used exoenzyme S (ExoS), one of the key P. aeruginosa-secreted exoproducts, which is known to stimulate cells via the Toll-like receptor (TLR) pathway. We found that ExoS induced proinflammatory cytokine production via the NF-kappaB, Erk1/2, and Src kinase pathways. Because Src kinases are concentrated within cholesterol-containing, detergent-resistant membrane microdomains (DRM) (also called lipid rafts) and DRM act as signaling platforms and amplifiers on the surface of cells, we addressed the role of DRM in ExoS signaling. ExoS bound directly to a subset of DRM and induced the phosphorylation of multiple proteins within DRM, including Src kinases. Disruption of DRM by cholesterol extraction prevented NF-kappaB and Erk 1/2 activation and TNF-alpha production in response to ExoS. Activation of monocytic cells by other TLR and Nod-like receptor agonists, such as lipoteichoic acid, lipopolysaccharide, and peptidoglycan, were also dependent on DRM, and disruption prevented TNF-alpha production. Disruption of DRM did not prevent ExoS binding but did release the Src kinase, Lyn, from the DRM fraction into the detergent-soluble fraction, a site in which Src kinases are not active. These studies show that ExoS, a TLR agonist, requires direct binding to DRM for optimal signaling, which suggests that DRM are possible therapeutic targets in cystic fibrosis.

To speak or not to speak - A multiple resource perspective

NASA Technical Reports Server (NTRS)

Tsang, P. S.; Hartzell, E. J.; Rothschild, R. A.

1985-01-01

The desirability of employing speech response in a dynamic dual task situation was discussed from a multiple resource perspective. A secondary task technique was employed to examine the time-sharing performance of five dual tasks with various degrees of resource overlap according to the structure-specific resource model of Wickens (1980). The primary task was a visual/manual tracking task which required spatial processing. The secondary task was either another tracking task or a spatial transformation task with one of four input (visual or auditory) and output (manual or speech) configurations. The results show that the dual task performance was best when the primary tracking task was paired with the visual/speech transformation task. This finding was explained by an interaction of the stimulus-central processing-response compatibility of the transformation task and the degree of resource competition between the time-shared tasks. Implications on the utility of speech response were discussed.

Sleep deprivation influences some but not all processes of supervisory attention

NASA Technical Reports Server (NTRS)

Jennings, J. R.; Monk, T. H.; van der Molen, M. W.

2003-01-01

Does one night of sleep deprivation alter processes of supervisory attention in general or only a specific subset of such processes? Twenty college-aged volunteers, half female, performed a choice reaction time task. A cue indicated that compatible (e.g., right button, right-pointing arrow) or incompatible (e.g., left button, right-pointing arrow) responses were to be given to a stimulus that followed 50 or 500 ms later. The paradigm assessed response inhibition, task-shifting skill, and task strategy-processes inherent in supervisory attention. Performance, along with heart rate, was assessed for 12 hr following normal sleep or a night of complete sleep deprivation. Sleep deprivation altered neither preparation for task shifting nor response inhibition. The ability to use preparatory bias to speed performance did decrease with sleep deprivation. Sleep deprivation appears to selectively affect this supervisory attention process, which is perceived as an active effort to cope with a challenging task.

Membrane potential correlates of sensory perception in mouse barrel cortex.

PubMed

Sachidhanandam, Shankar; Sreenivasan, Varun; Kyriakatos, Alexandros; Kremer, Yves; Petersen, Carl C H

2013-11-01

Neocortical activity can evoke sensory percepts, but the cellular mechanisms remain poorly understood. We trained mice to detect single brief whisker stimuli and report perceived stimuli by licking to obtain a reward. Pharmacological inactivation and optogenetic stimulation demonstrated a causal role for the primary somatosensory barrel cortex. Whole-cell recordings from barrel cortex neurons revealed membrane potential correlates of sensory perception. Sensory responses depended strongly on prestimulus cortical state, but both slow-wave and desynchronized cortical states were compatible with task performance. Whisker deflection evoked an early (<50 ms) reliable sensory response that was encoded through cell-specific reversal potentials. A secondary late (50-400 ms) depolarization was enhanced on hit trials compared to misses. Optogenetic inactivation revealed a causal role for late excitation. Our data reveal dynamic processing in the sensory cortex during task performance, with an early sensory response reliably encoding the stimulus and later secondary activity contributing to driving the subjective percept.

Sleep deprivation influences some but not all processes of supervisory attention.

PubMed

Jennings, J R; Monk, T H; van der Molen, M W

2003-09-01

Does one night of sleep deprivation alter processes of supervisory attention in general or only a specific subset of such processes? Twenty college-aged volunteers, half female, performed a choice reaction time task. A cue indicated that compatible (e.g., right button, right-pointing arrow) or incompatible (e.g., left button, right-pointing arrow) responses were to be given to a stimulus that followed 50 or 500 ms later. The paradigm assessed response inhibition, task-shifting skill, and task strategy-processes inherent in supervisory attention. Performance, along with heart rate, was assessed for 12 hr following normal sleep or a night of complete sleep deprivation. Sleep deprivation altered neither preparation for task shifting nor response inhibition. The ability to use preparatory bias to speed performance did decrease with sleep deprivation. Sleep deprivation appears to selectively affect this supervisory attention process, which is perceived as an active effort to cope with a challenging task.

Parallel processing streams for motor output and sensory prediction during action preparation

PubMed Central

Bauer, Markus; Heinze, Hans-Jochen; Haggard, Patrick; Dolan, Raymond J.

2014-01-01

Sensory consequences of one's own actions are perceived as less intense than identical, externally generated stimuli. This is generally taken as evidence for sensory prediction of action consequences. Accordingly, recent theoretical models explain this attenuation by an anticipatory modulation of sensory processing prior to stimulus onset (Roussel et al. 2013) or even action execution (Brown et al. 2013). Experimentally, prestimulus changes that occur in anticipation of self-generated sensations are difficult to disentangle from more general effects of stimulus expectation, attention and task load (performing an action). Here, we show that an established manipulation of subjective agency over a stimulus leads to a predictive modulation in sensory cortex that is independent of these factors. We recorded magnetoencephalography while subjects performed a simple action with either hand and judged the loudness of a tone caused by the action. Effector selection was manipulated by subliminal motor priming. Compatible priming is known to enhance a subjective experience of agency over a consequent stimulus (Chambon and Haggard 2012). In line with this effect on subjective agency, we found stronger sensory attenuation when the action that caused the tone was compatibly primed. This perceptual effect was reflected in a transient phase-locked signal in auditory cortex before stimulus onset and motor execution. Interestingly, this sensory signal emerged at a time when the hemispheric lateralization of motor signals in M1 indicated ongoing effector selection. Our findings confirm theoretical predictions of a sensory modulation prior to self-generated sensations and support the idea that a sensory prediction is generated in parallel to motor output (Walsh and Haggard 2010), before an efference copy becomes available. PMID:25540223

Parallel processing streams for motor output and sensory prediction during action preparation.

PubMed

Stenner, Max-Philipp; Bauer, Markus; Heinze, Hans-Jochen; Haggard, Patrick; Dolan, Raymond J

2015-03-15

Sensory consequences of one's own actions are perceived as less intense than identical, externally generated stimuli. This is generally taken as evidence for sensory prediction of action consequences. Accordingly, recent theoretical models explain this attenuation by an anticipatory modulation of sensory processing prior to stimulus onset (Roussel et al. 2013) or even action execution (Brown et al. 2013). Experimentally, prestimulus changes that occur in anticipation of self-generated sensations are difficult to disentangle from more general effects of stimulus expectation, attention and task load (performing an action). Here, we show that an established manipulation of subjective agency over a stimulus leads to a predictive modulation in sensory cortex that is independent of these factors. We recorded magnetoencephalography while subjects performed a simple action with either hand and judged the loudness of a tone caused by the action. Effector selection was manipulated by subliminal motor priming. Compatible priming is known to enhance a subjective experience of agency over a consequent stimulus (Chambon and Haggard 2012). In line with this effect on subjective agency, we found stronger sensory attenuation when the action that caused the tone was compatibly primed. This perceptual effect was reflected in a transient phase-locked signal in auditory cortex before stimulus onset and motor execution. Interestingly, this sensory signal emerged at a time when the hemispheric lateralization of motor signals in M1 indicated ongoing effector selection. Our findings confirm theoretical predictions of a sensory modulation prior to self-generated sensations and support the idea that a sensory prediction is generated in parallel to motor output (Walsh and Haggard 2010), before an efference copy becomes available. Copyright © 2015 the American Physiological Society.

Evidence that activation of ASIC1a by acidosis increases osteoclast migration and adhesion by modulating integrin/Pyk2/Src signaling pathway.

PubMed

Li, X; Ye, J-X; Xu, M-H; Zhao, M-D; Yuan, F-L

2017-07-01

Activated acid-sensing ion channel 1a (ASIC1a) is involved in acid-induced osteoclastogenesis by regulating activation of the transcription factor NFATc1. These results indicated that ASIC1a activation by extracellular acid may cause osteoclast migration and adhesion through Ca 2+ -dependent integrin/Pyk2/Src signaling pathway. Osteoclast adhesion and migration are responsible for osteoporotic bone loss. Acidic conditions promote osteoclastogenesis. ASIC1a in osteoclasts is associated with acid-induced osteoclastogenesis through modulating transcription factor NFATc1 activation. However, the influence and the detailed mechanism of ASIC1a in regulating osteoclast adhesion and migration, in response to extracellular acid, are not well characterized. In this study, knockdown of ASIC1a was achieved in bone marrow macrophage cells using small interfering RNA (siRNA). The adhesion and migration abilities of osteoclast precursors and osteoclasts were determined by adhesion and migration assays, in vitro. Bone resorption was performed to measure osteoclast function. Cytoskeletal changes were assessed by F-actin ring formation. αvβ3 integrin expression in osteoclasts was measured by flow cytometry. Western blotting and co-immunoprecipitation were performed to measure alterations in integrin/Pyk2/Src signaling pathway. Our results showed that blockade of ASIC1a using ASIC1a-siRNA inhibited acid-induced osteoclast precursor migration and adhesion, as well as osteoclast adhesion and bone resorption; we also demonstrated that inhibition of ASIC1a decreased the cell surface αvβ3 integrin and β3 protein expression. Moreover, blocking of ASIC1a inhibited acidosis-induced actin ring formation and reduced Pyk2 and Src phosphorylation in osteoclasts and also inhibited the acid-induced association of the αvβ3 integrin/Src/Pyk2. Together, these results highlight a key functional role of ASIC1a/αvβ3 integrin/Pyk2/Src signaling pathway in migration and adhesion of osteoclasts.

Post-Traumatic Stress Avoidance is Attenuated by Corticosterone and Associated with Brain Levels of Steroid Receptor Co-Activator-1 in Rats

PubMed Central

Whitaker, Annie M.; Farooq, Muhammad A.; Edwards, Scott; Gilpin, Nicholas W.

2016-01-01

Individuals with post-traumatic stress disorder (PTSD) avoid trauma-related stimuli and exhibit blunted hypothalamic-pituitary-adrenal (HPA) axis activation at the time of stress. Our laboratory has established a rodent model of stress that mimics the avoidance symptom cluster of PTSD. Rats are classified as ‘Avoiders’ or ‘Non-Avoiders’ post-stress based on avoidance of a predator-odor paired context. Previously, we demonstrated that Avoiders exhibit an attenuated HPA stress response to predator odor. We hypothesized that corticosterone administration prior to stress would reduce magnitude and incidence of avoidance of a stress-paired context. Furthermore, we predicted that Avoiders would exhibit altered expression of GR signaling machinery elements, such as steroid receptor co-activator (SRC)-1. Male Wistar rats (n = 16) were pre-treated with corticosterone (25 mg/kg) or saline and exposed to predator odor stress paired with a context, and tested for avoidance 24 h later, A second group of corticosterone-naïve rats (n = 24) were stressed (or not stressed), indexed for avoidance 24 h later, and killed 48 h post-odor exposure for analysis of phosphorylated GR, FKBP51, and SRC-1 levels in the paraventricular nucleus (PVN), central amygdala (CeA) and ventral hippocampus (VH), all brain sites that express high quantities of GRs and regulate HPA function. Rats pre-treated with corticosterone exhibited lower magnitude and incidence of avoidance. Predator odor exposure also reduced SRC-1 expression in the PVN and CeA of Avoiders, and increased SRC-1 expression in the VH of Avoiders. SRC-1 expression in PVN, CeA, and VH was predicted by prior avoidance behavior. These results suggest that blunted HPA stress response may contribute to stress-induced neuroadaptations in central SRC-1 levels and behavioral dysfunction in Avoider rats. PMID:26482332

Low-level laser therapy regulates microglial function through Src-mediated signaling pathways: implications for neurodegenerative diseases

PubMed Central

2012-01-01

Background Activated microglial cells are an important pathological component in brains of patients with neurodegenerative diseases. The purpose of this study was to investigate the effect of He-Ne (632.8 nm, 64.6 mW/cm2) low-level laser therapy (LLLT), a non-damaging physical therapy, on activated microglia, and the subsequent signaling events of LLLT-induced neuroprotective effects and phagocytic responses. Methods To model microglial activation, we treated the microglial BV2 cells with lipopolysaccharide (LPS). For the LLLT-induced neuroprotective study, neuronal cells with activated microglial cells in a Transwell™ cell-culture system were used. For the phagocytosis study, fluorescence-labeled microspheres were added into the treated microglial cells to confirm the role of LLLT. Results Our results showed that LLLT (20 J/cm2) could attenuate toll-like receptor (TLR)-mediated proinflammatory responses in microglia, characterized by down-regulation of proinflammatory cytokine expression and nitric oxide (NO) production. LLLT-triggered TLR signaling inhibition was achieved by activating tyrosine kinases Src and Syk, which led to MyD88 tyrosine phosphorylation, thus impairing MyD88-dependent proinflammatory signaling cascade. In addition, we found that Src activation could enhance Rac1 activity and F-actin accumulation that typify microglial phagocytic activity. We also found that Src/PI3K/Akt inhibitors prevented LLLT-stimulated Akt (Ser473 and Thr308) phosphorylation and blocked Rac1 activity and actin-based microglial phagocytosis, indicating the activation of Src/PI3K/Akt/Rac1 signaling pathway. Conclusions The present study underlines the importance of Src in suppressing inflammation and enhancing microglial phagocytic function in activated microglia during LLLT stimulation. We have identified a new and important neuroprotective signaling pathway that consists of regulation of microglial phagocytosis and inflammation under LLLT treatment. Our research may provide a feasible therapeutic approach to control the progression of neurodegenerative diseases. PMID:22989325

Negative stimulus-response compatibility observed with a briefly displayed image of a hand.

PubMed

Vainio, Lari

2011-12-01

Manual responses can be primed by viewing an image of a hand. The left-right identity of the viewed hand reflexively facilitates responses of the hand that corresponds to the identity. Previous research also suggests that when the response activation is triggered by an arrow, which is backward-masked and presented briefly, the activation manifests itself in the negative priming effect. The present study showed that response activation, which is produced by an identity of a briefly presented image of a hand, can be similarly associated with a negative priming effect. However, in contrast to the previously reported negative priming effects, the hand stimuli produced negative priming even when the hand was not backward-masked and did not contain task-relevant information. The study supports the view that the automatic inhibition of motor activation triggered by briefly viewed objects is a general and basic functional principle in exogenous motor control processes. Copyright © 2011 Elsevier Inc. All rights reserved.

The personification of animals: coding of human and nonhuman body parts based on posture and function.

PubMed

Welsh, Timothy N; McDougall, Laura; Paulson, Stephanie

2014-09-01

The purpose of the present research was to determine how humans represent the bodies and limbs of nonhuman mammals based on anatomical and functional properties. To this end, participants completed a series of body-part compatibility tasks in which they responded with a thumb or foot response to the color of a stimulus (red or blue, respectively) presented on different limbs of several animals. Across the studies, this compatibility task was conducted with images of human and nonhuman animals (bears, cows, and monkeys) in bipedal or quadrupedal postures. The results revealed that the coding of the limbs of nonhuman animals is strongly influenced by the posture of the body, but not the functional capacity of the limb. Specifically, body-part compatibility effects were present for both human and nonhuman animals when the figures were in a bipedal posture, but were not present when the animals were in a quadrupedal stance (Experiments 1a-c). Experiments 2a and 2b revealed that the posture-based body-part compatibility effects were not simply a vertical spatial compatibility effect or due to a mismatch between the posture of the body in the image and the participant. These data indicate that nonhuman animals in a bipedal posture are coded with respect to the "human" body representation, whereas nonhuman animals in a quadrupedal posture are not mapped to the human body representation. Overall, these studies provide new insight into the processes through which humans understand, mimic, and learn from the actions of nonhuman animals. Copyright © 2014 Elsevier B.V. All rights reserved.

Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC-dependence in intrahepatic cholangiocarcinoma

PubMed Central

Saha, Supriya K.; Gordan, John D.; Kleinstiver, Benjamin P.; Vu, Phuong; Najem, Mortada S.; Yeo, Jia-Chi; Shi, Lei; Kato, Yasutaka; Levin, Rebecca S.; Webber, James T.; Damon, Leah J.; Egan, Regina K.; Greninger, Patricia; McDermott, Ultan; Garnett, Mathew J.; Jenkins, Roger L.; Rieger-Christ, Kimberly M.; Sullivan, Travis B.; Hezel, Aram F.; Liss, Andrew S.; Mizukami, Yusuke; Goyal, Lipika; Ferrone, Cristina R.; Zhu, Andrew X.; Joung, J. Keith; Shokat, Kevan M.; Benes, Cyril H.; Bardeesy, Nabeel

2017-01-01

Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations. Through a high-throughput drug screen of a large panel of cancer cell lines including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multi-kinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines. Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant ‘gatekeeper’ mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC. Importantly, dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC. Moreover, these proteomic and genome-editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness. PMID:27231123

Moving Stimuli Facilitate Synchronization But Not Temporal Perception

PubMed Central

Silva, Susana; Castro, São Luís

2016-01-01

Recent studies have shown that a moving visual stimulus (e.g., a bouncing ball) facilitates synchronization compared to a static stimulus (e.g., a flashing light), and that it can even be as effective as an auditory beep. We asked a group of participants to perform different tasks with four stimulus types: beeps, siren-like sounds, visual flashes (static) and bouncing balls. First, participants performed synchronization with isochronous sequences (stimulus-guided synchronization), followed by a continuation phase in which the stimulus was internally generated (imagery-guided synchronization). Then they performed a perception task, in which they judged whether the final part of a temporal sequence was compatible with the previous beat structure (stimulus-guided perception). Similar to synchronization, an imagery-guided variant was added, in which sequences contained a gap in between (imagery-guided perception). Balls outperformed flashes and matched beeps (powerful ball effect) in stimulus-guided synchronization but not in perception (stimulus- or imagery-guided). In imagery-guided synchronization, performance accuracy decreased for beeps and balls, but not for flashes and sirens. Our findings suggest that the advantages of moving visual stimuli over static ones are grounded in action rather than perception, and they support the hypothesis that the sensorimotor coupling mechanisms for auditory (beeps) and moving visual stimuli (bouncing balls) overlap. PMID:27909419

Moving Stimuli Facilitate Synchronization But Not Temporal Perception.

PubMed

Silva, Susana; Castro, São Luís

2016-01-01

Recent studies have shown that a moving visual stimulus (e.g., a bouncing ball) facilitates synchronization compared to a static stimulus (e.g., a flashing light), and that it can even be as effective as an auditory beep. We asked a group of participants to perform different tasks with four stimulus types: beeps, siren-like sounds, visual flashes (static) and bouncing balls. First, participants performed synchronization with isochronous sequences (stimulus-guided synchronization), followed by a continuation phase in which the stimulus was internally generated (imagery-guided synchronization). Then they performed a perception task, in which they judged whether the final part of a temporal sequence was compatible with the previous beat structure (stimulus-guided perception). Similar to synchronization, an imagery-guided variant was added, in which sequences contained a gap in between (imagery-guided perception). Balls outperformed flashes and matched beeps (powerful ball effect) in stimulus-guided synchronization but not in perception (stimulus- or imagery-guided). In imagery-guided synchronization, performance accuracy decreased for beeps and balls, but not for flashes and sirens. Our findings suggest that the advantages of moving visual stimuli over static ones are grounded in action rather than perception, and they support the hypothesis that the sensorimotor coupling mechanisms for auditory (beeps) and moving visual stimuli (bouncing balls) overlap.

Inhibiting Src family tyrosine kinase activity blocks glutamate signalling to ERK1/2 and Akt/PKB but not JNK in cultured striatal neurones.

PubMed

Crossthwaite, Andrew J; Valli, Haseeb; Williams, Robert J

2004-03-01

Glutamate receptor activation of mitogen-activated protein (MAP) kinase signalling cascades has been implicated in diverse neuronal functions such as synaptic plasticity, development and excitotoxicity. We have previously shown that Ca2+-influx through NMDA receptors in cultured striatal neurones mediates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt/protein kinase B (PKB) through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. Exposing neurones to the Src family tyrosine kinase inhibitor PP2, but not the inactive analogue PP3, inhibited NMDA receptor-induced phosphorylation of ERK1/2 and Akt/PKB in a concentration-dependent manner, and reduced cAMP response element-binding protein (CREB) phosphorylation. To establish a link between Src family tyrosine kinase-mediated phosphorylation and PI 3-kinase signalling, affinity precipitation experiments were performed with the SH2 domains of the PI 3-kinase regulatory subunit p85. This revealed a Src-dependent phosphorylation of a focal adhesion kinase (FAK)-p85 complex on glutamate stimulation. Demonstrating that PI3-kinase is not ubiquitously involved in NMDA receptor signal transduction, the PI 3-kinase inhibitors wortmannin and LY294002 did not prevent NMDA receptor Ca2+-dependent phosphorylation of c-Jun N-terminal kinase 1/2 (JNK1/2). Further, inhibiting Src family kinases increased NMDA receptor-dependent JNK1/2 phosphorylation, suggesting that Src family kinase-dependent cascades may physiologically limit signalling to JNK. These results demonstrate that Src family tyrosine kinases and PI3-kinase are pivotal regulators of NMDA receptor signalling to ERK/Akt and JNK in striatal neurones.

Letrozole regulates actin cytoskeleton polymerization dynamics in a SRC-1 dependent manner in the hippocampus of mice.

PubMed

Zhao, Yangang; Yu, Yanlan; Zhang, Yuanyuan; He, Li; Qiu, Linli; Zhao, Jikai; Liu, Mengying; Zhang, Jiqiang

2017-03-01

In the hippocampus, local estrogens (E 2 ) derived from testosterone that is catalyzed by aromatase play important roles in the regulation of hippocampal neural plasticity, but the underlying mechanisms remain unclear. The actin cytoskeleton contributes greatly to hippocampal synaptic plasticity; however, whether it is regulated by local E 2 and the related mechanisms remain to be elucidated. In this study, we first examined the postnatal developmental profiles of hippocampal aromatase and specific proteins responsible for actin cytoskeleton dynamics. Then we used aromatase inhibitor letrozole (LET) to block local E 2 synthesis and examined the changes of these proteins and steroid receptor coactivator-1 (SRC-1), the predominant coactivator for steroid nuclear receptors. Finally, SRC-1 specific RNA interference was used to examine the effects of SRC-1 on the expression of these actin remodeling proteins. The results showed a V-type profile for aromatase and increased profiles for actin cytoskeleton proteins in both male and female hippocampus without obvious sex differences. LET treatment dramatically decreased the F-actin/G-actin ratio, the expression of Rictor, phospho-AKT (ser473), Profilin-1, phospho-Cofilin (Ser3), and SRC-1 in a dose-dependent manner. In vitro studies demonstrated that LET induced downregulation of these proteins could be reversed by E 2 , and E 2 induced increase of these proteins were significantly suppressed by SRC-1 shRNA interference. These results for the first time clearly demonstrated that local E 2 inhibition could induce aberrant actin polymerization; they also showed an important role of SRC-1 in the mediation of local E 2 action on hippocampal synaptic plasticity by regulation of actin cytoskeleton dynamics. Copyright © 2016 Elsevier Ltd. All rights reserved.

REVERSE SIGNALING BY GPI-LINKED MANDUCA EPHRIN REQUIRES A SRC FAMILY KINASE TO RESTRICT NEURONAL MIGRATION IN VIVO

PubMed Central

Coate, Thomas M.; Swanson, Tracy L.; Copenhaver, Philip F.

2011-01-01

Reverse signaling via GPI-linked Ephrins may help control cell proliferation and outgrowth within the nervous system, but the mechanisms underlying this process remain poorly understood. In the embryonic enteric nervous system (ENS) of the moth Manduca sexta, migratory neurons forming the enteric plexus (EP cells) express a single Ephrin ligand (GPI-linked MsEphrin), while adjacent midline cells that are inhibitory to migration express the cognate receptor (MsEph). Knocking down MsEph receptor expression in cultured embryos with antisense morpholino oligonucleotides allowed the EP cells to cross the midline inappropriately, consistent with the model that reverse signaling via MsEphrin mediates a repulsive response in the ENS. Src family kinases have been implicated in reverse signaling by type-A Ephrins in other contexts, and MsEphrin colocalizes with activated forms of endogenous Src in the leading processes of the EP cells. Pharmacological inhibition of Src within the developing ENS induced aberrant midline crossovers, similar to the effect of blocking MsEphrin reverse signaling. Hyperstimulating MsEphrin reverse signaling with MsEph-Fc fusion proteins induced the rapid activation of endogenous Src specifically within the EP cells, as assayed by Western blots of single embryonic gut explants and by whole-mount immunostaining of cultured embryos. In longer cultures, treatment with MsEph-Fc caused a global inhibition of EP cell migration and outgrowth, an effect that was prevented by inhibiting Src activation. These results support the model that MsEphrin reverse signaling induces the Src-dependent retraction of EP cell processes away from the enteric midline, thereby helping to confine the neurons to their appropriate pathways. PMID:19295147

The prostaglandin receptor EP2 activates multiple signaling pathways and β-arrestin1 complex formation during mouse skin papilloma development

PubMed Central

Chun, Kyung-Soo; Lao, Huei-Chen; Trempus, Carol S.; Okada, Manabu; Langenbach, Robert

2009-01-01

Prostaglandin E2 (PGE2) is elevated in many tumor types, but PGE2's contributions to tumor growth are largely unknown. To investigate PGE2's roles, the contributions of one of its receptors, EP2, were studied using the mouse skin initiation/promotion model. Initial studies indicated that protein kinase A (PKA), epidermal growth factor receptor (EGFR) and several effectors—cyclic adenosine 3′,5′-monophosphate response element-binding protein (CREB), H-Ras, Src, protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2—were activated in 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted papillomas and that PKA and EGFR inhibition (H89 and AG1478, respectively) decreased papilloma formation. EP2's contributions to the activation of these pathways and papilloma development were determined by inhibiting endogenous TPA-induced PGE2 production with indomethacin (Indo) and concomitantly treating with the EP2 agonist, CAY10399 (CAY). CAY treatment restored papilloma formation in TPA/Indo-treated mice and increased cyclic adenosine 3′,5′-monophosphate and PKA activation as measured by p-CREB formation. CAY treatment also increased EGFR and Src activation and their inhibition by AG1478 and PP2 indicated that Src was upstream of EGFR. CAY also increased H-Ras, ERK1/2 and AKT activation, and AG1478 decreased their activation indicating EGFR being upstream. Supporting EP2's contribution, EP2−/− mice exhibited 65% fewer papillomas and reduced Src, EGFR, H-Ras, AKT and ERK1/2 activation. G protein-coupled receptor (GPCR) activation of EGFR has been reported to involve Src's activation via a GPCR–β-arrestin–Src complex. Indeed, immunoprecipitation of β-arrestin1 or p-Src indicated the presence of an EP2–β-arrestin1–p-Src complex in papillomas. The data indicated that EP2 contributed to tumor formation via activation of PKA and EGFR and that EP2 formed a complex with β-arrestin1 and Src that contributed to signaling and/or EP2 desensitization. PMID:19587094

Joint Simon effects in extrapersonal space.

PubMed

Welsh, Timothy N; Kiernan, Dovin; Neyedli, Heather F; Ray, Matthew; Pratt, Jay; Potruff, Andrew; Weeks, Daniel J

2013-01-01

Numerous studies have revealed that when people sit next to each other and complete separate parts of a Simon task, response times are shorter when the participants' stimulus appears in front of them than when the stimulus appears in the opposite side of space. According to the action co-representation account of this joint Simon effect (JSE), participants represent each other's responses and the compatibility effects emerge because of a set of facilitatory and inhibitory processes that are similar to those that are activated when individuals perform the entire Simon task alone. D. Guagnano, E. Rusconi, and C. A. Umiltà (2010) argued against this account as the sole mechanism based on their finding that a JSE was not observed when participants sat outside of each other's peripersonal space. Notably, the task in the Guagnano et al.'s was a modified version of the conventional JSE task designed to increase the independence of the partners. Here, we reconsider the arguments of Guagnano et al. and report a study in which the authors failed to replicate their key finding. Considering the extant JSE literature, we conclude that the null effect in Guagnano et al.'s study may be an anomaly and that co-representation remains a leading candidate for the critical process underlying JSEs.

FocusStack and StimServer: a new open source MATLAB toolchain for visual stimulation and analysis of two-photon calcium neuronal imaging data.

PubMed

Muir, Dylan R; Kampa, Björn M

2014-01-01

Two-photon calcium imaging of neuronal responses is an increasingly accessible technology for probing population responses in cortex at single cell resolution, and with reasonable and improving temporal resolution. However, analysis of two-photon data is usually performed using ad-hoc solutions. To date, no publicly available software exists for straightforward analysis of stimulus-triggered two-photon imaging experiments. In addition, the increasing data rates of two-photon acquisition systems imply increasing cost of computing hardware required for in-memory analysis. Here we present a Matlab toolbox, FocusStack, for simple and efficient analysis of two-photon calcium imaging stacks on consumer-level hardware, with minimal memory footprint. We also present a Matlab toolbox, StimServer, for generation and sequencing of visual stimuli, designed to be triggered over a network link from a two-photon acquisition system. FocusStack is compatible out of the box with several existing two-photon acquisition systems, and is simple to adapt to arbitrary binary file formats. Analysis tools such as stack alignment for movement correction, automated cell detection and peri-stimulus time histograms are already provided, and further tools can be easily incorporated. Both packages are available as publicly-accessible source-code repositories.

FocusStack and StimServer: a new open source MATLAB toolchain for visual stimulation and analysis of two-photon calcium neuronal imaging data

PubMed Central

Muir, Dylan R.; Kampa, Björn M.

2015-01-01

Two-photon calcium imaging of neuronal responses is an increasingly accessible technology for probing population responses in cortex at single cell resolution, and with reasonable and improving temporal resolution. However, analysis of two-photon data is usually performed using ad-hoc solutions. To date, no publicly available software exists for straightforward analysis of stimulus-triggered two-photon imaging experiments. In addition, the increasing data rates of two-photon acquisition systems imply increasing cost of computing hardware required for in-memory analysis. Here we present a Matlab toolbox, FocusStack, for simple and efficient analysis of two-photon calcium imaging stacks on consumer-level hardware, with minimal memory footprint. We also present a Matlab toolbox, StimServer, for generation and sequencing of visual stimuli, designed to be triggered over a network link from a two-photon acquisition system. FocusStack is compatible out of the box with several existing two-photon acquisition systems, and is simple to adapt to arbitrary binary file formats. Analysis tools such as stack alignment for movement correction, automated cell detection and peri-stimulus time histograms are already provided, and further tools can be easily incorporated. Both packages are available as publicly-accessible source-code repositories1. PMID:25653614

Filtering versus parallel processing in RSVP tasks.

PubMed

Botella, J; Eriksen, C W

1992-04-01

An experiment of McLean, D. E. Broadbent, and M. H. P. Broadbent (1983) using rapid serial visual presentation (RSVP) was replicated. A series of letters in one of 5 colors was presented, and the subject was asked to identify the letter that appeared in a designated color. There were several innovations in our procedure, the most important of which was the use of a response menu. After each trial, the subject was presented with 7 candidate letters from which to choose his/her response. In three experimental conditions, the target, the letter following the target, and all letters other than the target were, respectively, eliminated from the menu. In other conditions, the stimulus list was manipulated by repeating items in the series, repeating the color of successive items, or even eliminating the target color. By means of these manipulations, we were able to determine more precisely the information that subjects had obtained from the presentation of the stimulus series. Although we replicated the results of McLean et al. (1983), the more extensive information that our procedure produced was incompatible with the serial filter model that McLean et al. had used to describe their data. Overall, our results were more compatible with a parallel-processing account. Furthermore, intrusion errors are apparently not only a perceptual phenomenon but a memory problem as well.

Simple and powerful visual stimulus generator.

PubMed

Kremlácek, J; Kuba, M; Kubová, Z; Vít, F

1999-02-01

We describe a cheap, simple, portable and efficient approach to visual stimulation for neurophysiology which does not need any special hardware equipment. The method based on an animation technique uses the FLI autodesk animator format. This form of the animation is replayed by a special program ('player') providing synchronisation pulses toward recording system via parallel port. The 'player is running on an IBM compatible personal computer under MS-DOS operation system and stimulus is displayed on a VGA computer monitor. Various stimuli created with this technique for visual evoked potentials (VEPs) are presented.

Iron depletion results in Src kinase inhibition with associated cell cycle arrest in neuroblastoma cells

PubMed Central

Siriwardana, Gamini; Seligman, Paul A

2015-01-01

Iron is required for cellular proliferation. Recently, using systematic time studies of neuroblastoma cell growth, we better defined the G1 arrest caused by iron chelation to a point in mid-G1, where cyclin E protein is present, but the cyclin E/CDK2 complex kinase activity is inhibited. In this study, we again used the neuroblastoma SKNSH cells lines to pinpoint the mechanism responsible for this G1 block. Initial studies showed in the presence of DFO, these cells have high levels of p27 and after reversal of iron chelation p27 is degraded allowing for CDK2 kinase activity. The initial activation of CDK2 kinase allows cells to exit G1 and enter S phase. Furthermore, we found that inhibition of p27 degradation by DFO is directly associated with inhibition of Src kinase activity measured by lack of phosphorylation of Src at the 416 residue. Activation of Src kinase occurs very early after reversal from the DFO G1 block and is temporally associated with initiation of cellular proliferation associated with entry into S phase. For the first time therefore we show that iron chelation inhibits Src kinase activity and this activity is a requirement for cellular proliferation. PMID:25825542

Decipher the dynamic coordination between enzymatic activity and structural modulation at focal adhesions in living cells

NASA Astrophysics Data System (ADS)

Lu, Shaoying; Seong, Jihye; Wang, Yi; Chang, Shiou-Chi; Eichorst, John Paul; Ouyang, Mingxing; Li, Julie Y.-S.; Chien, Shu; Wang, Yingxiao

2014-07-01

Focal adhesions (FAs) are dynamic subcellular structures crucial for cell adhesion, migration and differentiation. It remains an enigma how enzymatic activities in these local complexes regulate their structural remodeling in live cells. Utilizing biosensors based on fluorescence resonance energy transfer (FRET), we developed a correlative FRET imaging microscopy (CFIM) approach to quantitatively analyze the subcellular coordination between the enzymatic Src activation and the structural FA disassembly. CFIM reveals that the Src kinase activity only within the microdomain of lipid rafts at the plasma membrane is coupled with FA dynamics. FA disassembly at cell periphery was linearly dependent on this raft-localized Src activity, although cells displayed heterogeneous levels of response to stimulation. Within lipid rafts, the time delay between Src activation and FA disassembly was 1.2 min in cells seeded on low fibronectin concentration ([FN]) and 4.3 min in cells on high [FN]. CFIM further showed that the level of Src-FA coupling, as well as the time delay, was regulated by cell-matrix interactions, as a tight enzyme-structure coupling occurred in FA populations mediated by integrin αvβ3, but not in those by integrin α5β1. Therefore, different FA subpopulations have distinctive regulation mechanisms between their local kinase activity and structural FA dynamics.

A test of the embodied simulation theory of object perception: potentiation of responses to artifacts and animals.

PubMed

Matheson, Heath E; White, Nicole C; McMullen, Patricia A

2014-07-01

Theories of embodied object representation predict a tight association between sensorimotor processes and visual processing of manipulable objects. Previous research has shown that object handles can 'potentiate' a manual response (i.e., button press) to a congruent location. This potentiation effect is taken as evidence that objects automatically evoke sensorimotor simulations in response to the visual presentation of manipulable objects. In the present series of experiments, we investigated a critical prediction of the theory of embodied object representations that potentiation effects should be observed with manipulable artifacts but not non-manipulable animals. In four experiments we show that (a) potentiation effects are observed with animals and artifacts; (b) potentiation effects depend on the absolute size of the objects and (c) task context influences the presence/absence of potentiation effects. We conclude that potentiation effects do not provide evidence for embodied object representations, but are suggestive of a more general stimulus-response compatibility effect that may depend on the distribution of attention to different object features.

4-Hydroxynonenal activates Src through a non-canonical pathway that involves EGFR/PTP1B

PubMed Central

Zhang, Hongqiao; Forman, Henry Jay

2015-01-01

Src, a non-receptor protein tyrosine kinase involved in many biological processes, can be activated through both redox-dependent and independent mechanisms. 4-Hydroxy-2-nonenal (HNE) is a lipid peroxidation product that is increased in pathophysiological conditions associated with Src activation. This study examined how HNE activates human c-Src. In the canonical pathway Src activation is initiated by dephosphorylation of pTyr530 followed by conformational change that causes Src auto-phosphorylation at Tyr419 and its activation. HNE increased Src activation in both dose- and time-dependent manner, while it also increased Src phosphorylation at Tyr530 (pTyr530 Src), suggesting that HNE activated Src via a non-canonical mechanism. Protein tyrosine phosphatase 1B inhibitor (539741), at concentrations that increased basal pTyr530 Src, also increased basal Src activity and significantly reduced HNE-mediated Src activation. The EGFR inhibitor, AG1478, and EGFR silencing, abrogated HNE-mediated EGFR activation and inhibited basal and HNE-induced Src activity. In addition, AG1478 also eliminated the increase of basal Src activation by a PTP1B inhibitor. Taken together these data suggest that HNE can activate Src partly through a non-canonical pathway involving activation of EGFR and inhibition of PTP1B. PMID:26453921

Functional difference between sustained and transient modulations of cognitive control in the simon task: evidence from false alarm responses on no-go trials.

PubMed

Hasegawa, Kunihiro; Takahashi, Shin'ya

2013-01-01

Cognitive control in response compatibility tasks is modulated by the task context. Two types of contextual modulations have been demonstrated; sustained (block-wise) and transient (trial-by-trial). Recent research suggests that these modulations have different underlying mechanisms. This study presents new evidence supporting this claim by comparing false alarm (FA) responses on no-go trials of the Simon task between the sustained and transient contexts. In Experiment 1, the sustained context was manipulated so that a block included a larger number of incongruent trials. Results showed that participants made more FA responses by the hand opposite to the stimulus location. This suggests a generation of response bias in which the task-irrelevant location information is utilized in a reversed manner (i.e., to respond with the right hand to a stimulus presented on the left side and vice versa). Next, Experiment 2 examined the effect of the transient context and found that overall FA rate was lower when a no-go trial was preceded by an incongruent trial than by a congruent trial, whereas such response bias as that shown in Experiment 1 was not demonstrated. This suggests that the transient conflict context enhances inhibition of the task-irrelevant process but does not make the task-irrelevant information actively usable. Based on these results, we propound two types of cognitive control modulations as adaptive behaviors: response biasing based on utilization of the task-irrelevant information under the sustained conflict context and transient enhancement of inhibition of the task-irrelevant process based on the online conflict monitoring.

Two Simon tasks with different sources of conflict: an ERP study of motion- and location-based compatibility effects.

PubMed

Galashan, Daniela; Wittfoth, Matthias; Fehr, Thorsten; Herrmann, Manfred

2008-07-01

Behavioral and electrophysiological correlates of two Simon tasks were examined using comparable stimuli but different task-irrelevant and conflict-inducing stimulus features. Whereas target shape was always the task-relevant stimulus attribute, either target location (location-based task) or motion direction within the target stimuli (motion-based task) was used as a source of conflict. Data from ten healthy participants who performed both tasks are presented. In the motion-based task the incompatible condition showed smaller P300 amplitudes at Pz than the compatible condition and the location-based task yielded a trend towards a reduced P300 amplitude in the incompatible condition. For both tasks, no P300 latency differences between the conditions were found at Pz. The results suggest that the motion-based task elicits behavioral and electrophysiological effects comparable with regular Simon tasks. As all stimuli in the motion-based Simon task were presented centrally the present data strongly argue against the attention-shifting account as an explanatory approach.

Dissociating Stimulus-Set and Response-Set in the Context of Task-Set Switching

PubMed Central

Kieffaber, Paul D.; Kruschke, John K.; Cho, Raymond Y.; Walker, Philip M.; Hetrick, William P.

2014-01-01

The primary aim of the present research was to determine how stimulus-set and response-set components of task-set contribute to switch costs and conflict processing. Three experiments are described wherein participants completed an explicitly cued task-switching procedure. Experiment 1 established that task switches requiring a reconfiguration of both stimulus- and response-set incurred larger residual switch costs than task switches requiring the reconfiguration of stimulus-set alone. Between-task interference was also drastically reduced for response-set conflict compared with stimulus-set conflict. A second experiment replicated these findings and demonstrated that stimulus- and response-conflict have dissociable effects on the “decision time” and “motor time” components of total response time. Finally, a third experiment replicated Experiment 2 and demonstrated that the stimulus- and response- components of task switching and conflict processing elicit dissociable neural activity as evidence by event-related brain potentials. PMID:22984990

Method and apparatus for in-situ characterization of energy storage and energy conversion devices

DOEpatents

Christophersen, Jon P [Idaho Falls, ID; Motloch, Chester G [Idaho Falls, ID; Morrison, John L [Butte, MT; Albrecht, Weston [Layton, UT

2010-03-09

Disclosed are methods and apparatuses for determining an impedance of an energy-output device using a random noise stimulus applied to the energy-output device. A random noise signal is generated and converted to a random noise stimulus as a current source correlated to the random noise signal. A bias-reduced response of the energy-output device to the random noise stimulus is generated by comparing a voltage at the energy-output device terminal to an average voltage signal. The random noise stimulus and bias-reduced response may be periodically sampled to generate a time-varying current stimulus and a time-varying voltage response, which may be correlated to generate an autocorrelated stimulus, an autocorrelated response, and a cross-correlated response. Finally, the autocorrelated stimulus, the autocorrelated response, and the cross-correlated response may be combined to determine at least one of impedance amplitude, impedance phase, and complex impedance.

Carving Executive Control at Its Joints: Working Memory Capacity Predicts Stimulus-Stimulus, but Not Stimulus-Response, Conflict

ERIC Educational Resources Information Center

Meier, Matt E.; Kane, Michael J.

2015-01-01

Three experiments examined the relation between working memory capacity (WMC) and 2 different forms of cognitive conflict: stimulus-stimulus (S-S) and stimulus-response (S-R) interference. Our goal was to test whether WMC's relation to conflict-task performance is mediated by stimulus-identification processes (captured by S-S conflict),…

v-Src-driven transformation is due to chromosome abnormalities but not Src-mediated growth signaling.

PubMed

Honda, Takuya; Morii, Mariko; Nakayama, Yuji; Suzuki, Ko; Yamaguchi, Noritaka; Yamaguchi, Naoto

2018-01-18

v-Src is the first identified oncogene product and has a strong tyrosine kinase activity. Much of the literature indicates that v-Src expression induces anchorage-independent and infinite cell proliferation through continuous stimulation of growth signaling by v-Src activity. Although all of v-Src-expressing cells are supposed to form transformed colonies, low frequencies of v-Src-induced colony formation have been observed so far. Using cells that exhibit high expression efficiencies of inducible v-Src, we show that v-Src expression causes cell-cycle arrest through p21 up-regulation despite ERK activation. v-Src expression also induces chromosome abnormalities and unexpected suppression of v-Src expression, leading to p21 down-regulation and ERK inactivation. Importantly, among v-Src-suppressed cells, only a limited number of cells gain the ability to re-proliferate and form transformed colonies. Our findings provide the first evidence that v-Src-driven transformation is attributed to chromosome abnormalities, but not continuous stimulation of growth signaling, possibly through stochastic genetic alterations.

Lack of Csk-mediated negative regulation in a unicellular SRC kinase.

PubMed

Schultheiss, Kira P; Suga, Hiroshi; Ruiz-Trillo, Iñaki; Miller, W Todd

2012-10-16

Phosphotyrosine-based signaling plays a vital role in cellular communication in multicellular organisms. Unexpectedly, unicellular choanoflagellates (the closest phylogenetic group to metazoans) possess numbers of tyrosine kinases that are comparable to those in complex metazoans. Here, we have characterized tyrosine kinases from the filasterean Capsaspora owczarzaki, a unicellular protist representing the sister group to choanoflagellates and metazoans. Two Src-like tyrosine kinases have been identified in C. owczarzaki (CoSrc1 and CoSrc2), both of which have the arrangement of SH3, SH2, and catalytic domains seen in mammalian Src kinases. In Capsaspora cells, CoSrc1 and CoSrc2 localize to punctate structures in filopodia that may represent primordial focal adhesions. We have cloned, expressed, and purified both enzymes. CoSrc1 and CoSrc2 are active tyrosine kinases. Mammalian Src kinases are normally regulated in a reciprocal fashion by autophosphorylation in the activation loop (which increases activity) and by Csk-mediated phosphorylation of the C-terminal tail (which inhibits activity). Similar to mammalian Src kinases, the enzymatic activities of CoSrc1 and CoSrc2 are increased by autophosphorylation in the activation loop. We have identified a Csk-like kinase (CoCsk) in the genome of C. owczarzaki. We cloned, expressed, and purified CoCsk and found that it has no measurable tyrosine kinase activity. Furthermore, CoCsk does not phosphorylate or regulate CoSrc1 or CoSrc2 in cells or in vitro, and CoSrc1 and CoSrc2 are active in Capsaspora cell lysates. Thus, the function of Csk as a negative regulator of Src family kinases appears to have arisen with the emergence of metazoans.

SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis

PubMed Central

Fleet, Tiffany; Zhang, Bin; Lin, Fumin; Zhu, Bokai; Dasgupta, Subhamoy; Stashi, Erin; Tackett, Bryan; Thevananther, Sundararajah; Rajapakshe, Kimal I.; Gonzales, Naomi; Dean, Adam; Mao, Jianqiang; Timchenko, Nikolai; Malovannaya, Anna; Qin, Jun; Coarfa, Cristian; DeMayo, Francesco; Dacso, Clifford C.; Foulds, Charles E.; O’Malley, Bert W.; York, Brian

2015-01-01

Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation. PMID:26487680

The Gβγ-Src signaling pathway regulates TNF-induced necroptosis via control of necrosome translocation

PubMed Central

Li, Lisheng; Chen, Wanze; Liang, Yaoji; Ma, Huabin; Li, Wenjuan; Zhou, Zhenru; Li, Jie; Ding, Yan; Ren, Junming; Lin, Juan; Han, Felicia; Wu, Jianfeng; Han, Jiahuai

2014-01-01

Formation of multi-component signaling complex necrosomes is essential for tumor necrosis factor α (TNF)-induced programmed necrosis (also called necroptosis). However, the mechanisms of necroptosis are still largely unknown. We isolated a TNF-resistant L929 mutant cell line generated by retrovirus insertion and identified that disruption of the guanine nucleotide-binding protein γ 10 (Gγ10) gene is responsible for this phenotype. We further show that Gγ10 is involved in TNF-induced necroptosis and Gβ2 is the partner of Gγ10. Src is the downstream effector of Gβ2γ10 in TNF-induced necroptosis because TNF-induced Src activation was impaired upon Gγ10 knockdown. Gγ10 does not affect TNF-induced activation of NF-κB and MAPKs and the formation of necrosomes, but is required for trafficking of necrosomes to their potential functioning site, an unidentified subcellular organelle that can be fractionated into heterotypic membrane fractions. The TNF-induced Gβγ-Src signaling pathway is independent of RIP1/RIP3 kinase activity and necrosome formation, but is required for the necrosome to function. PMID:24513853

Dasatinib is preclinically active against Src-overexpressing human transitional cell carcinoma of the urothelium with activated Src signaling.

PubMed

Levitt, Jonathan M; Yamashita, Hideyuki; Jian, Weiguo; Lerner, Seth P; Sonpavde, Guru

2010-05-01

Dasatinib is an orally administered multitargeted kinase inhibitor that targets Src family tyrosine kinases, Abl, c-Kit, and PDGFR. A preclinical study was conducted to evaluate dasatinib alone or combined with cisplatin for human transitional cell carcinoma (TCC). Expression of Src in a human TCC tissue microarray was evaluated by immunohistochemistry. The activity of dasatinib and/or cisplatin was evaluated in six human TCC cell lines. Western blot was done to assess Src and phosphorylated-Src (p-Src) expression. The activity of dasatinib alone and in combination with cisplatin was determined in murine subcutaneous xenografts. Sixty-two percent to 75% of human TCC expressed Src. Dasatinib displayed significant antiproliferative activity at nanomolar concentrations against two human TCC cell lines (RT4 and Hu456) that exhibited high Src and p-Src expression and were cisplatin-resistant. RT4 cells were the most sensitive and displayed the highest level of Src pathway activation (p-Src/Src ratio). Dasatinib downregulated p-Src in either sensitive or resistant cells. TCC cells that were sensitive to cisplatin (5637 and TCC-SUP) were highly resistant to dasatinib and exhibited low Src expression. Dasatinib showed antitumor activity in RT4 murine xenografts, and the combination of dasatinib and cisplatin was significantly more active than placebo. Combination dasatinib plus cisplatin significantly inhibited proliferation and promoted apoptosis in vivo. In conclusion, dasatinib displayed significant preclinical antitumor activity against Src-overexpressing human TCC with active Src signaling and was highly active in combination with cisplatin in vivo. Further clinical development might be warranted in selected human subjects.

PDGF-induced migration of synthetic vascular smooth muscle cells through c-Src-activated L-type Ca2+ channels with full-length CaV1.2 C-terminus.

PubMed

Guo, Xiaoguang; Kashihara, Toshihide; Nakada, Tsutomu; Aoyama, Toshifumi; Yamada, Mitsuhiko

2018-06-01

In atherosclerosis, vascular smooth muscle cells (VSMC) migrate from the media toward the intima of the arteries in response to cytokines, such as platelet-derived growth factor (PDGF). However, molecular mechanism underlying the PDGF-induced migration of VSMCs remains unclear. The migration of rat aorta-derived synthetic VSMCs, A7r5, in response to PDGF was potently inhibited by a Ca V 1.2 channel inhibitor, nifedipine, and a Src family tyrosine kinase (SFK)/Abl inhibitor, bosutinib, in a less-than-additive manner. PDGF significantly increased Ca V 1.2 channel currents without altering Ca V 1.2 protein expression levels in A7r5 cells. This reaction was inhibited by C-terminal Src kinase, a selective inhibitor of SFKs. In contractile VSMCs, the C-terminus of Ca V 1.2 is proteolytically cleaved into proximal and distal C-termini (PCT and DCT, respectively). Clipped DCT is noncovalently reassociated with PCT to autoinhibit the channel activity. Conversely, in synthetic A7r5 cells, full-length Ca V 1.2 (Ca V 1.2FL) is expressed much more abundantly than truncated Ca V 1.2. In a heterologous expression system, c-Src activated Ca V 1.2 channels composed of Ca V 1.2FL but not truncated Ca V 1.2 (Ca V 1.2Δ1763) or Ca V 1.2Δ1763 plus clipped DCT. Further, c-Src enhanced the coupling efficiency between the voltage-sensing domain and activation gate of Ca V 1.2FL channels by phosphorylating Tyr1709 and Tyr1758 in PCT. Compared with Ca V 1.2Δ1763, c-Src could more efficiently bind to and phosphorylate Ca V 1.2FL irrespective of the presence or absence of clipped DCT. Therefore, in atherosclerotic lesions, phenotypic switching of VSMCs may facilitate pro-migratory effects of PDGF on VSMCs by suppressing posttranslational Ca V 1.2 modifications.

Aldosterone rapidly activates Src kinase in M-1 cells involving the mineralocorticoid receptor and HSP84.

PubMed

Braun, Sabine; Lösel, Ralf; Wehling, Martin; Boldyreff, Brigitte

2004-07-16

We investigated the effect of aldosterone on Src kinase. In the kidney cell line, M-1 aldosterone leads to a >2-fold transient activation of Src kinase seen as early as 2 min after aldosterone administration. Maximal Src kinase activation was measured at an aldosterone concentration of 1 nM. In parallel to activation, autophosphorylation at Tyr-416 of Src kinase increased. Src kinase activation was blocked by spironolactone. Aldosterone led to increased association of Src with HSP84. Furthermore, rapamycin blocked aldosterone-induced Src activation. We conclude that Src activation by aldosterone is mediated through the mineralocorticoid receptor and HSP84.

Second-order schedules: comparison of different procedures for scheduling paired and nonpaired brief stimuli.

PubMed

Stubbs, D A; Cohen, S L

1972-11-01

Pigeons performed on a second-order schedule in which fixed-interval components were maintained under a variable-interval schedule. Completion of each fixed-interval component resulted in a brief-stimulus presentation and/or food. The relation of the brief stimulus and food was varied across conditions. Under some conditions, the brief stimulus was never paired with food. Under other conditions, the brief stimulus was paired with food; three different pairing procedures were used: (a) a response produced the simultaneous onset of the stimulus and food; (b) a response produced the stimulus before food with the stimulus remaining on during food presentation; (c) a response produced the stimulus and the offset of the stimulus was simultaneous with the onset of the food cycle. The various pairing and nonpairing operations all produced similar effects on performance. Under all conditions, response rates were positively accelerated within fixed-interval components. Total response rates and Index of Curvature measures were similar across conditions. In one condition, a blackout was paired with food; with this different stimulus in effect, less curvature resulted. The results suggest that pairing of a stimulus is not a necessary condition for within-component patterning under some second-order schedules.

Second-order schedules: comparison of different procedures for scheduling paired and nonpaired brief stimuli

PubMed Central

Stubbs, D. Alan; Cohen, Steven L.

1972-01-01

Pigeons performed on a second-order schedule in which fixed-interval components were maintained under a variable-interval schedule. Completion of each fixed-interval component resulted in a brief-stimulus presentation and/or food. The relation of the brief stimulus and food was varied across conditions. Under some conditions, the brief stimulus was never paired with food. Under other conditions, the brief stimulus was paired with food; three different pairing procedures were used: (a) a response produced the simultaneous onset of the stimulus and food; (b) a response produced the stimulus before food with the stimulus remaining on during food presentation; (c) a response produced the stimulus and the offset of the stimulus was simultaneous with the onset of the food cycle. The various pairing and nonpairing operations all produced similar effects on performance. Under all conditions, response rates were positively accelerated within fixed-interval components. Total response rates and Index of Curvature measures were similar across conditions. In one condition, a blackout was paired with food; with this different stimulus in effect, less curvature resulted. The results suggest that pairing of a stimulus is not a necessary condition for within-component patterning under some second-order schedules. PMID:16811634

Roles of Raft-Anchored Adaptor Cbp/PAG1 in Spatial Regulation of c-Src Kinase

PubMed Central

Oneyama, Chitose; Suzuki, Takashi; Okada, Masato

2014-01-01

The tyrosine kinase c-Src is upregulated in numerous human cancers, implying a role for c-Src in cancer progression. Previously, we have shown that sequestration of activated c-Src into lipid rafts via a transmembrane adaptor, Cbp/PAG1, efficiently suppresses c-Src-induced cell transformation in Csk-deficient cells, suggesting that the transforming activity of c-Src is spatially regulated via Cbp in lipid rafts. To dissect the molecular mechanisms of the Cbp-mediated regulation of c-Src, a combined analysis was performed that included mathematical modeling and in vitro experiments in a c-Src- or Cbp-inducible system. c-Src activity was first determined as a function of c-Src or Cbp levels, using focal adhesion kinase (FAK) as a crucial c-Src substrate. Based on these experimental data, two mathematical models were constructed, the sequestration model and the ternary model. The computational analysis showed that both models supported our proposal that raft localization of Cbp is crucial for the suppression of c-Src function, but the ternary model, which includes a ternary complex consisting of Cbp, c-Src, and FAK, also predicted that c-Src function is dependent on the lipid-raft volume. Experimental analysis revealed that c-Src activity is elevated when lipid rafts are disrupted and the ternary complex forms in non-raft membranes, indicating that the ternary model accurately represents the system. Moreover, the ternary model predicted that, if Cbp enhances the interaction between c-Src and FAK, Cbp could promote c-Src function when lipid rafts are disrupted. These findings underscore the crucial role of lipid rafts in the Cbp-mediated negative regulation of c-Src-transforming activity, and explain the positive role of Cbp in c-Src regulation under particular conditions where lipid rafts are perturbed. PMID:24675741

Role of c-Src in cellular events associated with colony-stimulating factor-1-induced spreading in osteoclasts.

PubMed

Insogna, K; Tanaka, S; Neff, L; Horne, W; Levy, J; Baron, R

1997-01-01

We and others have observed that in response to treatment with Colony Stimulating Factor-1 (CSF-1) neonatal rat osteoclasts demonstrate rapid cytoplasmic spreading. The receptor for CSF-1, c-Fms, is expressed in osteoclasts, possesses intrinsic tyrosine-kinase activity, and signals via rapid phosphorylation of selected proteins. It has been reported previously that c-Src becomes tyrosine phosphorylated following CSF-1 treatment of fibroblasts overexpressing c-Fms. We therefore examined the cellular events associated with CSF-1-induced spreading in osteoclasts and what role, if any, c-Src played in these processes. Confocal microscopic studies using phosphotyrosine (P-tyr) monoclonal antibodies demonstrated that CSF-1 induced a significant dose- and time-dependent increase in P-tyr labeling of neonatal rat osteoclasts. Phalloidin staining was consistent with partial to complete disassembly of the actin attachment ring with redistribution of actin to the spreading cytoplasmic edge of the cell. Quantitation of cellular F-actin using NBD-phallicidin confirmed a decrease in polymerized actin following exposure to CSF-1. In contrast, CSF-1 failed to induce any cytoplasmic spreading in osteoclasts isolated from mice with targeted disruption of the src gene. Further, in src- osteoclasts no well defined attachment ring could be identified. To investigate cell-signaling events associated with osteoclast spreading, detergent lysates were made from purified multinucleated osteoclast-like cells (OCLs) obtained by coculturing murine bone marrow and osteoblasts with calcitriol. Western blot analyses of lysates from control and CSF-1-treated normal cells indicated that several proteins were specifically phosphorylated in response to CSF-1, most notably proteins of 165, 60, and 85-90 kDa. Immunoprecipitation studies revealed that the 165 and 60 kDa proteins were, respectively, c-Fms and c-Src. The c-Src kinase activity was increased 2.9-fold following CSF-1 treatment. The 85-90 kDa protein is as yet unidentified. Since activated receptor tyrosine kinases may induce spreading in part by reducing phosphoinositol 4,5-bisphosphate (PIP2) binding to actin-associated proteins, a monoclonal antibody to PIP2 was used to assess the nature of PIP2 binding proteins in OCLs. Proteins of 85-90 kDa, 43 kDa, and 30 kDa were consistently demonstrated to bind PIP2. Further, the PIP2 content of the 85-90 kDa protein appeared to decrease with CSF-1 treatment. Whether this protein represents the phosphoprotein of the same M.W. is unclear. We also examined the effect of CSF-1 on the PIP2 content of alpha-actinin. Alpha-actinin showed low-level PIP2 binding, which was demonstrable only after immuno-precipitation and did not change with CSF-1 treatment. However, CSF-1 did cause a significant decline in the phosphotyrosine content of alpha-actinin. In contrast, in src- OCLs, CSF-1 induced more prolonged phosphorylation of c-Fms, and the 85-90 kDa protein was markedly hypophosphorylated. Further, alpha-actinin did not dephosphorylate in src- cells. We conclude that CSF-1-induced osteoclast spreading is accompanied by rapid reorganization of the actin cytoskeleton and phosphorylation of several cellular substrates, including c-Fms and c-Src. PIP2 binding to at least one protein appears to decrease with CSF-1 treatment, which may favor actin depolymerization. The reduced tyrosine phosphorylation of alpha-actinin could effect its ability to bind to actin. Thus c-Src may play an important role in these cellular events since in its absence, osteoclasts do not spread and signaling events downstream are altered. Whether these changes relate in part to the basal abnormalities in the cytoskeletal organization of src- osteoclasts remains to be determined.

SH2 Ligand-Like Effects of Second Cytosolic Domain of Na/K-ATPase α1 Subunit on Src Kinase.

PubMed

Banerjee, Moumita; Duan, Qiming; Xie, Zijian

2015-01-01

Our previous studies have suggested that the α1 Na/K-ATPase interacts with Src to form a receptor complex. In vitro binding assays indicate an interaction between second cytosolic domain (CD2) of Na/K-ATPase α1 subunit and Src SH2 domain. Since SH2 domain targets Src to specific signaling complexes, we expressed CD2 as a cytosolic protein and studied whether it could act as a Src SH2 ligand in LLC-PK1 cells. Co-immunoprecipitation analyses indicated a direct binding of CD2 to Src, consistent with the in vitro binding data. Functionally, CD2 expression increased basal Src activity, suggesting a Src SH2 ligand-like property of CD2. Consistently, we found that CD2 expression attenuated several signaling pathways where Src plays an important role. For instance, although it increased surface expression of Na/K-ATPase, it decreased ouabain-induced activation of Src and ERK by blocking the formation of Na/K-ATPase/Src complex. Moreover, it also attenuated cell attachment-induced activation of Src/FAK. Consequently, CD2 delayed cell spreading, and inhibited cell proliferation. Furthermore, these effects appear to be Src-specific because CD2 expression had no effect on EGF-induced activation of EGF receptor and ERK. Hence, the new findings indicate the importance of Na/K-ATPase/Src interaction in ouabain-induced signal transduction, and support the proposition that the CD2 peptide may be utilized as a Src SH2 ligand capable of blocking Src-dependent signaling pathways via a different mechanism from a general Src kinase inhibitor.

Ingroup categorization and response conflict: Interactive effects of target race, flanker compatibility, and infrequency on N2 amplitude.

PubMed

Dickter, Cheryl L; Bartholow, Bruce D

2010-05-01

Three largely independent lines of research have investigated experimental manipulations that influence the amplitude of the N2 component of the event-related brain potential (ERP), one linking heightened N2 amplitude to response conflict, another showing that N2 is sensitive to stimulus infrequency, and the third showing larger N2 amplitude during categorization of racial ingroup relative to racial outgroup targets. The purpose of this research was to investigate potential interactions between these three features on the amplitude of the N2. ERPs were recorded while participants completed a modified flanker task using pictures of ingroup and outgroup faces. Results showed a 3-way interaction, indicating that the N2 was largest for ingroup targets on high-conflict trials but only when such trials were relatively infrequent. Implications of these findings for theories of both conflict monitoring and person perception are discussed.

Ableson Kinases Negatively Regulate Invadopodia Function and Invasion in Head and Neck Squamous Cell Carcinoma by Inhibiting an HB-EGF Autocrine Loop

PubMed Central

Hayes, Karen E.; Walk, Elyse L.; Ammer, Amanda Gatesman; Kelley, Laura C.; Martin, Karen H.; Weed, Scott A.

2014-01-01

Head and neck squamous cell carcinoma (HNSCC) has a proclivity for locoregional invasion. HNSCC mediates invasion in part through invadopodia-based proteolysis of the extracellular matrix (ECM). Activation of Src, Erk1/2, Abl and Arg downstream of epidermal growth factor receptor (EGFR) modulates invadopodia activity through phosphorylation of the actin regulatory protein cortactin. In MDA-MB-231 breast cancer cells, Abl and Arg function downstream of Src to phosphorylate cortactin, promoting invadopodia ECM degradation activity and thus assigning a pro-invasive role for Ableson kinases. We report that Abl kinases have an opposite, negative regulatory role in HNSCC where they suppress invadopodia and tumor invasion. Impairment of Abl expression or Abl kinase activity with imatinib mesylate enhanced HNSCC matrix degradation and 3D collagen invasion, functions that were impaired in MDA-MB-231. HNSCC lines with elevated EGFR and Src activation did not contain increased Abl or Arg kinase activity, suggesting Src could bypass Abl/Arg to phosphorylate cortactin and promote invadopodia ECM degradation. Src transformed Abl−/−/Arg−/− fibroblasts produced ECM degrading invadopodia containing pY421 cortactin, indicating that Abl/Arg are dispensable for invadopodia function in this system. Imatinib treated HNSCC cells had increased EGFR, Erk1/2 and Src activation, enhancing cortactin pY421 and pS405/418 required for invadopodia function. Imatinib stimulated shedding of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) from HNSCC cells, where soluble HB-EGF enhanced invadopodia ECM degradation in HNSCC but not in MDA-MB-231. HNSCC cells treated with inhibitors of the EGFR invadopodia pathway indicated that EGFR and Src are required for invadopodia function. Collectively our results indicate that Abl kinases negatively regulate HNSCC invasive processes through suppression of an HB-EGF autocrine loop responsible for activating a EGFR-Src-cortactin cascade, in contrast to the invasion promoting functions of Abl kinases in breast and other cancer types. Our results provide mechanistic support for recent failed HNSCC clinical trials utilizing imatinib. PMID:23146907

Identification and functional characterization of an Src homology domain 3 domain-binding site on Cbl.

PubMed

Sanjay, Archana; Miyazaki, Tsuyoshi; Itzstein, Cecile; Purev, Enkhtsetseg; Horne, William C; Baron, Roland

2006-12-01

Cbl is an adaptor protein and ubiquitin ligase that binds and is phosphorylated by the nonreceptor tyrosine kinase Src. We previously showed that the primary interaction between Src and Cbl is mediated by the Src homology domain 3 (SH3) of Src binding to proline-rich sequences of Cbl. The peptide Cbl RDLPPPPPPDRP(540-551), which corresponds to residues 540-551 of Cbl, inhibited the binding of a GST-Src SH3 fusion protein to Cbl, whereas RDLAPPAPPPDR(540-551) did not, suggesting that Src binds to this site on Cbl in a class I orientation. Mutating prolines 543-548 reduced Src binding to the Cbl 479-636 fragment significantly more than mutating the prolines in the PPVPPR(494-499) motif, which was previously reported to bind Src SH3. Mutating Cbl prolines 543-548 to alanines substantially reduced Src binding to Cbl, Src-induced phosphorylation of Cbl, and the inhibition of Src kinase activity by Cbl. Expressing the mutated Cbl in osteoclasts induced a moderate reduction in bone-resorbing activity and increased amounts of Src protein. In contrast, disabling the tyrosine kinase-binding domain of full-length Cbl by mutating glycine 306 to glutamic acid, and thereby preventing the previously described binding of the tyrosine kinase-binding domain to the Src phosphotyrosine 416, had no effect on Cbl phosphorylation, the inhibition of Src activity by full-length Cbl, or bone resorption. These data indicate that the Cbl RDLPPPP(540-546) sequence is a functionally important binding site for Src.

Iron depletion results in Src kinase inhibition with associated cell cycle arrest in neuroblastoma cells.

PubMed

Siriwardana, Gamini; Seligman, Paul A

2015-03-01

Iron is required for cellular proliferation. Recently, using systematic time studies of neuroblastoma cell growth, we better defined the G1 arrest caused by iron chelation to a point in mid-G1, where cyclin E protein is present, but the cyclin E/CDK2 complex kinase activity is inhibited. In this study, we again used the neuroblastoma SKNSH cells lines to pinpoint the mechanism responsible for this G1 block. Initial studies showed in the presence of DFO, these cells have high levels of p27 and after reversal of iron chelation p27 is degraded allowing for CDK2 kinase activity. The initial activation of CDK2 kinase allows cells to exit G1 and enter S phase. Furthermore, we found that inhibition of p27 degradation by DFO is directly associated with inhibition of Src kinase activity measured by lack of phosphorylation of Src at the 416 residue. Activation of Src kinase occurs very early after reversal from the DFO G1 block and is temporally associated with initiation of cellular proliferation associated with entry into S phase. For the first time therefore we show that iron chelation inhibits Src kinase activity and this activity is a requirement for cellular proliferation. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Elevated Src family kinase activity stabilizes E-cadherin-based junctions and collective movement of head and neck squamous cell carcinomas

PubMed Central

Veracini, Laurence; Grall, Dominique; Schaub, Sébastien; Divonne, Stéphanie Beghelli-de la Forest; Etienne-Grimaldi, Marie-Christine; Milano, Gérard; Bozec, Alexandre; Babin, Emmanuel; Sudaka, Anne; Thariat, Juliette; Van Obberghen-Schilling, Ellen

2015-01-01

EGF receptor (EGFR) overexpression is thought to drive head and neck carcinogenesis however clinical responses to EGFR-targeting agents have been modest and alternate targets are actively sought to improve results. Src family kinases (SFKs), reported to act downstream of EGFR are among the alternative targets for which increased expression or activity in epithelial tumors is commonly associated to the dissolution of E-cadherin-based junctions and acquisition of a mesenchymal-like phenotype. Robust expression of total and activated Src was observed in advanced stage head and neck tumors (N=60) and in head and neck squamous cell carcinoma lines. In cultured cancer cells Src co-localized with E-cadherin in cell-cell junctions and its phosphorylation on Y419 was both constitutive and independent of EGFR activation. Selective inhibition of SFKs with SU6656 delocalized E-cadherin and disrupted cellular junctions without affecting E-cadherin expression and this effect was phenocopied by knockdown of Src or Yes. These findings reveal an EGFR-independent role for SFKs in the maintenance of intercellular junctions, which likely contributes to the cohesive invasion E-cadherin-positive cells in advanced tumors. Further, they highlight the need for a deeper comprehension of molecular pathways that drive collective cell invasion, in absence of mesenchymal transition, in order to combat tumor spread. PMID:25779657

Src Family Kinases and p38 Mitogen-Activated Protein Kinases Regulate Pluripotent Cell Differentiation in Culture

PubMed Central

Tan, Boon Siang Nicholas; Kwek, Joly; Wong, Chong Kum Edwin; Saner, Nicholas J.; Yap, Charlotte; Felquer, Fernando; Morris, Michael B.; Gardner, David K.; Rathjen, Peter D.; Rathjen, Joy

2016-01-01

Multiple pluripotent cell populations, which together comprise the pluripotent cell lineage, have been identified. The mechanisms that control the progression between these populations are still poorly understood. The formation of early primitive ectoderm-like (EPL) cells from mouse embryonic stem (mES) cells provides a model to understand how one such transition is regulated. EPL cells form from mES cells in response to l-proline uptake through the transporter Slc38a2. Using inhibitors of cell signaling we have shown that Src family kinases, p38 MAPK, ERK1/2 and GSK3β are required for the transition between mES and EPL cells. ERK1/2, c-Src and GSK3β are likely to be enforcing a receptive, primed state in mES cells, while Src family kinases and p38 MAPK are involved in the establishment of EPL cells. Inhibition of these pathways prevented the acquisition of most, but not all, features of EPL cells, suggesting that other pathways are required. L-proline activation of differentiation is mediated through metabolism and changes to intracellular metabolite levels, specifically reactive oxygen species. The implication of multiple signaling pathways in the process suggests a model in which the context of Src family kinase activation determines the outcomes of pluripotent cell differentiation. PMID:27723793

Tyrosine Phosphatases ε and α Perform Specific and Overlapping Functions in Regulation of Voltage-gated Potassium Channels in Schwann Cells

PubMed Central

Tiran, Zohar; Peretz, Asher; Sines, Tal; Shinder, Vera; Sap, Jan; Attali, Bernard

2006-01-01

Tyrosine phosphatases (PTPs) ε and α are closely related and share several molecular functions, such as regulation of Src family kinases and voltage-gated potassium (Kv) channels. Functional interrelationships between PTPε and PTPα and the mechanisms by which they regulate K+ channels and Src were analyzed in vivo in mice lacking either or both PTPs. Lack of either PTP increases Kv channel activity and phosphorylation in Schwann cells, indicating these PTPs inhibit Kv current amplitude in vivo. Open probability and unitary conductance of Kv channels are unchanged, suggesting an effect on channel number or organization. PTPα inhibits Kv channels more strongly than PTPε; this correlates with constitutive association of PTPα with Kv2.1, driven by membranal localization of PTPα. PTPα, but not PTPε, activates Src in sciatic nerve extracts, suggesting Src deregulation is not responsible exclusively for the observed phenotypes and highlighting an unexpected difference between both PTPs. Developmentally, sciatic nerve myelination is reduced transiently in mice lacking either PTP and more so in mice lacking both PTPs, suggesting both PTPs support myelination but are not fully redundant. We conclude that PTPε and PTPα differ significantly in their regulation of Kv channels and Src in the system examined and that similarity between PTPs does not necessarily result in full functional redundancy in vivo. PMID:16870705

Targeting Src and tubulin in mucinous ovarian carcinoma

PubMed Central

Liu, Tao; Hu, Wei; Dalton, Heather J.; Choi, Hyun Jin; Huang, Jie; Kang, Yu; Pradeep, Sunila; Miyake, Takahito; Song, Jian H.; Wen, Yunfei; Lu, Chunhua; Pecot, Chad V.; Bottsford-Miller, Justin; Zand, Behrouz; Jennings, Nicholas B; Ivan, Cristina; Gallick, Gary E.; Baggerly, Keith A; Hangauer, David G.; Coleman, Robert L.; Frumovitz, Michael; Sood, Anil K.

2013-01-01

Purpose To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma. Experimental design The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models. Results In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2/M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01-sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules. Conclusion Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma. PMID:24100628

Processing of Visual--Action Codes by Deaf and Hearing Children: Coding Orientation or "M"-Capacity?

ERIC Educational Resources Information Center

Todman, John; Cowdy, Natascha

1993-01-01

Results from a study in which 25 deaf children and 25 hearing children completed a vocabulary test and a compound stimulus visual information task support the hypothesis that performance on cognitive tasks is dependent on compatibility of task demands with a coding orientation. (SLD)

Phases of female sexual response cycle among Malaysian women with infertility: a factor analysis study.

PubMed

Seen Heng, Yeoh; Sidi, Hatta; Nik Jaafar, Nik Ruzyanei; Razali, Rosdinom; Ram, Hari

2013-04-01

This cross-sectional study aimed to determine the construct of the phases of the female sexual response cycle (SRC) among women attending an infertility clinic in a Malaysian tertiary center. The sexual response phases were measured with a validated Malay version of the Female Sexual Function Index (FSFI). The correlation structure of the items of the SRC phases (i.e. desire, arousal, orgasm, satisfaction and pain) was determined using principal component analysis (PCA), with varimax rotation method. The number of factors obtained was decided using Kaiser's criteria. A total of 150 married women with a mean age of 32 years participated in this study. Factor loadings using PCA with varimax rotation divided the sexual domains into three components. The first construct comprised sexual arousal, lubrication and pain (suggesting a mechanical component). The second construct were orgasm and sexual satisfaction (suggesting a physical achievement). Sexual desire, suggesting a psychological component, stood on its own as the third. The findings suggest that three constructs could be identified and in favor of the Basson model (a non-linear concept of SRC) for Malaysian women's sexual functioning. Understanding this would help clinicians to strategize the treatment approach of sexual dysfunction in women with infertility. Copyright © 2013 Wiley Publishing Asia Pty Ltd.

Second-order schedules: discrimination of components1

PubMed Central

Squires, Nancy; Norborg, James; Fantino, Edmund

1975-01-01

Pigeons were exposed to a series of second-order schedules in which the completion of a fixed number of fixed-interval components produced food. In Experiment 1, brief (2 sec) stimulus presentations occurred as each fixed-interval component was completed. During the brief-stimulus presentation terminating the last fixed-interval component, a response was required on a second key, the brief-stimulus key, to produce food. Responses on the brief-stimulus key before the last brief-stimulus presentation had no scheduled consequences, but served as a measure of the extent to which the final component was discriminated from preceding components. Whether there were one, two, four, or eight fixed-interval components, responses on the brief-stimulus key occurred during virtually every brief-stimulus presentation. In Experiment 2, an attempt was made to punish unnecessary responses on the brief-stimulus key, i.e., responses on the brief-stimulus key that occurred before the last component. None of the pigeons learned to withhold these responses, even though they produced a 15-sec timeout and loss of primary reinforcement. In Experiment 3, different key colors were associated with each component of a second-order schedule (a chain schedule). In contrast to Experiment 1, brief-stimulus key responses were confined to the last component. It was concluded that pigeons do not discriminate well between components of second-order schedules unless a unique exteroceptive cue is provided for each component. The relative discriminability of the components may account for the observed differences in initial-component response rates between comparable brief-stimulus, tandem, and chain schedules. PMID:16811868

Logical recoding of S-R rules can reverse the effects of spatial S-R correspondence.

PubMed

Wühr, Peter; Biebl, Rupert

2009-02-01

Two experiments investigated competing explanations for the reversal of spatial stimulus-response (S-R) correspondence effects (i.e., Simon effects) with an incompatible S-R mapping on the relevant, nonspatial dimension. Competing explanations were based on generalized S-R rules (logical-recoding account) or referred to display-control arrangement correspondence or to S-S congruity. In Experiment 1, compatible responses to finger-name stimuli presented at left/right locations produced normal Simon effects, whereas incompatible responses to finger-name stimuli produced an inverted Simon effect. This finding supports the logical-recoding account. In Experiment 2, spatial S-R correspondence and color S-R correspondence were varied independently, and main effects of these variables were observed. The lack of an interaction between these variables, however, disconfirms a prediction of the display-control arrangement correspondence account. Together, the results provide converging evidence for the logical-recoding account. This account claims that participants derive generalized response selection rules (e.g., the identity or reversal rule) from specific S-R rules and inadvertently apply the generalized rules to the irrelevant (spatial) S-R dimension when selecting their response.

Mapping the identity of a viewed hand in the motor system: evidence from stimulus-response compatibility.

PubMed

Vainio, Lari; Mustonen, Terhi

2011-02-01

Brain-imaging research has shown that a viewed acting hand is mapped to the observer's hand representation that corresponds with the identity of the hand. In contrast, behavioral research has suggested that rather than representing a seen hand in relation to one's own manual system, it is represented in relation to the midline of an imaginary body. This view was drawn from the finding that indicated that the posture of the viewed hand determines how the hand facilitates responses. The present study explored how an identity of a viewed static hand facilitates responses by varying the onset time and the posture of the hand. The results were in line with the view that an observed hand can activate the observer's hand representation that corresponds with the identity of the hand. However, the posture of the hand did not influence these mapping processes. What mattered was the perspective (i.e., egocentric vs. allocentric) from which the hand was viewed. (c) 2010 APA, all rights reserved.

Dissociation of binding and learning processes.

PubMed

Moeller, Birte; Frings, Christian

2017-11-01

A single encounter of a stimulus together with a response can result in a short-lived association between the stimulus and the response [sometimes called an event file, see Hommel, Müsseler, Aschersleben, & Prinz, (2001) Behavioral and Brain Sciences, 24, 910-926]. The repetition of stimulus-response pairings typically results in longer lasting learning effects indicating stimulus-response associations (e.g., Logan & Etherton, (1994) Journal of Experimental Psychology: Learning, Memory, and Cognition, 20, 1022-1050]. An important question is whether or not what has been described as stimulus-response binding in action control research is actually identical with an early stage of incidental learning (e.g., binding might be seen as single-trial learning). Here, we present evidence that short-lived binding effects can be distinguished from learning of longer lasting stimulus-response associations. In two experiments, participants always responded to centrally presented target letters that were flanked by response irrelevant distractor letters. Experiment 1 varied whether distractors flanked targets on the horizontal or vertical axis. Binding effects were larger for a horizontal than for a vertical distractor-target configuration, while stimulus configuration did not influence incidental learning of longer lasting stimulus-response associations. In Experiment 2, the duration of the interval between response n - 1 and presentation of display n (500 ms vs. 2000 ms) had opposing influences on binding and learning effects. Both experiments indicate that modulating factors influence stimulus-response binding and incidental learning effects in different ways. We conclude that distinct underlying processes should be assumed for binding and incidental learning effects.

Coding “What” and “When” in the Archer Fish Retina

PubMed Central

Vasserman, Genadiy; Shamir, Maoz; Ben Simon, Avi; Segev, Ronen

2010-01-01

Traditionally, the information content of the neural response is quantified using statistics of the responses relative to stimulus onset time with the assumption that the brain uses onset time to infer stimulus identity. However, stimulus onset time must also be estimated by the brain, making the utility of such an approach questionable. How can stimulus onset be estimated from the neural responses with sufficient accuracy to ensure reliable stimulus identification? We address this question using the framework of colour coding by the archer fish retinal ganglion cell. We found that stimulus identity, “what”, can be estimated from the responses of best single cells with an accuracy comparable to that of the animal's psychophysical estimation. However, to extract this information, an accurate estimation of stimulus onset is essential. We show that stimulus onset time, “when”, can be estimated using a linear-nonlinear readout mechanism that requires the response of a population of 100 cells. Thus, stimulus onset time can be estimated using a relatively simple readout. However, large nerve cell populations are required to achieve sufficient accuracy. PMID:21079682

Thyroid function in mice with compound heterozygous and homozygous disruptions of SRC-1 and TIF-2 coactivators: evidence for haploinsufficiency.

PubMed

Weiss, Roy E; Gehin, Martine; Xu, Jianming; Sadow, Peter M; O'Malley, Bert W; Chambon, Pierre; Refetoff, Samuel

2002-04-01

Steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF)-2 are homologous nuclear receptor coactivators. We have investigated their possible redundancy as thyroid hormone (TH) coactivators by measuring thyroid function in compound SRC-1 and TIF-2 knock out (KO) mice. Whereas SRC-1 KO (SRC-1(-/-)) mice are resistant to TH and SRC-1(+/-) are not, we now demonstrate that TIF-2 KO (TIF-2(-/-)) mice have normal thyroid function. Yet double heterozygous, SRC-1(+/-)/TIF-2(+/-) mice manifested resistance to TH of a similar degree as that in mice completely deficient in SRC-1. KO of both SRC-1 and TIF-2 resulted in marked increases of serum TH and thyrotropin concentrations. This work demonstrates gene dosage effect in nuclear coactivators manifesting as haploinsufficiency and functional redundancy of SRC-1 and TIF-2.

Frontal and occipital-parietal alpha oscillations distinguish between stimulus conflict and response conflict

PubMed Central

Tang, Dandan; Hu, Li; Lei, Yi; Li, Hong; Chen, Antao

2015-01-01

Conflicts between target and distraction can occur at the level of both stimulus and response processing. However, the neural oscillations underlying occurrence of the interference in different levels have not been understood well. Here, we reveal such a neural oscillation modulation by combining a 4:2 mapping design (two targets are mapped into one response key) with a practice paradigm (pretest, practice, and posttest) when healthy human participants were performing a novel color-word flanker task. Response time (RT) results revealed constant stimulus conflict (SC, stimulus incongruent minus congruent, SI-CO) but increased response conflict (RC, response incongruent minus stimulus incongruent, RI-SI) with practice. Event-related potential (ERP) results demonstrated stable P3 amplitude differences for the SI-CO in the centro-parietal region across practice, which may reflect maintenance of the stimulus processing; and significantly larger P3 amplitudes in the same region for the RI relative to SI trial type in posttest, which may reflect inhibition of the distraction response. Further, neural oscillatory results showed that with practice, the lower alpha band in the frontal region and the upper alpha band in the occipital-parietal region distinguished between stimulus- and response-conflicts, respectively, suggesting that practice reduces the alertness (sensitiveness) of the brain to conflict occurrence, and enhances stimulus-response associations. PMID:26300758

Measuring the motor output of the pontomedullary reticular formation in the monkey: do stimulus-triggered averaging and stimulus trains produce comparable results in the upper limbs?

PubMed

Herbert, Wendy J; Davidson, Adam G; Buford, John A

2010-06-01

The pontomedullary reticular formation (PMRF) of the monkey produces motor outputs to both upper limbs. EMG effects evoked from stimulus-triggered averaging (StimulusTA) were compared with effects from stimulus trains to determine whether both stimulation methods produced comparable results. Flexor and extensor muscles of scapulothoracic, shoulder, elbow, and wrist joints were studied bilaterally in two male M. fascicularis monkeys trained to perform a bilateral reaching task. The frequency of facilitation versus suppression responses evoked in the muscles was compared between methods. Stimulus trains were more efficient (94% of PMRF sites) in producing responses than StimulusTA (55%), and stimulus trains evoked responses from more muscles per site than from StimulusTA. Facilitation (72%) was more common from stimulus trains than StimulusTA (39%). In the overall results, a bilateral reciprocal activation pattern of ipsilateral flexor and contralateral extensor facilitation was evident for StimulusTA and stimulus trains. When the comparison was restricted to cases where both methods produced a response in a given muscle from the same site, agreement was very high, at 80%. For the remaining 20%, discrepancies were accounted for mainly by facilitation from stimulus trains when StimulusTA produced suppression, which was in agreement with the under-representation of suppression in the stimulus train data as a whole. To the extent that the stimulus train method may favor transmission through polysynaptic pathways, these results suggest that polysynaptic pathways from the PMRF more often produce facilitation in muscles that would typically demonstrate suppression with StimulusTA.

Age-related differences in BOLD modulation to cognitive control costs in a multitasking paradigm: Global switch, local switch, and compatibility-switch costs.

PubMed

Nashiro, Kaoru; Qin, Shuo; O'Connell, Margaret A; Basak, Chandramallika

2018-05-15

It is well documented that older adults recruit additional brain regions compared to those recruited by younger adults while performing a wide variety of cognitive tasks. However, it is unclear how such age-related over-recruitment interacts with different types of cognitive control, and whether this over-recruitment is compensatory. To test this, we used a multitasking paradigm, which allowed us to examine age-related over-activation associated with three types of cognitive costs (i.e., global switch, local switch, compatibility-switch costs). We found age-related impairments in global switch cost (GSC), evidenced by slower response times for maintaining and coordinating two tasks vs. performing only one task. However, no age-related declines were observed in either local switch cost (LSC), a cognitive cost associated with switching between the two tasks while maintaining two task loads, or compatibility-switch cost (CSC), a cognitive cost associated with incompatible vs. compatible stimulus-response mappings across the two tasks. The fMRI analyses allowed for identification of distinct cognitive cost-sensitive brain regions associated with GSC and LSC. In fronto-parietal GSC and LSC regions, older adults' increased activations were associated with poorer performance (greater costs), whereas a reverse relationship was observed in younger adults. Older adults also recruited additional fronto-parietal brain regions outside the cognitive cost-sensitive areas, which was associated with poorer performance or no behavioral benefits. Our results suggest that older adults exhibit a combination of inefficient activation within cognitive cost-sensitive regions, specifically the GSC and LSC regions, and non-compensatory over-recruitment in age-sensitive regions. Age-related declines in global switching, compared to local switching, was observed earlier in old age at both neural and behavioral levels. Copyright © 2018 Elsevier Inc. All rights reserved.

Cbl Associates with Pyk2 and Src to Regulate Src Kinase Activity, αvβ3 Integrin-Mediated Signaling, Cell Adhesion, and Osteoclast Motility

PubMed Central

Sanjay, Archana; Houghton, Adam; Neff, Lynn; DiDomenico, Emilia; Bardelay, Chantal; Antoine, Evelyne; Levy, Joan; Gailit, James; Bowtell, David; Horne, William C.; Baron, Roland

2001-01-01

The signaling events downstream of integrins that regulate cell attachment and motility are only partially understood. Using osteoclasts and transfected 293 cells, we find that a molecular complex comprising Src, Pyk2, and Cbl functions to regulate cell adhesion and motility. The activation of integrin αvβ3 induces the [Ca2+]i-dependent phosphorylation of Pyk2 Y402, its association with Src SH2, Src activation, and the Src SH3-dependent recruitment and phosphorylation of c-Cbl. Furthermore, the PTB domain of Cbl is shown to bind to phosphorylated Tyr-416 in the activation loop of Src, the autophosphorylation site of Src, inhibiting Src kinase activity and integrin-mediated adhesion. Finally, we show that deletion of c Src or c-Cbl leads to a decrease in osteoclast migration. Thus, binding of αvβ3 integrin induces the formation of a Pyk2/Src/Cbl complex in which Cbl is a key regulator of Src kinase activity and of cell adhesion and migration. These findings may explain the osteopetrotic phenotype in the Src−/− mice. PMID:11149930

Phosphopeptide occupancy and photoaffinity cross-linking of the v-Src SH2 domain attenuates tyrosine kinase activity.

PubMed

Garcia, P; Shoelson, S E; Drew, J S; Miller, W T

1994-12-02

Phosphorylation of c-Src at carboxyl-terminal Tyr-527 suppresses tyrosine kinase activity and transforming potential, presumably by facilitating the intramolecular interaction of the C terminus of Src with its SH2 domain. In addition, it has been shown previously that occupancy of the c-Src SH2 domain with a phosphopeptide stimulates c-Src kinase catalytic activity. We have performed analogous studies with v-Src, the transforming protein from Rous sarcoma virus, which has extensive homology with c-Src. v-Src lacks an autoregulatory phosphorylation site, and its kinase domain is constitutively active. Phosphopeptides corresponding to the sequences surrounding c-Src Tyr-527 and a Tyr-Glu-Glu-Ile motif from the hamster polyoma virus middle T antigen inhibit tyrosine kinase activity of baculovirus-expressed v-Src 2- and 4-fold, respectively. To determine the mechanism of this regulation, the Tyr-527 phosphopeptide was substituted with the photoactive amino acid p-benzoylphenylalanine at the adjacent positions (N- and C-terminal) to phosphotyrosine. These peptides photoinactivate the v-Src tyrosine kinase 5-fold in a time- and concentration-dependent manner. Furthermore, the peptides cross-link an isolated Src SH2 domain with similar rates and specificity. These data indicate that occupancy of the v-Src SH2 domain induces a conformational change that is transmitted to the kinase domain and attenuates tyrosine kinase activity.

Immunohistochemical localization of steroid receptor coactivators in chondrosarcoma: an in vivo tissue microarray study.

PubMed

Li, Wei; Fu, Jingshu; Bian, Chen; Zhang, Jiqiang; Xie, Zhao

2014-12-01

Chondrosarcoma is the second most common type of primary bone malignancy following up osteosarcoma, characterized by resistance to conventional chemotherapeutic agents and radiation regimens. The p160 family members steroid receptor coactivator-1 and -3 (SRC-1 and SRC-3) have been implied in the regulation of cancer growth, migration, invasion, metastasis and chemotherapeutic resistance; but we still lack detailed information about the levels of SRCs in chondrosarcoma. In this study, expression of SRC-1 and SRC-3 in chondrosarcoma was examined by immunohistochemistry with tissue microarrays; the four score system (0, 1, 2 and 3) was used to evaluate the staining. The results showed that there were no gender-, site- or age-differences regarding the expression of SRC-1 or SRC-3 (p>0.05); organ (bone or cartilage) -differences were only detected for SRC-1 but not SRC-3 (p<0.05). Significant higher levels of SRC-1 and SRC-3 were detected in MDC and PDC when compared to WDC. Our study clearly demonstrated differentiation-dependant expression of SRC-1 and SRC-3 in chondrosarcoma, may be novel targets for the prognosis and/or treatment of chondrosarcoma, would have opened a new avenue and established foundation for studying chondrosarcoma. Copyright © 2014 Elsevier GmbH. All rights reserved.

Cytokinesis Failure Leading to Chromosome Instability in v-Src-Induced Oncogenesis.

PubMed

Nakayama, Yuji; Soeda, Shuhei; Ikeuchi, Masayoshi; Kakae, Keiko; Yamaguchi, Naoto

2017-04-12

v-Src, an oncogene found in Rous sarcoma virus, is a constitutively active variant of c-Src. Activation of Src is observed frequently in colorectal and breast cancers, and is critical in tumor progression through multiple processes. However, in some experimental conditions, v-Src causes growth suppression and apoptosis. In this review, we highlight recent progress in our understanding of cytokinesis failure and the attenuation of the tetraploidy checkpoint in v-Src-expressing cells. v-Src induces cell cycle changes-such as the accumulation of the 4N cell population-and increases the number of binucleated cells, which is accompanied by an excess number of centrosomes. Time-lapse analysis of v-Src-expressing cells showed that cytokinesis failure is caused by cleavage furrow regression. Microscopic analysis revealed that v-Src induces delocalization of cytokinesis regulators including Aurora B and Mklp1. Tetraploid cell formation is one of the causes of chromosome instability; however, tetraploid cells can be eliminated at the tetraploidy checkpoint. Interestingly, v-Src weakens the tetraploidy checkpoint by inhibiting the nuclear exclusion of the transcription coactivator YAP, which is downstream of the Hippo pathway and its nuclear exclusion is critical in the tetraploidy checkpoint. We also discuss the relationship between v-Src-induced chromosome instability and growth suppression in v-Src-induced oncogenesis.

syk kinase activation by a src kinase-initiated activation loop phosphorylation chain reaction

PubMed Central

El-Hillal, O.; Kurosaki, T.; Yamamura, H.; Kinet, J.-P.; Scharenberg, A. M.

1997-01-01

Activation of the syk tyrosine kinase occurs almost immediately following engagement of many types of antigen receptors, including Fc receptors, but the mechanism through which syk is activated is currently unclear. Here we demonstrate that Fc receptor-induced syk activation occurs as the result of phosphorylation of the syk activation loop by both src family kinases and other molecules of activated syk, suggesting that syk activation occurs as the result of a src kinase-initiated activation loop phosphorylation chain reaction. This type of activation mechanism predicts that syk activation would exhibit exponential kinetics, providing a potential explanation for its rapid and robust activation by even weak antigen receptor stimuli. We propose that a similar mechanism may be responsible for generating rapid activation of other cytoplasmic tyrosine kinases, such as those of the Bruton tyrosine kinase/tec family, as well. PMID:9050880

The Challenge of Problem-Based Learning. 2nd Edition.

ERIC Educational Resources Information Center

Boud, David, Ed.; Feletti, Grahame I., Ed.

Problem-based learning is an approach to structuring the curriculum which involves confronting students with problems from practice which provide a stimulus for learning. However, there are many possible forms that a curriculum and process for teaching and learning might take and still be compatible with this definition. This book explores these…

Visual and auditory accessory stimulus offset and the Simon effect.

PubMed

Nishimura, Akio; Yokosawa, Kazuhiko

2010-10-01

We investigated the effect on the right and left responses of the disappearance of a task-irrelevant stimulus located on the right or left side. Participants pressed a right or left response key on the basis of the color of a centrally located visual target. Visual (Experiment 1) or auditory (Experiment 2) task-irrelevant accessory stimuli appeared or disappeared at locations to the right or left of the central target. In Experiment 1, responses were faster when onset or offset of the visual accessory stimulus was spatially congruent with the response. In Experiment 2, responses were again faster when onset of the auditory accessory stimulus and the response were on the same side. However, responses were slightly slower when offset of the auditory accessory stimulus and the response were on the same side than when they were on opposite sides. These findings indicate that transient change information is crucial for a visual Simon effect, whereas sustained stimulation from an ongoing stimulus also contributes to an auditory Simon effect.

Role of inhibition in the specification of orientation selectivity of cells in the cat striate cortex.

PubMed

Bonds, A B

1989-01-01

Mechanisms supporting orientation selectivity of cat striate cortical cells were studied by stimulation with two superimposed sine-wave gratings of different orientations. One grating (base) generated a discharge of known amplitude which could be modified by the second grating (mask). Masks presented at nonoptimal orientations usually reduced the base-generated response, but the degree of reduction varied widely between cells. Cells with narrow orientation tuning tended to be more susceptible to mask presence than broadly tuned cells; similarly, simple cells generally showed more response reduction than did complex cells. The base and mask stimuli were drifted at different temporal frequencies which, in simple cells, permitted the identification of individual response components from each stimulus. This revealed that the reduction of the base response by the mask usually did not vary regularly with mask orientation, although response facilitation from the mask was orientation selective. In some sharply tuned simple cells, response reduction had clear local maxima near the limits of the cell's orientation-tuning function. Response reduction resulted from a nearly pure rightward shift of the response versus log contrast function. The lowest mask contrast yielding reduction was within 0.1-0.3 log unit of the lowest contrast effective for excitation. The temporal-frequency bandpass of the response-reduction mechanism resembled that of most cortical cells. The spatial-frequency bandpass was much broader than is typical for single cortical cells, spanning essentially the entire visual range of the cat. These findings are compatible with a model in which weak intrinsic orientation-selective excitation is enhanced in two stages: (1) control of threshold by nonorientation-selective inhibition that is continuously dependent on stimulus contrast; and (2) in the more narrowly tuned cells, orientation-selective inhibition that has local maxima serving to increase the slope of the orientation-tuning function.

Signaling network of the Btk family kinases.

PubMed

Qiu, Y; Kung, H J

2000-11-20

The Btk family kinases represent new members of non-receptor tyrosine kinases, which include Btk/Atk, Itk/Emt/Tsk, Bmx/Etk, and Tec. They are characterized by having four structural modules: PH (pleckstrin homology) domain, SH3 (Src homology 3) domain, SH2 (Src homology 2) domain and kinase (Src homology 1) domain. Increasing evidence suggests that, like Src-family kinases, Btk family kinases play central but diverse modulatory roles in various cellular processes. They participate in signal transduction in response to virtually all types of extracellular stimuli which are transmitted by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen-receptors and integrins. They are regulated by many non-receptor tyrosine kinases such as Src, Jak, Syk and FAK family kinases. In turn, they regulate many of major signaling pathways including those of PI3K, PLCgamma and PKC. Both genetic and biochemical approaches have been used to dissect the signaling pathways and elucidate their roles in growth, differentiation and apoptosis. An emerging new role of this family of kinases is cytoskeletal reorganization and cell motility. The physiological importance of these kinases was amply demonstrated by their link to the development of immunodeficiency diseases, due to germ-line mutations. The present article attempts to review the structure and functions of Btk family kinases by summarizing our current knowledge on the interacting partners associated with the different modules of the kinases and the diverse signaling pathways in which they are involved.

Hck is a key regulator of gene expression in alternatively activated human monocytes.

PubMed

Bhattacharjee, Ashish; Pal, Srabani; Feldman, Gerald M; Cathcart, Martha K

2011-10-21

IL-13 is a Th2 cytokine that promotes alternative activation (M2 polarization) in primary human monocytes. Our studies have characterized the functional IL-13 receptor complex and the downstream signaling events in response to IL-13 stimulation in alternatively activated monocytes/macrophages. In this report, we present evidence that IL-13 induces the activation of a Src family tyrosine kinase, which is required for IL-13 induction of M2 gene expression, including 15-lipoxygenase (15-LO). Our data show that Src kinase activity regulates IL-13-induced p38 MAPK tyrosine phosphorylation via the upstream kinases MKK3 or MKK6. Our findings also reveal that the IL-13 receptor-associated tyrosine kinase Jak2 is required for the activation of both Src kinase as well as p38 MAPK. Further, we found that Src tyrosine kinase-mediated activation of p38 MAPK is required for Stat1 and Stat3 serine 727 phosphorylation in alternatively activated monocytes/macrophages. Additional studies identify Hck as the specific Src family member, stimulated by IL-13 and involved in regulating both p38 MAPK activation and p38 MAPK-mediated 15-LO expression. Finally we show that the Hck regulates the expression of other alternative state (M2)-specific genes (Mannose receptor, MAO-A, and CD36) and therefore conclude that Hck acts as a key regulator controlling gene expression in alternatively activated monocytes/macrophages.

Requirement and Redundancy of the Src Family Kinases Fyn and Lyn in Perforin-Dependent Killing of Cryptococcus neoformans by NK Cells

PubMed Central

Oykhman, Paul; Timm-McCann, Martina; Xiang, Richard F.; Islam, Anowara; Li, Shu Shun; Stack, Danuta; Huston, Shaunna M.; Ma, Ling Ling

2013-01-01

Natural killer (NK) cells directly recognize and kill fungi, such as the pathogenic fungus Cryptococcus neoformans, via cytolytic mechanisms. However, the precise signaling pathways governing this NK cell microbicidal activity and the implications for fungal recognition are still unknown. Previously, it was reported that NK cell anticryptococcal activity is mediated through a conserved phosphatidylinositol 3-kinase–extracellular signal-regulated kinase 1/2 (PI3K-ERK1/2) pathway. Using YT (a human NK-like cell line) and primary human NK cells, we sought to identify the upstream, receptor-proximal signaling elements that led to fungal cytolysis. We demonstrate that Src family kinases were activated in response to C. neoformans. Furthermore, pharmacologic inhibition with an Src kinase inhibitor blocked C. neoformans-induced downstream activation of PI3K and ERK1/2 and abrogated cryptococcal killing. At the same time, the inhibitor disrupted the polarization of perforin-containing granules toward the NK cell-cryptococcal synapse but had no effect on conjugate formation between the organism and the NK cell. Finally, small interfering RNA (siRNA) double (but not single) knockdown of two Src family kinases, Fyn and Lyn, blocked cryptococcal killing. Together these data demonstrate a mechanism whereby the Src family kinases, Fyn and Lyn, redundantly mediate anticryptococcal activity through the activation of PI3K and ERK1/2, which in turn facilitates killing by inducing the polarization of perforin-containing granules to the NK cell-cryptococcal synapse. PMID:23918783

Stimulus and response conflict processing during perceptual decision making.

PubMed

Wendelken, Carter; Ditterich, Jochen; Bunge, Silvia A; Carter, Cameron S

2009-12-01

Encoding and dealing with conflicting information is essential for successful decision making in a complex environment. In the present fMRI study, stimulus conflict and response conflict are contrasted in the context of a perceptual decision-making dot-motion discrimination task. Stimulus conflict was manipulated by varying dot-motion coherence along task-relevant and task-irrelevant dimensions. Response conflict was manipulated by varying whether or not competing stimulus dimensions provided evidence for the same or different responses. The right inferior frontal gyrus was involved specifically in the resolution of stimulus conflict, whereas the dorsal anterior cingulate cortex was shown to be sensitive to response conflict. Additionally, two regions that have been linked to perceptual decision making with dot-motion stimuli in monkey physiology studies were differentially engaged by stimulus conflict and response conflict. The middle temporal area, previously linked to processing of motion, was strongly affected by the presence of stimulus conflict. On the other hand, the superior parietal lobe, previously associated with accumulation of evidence for a response, was affected by the presence of response conflict. These results shed light on the neural mechanisms that support decision making in the presence of conflict, a cognitive operation fundamental to both basic survival and high-level cognition.

Orientation-specific responses to sustained uniaxial stretching in focal adhesion growth and turnover

PubMed Central

Chen, Yun; Pasapera, Ana M.; Koretsky, Alan P.; Waterman, Clare M.

2013-01-01

Cells are mechanosensitive to extracellular matrix (ECM) deformation, which can be caused by muscle contraction or changes in hydrostatic pressure. Focal adhesions (FAs) mediate the linkage between the cell and the ECM and initiate mechanically stimulated signaling events. We developed a stretching apparatus in which cells grown on fibronectin-coated elastic substrates can be stretched and imaged live to study how FAs dynamically respond to ECM deformation. Human bone osteosarcoma epithelial cell line U2OS was transfected with GFP-paxillin as an FA marker and subjected to sustained uniaxial stretching. Two responses at different timescales were observed: rapid FA growth within seconds after stretching, and delayed FA disassembly and loss of cell polarity that occurred over tens of minutes. Rapid FA growth occurred in all cells; however, delayed responses to stretch occurred in an orientation-specific manner, specifically in cells with their long axes perpendicular to the stretching direction, but not in cells with their long axes parallel to stretch. Pharmacological treatments demonstrated that FA kinase (FAK) promotes but Src inhibits rapid FA growth, whereas FAK, Src, and calpain 2 all contribute to delayed FA disassembly and loss of polarity in cells perpendicular to stretching. Immunostaining for phospho-FAK after stretching revealed that FAK activation was maximal at 5 s after stretching, specifically in FAs oriented perpendicular to stretch. We hypothesize that orientation-specific activation of strain/stress-sensitive proteins in FAs upstream to FAK and Src promote orientation-specific responses in FA growth and disassembly that mediate polarity rearrangement in response to sustained stretch. PMID:23754369

Methanol extract of Osbeckia stellata suppresses lipopolysaccharide- and HCl/ethanol-induced inflammatory responses by inhibiting Src/Syk and IRAK1.

PubMed

Yang, Yanyan; Hyun Moh, Sang; Yu, Tao; Gwang Park, Jae; Hyo Yoon, Deok; Woong Kim, Tae; Hwan Kim, Seong; Lee, Sukchan; Hong, Sungyoul; Youl Cho, Jae

2012-10-11

Osbeckia stellata Buch.-Ham. ex D.Don is traditionally prescribed to treat various inflammatory diseases. However, how this plant is able to modulate inflammatory responses is unknown. This study explored the anti-inflammatory effects of 99% methanol extracts of O. stellata (Os-ME). The anti-inflammatory effect of Os-ME was evaluated by measuring the levels of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells and by determining gastric inflammatory lesions in mice induced by HCl/ethanol (EtOH). The molecular mechanisms of the inhibitions were elucidated by analyzing the activation of transcription factors, upstream signaling cascade, and the kinase activities of target enzymes. Os-ME dose-dependently diminished the release of NO and PGE(2), and suppressed the expression of inducible NO synthase and cyclooxygenase-2 in LPS-treated RAW264.7 cells. Os-ME clearly inhibited the translocation of c-Rel, a subunit of nuclear factor κB (NF-κB), and c-Fos, a subunit of activator protein-1 (AP-1), and their regulatory upstream enzymes including Src, Syk, and IRAK1. Interestingly, orally administered Os-ME ameliorated acute inflammatory symptoms and suppressed the activation of Src, Syk, and IRAK1 induced by HCl/EtOH treatment in mouse stomach. Os-ME can be considered as an orally available anti-inflammatory herbal remedy with Src/Syk/NF-κB and IRAK1/AP-1 inhibitory properties. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Src kinase regulation by phosphorylation and dephosphorylation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roskoski, Robert

2005-05-27

Src and Src-family protein-tyrosine kinases are regulatory proteins that play key roles in cell differentiation, motility, proliferation, and survival. The initially described phosphorylation sites of Src include an activating phosphotyrosine 416 that results from autophosphorylation, and an inhibiting phosphotyrosine 527 that results from phosphorylation by C-terminal Src kinase (Csk) and Csk homologous kinase. Dephosphorylation of phosphotyrosine 527 increases Src kinase activity. Candidate phosphotyrosine 527 phosphatases include cytoplasmic PTP1B, Shp1 and Shp2, and transmembrane enzymes include CD45, PTP{alpha}, PTP{epsilon}, and PTP{lambda}. Dephosphorylation of phosphotyrosine 416 decreases Src kinase activity. Thus far PTP-BL, the mouse homologue of human PTP-BAS, has been shownmore » to dephosphorylate phosphotyrosine 416 in a regulatory fashion. The platelet-derived growth factor receptor protein-tyrosine kinase mediates the phosphorylation of Src Tyr138; this phosphorylation has no direct effect on Src kinase activity. The platelet-derived growth factor receptor and the ErbB2/HER2 growth factor receptor protein-tyrosine kinases mediate the phosphorylation of Src Tyr213 and activation of Src kinase activity. Src kinase is also a substrate for protein-serine/threonine kinases including protein kinase C (Ser12), protein kinase A (Ser17), and CDK1/cdc2 (Thr34, Thr46, and Ser72). Of the three protein-serine/threonine kinases, only phosphorylation by CDK1/cdc2 has been demonstrated to increase Src kinase activity. Although considerable information on the phosphoprotein phosphatases that catalyze the hydrolysis of Src phosphotyrosine 527 is at hand, the nature of the phosphatases that mediate the hydrolysis of phosphotyrosine 138 and 213, and phosphoserine and phosphothreonine residues has not been determined.« less

miR-137 Targets p160 Steroid Receptor Coactivators SRC1, SRC2, and SRC3 and Inhibits Cell Proliferation

PubMed Central

Eedunuri, Vijay Kumar; Rajapakshe, Kimal; Fiskus, Warren; Geng, Chuandong; Chew, Sue Anne; Foley, Christopher; Shah, Shrijal S.; Shou, John; Mohamed, Junaith S.; O'Malley, Bert W.

2015-01-01

The p160 family of steroid receptor coactivators (SRCs) are pleiotropic transcription factor coactivators and “master regulators” of gene expression that promote cancer cell proliferation, survival, metabolism, migration, invasion, and metastasis. Cancers with high p160 SRC expression exhibit poor clinical outcomes and resistance to therapy, highlighting the SRCs as critical oncogenic drivers and, thus, therapeutic targets. microRNAs are important epigenetic regulators of protein expression. To examine the regulation of p160 SRCs by microRNAs, we used and combined 4 prediction algorithms to identify microRNAs that could target SRC1, SRC2, and SRC3 expression. For validation of these predictions, we assessed p160 SRC protein expression and cell viability after transfection of corresponding microRNA mimetics in breast cancer, uveal melanoma, and prostate cancer (PC) cell lines. Transfection of selected microRNA mimetics into breast cancer, uveal melanoma, and PC cells depleted SRC protein expression levels and exerted potent antiproliferative activity in these cell types. In particular, microRNA-137 (miR-137) depleted expression of SRC1, SRC2, and very potently, SRC3. The latter effect can be attributed to the presence of 3 miR-137 recognition sequences within the SRC3 3′-untranslated region. Using reverse phase protein array analysis, we identified a network of proteins, in addition to SRC3, that were modulated by miR-137 in PC cells. We also found that miR-137 and its host gene are epigenetically silenced in human cancer specimens and cell lines. These results support the development and testing of microRNA-based therapies (in particular based on restoring miR-137 levels) for targeting the oncogenic family of p160 SRCs in cancer. PMID:26066330

Differential subcellular membrane recruitment of Src may specify its downstream signalling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diesbach, Philippe de; Medts, Thierry; Carpentier, Sarah

2008-04-15

Most Src family members are diacylated and constitutively associate with membrane 'lipid rafts' that coordinate signalling. Whether the monoacylated Src, frequently hyperactive in carcinomas, also localizes at 'rafts' remains controversial. Using polarized MDCK cells expressing the thermosensitive v-Src/tsLA31 variant, we here addressed how Src tyrosine-kinase activation may impact on its (i) membrane recruitment, in particular to 'lipid rafts'; (ii) subcellular localization; and (iii) signalling. The kinetics of Src-kinase thermoactivation correlated with its recruitment from the cytosol to sedimentable membranes where Src largely resisted solubilisation by non-ionic detergents at 4 deg. C and floated into sucrose density gradients like caveolin-1 andmore » flotillin-2, i.e. 'lipid rafts'. By immunofluorescence, activated Src showed a dual localization, at apical endosomes/macropinosomes and at the apical plasma membrane. The plasma membrane Src pool did not colocalize with caveolin-1 and flotillin-2, but extensively overlapped GM1 labelling by cholera toxin. Severe ({approx} 70%) cholesterol extraction with methyl-{beta}-cyclodextrin (M{beta}CD) did not abolish 'rafts' floatation, but strongly decreased Src association with floating 'rafts' and abolished its localization at the apical plasma membrane. Src activation independently activated first the MAP-kinase - ERK1/2 pathway, then the PI3-kinase - Akt pathway. MAP-kinase - ERK1/2 activation was insensitive to M{beta}CD, which suppressed Akt phosphorylation and apical endocytosis induced by Src, both depending on the PI3-kinase pathway. We therefore suggest that activated Src is recruited at two membrane compartments, allowing differential signalling, first via ERK1/2 at 'non-raft' domains on endosomes, then via PI3-kinase-Akt on a distinct set of 'rafts' at the apical plasma membrane. Whether this model is applicable to c-Src remains to be examined.« less

The adequate stimulus for avian short latency vestibular responses to linear translation

NASA Technical Reports Server (NTRS)

Jones, T. A.; Jones, S. M.; Colbert, S.

1998-01-01

Transient linear acceleration stimuli have been shown to elicit eighth nerve vestibular compound action potentials in birds and mammals. The present study was undertaken to better define the nature of the adequate stimulus for neurons generating the response in the chicken (Gallus domesticus). In particular, the study evaluated the question of whether the neurons studied are most sensitive to the maximum level of linear acceleration achieved or to the rate of change in acceleration (da/dt, or jerk). To do this, vestibular response thresholds were measured as a function of stimulus onset slope. Traditional computer signal averaging was used to record responses to pulsed linear acceleration stimuli. Stimulus onset slope was systematically varied. Acceleration thresholds decreased with increasing stimulus onset slope (decreasing stimulus rise time). When stimuli were expressed in units of jerk (g/ms), thresholds were virtually constant for all stimulus rise times. Moreover, stimuli having identical jerk magnitudes but widely varying peak acceleration levels produced virtually identical responses. Vestibular response thresholds, latencies and amplitudes appear to be determined strictly by stimulus jerk magnitudes. Stimulus attributes such as peak acceleration or rise time alone do not provide sufficient information to predict response parameter quantities. Indeed, the major response parameters were shown to be virtually independent of peak acceleration levels or rise time when these stimulus features were isolated and considered separately. It is concluded that the neurons generating short latency vestibular evoked potentials do so as "jerk encoders" in the chicken. Primary afferents classified as "irregular", and which traditionally fall into the broad category of "dynamic" or "phasic" neurons, would seem to be the most likely candidates for the neural generators of short latency vestibular compound action potentials.

Differential Prognostic Implications of Gastric Signet Ring Cell Carcinoma

PubMed Central

Chon, Hong Jae; Hyung, Woo Jin; Kim, Chan; Park, Sohee; Kim, Jie-Hyun; Park, Chan Hyuk; Ahn, Joong Bae; Kim, Hyunki; Chung, Hyun Cheol; Rha, Sun Young; Noh, Sung Hoon; Jeung, Hei-Cheul

2017-01-01

Objective: The aim of this study was to analyze the clinicopathologic characteristics and prognosis of signet ring cell carcinoma (SRC) according to disease status (early vs advanced gastric cancer) in gastric cancer patients. Background: The prognostic implication of gastric SRC remains a subject of debate. Methods: A retrospective analysis was performed using the clinical records of 7667 patients including 1646 SRC patients who underwent radical gastrectomy between 2001 and 2010. A further analysis was also performed after dividing patients into three groups according to histologic subtype: SRC, well-to-moderately differentiated (WMD), and poorly differentiated adenocarcinoma. Results: SRC patients have younger age distribution and female predominance compared with other histologic subtypes. Notably, the distribution of T stage of SRC patients was distinct, located in extremes (T1: 66.2% and T4: 20%). Moreover, the prognosis of SRC in early gastric cancer and advanced gastric cancer was contrasting. In early gastric cancer, SRC demonstrated more favorable prognosis than WMD after adjusting for age, sex, and stage. In contrast, SRC in advanced gastric cancer displayed worse prognosis than WMD. As stage increased, survival outcomes of SRC continued to worsen compared with WMD. Conclusions: Although conferring favorable prognosis in early stage, SRC has worse prognostic impact as disease progresses. The longstanding controversy of SRC on prognosis may result from disease status at presentation, which leads to differing prognosis compared with tubular adenocarinoma. PMID:27232252

Focal adhesion kinase-dependent focal adhesion recruitment of SH2 domains directs SRC into focal adhesions to regulate cell adhesion and migration

PubMed Central

Wu, Jui-Chung; Chen, Yu-Chen; Kuo, Chih-Ting; Wenshin Yu, Helen; Chen, Yin-Quan; Chiou, Arthur; Kuo, Jean-Cheng

2015-01-01

Directed cell migration requires dynamical control of the protein complex within focal adhesions (FAs) and this control is regulated by signaling events involving tyrosine phosphorylation. We screened the SH2 domains present in tyrosine-specific kinases and phosphatases found within FAs, including SRC, SHP1 and SHP2, and examined whether these enzymes transiently target FAs via their SH2 domains. We found that the SRC_SH2 domain and the SHP2_N-SH2 domain are associated with FAs, but only the SRC_SH2 domain is able to be regulated by focal adhesion kinase (FAK). The FAK-dependent association of the SRC_SH2 domain is necessary and sufficient for SRC FA targeting. When the targeting of SRC into FAs is inhibited, there is significant suppression of SRC-mediated phosphorylation of paxillin and FAK; this results in an inhibition of FA formation and maturation and a reduction in cell migration. This study reveals an association between FAs and the SRC_SH2 domain as well as between FAs and the SHP2_N-SH2 domains. This supports the hypothesis that the FAK-regulated SRC_SH2 domain plays an important role in directing SRC into FAs and that this SRC-mediated FA signaling drives cell migration. PMID:26681405

Focal adhesion kinase-dependent focal adhesion recruitment of SH2 domains directs SRC into focal adhesions to regulate cell adhesion and migration.

PubMed

Wu, Jui-Chung; Chen, Yu-Chen; Kuo, Chih-Ting; Wenshin Yu, Helen; Chen, Yin-Quan; Chiou, Arthur; Kuo, Jean-Cheng

2015-12-18

Directed cell migration requires dynamical control of the protein complex within focal adhesions (FAs) and this control is regulated by signaling events involving tyrosine phosphorylation. We screened the SH2 domains present in tyrosine-specific kinases and phosphatases found within FAs, including SRC, SHP1 and SHP2, and examined whether these enzymes transiently target FAs via their SH2 domains. We found that the SRC_SH2 domain and the SHP2_N-SH2 domain are associated with FAs, but only the SRC_SH2 domain is able to be regulated by focal adhesion kinase (FAK). The FAK-dependent association of the SRC_SH2 domain is necessary and sufficient for SRC FA targeting. When the targeting of SRC into FAs is inhibited, there is significant suppression of SRC-mediated phosphorylation of paxillin and FAK; this results in an inhibition of FA formation and maturation and a reduction in cell migration. This study reveals an association between FAs and the SRC_SH2 domain as well as between FAs and the SHP2_N-SH2 domains. This supports the hypothesis that the FAK-regulated SRC_SH2 domain plays an important role in directing SRC into FAs and that this SRC-mediated FA signaling drives cell migration.

Observational learning without a model is influenced by the observer's possibility to act: evidence from the Simon task.

PubMed

Iani, Cristina; Rubichi, Sandro; Ferraro, Luca; Nicoletti, Roberto; Gallese, Vittorio

2013-07-01

We assessed whether observational learning in perceptual-motor tasks is affected by the visibility of an action producing perceived environmental effects and by the observer's possibility to act during observation. To this end, we conducted three experiments in which participants were required to observe a spatial compatibility task in which only the effects of computer-generated responses were visible before executing a Simon task. In Experiment 1, we compared the effects of a passively observed practice with either a spatially compatible or incompatible stimulus-response (S-R) association. In Experiment 2, during the observed spatially incompatible practice participants were prevented from potentially acting, either because a plexiglas barrier separated the participant from the response device rendering it out of reach; or because the participant's hands were tied; or the device affording a response was absent. In Experiment 3, the plexiglas presented an opening that could allow the participant to potentially reach and interact with it. As when the practice is physically performed, we found an elimination of the Simon effect following a spatially incompatible observed practice, suggesting that participants learned an incompatible S-R association by observing and transferred this knowledge to the subsequent Simon task. No evidence of transfer of learning was found when, during passive observation, the participant's hands were tied, or a barrier prevented him/her from potentially interacting with the device, or no response device was present. Differently, a transfer-of-learning effect was observed when the barrier presented an opening. These results suggest that learning can derive from the mere observation of action effects, even when an action is not visible, as long as the observer has the potential to act. Copyright © 2013 Elsevier B.V. All rights reserved.

Preliminary study of semi-refined carrageenan (SRC) as secondary gelling agent in natural rubber (NR) latex foam

NASA Astrophysics Data System (ADS)

Norhazariah, S.; Azura, A. R.; Azahari, B.; Sivakumar, R.

2017-12-01

Semi-refined carrageenan (SRC) product is considerably cheaper and easier to produce as a natural polysaccharide, which was utilized in food and other product application. However, the application in latex is limited. The aim of this work is to evaluate the SRC produced from low industrial grade seaweed (LIGS) in the latex foam application. The FTIR spectra showed the SRC produced as kappa type carrageenan with lower sulfur content compared to native LIGS. NR latex foam is produced by using the Dunlop method with some modifications. The effect of SRC loading as a secondary gelling agent in NR latex foam is investigated. The density and morphology of the NR latex foam with the addition of the SRC are analyzed. NR latex foam density increased with SRC loading and peaked at 1.8 phr SRC. The addition of SRC has induced the bigger cell size compared to the cell size of the control NR latex foam, as shown in the optical micrograph. It can be concluded that SRC LIGS could be acted as secondary gelling agent in NR latex foam.

Endosomal-sorting complexes required for transport (ESCRT) pathway-dependent endosomal traffic regulates the localization of active Src at focal adhesions.

PubMed

Tu, Chun; Ortega-Cava, Cesar F; Winograd, Paul; Stanton, Marissa Jo; Reddi, Alagarsamy Lakku; Dodge, Ingrid; Arya, Ranjana; Dimri, Manjari; Clubb, Robert J; Naramura, Mayumi; Wagner, Kay-Uwe; Band, Vimla; Band, Hamid

2010-09-14

Active Src localization at focal adhesions (FAs) is essential for cell migration. How this pool is linked mechanistically to the large pool of Src at late endosomes (LEs)/lysosomes (LY) is not well understood. Here, we used inducible Tsg101 gene deletion, TSG101 knockdown, and dominant-negative VPS4 expression to demonstrate that the localization of activated cellular Src and viral Src at FAs requires the endosomal-sorting complexes required for transport (ESCRT) pathway. Tsg101 deletion also led to impaired Src-dependent activation of STAT3 and focal adhesion kinase and reduced cell migration. Impairment of the ESCRT pathway or Rab7 function led to the accumulation of active Src at aberrant LE/LY compartments followed by its loss. Analyses using fluorescence recovery after photo-bleaching show that dynamic mobility of Src in endosomes is ESCRT pathway-dependent. These results reveal a critical role for an ESCRT pathway-dependent LE/LY trafficking step in Src function by promoting localization of active Src to FAs.

SRC activates TAZ for intestinal tumorigenesis and regeneration.

PubMed

Byun, Mi Ran; Hwang, Jun-Ha; Kim, A Rum; Kim, Kyung Min; Park, Jung Il; Oh, Ho Taek; Hwang, Eun Sook; Hong, Jeong-Ho

2017-12-01

Proto-oncogene tyrosine-protein kinase Src (cSRC) is involved in colorectal cancer (CRC) development and damage-induced intestinal regeneration, although the cellular mechanisms involved are poorly understood. Here, we report that transcriptional coactivator with PDZ binding domain (TAZ) is activated by cSRC, regulating CRC cell proliferation and tumor formation, where cSRC overexpression increases TAZ expression in CRC cells. In contrast, knockdown of cSRC decreases TAZ expression. Additionally, direct phosphorylation of TAZ at Tyr316 by cSRC stimulates nuclear localization and facilitates transcriptional enhancer factor TEF-3 (TEAD4)-mediated transcription. However, a TAZ phosphorylation mutant significantly decreased cell proliferation, wound healing, colony forming, and tumor formation. In a CRC mouse model, Apc Min/+ , activated SRC expression was associated with increased TAZ expression in polyps and TAZ depletion decreased polyp formation. Moreover, intestinal TAZ knockout mice had intestinal regeneration defects following γ-irradiation. Finally, significant correspondence between SRC activation and TAZ overexpression was observed in CRC patients. These results suggest that TAZ is a critical factor for SRC-mediated intestinal tumor formation and regeneration. Copyright © 2017 Elsevier B.V. All rights reserved.

Protective equipment and player characteristics associated with the incidence of sport-related concussion in high school football players: a multifactorial prospective study.

PubMed

McGuine, Timothy A; Hetzel, Scott; McCrea, Michael; Brooks, M Alison

2014-10-01

The incidence of sport-related concussion (SRC) in high school football is well documented. However, limited prospective data are available regarding how player characteristics and protective equipment affect the incidence of SRC. To determine whether the type of protective equipment (helmet and mouth guard) and player characteristics affect the incidence of SRC in high school football players. Cohort study; Level of evidence, 2. Certified athletic trainers (ATs) at each high school recorded the type of helmet worn (brand, model, purchase year, and recondition status) by each player as well as information regarding players' demographics, type of mouth guard used, and history of SRC. The ATs also recorded the incidence and days lost from participation for each SRC. Incidence of SRC was compared for various helmets, type of mouth guard, history of SRC, and player demographics. A total of 2081 players (grades 9-12) enrolled during the 2012 and/or 2013 football seasons (2287 player-seasons) and participated in 134,437 football (practice or competition) exposures. Of these players, 206 (9%) sustained a total of 211 SRCs (1.56/1000 exposures). There was no difference in the incidence of SRC (number of helmets, % SRC [95% CI]) for players wearing Riddell (1171, 9.1% [7.6%-11.0%]), Schutt (680, 8.7% [6.7%-11.1%]), or Xenith (436, 9.2% [6.7%-12.4%]) helmets. Helmet age and recondition status did not affect the incidence of SRC. The rate of SRC (hazard ratio [HR]) was higher in players who wore a custom mouth guard (HR = 1.69 [95% CI, 1.20-2.37], P < .001) than in players who wore a generic mouth guard. The rate of SRC was also higher (HR = 1.96 [95% CI, 1.40-2.73], P < .001) in players who had sustained an SRC within the previous 12 months (15.1% of the 259 players [95% CI, 11.0%-20.1%]) than in players without a previous SRC (8.2% of the 2028 players [95% CI, 7.1%-9.5%]). Incidence of SRC was similar regardless of the helmet brand (manufacturer) worn by high school football players. Players who had sustained an SRC within the previous 12 months were more likely to sustain an SRC than were players without a history of SRC. Sports medicine providers who work with high school football players need to realize that factors other than the type of protective equipment worn affect the risk of SRC in high school players. © 2014 The Author(s).

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Science.gov Websites

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Integrin αv in the mechanical response of osteoblast lineage cells.

PubMed

Kaneko, Keiko; Ito, Masako; Naoe, Yoshinori; Lacy-Hulbert, Adam; Ikeda, Kyoji

2014-05-02

Although osteoblast lineage cells, especially osteocytes, are thought to be a primary mechanosensory cell in bone, the identity of the mechano-receptor and downstream mechano-signaling pathways remain largely unknown. Here we show using osteoblastic cell model of mechanical stimulation with fluid shear stress that in the absence of integrin αv, phosphorylation of the Src substrate p130Cas and JNK was impaired, culminating in an inhibition of nuclear translocation of YAP/TAZ and subsequent transcriptional activation of target genes. Targeted deletion of the integrin αv in osteoblast lineage cells results in an attenuated response to mechanical loading in terms of Sost gene expression, indicative of a role for integrin αv in mechanoreception in vivo. Thus, integrin αv may be integral to a mechanosensing machinery in osteoblastic cells and involved in activation of a Src-JNK-YAP/TAZ pathway in response to mechanical stimulation. Copyright © 2014 Elsevier Inc. All rights reserved.

Playing the Simon game: use of the Simon task for investigating human information processing.

PubMed

Proctor, Robert W

2011-02-01

A little more than 40 years ago, J. R. Simon and colleagues introduced what is now called the Simon task, which yielded a correspondence effect known as the Simon effect. In this paper, I set Simon's contribution in the context of research on stimulus-response compatibility. The novel contribution of the Simon task is described, along with foundational findings using the task that Simon and colleagues reported. I acknowledge the significance of Simon's (1990) review chapter in generating my own interests in the Simon task and describe four selected lines of research from my lab that have been a result of those interests. The article concludes with a brief tribute to Simon and his contribution to experimental psychology. Copyright © 2010 Elsevier B.V. All rights reserved.

Sex Differences in High School Athletes' Knowledge of Sport-Related Concussion Symptoms and Reporting Behaviors.

PubMed

Wallace, Jessica; Covassin, Tracey; Beidler, Erica

2017-07-01

  Recent researchers have reported that athletes' knowledge of sport-related concussion (SRC) has increased but that athletes still lack knowledge of all the signs and symptoms of SRC. Understanding the signs and symptoms of SRC and the dangers of playing while symptomatic are critical to reporting behaviors in high school athletes.   To examine sex differences in knowledge of SRC symptoms and reasons for not reporting a suspected SRC to an authoritative figure in high school athletes.   Cross-sectional study.   Survey.   A total of 288 athletes across 7 sports (198 males [68.8%] and 90 females [31.2%]).   A validated knowledge-of-SRC survey consisted of demographic questions, a list of 21 signs and symptoms of SRC, and reasons why athletes would not report their SRC. The independent variable was sex. Athlete knowledge of SRC symptoms was assessed by having participants identify the signs and symptoms of SRC from a list of 21 symptoms. Knowledge scores were calculated by summing the number of correct answers; scores ranged from 0 to 21, with a score closer to 21 representing greater knowledge. Reporting-behavior questions asked athletes to choose reasons why they decided not to report any possible SRC signs and symptoms to an authoritative figure.   A sex difference in total SRC symptom knowledge was found (F 286 = 4.97, P = .03, d = 0.26). Female high school athletes had more total SRC symptom knowledge (mean ± standard deviation = 15.06 ± 2.63; 95% confidence interval = 14.54, 15.57) than males (14.36 ± 2.76; 95% confidence interval = 13.97, 14.74). Chi-square tests identified significant relationships between sex and 8 different reasons for not reporting an SRC.   High school males and females had similar SRC symptom knowledge; however, female athletes were more likely to report their concussive symptoms to an authoritative figure.

Transforming growth factor‐β enhances Rho‐kinase activity and contraction in airway smooth muscle via the nucleotide exchange factor ARHGEF1

PubMed Central

Shaifta, Yasin; MacKay, Charles E.; Irechukwu, Nneka; O'Brien, Katie A.; Wright, David B.; Ward, Jeremy P. T.

2017-01-01

Key points Transforming growth‐factor‐β (TGF‐β) and RhoA/Rho‐kinase are independently implicated in the airway hyper‐responsiveness associated with asthma, but how these proteins interact is not fully understood.We examined the effects of pre‐treatment with TGF‐β on expression and activity of RhoA, Rho‐kinase and ARHGEF1, an activator of RhoA, as well as on bradykinin‐induced contraction, in airway smooth muscle.TGF‐β enhanced bradykinin‐induced RhoA translocation, Rho‐kinase‐dependent phosphorylation and contraction, but partially suppressed bradykinin‐induced RhoA activity (RhoA‐GTP content).TGF‐β enhanced the expression of ARHGEF1, while a small interfering RNA against ARHGEF1 and a RhoGEF inhibitor prevented the effects of TGF‐β on RhoA and Rho‐kinase activity and contraction, respectively.ARHGEF1 expression was also enhanced in airway smooth muscle from asthmatic patients and ovalbumin‐sensitized mice.ARHGEF1 is a key TGF‐β target gene, an important regulator of Rho‐kinase activity and therefore a potential therapeutic target for the treatment of asthmatic airway hyper‐responsiveness. Abstract Transforming growth factor‐β (TGF‐β), RhoA/Rho‐kinase and Src‐family kinases (SrcFK) have independently been implicated in airway hyper‐responsiveness, but how they interact to regulate airway smooth muscle contractility is not fully understood. We found that TGF‐β pre‐treatment enhanced acute contractile responses to bradykinin (BK) in isolated rat bronchioles, and inhibitors of RhoGEFs (Y16) and Rho‐kinase (Y27632), but not the SrcFK inhibitor PP2, prevented this enhancement. In cultured human airway smooth muscle cells (hASMCs), TGF‐β pre‐treatment enhanced the protein expression of the Rho guanine nucleotide exchange factor ARHGEF1, MLC20, MYPT‐1 and the actin‐severing protein cofilin, but not of RhoA, ROCK2 or c‐Src. In hASMCs, acute treatment with BK triggered subcellular translocation of ARHGEF1 and RhoA and enhanced auto‐phosphorylation of SrcFK and phosphorylation of MYPT1 and MLC20, but induced de‐phosphorylation of cofilin. TGF‐β pre‐treatment amplified the effects of BK on RhoA translocation and MYPT1/MLC20 phosphorylation, but suppressed the effects of BK on RhoA‐GTP content, SrcFK auto‐phosphorylation and cofilin de‐phosphorylation. In hASMCs, an ARHGEF1 small interfering RNA suppressed the effects of BK and TGF‐β on RhoA‐GTP content, RhoA translocation and MYPT1 and MLC20 phosphorylation, but minimally influenced the effects of TGF‐β on cofilin expression and phosphorylation. ARHGEF1 expression was also enhanced in ASMCs of asthmatic patients and in lungs of ovalbumin‐sensitized mice. Our data indicate that TGF‐β enhances BK‐induced contraction, RhoA translocation and Rho‐kinase activity in airway smooth muscle largely via ARHGEF1, but independently of SrcFK and total RhoA‐GTP content. A role for smooth muscle ARHGEF1 in asthmatic airway hyper‐responsiveness is worthy of further investigation. PMID:29071730

Effects of an ethanol-paired CS on responding for ethanol and food: Comparisons with a stimulus in a Truly-Random-Control group and to a food-paired CS on responding for food.

PubMed

Lamb, R J; Ginsburg, Brett C; Schindler, Charles W

2016-12-01

Motivational increases due to exposure to alcohol-paired Conditioned Stimuli (CS) are central to some accounts of alcoholism. However, few studies isolate a stimulus's function as a CS from its other potential functions. Pavlovian-Instrumental-Transfer (PIT) procedures isolate a stimulus's function as a CS from its other functions. Though there are several relevant studies using PIT, knowledge gaps exist. Particularly, it is not clear that an alcohol-paired CS will increase alcohol seeking compared to the same stimulus in a Truly-Random-Control group, nor whether such increases are specific to alcohol seeking. To address these knowledge gaps in Experiment 1, rats responded for ethanol (0.1 ml 8% w/v) under an RI 30-sec schedule, then the lever was removed and half the rats had ethanol delivered during occasional 120-sec light presentations, while the remainder had ethanol and the light presented under independent RT schedules. Later the lever was returned and the light was presented during responding in extinction (PIT test). Following this test, levers were again removed and the light was presented without ethanol (light extinction), following again by a PIT test. Responding in the two groups during light presentations did not differ in either PIT test. Experiment 2 repeated Experiment 1 using food instead of ethanol. In Experiment 2, responding during light presentations increased in the paired group. In Experiment 3, rats were trained on a concurrent FR schedule of food and ethanol delivery. Ethanol was delivered following 5 responses and the response requirement for food adjusted so that similar numbers of food and ethanol deliveries were obtained. Subsequently, rats underwent conditioning, control and testing procedures identical to those in Experiment 1. In Experiment 3, the ethanol-paired CS increased ethanol-responding, but not food-responding. These results are most easily interpreted as changes in responding resulting from CS-elicited behavior rather than motivational changes. This interpretation is more compatible with some descriptions of the role of an alcohol-paired CS in alcoholism than others. Copyright © 2016 Elsevier Inc. All rights reserved.

Myristoylation of Src kinase mediates Src-induced and high-fat diet-accelerated prostate tumor progression in mice.

PubMed

Kim, Sungjin; Yang, Xiangkun; Li, Qianjin; Wu, Meng; Costyn, Leah; Beharry, Zanna; Bartlett, Michael G; Cai, Houjian

2017-11-10

Exogenous fatty acids provide substrates for energy production and biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high-fat diet-accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the in vivo prostate regeneration assay, host SCID mice carrying Src(Y529F)-transduced regeneration tissues were fed a low-fat diet or a high-fat diet and treated with vehicle or dasatinib. The high-fat diet not only accelerated Src-induced prostate tumorigenesis in mice but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential in vivo We further show that myristoylation of Src kinase is essential to facilitate Src-induced and high-fat diet-accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src and promoted Src kinase-mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat-accelerated tumorigenesis in vivo Our findings uncover the molecular basis of how the metabolism of myristic acid stimulates high-fat diet-mediated prostate tumor progression. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Cyr61 as mediator of Src signaling in triple negative breast cancer cells

PubMed Central

Molinari, Agnese; Wagner, Kay-Uwe; Losada, Jesús Pérez; Ciordia, Sergio; Albar, Juan Pablo; Martín-Pérez, Jorge

2015-01-01

SFKs are involved in tumorigenesis and metastasis. Here we analyzed c-Src contribution to initial steps of metastasis by tetracycline-dependent expression of a specific shRNA-c-Src, which suppressed c-Src mRNA and protein levels in metastatic MDA-MB-231 cells. c-Src suppression did not alter cell proliferation or survival, but it significantly reduced anchorage-independent growth. Concomitantly with diminished tyrosine-phosphorylation/activation of Fak, caveolin-1, paxillin and p130CAS, c-Src depletion also inhibited cellular migration, invasion and transendothelial migration. Quantitative proteomic analyses of the secretome showed that Cyr61 levels, which were detected in the exosomal fraction, were diminished upon shRNA-c-Src expression. In contrast, Cyr61 expression was unaltered inside cells. Cyr61 partially colocalized with cis-Golgi gp74 marker and with exosomal marker CD63, but c-Src depletion did not alter their cellular distribution. In SUM159PT cells, transient c-Src suppression also reduced secreted exosomal Cyr61 levels. Furthermore, conditional expression of a c-Src dominant negative mutant (SrcDN, c-Src-K295M/Y527F) in MDA-MB-231 and in SUM159PT diminished secreted Cyr61 as well. Cyr61 transient suppression in MDA-MB-231 inhibited invasion and transendothelial migration. Finally, in both MDA-MB-231 and SUM159PT, a neutralizing Cyr61 antibody restrained migration. Collectively, these results suggest that c-Src regulates secreted proteins, including the exosomal Cyr61, which are involved in modulating the metastatic potential of triple negative breast cancer cells. PMID:25980494

The Tyrosine Kinase Activity of c-Src Regulates Actin Dynamics and Organization of Podosomes in Osteoclasts

PubMed Central

Destaing, Olivier; Sanjay, Archana; Itzstein, Cecile; Horne, William C.; Toomre, Derek

2008-01-01

Podosomes are dynamic actin-rich structures composed of a dense F-actin core surrounded by a cloud of more diffuse F-actin. Src performs one or more unique functions in osteoclasts (OCLs), and podosome belts and bone resorption are impaired in the absence of Src. Using Src−/− OCLs, we investigated the specific functions of Src in the organization and dynamics of podosomes. We found that podosome number and the podosome-associated actin cloud were decreased in Src−/− OCLs. Videomicroscopy and fluorescence recovery after photobleaching analysis revealed that the life span of Src−/− podosomes was increased fourfold and that the rate of actin flux in the core was decreased by 40%. Thus, Src regulates the formation, structure, life span, and rate of actin polymerization in podosomes and in the actin cloud. Rescue of Src−/− OCLs with Src mutants showed that both the kinase activity and either the SH2 or the SH3 binding domain are required for Src to restore normal podosome organization and dynamics. Moreover, inhibition of Src family kinase activities in Src−/− OCLs by Src inhibitors or by expressing dominant-negative SrcK295M induced the formation of abnormal podosomes. Thus, Src is an essential regulator of podosome structure, dynamics and organization. PMID:17978100

Effect of Interocular Delay on Disparity-Selective V1 Neurons: Relationship to Stereoacuity and the Pulfrich Effect

PubMed Central

Read, Jenny C. A.; Cumming, Bruce G.

2006-01-01

The temporal properties of disparity-sensitive neurons place important temporal constraints on stereo matching. We examined these constraints by measuring the responses of disparity-selective neurons in striate cortex of awake behaving monkeys to random-dot stereograms that contained interocular delays. Disparity selectivity was gradually abolished by increasing interocular delay (when the delay exceeds the integration time, the inputs from the 2 eyes become uncorrelated). The amplitude of the disparity-selective response was a Gaussian function of interocular delay, with a mean of 16 ms (±5 ms, SD). Psychophysical measures of stereoacuity, in both monkey and human observers, showed a closely similar dependency on time, suggesting that temporal integration in V1 neurons is what determines psychophysical matching constraints over time. There was a slight but consistent asymmetry in the neuronal responses, as if the optimum stimulus is one in which the right stimulus leads by about 4 ms. Because all recordings were made in the left hemisphere, this probably reflects nasotemporal differences in conduction times; psychophysical data are compatible with this interpretation. In only a few neurons (5/72), interocular delay caused a change in the preferred disparity. Such tilted disparity/delay profiles have been invoked previously to explain depth perception in the stroboscopic version of the Pulfrich effect (and other variants). However, the great majority of the neurons did not show tilted disparity/delay profiles. This suggests that either the activity of these neurons is ignored when viewing Pulfrich stimuli, or that current theories relating neuronal properties to perception in the Pulfrich effect need to be reevaluated. PMID:15788521

76 FR 21404 - National Park Service Alaska Region's Subsistence Resource Commission (SRC) Program

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-15

... Resource Commission (SRC) program. SUMMARY: The Gates of the Arctic National Park SRC will meet to develop... to do so. Gates of the Arctic National Park SRC Meeting Date and Location: The Gates of the Arctic... weather or local circumstances. For Further Information on the Gates of the Arctic National Park SRC...

75 FR 51103 - Notice of Public Meetings for the National Park Service (NPS) Alaska Region's Subsistence...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-18

... SRC and Wrangell-St. Elias SRC plan to meet to develop and continue work on National Park Service (NPS... SRC Meeting Date and Location: The Lake Clark National Park SRC meeting will be held on Tuesday... Alaska Regional Office, at (907) 644- 3603. Aniakchak National Monument SRC Meeting Date and Location...

The effect of changes in stimulus level on electrically evoked cortical auditory potentials.

PubMed

Kim, Jae-Ryong; Brown, Carolyn J; Abbas, Paul J; Etler, Christine P; O'Brien, Sara

2009-06-01

The purpose of this study was to determine whether the electrically evoked acoustic change complex (EACC) could be used to assess sensitivity to changes in stimulus level in cochlear implant (CI) recipients and to investigate the relationship between EACC amplitude and rate of growth of the N1-P2 onset response with increases in stimulus level. Twelve postlingually deafened adults using Nucleus CI24 CIs participated in this study. Nucleus Implant Communicator (NIC) routines were used to bypass the speech processor and to control the stimulation of the implant directly. The stimulus consisted of an 800 msec burst of a 1000 pps biphasic pulse train. A change in the stimulus level was introduced 400 msec after stimulus onset. Band-pass filtering (1 to 100 Hz) was used to minimize stimulus artifact. Four to six recordings of 50 sweeps were obtained for each condition, and averaged responses were analyzed in the time domain using standard peak picking procedures. Cortical auditory change potentials were recorded from CI users in response to both increases and decreases in stimulation level. The amplitude of the EACC was found to be dependent on the magnitude of the stimulus change. Increases in stimulus level elicited more robust EACC responses than decreases in stimulus level. Also, EACC amplitudes were significantly correlated with the slope of the growth of the onset response. This work describes the effect of change in stimulus level on electrically evoked auditory change potentials in CI users. The amplitude of the EACC was found to be related both to the magnitude of the stimulus change introduced and to the rate of growth of the N1-P2 onset response. To the extent that the EACC reflects processing of stimulus change, it could potentially be a valuable tool for assessing neural processing of the kinds of stimulation patterns produced by a CI. Further studies are needed, however, to determine the relationships between the EACC and psychophysical measures of intensity discrimination in CI recipients.

When do humans spontaneously adopt another's visuospatial perspective?

PubMed

Freundlieb, Martin; Kovács, Ágnes M; Sebanz, Natalie

2016-03-01

Perspective-taking is a key component of social interactions. However, there is an ongoing controversy about whether, when and how instances of spontaneous visuospatial perspective-taking occur. The aim of this study was to investigate the underlying factors as well as boundary conditions that characterize the spontaneous adoption of another person's visuospatial perspective (VSP) during social interactions. We used a novel paradigm, in which a participant and a confederate performed a simple stimulus-response (SR) compatibility task sitting at a 90° angle to each other. In this set-up, participants would show a spatial compatibility effect only if they adopted the confederate's VSP. In a series of 5 experiments we found that participants reliably adopted the VSP of the confederate, as long as he was perceived as an intentionally acting agent. Our results therefore show that humans are able to spontaneously adopt the differing VSP of another agent and that there is a tight link between perspective-taking and performing actions together. The results suggest that spontaneous VSP-taking can effectively facilitate and speed up spatial alignment processes accruing from dynamic interactions in multiagent environments. (c) 2016 APA, all rights reserved).

Sex and the stimulus-movement effect: Differences in acquisition of autoshaped responding in cynomolgus monkeys.

PubMed

Rice, Nathaniel C; Makar, Jennifer R; Myers, Todd M

2017-03-15

The stimulus-movement effect refers to the phenomenon in which stimulus discrimination or acquisition of a response is facilitated by moving stimuli as opposed to stationary stimuli. The effect has been found in monkeys, rats, and humans, but the experiments conducted did not provide adequate female representation to investigate potential sex differences. The current experiment analyzed acquisition of stimulus touching in a progressive series of classical conditioning procedures in cynomolgus monkeys (Macaca fascicularis) as a function of sex and stimulus movement. Classical conditioning tasks arrange two or more stimuli in relation to each other with different temporal and predictive relations. Autoshaping procedures overlay operant contingencies onto a classical-conditioning stimulus arrangement. In the present case, a neutral stimulus (a small gray square displayed on a touchscreen) functioned as the conditional stimulus and a food pellet functioned as the unconditional stimulus. Although touching is not required to produce food, with repeated stimulus pairings subjects eventually touch the stimulus. Across conditions of increasing stimulus correlation and temporal contiguity, male monkeys acquired the response faster with a moving stimulus. In contrast, females acquired the response faster with a stationary stimulus. These results demonstrate that the stimulus-movement effect may be differentially affected by sex and indicate that additional experiments with females are needed to determine how sex interacts with behavioral phenomena discovered and elaborated almost exclusively using males. Published by Elsevier Inc.

Stimulus Responsive Nanoparticles

NASA Technical Reports Server (NTRS)

Sierros, Konstantinos A. (Inventor); Cairns, Darran Robert (Inventor); Huebsch, Wade W. (Inventor); Shafran, Matthew S. (Inventor)

2017-01-01

Disclosed are various embodiments of methods and systems related to stimulus responsive nanoparticles. In one embodiment including a stimulus responsive nanoparticle system, the system includes a first electrode, a second electrode, and a plurality of elongated electro-responsive nanoparticles dispersed between the first and second electrodes, the plurality of electro-responsive nanorods configured to respond to an electric field established between the first and second electrodes.

Stimulus responsive nanoparticles

NASA Technical Reports Server (NTRS)

Cairns, Darren Robert (Inventor); Shafran, Matthew S. (Inventor); Huebsch, Wade W. (Inventor); Sierros, Konstantinos A. (Inventor)

2013-01-01

Disclosed are various embodiments of methods and systems related to stimulus responsive nanoparticles. In one embodiment includes a stimulus responsive nanoparticle system, the system includes a first electrode, a second electrode, and a plurality of elongated electro-responsive nanoparticles dispersed between the first and second electrodes, the plurality of electro-responsive nanorods configured to respond to an electric field established between the first and second electrodes.

Stimulus Responsive Nanoparticles

NASA Technical Reports Server (NTRS)

Cairns, Darran Robert (Inventor); Huebsch, Wade W. (Inventor); Sierros, Konstantinos A. (Inventor); Shafran, Matthew S. (Inventor)

2015-01-01

Disclosed are various embodiments of methods and systems related to stimulus responsive nanoparticles. In one embodiment includes a stimulus responsive nanoparticle system, the system includes a first electrode, a second electrode, and a plurality of elongated electro-responsive nanoparticles dispersed between the first and second electrodes, the plurality of electro-responsive nanorods configured to respond to an electric field established between the first and second electrodes.

Quantifying interactions between accommodation and vergence in a binocularly normal population.

PubMed

Sweeney, Laura E; Seidel, Dirk; Day, Mhairi; Gray, Lyle S

2014-12-01

Stimulation of the accommodation system results in a response in the vergence system via accommodative vergence cross-link interactions, and stimulation of the vergence system results in an accommodation response via vergence accommodation cross-link interactions. Cross-link interactions are necessary in order to ensure simultaneous responses in the accommodation and vergence systems. The crosslink interactions are represented most comprehensively by the response AC/A (accommodative vergence) and CA/C (vergence accommodation) ratios, although the stimulus AC/A ratio is measured clinically, and the stimulus CA/C ratio is seldom measured in clinical practice. The present study aims to quantify both stimulus and response AC/A and CA/C ratios in a binocularly normal population, and determine the relationship between them. 25 Subjects (mean ± SD age 21.0 ± 1.9 years) were recruited from the university population. A significant linear relationship was found between the stimulus and response ratios, for both AC/A (r² = 0.96, p < 0.001) and CA/C ratios (r² = 0.40, p < 0.05). Good agreement was found between the stimulus and response AC/A ratios (95% CI -0.06 to 0.24 MA/D). Stimulus and response CA/C ratios are linearly related. Stimulus CA/C ratios were higher than response ratios at low values, and lower than response ratios at high values (95% CI -0.46 to 0.42 D/MA). Agreement between stimulus and response CA/C ratios is poorer than that found for AC/A ratios due to increased variability in vergence responses when viewing the Gaussian blurred target. This study has shown that more work is needed to refine the methodology of CA/C ratio measurement.

v-Src-induced nuclear localization of YAP is involved in multipolar spindle formation in tetraploid cells.

PubMed

Kakae, Keiko; Ikeuchi, Masayoshi; Kuga, Takahisa; Saito, Youhei; Yamaguchi, Naoto; Nakayama, Yuji

2017-01-01

The protein-tyrosine kinase, c-Src, is involved in a variety of signaling events, including cell division. We have reported that v-Src, which is a mutant variant of the cellular proto-oncogene, c-Src, causes delocalization of Aurora B kinase, resulting in a furrow regression in cytokinesis and the generation of multinucleated cells. However, the effect of v-Src on mitotic spindle formation is unknown. Here we show that v-Src-expressing HCT116 and NIH3T3 cells undergo abnormal cell division, in which cells separate into more than two cells. Upon v-Src expression, the proportion of multinucleated cells is increased in a time-dependent manner. Flow cytometry analysis revealed that v-Src increases the number of cells having a ≥4N DNA content. Microscopic analysis showed that v-Src induces the formation of multipolar spindles with excess centrosomes. These results suggest that v-Src induces multipolar spindle formation by generating multinucleated cells. Tetraploidy activates the tetraploidy checkpoint, leading to a cell cycle arrest of tetraploid cells at the G1 phase, in which the nuclear exclusion of the transcription co-activator YAP plays a critical role. In multinucleated cells that are induced by cytochalasin B and the Plk1 inhibitor, YAP is excluded from the nucleus. However, v-Src prevents this nuclear exclusion of YAP through a decrease in the phosphorylation of YAP at Ser127 in multinucleated cells. Furthermore, v-Src decreases the expression level of p53, which also plays a critical role in the cell cycle arrest of tetraploid cells. These results suggest that v-Src promotes abnormal spindle formation in at least two ways: generation of multinucleated cells and a weakening of the tetraploidy checkpoint. Copyright © 2016 Elsevier Inc. All rights reserved.

Protective Equipment and Player Characteristics Associated With the Incidence of Sport-Related Concussion in High School Football Players

PubMed Central

McGuine, Timothy A.; Hetzel, Scott; McCrea, Michael; Brooks, M. Alison

2015-01-01

Background The incidence of sport-related concussion (SRC) in high school football is well documented. However, limited prospective data are available regarding how player characteristics and protective equipment affect the incidence of SRC. Purpose To determine whether the type of protective equipment (helmet and mouth guard) and player characteristics affect the incidence of SRC in high school football players. Design Cohort study; Level of evidence, 2. Methods Certified athletic trainers (ATs) at each high school recorded the type of helmet worn (brand, model, purchase year, and recondition status) by each player as well as information regarding players’ demographics, type of mouth guard used, and history of SRC. The ATs also recorded the incidence and days lost from participation for each SRC. Incidence of SRC was compared for various helmets, type of mouth guard, history of SRC, and player demographics. Results A total of 2081 players (grades 9–12) enrolled during the 2012 and/or 2013 football seasons (2287 player-seasons) and participated in 134,437 football (practice or competition) exposures. Of these players, 206 (9%) sustained a total of 211 SRCs (1.56/1000 exposures). There was no difference in the incidence of SRC (number of helmets, % SRC [95% CI]) for players wearing Riddell (1171, 9.1% [7.6%–11.0%]), Schutt (680, 8.7% [6.7%–11.1%]), or Xenith (436, 9.2% [6.7%–12.4%]) helmets. Helmet age and recondition status did not affect the incidence of SRC. The rate of SRC (hazard ratio [HR]) was higher in players who wore a custom mouth guard (HR = 1.69 [95% CI, 1.20–2.37], P <.001) than in players who wore a generic mouth guard. The rate of SRC was also higher (HR = 1.96 [95% CI, 1.40–2.73], P <.001) in players who had sustained an SRC within the previous 12 months (15.1% of the 259 players [95% CI, 11.0%–20.1%]) than in players without a previous SRC (8.2% of the 2028 players [95% CI, 7.1%–9.5%]). Conclusion Incidence of SRC was similar regardless of the helmet brand (manufacturer) worn by high school football players. Players who had sustained an SRC within the previous 12 months were more likely to sustain an SRC than were players without a history of SRC. Sports medicine providers who work with high school football players need to realize that factors other than the type of protective equipment worn affect the risk of SRC in high school players. PMID:25060072

Generalization of a tactile stimulus in horses.

PubMed Central

Dougherty, D M; Lewis, P

1993-01-01

Using horses, we investigated the control of operant behavior by a tactile stimulus (the training stimulus) and the generalization of behavior to six other similar test stimuli. In a stall, the experimenters mounted a response panel in the doorway. Located on this panel were a response lever and a grain dispenser. The experimenters secured a tactile-stimulus belt to the horse's back. The stimulus belt was constructed by mounting seven solenoids along a piece of burlap in a manner that allowed each to provide the delivery of a tactile stimulus, a repetitive light tapping, at different locations (spaced 10.0 cm apart) along the horse's back. Two preliminary steps were necessary before generalization testing: training a measurable response (lip pressing) and training on several reinforcement schedules in the presence of a training stimulus (tapping by one of the solenoids). We then gave each horse two generalization test sessions. Results indicated that the horses' behavior was effectively controlled by the training stimulus. Horses made the greatest number of responses to the training stimulus, and the tendency to respond to the other test stimuli diminished as the stimuli became farther away from the training stimulus. These findings are discussed in the context of behavioral principles and their relevance to the training of horses. PMID:8315368

Generalization of a tactile stimulus in horses.

PubMed

Dougherty, D M; Lewis, P

1993-05-01

Using horses, we investigated the control of operant behavior by a tactile stimulus (the training stimulus) and the generalization of behavior to six other similar test stimuli. In a stall, the experimenters mounted a response panel in the doorway. Located on this panel were a response lever and a grain dispenser. The experimenters secured a tactile-stimulus belt to the horse's back. The stimulus belt was constructed by mounting seven solenoids along a piece of burlap in a manner that allowed each to provide the delivery of a tactile stimulus, a repetitive light tapping, at different locations (spaced 10.0 cm apart) along the horse's back. Two preliminary steps were necessary before generalization testing: training a measurable response (lip pressing) and training on several reinforcement schedules in the presence of a training stimulus (tapping by one of the solenoids). We then gave each horse two generalization test sessions. Results indicated that the horses' behavior was effectively controlled by the training stimulus. Horses made the greatest number of responses to the training stimulus, and the tendency to respond to the other test stimuli diminished as the stimuli became farther away from the training stimulus. These findings are discussed in the context of behavioral principles and their relevance to the training of horses.

Oculomotor Cognitive Control Abnormalities in Australian Rules Football Players with a History of Concussion.

PubMed

Clough, Meaghan; Mutimer, Steven; Wright, David K; Tsang, Adrian; Costello, Daniel M; Gardner, Andrew J; Stanwell, Peter; Mychasiuk, Richelle; Sun, Mujun; Brady, Rhys D; McDonald, Stuart J; Webster, Kyria M; Johnstone, Maddison R; Semple, Bridgette D; Agoston, Denes V; White, Owen B; Frayne, Richard; Fielding, Joanne; O'Brien, Terence J; Shultz, Sandy R

2018-03-01

This study used oculomotor, cognitive, and multi-modal magnetic resonance imaging (MRI) measures to assess for neurological abnormalities in current asymptomatic amateur Australian rules footballers (i.e., Australia's most participated collision sport) with a history of sports-related concussion (SRC). Participants were 15 male amateur Australian rules football players with a history of SRC greater than 6 months previously, and 15 sex-, age-, and education-matched athlete control subjects that had no history of neurotrauma or participation in collision sports. Participants completed a clinical interview, neuropsychological measures, and oculomotor measures of cognitive control. MRI investigation involved structural imaging, as well as diffusion tensor imaging and resting-state functional MRI sequences. Despite no group differences on conventional neuropsychological tests and multi-modal MRI measures, Australian rules football players with a history of SRC performed significantly worse on an oculomotor switch task: a measure of cognitive control that interleaves the response of looking towards a target (i.e., a prosaccade) with the response of looking away from a target (i.e., an antisaccade). Specifically, Australian footballers performed significantly shorter latency prosaccades and found changing from an antisaccade trial to a prosaccade trial (switch cost) significantly more difficult than control subjects. Poorer switch cost was related to poorer performance on a number of neuropsychological measures of inhibitory control. Further, when comparing performance on the cognitively more demanding switch task with performance on simpler, antisaccade/prosaccades tasks which require a single response, Australian footballers demonstrated a susceptibility to increased cognitive load, compared to the control group who were unaffected. These initial results suggest that current asymptomatic amateur Australian rules football players with a history of SRC may have persisting, subtle, cognitive changes, which are demonstrable on oculomotor cognitive measures. Future studies are required in order to further elucidate the full nature and clinical relevance of these findings.

Heterogeneity of signal transduction by Na-K-ATPase α-isoforms: role of Src interaction.

PubMed

Yu, Hui; Cui, Xiaoyu; Zhang, Jue; Xie, Joe X; Banerjee, Moumita; Pierre, Sandrine V; Xie, Zijian

2018-02-01

Of the four Na-K-ATPase α-isoforms, the ubiquitous α1 Na-K-ATPase possesses both ion transport and Src-dependent signaling functions. Mechanistically, we have identified two putative pairs of domain interactions between α1 Na-K-ATPase and Src that are critical for α1 signaling function. Our subsequent report that α2 Na-K-ATPase lacks these putative Src-binding sites and fails to carry on Src-dependent signaling further supported our proposed model of direct interaction between α1 Na-K-ATPase and Src but fell short of providing evidence for a causative role. This hypothesis was specifically tested here by introducing key residues of the two putative Src-interacting domains present on α1 but not α2 sequence into the α2 polypeptide, generating stable cell lines expressing this mutant, and comparing its signaling properties to those of α2-expressing cells. The mutant α2 was fully functional as a Na-K-ATPase. In contrast to wild-type α2, the mutant gained α1-like signaling function, capable of Src interaction and regulation. Consistently, the expression of mutant α2 redistributed Src into caveolin-1-enriched fractions and allowed ouabain to activate Src-mediated signaling cascades, unlike wild-type α2 cells. Finally, mutant α2 cells exhibited a growth phenotype similar to that of the α1 cells and proliferated much faster than wild-type α2 cells. These findings reveal the structural requirements for the Na-K-ATPase to function as a Src-dependent receptor and provide strong evidence of isoform-specific Src interaction involving the identified key amino acids. The sequences surrounding the putative Src-binding sites in α2 are highly conserved across species, suggesting that the lack of Src binding may play a physiologically important and isoform-specific role.

H-Ras Modulates N-Methyl-d-aspartate Receptor Function via Inhibition of Src Tyrosine Kinase Activity*

PubMed Central

Thornton, Claire; Yaka, Rami; Dinh, Son; Ron, Dorit

2005-01-01

Tyrosine phosphorylation of the NR2A and NR2B subunits of the N-methyl-d-aspartate (NMDA) receptor by Src protein-tyrosine kinases modulates receptor channel activity and is necessary for the induction of long term potentiation (LTP). Deletion of H-Ras increases both NR2 tyrosine phosphorylation and NMDA receptor-mediated hippocampal LTP. Here we investigated whether H-Ras regulates phosphorylation and function of the NMDA receptor via Src family protein-tyrosine kinases. We identified Src as a novel H-Ras binding partner. H-Ras bound to Src but not Fyn both in vitro and in brain via the Src kinase domain. Cotransfection of H-Ras and Src inhibited Src activity and decreased NR2A tyrosine phosphorylation. Treatment of rat brain slices with Tat-H-Ras depleted NR2A from the synaptic membrane, decreased endogenous Src activity and NR2A phosphorylation, and decreased the magnitude of hip-pocampal LTP. No change was observed for NR2B. We suggest that H-Ras negatively regulates Src phosphorylation of NR2A and retention of NR2A into the synaptic membrane leading to inhibition of NMDA receptor function. This mechanism is specific for Src and NR2A and has implications for studies in which regulation of NMDA receptor-mediated LTP is important, such as synaptic plasticity, learning, and memory and addiction. PMID:12695509

Targeting the yin and the yang: combined inhibition of the tyrosine kinase c-Src and the tyrosine phosphatase SHP-2 disrupts pancreatic cancer signaling and biology in vitro and tumor formation in vivo.

PubMed

Gomes, Evan G; Connelly, Sarah F; Summy, Justin M

2013-07-01

Although c-Src (Src) has emerged as a potential pancreatic cancer target in preclinical studies, Src inhibitors have not demonstrated a significant therapeutic benefit in clinical trials. The objective of these studies was to examine the effects of combining Src inhibition with inhibition of the protein tyrosine phosphatase SHP-2 in pancreatic cancer cells in vitro and in vivo. SHP-2 and Src functions were inhibited by siRNA or small molecule inhibitors. The effects of dual Src/SHP-2 functional inhibition were evaluated by Western blot analysis of downstream signaling pathways; cell biology assays to examine caspase activity, viability, adhesion, migration, and invasion in vitro; and an orthotopic nude mouse model to observe pancreatic tumor formation in vivo. Dual targeting of Src and SHP-2 induces an additive or supra-additive loss of phosphorylation of Akt and ERK-1/2 and corresponding increases in expression of apoptotic markers, relative to targeting either protein individually. Combinatorial inhibition of Src and SHP-2 significantly reduces viability, adhesion, migration, and invasion of pancreatic cancer cells in vitro and tumor formation in vivo, relative to individual Src/SHP-2 inhibition. These data suggest that the antitumor effects of Src inhibition in pancreatic cancer may be enhanced through simultaneous inhibition of SHP-2.

SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

PubMed Central

Zhou, Xiaorong; Comerford, Sarah A.; York, Brian; O’Donnell, Kathryn A.

2017-01-01

Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver. PMID:28273073

Acetylation within the N- and C-Terminal Domains of Src Regulates Distinct Roles of STAT3-Mediated Tumorigenesis.

PubMed

Huang, Chao; Zhang, Zhe; Chen, Lihan; Lee, Hank W; Ayrapetov, Marina K; Zhao, Ting C; Hao, Yimei; Gao, Jinsong; Yang, Chunzhang; Mehta, Gautam U; Zhuang, Zhengping; Zhang, Xiaoren; Hu, Guohong; Chin, Y Eugene

2018-06-01

Posttranslational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions. Myristoylation of G 2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylates an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylates the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activates transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation. Significance: CBP-mediated acetylation of lysine clusters in both the N-terminal and C-terminal regions of c-Src provides additional levels of control over STAT3 transcriptional activity. Cancer Res; 78(11); 2825-38. ©2018 AACR . ©2018 American Association for Cancer Research.

Stimulus change as a factor in response maintenance with free food available.

PubMed Central

Osborne, S R; Shelby, M

1975-01-01

Rats bar pressed for food on a reinforcement schedule in which every response was reinforced, even though a dish of pellets was present. Initially, auditory and visual stimuli accompanied response-produced food presentation. With stimulus feedback as an added consequence of bar pressing, responding was maintained in the presence of free food; without stimulus feedback, responding decreased to a low level. Auditory feedback maintained slightly more responding than did visual feedback, and both together maintained more responding than did either separately. Almost no responding occurred when the only consequence of bar pressing was stimulus feedback. The data indicated conditioned and sensory reinforcement effects of response-produced stimulus feedback. PMID:1202121

Roles of stimulus control and reinforcement frequency in modulating the behavioral effects of d-amphetamine in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rees, D.C.; Wood, R.W.; Laties, V.G.

1984-03-01

The behavioral effects of d-amphetamine have been shown to be modulated by stimulus control, with less impairment of performance occurring when control is great. When the fixed-consecutive-number schedule is used (on which at least a specified consecutive number of responses must be made on one operandum before a single response on another will produce a reinforcer), response rate tends to invariant but reinforcement frequency is not. This study asks whether the differences in reinforcement frequency that usually accompany changes in stimulus control could themselves be responsible for the performance differences. Two versions of the fixed-consecutive-number schedule of reinforcement were combinedmore » into a multiple schedule within which stimulus control was varied but differences in reinforcement frequency were minimized by omitting some reinforcer deliveries during the component that usually had the higher reinforcement frequency. In one component, a compound discriminative stimulus was added with the eighth consecutive response on the first lever, a single response on the second lever was then reinforced. In the other component, no such stimulus was presented. With no added stimulus, large decreases occurred in the number of runs satisfying the minimum requirement for reinforcement at doses of drug that produced only minimal changes when an added stimulus controlled behavior. Thus, increased stimulus control diminishes the behavioral changes produced by d-amphetamine even when the possible contribution by baseline reinforcement rate is minimized. 17 references, 6 figures, 4 tables.« less

Automatic and Controlled Response Inhibition: Associative Learning in the Go/No-Go and Stop-Signal Paradigms

PubMed Central

Verbruggen, Frederick; Logan, Gordon D.

2008-01-01

In five experiments, the authors examined the development of automatic response inhibition in the go/no-go paradigm and a modified version of the stop-signal paradigm. They hypothesized that automatic response inhibition may develop over practice when stimuli are consistently associated with stopping. All five experiments consisted of a training phase and a test phase in which the stimulus mapping was reversed for a subset of the stimuli. Consistent with the automatic-inhibition hypothesis, the authors found that responding in the test phase was slowed when the stimulus had been consistently associated with stopping in the training phase. In addition, they found that response inhibition benefited from consistent stimulus-stop associations. These findings suggest that response inhibition may rely on the retrieval of stimulus-stop associations after practice with consistent stimulus-stop mappings. Stimulus-stop mapping is typically consistent in the go/no-go paradigm, so automatic inhibition is likely to occur. However, stimulus-stop mapping is typically inconsistent in the stop-signal paradigm, so automatic inhibition is unlikely to occur. Thus, the results suggest that the two paradigms are not equivalent because they allow different kinds of response inhibition. PMID:18999358

Changes in stimulus and response AC/A ratio with vision therapy in Convergence Insufficiency.

PubMed

Singh, Neeraj Kumar; Mani, Revathy; Hussaindeen, Jameel Rizwana

To evaluate the changes in the stimulus and response Accommodative Convergence to Accommodation (AC/A) ratio following vision therapy (VT) in Convergence Insufficiency (CI). Stimulus and response AC/A ratio were measured on twenty five CI participants, pre and post 10 sessions of VT. Stimulus AC/A ratio was measured using the gradient method and response AC/A ratio was calculated using modified Thorington technique with accommodative responses measured using WAM-5500 open-field autorefractor. The gradient stimulus and response AC/A cross-link ratios were compared with thirty age matched controls. Mean age of the CI and control participants were 23.3±5.2 years and 22.7±4.2 years, respectively. The mean stimulus and response AC/A ratio for CI pre therapy was 2.2±0.72 and 6.3±2.0 PD/D that changed to 4.2±0.9 and 8.28±3.31 PD/D respectively post vision therapy and these changes were statistically significant (paired t-test; p<0.001). The mean stimulus and response AC/A ratio for controls was 3.1±0.81 and 8.95±2.5 PD/D respectively. Stimulus and response AC/A ratio increased following VT, accompanied by clinically significant changes in vergence and accommodation parameters in subjects with convergence insufficiency. This represents the plasticity of the AC/A crosslink ratios that could be achieved with vision therapy in CI. Copyright © 2016 Spanish General Council of Optometry. Published by Elsevier España, S.L.U. All rights reserved.

Myosin light chain kinase and Src control membrane dynamics in volume recovery from cell swelling

PubMed Central

Barfod, Elisabeth T.; Moore, Ann L.; Van de Graaf, Benjamin G.; Lidofsky, Steven D.

2011-01-01

 The expansion of the plasma membrane, which occurs during osmotic swelling of epithelia, must be retrieved for volume recovery, but the mechanisms are unknown. Here we have identified myosin light chain kinase (MLCK) as a regulator of membrane internalization in response to osmotic swelling in a model liver cell line. On hypotonic exposure, we found that there was time-dependent phosphorylation of the MLCK substrate myosin II regulatory light chain. At the sides of the cell, MLCK and myosin II localized to swelling-induced membrane blebs with actin just before retraction, and MLCK inhibition led to persistent blebbing and attenuated cell volume recovery. At the base of the cell, MLCK also localized to dynamic actin-coated rings and patches upon swelling, which were associated with uptake of the membrane marker FM4-64X, consistent with sites of membrane internalization. Hypotonic exposure evoked increased biochemical association of the cell volume regulator Src with MLCK and with the endocytosis regulators cortactin and dynamin, which colocalized within these structures. Inhibition of either Src or MLCK led to altered patch and ring lifetimes, consistent with the concept that Src and MLCK form a swelling-induced protein complex that regulates volume recovery through membrane turnover and compensatory endocytosis under osmotic stress. PMID:21209319

Clonorchis sinensis excretory-secretory products promote the migration and invasion of cholangiocarcinoma cells by activating the integrin β4-FAK/Src signaling pathway.

PubMed

Pak, Jhang Ho; Bashir, Qudsia; Kim, In Ki; Hong, Sung-Jong; Maeng, Sejung; Bahk, Young Yil; Kim, Tong-Soo

2017-06-01

Cholangiocarcinoma (CCA) is a slow-growing but highly metastatic cancer. Its metastatic potential largely explains its high mortality rate. A recognized risk factor for CCA development is infection with the liver flukes Opisthorchis viverrini and Clonorchis sinensis. We previously reported that the excretory-secretory products (ESPs) of C. sinensis promoted the three-dimensional aggregation and invasion of CCA cells. In the present study, a quantitative real-time PCR array of extracellular matrix (ECM) and adhesion molecules was used to examine the regulatory mechanism of ESP-mediated CCA cell migration and invasion. In particular, the expression levels of integrin α isoforms and β4 were upregulated in response to ESPs. Increased expression of integrin β4 was probably correlated with activation of focal adhesion kinase (FAK) and the steroid receptor coactivator (Src) family kinase and the subsequent activation of two downstream focal adhesion molecules, paxillin and vinculin. Moreover, inhibition of FAK/Src activation reduced paxillin and vinculin phosphorylation and attenuated ESP-induced CCA cell migration and invasion. These findings suggest that the integrin β4-FAK/Src signaling axis may play a crucial role in clonorchiasis-associated CCA metastasis during tumor progression. Copyright © 2017 Elsevier B.V. All rights reserved.

Specificity of Mechanisms of Memory Reconsolidation in Snails Trained for Rejection of Two Types of Food.

PubMed

Nikitin, V P; Kozyrev, S A; Solntseva, S V

2017-01-01

Specificity of behavioral and neuronal mechanisms of impairment of long-term memory reconsolidation was studied in edible snails trained for associative skill of rejection of two types of food: raw carrots (conditioned stimulus 1) and apple (conditioned stimulus 2). In 2 days after training, the snails received protein synthesis inhibitor cycloheximide and a reminder (conditioned stimulus 1 or 2). In 3 and 14 days after cycloheximide/reminder, we observed the absence of aversive responses to the conditioned stimulus used as the reminder and preserved responses to the conditioned stimulus not used as the reminder. Moreover, we observed specific suppression of synaptic responses of command neurons of snail defensive behavior induced by the conditioned stimulus used as the reminder after cycloheximide injection and preserved synaptic responses of neurons to the other conditioned stimulus. It was hypothesized that protein synthesis-dependent synapse-specific plasticity of command neurons can be a mechanism of selective preservation of conditioned food aversion memory in snails.

Gallic acid abolishes the EGFR/Src/Akt/Erk-mediated expression of matrix metalloproteinase-9 in MCF-7 breast cancer cells.

PubMed

Chen, Ying-Jung; Lin, Ku-Nan; Jhang, Li-Mei; Huang, Chia-Hui; Lee, Yuan-Chin; Chang, Long-Sen

2016-05-25

Several studies have revealed that natural compounds are valuable resources to develop novel agents against dysregulation of the EGF/EGFR-mediated matrix metalloproteinase-9 (MMP-9) expression in cancer cells. In view of the findings that EGF/EGFR-mediated MMP-9 expression is closely related to invasion and metastasis of breast cancer. To determine the beneficial effects of gallic acid on the suppression of breast cancer metastasis, we explored the effect of gallic acid on MMP-9 expression in EGF-treated MCF-7 breast cancer cells. Treatment with EGF up-regulated MMP-9 mRNA and protein levels in MCF-7 cells. EGF treatment induced phosphorylation of EGFR and elicited Src activation, subsequently promoting Akt/NFκB (p65) and ERK/c-Jun phosphorylation in MCF-7 cells. Activation of Akt/p65 and ERK/c-Jun was responsible for the MMP-9 up-regulation in EGF-treated cells. Gallic acid repressed the EGF-induced activation of EGFR and Src; furthermore, inactivation of Akt/p65 and ERK/c-Jun was a result of the inhibitory effect of gallic acid on the EGF-induced MMP-9 up-regulation. Over-expression of constitutively active Akt and MEK1 or over-expression of constitutively active Src eradicated the inhibitory effect of gallic acid on the EGF-induced MMP-9 up-regulation. A chromosome conformation capture assay showed that EGF induced a chromosomal loop formation in the MMP-9 promoter via NFκB/p65 and AP-1/c-Jun activation. Treatment with gallic acid, EGFR inhibitor, or Src inhibitor reduced DNA looping. Taken together, our data suggest that gallic acid inhibits the activation of EGFR/Src-mediated Akt and ERK, leading to reduced levels of p65/c-Jun-mediated DNA looping and thus inhibiting MMP-9 expression in EGF-treated MCF-7 cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in steroid-associated osteonecrotic lesions in rabbits.

PubMed

He, Yi-Xin; Liu, Jin; Guo, Baosheng; Wang, Yi-Xiang; Pan, Xiaohua; Li, Defang; Tang, Tao; Chen, Yang; Peng, Songlin; Bian, Zhaoxiang; Liang, Zicai; Zhang, Bao-Ting; Lu, Aiping; Zhang, Ge

2015-03-09

To examine the therapeutic effect of Src inhibitor on the VEGF mediating vascular hyperpermeability and bone destruction within steroid-associated osteonecrotic lesions in rabbits. Rabbits with high risk for progress to destructive repair in steroid-associated osteonecrosis were selected according to our published protocol. The selected rabbits were systemically administrated with either Anti-VEGF antibody (Anti-VEGF Group) or Src inhibitor (Src-Inhibition Group) or VEGF (VEGF-Supplement Group) or a combination of VEGF and Src inhibitor (Supplement &Inhibition Group) or control vehicle (Control Group) for 4 weeks. At 0, 2 and 4 weeks after administration, in vivo dynamic MRI, micro-CT based-angiography, histomorphometry and immunoblotting were employed to evaluate the vascular and skeletal events in different groups. The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group was all significantly lower than that in the Control Group. The angiogenesis was promoted in VEGF-Supplement Group, Src-Inhibition Group and Supplement &Inhibition Group, while the hyperpermeability was inhibited in Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group. The trabecular structure was improved in Src-Inhibition Group and Supplement &Inhibition Group. Src inhibitor could reduce permeability without disturbing vascularization and prevent destructive repair in steroid-associated osteonecrosis.

Phosphatase of Regenerating Liver 3 (PRL3) Provokes a Tyrosine Phosphoproteome to Drive Prometastatic Signal Transduction*

PubMed Central

Walls, Chad D.; Iliuk, Anton; Bai, Yunpeng; Wang, Mu; Tao, W. Andy; Zhang, Zhong-Yin

2013-01-01

Phosphatase of regenerating liver 3 (PRL3) is suspected to be a causative factor toward cellular metastasis when in excess. To date, the molecular basis for PRL3 function remains an enigma, making efforts at distilling a concerted mechanism for PRL3-mediated metastatic dissemination very difficult. We previously discovered that PRL3 expressing cells exhibit a pronounced increase in protein tyrosine phosphorylation. Here we take an unbiased mass spectrometry-based approach toward identifying the phosphoproteins exhibiting enhanced levels of tyrosine phosphorylation with a goal to define the “PRL3-mediated signaling network.” Phosphoproteomic data support intracellular activation of an extensive signaling network normally governed by extracellular ligand-activated transmembrane growth factor, cytokine, and integrin receptors in the PRL3 cells. Additionally, data implicate the Src tyrosine kinase as the major intracellular kinase responsible for “hijacking” this network and provide strong evidence that aberrant Src activation is a major consequence of PRL3 overexpression. Importantly, the data support a PDGF(α/β)-, Eph (A2/B3/B4)-, and Integrin (β1/β5)-receptor array as being the predominant network coordinator in the PRL3 cells, corroborating a PRL3-induced mesenchymal-state. Within this network, we find that tyrosine phosphorylation is increased on a multitude of signaling effectors responsible for Rho-family GTPase, PI3K-Akt, STAT, and ERK activation, linking observations made by the field as a whole under Src as a primary signal transducer. Our phosphoproteomic data paint the most comprehensive picture to date of how PRL3 drives prometastatic molecular events through Src activation. PMID:24030100

Src kinase-targeted anti-inflammatory activity of davallialactone from Inonotus xeranticus in lipopolysaccharide-activated RAW264.7 cells.

PubMed

Lee, Y G; Lee, W M; Kim, J Y; Lee, J Y; Lee, I-K; Yun, B-S; Rhee, M H; Cho, J Y

2008-06-01

Mushrooms are popular both as food and as a source of natural compounds of biopharmaceutical interest. Some mushroom-derived compounds such as beta-glucan have been shown to be immunostimulatory; this study explores the anti-inflammatory properties of hispidin analogues derived from the mushroom, Inonotus xeranticus. We sought to identify the molecular mechanism of action of these hispidin analogues by determining their effects on lipopolysaccharide (LPS)-mediated inflammatory responses in a macrophage cell line. The production of inflammatory mediators was determined by Griess assay, reverse transcription-PCR and ELISA. The inhibitory effect of davalliactone on LPS-induced activation of signalling cascades was assessed by western blotting, immunoprecipitation and direct kinase assay. In activated RAW264.7 cells, davallialactone strongly downregulated LPS-mediated inflammatory responses, including NO production, prostaglandin E2 release, expression of proinflammatory cytokine genes and cell surface expression of co-stimulatory molecules. Davallialactone treatment did not alter cell viability or morphology. Davallialactone was found to exert its anti-inflammatory effects by inhibiting a signalling cascade that activates nuclear factor kappa B via PI3K, Akt and IKK, but not mitogen-activated protein kinases. Treatment with davallialactone affected the phosphorylation of these signalling proteins, but not their level of expression. These inhibitory effects were not due to the interruption of toll-like receptor 4 binding to CD14. In particular, davallialactone strongly inhibited the LPS-induced phosphorylation and kinase activity of Src, implying that Src may be a potential pharmacological target of davallialactone. Our data suggest that davallialactone, a small molecule found in edible mushrooms, has anti-inflammatory activity. Davallialactone can be developed as a pharmaceutically valuable anti-Src kinase agent.

Peroxide generation by p47phox-Src activation of Nox2 has a key role in protein kinase C-induced arterial smooth muscle contraction.

PubMed

Gupte, Sachin A; Kaminski, Pawel M; George, Shimran; Kouznestova, Lioubov; Olson, Susan C; Mathew, Rajamma; Hintze, Thomas H; Wolin, Michael S

2009-04-01

Protein kinase C (PKC) stimulation of NAD(P)H oxidases (Nox) is an important component of multiple vascular disease processes; however, the relationship between oxidase activation and the regulation of vascular smooth muscle contraction by PKC remains poorly understood. Therefore, we examined the signaling cascade of PKC-elicited Nox activation and the role of superoxide and hydrogen peroxide in mediating PKC-induced vascular contraction. Endothelium-denuded bovine coronary arteries showed a PKC-dependent basal production of lucigenin (5 muM)-detected Nox oxidase-derived superoxide, which was stimulated fourfold by PKC activation with 10 muM phorbol 12,13-dibutyrate (PDBu). PDBu appeared to increase superoxide generation by Nox2 through both p47(phox) and peroxide-dependent Src activation mechanisms based on the actions of inhibitors, properties of Src phosphorylation, and the loss of responses in aorta from mice deficient in Nox2 and p47(phox). The actions of inhibitors of contractile regulating mechanisms, scavengers of superoxide and peroxide, and responses in knockout mouse aortas suggest that a major component of the contraction elicited by PDBu appeared to be mediated through peroxide derived from Nox2 activation stimulating force generation through Rho kinase and calmodulin kinase-II mechanisms. Superoxide generated by PDBu also attenuated relaxation to nitroglycerin. Peroxide-derived from Nox2 activation by PKC appeared to be a major contributor to the thromboxane A(2) receptor agonist U46619 (100 nM)-elicited contraction of coronary arteries. Thus a p47(phox) and Src kinase activation of peroxide production by Nox2 appears to be an important contributor to vascular contractile mechanisms mediated through activation of PKC.

Inferring bread doneness with air-pulse/ultrasonic ranging measurements of the loaf elastic response

NASA Astrophysics Data System (ADS)

Faeth, Loren Elbert

This research marks the discovery of a method by which bread doneness may be determined based on the elastic properties of the loaf as it bakes. The purpose of the study was to determine if changes in bread characteristics could be determined by non-contact methods during baking, as the basis for improved control of the baking process. Current control of the baking process is based on temperature and dwell time, which are determined by experience to produce a produce which is approximately ``done.'' There is no direct measurement of the property of interest, doneness. An ultrasonic measurement system was developed to measure the response of the loaf to an external stimulus. ``Doneness,'' as reflected in the internal elastic consistency of the bakery product, is assessed in less than 1/2 second, and requires no closer approach to the moving bakery product than about 2 inches. The system is designed to be compatible with strapped bread pans in a standard traveling-tray commercial oven.

Direct visuomotor mapping for fast visually-evoked arm movements.

PubMed

Reynolds, Raymond F; Day, Brian L

2012-12-01

In contrast to conventional reaction time (RT) tasks, saccadic RT's to visual targets are very fast and unaffected by the number of possible targets. This can be explained by the sub-cortical circuitry underlying eye movements, which involves direct mapping between retinal input and motor output in the superior colliculus. Here we asked if the choice-invariance established for the eyes also applies to a special class of fast visuomotor responses of the upper limb. Using a target-pointing paradigm we observed very fast reaction times (<150 ms) which were completely unaffected as the number of possible target choices was increased from 1 to 4. When we introduced a condition of altered stimulus-response mapping, RT went up and a cost of choice was observed. These results can be explained by direct mapping between visual input and motor output, compatible with a sub-cortical pathway for visual control of the upper limb. Copyright © 2012 Elsevier Ltd. All rights reserved.

Src promotes cutaneous wound healing by regulating MMP-2 through the ERK pathway.

PubMed

Wu, Xue; Yang, Longlong; Zheng, Zhao; Li, Zhenzhen; Shi, Jihong; Li, Yan; Han, Shichao; Gao, Jianxin; Tang, Chaowu; Su, Linlin; Hu, Dahai

2016-03-01

Wound healing is a highly orchestrated, multistep process, and delayed wound healing is a significant symptomatic clinical problem. Keratinocyte migration and re-epithelialization play the most important roles in wound healing, as they determine the rate of wound healing. In our previous study, we found that Src, one of the oldest proto‑oncogenes encoding a membrane-associated, non-receptor protein tyrosine kinase, promotes keratinocyte migration. We therefore hypothesized that Src promotes wound healing through enhanced keratinocyte migration. In order to test this hypothesis, vectors for overexpressing Src and small interfering RNAs (siRNAs) for silencing of Src were used in the present study. We found that the overexpression of Src accelerated keratinocyte migration in vitro and promoted wound healing in vivo without exerting a marked effect on cell proliferation. The extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways play important roles in Src-accelerated keratinocyte migration. Further experiments demonstrated that Src induced the protein expression of matrix metalloproteinase-2 (MMP-2) and decreased the protein expression of E-cadherin. We suggest that ERK signaling is involved in the Src-mediated regulation of MMP-2 expression. The present study provided evidence that Src promotes keratinocyte migration and cutaneous wound healing, in which the regulation of MMP-2 through the ERK pathway plays an important role, and thus we also demonstrated a potential therapeutic role for Src in cutaneous wound healing.

Photoresponse and learning behavior of ascidian larvae, a primitive chordate, to repeated stimuli of step-up and step-down of light.

PubMed

Kawakami, I; Shiraishi, S; Tsuda, M

2002-09-01

Ascidians are lower chordates and their simple tadpole-like larvae share a basic body plan with vertebrates. Newly hatched larvae show no response to a stimulus of light. 4 h after hatching, the larvae were induced to swim upon a step-down of light and stop swimming upon a step-up of light. At weaker intensity of light, the larvae show the same response to a stimulus after presentation of repeated stimuli. When intensity of actinic light was increased, the larvae show sensitization and habituation of the swimming response to a stimulus after repeated stimuli of step-down and step-up of the light. Between 2 h 20 min and 3 h 40 min after hatching the larvae did not show any response to the first stimulus, but after several repeatedstimuli they show swimming response to a step-down of light. A repeated series of stimulus cause sensitization. Between 4 h and 7 h after hatching, the larvae show photoresponse to the first stimulus, but after several repetition of the stimuli, the larvae could not stop swimming to a stimulus of a step-up of the actinic light. A repeated series of stimulus cause greaterhabituation. Both sensitization and habituation depend upon intensity ofactinic light.

Deposition and material response from Mach 0.3 burner rig combustion of SRC 2 fuels

NASA Technical Reports Server (NTRS)

Santoro, G. J.; Kohl, F. J.; Stearns, C. A.; Fryburg, G. C.; Johnson, J. R.

1980-01-01

Collectors at 1173K (900 C) were exposed to the combustion products of a Mach 0.3 burner rig fueled with various industrial turbine liquid fuels from solvent refined coals. Four fuels were employed: a naphtha, a light oil, a wash solvent and a mid-heavy distillate blend. The response of four superalloys (IN-100, U 700, IN 792 and M-509) to exposure to the combustion gases from the SRC-2 naphtha and resultant deposits was also determined. The SRC-2 fuel analysis and insights obtained during the combustion experience are discussed. Particular problems encountered were fuel instability and reactions of the fuel with hardware components. The major metallic elements which contributed to the deposits were copper, iron, chromium, calcium, aluminum, nickel, silicon, titanium, zinc, and sodium. The deposits were found to be mainly metal oxides. An equilibrium thermodynamic analysis was employed to predict the chemical composition of the deposits. The agreement between the predicted and observed compounds was excellent. No hot corrosion was observed. This was expected because the deposits contained very little sodium or potassium and consisted mainly of the unreactive oxides. However, the amounts of deposits formed indicated that fouling is a potential problem with the use of these fuels.

Does sensitivity in binary choice tasks depend on response modality?

PubMed

Szumska, Izabela; van der Lubbe, Rob H J; Grzeczkowski, Lukasz; Herzog, Michael H

2016-07-01

In most models of vision, a stimulus is processed in a series of dedicated visual areas, leading to categorization of this stimulus, and possible decision, which subsequently may be mapped onto a motor-response. In these models, stimulus processing is thought to be independent of the response modality. However, in theories of event coding, common coding, and sensorimotor contingency, stimuli may be very specifically mapped onto certain motor-responses. Here, we compared performance in a shape localization task and used three different response modalities: manual, saccadic, and verbal. Meta-contrast masking was employed at various inter-stimulus intervals (ISI) to manipulate target visibility. Although we found major differences in reaction times for the three response modalities, accuracy remained at the same level for each response modality (and all ISIs). Our results support the view that stimulus-response (S-R) associations exist only for specific instances, such as reflexes or skills, but not for arbitrary S-R pairings. Copyright © 2016 Elsevier Inc. All rights reserved.

Nanoscale theranostics for physical stimulus-responsive cancer therapies.

PubMed

Chen, Qian; Ke, Hengte; Dai, Zhifei; Liu, Zhuang

2015-12-01

Physical stimulus-responsive therapies often employing multifunctional theranostic agents responsive to external physical stimuli such as light, magnetic field, ultra-sound, radiofrequency, X-ray, etc., have been widely explored as novel cancer therapy strategies, showing encouraging results in many pre-clinical animal experiments. Unlike conventional cancer chemotherapy which often accompanies with severe toxic side effects, physical stimulus-responsive agents usually are non-toxic by themselves and would destruct cancer cells only under specific external stimuli, and thus could offer greatly reduced toxicity and enhanced treatment specificity. In addition, physical stimulus-responsive therapies can also be combined with other traditional therapeutics to achieve synergistic anti-tumor effects via a variety of mechanisms. In this review, we will summarize the latest progress in the development of physical stimulus-responsive therapies, and discuss the important roles of nanoscale theranostic agents involved in those non-conventional therapeutic strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Excitation of the corticospinal tract by electromagnetic and electrical stimulation of the scalp in the macaque monkey.

PubMed Central

Edgley, S A; Eyre, J A; Lemon, R N; Miller, S

1990-01-01

1. The responses evoked by non-invasive electromagnetic and surface anodal electrical stimulation of the scalp (scalp stimulation) have been studied in the monkey. Conventional recording and stimulating electrodes, placed in the corticospinal pathway in the hand area of the left motor cortex, left medullary pyramid and the right spinal dorsolateral funiculus (DLF), allowed comparison of the actions of non-invasive stimuli and conventional electrical stimulation. 2. Responses to electromagnetic stimulation (with the coil tangential to the skull) were studied in four anaesthetized monkeys. In each case short-latency descending volleys were recorded in the contralateral DLF at threshold. In two animals later responses were also seen at higher stimulus intensities. Both early and late responses were of corticospinal origin since they could be completely collided by appropriately timed stimulation of the pyramidal tract. The latency of the early response in the DLF indicated that it resulted from direct activation of corticospinal neurones: its latency was the same as the latency of the antidromic action potentials evoked in the motor cortex from the recording site in the DLF. 3. Scalp stimulation, which was also investigated in three of the monkeys, evoked short-latency volleys at threshold and at higher stimulus intensities these were followed by later waves. The short-latency volleys could be collided from the pyramid and, at threshold, had latencies compatible with direct activation of corticospinal neurones. The longer latency volleys were also identified as corticospinal in origin. 4. The latency of the early volley evoked by electromagnetic stimulation remained constant with increasing stimulus intensities. In contrast, with scalp stimulation above threshold the latency of the early volleys decreased considerably, indicating remote activation of the corticospinal pathway below the level of the motor cortex. In two monkeys both collision and latency data suggest activation of the corticospinal pathway as far caudal as the medulla. 5. The majority of fast corticospinal fibres could be excited by scalp stimulation with intensities of 20% of maximum stimulator output. Electromagnetic stimulation at maximum stimulator output elicited a volley of between 70 and 90% of the size of the maximal volley evoked from the pyramidal electrodes. 6. Electromagnetic stimulation was also investigated in one awake monkey during the performance of a precision grip task. Short-latency EMG responses were evoked in hand and forearm muscles. The onsets of these responses were approximately 0.8 ms longer than the responses evoked by electrical stimulation of the pyramid.(ABSTRACT TRUNCATED AT 400 WORDS) Images Fig. 1 PMID:2213581

A biochemical network can control formation of a synthetic material by sensing numerous specific stimuli

NASA Astrophysics Data System (ADS)

Hun Yeon, Ju; Chan, Karen Y. T.; Wong, Ting-Chia; Chan, Kelvin; Sutherland, Michael R.; Ismagilov, Rustem F.; Pryzdial, Edward L. G.; Kastrup, Christian J.

2015-05-01

Developing bio-compatible smart materials that assemble in response to environmental cues requires strategies that can discriminate multiple specific stimuli in a complex milieu. Synthetic materials have yet to achieve this level of sensitivity, which would emulate the highly evolved and tailored reaction networks of complex biological systems. Here we show that the output of a naturally occurring network can be replaced with a synthetic material. Exploiting the blood coagulation system as an exquisite biological sensor, the fibrin clot end-product was replaced with a synthetic material under the biological control of a precisely regulated cross-linking enzyme. The functions of the coagulation network remained intact when the material was incorporated. Clot-like polymerization was induced in indirect response to distinct small molecules, phospholipids, enzymes, cells, viruses, an inorganic solid, a polyphenol, a polysaccharide, and a membrane protein. This strategy demonstrates for the first time that an existing stimulus-responsive biological network can be used to control the formation of a synthetic material by diverse classes of physiological triggers.

ESTROGENIC RESPONSES TO XENOBIOTICS IN CHANNEL CATFISH (ICTALURUS PUNCTATUS) (R823450)

EPA Science Inventory

Abstract

Several environmentally relevant contaminants are characterized as xenoestrogens by virtue of their ability to induce responses similar to 17-estradiol (E2). T...

Effects of Response-Contingent Stimulus Pairing on Vocalizations of Nonverbal Children with Autism

ERIC Educational Resources Information Center

Lepper, Tracy L.; Petursdottir, Anna Ingeborg

2017-01-01

Research on stimulus-stimulus pairing to induce novel vocalizations in nonverbal children has typically employed response-independent pairing (RIP) procedures to condition speech sounds as reinforcers. The purpose of the present study was to evaluate the effects of a response-contingent pairing (RCP) procedure on the vocalizations of three…

Asymmetry in stimulus and response conflict processing across the adult lifespan: ERP and EMG evidence☆

PubMed Central

Killikelly, Clare; Szűcs, Dénes

2013-01-01

Several studies have shown that conflict processing improves from childhood to adulthood and declines from adulthood to old age. However the neural mechanisms underlying this lifespan asymmetry were previously unexplored. We combined event-related potentials (ERPs) and electromyography (EMG) to examine lifespan changes in stimulus and response conflict processing using a modified Stroop task. We used a Stroop task that a priori dissociated stimulus and response conflict. Delayed P3b latency and increased amplitude revealed that middle age adults have a deficit in stimulus processing. Additionally a sustained P3a across frontal and central electrodes occurred only in middle age adults indicating the recruitment of frontal activity. Conversely, decreased lateralized readiness potential (LRP) amplitude and increased EMG activity in the incorrect hand in adolescents reveal protracted development of response processing into late adolescence. The N450, a measure of conflict processing, was found to be sensitive to both stimulus and response conflict. Altogether these results provide evidence for asymmetrical differences in stimulus and response conflict processing across adolescence, young adulthood and middle age. PMID:24134924

Decoding the auditory brain with canonical component analysis.

PubMed

de Cheveigné, Alain; Wong, Daniel D E; Di Liberto, Giovanni M; Hjortkjær, Jens; Slaney, Malcolm; Lalor, Edmund

2018-05-15

The relation between a stimulus and the evoked brain response can shed light on perceptual processes within the brain. Signals derived from this relation can also be harnessed to control external devices for Brain Computer Interface (BCI) applications. While the classic event-related potential (ERP) is appropriate for isolated stimuli, more sophisticated "decoding" strategies are needed to address continuous stimuli such as speech, music or environmental sounds. Here we describe an approach based on Canonical Correlation Analysis (CCA) that finds the optimal transform to apply to both the stimulus and the response to reveal correlations between the two. Compared to prior methods based on forward or backward models for stimulus-response mapping, CCA finds significantly higher correlation scores, thus providing increased sensitivity to relatively small effects, and supports classifier schemes that yield higher classification scores. CCA strips the brain response of variance unrelated to the stimulus, and the stimulus representation of variance that does not affect the response, and thus improves observations of the relation between stimulus and response. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Encoding of a spectrally-complex communication sound in the bullfrog's auditory nerve.

PubMed

Schwartz, J J; Simmons, A M

1990-02-01

1. A population study of eighth nerve responses in the bullfrog, Rana catesbeiana, was undertaken to analyze how the eighth nerve codes the complex spectral and temporal structure of the species-specific advertisement call over a biologically-realistic range of intensities. Synthetic advertisement calls were generated by Fourier synthesis and presented to individual eighth nerve fibers of anesthetized bullfrogs. Fiber responses were analyzed by calculating rate responses based on post-stimulus-time (PST) histograms and temporal responses based on Fourier transforms of period histograms. 2. At stimulus intensities of 70 and 80 dB SPL, normalized rate responses provide a fairly good representation of the complex spectral structure of the stimulus, particularly in the low- and mid-frequency range. At higher intensities, rate responses saturate, and very little of the spectral structure of the complex stimulus can be seen in the profile of rate responses of the population. 3. Both AP and BP fibers phase-lock strongly to the fundamental (100 Hz) of the complex stimulus. These effects are relatively resistant to changes in stimulus intensity. Only a small number of fibers synchronize to the low-frequency spectral energy in the stimulus. The underlying spectral complexity of the stimulus is not accurately reflected in the timing of fiber firing, presumably because firing is 'captured' by the fundamental frequency. 4. Plots of average localized synchronized rate (ALSR), which combine both spectral and temporal information, show a similar, low-pass shape at all stimulus intensities. ALSR plots do not generally provide an accurate representation of the structure of the advertisement call. 5. The data suggest that anuran peripheral auditory fibers may be particularly sensitive to the amplitude envelope of sounds.

Adaptor protein GRB2 promotes Src tyrosine kinase activation and podosomal organization by protein-tyrosine phosphatase ϵ in osteoclasts.

PubMed

Levy-Apter, Einat; Finkelshtein, Eynat; Vemulapalli, Vidyasiri; Li, Shawn S-C; Bedford, Mark T; Elson, Ari

2014-12-26

The non-receptor isoform of protein-tyrosine phosphatase ϵ (cyt-PTPe) supports adhesion of bone-resorbing osteoclasts by activating Src downstream of integrins. Loss of cyt-PTPe reduces Src activity in osteoclasts, reduces resorption of mineralized matrix both in vivo and in cell culture, and induces mild osteopetrosis in young female PTPe KO mice. Activation of Src by cyt-PTPe is dependent upon this phosphatase undergoing phosphorylation at its C-terminal Tyr-638 by partially active Src. To understand how cyt-PTPe activates Src, we screened 73 Src homology 2 (SH2) domains for binding to Tyr(P)-638 of cyt-PTPe. The SH2 domain of GRB2 bound Tyr(P)-638 of cyt-PTPe most prominently, whereas the Src SH2 domain did not bind at all, suggesting that GRB2 may link PTPe with downstream molecules. Further studies indicated that GRB2 is required for activation of Src by cyt-PTPe in osteoclast-like cells (OCLs) in culture. Overexpression of GRB2 in OCLs increased activating phosphorylation of Src at Tyr-416 and of cyt-PTPe at Tyr-638; opposite results were obtained when GRB2 expression was reduced by shRNA or by gene inactivation. Phosphorylation of cyt-PTPe at Tyr-683 and its association with GRB2 are integrin-driven processes in OCLs, and cyt-PTPe undergoes autodephosphorylation at Tyr-683, thus limiting Src activation by integrins. Reduced GRB2 expression also reduced the ability of bone marrow precursors to differentiate into OCLs and reduced the fraction of OCLs in which podosomal adhesion structures assume organization typical of active, resorbing cells. We conclude that GRB2 physically links cyt-PTPe with Src and enables cyt-PTPe to activate Src downstream of activated integrins in OCLs. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Visual Attention in Deaf and Normal Hearing Adults: Effects of Stimulus Compatibility

ERIC Educational Resources Information Center

Sladen, Douglas P.; Tharpe, Anne Marie; Ashmead, Daniel H.; Grantham, D. Wesley; Chun, Marvin M.

2005-01-01

Visual perceptual skills of deaf and normal hearing adults were measured using the Eriksen flanker task. Participants were seated in front of a computer screen while a series of target letters flanked by similar or dissimilar letters was flashed in front of them. Participants were instructed to press one button when they saw an "H," and another…

Significant Deregulated Pathways in Diabetes Type II Complications Identified through Expression Based Network Biology

NASA Astrophysics Data System (ADS)

Ukil, Sanchaita; Sinha, Meenakshee; Varshney, Lavneesh; Agrawal, Shipra

Type 2 Diabetes is a complex multifactorial disease, which alters several signaling cascades giving rise to serious complications. It is one of the major risk factors for cardiovascular diseases. The present research work describes an integrated functional network biology approach to identify pathways that get transcriptionally altered and lead to complex complications thereby amplifying the phenotypic effect of the impaired disease state. We have identified two sub-network modules, which could be activated under abnormal circumstances in diabetes. Present work describes key proteins such as P85A and SRC serving as important nodes to mediate alternate signaling routes during diseased condition. P85A has been shown to be an important link between stress responsive MAPK and CVD markers involved in fibrosis. MAPK8 has been shown to interact with P85A and further activate CTGF through VEGF signaling. We have traced a novel and unique route correlating inflammation and fibrosis by considering P85A as a key mediator of signals. The next sub-network module shows SRC as a junction for various signaling processes, which results in interaction between NF-kB and beta catenin to cause cell death. The powerful interaction between these important genes in response to transcriptionally altered lipid metabolism and impaired inflammatory response via SRC causes apoptosis of cells. The crosstalk between inflammation, lipid homeostasis and stress, and their serious effects downstream have been explained in the present analyses.

Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling

PubMed Central

Louria-Hayon, Igal; Frelin, Catherine; Ruston, Julie; Gish, Gerald; Jin, Jing; Kofler, Michael M.; Lambert, Jean-Philippe; Adissu, Hibret A.; Milyavsky, Michael; Herrington, Robert; Minden, Mark D.; Dick, John E.; Gingras, Anne-Claude; Iscove, Norman N.; Pawson, Tony

2013-01-01

The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors (HSPCs) to a variety of cytokines by inhibiting JAK2 signaling. As a consequence, Lnk−/− mice develop hematopoietic hyperplasia, which progresses to a phenotype resembling the nonacute phase of myeloproliferative neoplasm. In addition, Lnk mutations have been identified in human myeloproliferative neoplasms and acute leukemia. We find that Lnk suppresses the development of radiation-induced acute B-cell malignancies in mice. Lnk-deficient HSPCs recover more effectively from irradiation than their wild-type counterparts, and this resistance of Lnk−/− HSPCs to radiation underlies the subsequent emergence of leukemia. A search for the mechanism responsible for radiation resistance identified the cytokine IL-11 as being critical for the ability of Lnk−/− HSPCs to recover from irradiation and subsequently become leukemic. In IL-11 signaling, wild-type Lnk suppresses tyrosine phosphorylation of the Src homology region 2 domain-containing phosphatase-2/protein tyrosine phosphatase nonreceptor type 11 and its association with the growth factor receptor-bound protein 2, as well as activation of the Erk MAP kinase pathway. Indeed, Src homology region 2 domain-containing phosphatase-2 has a binding motif for the Lnk Src Homology 2 domain that is phosphorylated in response to IL-11 stimulation. IL-11 therefore drives a pathway that enhances HSPC radioresistance and radiation-induced B-cell malignancies, but is normally attenuated by the inhibitory adaptor Lnk. PMID:24297922

Activation of the Low Molecular Weight Protein Tyrosine Phosphatase in Keratinocytes Exposed to Hyperosmotic Stress

PubMed Central

Cavalheiro, Renan P.; Machado, Daisy; Cruz, Bread L. G.; Paredes-Gamero, Edgar J.; Gomes-Marcondes, Maria C. C.; Zambuzzi, Willian F.; Vasques, Luciana; Nader, Helena B.; Souza, Ana Carolina S.; Justo, Giselle Z.

2015-01-01

Herein, we provide new contribution to the mechanisms involved in keratinocytes response to hyperosmotic shock showing, for the first time, the participation of Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP) activity in this event. We reported that sorbitol-induced osmotic stress mediates alterations in the phosphorylation of pivotal cytoskeletal proteins, particularly Src and cofilin. Furthermore, an increase in the expression of the phosphorylated form of LMWPTP, which was followed by an augment in its catalytic activity, was observed. Of particular importance, these responses occurred in an intracellular milieu characterized by elevated levels of reduced glutathione (GSH) and increased expression of the antioxidant enzymes glutathione peroxidase and glutathione reductase. Altogether, our results suggest that hyperosmostic stress provides a favorable cellular environment to the activation of LMWPTP, which is associated with increased expression of antioxidant enzymes, high levels of GSH and inhibition of Src kinase. Finally, the real contribution of LMWPTP in the hyperosmotic stress response of keratinocytes was demonstrated through analysis of the effects of ACP1 gene knockdown in stressed and non-stressed cells. LMWPTP knockdown attenuates the effects of sorbitol induced-stress in HaCaT cells, mainly in the status of Src kinase, Rac and STAT5 phosphorylation and activity. These results describe for the first time the participation of LMWPTP in the dynamics of cytoskeleton rearrangement during exposure of human keratinocytes to hyperosmotic shock, which may contribute to cell death. PMID:25781955

Task-dependent V1 responses in human retinitis pigmentosa.

PubMed

Masuda, Yoichiro; Horiguchi, Hiroshi; Dumoulin, Serge O; Furuta, Ayumu; Miyauchi, Satoru; Nakadomari, Satoshi; Wandell, Brian A

2010-10-01

During measurement with functional MRI (fMRI) during passive viewing, subjects with macular degeneration (MD) have a large unresponsive lesion projection zone (LPZ) in V1. fMRI responses can be evoked from the LPZ when subjects engage in a stimulus-related task. The authors report fMRI measurements on a different class of subjects, those with retinitis pigmentosa (RP), who have intact foveal vision but peripheral visual field loss. The authors measured three RP subjects and two control subjects. fMRI was performed while the subjects viewed drifting contrast pattern stimuli. The subjects passively viewed the stimuli or performed a stimulus-related task. During passive viewing, the BOLD response in the posterior calcarine cortex of all RP subjects was in phase with the stimulus. A bordering, anterior LPZ could be identified by responses that were in opposite phase to the stimulus. When the RP subjects made stimulus-related judgments, however, the LPZ responses changed: the responses modulated in phase with the stimulus and task. In control subjects, the responses in a simulated V1 LPZ were unchanged between the passive and the stimulus-related judgment conditions. Task-dependent LPZ responses are present in RP subjects, similar to responses measured in MD subjects. The results are consistent with the hypothesis that deleting the retinal input to the LPZ unmasks preexisting extrastriate feedback signals that are present across V1. The authors discuss the implications of this hypothesis for visual therapy designed to replace the missing V1 LPZ inputs and to restore vision.

Cooperative Atmosphere-Surface Exchange Study-1999.

NASA Astrophysics Data System (ADS)

Moeng, Chin-Hoh; Poulos, Gregory S.; Lemone, Margaret A.

2003-10-01

Surface-station, radiosonde, and Doppler minisodar data from the Cooperative Atmosphere-Surface Exchange Study-1997 (CASES-97) field project, collected in a 60-km-wide array in the lower Walnut River watershed (terrain variation 150 m) southeast of Wichita, Kansas, are used to study the relationship of the change of the 2-m potential temperature 2m with station elevation ze, 2m/ze ,ze to the ambient wind and thermal stratification /z ,z during fair-weather nights. As in many previous studies, predawn 2m varies linearly with ze, and ,ze ,z over a depth h that represents the maximum elevation range of the stations. Departures from the linear 2m-elevation relationship (,ze line) are related to vegetation (cool for vegetation, warm for bare ground), local terrain (drainage flows from nearby hills, although a causal relationship is not established), and the formation of a cold pool at lower elevations on some days.The near-surface flow and its evolution are functions of the Froude number Fr = S/(Nh), where S is the mean wind speed from the surface to h, and N is the corresponding Brunt-Väisälä frequency. The near-surface wind is coupled to the ambient flow for Fr = 3.3, based on where the straight line relating ,ze to ln Fr intersects the ln Fr axis. Under these conditions, 2m is constant horizontally even though ,z > 0, suggesting that near-surface air moves up- and downslope dry adiabatically. However, 2m cools (or warms) everywhere at the same rate. The lowest Froude numbers are associated with drainage flows, while intermediate values characterize regimes with intermediate behavior. The evolution of 2m horizontal variability σ through the night is also a function of the predawn Froude number. For the nights with the lowest Fr, the σ maximum occurs in the last 1-3 h before sunrise. For nights with Fr 3.3 (,ze 0) and for intermediate values, σ peaks 2-3 h after sunset. The standard deviations relative to the ,ze line reach their lowest values in the last hours of darkness. Thus, it is not surprising that the relationships of ,ze to Fr and ,z based on data through the night show more scatter, and ,ze 0.5,z in contrast to the predawn relationship. However, ,ze 0 for ln Fr = 3.7, a value similar to that just before sunrise.A heuristic Lagrangian parcel model is used to explain the horizontal uniformity of time-evolving 2m when the surface flow is coupled with the ambient wind, as well as both the linear variation of 2m with elevation and the time required to reach maximum values of σ under drainage-flow conditions.

Distribution and associations of intraocular pressure in 7- and 12-year-old Chinese children: The Anyang Childhood Eye Study.

PubMed

Li, Shuning; Li, Shi-Ming; Wang, Xiao-Lei; Kang, Meng-Tian; Liu, Luo-Ru; Li, He; Wei, Shi-Fei; Ran, An-Ran; Zhan, Siyan; Thomas, Ravi; Wang, Ningli

2017-01-01

To report the intraocular pressure (IOP) and its association with myopia and other factors in 7 and 12-year-old Chinese children. All children participating in the Anyang Childhood Eye Study underwent non-contact tonometry as well as measurement of central corneal thickness (CCT), axial length, cycloplegic auto-refraction, blood pressure, height and weight. A questionnaire was used to collect other relevant information. Univariable and multivariable analysis were performed to determine the associations of IOP. A total of 2760 7-year-old children (95.4%) and 2198 12-year-old children (97.0%) were included. The mean IOP was 13.5±3.1 mmHg in the younger cohort and 15.8±3.5 mmHg in older children (P<0.0001). On multivariable analysis, higher IOP in the younger cohort was associated with female gender (standardized regression coefficient [SRC], 0.11, P<0.0001), increasing central corneal thickness (SRC, 0.39, P<0.0001), myopia (SRC, 0.05, P = 0.03), deep anterior chamber (SRC, 0.07, P<0.01), smaller waist (SRC, 0.07, P<0.01) and increasing mean arterial pressure (SRC, 0.13, P<0.0001). In the older cohort, higher IOP was again associated with female gender (SRC, 0.16, P<0.0001), increasing central corneal thickness (SRC, 0.43, P<0.0001), deep anterior chamber (SRC, 0.09, P<0.01), higher body mass index (SRC, 0.07, P = 0.04) and with increasing mean arterial pressure (SRC, 0.09, P = 0.01), age at which reading commenced (SRC, 0.10, P<0.01) and birth method (SRC, 0.09, P = 0.01), but not with myopia (SRC, 0.09, P = 0.20). In Chinese children, higher IOP was associated with female gender, older age, thicker central cornea, deeper anterior chamber and higher mean arterial pressure. Higher body mass index, younger age at commencement of reading and being born of a caesarean section was also associated with higher IOP in adolescence.

The influence of spontaneous activity on stimulus processing in primary visual cortex.

PubMed

Schölvinck, M L; Friston, K J; Rees, G

2012-02-01

Spontaneous activity in the resting human brain has been studied extensively; however, how such activity affects the local processing of a sensory stimulus is relatively unknown. Here, we examined the impact of spontaneous activity in primary visual cortex on neuronal and behavioural responses to a simple visual stimulus, using functional MRI. Stimulus-evoked responses remained essentially unchanged by spontaneous fluctuations, combining with them in a largely linear fashion (i.e., with little evidence for an interaction). However, interactions between spontaneous fluctuations and stimulus-evoked responses were evident behaviourally; high levels of spontaneous activity tended to be associated with increased stimulus detection at perceptual threshold. Our results extend those found in studies of spontaneous fluctuations in motor cortex and higher order visual areas, and suggest a fundamental role for spontaneous activity in stimulus processing. Copyright © 2011. Published by Elsevier Inc.

Short-range order clustering in BCC Fe-Mn alloys induced by severe plastic deformation

NASA Astrophysics Data System (ADS)

Shabashov, V. A.; Kozlov, K. A.; Sagaradze, V. V.; Nikolaev, A. L.; Lyashkov, K. A.; Semyonkin, V. A.; Voronin, V. I.

2018-03-01

The effect of severe plastic deformation, namely, high-pressure torsion (HPT) at different temperatures and ball milling (BM) at different time intervals, has been investigated by means of Mössbauer spectroscopy in Fe100-xMnx (x = 4.1, 6.8, 9) alloys. Deformation affects the short-range clustering (SRC) in BCC lattice. Two processes occur: destruction of SRC by moving dislocations and enhancement of the SRC by migration of non-equilibrium defects. Destruction of SRC prevails during HPT at 80-293 K; whereas enhancement of SRC dominates at 473-573 K. BM starts enhancing the SRC formation at as low as 293 K due to local heating at impacts. The efficiency of HPT in terms of enhancing SRC increases with increasing temperature. The authors suppose that at low temperatures, a significant fraction of vacancies are excluded from enhancing SRC because of formation of mobile bi- and tri-vacancies having low efficiency of enhancing SRC as compared to that of mono vacancies. Milling of BCC Fe100-xMnx alloys stabilises the BCC phase with respect to α → γ transition at subsequent isothermal annealing because of a high degree of work hardening and formation of composition inhomogeneity.

Effect of wheat flour characteristics on sponge cake quality.

PubMed

Moiraghi, Malena; de la Hera, Esther; Pérez, Gabriela T; Gómez, Manuel

2013-02-01

To select the flour parameters that relate strongly to cake-making performance, in this study the relationship between sponge cake quality, solvent retention capacity (SRC) profile and flour physicochemical characteristics was investigated using 38 soft wheat samples of different origins. Particle size average, protein, damaged starch, water-soluble pentosans, total pentosans, SRC and pasting properties were analysed. Sponge cake volume and crumb texture were measured to evaluate cake quality. Cluster analysis was applied to assess differences in flour quality parameters among wheat lines based on the SRC profile. Cluster 1 showed significantly higher sponge cake volume and crumb softness, finer particle size and lower SRC sucrose, SRC carbonate, SRC water, damaged starch and protein content. Particle size, damaged starch, protein, thickening capacity and SRC parameters correlated negatively with sponge cake volume, while total pentosans and pasting temperature showed the opposite effect. The negative correlations between cake volume and SRC parameters along with the cluster analysis results indicated that flours with smaller particle size, lower absorption capacity and higher pasting temperature had better cake-making performance. Some simple analyses, such as SRC, particle size distribution and pasting properties, may help to choose flours suitable for cake making. Copyright © 2012 Society of Chemical Industry.

Roles of octopaminergic and dopaminergic neurons in appetitive and aversive memory recall in an insect.

PubMed

Mizunami, Makoto; Unoki, Sae; Mori, Yasuhiro; Hirashima, Daisuke; Hatano, Ai; Matsumoto, Yukihisa

2009-08-04

In insect classical conditioning, octopamine (the invertebrate counterpart of noradrenaline) or dopamine has been suggested to mediate reinforcing properties of appetitive or aversive unconditioned stimulus, respectively. However, the roles of octopaminergic and dopaminergic neurons in memory recall have remained unclear. We studied the roles of octopaminergic and dopaminergic neurons in appetitive and aversive memory recall in olfactory and visual conditioning in crickets. We found that pharmacological blockade of octopamine and dopamine receptors impaired aversive memory recall and appetitive memory recall, respectively, thereby suggesting that activation of octopaminergic and dopaminergic neurons and the resulting release of octopamine and dopamine are needed for appetitive and aversive memory recall, respectively. On the basis of this finding, we propose a new model in which it is assumed that two types of synaptic connections are formed by conditioning and are activated during memory recall, one type being connections from neurons representing conditioned stimulus to neurons inducing conditioned response and the other being connections from neurons representing conditioned stimulus to octopaminergic or dopaminergic neurons representing appetitive or aversive unconditioned stimulus, respectively. The former is called 'stimulus-response connection' and the latter is called 'stimulus-stimulus connection' by theorists studying classical conditioning in higher vertebrates. Our model predicts that pharmacological blockade of octopamine or dopamine receptors during the first stage of second-order conditioning does not impair second-order conditioning, because it impairs the formation of the stimulus-response connection but not the stimulus-stimulus connection. The results of our study with a cross-modal second-order conditioning were in full accordance with this prediction. We suggest that insect classical conditioning involves the formation of two kinds of memory traces, which match to stimulus-stimulus connection and stimulus-response connection. This is the first study to suggest that classical conditioning in insects involves, as does classical conditioning in higher vertebrates, the formation of stimulus-stimulus connection and its activation for memory recall, which are often called cognitive processes.

Signaling added response-independent reinforcement to assess Pavlovian processes in resistance to change and relapse.

PubMed

Podlesnik, Christopher A; Fleet, James D

2014-09-01

Behavioral momentum theory asserts Pavlovian stimulus-reinforcer relations govern the persistence of operant behavior. Specifically, resistance to conditions of disruption (e.g., extinction, satiation) reflects the relation between discriminative stimuli and the prevailing reinforcement conditions. The present study assessed whether Pavlovian stimulus-reinforcer relations govern resistance to disruption in pigeons by arranging both response-dependent and -independent food reinforcers in two components of a multiple schedule. In one component, discrete-stimulus changes preceded response-independent reinforcers, paralleling methods that reduce Pavlovian conditioned responding to contextual stimuli. Compared to the control component with no added stimuli preceding response-independent reinforcement, response rates increased as discrete-stimulus duration increased (0, 5, 10, and 15 s) across conditions. Although resistance to extinction decreased as stimulus duration increased in the component with the added discrete stimulus, further tests revealed no effect of discrete stimuli, including other disrupters (presession food, intercomponent food, modified extinction) and reinstatement designed to control for generalization decrement. These findings call into question a straightforward conception that the stimulus-reinforcer relations governing resistance to disruption reflect the same processes as Pavlovian conditioning, as asserted by behavioral momentum theory. © Society for the Experimental Analysis of Behavior.

Src- and Fyn-dependent apical membrane trafficking events control endothelial lumen formation during vascular tube morphogenesis.

PubMed

Kim, Dae Joong; Norden, Pieter R; Salvador, Jocelynda; Barry, David M; Bowers, Stephanie L K; Cleaver, Ondine; Davis, George E

2017-01-01

Here we examine the question of how endothelial cells (ECs) develop their apical membrane surface domain during lumen and tube formation. We demonstrate marked apical membrane targeting of activated Src kinases to this apical domain during early and late stages of this process. Immunostaining for phosphotyrosine or phospho-Src reveals apical membrane staining in intracellular vacuoles initially. This is then followed by vacuole to vacuole fusion events to generate an apical luminal membrane, which is similarly decorated with activated phospho-Src kinases. Functional blockade of Src kinases completely blocks EC lumen and tube formation, whether this occurs during vasculogenic tube assembly or angiogenic sprouting events. Multiple Src kinases participate in this apical membrane formation process and siRNA suppression of Src, Fyn and Yes, but not Lyn, blocks EC lumen formation. We also demonstrate strong apical targeting of Src-GFP and Fyn-GFP fusion proteins and increasing their expression enhances lumen formation. Finally, we show that Src- and Fyn-associated vacuoles track and fuse along a subapically polarized microtubule cytoskeleton, which is highly acetylated. These vacuoles generate the apical luminal membrane in a stereotypically polarized, perinuclear position. Overall, our study identifies a critical role for Src kinases in creating and decorating the EC apical membrane surface during early and late stages of lumen and tube formation, a central event in the molecular control of vascular morphogenesis.

Association of spiritual/religious coping with depressive symptoms in high- and low-risk pregnant women.

PubMed

Vitorino, Luciano M; Chiaradia, Raíssa; Low, Gail; Cruz, Jonas Preposi; Pargament, Kenneth I; Lucchetti, Alessandra L G; Lucchetti, Giancarlo

2018-02-01

To investigate the role of spiritual/religious coping (SRC) on depressive symptoms in high- and low-risk pregnant women. Spiritual/religious coping is associated with physical and mental health outcomes. However, only few studies investigated the role of these strategies during pregnancy and whether low- and high-risk pregnant women have different coping mechanisms. This study is a cross-sectional comparative study. This study included a total of 160 pregnant women, 80 with low-risk pregnancy and 80 with high-risk pregnancy. The Beck Depression Inventory, the brief SRC scale and a structured questionnaire on sociodemographic and obstetric aspects were used. General linear model regression analysis was used to identify the factors associated with positive and negative SRC strategies in both groups of pregnant women. Positive SRC use was high, whereas negative SRC use was low in both groups. Although we found no difference in SRC strategies between the two groups, negative SRC was associated with depression in women with high-risk pregnancy, but not in those with low-risk pregnancy. Furthermore, positive SRC was not associated with depressive symptoms in both groups. Results showed that only the negative SRC strategies of Brazilian women with high-risk pregnancies were associated with worsened mental health outcomes. Healthcare professionals, obstetricians and nurse midwives should focus on the use of negative SRC strategies in their pregnant patients. © 2017 John Wiley & Sons Ltd.

The effect of stimulus strength on the speed and accuracy of a perceptual decision.

PubMed

Palmer, John; Huk, Alexander C; Shadlen, Michael N

2005-05-02

Both the speed and the accuracy of a perceptual judgment depend on the strength of the sensory stimulation. When stimulus strength is high, accuracy is high and response time is fast; when stimulus strength is low, accuracy is low and response time is slow. Although the psychometric function is well established as a tool for analyzing the relationship between accuracy and stimulus strength, the corresponding chronometric function for the relationship between response time and stimulus strength has not received as much consideration. In this article, we describe a theory of perceptual decision making based on a diffusion model. In it, a decision is based on the additive accumulation of sensory evidence over time to a bound. Combined with simple scaling assumptions, the proportional-rate and power-rate diffusion models predict simple analytic expressions for both the chronometric and psychometric functions. In a series of psychophysical experiments, we show that this theory accounts for response time and accuracy as a function of both stimulus strength and speed-accuracy instructions. In particular, the results demonstrate a close coupling between response time and accuracy. The theory is also shown to subsume the predictions of Piéron's Law, a power function dependence of response time on stimulus strength. The theory's analytic chronometric function allows one to extend theories of accuracy to response time.

Identification of a functional interaction between Kv4.3 channels and c-Src tyrosine kinase.

PubMed

Gomes, Pedro; Saito, Tomoaki; Del Corsso, Cris; Alioua, Abderrahmane; Eghbali, Mansoureh; Toro, Ligia; Stefani, Enrico

2008-10-01

Voltage-gated K(+) (Kv) channels are key determinants of cardiac and neuronal excitability. A substantial body of evidence has accumulated in support of a role for Src family tyrosine kinases in the regulation of Kv channels. In this study, we examined the possibility that c-Src tyrosine kinase participates in the modulation of the transient voltage-dependent K(+) channel Kv4.3. Supporting a mechanistic link between Kv4.3 and c-Src, confocal microscopy analysis of HEK293 cells stably transfected with Kv4.3 showed high degree of co-localization of the two proteins at the plasma membrane. Our results further demonstrate an association between Kv4.3 and c-Src by co-immunoprecipitation and GST pull-down assays, this interaction being mediated by the SH2 and SH3 domains of c-Src. Furthermore, we show that Kv4.3 is tyrosine phosphorylated under basal conditions. The functional relevance of the observed interaction between Kv4.3 and c-Src was established in patch-clamp experiments, where application of the Src inhibitor PP2 caused a decrease in Kv4.3 peak current amplitude, but not the inactive structural analogue PP3. Conversely, intracellular application of recombinant c-Src kinase or the protein tyrosine phosphatase inhibitor bpV(phen) increased Kv4.3 peak current amplitude. In conclusion, our findings provide evidence that c-Src-induced Kv4.3 channel activation involves their association in a macromolecular complex and suggest a role for c-Src-Kv4.3 pathway in regulating cardiac and neuronal excitability.

Global Impact of Oncogenic Src on a Phosphotyrosine Proteome

PubMed Central

Luo, Weifeng; Slebos, Robbert J.; Hill, Salisha; Li, Ming; Brábek, Jan; Amanchy, Ramars; Chaerkady, Raghothama; Pandey, Akhilesh; Ham, Amy-Joan L.; Hanks, Steven K.

2008-01-01

Elevated activity of Src, the first characterized protein-tyrosine kinase, is associated with progression of many human cancers, and Src has attracted interest as a therapeutic target. Src is known to act in various receptor signaling systems to impact cell behavior, yet it remains likely that the spectrum of Src protein substrates relevant to cancer is incompletely understood. To better understand the cellular impact of deregulated Src kinase activity, we extensively applied a mass spectrometry shotgun phosphotyrosine (pTyr) proteomics strategy to obtain global pTyr profiles of Src-transformed mouse fibroblasts as well as their nontransformed counterparts. A total of 867 peptides representing 563 distinct pTyr sites on 374 different proteins were identified from the Src-transformed cells, while 514 peptides representing 275 pTyr sites on 167 proteins were identified from nontransformed cells. Distinct characteristics of the two profiles were revealed by spectral counting, indicative of pTyr site relative abundance, and by complementary quantitative analysis using stable isotope labeling with amino acids in cell culture (SILAC). While both pTyr profiles are replete with sites on signaling and adhesion/cytoskeletal regulatory proteins, the Src-transformed profile is more diverse with enrichment in sites on metabolic enzymes and RNA and protein synthesis and processing machinery. Forty-three pTyr sites (32 proteins) are predicted as major biologically relevant Src targets on the basis of frequent identification in both cell populations. This select group, of particular interest as diagnostic biomarkers, includes well-established Src sites on signaling/adhesion/cytoskeletal proteins, but also uncharacterized sites of potential relevance to the transformed cell phenotype. PMID:18563927

Control of preference in children by conditioned positive reinforcement.

PubMed

Favell, J E; Favell, J E

1972-07-01

A preference measure was employed with children to evaluate the conditioned positive reinforcing function of a stimulus that preceded reinforcement. A match-to-sample procedure was arranged in which subjects could respond to either the form or color dimension of a compound sample stimulus. Intermittent token reinforcement was provided equally for color and form matches. Two stimuli were employed (Stimulus A and Stimulus B), each consisting of a distinctive tone and colored light. One of these stimuli (the paired stimulus) preceded each token delivery, and the other did not (nonpaired stimulus). The paired stimulus was dependent upon each response to one match dimension, and the nonpaired stimulus followed each response to the other dimension. Three of the five subjects responded primarily to the dimension that was followed by the paired stimulus. This effect was obtained regardless of which stimulus (A or B) was paired and on which match dimension (color or form) the paired stimulus was dependent. These results were unaltered by discontinuing the nonpaired stimulus. The other two subjects demonstrated consistent preferences for the form dimension and Stimulus A, respectively.

The Relationship between Stimulus and Response Prompts under Two Types of Programmed Presentations.

ERIC Educational Resources Information Center

Young, Jon I.; And Others

Prompts in concept classification normally occur on the stimulus, while in memorization tasks prompts customarily are given on the response. Opposite results have been obtained for these two tasks with excessive prompting. This study used English-Russian word pairs to compare stimulus prompts (underlining the English word) with response prompts in…

Incongruent Abstract Stimulus-Response Bindings Result in Response Interference: fMRI and EEG Evidence from Visual Object Classification Priming

ERIC Educational Resources Information Center

Horner, Aidan J.; Henson, Richard N.

2012-01-01

Stimulus repetition often leads to facilitated processing, resulting in neural decreases (repetition suppression) and faster RTs (repetition priming). Such repetition-related effects have been attributed to the facilitation of repeated cognitive processes and/or the retrieval of previously encoded stimulus-response (S-R) bindings. Although…

Learning to fear a second-order stimulus following vicarious learning.

PubMed

Reynolds, Gemma; Field, Andy P; Askew, Chris

2017-04-01

Vicarious fear learning refers to the acquisition of fear via observation of the fearful responses of others. The present study aims to extend current knowledge by exploring whether second-order vicarious fear learning can be demonstrated in children. That is, whether vicariously learnt fear responses for one stimulus can be elicited in a second stimulus associated with that initial stimulus. Results demonstrated that children's (5-11 years) fear responses for marsupials and caterpillars increased when they were seen with fearful faces compared to no faces. Additionally, the results indicated a second-order effect in which fear-related learning occurred for other animals seen together with the fear-paired animal, even though the animals were never observed with fearful faces themselves. Overall, the findings indicate that for children in this age group vicariously learnt fear-related responses for one stimulus can subsequently be observed for a second stimulus without it being experienced in a fear-related vicarious learning event. These findings may help to explain why some individuals do not recall involvement of a traumatic learning episode in the development of their fear of a specific stimulus.

Improved low-cost, MR-compatible olfactometer to deliver tobacco smoke odor

PubMed Central

Lowen, Steven B.; Farmer, Stacey L.; Lukas, Scott E.

2016-01-01

We describe a low-cost, MRI-compatible olfactometer that delivers fresh cigarette smoke odor, a challenging odorant to present, as well as other odorants. This new olfactometer retains all of the advantages of an earlier design that was capable of only delivering volatile odors (Lowen & Lukas, 2006). The new system incorporates a novel switching mechanism that allows it to deliver fresh smoke generated from a burning cigarette during a stimulus presentation paradigm that might be employed in a cue-reactivity experiment. An evaluation study established that the olfactometer reliably delivered smoke to the participants and that tobacco smoke was discriminated from other odorants; there were no adverse reactions to the device. PMID:26896241

Significance of ERa and c-Src Interaction in the Progression of Hormone Independent Breast Cancer

DTIC Science & Technology

2005-12-01

defects in estrogen signaling [1]. Because of global defects in estrogen signaling observed in these c-Src deficient mice, we have recently generated...1998). Interestingly, the region of the kinase domain of ErbB-2 that correlates with c-Src association, referred to as TK2 (Segatto et al., 1991...ductive organs that are dependent on ERa in c-Src- deficient mice. We show that the loss of the c-Src tyrosine kinase correlates with defects in ductal

Simultaneous recording of multifocal VEP responses to short-wavelength and achromatic stimuli

PubMed Central

Wang, Min; Hood, Donald C.

2010-01-01

A paradigm is introduced that allows for simultaneous recording of the pattern-onset multifocal visual evoked potentials (mfVEP) to both short-wavelength (SW) and achromatic (A) stimuli. There were 5 sets of stimulus conditions, each of which is defined by two semi-concurrently presented stimuli, A64/SW (a 64% contrast achromatic stimulus and a short-wavelength stimulus), A64/A8 (64% achromatic/8% achromatic), A0/A8 (0% (gray) achromatic/8% achromatic), A64/A0 and A0/SW. When paired with A64 as part of A64/SW, the SW stimulus yielded mfVEP responses (SWmfVEP) with diminished amplitude in the fovea, consistent with the known sensitivity of the S-cone system. In addition, when A8, which is approximately equal to the L and M cone contribution of the SW stimulus, was recorded alone, the response to A8 was small, but significantly larger than noise. However, when A8 was paired with A64, the response to A8 was reduced to close to noise level, suggesting that the LM cone contribution of the SWmfVEP can be suppressed by A64. When A64 was recorded alone, the response to A64 was about 32% larger than the mfVEP for A64 when paired with the SW. Likewise, the presence of A64 stimulus also reduces the response of SWmfVEP by 35%. Finally, an intense narrow-band yellow background prolonged the latency of SW response for the A0/SW stimulus but not the latency of SW response for the A64/SW stimulus. These results indicate that it is possible to simultaneously record an SWmfVEP with little LM cone contribution along with an achromatic mfVEP. PMID:20499134

RULES OF COMPETITIVE STIMULUS SELECTION IN A CHOLINERGIC ISTHMIC NUCLEUS OF THE OWL MIDBRAIN

PubMed Central

Asadollahi, Ali; Mysore, Shreesh P.; Knudsen, Eric I.

2011-01-01

In a natural scene, multiple stimuli compete for the control of gaze direction and attention. The nucleus isthmi pars parvocellularis (Ipc) is a cholinergic, midbrain nucleus that is reciprocally interconnected to the optic tectum, a structure known to be involved in the control of gaze and attention. Previous research has shown that the responses of many Ipc units to a visual stimulus presented inside the classical receptive field (RF) can be powerfully inhibited when the strength of a distant, competing stimulus becomes the stronger stimulus. This study investigated further the nature of competitive interactions in the Ipc of owls by employing two complementary protocols: in the first protocol, we measured the effects of a distant stimulus on responses to an RF stimulus located at different positions inside the RF; in the second protocol, we measured the effects of a distant stimulus on responses to RF stimuli of different strengths. The first protocol demonstrated that the effect of a competing stimulus is purely divisive: the competitor caused a proportional reduction in responses to the RF stimulus that did not alter either the location or sharpness of spatial tuning. The second protocol demonstrated that, for most units, the strength of this divisive inhibition is regulated powerfully by the relative strengths of the competing stimuli: inhibition was strong when the competitor was the stronger stimulus and weak when the competitor was the weaker stimulus. The data indicate that competitive interactions in the Ipc depend on feedback and a globally divisive inhibitory network. PMID:21508234

Tyrosine Phosphorylation of the Human Serotonin Transporter: A Role in the Transporter Stability and Function

PubMed Central

Annamalai, Balasubramaniam; Mannangatti, Padmanabhan; Arapulisamy, Obulakshmi; Shippenberg, Toni S.; Jayanthi, Lankupalle D.

2012-01-01

The serotonin (5-HT) transporter (SERT) regulates serotoninergic neurotransmission by clearing 5-HT released into the synaptic space. Phosphorylation of SERT on serine and threonine mediates SERT regulation. Whether tyrosine phosphorylation regulates SERT is unknown. Here, we tested the hypothesis that tyrosine-phosphorylation of SERT regulates 5-HT transport. In support of this, alkali-resistant 32P-labeled SERT was found in rat platelets, and Src-tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4,d]pyrimidine (PP2) decreased platelet SERT function and expression. In human placental trophoblast cells expressing SERT, PP2 reduced transporter function, expression, and stability. Although siRNA silencing of Src expression decreased SERT function and expression, coexpression of Src resulted in PP2-sensitive increases in SERT function and expression. PP2 treatment markedly decreased SERT protein stability. Compared with WT-SERT, SERT tyrosine mutants Y47F and Y142F exhibited reduced 5-HT transport despite their higher total and cell surface expression levels. Moreover, Src-coexpression increased total and cell surface expression of Y47F and Y142F SERT mutants without affecting their 5-HT transport capacity. It is noteworthy that Y47F and Y142F mutants exhibited higher protein stability compared with WT-SERT. However, similar to WT-SERT, PP2 treatment decreased the stability of Y47F and Y142F mutants. Furthermore, compared with WT-SERT, Y47F and Y142F mutants exhibited lower basal tyrosine phosphorylation and no further enhancement of tyrosine phosphorylation in response to Src coexpression. These results provide the first evidence that SERT tyrosine phosphorylation supports transporter protein stability and 5HT transport. PMID:21992875

Endoplasmic reticulum stress (ER-stress) by 2-deoxy-D-glucose (2DG) reduces cyclooxygenase-2 (COX-2) expression and N-glycosylation and induces a loss of COX-2 activity via a Src kinase-dependent pathway in rabbit articular chondrocytes.

PubMed

Yu, Seon-Mi; Kim, Song-Ja

2010-11-30

Endoplasmic reticulum (ER) stress regulates a wide range of cellular responses including apoptosis, proliferation, inflammation, and differentiation in mammalian cells. In this study, we observed the role of 2-deoxy-D-glucose (2DG) on inflammation of chondrocytes. 2DG is well known as an inducer of ER stress, via inhibition of glycolysis and glycosylation. Treatment of 2DG in chondrocytes considerably induced ER stress in a dose- and time-dependent manner, which was demonstrated by a reduction of glucose regulated protein of 94 kDa (grp94), an ER stress-inducible protein, as determined by a Western blot analysis. In addition, induction of ER stress by 2DG led to the expression of COX-2 protein with an apparent molecular mass of 66-70kDa as compared with the normally expressed 72-74 kDa protein. The suppression of ER stress with salubrinal (Salub), a selective inhibitor of eif2-alpha dephosphorylation, successfully prevented grp94 induction and efficiently recovered 2DG- modified COX-2 molecular mass and COX-2 activity might be associated with COX-2 N-glycosylation. Also, treatment of 2DG increased phosphorylation of Src in chondrocytes. The inhibition of the Src signaling pathway with PP2 (Src tyrosine kinase inhibitor) suppressed grp94 expression and restored COX-2 expression, N-glycosylation, and PGE2 production, as determined by a Western blot analysis and PGE2 assay. Taken together, our results indicate that the ER stress induced by 2DG results in a decrease of the transcription level, the molecular mass, and the activity of COX-2 in rabbit articular chondrocytes via a Src kinase-dependent pathway.

EG-1 interacts with c-Src and activates its signaling pathway.

PubMed

Lu, Ming; Zhang, Liping; Sartippour, Maryam R; Norris, Andrew J; Brooks, Mai N

2006-10-01

EG-1 is significantly elevated in breast, colorectal, and prostate cancers. Overexpression of EG-1 stimulates cellular proliferation, and targeted inhibition blocks mouse xenograft tumor growth. To further clarify the function of EG-1, we investigated its role in c-Src activation. We observed that EG-1 overexpression results in activation of c-Src, but found no evidence that EG-1 is a direct Src substrate. EG-1 also binds to other members of the Src family. Furthermore, EG-1 shows interaction with multiple other SH3- and WW-containing molecules involved in various signaling pathways. These observations suggest that EG-1 may be involved in signaling pathways including c-Src activation.

Model-based decoding, information estimation, and change-point detection techniques for multineuron spike trains.

PubMed

Pillow, Jonathan W; Ahmadian, Yashar; Paninski, Liam

2011-01-01

One of the central problems in systems neuroscience is to understand how neural spike trains convey sensory information. Decoding methods, which provide an explicit means for reading out the information contained in neural spike responses, offer a powerful set of tools for studying the neural coding problem. Here we develop several decoding methods based on point-process neural encoding models, or forward models that predict spike responses to stimuli. These models have concave log-likelihood functions, which allow efficient maximum-likelihood model fitting and stimulus decoding. We present several applications of the encoding model framework to the problem of decoding stimulus information from population spike responses: (1) a tractable algorithm for computing the maximum a posteriori (MAP) estimate of the stimulus, the most probable stimulus to have generated an observed single- or multiple-neuron spike train response, given some prior distribution over the stimulus; (2) a gaussian approximation to the posterior stimulus distribution that can be used to quantify the fidelity with which various stimulus features are encoded; (3) an efficient method for estimating the mutual information between the stimulus and the spike trains emitted by a neural population; and (4) a framework for the detection of change-point times (the time at which the stimulus undergoes a change in mean or variance) by marginalizing over the posterior stimulus distribution. We provide several examples illustrating the performance of these estimators with simulated and real neural data.

Overlearned responses hinder S-R binding.

PubMed

Moeller, Birte; Frings, Christian

2017-01-01

Two mechanisms that are important for human action control are the integration of individual action plans (see Hommel, Müsseler, Aschersleben, & Prinz, 2001) and the automatization of overlearned actions to familiar stimuli (see Logan, 1988). In the present study, we analyzed the influence of automatization on action plan integration. Integration with pronunciation responses were compared for response incompatible word and nonword stimuli. Stimulus-response binding effects were observed for nonwords. In contrast, words that automatically triggered an overlearned pronunciation response were not integrated with pronunciation of a different word. That is, automatized response retrieval hindered binding effects regarding the retrieving stimulus and a new response. The results are a first indication of the way that binding and learning processes interact, and might also be a first step to understanding the more complex interdependency of the processes responsible for stimulus-response binding in action control and stimulus-response associations in learning research. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

76 FR 3653 - Alaska Region's Subsistence Resource Commission (SRC) Program; Public Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-20

... subsistence management issues. The NPS SRC program is authorized under Title VIII, Section 808 of the Alaska...: 1. Call to order. 2. SRC Roll Call and Confirmation of Quorum. 3. Welcome and Introductions. 4.... c. Resource Management Program Update. 14. Public and other Agency Comments. 15. SRC Work Session...

OH REACTION KINETICS OF GAS-PHASE A- AND G-HEXACHLOROCYCLOHEXANE AND HEXACHLOROBENZENE. (R825377)

EPA Science Inventory

Rate constants for the gas-phase reactions of the hydroxyl
radical (OH) with - and -hexachlorocyclohexane (-
and 78 FR 51207 - Kobuk Valley National Park Subsistence Resource Commission (SRC) and the Denali National Park SRC...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-20

... DEPARTMENT OF THE INTERIOR National Park Service [NPS-AKR-DENA-KOVA-DTS-13608; PPAKAKROR4; PPMPRLE1Y.LS0000] Kobuk Valley National Park Subsistence Resource Commission (SRC) and the Denali National Park SRC; Meetings AGENCY: National Park Service, Interior. ACTION: Meeting notice. SUMMARY: As...

76 FR 57763 - Alaska Region's Subsistence Resource Commission (SRC) Program

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-16

...) program. SUMMARY: The Gates of the Arctic National Park SRC will meet to develop and continue work on NPS... changed based on inclement weather or exceptional circumstances. Gates of the Arctic National Park SRC Meeting Dates and Location: The Gates of the Arctic National Park SRC will meet at Sophie Station Hotel...

Dynamic activation of Src induced by low-power laser irradiation in living cells mediated by reactive oxygen species

NASA Astrophysics Data System (ADS)

Zhang, Juntao; Gao, Xuejuan; Xing, Da; Liu, Lei

2007-11-01

Low-power laser irradiation (LPLI) leads to photochemical reaction and then activates intracellular several signaling pathway. Reactive oxygen species (ROS) are considered to be the primary messengers produced by LPLI. Here, we studied the signaling pathway mediated by ROS upon the stimulation of LPLI. Src tyrosine kinases are well-known targets of ROS and can be activated by oxidative events. Using a Src reporter based on fluorescence resonance energy transfer (FRET) technique, we visualized the dynamic Src activation in Hela cells immediately after LPLI. Moreover, Src activity was enhanced by increasing the duration of LPLI. In addition, our results suggested that ROS were key mediators of Src activation, as ROS scavenger, vitamin C decreased and exogenous H IIO II increased the activity of Src. Meanwhile, Gö6983 loading did not block the effect of LPLI. CCK-8 experiments proved that cell vitality was prominently improved by LPLI with all the doses we applied in our experiments ranging from 3 to 25J/cm2. The results indicated that LPLI/ROS/Src pathway may be involved in the LPLI biostimulation effects.

A Discovery Strategy for Selective Inhibitors of c-Src in Complex with the Focal Adhesion Kinase SH3/SH2-binding Region.

PubMed

Moroco, Jamie A; Baumgartner, Matthew P; Rust, Heather L; Choi, Hwan Geun; Hur, Wooyoung; Gray, Nathanael S; Camacho, Carlos J; Smithgall, Thomas E

2015-08-01

The c-Src tyrosine kinase co-operates with the focal adhesion kinase to regulate cell adhesion and motility. Focal adhesion kinase engages the regulatory SH3 and SH2 domains of c-Src, resulting in localized kinase activation that contributes to tumor cell metastasis. Using assay conditions where c-Src kinase activity required binding to a tyrosine phosphopeptide based on the focal adhesion kinase SH3-SH2 docking sequence, we screened a kinase-biased library for selective inhibitors of the Src/focal adhesion kinase peptide complex versus c-Src alone. This approach identified an aminopyrimidinyl carbamate compound, WH-4-124-2, with nanomolar inhibitory potency and fivefold selectivity for c-Src when bound to the phospho-focal adhesion kinase peptide. Molecular docking studies indicate that WH-4-124-2 may preferentially inhibit the 'DFG-out' conformation of the kinase active site. These findings suggest that interaction of c-Src with focal adhesion kinase induces a unique kinase domain conformation amenable to selective inhibition. © 2014 John Wiley & Sons A/S.

Association of p60c-src with endosomal membranes in mammalian fibroblasts

PubMed Central

1992-01-01

We have examined the subcellular localization of p60c-src in mammalian fibroblasts. Analysis of indirect immunofluorescence by three- dimensional optical sectioning microscopy revealed a granular cytoplasmic staining that co-localized with the microtubule organizing center. Immunofluorescence experiments with antibodies against a number of membrane markers demonstrated a striking co-localization between p60c-src and the cation-dependent mannose-6-phosphate receptor (CI- MPR), a marker that identifies endosomes. Both p60c-src and the CI-MPR were found to cluster at the spindle poles throughout mitosis. In addition, treatment of interphase and mitotic cells with brefeldin A resulted in a clustering of p60c-src and CI-MPR at a peri-centriolar position. Biochemical fractionation of cellular membranes showed that a major proportion of p60c-src co-enriched with endocytic membranes. Treatment of membranes containing HRP to alter their apparent density also altered the density of p60c-src-containing membranes. Similar density shift experiments with total cellular membranes revealed that the majority of membrane-associated p60c-src in the cell is associated with endosomes, while very little is associated with plasma membranes. These results support a role for p60c-src in the regulation of endosomal membranes and protein trafficking. PMID:1378446

Identification of the SRC pyrimidine-binding protein (SPy) as hnRNP K: implications in the regulation of SRC1A transcription

PubMed Central

Ritchie, Shawn A.; Pasha, Mohammed K.; Batten, Danielle J. P.; Sharma, Rajendra K.; Olson, Douglas J. H.; Ross, Andrew R. S.; Bonham, Keith

2003-01-01

The human SRC gene encodes pp60c–src, a non-receptor tyrosine kinase involved in numerous signaling pathways. Activation or overexpression of c-Src has also been linked to a number of important human cancers. Transcription of the SRC gene is complex and regulated by two closely linked but highly dissimilar promoters, each associated with its own distinct non-coding exon. In many tissues SRC expression is regulated by the housekeeping-like SRC1A promoter. In addition to other regulatory elements, three substantial polypurine:polypyrimidine (TC) tracts within this promoter are required for full transcriptional activity. Previously, we described an unusual factor called SRC pyrimidine-binding protein (SPy) that could bind to two of these TC tracts in their double-stranded form, but was also capable of interacting with higher affinity to all three pyrimidine tracts in their single-stranded form. Mutations in the TC tracts, which abolished the ability of SPy to interact with its double-stranded DNA target, significantly reduced SRC1A promoter activity, especially in concert with mutations in critical Sp1 binding sites. Here we expand upon our characterization of this interesting factor and describe the purification of SPy from human SW620 colon cancer cells using a DNA affinity-based approach. Subsequent in-gel tryptic digestion of purified SPy followed by MALDI-TOF mass spectrometric analysis identified SPy as heterogeneous nuclear ribonucleoprotein K (hnRNP K), a known nucleic-acid binding protein implicated in various aspects of gene expression including transcription. These data provide new insights into the double- and single-stranded DNA-binding specificity, as well as functional properties of hnRNP K, and suggest that hnRNP K is a critical component of SRC1A transcriptional processes. PMID:12595559

Antiangiogenic and Antitumor Effects of Src Inhibition in Ovarian Carcinoma

PubMed Central

Han, Liz Y.; Landen, Charles N.; Trevino, Jose G.; Halder, Jyotsnabaran; Lin, Yvonne G.; Kamat, Aparna A.; Kim, Tae-Jin; Merritt, William M.; Coleman, Robert L.; Gershenson, David M.; Shakespeare, William C.; Wang, Yihan; Sundaramoorth, Raji; Metcalf, Chester A.; Dalgarno, David C.; Sawyer, Tomi K.; Gallick, Gary E.; Sood, Anil K.

2011-01-01

Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma. PMID:16951177

v-Src oncogene product increases sphingosine kinase 1 expression through mRNA stabilization: alteration of AU-rich element-binding proteins.

PubMed

Sobue, S; Murakami, M; Banno, Y; Ito, H; Kimura, A; Gao, S; Furuhata, A; Takagi, A; Kojima, T; Suzuki, M; Nozawa, Y; Murate, T

2008-10-09

Sphingosine kinase 1 (SPHK1) is overexpressed in solid tumors and leukemia. However, the mechanism of SPHK1 overexpression by oncogenes has not been defined. We found that v-Src-transformed NIH3T3 cells showed a high SPHK1 mRNA, SPHK1 protein and SPHK enzyme activity. siRNA of SPHK1 inhibited the growth of v-Src-NIH3T3, suggesting the involvement of SPHK1 in v-Src-induced oncogenesis. v-Src-NIH3T3 showed activations of protein kinase C-alpha, signal transducers and activators of transcription 3 and c-Jun NH(2)-terminal kinase. Their inhibition suppressed SPHK1 expression in v-Src-NIH3T3, whereas their overexpression increased SPHK1 mRNA in NIH3T3. Unexpectedly, the nuclear run-on assay and the promoter analysis using 5'-promoter region of mouse SPHK1 did not show any significant difference between mock- and v-Src-NIH3T3. Furthermore, the half-life of SPHK1 mRNA in mock-NIH3T3 was nearly 15 min, whereas that of v-Src-NIH3T3 was much longer. Examination of two AU-rich region-binding proteins, AUF1 and HuR, that regulate mRNA decay reciprocally, showed decreased total AUF1 protein associated with increased tyrosine-phosphorylated form and increased serine-phosphorylated HuR protein in v-Src-NIH3T3. Modulation of AUF1 and HuR by their overexpression or siRNA revealed that SPHK1 mRNA in v-Src- and mock-NIH3T3 was regulated reciprocally by these factors. Our results showed, for the first time, a novel mechanism of v-Src-induced SPHK1 overexpression.

Platelet-derived growth factor-dependent association of the GTPase-activating protein of Ras and Src.

PubMed Central

Schlesinger, T K; Demali, K A; Johnson, G L; Kazlauskas, A

1999-01-01

Here we report that the platelet-derived growth factor beta receptor (betaPDGFR) is not the only tyrosine kinase able to associate with the GTPase-activating protein of Ras (RasGAP). The interaction of non-betaPDGFR kinase(s) with RasGAP was dependent on stimulation with platelet-derived growth factor (PDGF) and seemed to require tyrosine phosphorylation of RasGAP. Because the tyrosine phosphorylation site of RasGAP is in a sequence context that is favoured by the Src homology 2 ('SH2') domain of Src family members, we tested the possibility that Src was the kinase that associated with RasGAP. Indeed, Src interacted with phosphorylated RasGAP fusion proteins; immunodepletion of Src markedly decreased the recovery of the RasGAP-associated kinase activity. Thus PDGF-dependent tyrosine phosphorylation of RasGAP results in the formation of a complex between RasGAP and Src. To begin to address the relevance of these observations, we focused on the consequences of the interaction of Src and RasGAP. We found that a receptor mutant that did not activate Src was unable to efficiently mediate the tyrosine phosphorylation of phospholipase Cgamma (PLCgamma). Taken together, these observations support the following hypothesis. When RasGAP is recruited to the betaPDGFR, it is phosphorylated and associates with Src. Once bound to RasGAP, Src is no longer able to promote the phosphorylation of PLCgamma. This hypothesis offers a mechanistic explanation for our previously published findings that the recruitment of RasGAP to the betaPDGFR attenuates the tyrosine phosphorylation of PLCgamma. Finally, these findings suggest a novel way in which RasGAP negatively regulates signal relay by the betaPDGFR. PMID:10567236

Regulation of Discrete Functional Responses by Syk and Src Family Tyrosine Kinases in Human Neutrophils

PubMed Central

Ear, Thornin; Tatsiy, Olga; Allard, Frédérick L.

2017-01-01

Neutrophils play a critical role in innate immunity and also influence adaptive immune responses. This occurs in good part through their production of inflammatory and immunomodulatory cytokines, in conjunction with their prolonged survival at inflamed foci. While a picture of the signaling machinery underlying these neutrophil responses is now emerging, much remains to be uncovered. In this study, we report that neutrophils constitutively express various Src family isoforms (STKs), as well as Syk, and that inhibition of these protein tyrosine kinases selectively hinders inflammatory cytokine generation by acting posttranscriptionally. Accordingly, STK or Syk inhibition decreases the phosphorylation of signaling intermediates (e.g., eIF-4E, S6K, and MNK1) involved in translational control. By contrast, delayed apoptosis appears to be independent of either STKs or Syk. Our data therefore significantly extend our understanding of which neutrophil responses are governed by STKs and Syk and pinpoint some signaling intermediates that are likely involved. In view of the foremost role of neutrophils in several chronic inflammatory conditions, our findings identify potential molecular targets that could be exploited for future therapeutic intervention. PMID:28512645

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction.

PubMed

Otero, Jesse E; Stevens, Jeff W; Malandra, Allison E; Fredericks, Douglas C; Odgren, Paul R; Buckwalter, Joseph A; Morcuende, Jose

2014-12-01

Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague-Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off-target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC-induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma-mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Hydrogen Sulfide Recruits Macrophage Migration by Integrin β1-Src-FAK/Pyk2-Rac Pathway in Myocardial Infarction

NASA Astrophysics Data System (ADS)

Miao, Lei; Xin, Xiaoming; Xin, Hong; Shen, Xiaoyan; Zhu, Yi-Zhun

2016-03-01

Myocardial infarction (MI) triggers an inflammatory reaction, in which macrophages are of key importance for tissue repairing. Infiltration and/or migration of macrophages into the infarct area early after MI is critical for infarct healing, vascularization, and cardiac function. Hydrogen sulfide (H2S) has been demonstrated to possess cardioprotective effects post MI and during the progress of cardiac remodeling. However, the specific molecular and cellular mechanisms involved in macrophage recruitment by H2S remain to be identified. In this study, the NaHS (exogenous sources of H2S) treatment exerted an increased infiltration of macrophages into the infarcted myocardium at early stage of MI cardiac tissues in both wild type (WT) and cystathionine-γ-lyase-knockout (CSE-KO) mice. And NaHS accelerated the migration of macrophage cells in vitro. While, the inhibitors not only significantly diminished the migratory ability in response to NaHS, but also blocked the activation of phospho-Src, -Pyk2, -FAK397, and -FAK925. Furthermore, NaHS induced the internalization of integrin β1 on macrophage surface, but, integrin β1 silencing inhibited macrophage migration and Src signaling activation. These results indicate that H2S may have the potential as an anti-infarct of MI by governing macrophage migration, which was achieved by accelerating internalization of integrin β1 and activating downstream Src-FAK/Pyk2-Rac pathway.

Part I---Evaluating Effects of Oligomer Formation on Cytochrome P450 2C9 Electron Transfer and Drug Metabolism, Part II---Utilizing Molecular Modeling Techniques to Study the Src-Interacting Proteins Actin Filament Associated Protein of 110 kDa (AFAP-110) and Cortactin

NASA Astrophysics Data System (ADS)

Jett, John Edward, Jr.

The dissertation has been divided into two parts to accurately reflect the two distinct areas of interest pursued during my matriculation in the School of Pharmacy at West Virginia University. In Part I, I discuss research probing the nature of electron transfer in the Cytochrome P450 family of proteins, a group of proteins well-known for their role in drug metabolism. In Part II, I focus on in silico and in vitro work developed in concert to probe protein structure and protein-protein interactions involved in actin filament reorganization and cellular motility. Part I. Cytochrome P450s (P450s) are an important class of enzymes known to metabolize a variety of endogenous and xenobiotic compounds. P450s are most commonly found in liver and intestinal endothelial cells and are responsible for the metabolism of approximately 75% of pharmaceutical drugs on the market. CYP2C9---one of the six major P450 isoforms---is responsible for ˜20% of drug metabolism. Elucidation of the factors that affect in vitro drug metabolism is crucial to the accurate prediction of in vivo drug metabolism kinetics. Currently, the two major techniques for studying in vitro drug metabolism are solution-based. However, it is known that the results of solution-based studies can vary from in vivo drug metabolism. One reason suggested to account for this variation is the state of P450 oligomer formation in solution compared to the in vivo environment, where P450s are membrane-bound. To understand the details of how oligomer formation affects in vitro drug metabolism, it is imperative that techniques be developed which will allow for the unequivocal control of oligomer formation without altering other experimental parameters. Our long term goal of this research is to develop methods to more accurately predict in vivo drug metabolism from in vitro data. This section of the dissertation will discuss the development of a platform consisting of a doped silicon surface containing a large array of gold nanopillars, the immobilization of CYP2C9 enzymes to those nanopillars, and the utilization of the array to perform conductive probe atomic force microscopy experiments examining the electron transfer process of CYP2C9 in the absence and presence of substrate molecules. Part II. The Src protein has been known to play a role in cancer cell progression for over 30 years. The function of a non-receptor tyrosine kinase such as Src is to relay extracellular signals through intracellular tyrosine phosphorylation. As a tyrosine kinase, Src and the cellular signaling pathways it is involved in play many functional roles in the cell, both in cellular proliferation and in cytoskeletal dynamics, cell adhesion, motility and invasion. Two of the many proteins comprising Src cellular signaling pathways are actin filament associated protein of 110 kDa (AFAP-110) and cortactin. AFAP-110 is a known activator of Src; one mechanism to abrogate the AFAP-110-induced activation of Src is to inhibit their colocalization within the cell. This colocalization is expected to occur when the pleckstrin homology (PH1 and PH2) domains of AFAP-110 are allowed to interact with membrane-bound phospholipids. Cortactin, on the other hand, is a cytosolic protein capable of being phosphorylated on various tyrosine residues, activating it and allowing it to interact with actin. The Src homology 2 (SH2) domain of Src has been shown to be capable of interacting with cortactin, an association which will be probed here. This section of the dissertation will discuss the use of molecular modeling techniques to develop structural models of the AFAP-110 PH1 and PH2 domains and use them to make predictions about how the protein interacts with phospholipids in the plasma membrane and how they might be stabilized to interact with other proteins. Structural models were designed using homology modeling methods, docking programs were used to predict key residues of AFAP-110 involved in binding to phospholipids and mutational analyses was used to test those predictions. This section will also discuss the use of molecular modeling techniques to explore protein-protein interactions between cortactin and Src. These include docking experiments and binding interaction analyses between Src and key areas of cortactin known to be involved in protein-protein interactions with Src. The data point to a cysteine-cysteine interaction between the two proteins, a result which is confirmed through in vitro experiments in collaboration with the lab of Dr. Scott Weed.

Topography of Responses in Conditional Discrimination Influences Formation of Equivalence Classes

ERIC Educational Resources Information Center

Kato, Olivia M.; de Rose, Julio C.; Faleiros, Pedro B.

2008-01-01

The effects of response topography on stimulus class formation were studied in two experiments. In Experiment 1, 32 college students were assigned to 2 response topographies and 2 stimulus sets, in a 2 x 2 design. Students selected stimuli by either moving a mouse to lace an arrow-shaped cursor on the stimulus or pressing a key corresponding to…

Influence of double stimulation on sound-localization behavior in barn owls.

PubMed

Kettler, Lutz; Wagner, Hermann

2014-12-01

Barn owls do not immediately approach a source after they hear a sound, but wait for a second sound before they strike. This represents a gain in striking behavior by avoiding responses to random incidents. However, the first stimulus is also expected to change the threshold for perceiving the subsequent second sound, thus possibly introducing some costs. We mimicked this situation in a behavioral double-stimulus paradigm utilizing saccadic head turns of owls. The first stimulus served as an adapter, was presented in frontal space, and did not elicit a head turn. The second stimulus, emitted from a peripheral source, elicited the head turn. The time interval between both stimuli was varied. Data obtained with double stimulation were compared with data collected with a single stimulus from the same positions as the second stimulus in the double-stimulus paradigm. Sound-localization performance was quantified by the response latency, accuracy, and precision of the head turns. Response latency was increased with double stimuli, while accuracy and precision were decreased. The effect depended on the inter-stimulus interval. These results suggest that waiting for a second stimulus may indeed impose costs on sound localization by adaptation and this reduces the gain obtained by waiting for a second stimulus.

Mechanical Tension Increases CCN2/CTGF Expression and Proliferation in Gingival Fibroblasts via a TGFβ-Dependent Mechanism

PubMed Central

Guo, Fen; Carter, David E.; Leask, Andrew

2011-01-01

Unlike skin, oral gingival do not scar in response to tissue injury. Fibroblasts, the cell type responsible for connective tissue repair and scarring, are exposed to mechanical tension during normal and pathological conditions including wound healing and fibrogenesis. Understanding how human gingival fibroblasts respond to mechanical tension is likely to yield valuable insights not only into gingival function but also into the molecular basis of scarless repair. CCN2/connective tissue growth factor is potently induced in fibroblasts during tissue repair and fibrogenesis. We subjected gingival fibroblasts to cyclical strain (up to 72 hours) using the Flexercell system and showed that CCN2 mRNA and protein was induced by strain. Strain caused the rapid activation of latent TGFβ, in a fashion that was reduced by blebbistatin and FAK/src inhibition, and the induction of endothelin (ET-1) mRNA and protein expression. Strain did not cause induction of α-smooth muscle actin or collagen type I mRNAs (proteins promoting scarring); but induced a cohort of pro-proliferative mRNAs and cell proliferation. Compared to dermal fibroblasts, gingival fibroblasts showed reduced ability to respond to TGFβ by inducing fibrogenic mRNAs; addition of ET-1 rescued this phenotype. Pharmacological inhibition of the TGFβ type I (ALK5) receptor, the endothelin A/B receptors and FAK/src significantly reduced the induction of CCN2 and pro-proliferative mRNAs and cell proliferation. Controlling TGFβ, ET-1 and FAK/src activity may be useful in controlling responses to mechanical strain in the gingiva and may be of value in controlling fibroproliferative conditions such as gingival hyperplasia; controlling ET-1 may be of benefit in controlling scarring in response to injury in the skin. PMID:21611193

Autonomic responses to tonic pain are more closely related to stimulus intensity than to pain intensity.

PubMed

Nickel, Moritz M; May, Elisabeth S; Tiemann, Laura; Postorino, Martina; Ta Dinh, Son; Ploner, Markus

2017-11-01

Pain serves the protection of the body by translating noxious stimulus information into a subjective percept and protective responses. Such protective responses rely on autonomic responses that allocate energy resources to protective functions. However, the precise relationship between objective stimulus intensity, subjective pain intensity, autonomic responses, and brain activity is not fully clear yet. Here, we addressed this question by continuously recording pain ratings, skin conductance, heart rate, and electroencephalography during tonic noxious heat stimulation of the hand in 39 healthy human subjects. The results confirmed that pain intensity dissociates from stimulus intensity during 10 minutes of noxious stimulation. Furthermore, skin conductance measures were significantly related to stimulus intensity but not to pain intensity. Correspondingly, skin conductance measures were significantly related to alpha and beta oscillations in contralateral sensorimotor cortex, which have been shown to encode stimulus intensity rather than pain intensity. No significant relationships were found between heart rate and stimulus intensity or pain intensity. The findings were consistent for stimulation of the left and the right hands. These results suggest that sympathetic autonomic responses to noxious stimuli in part directly result from nociceptive rather than from perceptual processes. Beyond, these observations support concepts of pain and emotions in which sensory, motor, and autonomic components are partially independent processes that together shape emotional and painful experiences.

State-dependent changes in cortical gain control as measured by auditory evoked responses to varying intensity stimuli.

PubMed

Phillips, Derrick J; Schei, Jennifer L; Meighan, Peter C; Rector, David M

2011-11-01

Auditory evoked potential (AEP) components correspond to sequential activation of brain structures within the auditory pathway and reveal neural activity during sensory processing. To investigate state-dependent modulation of stimulus intensity response profiles within different brain structures, we assessed AEP components across both stimulus intensity and state. We implanted adult female Sprague-Dawley rats (N = 6) with electrodes to measure EEG, EKG, and EMG. Intermittent auditory stimuli (6-12 s) varying from 50 to 75 dBa were delivered over a 24-h period. Data were parsed into 2-s epochs and scored for wake/sleep state. All AEP components increased in amplitude with increased stimulus intensity during wake. During quiet sleep, however, only the early latency response (ELR) showed this relationship, while the middle latency response (MLR) increased at the highest 75 dBa intensity, and the late latency response (LLR) showed no significant change across the stimulus intensities tested. During rapid eye movement sleep (REM), both ELR and LLR increased, similar to wake, but MLR was severely attenuated. Stimulation intensity and the corresponding AEP response profile were dependent on both brain structure and sleep state. Lower brain structures maintained stimulus intensity and neural response relationships during sleep. This relationship was not observed in the cortex, implying state-dependent modification of stimulus intensity coding. Since AEP amplitude is not modulated by stimulus intensity during sleep, differences between paired 75/50 dBa stimuli could be used to determine state better than individual intensities.

Response of Ambulatory Human Subjects to Artificial Gravity (Short Radius Centrifugation)

NASA Technical Reports Server (NTRS)

Paloski, William H.; Arya, Maneesh; Newby, Nathaniel; Tucker, Jon-Michael; Jarchow, Thomas; Young, Laurence

2006-01-01

Prolonged exposure to microgravity results in significant adaptive changes, including cardiovascular deconditioning, muscle atrophy, bone loss, and sensorimotor reorganization, that place individuals at risk for performing physical activities after return to a gravitational environment. Planned missions to Mars include unprecedented hypogravity exposures that would likely result in unacceptable risks to crews. Artificial gravity (AG) paradigms may offer multisystem protection from the untoward effects of adaptation to the microgravity of space or the hypogravity of planetary surfaces. While the most effective AG designs would employ a rotating spacecraft, perceived issues may preclude their use. The questions of whether and how intermittent AG produced by a short radius centrifuge (SRC) could be employed have therefore sprung to the forefront of operational research. In preparing for a series of intermittent AG trials in subjects deconditioned by bed rest, we have examined the responses of several healthy, ambulatory subjects to SRC exposures.

Statistical context shapes stimulus-specific adaptation in human auditory cortex

PubMed Central

Henry, Molly J.; Fromboluti, Elisa Kim; McAuley, J. Devin

2015-01-01

Stimulus-specific adaptation is the phenomenon whereby neural response magnitude decreases with repeated stimulation. Inconsistencies between recent nonhuman animal recordings and computational modeling suggest dynamic influences on stimulus-specific adaptation. The present human electroencephalography (EEG) study investigates the potential role of statistical context in dynamically modulating stimulus-specific adaptation by examining the auditory cortex-generated N1 and P2 components. As in previous studies of stimulus-specific adaptation, listeners were presented with oddball sequences in which the presentation of a repeated tone was infrequently interrupted by rare spectral changes taking on three different magnitudes. Critically, the statistical context varied with respect to the probability of small versus large spectral changes within oddball sequences (half of the time a small change was most probable; in the other half a large change was most probable). We observed larger N1 and P2 amplitudes (i.e., release from adaptation) for all spectral changes in the small-change compared with the large-change statistical context. The increase in response magnitude also held for responses to tones presented with high probability, indicating that statistical adaptation can overrule stimulus probability per se in its influence on neural responses. Computational modeling showed that the degree of coadaptation in auditory cortex changed depending on the statistical context, which in turn affected stimulus-specific adaptation. Thus the present data demonstrate that stimulus-specific adaptation in human auditory cortex critically depends on statistical context. Finally, the present results challenge the implicit assumption of stationarity of neural response magnitudes that governs the practice of isolating established deviant-detection responses such as the mismatch negativity. PMID:25652920

Alterations to multisensory and unisensory integration by stimulus competition

PubMed Central

Rowland, Benjamin A.; Stanford, Terrence R.; Stein, Barry E.

2011-01-01

In environments containing sensory events at competing locations, selecting a target for orienting requires prioritization of stimulus values. Although the superior colliculus (SC) is causally linked to the stimulus selection process, the manner in which SC multisensory integration operates in a competitive stimulus environment is unknown. Here we examined how the activity of visual-auditory SC neurons is affected by placement of a competing target in the opposite hemifield, a stimulus configuration that would, in principle, promote interhemispheric competition for access to downstream motor circuitry. Competitive interactions between the targets were evident in how they altered unisensory and multisensory responses of individual neurons. Responses elicited by a cross-modal stimulus (multisensory responses) proved to be substantially more resistant to competitor-induced depression than were unisensory responses (evoked by the component modality-specific stimuli). Similarly, when a cross-modal stimulus served as the competitor, it exerted considerably more depression than did its individual component stimuli, in some cases producing more depression than predicted by their linear sum. These findings suggest that multisensory integration can help resolve competition among multiple targets by enhancing orientation to the location of cross-modal events while simultaneously suppressing orientation to events at alternate locations. PMID:21957224

Alterations to multisensory and unisensory integration by stimulus competition.

PubMed

Pluta, Scott R; Rowland, Benjamin A; Stanford, Terrence R; Stein, Barry E

2011-12-01

In environments containing sensory events at competing locations, selecting a target for orienting requires prioritization of stimulus values. Although the superior colliculus (SC) is causally linked to the stimulus selection process, the manner in which SC multisensory integration operates in a competitive stimulus environment is unknown. Here we examined how the activity of visual-auditory SC neurons is affected by placement of a competing target in the opposite hemifield, a stimulus configuration that would, in principle, promote interhemispheric competition for access to downstream motor circuitry. Competitive interactions between the targets were evident in how they altered unisensory and multisensory responses of individual neurons. Responses elicited by a cross-modal stimulus (multisensory responses) proved to be substantially more resistant to competitor-induced depression than were unisensory responses (evoked by the component modality-specific stimuli). Similarly, when a cross-modal stimulus served as the competitor, it exerted considerably more depression than did its individual component stimuli, in some cases producing more depression than predicted by their linear sum. These findings suggest that multisensory integration can help resolve competition among multiple targets by enhancing orientation to the location of cross-modal events while simultaneously suppressing orientation to events at alternate locations.

Dynamic Alignment Models for Neural Coding

PubMed Central

Kollmorgen, Sepp; Hahnloser, Richard H. R.

2014-01-01

Recently, there have been remarkable advances in modeling the relationships between the sensory environment, neuronal responses, and behavior. However, most models cannot encompass variable stimulus-response relationships such as varying response latencies and state or context dependence of the neural code. Here, we consider response modeling as a dynamic alignment problem and model stimulus and response jointly by a mixed pair hidden Markov model (MPH). In MPHs, multiple stimulus-response relationships (e.g., receptive fields) are represented by different states or groups of states in a Markov chain. Each stimulus-response relationship features temporal flexibility, allowing modeling of variable response latencies, including noisy ones. We derive algorithms for learning of MPH parameters and for inference of spike response probabilities. We show that some linear-nonlinear Poisson cascade (LNP) models are a special case of MPHs. We demonstrate the efficiency and usefulness of MPHs in simulations of both jittered and switching spike responses to white noise and natural stimuli. Furthermore, we apply MPHs to extracellular single and multi-unit data recorded in cortical brain areas of singing birds to showcase a novel method for estimating response lag distributions. MPHs allow simultaneous estimation of receptive fields, latency statistics, and hidden state dynamics and so can help to uncover complex stimulus response relationships that are subject to variable timing and involve diverse neural codes. PMID:24625448

Stimulus change detection in phasic auditory units in the frog midbrain: frequency and ear specific adaptation.

PubMed

Ponnath, Abhilash; Hoke, Kim L; Farris, Hamilton E

2013-04-01

Neural adaptation, a reduction in the response to a maintained stimulus, is an important mechanism for detecting stimulus change. Contributing to change detection is the fact that adaptation is often stimulus specific: adaptation to a particular stimulus reduces excitability to a specific subset of stimuli, while the ability to respond to other stimuli is unaffected. Phasic cells (e.g., cells responding to stimulus onset) are good candidates for detecting the most rapid changes in natural auditory scenes, as they exhibit fast and complete adaptation to an initial stimulus presentation. We made recordings of single phasic auditory units in the frog midbrain to determine if adaptation was specific to stimulus frequency and ear of input. In response to an instantaneous frequency step in a tone, 28% of phasic cells exhibited frequency specific adaptation based on a relative frequency change (delta-f=±16%). Frequency specific adaptation was not limited to frequency steps, however, as adaptation was also overcome during continuous frequency modulated stimuli and in response to spectral transients interrupting tones. The results suggest that adaptation is separated for peripheral (e.g., frequency) channels. This was tested directly using dichotic stimuli. In 45% of binaural phasic units, adaptation was ear specific: adaptation to stimulation of one ear did not affect responses to stimulation of the other ear. Thus, adaptation exhibited specificity for stimulus frequency and lateralization at the level of the midbrain. This mechanism could be employed to detect rapid stimulus change within and between sound sources in complex acoustic environments.

Stimulus change detection in phasic auditory units in the frog midbrain: frequency and ear specific adaptation

PubMed Central

Ponnath, Abhilash; Hoke, Kim L.

2013-01-01

Neural adaptation, a reduction in the response to a maintained stimulus, is an important mechanism for detecting stimulus change. Contributing to change detection is the fact that adaptation is often stimulus specific: adaptation to a particular stimulus reduces excitability to a specific subset of stimuli, while the ability to respond to other stimuli is unaffected. Phasic cells (e.g., cells responding to stimulus onset) are good candidates for detecting the most rapid changes in natural auditory scenes, as they exhibit fast and complete adaptation to an initial stimulus presentation. We made recordings of single phasic auditory units in the frog midbrain to determine if adaptation was specific to stimulus frequency and ear of input. In response to an instantaneous frequency step in a tone, 28 % of phasic cells exhibited frequency specific adaptation based on a relative frequency change (delta-f = ±16 %). Frequency specific adaptation was not limited to frequency steps, however, as adaptation was also overcome during continuous frequency modulated stimuli and in response to spectral transients interrupting tones. The results suggest that adaptation is separated for peripheral (e.g., frequency) channels. This was tested directly using dichotic stimuli. In 45 % of binaural phasic units, adaptation was ear specific: adaptation to stimulation of one ear did not affect responses to stimulation of the other ear. Thus, adaptation exhibited specificity for stimulus frequency and lateralization at the level of the midbrain. This mechanism could be employed to detect rapid stimulus change within and between sound sources in complex acoustic environments. PMID:23344947

Differentiation-induced Colocalization of the KH-type Splicing Regulatory Protein with Polypyrimidine Tract Binding Protein and the c-src Pre-mRNA

PubMed Central

Hall, Megan P.; Huang, Sui; Black, Douglas L.

2004-01-01

We have examined the subcellular localization of the KH-type splicing regulatory protein (KSRP). KSRP is a multidomain RNA-binding protein implicated in a variety of cellular processes, including splicing in the nucleus and mRNA localization in the cytoplasm. We find that KSRP is primarily nuclear with a localization pattern that most closely resembles that of polypyrimidine tract binding protein (PTB). Colocalization experiments of KSRP with PTB in a mouse neuroblastoma cell line determined that both proteins are present in the perinucleolar compartment (PNC), as well as in other nuclear enrichments. In contrast, HeLa cells do not show prominent KSRP staining in the PNC, even though PTB labeling identified the PNC in these cells. Because both PTB and KSRP interact with the c-src transcript to affect N1 exon splicing, we examined the localization of the c-src pre-mRNA by fluorescence in situ hybridization. The src transcript is present in specific foci within the nucleus that are presumably sites of src transcription but are not generally perinucleolar. In normally cultured neuroblastoma cells, these src RNA foci contain PTB, but little KSRP. However, upon induced neuronal differentiation of these cells, KSRP occurs in the same foci with src RNA. PTB localization remains unaffected. This differentiation-induced localization of KSRP with src RNA correlates with an increase in src exon N1 inclusion. These results indicate that PTB and KSRP do indeed interact with the c-src transcript in vivo, and that these associations change with the differentiated state of the cell. PMID:14657238

Inhibition of src family kinases by a combinatorial action of 5'-AMP and small heat shock proteins, identified from the adult heart.

PubMed

Kasi, V S; Kuppuswamy, D

1999-10-01

Src family kinases are implicated in cellular proliferation and transformation. Terminally differentiated myocytes have lost the ability to proliferate, indicating the existence of a down-regulatory mechanism(s) for these mitogenic kinases. Here we show that feline cardiomyocyte lysate contains thermostable components that inhibit c-Src kinase in vitro. This inhibitory activity, present predominantly in heart tissue, involves two components acting combinatorially. After purification by sequential chromatography, one component was identified by mass and nuclear magnetic resonance spectroscopies as 5'-AMP, while the other was identified by peptide sequencing as a small heat shock protein (sHSP). 5'-AMP and to a lesser extent 5'-ADP inhibit c-Src when combined with either HSP-27 or HSP-32. Other HSPs, including alphaB-crystallin, HSP-70, and HSP-90, did not exhibit this effect. The inhibition, observed preferentially on Src family kinases and independent of the Src tyrosine phosphorylation state, occurs via a direct interaction of the c-Src catalytic domain with the inhibitory components. Our study indicates that sHSPs increase the affinity of 5'-AMP for the c-Src ATP binding site, thereby facilitating the inhibition. In vivo, elevation of ATP levels in the cardiomyocytes results in the tyrosine phosphorylation of cellular proteins including c-Src at the activatory site, and this effect is blocked when the 5'-AMP concentration is raised. Thus, this study reveals a novel role for sHSPs and 5'-AMP in the regulation of Src family kinases, presumably for the maintenance of the terminally differentiated state.

Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with in vivo antiresorptive activity

PubMed Central

Shakespeare, William; Yang, Michael; Bohacek, Regine; Cerasoli, Franklin; Stebbins, Karin; Sundaramoorthi, Raji; Azimioara, Mihai; Vu, Chi; Pradeepan, Selvi; Metcalf, Chester; Haraldson, Chad; Merry, Taylor; Dalgarno, David; Narula, Surinder; Hatada, Marcos; Lu, Xiaode; van Schravendijk, Marie Rose; Adams, Susan; Violette, Shelia; Smith, Jeremy; Guan, Wei; Bartlett, Catherine; Herson, Jay; Iuliucci, John; Weigele, Manfred; Sawyer, Tomi

2000-01-01

Targeted disruption of the pp60src (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Herein we describe the discovery of a nonpeptide inhibitor (AP22408) of Src that demonstrates in vivo antiresorptive activity. Based on a cocrystal structure of the noncatalytic Src homology 2 (SH2) domain of Src complexed with citrate [in the phosphotyrosine (pTyr) binding pocket], we designed 3′,4′-diphosphonophenylalanine (Dpp) as a pTyr mimic. In addition to its design to bind Src SH2, the Dpp moiety exhibits bone-targeting properties that confer osteoclast selectivity, hence minimizing possible undesired effects on other cells that have Src-dependent activities. The chemical structure AP22408 also illustrates a bicyclic template to replace the post-pTyr sequence of cognate Src SH2 phosphopeptides such as Ac-pTyr-Glu-Glu-Ile (1). An x-ray structure of AP22408 complexed with Lck (S164C) SH2 confirmed molecular interactions of both the Dpp and bicyclic template of AP22408 as predicted from molecular modeling. Relative to the cognate phosphopeptide, AP22408 exhibits significantly increased Src SH2 binding affinity (IC50 = 0.30 μM for AP22408 and 5.5 μM for 1). Furthermore, AP22408 inhibits rabbit osteoclast-mediated resorption of dentine in a cellular assay, exhibits bone-targeting properties based on a hydroxyapatite adsorption assay, and demonstrates in vivo antiresorptive activity in a parathyroid hormone-induced rat model. PMID:10944210

Src promotes delta opioid receptor (DOR) desensitization by interfering with receptor recycling.

PubMed

Archer-Lahlou, Elodie; Audet, Nicolas; Amraei, Mohammad Gholi; Huard, Karine; Paquin-Gobeil, Mélanie; Pineyro, Graciela

2009-01-01

Abstract An important limitation in the clinical use of opiates is progressive loss of analgesic efficacy over time. Development of analgesic tolerance is tightly linked to receptor desensitization. In the case of delta opioid receptors (DOR), desensitization is especially swift because receptors are rapidly internalized and are poorly recycled to the membrane. In the present study, we investigated whether Src activity contributed to this sorting pattern and to functional desensitization of DORs. A first series of experiments demonstrated that agonist binding activates Src and destabilizes a constitutive complex formed by the spontaneous association of DORs with the kinase. Src contribution to DOR desensitization was then established by showing that pre-treatment with Src inhibitor PP2 (20 microM; 1 hr) or transfection of a dominant negative Src mutant preserved DOR signalling following sustained exposure to an agonist. This protection was afforded without interfering with endocytosis, but suboptimal internalization interfered with PP2 ability to preserve DOR signalling, suggesting a post-endocytic site of action for the kinase. This assumption was confirmed by demonstrating that Src inhibition by PP2 or its silencing by siRNA increased membrane recovery of internalized DORs and was further corroborated by showing that inhibition of recycling by monensin or dominant negative Rab11 (Rab11S25N) abolished the ability of Src blockers to prevent desensitization. Finally, Src inhibitors accelerated recovery of DOR-Galphal3 coupling after desensitization. Taken together, these results indicate that Src dynamically regulates DOR recycling and by doing so contributes to desensitization of these receptors.

A Ser75-to-Asp phospho-mimicking mutation in Src accelerates ageing-related loss of retinal ganglion cells in mice.

PubMed

Kashiwagi, Kenji; Ito, Sadahiro; Maeda, Shuichiro; Kato, Goro

2017-12-01

Src knockout mice show no detectable abnormalities in central nervous system (CNS) post-mitotic neurons, likely reflecting functional compensation by other Src family kinases. Cdk1- or Cdk5-dependent Ser75 phosphorylation in the amino-terminal Unique domain of Src, which shares no homology with other Src family kinases, regulates the stability of active Src. To clarify the roles of Src Ser75 phosphorylation in CNS neurons, we established two types of mutant mice with mutations in Src: phospho-mimicking Ser75Asp (SD) and non-phosphorylatable Ser75Ala (SA). In ageing SD/SD mice, retinal ganglion cell (RGC) number in whole retinas was significantly lower than that in young SD/SD mice in the absence of inflammation and elevated intraocular pressure, resembling the pathogenesis of progressive optic neuropathy. By contrast, SA/SA mice and wild-type (WT) mice exhibited no age-related RGC loss. The age-related retinal RGC number reduction was greater in the peripheral rather than the mid-peripheral region of the retina in SD/SD mice. Furthermore, Rho-associated kinase activity in whole retinas of ageing SD/SD mice was significantly higher than that in young SD/SD mice. These results suggest that Src regulates RGC survival during ageing in a manner that depends on Ser75 phosphorylation.

Pharmacological inhibition of Src kinase protects against acute kidney injury in a murine model of renal ischemia/reperfusion

PubMed Central

Zhou, Xiaoxu; Liu, Lirong; Masucci, Monica V.; Tang, Jinhua; Li, Xuezhu; Liu, Na; Bayliss, George; Zhao, Ting C.; Zhuang, Shougang

2017-01-01

Activation of Src kinase has been implicated in the pathogenesis of acute brain, liver, and lung injury. However, the role of Src in acute kidney injury (AKI) remains unestablished. To address this, we evaluated the effects of Src inhibition on renal dysfunction and pathological changes in a murine model of AKI induced by ischemia/reperfusion (I/R). I/R injury to the kidney resulted in increased Src phosphorylation at tyrosine 416 (activation). Administration of PP1, a highly selective Src inhibitor, blocked Src phosphorylation, improved renal function and ameliorated renal pathological damage. PP1 treatment also suppressed renal expression of neutrophil gelatinase-associated lipocalin and reduced apoptosis in the injured kidney. Moreover, Src inhibition prevented downregulation of several adherens and tight junction proteins, including E-cadherin, ZO-1, and claudins-1/−4 in the kidney after I/R injury as well as in cultured renal proximal tubular cells following oxidative stress. Finally, PP1 inhibited I/R–induced renal expression of matrix metalloproteinase-2 and -9, phosphorylation of extracellular signal–regulated kinases1/2, signal transducer and activator of transcription-3, and nuclear factor-κB, and the infiltration of macrophages into the kidney. These data indicate that Src is a pivotal mediator of renal epithelial injury and that its inhibition may have a therapeutic potential to treat AKI. PMID:28415724

Clinicopathological Characteristics and Prognostic Value of Signet Ring Cells in Gastric Carcinoma: A Meta-Analysis.

PubMed

Nie, Run-Cong; Yuan, Shu-Qiang; Li, Yuan-Fang; Chen, Yong-Ming; Chen, Xiao-Jiang; Zhu, Bao-Yan; Xu, Li-Pu; Zhou, Zhi-Wei; Chen, Shi; Chen, Ying-Bo

2017-01-01

Background and Objectives: Previous studies of the prognostic value of the signet ring cell (SRC) type have yielded inconsistent results. Therefore, the aim of the present meta-analysis is to explore the clinicopathological characteristics and prognostic value of SRCs. Methods: Relevant articles that compared SRC and non-SRC type in PubMed and Web of Science were comprehensively searched. Then, a meta-analysis was performed. Results: A total of 19 studies including 35947 cases were analyzed. Compared with non-SRC patients, SRC patients tended to be younger (WMD: -3.88, P=0.001) and predominantly female (OR: 1.60, P<0.001). Additionally, SRC patients exhibited less upper third tumor location (OR: 0.62, P<0.001) and less frequent hematogenous metastasis (OR: 0.41, P<0.001). There was no difference in overall survival (OS) between SRC and non-SRC patients in the total population (HR: 1.02, P=0.830). Early gastric cancer with SRCs was associated with better OS (HR: 0.57, P=0.002), while advanced gastric cancer with non-SRCs was associated with a worse prognosis (HR: 1.17, P<0.001). Conclusions: This meta-analysis revealed that SRC tends to affect young females and tends to be located in the middle and lower third of the stomach. Early SRCs are associated with better prognoses, while advanced SRCs are associated with worse prognoses.

40 CFR Appendix V to Part 86 - The Standard Road Cycle (SRC)

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 19 2010-07-01 2010-07-01 false The Standard Road Cycle (SRC) V... Appendix V to Part 86—The Standard Road Cycle (SRC) 1. The standard road cycle (SRC) is a mileage accumulation cycle that may be used for any vehicle which is covered by the applicability provisions of § 86...

N-terminal deletions in Rous sarcoma virus p60src: effects on tyrosine kinase and biological activities and on recombination in tissue culture with the cellular src gene.

PubMed Central

Cross, F R; Garber, E A; Hanafusa, H

1985-01-01

We have constructed deletions within the region of cloned Rous sarcoma virus DNA coding for the N-terminal 30 kilodaltons of p60src. Infectious virus was recovered after transfection. Deletions of amino acids 15 to 149, 15 to 169, or 149 to 169 attenuated but did not abolish transforming activity, as assayed by focus formation and anchorage-independent growth. These deletions also had only slight effects on the tyrosine kinase activity of the mutant src protein. Deletion of amino acids 169 to 264 or 15 to 264 completely abolished transforming activity, and src kinase activity was reduced at least 10-fold. However, these mutant viruses generated low levels of transforming virus by recombination with the cellular src gene. The results suggest that as well as previously identified functional domains for p60src myristylation and membrane binding (amino acids 1 to 14) and tyrosine kinase activity (amino acids 250 to 526), additional N-terminal sequences (particularly amino acids 82 to 169) can influence the transforming activity of the src protein. Images PMID:2426576

c-Src activity is differentially required by cancer cell motility modes.

PubMed

Logue, Jeremy S; Cartagena-Rivera, Alexander X; Chadwick, Richard S

2018-04-01

Cancer cell migration requires that cells respond and adapt to their surroundings. In the absence of extracellular matrix cues, cancer cells will undergo a mesenchymal to ameboid transition, whereas a highly confining space will trigger a switch to "leader bleb-based" migration. To identify oncogenic signaling pathways mediating these transitions, we undertook a targeted screen using clinically useful inhibitors. Elevated Src activity was found to change actin and focal adhesion dynamics, whereas inhibiting Src triggered focal adhesion disassembly and blebbing. On non-adherent substrates and in collagen matrices, amoeboid-like, blebbing cells having high Src activity formed protrusions of the plasma membrane. To evaluate the role of Src in confined cells, we use a novel approach that places cells under a slab of polydimethylsiloxane (PDMS), which is held at a defined height. Using this method, we find that leader bleb-based migration is resistant to Src inhibition. High Src activity was found to markedly change the architecture of cortical actomyosin, reduce cell mechanical properties, and the percentage of cells that undergo leader bleb-based migration. Thus, Src is a signal transducer that can potently influence transitions between migration modes with implications for the rational development of metastasis inhibitors.

Inhibition of SRC-3 enhances sensitivity of human cancer cells to histone deacetylase inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zou, Zhengzhi, E-mail: zouzhengzhi@m.scnu.edu.cn; Luo, Xiaoyong; Nie, Peipei

SRC-3 is widely expressed in multiple tumor types and involved in cancer cell proliferation and apoptosis. Histone deacetylase (HDAC) inhibitors are promising antitumor drugs. However, the poor efficacy of HDAC inhibitors in solid tumors has restricted its further clinical application. Here, we reported the novel finding that depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors (SAHA and romidepsin). In contrast, overexpression of SRC-3 decreased SAHA-induced cancer cell apoptosis. Furthermore, we found that SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. The combination of bufalin and SAHA was particular efficient in attenuatingmore » AKT activation and reducing Bcl-2 levels. Taken together, these accumulating data might guide development of new breast and lung cancer therapies. - Highlights: • Depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors. • Overexpression of SRC-3 enhanced cancer cell resistance to HDAC inhibitors. • SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. • Bufalin synergized with HDAC inhibitor attenuated AKT activation and reduced Bcl-2 levels in human cancer cell.« less

Effect of addition of semi refined carrageenan on mechanical characteristics of gum arabic edible film

NASA Astrophysics Data System (ADS)

Setyorini, D.; Nurcahyani, P. R.

2016-04-01

Currently the seaweed is processed flour and Semi Refined Carraagenan (SRC). However, total production is small, but both of these products have a high value and are used in a wide variety of products such as cosmetics, processed foods, medicines, and edible film. The aim of this study were (1) to determine the effect of SRC on mechanical characteristics of edible film, (2) to determine the best edible film which added by SRC with different concentration. The edible film added by SRC flour which divided into three concentrations of SRC. There are 1.5%; 3%; and 4.5% of SRC, then added 3% glycerol and 0.6% arabic gum. The mechanical properties of the film measured by a universal testing machine Orientec Co. Ltd., while the water vapor permeability measured by the gravimetric method dessicant modified. The experimental design used was completely randomized design with a further test of Duncan. The result show SRC concentration differences affect the elongation breaking point and tensile strength. But not significant effect on the thickness, yield strength and the modulus of elasticity. The best edible film is edible film with the addition of SRC 4.5%.

Estradiol-induced regulation of GLUT4 in 3T3-L1 cells: involvement of ESR1 and AKT activation.

PubMed

Campello, Raquel S; Fátima, Luciana A; Barreto-Andrade, João Nilton; Lucas, Thais F; Mori, Rosana C; Porto, Catarina S; Machado, Ubiratan F

2017-10-01

Impaired insulin-stimulated glucose uptake involves reduced expression of the GLUT4 (solute carrier family 2 facilitated glucose transporter member 4, SLC2A4 gene). 17β-estradiol (E 2 ) modulates SLC2A4 /GLUT4 expression, but the involved mechanisms are unclear. Although E 2 exerts biological effects by binding to estrogen receptors 1/2 (ESR1/2), which are nuclear transcriptional factors; extranuclear effects have also been proposed. We hypothesize that E 2 regulates GLUT4 through an extranuclear ESR1 mechanism. Thus, we investigated the effects of E 2 upon (1) subcellular distribution of ESRs and the proto-oncogene tyrosine-protein kinases (SRC) involvement; (2) serine/threonine-protein kinase (AKT) activation; (3) Slc2a4 /GLUT4 expression and (4) GLUT4 subcellular distribution and glucose uptake in 3T3-L1 adipocytes. Differentiated 3T3-L1 adipocytes were cultivated or not with E 2 for 24 h, and additionally treated or not with ESR1-selective agonist (PPT), ESR1-selective antagonist (MPP) or selective SRC inhibitor (PP2). Subcellular distribution of ESR1, ESR2 and GLUT4 was analyzed by immunocytochemistry; Slc2a4 mRNA and GLUT4 were quantified by qPCR and Western blotting, respectively; plasma membrane GLUT4 translocation and glucose uptake were analyzed under insulin stimulus for 20 min or not. E 2 induced (1) translocation of ESR1, but not of ESR2, from nucleus to plasma membrane and AKT phosphorylation, effects mimicked by PPT and blocked by MPP and PP2; (2) increased Slc2a4 /GLUT4 expression and (3) increased insulin-stimulated GLUT4 translocation and glucose uptake. In conclusion, E 2 treatment promoted a SRC-mediated nucleus-plasma membrane shuttle of ESR1, and increased AKT phosphorylation, Slc2a4 /GLUT4 expression and plasma membrane GLUT4 translocation; consequently, improving insulin-stimulated glucose uptake. These results unravel mechanisms through which estrogen improves insulin sensitivity. © 2017 Society for Endocrinology.

Performance consequences of alternating directional control-response compatibility: evidence from a coal mine shuttle car simulator.

PubMed

Zupanc, Christine M; Burgess-Limerick, Robin J; Wallis, Guy

2007-08-01

To investigate error and reaction time consequences of alternating compatible and incompatible steering arrangements during a simulated obstacle avoidance task. Underground coal mine shuttle cars provide an example of a vehicle in which operators are required to alternate between compatible and incompatible steering configurations. This experiment examines the performance of 48 novice participants in a virtual analogy of an underground coal mine shuttle car. Participants were randomly assigned to a compatible condition, an incompatible condition, an alternating condition in which compatibility alternated within and between hands, or an alternating condition in which compatibility alternated between hands. Participants made fewer steering direction errors and made correct steering responses more quickly in the compatible condition. Error rate decreased over time in the incompatible condition. A compatibility effect for both errors and reaction time was also found when the control-response relationship alternated; however, performance improvements over time were not consistent. Isolating compatibility to a hand resulted in reduced error rate and faster reaction time than when compatibility alternated within and between hands. The consequences of alternating control-response relationships are higher error rates and slower responses, at least in the early stages of learning. This research highlights the importance of ensuring consistently compatible human-machine directional control-response relationships.

Variability and Correlations in Primary Visual Cortical Neurons Driven by Fixational Eye Movements

PubMed Central

McFarland, James M.; Cumming, Bruce G.

2016-01-01

The ability to distinguish between elements of a sensory neuron's activity that are stimulus independent versus driven by the stimulus is critical for addressing many questions in systems neuroscience. This is typically accomplished by measuring neural responses to repeated presentations of identical stimuli and identifying the trial-variable components of the response as noise. In awake primates, however, small “fixational” eye movements (FEMs) introduce uncontrolled trial-to-trial differences in the visual stimulus itself, potentially confounding this distinction. Here, we describe novel analytical methods that directly quantify the stimulus-driven and stimulus-independent components of visual neuron responses in the presence of FEMs. We apply this approach, combined with precise model-based eye tracking, to recordings from primary visual cortex (V1), finding that standard approaches that ignore FEMs typically miss more than half of the stimulus-driven neural response variance, creating substantial biases in measures of response reliability. We show that these effects are likely not isolated to the particular experimental conditions used here, such as the choice of visual stimulus or spike measurement time window, and thus will be a more general problem for V1 recordings in awake primates. We also demonstrate that measurements of the stimulus-driven and stimulus-independent correlations among pairs of V1 neurons can be greatly biased by FEMs. These results thus illustrate the potentially dramatic impact of FEMs on measures of signal and noise in visual neuron activity and also demonstrate a novel approach for controlling for these eye-movement-induced effects. SIGNIFICANCE STATEMENT Distinguishing between the signal and noise in a sensory neuron's activity is typically accomplished by measuring neural responses to repeated presentations of an identical stimulus. For recordings from the visual cortex of awake animals, small “fixational” eye movements (FEMs) inevitably introduce trial-to-trial variability in the visual stimulus, potentially confounding such measures. Here, we show that FEMs often have a dramatic impact on several important measures of response variability for neurons in primary visual cortex. We also present an analytical approach for quantifying signal and noise in visual neuron activity in the presence of FEMs. These results thus highlight the importance of controlling for FEMs in studies of visual neuron function, and demonstrate novel methods for doing so. PMID:27277801

Regulation of mATG9 trafficking by Src- and ULK1-mediated phosphorylation in basal and starvation-induced autophagy.

PubMed

Zhou, Changqian; Ma, Kaili; Gao, Ruize; Mu, Chenglong; Chen, Linbo; Liu, Qiangqiang; Luo, Qian; Feng, Du; Zhu, Yushan; Chen, Quan

2017-02-01

Autophagy requires diverse membrane sources and involves membrane trafficking of mATG9, the only membrane protein in the ATG family. However, the molecular regulation of mATG9 trafficking for autophagy initiation remains unclear. Here we identified two conserved classic adaptor protein sorting signals within the cytosolic N-terminus of mATG9, which mediate trafficking of mATG9 from the plasma membrane and trans-Golgi network (TGN) via interaction with the AP1/2 complex. Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. Our findings uncover novel mechanisms of mATG9 trafficking and suggest a coordination of basal and stress-induced autophagy.

Stimulus onset predictability modulates proactive action control in a Go/No-go task

PubMed Central

Berchicci, Marika; Lucci, Giuliana; Spinelli, Donatella; Di Russo, Francesco

2015-01-01

The aim of the study was to evaluate whether the presence/absence of visual cues specifying the onset of an upcoming, action-related stimulus modulates pre-stimulus brain activity, associated with the proactive control of goal-directed actions. To this aim we asked 12 subjects to perform an equal probability Go/No-go task with four stimulus configurations in two conditions: (1) uncued, i.e., without any external information about the timing of stimulus onset; and (2) cued, i.e., with external visual cues providing precise information about the timing of stimulus onset. During task both behavioral performance and event-related potentials (ERPs) were recorded. Behavioral results showed faster response times in the cued than uncued condition, confirming existing literature. ERPs showed novel results in the proactive control stage, that started about 1 s before the motor response. We observed a slow rising prefrontal positive activity, more pronounced in the cued than the uncued condition. Further, also pre-stimulus activity of premotor areas was larger in cued than uncued condition. In the post-stimulus period, the P3 amplitude was enhanced when the time of stimulus onset was externally driven, confirming that external cueing enhances processing of stimulus evaluation and response monitoring. Our results suggest that different pre-stimulus processing come into play in the two conditions. We hypothesize that the large prefrontal and premotor activities recorded with external visual cues index the monitoring of the external stimuli in order to finely regulate the action. PMID:25964751

The Function Acquisition Speed Test (FAST): A Behavior Analytic Implicit Test for Assessing Stimulus Relations

ERIC Educational Resources Information Center

O'Reilly, Anthony; Roche, Bryan; Ruiz, Maria; Tyndall, Ian; Gavin, Amanda

2012-01-01

Subjects completed a baseline stimulus matching procedure designed to produce two symmetrical stimulus relations; A1-B1 and A2-B2. Using A1, B1, and two novel stimuli, subjects were then trained to produce a common key-press response for two stimuli and a second key-press response for two further stimuli across two blocks of response training.…

A Decline in Response Variability Improves Neural Signal Detection during Auditory Task Performance.

PubMed

von Trapp, Gardiner; Buran, Bradley N; Sen, Kamal; Semple, Malcolm N; Sanes, Dan H

2016-10-26

The detection of a sensory stimulus arises from a significant change in neural activity, but a sensory neuron's response is rarely identical to successive presentations of the same stimulus. Large trial-to-trial variability would limit the central nervous system's ability to reliably detect a stimulus, presumably affecting perceptual performance. However, if response variability were to decrease while firing rate remained constant, then neural sensitivity could improve. Here, we asked whether engagement in an auditory detection task can modulate response variability, thereby increasing neural sensitivity. We recorded telemetrically from the core auditory cortex of gerbils, both while they engaged in an amplitude-modulation detection task and while they sat quietly listening to the identical stimuli. Using a signal detection theory framework, we found that neural sensitivity was improved during task performance, and this improvement was closely associated with a decrease in response variability. Moreover, units with the greatest change in response variability had absolute neural thresholds most closely aligned with simultaneously measured perceptual thresholds. Our findings suggest that the limitations imposed by response variability diminish during task performance, thereby improving the sensitivity of neural encoding and potentially leading to better perceptual sensitivity. The detection of a sensory stimulus arises from a significant change in neural activity. However, trial-to-trial variability of the neural response may limit perceptual performance. If the neural response to a stimulus is quite variable, then the response on a given trial could be confused with the pattern of neural activity generated when the stimulus is absent. Therefore, a neural mechanism that served to reduce response variability would allow for better stimulus detection. By recording from the cortex of freely moving animals engaged in an auditory detection task, we found that variability of the neural response becomes smaller during task performance, thereby improving neural detection thresholds. Copyright © 2016 the authors 0270-6474/16/3611097-10$15.00/0.

A Decline in Response Variability Improves Neural Signal Detection during Auditory Task Performance

PubMed Central

Buran, Bradley N.; Sen, Kamal; Semple, Malcolm N.; Sanes, Dan H.

2016-01-01

The detection of a sensory stimulus arises from a significant change in neural activity, but a sensory neuron's response is rarely identical to successive presentations of the same stimulus. Large trial-to-trial variability would limit the central nervous system's ability to reliably detect a stimulus, presumably affecting perceptual performance. However, if response variability were to decrease while firing rate remained constant, then neural sensitivity could improve. Here, we asked whether engagement in an auditory detection task can modulate response variability, thereby increasing neural sensitivity. We recorded telemetrically from the core auditory cortex of gerbils, both while they engaged in an amplitude-modulation detection task and while they sat quietly listening to the identical stimuli. Using a signal detection theory framework, we found that neural sensitivity was improved during task performance, and this improvement was closely associated with a decrease in response variability. Moreover, units with the greatest change in response variability had absolute neural thresholds most closely aligned with simultaneously measured perceptual thresholds. Our findings suggest that the limitations imposed by response variability diminish during task performance, thereby improving the sensitivity of neural encoding and potentially leading to better perceptual sensitivity. SIGNIFICANCE STATEMENT The detection of a sensory stimulus arises from a significant change in neural activity. However, trial-to-trial variability of the neural response may limit perceptual performance. If the neural response to a stimulus is quite variable, then the response on a given trial could be confused with the pattern of neural activity generated when the stimulus is absent. Therefore, a neural mechanism that served to reduce response variability would allow for better stimulus detection. By recording from the cortex of freely moving animals engaged in an auditory detection task, we found that variability of the neural response becomes smaller during task performance, thereby improving neural detection thresholds. PMID:27798189

Prognostic Significance of Signet Ring Gastric Cancer

PubMed Central

Taghavi, Sharven; Jayarajan, Senthil N.; Davey, Adam; Willis, Alliric I.

2012-01-01

Purpose Studies in Asia have questioned the dictum that signet ring cell carcinoma (SRC) has a worse prognosis than other forms of gastric cancer. Our study determined differences in presentation and outcomes between SRC and gastric adenocarcinoma (AC) in the United States. Patients and Methods The National Cancer Institute Surveillance, Epidemiology, and End Results database was reviewed for SRC and AC from 2004 to 2007. Results We reviewed 10,246 cases of patients with gastric cancer, including 2,666 of SRC and 7,580 of AC. SRC presented in younger patients (61.9 v 68.7 years; P < .001) and less often in men (52.7% v 68.7%; P < .001). SRC patients were more frequently black (11.3% v 10.9%), Asian (16.4% v 13.2%), American Indian/Alaska Native (0.9% v 0.8%), or Hispanic (23.3% v 14.0%; P < .001). SRC was more likely to be stage T3-4 (45.8% v 33.3%), have lymph node spread (59.7% v 51.8%), and distant metastases (40.2% v 37.6%; P < .001). SRC was more likely to be found in the lower (30.7% v 24.2%) and middle stomach (30.6% v 20.7%; P < .001). Median survival was not different between the two (AC, 14.0 months v SRC, 13.0 months; P = .073). Multivariable analyses demonstrated SRC was not associated with mortality (hazard ratio [HR], 1.05; 95% CI, 0.96 to 1.11; P = .150). Mortality was associated with age (HR, 1.01; 95% CI, 1.01 to 1.02; P < .001), black race (HR, 1.10; 95% CI, 1.01 to 1.20; P = .026), and tumor grade. Variables associated with lower mortality risk included Asian race (HR, 0.83; 95% CI, 0.77 to 0.91; P < .001) and surgery (HR, 0.37; 95% CI, 0.34 to 0.39; P < .001). Conclusion In the United States, SRC significantly differs from AC in extent of disease at presentation. However, when adjusted for stage, SRC does not portend a worse prognosis. PMID:22927530

Lemongrass essential oil and citral inhibit Src/Stat3 activity and suppress the proliferation/survival of small-cell lung cancer cells, alone or in combination with chemotherapeutic agents.

PubMed

Maruoka, Takayuki; Kitanaka, Akira; Kubota, Yoshitsugu; Yamaoka, Genji; Kameda, Tomohiro; Imataki, Osamu; Dobashi, Hiroaki; Bandoh, Shuji; Kadowaki, Norimitsu; Tanaka, Terukazu

2018-03-13

Small-cell lung cancer (SCLC) is intractable due to its high propensity for relapse. Novel agents are thus needed for SCLC treatment. Lemongrass essential oil (LG-EO) and its major constituent, citral, have been reported to inhibit the proliferation and survival of several types of cancer cells. However, the precise mechanisms through which LG-EO and citral exert their effects on SCLC cells have not been fully elucidated. SCLC cells express Src and have high levels of Src-tyrosine kinase (Src-TK) activity. In most SCLC cell lines, constitutive phosphorylation of Stat3(Y705), which is essential for its activation, has been detected. Src-TK can phosphorylate Stat3(Y705), and activated Stat3 promotes the expression of the anti-apoptotic factors Bcl-xL and Mcl-1. In the present study, LG-EO and citral prevented Src-TK from phosphorylating Stat3(Y705), resulting in decreased Bcl-xL and Mcl-1 expression, in turn suppressing the proliferation/survival of SCLC cells. To confirm these findings, the wild-type-src gene was transfected into the LU135 SCLC cell line (LU135‑wt-src), in which Src and activated phospho-Stat3(Y705) were overexpressed. The suppression of cell proliferation and the induction of apoptosis by treatment with LG-EO or citral were significantly attenuated in the LU135-wt-src cells compared with the control LU135-mock cells. The signal transducer and activator of transcription 3 (Stat3) signaling pathway is also associated with intrinsic drug resistance. LU135-wt-src cells were significantly resistant to conventional chemotherapeutic agents compared with LU135-mock cells. The combined effects of citral and each conventional chemotherapeutic agent on SCLC cells were also evaluated. The combination treatment exerted additive or more prominent effects on LU135-wt-src, LU165 and MN1112 cells, which are relatively chemoresistant SCLC cells. These findings suggest that either LG-EO or citral, alone or in combination with chemotherapeutic agents, may be a novel therapeutic option for SCLC patients.

The role of Src kinase in the biology and pathogenesis of Acanthamoeba castellanii

PubMed Central

2012-01-01

Background Acanthamoeba species are the causative agents of fatal granulomatous encephalitis in humans. Haematogenous spread is thought to be a primary step, followed by blood–brain barrier penetration, in the transmission of Acanthmaoeba into the central nervous system, but the associated molecular mechanisms remain unclear. Here, we evaluated the role of Src, a non-receptor protein tyrosine kinase in the biology and pathogenesis of Acanthamoeba. Methods Amoebistatic and amoebicidal assays were performed by incubating amoeba in the presence of Src kinase-selective inhibitor, PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) and its inactive analog, PP3 (4-amino-7-phenylpyrazolo[3,4-d]pyrimidine). Using this inhibitor, the role of Src kinase in A. castellanii interactions with Escherichia coli was determined. Zymographic assays were performed to study effects of Src kinase on extracellular proteolytic activities of A. castellanii. The human brain microvascular endothelial cells were used to determine the effects of Src kinase on A. castellanii adhesion to and cytotoxicity of host cells. Results Inhibition of Src kinase using a specific inhibitor, PP2 (4-amino-5-(4 chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d] pyrimidine) but not its inactive analog, PP3 (4-amino-7-phenylpyrazolo[3,4-d] pyrimidine), had detrimental effects on the growth of A. castellanii (keratitis isolate, belonging to the T4 genotype). Interestingly, inhibition of Src kinase hampered the phagocytic ability of A. castellanii, as measured by the uptake of non-invasive bacteria, but, on the contrary, invasion by pathogenic bacteria was enhanced. Zymographic assays revealed that inhibition of Src kinases reduced extracellular protease activities of A. castellanii. Src kinase inhibition had no significant effect on A. castellanii binding to and cytotoxicity of primary human brain microvascular endothelial cells, which constitute the blood–brain barrier. Conclusions For the first time, these findings demonstrated that Src kinase is involved in A. castellanii proliferation, protease secretions and phagocytic properties. Conversely, invasion of Acanthamoeba by pathogenic bacteria was stimulated by Src kinase inhibition. PMID:22676352

The coupling of cerebral blood flow and oxygen metabolism with brain activation is similar for simple and complex stimuli in human primary visual cortex.

PubMed

Griffeth, Valerie E M; Simon, Aaron B; Buxton, Richard B

2015-01-01

Quantitative functional MRI (fMRI) experiments to measure blood flow and oxygen metabolism coupling in the brain typically rely on simple repetitive stimuli. Here we compared such stimuli with a more naturalistic stimulus. Previous work on the primary visual cortex showed that direct attentional modulation evokes a blood flow (CBF) response with a relatively large oxygen metabolism (CMRO2) response in comparison to an unattended stimulus, which evokes a much smaller metabolic response relative to the flow response. We hypothesized that a similar effect would be associated with a more engaging stimulus, and tested this by measuring the primary human visual cortex response to two contrast levels of a radial flickering checkerboard in comparison to the response to free viewing of brief movie clips. We did not find a significant difference in the blood flow-metabolism coupling (n=%ΔCBF/%ΔCMRO2) between the movie stimulus and the flickering checkerboards employing two different analysis methods: a standard analysis using the Davis model and a new analysis using a heuristic model dependent only on measured quantities. This finding suggests that in the primary visual cortex a naturalistic stimulus (in comparison to a simple repetitive stimulus) is either not sufficient to provoke a change in flow-metabolism coupling by attentional modulation as hypothesized, that the experimental design disrupted the cognitive processes underlying the response to a more natural stimulus, or that the technique used is not sensitive enough to detect a small difference. Copyright © 2014 Elsevier Inc. All rights reserved.

Processing of prosodic changes in natural speech stimuli in school-age children.

PubMed

Lindström, R; Lepistö, T; Makkonen, T; Kujala, T

2012-12-01

Speech prosody conveys information about important aspects of communication: the meaning of the sentence and the emotional state or intention of the speaker. The present study addressed processing of emotional prosodic changes in natural speech stimuli in school-age children (mean age 10 years) by recording the electroencephalogram, facial electromyography, and behavioral responses. The stimulus was a semantically neutral Finnish word uttered with four different emotional connotations: neutral, commanding, sad, and scornful. In the behavioral sound-discrimination task the reaction times were fastest for the commanding stimulus and longest for the scornful stimulus, and faster for the neutral than for the sad stimulus. EEG and EMG responses were measured during non-attentive oddball paradigm. Prosodic changes elicited a negative-going, fronto-centrally distributed neural response peaking at about 500 ms from the onset of the stimulus, followed by a fronto-central positive deflection, peaking at about 740 ms. For the commanding stimulus also a rapid negative deflection peaking at about 290 ms from stimulus onset was elicited. No reliable stimulus type specific rapid facial reactions were found. The results show that prosodic changes in natural speech stimuli activate pre-attentive neural change-detection mechanisms in school-age children. However, the results do not support the suggestion of automaticity of emotion specific facial muscle responses to non-attended emotional speech stimuli in children. Copyright © 2012 Elsevier B.V. All rights reserved.

The effects of arm movement on reaction time in patients with latent and active upper trapezius myofascial trigger point.

PubMed

Yassin, Marzieh; Talebian, Saeed; Ebrahimi Takamjani, Ismail; Maroufi, Nader; Ahmadi, Amir; Sarrafzadeh, Javad; Emrani, Anita

2015-01-01

Myofascial pain syndrome is a significant source of mechanical pain. The aim of this study was to investigate the effects of arm movement on reaction time in females with latent and active upper trapezius myofascial trigger point. In this interventional study, a convenience sample of fifteen women with one active MTP, fifteen women with one latent MTP in the upper trapezius, and fifteen normal healthy women were participated. Participants were asked to stand for 10 seconds in an erect standing position. Muscle reaction times were recorded including anterior deltoid (AD), cervical paraspinal (CP) lumbar paraspinal (LP), both of upper trapezius (UT), sternocleidomastoid (SCM) and medial head of gastrocnemius (GcM). Participants were asked to flex their arms in response to a sound stimulus preceded by a warning sound stimulus. Data were analyzed using one-way ANOVA Test. There was significant differences in motor time and reaction time between active and control groups (p< 0.05) except for GcM. There was no significant difference in motor time between active and passive groups except for UT without MTP and SCM (p< 0.05). Also, there were no significant differences in motor times between latent MTP and control groups. Furthermore, there was no significant difference in premotor times between the three groups. The present study shows that patients with active MTP need more time to react to stimulus, but patients with latent MTP are similar to healthy subjects in the reaction time. Patients with active MTP had less compatibility with environmental stimulations, and they responded to a specific stimulation with variability in Surface Electromyography (SEMG).

Effects of stimulus intensity on frontal, central and parietal somatosensory evoked potentials after median nerve stimulation.

PubMed

Huttunen, J

1995-01-01

Effects of the intensity of electrical median nerve stimulation were previously reported for the subcortical and first cortical somatosensory evoked potentials (SEPs) but not for later cortical waves whose applications in neurology have gained growing interest in recent years. This paper therefore describes the stimulus intensity effects on frontal, central and parietal SEP waveforms up to 90 msec after stimulus. The intensities were 1.5 and 2 times sensory threshold (ST), motor threshold (MT), and 1.5 and 2 times MT. Between 1.5 x ST and MT all SEP components grew in amplitude, except N60 which was essentially saturated already at 1.5 x ST. The growth was most marked for P14 and N20 whereas later potentials changed less, i.e. the slopes of the intensity-amplitude curves progressively flattened with increasing latency of SEP component. Between MT and 2 x MT no significant further alterations occurred in the early cortical potentials up to 30 msec. However, subtle changes occurred in the P40-N60 waveforms and subtraction of responses revealed a small centroparietal P35-N45 difference wave elicited only by high-intensity (2 x MT) stimulation. It is concluded that for practical purposes stimulation slightly above MT yields maximum cortical SEPs. The results are not generally compatible with the proposition that P40 and N60 are conveyed by higher threshold, small-diameter afferent fibers compared with N20. However, the P35-N45 difference wave at 2 x MT indicates that small-diameter afferent components may be embedded in the waveforms obtained at high intensity.

Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases.

PubMed

Schlaepfer, D D; Hunter, T

1996-10-01

Focal adhesion kinase (FAK) is a nonreceptor protein-tyrosine kinase (PTK) that associates with integrin receptors and participates in extracellular matrix-mediated signal transduction events. We showed previously that the c-Src nonreceptor PTK and the Grb2 SH2/SH3 adaptor protein bound directly to FAK after fibronectin stimulation (D. D. Schlaepfer, S.K. Hanks, T. Hunter, and P. van der Geer, Nature [London] 372:786-791, 1994). Here, we present evidence that c-Src association with FAK is required for Grb2 binding to FAK. Using a tryptic phosphopeptide mapping approach, the in vivo phosphorylation of the Grb2 binding site on FAK (Tyr-925) was detected after fibronectin stimulation of NIH 3T3 cells and was constitutively phosphorylated in v-Src-transformed NIH 3T3 cells. In vitro, c-Src phosphorylated FAK Tyr-925 in a glutathione S-transferase-FAK C-terminal domain fusion protein, whereas FAK did not. Using epitope-tagged FAK constructs, transiently expressed in human 293 cells, we determined the effect of site-directed mutations on c-Src and Grb2 binding to FAK. Mutation of FAK Tyr-925 disrupted Grb2 binding, whereas mutation of the c-Src binding site on FAK (Tyr-397) disrupted both c-Src and Grb2 binding to FAK in vivo. These results support a model whereby Src-family PTKs are recruited to FAK and focal adhesions following integrin-induced autophosphorylation and exposure of FAK Tyr-397. Src-family binding and phosphorylation of FAK at Tyr-925 creates a Grb2 SH2-domain binding site and provides a link to the activation of the Ras signal transduction pathway. In Src-transformed cells, this pathway may be constitutively activated as a result of FAK Tyr-925 phosphorylation in the absence of integrin stimulation.

Glucocorticoids mediate stress-induced impairment of retrieval of stimulus-response memory.

PubMed

Atsak, Piray; Guenzel, Friederike M; Kantar-Gok, Deniz; Zalachoras, Ioannis; Yargicoglu, Piraye; Meijer, Onno C; Quirarte, Gina L; Wolf, Oliver T; Schwabe, Lars; Roozendaal, Benno

2016-05-01

Acute stress and elevated glucocorticoid hormone levels are well known to impair the retrieval of hippocampus-dependent 'declarative' memory. Recent findings suggest that stress might also impair the retrieval of non-hippocampal memories. In particular, stress shortly before retention testing was shown to impair the retrieval of striatal stimulus-response associations in humans. However, the mechanism underlying this stress-induced retrieval impairment of non-hippocampal stimulus-response memory remains elusive. In the present study, we investigated whether an acute elevation in glucocorticoid levels mediates the impairing effects of stress on retrieval of stimulus-response memory. Male Sprague-Dawley rats were trained on a stimulus-response task in an eight-arm radial maze until they learned to associate a stimulus, i.e., cue, with a food reward in one of the arms. Twenty-four hours after successful acquisition, they received a systemic injection of vehicle, corticosterone (1mg/kg), the corticosterone-synthesis inhibitor metyrapone (35mg/kg) or were left untreated 1h before retention testing. We found that the corticosterone injection impaired the retrieval of stimulus-response memory. We further found that the systemic injection procedure per se was stressful as the vehicle administration also increased plasma corticosterone levels and impaired the retrieval of stimulus-response memory. However, memory retrieval was not impaired when rats were tested 2min after the systemic vehicle injection, before any stress-induced elevation in corticosterone levels had occurred. Moreover, metyrapone treatment blocked the effect of injection stress on both plasma corticosterone levels and memory retrieval impairment, indicating that the endogenous corticosterone response mediates the stress-induced memory retrieval impairment. None of the treatments affected rats' locomotor activity or motivation to search for the food reward within the maze. These findings show that stress may affect memory processes beyond the hippocampus and that these stress effects are due to the action of glucocorticoids. Copyright © 2016 Elsevier Ltd. All rights reserved.

Some considerations of two alleged kinds of selective attention.

PubMed

Keren, G

1976-12-01

The present article deals with selective attention phenomena and elaborates on a stimulus material classification, "stimulus set" versus "response set," proposed by Broadbent (1970, 1971)9 Stimulus set is defined by some distinct and conspicuous physical properties that are inherent in the stimulus. Response set is characterized by the meaning it conveys, and thus its properties are determined by cognitive processing on the part of the organism. Broadbent's framework is related to Neisser's (1967) distinction between two perceptual-cognitive processes, namely, preattentive control and focal attention. Three experiments are reported. A before-after paradigm was employed in Experiment 1, together with a sptial arrangement manipulation of relevant versus irrelevant stimuli (being grouped or mixed). The results indicated that before-after instruction had a stronger effect under stimulus set than under response set conditions. Spatial arrangement, on the other hand, affected performances under response set but not under stimulus set conditions. These results were interpreted as supporting the idea that stimulus set material, which is handled by preattentive mechanisms, may be processed in parallel, while response set material requires focal attention that is probably serial in nature. Experiment 2 used a search task with different levels of noise elements. Although subjects were not able to avoid completely the processing of noise elements, they had much more control under stimulus set than under response set conditions. Experiment 3 dealt with memory functions and suggests differential levels of perceptual processing depending on the nature of the stimulus material. This extends the memory framework suggested by Craik and Lockhart (1972). The results of these experiments, together with evidence from other behavioral and physiological studies, lend strong support to the proposed theory. At the theoretical level, it is suggested that the distinction between stimulus and response set, and the corresponding one between preattentive mechanisms and focal attention, are on a continuum rather than being an all-or-none classification. Thus, it permits greater congnitive flexibility on the part of the organism, which is reflected through the assumption that both preattentive mechanisms and focal attention may operate simultaneously and differ only in the salience of their functioning. From a methodological point of view, the distinction between stimulus material and organismic processes is emphasized. It is argued that researchers have not given sufficient attention to the properties of the stimulus materials that they have used, and as a consequence have reached unwarranted conclusions, as exemplified by a few studies that are briefly discussed.

Learning and remembering strategies of novice and advanced jazz dancers for skill level appropriate dance routines.

PubMed

Poon, P P; Rodgers, W M

2000-06-01

This study examined the influence of the challenge level of to-be-learned stimulus on learning strategies in novice and advanced dancers. In Study 1, skill-level appropriate dance routines were developed for novice and advanced jazz dancers. In Study 2, 8 novice and 9 advanced female jazz dancers attempted to learn and remember the two routines in mixed model factorial design, with one between-participants factor: skill level (novice or advanced) and two within-participants factors: routine (easy or difficult) and performance (immediate or delayed). Participants were interviewed regarding the strategies used to learn and remember the routines. Results indicated that advanced performers used atypical learning strategies for insufficiently challenging stimuli, which may reflect characteristics of the stimuli rather than the performer. The qualitative data indicate a clear preference of novice and advanced performers for spatial compatibility of stimuli and response.

Task choice and semantic interference in picture naming.

PubMed

Piai, Vitória; Roelofs, Ardi; Schriefers, Herbert

2015-05-01

Evidence from dual-task performance indicates that speakers prefer not to select simultaneous responses in picture naming and another unrelated task, suggesting a response selection bottleneck in naming. In particular, when participants respond to tones with a manual response and name pictures with superimposed semantically related or unrelated distractor words, semantic interference in naming tends to be constant across stimulus onset asynchronies (SOAs) between the tone stimulus and the picture-word stimulus. In the present study, we examine whether semantic interference in picture naming depends on SOA in case of a task choice (naming the picture vs reading the word of a picture-word stimulus) based on tones. This situation requires concurrent processing of the tone stimulus and the picture-word stimulus, but not a manual response to the tones. On each trial, participants either named a picture or read aloud a word depending on the pitch of a tone, which was presented simultaneously with picture-word onset or 350 ms or 1000 ms before picture-word onset. Semantic interference was present with tone pre-exposure, but absent when tone and picture-word stimulus were presented simultaneously. Against the background of the available studies, these results support an account according to which speakers tend to avoid concurrent response selection, but can engage in other types of concurrent processing, such as task choices. Copyright © 2015 Elsevier B.V. All rights reserved.

Heterogeneity in the spatial receptive field architecture of multisensory neurons of the superior colliculus and its effects on multisensory integration

PubMed Central

Ghose, Dipanwita; Wallace, Mark T.

2013-01-01

Multisensory integration has been widely studied in neurons of the mammalian superior colliculus (SC). This has led to the description of various determinants of multisensory integration, including those based on stimulus- and neuron-specific factors. The most widely characterized of these illustrate the importance of the spatial and temporal relationships of the paired stimuli as well as their relative effectiveness in eliciting a response in determining the final integrated output. Although these stimulus-specific factors have generally been considered in isolation (i.e., manipulating stimulus location while holding all other factors constant), they have an intrinsic interdependency that has yet to be fully elucidated. For example, changes in stimulus location will likely also impact both the temporal profile of response and the effectiveness of the stimulus. The importance of better describing this interdependency is further reinforced by the fact that SC neurons have large receptive fields, and that responses at different locations within these receptive fields are far from equivalent. To address these issues, the current study was designed to examine the interdependency between the stimulus factors of space and effectiveness in dictating the multisensory responses of SC neurons. The results show that neuronal responsiveness changes dramatically with changes in stimulus location – highlighting a marked heterogeneity in the spatial receptive fields of SC neurons. More importantly, this receptive field heterogeneity played a major role in the integrative product exhibited by stimulus pairings, such that pairings at weakly responsive locations of the receptive fields resulted in the largest multisensory interactions. Together these results provide greater insight into the interrelationship of the factors underlying multisensory integration in SC neurons, and may have important mechanistic implications for multisensory integration and the role it plays in shaping SC mediated behaviors. PMID:24183964

Statistical context shapes stimulus-specific adaptation in human auditory cortex.

PubMed

Herrmann, Björn; Henry, Molly J; Fromboluti, Elisa Kim; McAuley, J Devin; Obleser, Jonas

2015-04-01

Stimulus-specific adaptation is the phenomenon whereby neural response magnitude decreases with repeated stimulation. Inconsistencies between recent nonhuman animal recordings and computational modeling suggest dynamic influences on stimulus-specific adaptation. The present human electroencephalography (EEG) study investigates the potential role of statistical context in dynamically modulating stimulus-specific adaptation by examining the auditory cortex-generated N1 and P2 components. As in previous studies of stimulus-specific adaptation, listeners were presented with oddball sequences in which the presentation of a repeated tone was infrequently interrupted by rare spectral changes taking on three different magnitudes. Critically, the statistical context varied with respect to the probability of small versus large spectral changes within oddball sequences (half of the time a small change was most probable; in the other half a large change was most probable). We observed larger N1 and P2 amplitudes (i.e., release from adaptation) for all spectral changes in the small-change compared with the large-change statistical context. The increase in response magnitude also held for responses to tones presented with high probability, indicating that statistical adaptation can overrule stimulus probability per se in its influence on neural responses. Computational modeling showed that the degree of coadaptation in auditory cortex changed depending on the statistical context, which in turn affected stimulus-specific adaptation. Thus the present data demonstrate that stimulus-specific adaptation in human auditory cortex critically depends on statistical context. Finally, the present results challenge the implicit assumption of stationarity of neural response magnitudes that governs the practice of isolating established deviant-detection responses such as the mismatch negativity. Copyright © 2015 the American Physiological Society.

Improved low-cost, MR-compatible olfactometer to deliver tobacco smoke odor.

PubMed

Lowen, Steven B; Farmer, Stacey L; Lukas, Scott E

2017-02-01

We describe a low-cost, MRI-compatible olfactometer that delivers fresh cigarette smoke odor, a challenging odorant to present, as well as other odorants. This new olfactometer retains all of the advantages of an earlier design that was capable of only delivering volatile odors (Lowen & Lukas, Behavior Research Methods, 38, 307-313, 2006). The new system incorporates a novel switching mechanism that allows it to deliver fresh smoke generated from a burning cigarette during a stimulus presentation paradigm that might be employed in a cue-reactivity experiment. An evaluation study established that the olfactometer reliably delivered smoke to the participants and that tobacco smoke was discriminated from other odorants; there were no adverse reactions to the device.

Inhibition of Src Family Kinases by a Combinatorial Action of 5′-AMP and Small Heat Shock Proteins, Identified from the Adult Heart

PubMed Central

Kasi, Vijaykumar S.; Kuppuswamy, Dhandapani

1999-01-01

Src family kinases are implicated in cellular proliferation and transformation. Terminally differentiated myocytes have lost the ability to proliferate, indicating the existence of a down-regulatory mechanism(s) for these mitogenic kinases. Here we show that feline cardiomyocyte lysate contains thermostable components that inhibit c-Src kinase in vitro. This inhibitory activity, present predominantly in heart tissue, involves two components acting combinatorially. After purification by sequential chromatography, one component was identified by mass and nuclear magnetic resonance spectroscopies as 5′-AMP, while the other was identified by peptide sequencing as a small heat shock protein (sHSP). 5′-AMP and to a lesser extent 5′-ADP inhibit c-Src when combined with either HSP-27 or HSP-32. Other HSPs, including αB-crystallin, HSP-70, and HSP-90, did not exhibit this effect. The inhibition, observed preferentially on Src family kinases and independent of the Src tyrosine phosphorylation state, occurs via a direct interaction of the c-Src catalytic domain with the inhibitory components. Our study indicates that sHSPs increase the affinity of 5′-AMP for the c-Src ATP binding site, thereby facilitating the inhibition. In vivo, elevation of ATP levels in the cardiomyocytes results in the tyrosine phosphorylation of cellular proteins including c-Src at the activatory site, and this effect is blocked when the 5′-AMP concentration is raised. Thus, this study reveals a novel role for sHSPs and 5′-AMP in the regulation of Src family kinases, presumably for the maintenance of the terminally differentiated state. PMID:10490624

Discovery of Diffuse Hard X-Ray Emission from the Vicinity of PSR J1648-4611 with Suzaku

NASA Astrophysics Data System (ADS)

Sakai, Michito; Matsumoto, Hironori; Haba, Yoshito; Kanou, Yasufumi; Miyamoto, Youhei

2013-06-01

We observed the pulsar PSR J1648-4611 with Suzaku. Two X-ray sources, Suzaku J1648-4610 (Src A) and Suzaku J1648-4615 (Src B), were found in the field of view. Src A is coincident with the pulsar PSR J1648-4611, which was also detected by the Fermi Gamma-ray Space Telescope. A hard-band image indicates that Src A is spatially extended. We found point sources in the vicinity of Src A by using a Chandra image of the same region, but the point sources have soft X-ray emission, and cannot explain the hard X-ray emission of Src A. The hard-band spectrum of Src A can be reproduced by a power-law model with a photon index of 2.0+0.9-0.7. The X-ray flux in the 2-10 keV band is 1.4 × 10-13 erg cm-2 s-1. The diffuse emission suggests a pulsar wind nebula around PSR J1648&"8211;4611, but the luminosity of Src A is much larger than that expected from the spin-down luminosity of the pulsar. Parts of the very-high-energy γ-ray emission of HESS J1646-458 may be powered by this pulsar wind nebula driven by PSR J1648-4611. Src B has soft emission, and its X-ray spectrum can be described by a power-law model with a photon index of 3.0+1.4-0.8. The X-ray flux in the 0.4-10 keV band is 6.4 × 10-14 erg s-1 cm-2. No counterpart for Src B has been found in the literature.

The Chromatin Assembly Factor Complex 1 (CAF1) and 5-Azacytidine (5-AzaC) Affect Cell Motility in Src-transformed Human Epithelial Cells.

PubMed

Endo, Akinori; Ly, Tony; Pippa, Raffaella; Bensaddek, Dalila; Nicolas, Armel; Lamond, Angus I

2017-01-06

Tumor invasion into surrounding stromal tissue is a hallmark of high grade, metastatic cancers. Oncogenic transformation of human epithelial cells in culture can be triggered by activation of v-Src kinase, resulting in increased cell motility, invasiveness, and tumorigenicity and provides a valuable model for studying how changes in gene expression cause cancer phenotypes. Here, we show that epithelial cells transformed by activated Src show increased levels of DNA methylation and that the methylation inhibitor 5-azacytidine (5-AzaC) potently blocks the increased cell motility and invasiveness induced by Src activation. A proteomic screen for chromatin regulators acting downstream of activated Src identified the replication-dependent histone chaperone CAF1 as an important factor for Src-mediated increased cell motility and invasion. We show that Src causes a 5-AzaC-sensitive decrease in both mRNA and protein levels of the p150 (CHAF1A) and p60 (CHAF1B), subunits of CAF1. Depletion of CAF1 in untransformed epithelial cells using siRNA was sufficient to recapitulate the increased motility and invasive phenotypes characteristic of transformed cells without activation of Src. Maintaining high levels of CAF1 by exogenous expression suppressed the increased cell motility and invasiveness phenotypes when Src was activated. These data identify a critical role of CAF1 in the dysregulation of cell invasion and motility phenotypes seen in transformed cells and also highlight an important role for epigenetic remodeling through DNA methylation for Src-mediated induction of cancer phenotypes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Multiple Kernel Sparse Representation based Orthogonal Discriminative Projection and Its Cost-Sensitive Extension.

PubMed

Zhang, Guoqing; Sun, Huaijiang; Xia, Guiyu; Sun, Quansen

2016-07-07

Sparse representation based classification (SRC) has been developed and shown great potential for real-world application. Based on SRC, Yang et al. [10] devised a SRC steered discriminative projection (SRC-DP) method. However, as a linear algorithm, SRC-DP cannot handle the data with highly nonlinear distribution. Kernel sparse representation-based classifier (KSRC) is a non-linear extension of SRC and can remedy the drawback of SRC. KSRC requires the use of a predetermined kernel function and selection of the kernel function and its parameters is difficult. Recently, multiple kernel learning for SRC (MKL-SRC) [22] has been proposed to learn a kernel from a set of base kernels. However, MKL-SRC only considers the within-class reconstruction residual while ignoring the between-class relationship, when learning the kernel weights. In this paper, we propose a novel multiple kernel sparse representation-based classifier (MKSRC), and then we use it as a criterion to design a multiple kernel sparse representation based orthogonal discriminative projection method (MK-SR-ODP). The proposed algorithm aims at learning a projection matrix and a corresponding kernel from the given base kernels such that in the low dimension subspace the between-class reconstruction residual is maximized and the within-class reconstruction residual is minimized. Furthermore, to achieve a minimum overall loss by performing recognition in the learned low-dimensional subspace, we introduce cost information into the dimensionality reduction method. The solutions for the proposed method can be efficiently found based on trace ratio optimization method [33]. Extensive experimental results demonstrate the superiority of the proposed algorithm when compared with the state-of-the-art methods.

Mouse fibroblasts homozygous for c-Src oncogene disruption shows dramatic suppression of expression of the gene encoding osteopontin, and adhesive phosphoprotein implicated in bone differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chackalaparampil, I.; Mukherjee, B.B.; Peri, A.

1994-09-01

Osteopetrosis, affecting mice and humans alike, arises from reduced or impaired bone resorption, causing abnormally dense bone formation. Normal bone differentiation requires continuous resorption and remodeling by osteoclasts which are derived from monocyte/macrophage lineage in the bone marrow. It has been reported that targeted homozygous disruption of c-src proto-oncogene in mice results in the development of osteopetrosis due to impaired bone-resorbing function of osteoclast cells. However, the molecular mechanism(s) which leads to osteoclast dysfunction in c-src deficient (src{sup -/-}) mice remains unclear. Here, we report that in embryonic fibroblasts derived from homozygous Src{sup -/-} mice, the expression of the genemore » coding for osteopontin (OP), a phosphorylated glycoprotein involved in bone differentiation, is drastically repressed. OP gene expression is not, however, affected in the heterozygous (Src{sup +/-}) mutant cells of identical origin, or in the c-src expression and OP production. Moreover, OP expression in c-src-deficient cells could be rescued upon treatment with 12-0-tetradecanoyl phorbol-13-myristate-acetate or okadaic acid. These observations indicate that OP expression is regulated via an src-mediated protein kinase C signaling pathway. Since it is known that OP mediates osteoclast adherence to the bone matrix, a key event in bone differentiation, our data is most significant in that they strongly suggest that drastic inhibition of synthesis of OP prevents osteoclasts in Src{sup -/-} mice from anchoring to the bone matrix. Consequently, this disruption of osteoclast adherence impairs their ability to form bone-resorbing ruffled border, causing osteopetrosis.« less

A Multifactorial Approach to Sport-Related Concussion Prevention and Education: Application of the Socioecological Framework.

PubMed

Register-Mihalik, Johna; Baugh, Christine; Kroshus, Emily; Y Kerr, Zachary; Valovich McLeod, Tamara C

2017-03-01

To offer an overview of sport-related concussion (SRC) prevention and education strategies in the context of the socioecological framework (SEF). Athletic trainers (ATs) will understand the many factors that interact to influence SRC prevention and the implications of these interactions for effective SRC education. Concussion is a complex injury that is challenging to identify and manage, particularly when athletes fail to disclose symptoms to their health care providers. Education is 1 strategy for increasing disclosure. However, limited information addresses how ATs can integrate the many factors that may influence the effectiveness of SRC education into their specific settings. Public health models provide an example through the SEF, which highlights the interplay among various levels of society and sport that can facilitate SRC prevention strategies, including education. For ATs to develop appropriate SRC prevention strategies, a framework for application is needed. A growing body of information concerning SRC prevention indicates that knowledge alone is insufficient to change concussion-related behaviors. The SEF allows this information to be considered at levels such as policy and societal, community, interpersonal (relationships), and intrapersonal (athlete). The use of such a framework will facilitate more comprehensive SRC prevention efforts that can be applied in all athletic training practice settings. Clinical Applications: Athletic trainers can use this information as they plan SRC prevention strategies in their specific settings. This approach will aid in addressing the layers of complexity that exist when developing a concussion-management policy and plan.

Steroid receptor coactivator-3 regulates glucose metabolism in bladder cancer cells through coactivation of hypoxia inducible factor 1α.

PubMed

Zhao, Wei; Chang, Cunjie; Cui, Yangyan; Zhao, Xiaozhi; Yang, Jun; Shen, Lan; Zhou, Ji; Hou, Zhibo; Zhang, Zhen; Ye, Changxiao; Hasenmayer, Donald; Perkins, Robert; Huang, Xiaojing; Yao, Xin; Yu, Like; Huang, Ruimin; Zhang, Dianzheng; Guo, Hongqian; Yan, Jun

2014-04-18

Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as "Warburg effect," to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1α (HIF1α), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1α-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1α to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy.

Different mechanisms are responsible for dishabituation of electrophysiological auditory responses to a change in acoustic identity than to a change in stimulus location.

PubMed

Smulders, Tom V; Jarvis, Erich D

2013-11-01

Repeated exposure to an auditory stimulus leads to habituation of the electrophysiological and immediate-early-gene (IEG) expression response in the auditory system. A novel auditory stimulus reinstates this response in a form of dishabituation. This has been interpreted as the start of new memory formation for this novel stimulus. Changes in the location of an otherwise identical auditory stimulus can also dishabituate the IEG expression response. This has been interpreted as an integration of stimulus identity and stimulus location into a single auditory object, encoded in the firing patterns of the auditory system. In this study, we further tested this hypothesis. Using chronic multi-electrode arrays to record multi-unit activity from the auditory system of awake and behaving zebra finches, we found that habituation occurs to repeated exposure to the same song and dishabituation with a novel song, similar to that described in head-fixed, restrained animals. A large proportion of recording sites also showed dishabituation when the same auditory stimulus was moved to a novel location. However, when the song was randomly moved among 8 interleaved locations, habituation occurred independently of the continuous changes in location. In contrast, when 8 different auditory stimuli were interleaved all from the same location, a separate habituation occurred to each stimulus. This result suggests that neuronal memories of the acoustic identity and spatial location are different, and that allocentric location of a stimulus is not encoded as part of the memory for an auditory object, while its acoustic properties are. We speculate that, instead, the dishabituation that occurs with a change from a stable location of a sound is due to the unexpectedness of the location change, and might be due to different underlying mechanisms than the dishabituation and separate habituations to different acoustic stimuli. Copyright © 2013 Elsevier Inc. All rights reserved.

Ocular vestibular evoked myogenic potentials elicited with vibration applied to the teeth.

PubMed

Parker-George, Jennifer C; Bell, Steven L; Griffin, Michael J

2016-01-01

This study investigated whether the method for eliciting vibration-induced oVEMPs could be improved by applying vibration directly to the teeth, and how vibration-induced oVEMP responses depend on the duration of the applied vibration. In 10 participants, a hand-held shaker was used to present 100-Hz vibration tone pips to the teeth via a customised bite-bar or to other parts of the head. oVEMP potentials were recorded in response to vibration in three orthogonal directions and five stimulus durations (10-180 ms). The oVEMP responses were analysed in terms of the peak latency onset, peak-to-peak amplitude, and the quality of the trace. Vibration applied to the teeth via the bite-bar produced oVEMPs that were more consistent, of higher quality and of greater amplitude than those evoked by vibration applied to the head. Longer duration stimuli produced longer duration oVEMP responses. One cycle duration stimuli produced responses that were smaller in amplitude and lower quality than the longer stimulus durations. Application of vibration via the teeth using a bite-bar is an effective means of producing oVEMPs. A 1-cycle stimulus is not optimal to evoke an oVEMP because it produces less robust responses than those of longer stimulus duration. A positive relationship between the duration of the stimulus and the response is consistent with the notion that the vibration-induced oVEMP is an oscillatory response to the motion of the head, rather than being a simple reflex response that occurs when the stimulus exceeds a threshold level of stimulation. Applying acceleration to the teeth through a bite-bar elicits clearer oVEMP responses than direct application to other parts of the head and has potential to improve clinical measurements. A 100-Hz 1-cycle stimulus produces less robust oVEMP responses than longer 100-Hz stimuli. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Stimulus-related activity during conditional associations in monkey perirhinal cortex neurons depends on upcoming reward outcome.

PubMed

Ohyama, Kaoru; Sugase-Miyamoto, Yasuko; Matsumoto, Narihisa; Shidara, Munetaka; Sato, Chikara

2012-11-28

Acquiring the significance of events based on reward-related information is critical for animals to survive and to conduct social activities. The importance of the perirhinal cortex for reward-related information processing has been suggested. To examine whether or not neurons in this cortex represent reward information flexibly when a visual stimulus indicates either a rewarded or unrewarded outcome, neuronal activity in the macaque perirhinal cortex was examined using a conditional-association cued-reward task. The task design allowed us to study how the neuronal responses depended on the animal's prediction of whether it would or would not be rewarded. Two visual stimuli, a color stimulus as Cue1 followed by a pattern stimulus as Cue2, were sequentially presented. Each pattern stimulus was conditionally associated with both rewarded and unrewarded outcomes depending on the preceding color stimulus. We found an activity depending upon the two reward conditions during Cue2, i.e., pattern stimulus presentation. The response appeared after the response dependent upon the image identity of Cue2. The response delineating a specific cue sequence also appeared between the responses dependent upon the identity of Cue2 and reward conditions. Thus, when Cue1 sets the context for whether or not Cue2 indicates a reward, this region represents the meaning of Cue2, i.e., the reward conditions, independent of the identity of Cue2. These results suggest that neurons in the perirhinal cortex do more than associate a single stimulus with a reward to achieve flexible representations of reward information.

Histochemical assessment for osteoblastic activity coupled with dysfunctional osteoclasts in c-src deficient mice.

PubMed

Toray, Hisashi; Hasegawa, Tomoka; Sakagami, Naoko; Tsuchiya, Erika; Kudo, Ai; Zhao, Shen; Moritani, Yasuhito; Abe, Miki; Yoshida, Taiji; Yamamoto, Tomomaya; Yamamoto, Tsuneyuki; Oda, Kimimitsu; Udagawa, Nobuyuki; Luiz de Freitas, Paulo Henrique; Li, Minqi

2017-01-01

Since osteoblastic activities are believed to be coupled with osteoclasts, we have attempted to histologically verify which of the distinct cellular circumstances, the presence of osteoclasts themselves or bone resorption by osteoclasts, is essential for coupled osteoblastic activity, by examining c-fos -/- or c-src -/- mice. Osteopetrotic c-fos deficient (c-fos -/- ) mice have no osteoclasts, while c-src deficient (c-src -/- ) mice, another osteopetrotic model, develop dysfunctional osteoclasts due to a lack of ruffled borders. c-fos -/- mice possessed no tartrate-resistant acid phosphatase (TRAPase)-reactive osteoclasts, and showed very weak tissue nonspecific alkaline phosphatase (TNALPase)-reactive mature osteoblasts. In contrast, c-src -/- mice had many TNALPase-positive osteoblasts and TRAPase-reactive osteoclasts. Interestingly, the parallel layers of TRAPase-reactive/osteopontin-positive cement lines were observed in the superficial region of c-src -/- bone matrix. This indicates the possibility that in c-src -/- mice, osteoblasts were activated to deposit new bone matrices on the surfaces that osteoclasts previously passed along, even without bone resorption. Transmission electron microscopy demonstrated cell-to-cell contacts between mature osteoblasts and neighboring ruffled border-less osteoclasts, and osteoid including many mineralized nodules in c-src -/- mice. Thus, it seems likely that osteoblastic activities would be maintained in the presence of osteoclasts, even if they are dysfunctional.

v-src induces clonal sarcomas and rapid metastasis following transduction with a replication-defective retrovirus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stoker, A.W.; Sieweke, M.H.

1989-12-01

v-src is an effective carcinogen when expressed from Rous sarcoma virus (RSV) in vivo. Whereas RSV tumors require sustained oncogene expression, their growth is largely a balance between viral recruitment of tissues and host immune destruction of infected cells. The authors have therefore examined the tumorigenic potential of v-src in the absence of viral recruitment and viral antigen expression. v-src was introduced with high efficiency into chicken wing web tissues using replication-defective (rd) retroviral vectors. Clonal sarcomas were induced rapidly, and furthermore, v-src potentiated metastatic progression in {approx} 0.1%-1% of tumor clones with unexpectedly short latency. rd vectors proved effectivemore » not only in transducing v-src into tissues but also as insertional markers of tumor clonality. The rd vector present in most primary and metastatic tumors was a highly truncated form of RSV derived by viral transmission of spliced v-src mRNA; this vector should thus avoid viral recruitment and host anti-viral immune reaction through its complete lack of viral structural genes. Under such conditions v-src maintains strong carcinogenicity in vivo when restricted to clonal tumor growth and can confer rapid metastatic potential on a discrete subset of tumor clones.« less

Two Sides of the Same Coin: The Positive and Negative Impact of Spiritual Religious Coping on Quality of Life and Depression in Dialysis Patients.

PubMed

Vitorino, Luciano Magalhães; Soares, Renata de Castro E Santos; Santos, Ana Eliza Oliveira; Lucchetti, Alessandra Lamas Granero; Cruz, Jonas Preposi; Cortez, Paulo José Oliveira; Lucchetti, Giancarlo

2017-08-01

Studies have shown that spiritual/religious beliefs are associated with mental health and health-related quality of life (HRQoL). However, few studies evaluated how spiritual/religious coping (SRC) could affect hemodialysis patients. The present study investigated the role of SRC behaviors on HRQoL and depressive symptoms in hemodialysis patients. This was cross-sectional study with 184 patients. Patients completed the Beck Depression Inventory, Brief SRC Scale, Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and a Sociodemographic and Health Characterization Questionnaire. From 218 patients, 184 (84.4%) were included (53.8% male with a median age of 55.9 years). Negative SRC, but not positive SRC, was associated with depressive symptoms. Positive SRC presented significant effects in SF-36 pain and physical and social functioning. On the other hand, negative SRC exhibited significant effects in SF-36 role emotional, energy/fatigue, pain, and physical functioning. SRC influences the mental health and HRQoL in Brazilian hemodialysis patients in two distinct ways. If used positively, it may have positive outcomes. However, if used negatively, it may lead to dysfunctional consequences such as greater depressive symptomatology and affect HRQoL. Health professionals must be aware of these "two sides of the same coin."

Proteinase-activated receptor 4 stimulation-induced epithelial-mesenchymal transition in alveolar epithelial cells

PubMed Central

Ando, Seijitsu; Otani, Hitomi; Yagi, Yasuhiro; Kawai, Kenzo; Araki, Hiromasa; Fukuhara, Shirou; Inagaki, Chiyoko

2007-01-01

Background Proteinase-activated receptors (PARs; PAR1–4) that can be activated by serine proteinases such as thrombin and neutrophil catepsin G are known to contribute to the pathogenesis of various pulmonary diseases including fibrosis. Among these PARs, especially PAR4, a newly identified subtype, is highly expressed in the lung. Here, we examined whether PAR4 stimulation plays a role in the formation of fibrotic response in the lung, through alveolar epithelial-mesenchymal transition (EMT) which contributes to the increase in myofibroblast population. Methods EMT was assessed by measuring the changes in each specific cell markers, E-cadherin for epithelial cell, α-smooth muscle actin (α-SMA) for myofibroblast, using primary cultured mouse alveolar epithelial cells and human lung carcinoma-derived alveolar epithelial cell line (A549 cells). Results Stimulation of PAR with thrombin (1 U/ml) or a synthetic PAR4 agonist peptide (AYPGKF-NH2, 100 μM) for 72 h induced morphological changes from cobblestone-like structure to elongated shape in primary cultured alveolar epithelial cells and A549 cells. In immunocytochemical analyses of these cells, such PAR4 stimulation decreased E-cadherin-like immunoreactivity and increased α-SMA-like immunoreactivity, as observed with a typical EMT-inducer, tumor growth factor-β (TGF-β). Western blot analyses of PAR4-stimulated A549 cells also showed similar changes in expression of these EMT-related marker proteins. Such PAR4-mediated changes were attenuated by inhibitors of epidermal growth factor receptor (EGFR) kinase and Src. PAR4-mediated morphological changes in primary cultured alveolar epithelial cells were reduced in the presence of these inhibitors. PAR4 stimulation increased tyrosine phosphorylated EGFR or tyrosine phosphorylated Src level in A549 cells, and the former response being inhibited by Src inhibitor. Conclusion PAR4 stimulation of alveolar epithelial cells induced epithelial-mesenchymal transition (EMT) as monitored by cell shapes, and epithelial or myofibroblast marker at least partly through EGFR transactivation via receptor-linked Src activation. PMID:17433115

Visual motion direction is represented in population-level neural response as measured by magnetoencephalography.

PubMed

Kaneoke, Y; Urakawa, T; Kakigi, R

2009-05-19

We investigated whether direction information is represented in the population-level neural response evoked by the visual motion stimulus, as measured by magnetoencephalography. Coherent motions with varied speed, varied direction, and different coherence level were presented using random dot kinematography. Peak latency of responses to motion onset was inversely related to speed in all directions, as previously reported, but no significant effect of direction on latency changes was identified. Mutual information entropy (IE) calculated using four-direction response data increased significantly (>2.14) after motion onset in 41.3% of response data and maximum IE was distributed at approximately 20 ms after peak response latency. When response waveforms showing significant differences (by multivariate discriminant analysis) in distribution of the three waveform parameters (peak amplitude, peak latency, and 75% waveform width) with stimulus directions were analyzed, 87 waveform stimulus directions (80.6%) were correctly estimated using these parameters. Correct estimation rate was unaffected by stimulus speed, but was affected by coherence level, even though both speed and coherence affected response amplitude similarly. Our results indicate that speed and direction of stimulus motion are represented in the distinct properties of a response waveform, suggesting that the human brain processes speed and direction separately, at least in part.

SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2

NASA Astrophysics Data System (ADS)

Naudin, Cécile; Sirvent, Audrey; Leroy, Cédric; Larive, Romain; Simon, Valérie; Pannequin, Julie; Bourgaux, Jean-François; Pierre, Josiane; Robert, Bruno; Hollande, Frédéric; Roche, Serge

2014-01-01

The adaptor SLAP is a negative regulator of receptor signalling in immune cells but its role in human cancer is ill defined. Here we report that SLAP is abundantly expressed in healthy epithelial intestine but strongly downregulated in 50% of colorectal cancer. SLAP overexpression suppresses cell tumorigenicity and invasiveness while SLAP silencing enhances these transforming properties. Mechanistically, SLAP controls SRC/EPHA2/AKT signalling via destabilization of the SRC substrate and receptor tyrosine kinase EPHA2. This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2. SRC phosphorylates EPHA2 on Tyr594, thus creating a feedback loop that promotes EPHA2 destruction and thereby self-regulates its transforming potential. SLAP silencing enhances SRC oncogenicity and sensitizes colorectal tumour cells to SRC inhibitors. Collectively, these data establish a tumour-suppressive role for SLAP in colorectal cancer and a mechanism of SRC oncogenic induction through stabilization of its cognate substrates.

Lipid binding by the Unique and SH3 domains of c-Src suggests a new regulatory mechanism

PubMed Central

Pérez, Yolanda; Maffei, Mariano; Igea, Ana; Amata, Irene; Gairí, Margarida; Nebreda, Angel R.; Bernadó, Pau; Pons, Miquel

2013-01-01

c-Src is a non-receptor tyrosine kinase involved in numerous signal transduction pathways. The kinase, SH3 and SH2 domains of c-Src are attached to the membrane-anchoring SH4 domain through the flexible Unique domain. Here we show intra- and intermolecular interactions involving the Unique and SH3 domains suggesting the presence of a previously unrecognized additional regulation layer in c-Src. We have characterized lipid binding by the Unique and SH3 domains, their intramolecular interaction and its allosteric modulation by a SH3-binding peptide or by Calcium-loaded calmodulin binding to the Unique domain. We also show reduced lipid binding following phosphorylation at conserved sites of the Unique domain. Finally, we show that injection of full-length c-Src with mutations that abolish lipid binding by the Unique domain causes a strong in vivo phenotype distinct from that of wild-type c-Src in a Xenopus oocyte model system, confirming the functional role of the Unique domain in c-Src regulation. PMID:23416516

Stimulus Effects on Local Preference: Stimulus-Response Contingencies, Stimulus-Food Pairing, and Stimulus-Food Correlation

ERIC Educational Resources Information Center

Davison, Michael; Baum, William M.

2010-01-01

Four pigeons were trained in a procedure in which concurrent-schedule food ratios changed unpredictably across seven unsignaled components after 10 food deliveries. Additional green-key stimulus presentations also occurred on the two alternatives, sometimes in the same ratio as the component food ratio, and sometimes in the inverse ratio. In eight…

Temporal Response Properties of Accessory Olfactory Bulb Neurons: Limitations and Opportunities for Decoding.

PubMed

Yoles-Frenkel, Michal; Kahan, Anat; Ben-Shaul, Yoram

2018-05-23

The vomeronasal system (VNS) is a major vertebrate chemosensory system that functions in parallel to the main olfactory system (MOS). Despite many similarities, the two systems dramatically differ in the temporal domain. While MOS responses are governed by breathing and follow a subsecond temporal scale, VNS responses are uncoupled from breathing and evolve over seconds. This suggests that the contribution of response dynamics to stimulus information will differ between these systems. While temporal dynamics in the MOS are widely investigated, similar analyses in the accessory olfactory bulb (AOB) are lacking. Here, we have addressed this issue using controlled stimulus delivery to the vomeronasal organ of male and female mice. We first analyzed the temporal properties of AOB projection neurons and demonstrated that neurons display prolonged, variable, and neuron-specific characteristics. We then analyzed various decoding schemes using AOB population responses. We showed that compared with the simplest scheme (i.e., integration of spike counts over the entire response period), the division of this period into smaller temporal bins actually yields poorer decoding accuracy. However, optimal classification accuracy can be achieved well before the end of the response period by integrating spike counts within temporally defined windows. Since VNS stimulus uptake is variable, we analyzed decoding using limited information about stimulus uptake time, and showed that with enough neurons, such time-invariant decoding is feasible. Finally, we conducted simulations that demonstrated that, unlike the main olfactory bulb, the temporal features of AOB neurons disfavor decoding with high temporal accuracy, and, rather, support decoding without precise knowledge of stimulus uptake time. SIGNIFICANCE STATEMENT A key goal in sensory system research is to identify which metrics of neuronal activity are relevant for decoding stimulus features. Here, we describe the first systematic analysis of temporal coding in the vomeronasal system (VNS), a chemosensory system devoted to socially relevant cues. Compared with the main olfactory system, timescales of VNS function are inherently slower and variable. Using various analyses of real and simulated data, we show that the consideration of response times relative to stimulus uptake can aid the decoding of stimulus information from neuronal activity. However, response properties of accessory olfactory bulb neurons favor decoding schemes that do not rely on the precise timing of stimulus uptake. Such schemes are consistent with the variable nature of VNS stimulus uptake. Copyright © 2018 the authors 0270-6474/18/384957-20$15.00/0.

Training methods for horses: habituation to a frightening stimulus.

PubMed

Christensen, J W; Rundgren, M; Olsson, K

2006-09-01

Responses of horses in frightening situations are important for both equine and human safety. Considerable scientific interest has been shown in development of reactivity tests, but little effort has been dedicated to the development of appropriate training methods for reducing fearfulness. To investigate which of 3 different training methods (habituation, desensitisation and counter-conditioning) was most effective in teaching horses to react calmly in a potentially frightening situation. 1) Horses are able to generalise about the test stimulus such that, once familiar with the test stimulus in one situation, it appears less frightening and elicits a reduced response even when the stimulus intensity is increased or the stimulus is presented differently; and 2) alternative methods such as desensitisation and counter-conditioning would be more efficient than a classic habituation approach. Twenty-seven naive 2-year-old Danish Warmblood stallions were trained according to 3 different methods, based on classical learning theory: 1) horses (n = 9) were exposed to the full stimulus (a moving, white nylon bag, 1.2 x 0.75 m) in 5 daily training sessions until they met a predefined habituation criterion (habituation); 2) horses (n = 9) were introduced gradually to the stimulus and habituated to each step before the full stimulus was applied (desensitisation); 3) horses (n = 9) were trained to associate the stimulus with a positive reward before being exposed to the full stimulus (counter-conditioning). Each horse received 5 training sessions of 3 min per day. Heart rate and behavioural responses were recorded. Horses trained with the desensitisation method showed fewer flight responses in total and needed fewer training sessions to learn to react calmly to test stimuli. Variations in heart rate persisted even when behavioural responses had ceased. In addition, all horses on the desensitisation method eventually habituated to the test stimulus whereas some horses on the other methods did not. Desensitisation appeared to be the most effective training method for horses in frightening situations. Further research is needed in order to investigate the role of positive reinforcement, such as offering food, in the training of horses.

Brainstem auditory evoked responses in man. 1: Effect of stimulus rise-fall time and duration

NASA Technical Reports Server (NTRS)

Hecox, K.; Squires, N.; Galambos, R.

1975-01-01

Short latency (under 10 msec) responses elicited by bursts of white noise were recorded from the scalps of human subjects. Response alterations produced by changes in the noise burst duration (on-time), inter-burst interval (off-time), and onset and offset shapes were analyzed. The latency of the most prominent response component, wave V, was markedly delayed with increases in stimulus rise time but was unaffected by changes in fall time. Increases in stimulus duration, and therefore in loudness, resulted in a systematic increase in latency. This was probably due to response recovery processes, since the effect was eliminated with increases in stimulus off-time. The amplitude of wave V was insensitive to changes in signal rise and fall times, while increasing signal on-time produced smaller amplitude responses only for sufficiently short off-times. It was concluded that wave V of the human auditory brainstem evoked response is solely an onset response.

Startle reveals an absence of advance motor programming in a Go/No-go task.

PubMed

Carlsen, Anthony N; Chua, Romeo; Dakin, Chris J; Sanderson, David J; Inglis, J Timothy; Franks, Ian M

2008-03-21

Presenting a startling stimulus in a simple reaction time (RT) task, can involuntarily trigger the pre-programmed response. However, this effect is not seen when the response is programmed following the imperative stimulus (IS) providing evidence that a startle can only trigger pre-programmed responses. In a "Go/No-go" (GNG) RT task the response may be programmed in advance of the IS because there exists only a single predetermined response. The purpose of the current investigation was to examine if startle could elicit a response in a GNG task. Participants completed a wrist extension task in response to a visual stimulus. A startling acoustic stimulus (124dB) was presented in both Go and No-go trials with Go probability manipulated between groups. The inclusion of a startle did not significantly speed RT and led to more response errors. This result is similar to that observed in a startled choice RT task, indicating that in a GNG task participants waited until the IS complete motor programming.

Measurement, time-stamping, and analysis of electrodermal activity in fMRI

NASA Astrophysics Data System (ADS)

Smyser, Christopher; Grabowski, Thomas J.; Rainville, Pierre; Bechara, Antione; Razavi, Mehrdad; Mehta, Sonya; Eaton, Brent L.; Bolinger, Lizann

2002-04-01

A low cost fMRI-compatible system was developed for detecting electrodermal activity without inducing image artifact. Subject electrodermal activity was measured on the plantar surface of the foot using a standard recording circuit. Filtered analog skin conductance responses (SCR) were recorded with a general purpose, time-stamping data acquisition system. A conditioning paradigm involving painful thermal stimulation was used to demonstrate SCR detection and investigate neural correlates of conditioned autonomic activity. 128x128 pixel EPI-BOLD images were acquired with a GE 1.5T Signa scanner. Image analysis was performed using voxel-wise multiple linear regression. The covariate of interest was generated by convolving stimulus event onset with a standard hemodynamic response function. The function was time-shifted to determine optimal activation. Significance was tested using the t-statistic. Image quality was unaffected by the device, and conditioned and unconditioned SCRs were successfully detected. Conditioned SCRs correlated significantly with activity in the right anterior insular cortex. The effect was more robust when responses were scaled by SCR amplitude. The ability to measure and time register SCRs during fMRI acquisition enables studies of cognitive processes marked by autonomic activity, including those involving decision-making, pain, emotion, and addiction.

Selective inhibition of a multicomponent response can be achieved without cost

PubMed Central

Westrick, Zachary; Ivry, Richard B.

2014-01-01

Behavioral flexibility frequently requires the ability to modify an on-going action. In some situations, optimal performance requires modifying some components of an on-going action without interrupting other components of that action. This form of control has been studied with the selective stop-signal task, in which participants are instructed to abort only one movement of a multicomponent response. Previous studies have shown a transient disruption of the nonaborted component, suggesting limitations in our ability to use selective inhibition. This cost has been attributed to a structural limitation associated with the recruitment of a cortico-basal ganglia pathway that allows for the rapid inhibition of action but operates in a relatively generic manner. Using a model-based approach, we demonstrate that, with a modest amount of training and highly compatible stimulus-response mappings, people can perform a selective-stop task without any cost on the nonaborted component. Prior reports of behavioral costs in selective-stop tasks reflect, at least in part, a sampling bias in the method commonly used to estimate such costs. These results suggest that inhibition can be selectively controlled and present a challenge for models of inhibitory control that posit the operation of generic processes. PMID:25339712

Hippo, TGF-β, and Src-MAPK pathways regulate transcription of the upd3 cytokine in Drosophila enterocytes upon bacterial infection.

PubMed

Houtz, Philip; Bonfini, Alessandro; Liu, Xi; Revah, Jonathan; Guillou, Aurélien; Poidevin, Mickael; Hens, Korneel; Huang, Hsin-Yi; Deplancke, Bart; Tsai, Yu-Chen; Buchon, Nicolas

2017-11-01

Cytokine signaling is responsible for coordinating conserved epithelial regeneration and immune responses in the digestive tract. In the Drosophila midgut, Upd3 is a major cytokine, which is induced in enterocytes (EC) and enteroblasts (EB) upon oral infection, and initiates intestinal stem cell (ISC) dependent tissue repair. To date, the genetic network directing upd3 transcription remains largely uncharacterized. Here, we have identified the key infection-responsive enhancers of the upd3 gene and show that distinct enhancers respond to various stresses. Furthermore, through functional genetic screening, bioinformatic analyses and yeast one-hybrid screening, we determined that the transcription factors Scalloped (Sd), Mothers against dpp (Mad), and D-Fos are principal regulators of upd3 expression. Our study demonstrates that upd3 transcription in the gut is regulated by the activation of multiple pathways, including the Hippo, TGF-β/Dpp, and Src, as well as p38-dependent MAPK pathways. Thus, these essential pathways, which are known to control ISC proliferation cell-autonomously, are also activated in ECs to promote tissue turnover the regulation of upd3 transcription.

Task representation in individual and joint settings

PubMed Central

Prinz, Wolfgang

2015-01-01

This paper outlines a framework for task representation and discusses applications to interference tasks in individual and joint settings. The framework is derived from the Theory of Event Coding (TEC). This theory regards task sets as transient assemblies of event codes in which stimulus and response codes interact and shape each other in particular ways. On the one hand, stimulus and response codes compete with each other within their respective subsets (horizontal interactions). On the other hand, stimulus and response code cooperate with each other (vertical interactions). Code interactions instantiating competition and cooperation apply to two time scales: on-line performance (i.e., doing the task) and off-line implementation (i.e., setting the task). Interference arises when stimulus and response codes overlap in features that are irrelevant for stimulus identification, but relevant for response selection. To resolve this dilemma, the feature profiles of event codes may become restructured in various ways. The framework is applied to three kinds of interference paradigms. Special emphasis is given to joint settings where tasks are shared between two participants. Major conclusions derived from these applications include: (1) Response competition is the chief driver of interference. Likewise, different modes of response competition give rise to different patterns of interference; (2) The type of features in which stimulus and response codes overlap is also a crucial factor. Different types of such features give likewise rise to different patterns of interference; and (3) Task sets for joint settings conflate intraindividual conflicts between responses (what), with interindividual conflicts between responding agents (whom). Features of response codes may, therefore, not only address responses, but also responding agents (both physically and socially). PMID:26029085

The imaging performance of the SRC on Mars Express

USGS Publications Warehouse

Oberst, J.; Schwarz, G.; Behnke, T.; Hoffmann, H.; Matz, K.-D.; Flohrer, J.; Hirsch, H.; Roatsch, T.; Scholten, F.; Hauber, E.; Brinkmann, B.; Jaumann, R.; Williams, D.; Kirk, R.; Duxbury, T.; Leu, C.; Neukum, G.

2008-01-01

The Mars Express spacecraft carries the pushbroom scanner high-resolution stereo camera (HRSC) and its added imaging subsystem super resolution channel (SRC). The SRC is equipped with its own optical system and a 1024??1024 framing sensor. SRC produces snapshots with 2.3 m ground pixel size from the nominal spacecraft pericenter height of 250 km, which are typically embedded in the central part of the large HRSC scenes. The salient features of the SRC are its light-weight optics, a reliable CCD detector, and high-speed read-out electronics. The quality and effective visibility of details in the SRC images unfortunately falls short of what has been expected. In cases where thermal balance cannot be reached, artifacts, such as blurring and "ghost features" are observed in the images. In addition, images show large numbers of blemish pixels and are plagued by electronic noise. As a consequence, we have developed various image improving algorithms, which are discussed in this paper. While results are encouraging, further studies of image restoration by dedicated processing appear worthwhile. The SRC has obtained more than 6940 images at the time of writing (1 September 2007), which often show fascinating details in surface morphology. SRC images are highly useful for a variety of applications in planetary geology, for studies of the Mars atmosphere, and for astrometric observations of the Martian satellites. This paper will give a full account of the design philosophy, technical concept, calibration, operation, integration with HRSC, and performance, as well as science accomplishments of the SRC. ?? 2007 Elsevier Ltd. All rights reserved.

Shifts of Gamma Phase across Primary Visual Cortical Sites Reflect Dynamic Stimulus-Modulated Information Transfer.

PubMed

Besserve, Michel; Lowe, Scott C; Logothetis, Nikos K; Schölkopf, Bernhard; Panzeri, Stefano

2015-01-01

Distributed neural processing likely entails the capability of networks to reconfigure dynamically the directionality and strength of their functional connections. Yet, the neural mechanisms that may allow such dynamic routing of the information flow are not yet fully understood. We investigated the role of gamma band (50-80 Hz) oscillations in transient modulations of communication among neural populations by using measures of direction-specific causal information transfer. We found that the local phase of gamma-band rhythmic activity exerted a stimulus-modulated and spatially-asymmetric directed effect on the firing rate of spatially separated populations within the primary visual cortex. The relationships between gamma phases at different sites (phase shifts) could be described as a stimulus-modulated gamma-band wave propagating along the spatial directions with the largest information transfer. We observed transient stimulus-related changes in the spatial configuration of phases (compatible with changes in direction of gamma wave propagation) accompanied by a relative increase of the amount of information flowing along the instantaneous direction of the gamma wave. These effects were specific to the gamma-band and suggest that the time-varying relationships between gamma phases at different locations mark, and possibly causally mediate, the dynamic reconfiguration of functional connections.

Shifts of Gamma Phase across Primary Visual Cortical Sites Reflect Dynamic Stimulus-Modulated Information Transfer

PubMed Central

Besserve, Michel; Lowe, Scott C.; Logothetis, Nikos K.; Schölkopf, Bernhard; Panzeri, Stefano

2015-01-01

Distributed neural processing likely entails the capability of networks to reconfigure dynamically the directionality and strength of their functional connections. Yet, the neural mechanisms that may allow such dynamic routing of the information flow are not yet fully understood. We investigated the role of gamma band (50–80 Hz) oscillations in transient modulations of communication among neural populations by using measures of direction-specific causal information transfer. We found that the local phase of gamma-band rhythmic activity exerted a stimulus-modulated and spatially-asymmetric directed effect on the firing rate of spatially separated populations within the primary visual cortex. The relationships between gamma phases at different sites (phase shifts) could be described as a stimulus-modulated gamma-band wave propagating along the spatial directions with the largest information transfer. We observed transient stimulus-related changes in the spatial configuration of phases (compatible with changes in direction of gamma wave propagation) accompanied by a relative increase of the amount of information flowing along the instantaneous direction of the gamma wave. These effects were specific to the gamma-band and suggest that the time-varying relationships between gamma phases at different locations mark, and possibly causally mediate, the dynamic reconfiguration of functional connections. PMID:26394205

An intra-neural microstimulation system for ultra-high field magnetic resonance imaging and magnetoencephalography.

PubMed

Glover, Paul M; Watkins, Roger H; O'Neill, George C; Ackerley, Rochelle; Sanchez-Panchuelo, Rosa; McGlone, Francis; Brookes, Matthew J; Wessberg, Johan; Francis, Susan T

2017-10-01

Intra-neural microstimulation (INMS) is a technique that allows the precise delivery of low-current electrical pulses into human peripheral nerves. Single unit INMS can be used to stimulate individual afferent nerve fibres during microneurography. Combining this with neuroimaging allows the unique monitoring of central nervous system activation in response to unitary, controlled tactile input, with functional magnetic resonance imaging (fMRI) providing exquisite spatial localisation of brain activity and magnetoencephalography (MEG) high temporal resolution. INMS systems suitable for use within electrophysiology laboratories have been available for many years. We describe an INMS system specifically designed to provide compatibility with both ultra-high field (7T) fMRI and MEG. Numerous technical and safety issues are addressed. The system is fully analogue, allowing for arbitrary frequency and amplitude INMS stimulation. Unitary recordings obtained within both the MRI and MEG screened-room environments are comparable with those obtained in 'clean' electrophysiology recording environments. Single unit INMS (current <7μA, 200μs pulses) of individual mechanoreceptive afferents produces appropriate and robust responses during fMRI and MEG. This custom-built MRI- and MEG-compatible stimulator overcomes issues with existing INMS approaches; it allows well-controlled switching between recording and stimulus mode, prevents electrical shocks because of long cable lengths, permits unlimited patterns of stimulation, and provides a system with improved work-flow and participant comfort. We demonstrate that the requirements for an INMS-integrated system, which can be used with both fMRI and MEG imaging systems, have been fully met. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

New efficient stimuli for evoking frequency-specific auditory steady-state responses.

PubMed

Stürzebecher, Ekkehard; Cebulla, Mario; Elberling, Claus; Berger, Thomas

2006-06-01

ASSR is a promising tool for the objective frequency-specific assessment of hearing thresholds in children. The stimulus generally used for ASSR recording (single amplitude-modulated carrier) only activates a small area on the basilar membrane. Therefore, the response amplitude is low. A stimulus with a broader frequency spectrum can be composed by adding several cosines whose frequency intervals comply with the desired stimulus repetition rate. Compensation of the travelling wave delay on the basilar membrane is possible with a stimulus of this type. Through this, a better synchronization of the neural response can be obtained and, as a result, higher response amplitudes can be expected, particularly for low-frequency stimuli. The additional introduction of a frequency offset enables the use of a q-sample test for the response detection, especially important at 500 Hz. The results of investigations carried out on a large group of normally hearing test subjects have confirmed the efficiency of this stimulus design. The new stimuli lead to significantly improved ASSRs with higher SNRs and thus higher detection rates and shorter detection times.

Task by stimulus interactions in brain responses during Chinese character processing.

PubMed

Yang, Jianfeng; Wang, Xiaojuan; Shu, Hua; Zevin, Jason D

2012-04-02

In the visual word recognition literature, it is well understood that various stimulus effects interact with behavioral task. For example, effects of word frequency are exaggerated and effects of spelling-to-sound regularity are reduced in the lexical decision task, relative to reading aloud. Neuroimaging studies of reading often examine effects of task and stimulus properties on brain activity independently, but potential interactions between task demands and stimulus effects have not been extensively explored. To address this issue, we conducted lexical decision and symbol detection tasks using stimuli that varied parametrically in their word-likeness, and tested for task by stimulus class interactions. Interactions were found throughout the reading system, such that stimulus selectivity was observed during the lexical decision task, but not during the symbol detection task. Further, the pattern of stimulus selectivity was directly related to task difficulty, so that the strongest brain activity was observed to the most word-like stimuli that required "no" responses, whereas brain activity to words, which elicit rapid and accurate "yes" responses were relatively weak. This is in line with models that argue for task-dependent specialization of brain regions, and contrasts with the notion of task-independent stimulus selectivity in the reading system. Copyright © 2012 Elsevier Inc. All rights reserved.

Autoshaping the pigeon's gape response: acquisition and topography as a function of reinforcer type and magnitude.

PubMed Central

Allan, R W; Zeigler, H P

1994-01-01

The pigeon's key-pecking response is experimentally dissociable into transport (head movement) and gape (jaw movement) components. During conditioning of the key-pecking response, both components come under the control of the conditioned stimulus. To study the acquisition of gape conditioned responses and to clarify the contribution of unconditioned stimulus (reinforcer) variables to the form of the response, gape and key-contact responses were recorded during an autoshaping procedure and reinforcer properties were systematically varied. One group of 8 pigeons was food deprived and subgroups of 2 birds each were exposed to four different pellet sizes as reinforcers, each reinforcer signaled by a keylight conditioned stimulus. A second group was water deprived and received water reinforcers paired with the conditioned stimulus. Water- or food-deprived control groups received appropriate water or food reinforcers that were randomly delivered with respect to the keylight stimulus. Acquisition of the conditioned gape response frequently preceded key-contact responses, and gape conditioned responses were generally elicited at higher rates than were key contacts. The form of the conditioned gape was similar to, but not identical with, the form of the unconditioned gape. The gape component is a critical topographical feature of the conditioned key peck, a sensitive measure of conditioning during autoshaping, and an important source of the observed similarities in the form of conditioned and consummatory responses. PMID:7964365

Autoshaping the pigeon's gape response: acquisition and topography as a function of reinforcer type and magnitude.

PubMed

Allan, R W; Zeigler, H P

1994-09-01

The pigeon's key-pecking response is experimentally dissociable into transport (head movement) and gape (jaw movement) components. During conditioning of the key-pecking response, both components come under the control of the conditioned stimulus. To study the acquisition of gape conditioned responses and to clarify the contribution of unconditioned stimulus (reinforcer) variables to the form of the response, gape and key-contact responses were recorded during an autoshaping procedure and reinforcer properties were systematically varied. One group of 8 pigeons was food deprived and subgroups of 2 birds each were exposed to four different pellet sizes as reinforcers, each reinforcer signaled by a keylight conditioned stimulus. A second group was water deprived and received water reinforcers paired with the conditioned stimulus. Water- or food-deprived control groups received appropriate water or food reinforcers that were randomly delivered with respect to the keylight stimulus. Acquisition of the conditioned gape response frequently preceded key-contact responses, and gape conditioned responses were generally elicited at higher rates than were key contacts. The form of the conditioned gape was similar to, but not identical with, the form of the unconditioned gape. The gape component is a critical topographical feature of the conditioned key peck, a sensitive measure of conditioning during autoshaping, and an important source of the observed similarities in the form of conditioned and consummatory responses.

The Mere Exposure Effect: Relationship to Response Competition and Imagery Ability.

ERIC Educational Resources Information Center

Vrana, Scott R.

Exposure to novel stimuli increases one's liking for such stimuli. Response competition is one theory attempting to account for this effect: as a stimulus becomes more familiar, competing responses drop out in favor of one dominant response and the stimulus becomes better liked. Imagery ability refers to the regeneration of responses during…

Src kinases in chondrosarcoma chemoresistance and migration: dasatinib sensitises to doxorubicin in TP53 mutant cells

PubMed Central

van Oosterwijk, J G; van Ruler, M A J H; Briaire-de Bruijn, I H; Herpers, B; Gelderblom, H; van de Water, B; Bovée, J V M G

2013-01-01

Background: Chondrosarcomas are malignant cartilage-forming tumours of bone. Because of their resistance to conventional chemotherapy and radiotherapy, currently no treatment strategies exist for unresectable and metastatic chondrosarcoma. Previously, PI3K/AKT/GSK3β and Src kinase pathways were shown to be activated in chondrosarcoma cell lines. Our aim was to investigate the role of these kinases in chemoresistance and migration in chondrosarcoma in relation to TP53 mutation status. Methods: We used five conventional and three dedifferentiated chondrosarcoma cell lines and investigated the effect of PI3K/AKT/GSK3β pathway inhibition (enzastaurin) and Src pathway inhibition (dasatinib) in chemoresistance using WST assay and live cell imaging with AnnexinV staining. Immunohistochemistry on tissue microarrays (TMAs) containing 157 cartilaginous tumours was performed for Src family members. Migration assays were performed with the RTCA xCelligence System. Results: Src inhibition was found to overcome chemoresistance, to induce apoptosis and to inhibit migration. Cell lines with TP53 mutations responded better to combination therapy than wild-type cell lines (P=0.002). Tissue microarray immunohistochemistry confirmed active Src (pSrc) signalling, with Fyn being most abundantly expressed (76.1%). Conclusion: These results strongly indicate Src family kinases, in particular Fyn, as a potential target for the treatment of inoperable and metastatic chondrosarcomas, and to sensitise for doxorubicin especially in the presence of TP53 mutations. PMID:23922104

An epitope localized in c-Src negative regulatory domain is a potential marker in early stage of colonic neoplasms.

PubMed

Sakai, T; Kawakatsu, H; Fujita, M; Yano, J; Owada, M K

1998-02-01

In previous work, we established a new monoclonal antibody that specifically recognizes the active form of c-Src tyrosine kinase (Kawakatsu et al, 1996). To determine whether c-Src is active in colorectal tumorigenesis, we examined the expression of an active form of c-Src in human normal mucosa, hyperplastic polyps, adenomas, and adenocarcinomas. The tissue distribution of the active form of c-Src was studied by immunohistochemistry using this antibody, termed Clone 28. Among 66 cases of adenoma tested, 61 (92%) showed positive staining (adenoma with mild atypia, 3 of 3; adenoma with moderate atypia, 38 of 42; adenoma with severe atypia, 20 of 21). In contrast to the frequent and intense staining in adenomas, adenocarcinoma showed weak staining with less frequency in 4 of 16 (25%) cases. The number of specimens with positive staining in well- and moderately differentiated adenocarcinomas was limited to an early stage. The active form of c-Src mainly localized to the nuclear membrane and the perinuclear region. These results provide the first direct evidence that the activation of c-Src appears to be an early event in colonic carcinogenesis in situ. The findings of the present study thus allow us to propose a molecular mechanism involving c-Src activation in the process of malignant transformation of the human colonic neoplastic cells.

Interfacing with USSTRATCOM and UTTR during Stardust Earth Return

NASA Technical Reports Server (NTRS)

Jefferson, David C.; Baird, Darren T.; Cangahuala, Laureano A.; Lewis, George D.

2006-01-01

The Stardust Sample Return Capsule separated from the main spacecraft four hours prior to atmospheric entry. Between this time and the time at which the SRC touched down at the Utah Test and Training Range, two organizations external to JPL were involved in tracking the Sample Return Capsule. Orbit determination for the Stardust spacecraft during deep space cruise, the encounters of asteroid Annefrank and comet Wild 2, and the final approach to Earth used X-band radio metric Doppler and range data obtained through the Deep Space Network. The SRC lacked the electronics needed for coherently transponded radio metric tracking, so the DSN was not able to track the SRC after it separated from the main spacecraft. Although the expected delivery accuracy at atmospheric entry was well within the capability needed to target the SRC to the desired ground location, it was still desirable to obtain direct knowledge of the SRC trajectory in case of anomalies. For this reason U.S. Strategic Command was engaged to track the SRC between separation and atmospheric entry. Once the SRC entered the atmosphere, ground sensors at UTTR were tasked to acquire the descending SRC and maintain track during the descent in order to determine the landing location, to which the ground recovery team was then directed. This paper discusses organizational interfaces, data products, and delivery schedules, and the actual tracking operations are described.

PLC-γ directly binds activated c-Src, which is necessary for carbachol-mediated inhibition of NHE3 activity in Caco-2/BBe cells

PubMed Central

Lee, Luke J.; Kovbasnjuk, Olga; Li, Xuhang; Donowitz, Mark

2013-01-01

Elevated levels of intracellular Ca2+ ([Ca2+]i) inhibit Na+/H+ exchanger 3 (NHE3) activity in the intact intestine. We previously demonstrated that PLC-γ directly binds NHE3, an interaction that is necessary for [Ca2+]i inhibition of NHE3 activity, and that PLC-γ Src homology 2 (SH2) domains may scaffold Ca2+ signaling proteins necessary for regulation of NHE3 activity. [Ca2+]i regulation of NHE3 activity is also c-Src dependent; however, the mechanism by which c-Src is involved is undetermined. We hypothesized that the SH2 domains of PLC-γ might link c-Src to NHE3-containing complexes to mediate [Ca2+]i inhibition of NHE3 activity. In Caco-2/BBe cells, carbachol (CCh) decreased NHE3 activity by ∼40%, an effect abolished with the c-Src inhibitor PP2. CCh treatment increased the amount of active c-Src as early as 1 min through increased Y416 phosphorylation. Coimmunoprecipitation demonstrated that c-Src associated with PLC-γ, but not NHE3, under basal conditions, an interaction that increased rapidly after CCh treatment and occurred before the dissociation of PLC-γ and NHE3 that occurred 10 min after CCh treatment. Finally, direct binding to c-Src only occurred through the PLC-γ SH2 domains, an interaction that was prevented by blocking the PLC-γ SH2 domain. This study demonstrated that c-Src 1) activity is necessary for [Ca2+]i inhibition of NHE3 activity, 2) activation occurs rapidly (∼1 min) after CCh treatment, 3) directly binds PLC-γ SH2 domains and associates dynamically with PLC-γ under elevated [Ca2+]i conditions, and 4) does not directly bind NHE3. Under elevated [Ca2+]i conditions, PLC-γ scaffolds c-Src into NHE3-containing multiprotein complexes before dissociation of PLC-γ from NHE3 and subsequent endocytosis of NHE3. PMID:23703528

Targeting Drug-Sensitive and -Resistant Strains of Mycobacterium tuberculosis by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology.

PubMed

Chandra, Pallavi; Rajmani, R S; Verma, Garima; Bhavesh, Neel Sarovar; Kumar, Dhiraj

2016-01-01

In view of emerging drug resistance among bacterial pathogens, including Mycobacterium tuberculosis, the development of novel therapeutic strategies is increasingly being sought. A recent paradigm in antituberculosis (anti-TB) drug development is to target the host molecules that are crucial for intracellular survival of the pathogen. We previously showed the importance of Src tyrosine kinases in mycobacterial pathogenesis. Here, we report that inhibition of Src significantly reduced survival of H37Rv as well as multidrug-resistant (MDR) and extremely drug-resistant (XDR) strains of M. tuberculosis in THP-1 macrophages. Src inhibition was also effective in controlling M. tuberculosis infection in guinea pigs. In guinea pigs, reduced M. tuberculosis burden due to Src inhibition also led to a marked decline in the disease pathology. In agreement with the theoretical framework of host-directed approaches against the pathogen, Src inhibition was equally effective against an XDR strain in controlling infection in guinea pigs. We propose that Src inhibitors could be developed into effective host-directed anti-TB drugs, which could be indiscriminately used against both drug-sensitive and drug-resistant strains of M. tuberculosis. IMPORTANCE The existing treatment regimen for tuberculosis (TB) suffers from deficiencies like high doses of antibiotics, long treatment duration, and inability to kill persistent populations in an efficient manner. Together, these contribute to the emergence of drug-resistant tuberculosis. Recently, several host factors were identified which help intracellular survival of Mycobacterium tuberculosis within the macrophage. These factors serve as attractive targets for developing alternate therapeutic strategies against M. tuberculosis. This strategy promises to be effective against drug-resistant strains. The approach also has potential to considerably lower the risk of emergence of new drug-resistant strains. We explored tyrosine kinase Src as a host factor exploited by virulent M. tuberculosis for intracellular survival. We show that Src inhibition can effectively control tuberculosis in infected guinea pigs. Moreover, Src inhibition ameliorated TB-associated pathology in guinea pigs. Thus, Src inhibitors have strong potential to be developed as possible anti-TB drugs.

Subject-specific increases in serum S-100B distinguish sports-related concussion from sports-related exertion.

PubMed

Kiechle, Karin; Bazarian, Jeffrey J; Merchant-Borna, Kian; Stoecklein, Veit; Rozen, Eric; Blyth, Brian; Huang, Jason H; Dayawansa, Samantha; Kanz, Karl; Biberthaler, Peter

2014-01-01

The on-field diagnosis of sports-related concussion (SRC) is complicated by the lack of an accurate and objective marker of brain injury. To compare subject-specific changes in the astroglial protein, S100B, before and after SRC among collegiate and semi-professional contact sport athletes, and compare these changes to differences in S100B before and after non-contact exertion. Longitudinal cohort study. From 2009-2011, we performed a prospective study of athletes from Munich, Germany, and Rochester, New York, USA. Serum S100B was measured in all SRC athletes at pre-season baseline, within 3 hours of injury, and at days 2, 3 and 7 post-SRC. Among a subset of athletes, S100B was measured after non-contact exertion but before injury. All samples were collected identically and analyzed using an automated electrochemiluminescent assay to quantify serum S100B levels. Forty-six athletes (30 Munich, 16 Rochester) underwent baseline testing. Thirty underwent additional post-exertion S100B testing. Twenty-two athletes (16 Rochester, 6 Munich) sustained a SRC, and 17 had S100B testing within 3 hours post-injury. The mean 3-hour post-SRC S100B was significantly higher than pre-season baseline (0.099±0.008 µg/L vs. 0.058±0.006 µg/L, p = 0.0002). Mean post-exertion S100B was not significantly different than the preseason baseline. S100B levels at post-injury days 2, 3 and 7 were significantly lower than the 3-hour level, and not different than baseline. Both the absolute change and proportional increase in S100B 3-hour post-injury were accurate discriminators of SRC from non-contact exertion without SRC (AUC 0.772 and 0.904, respectively). A 3-hour post-concussion S100B >0.122 µg/L and a proportional S100B increase of >45.9% over baseline were both 96.7% specific for SRC. Relative and absolute increases in serum S100B can accurately distinguish SRC from sports-related exertion, and may be a useful adjunct to the diagnosis of SRC.

PLC-γ directly binds activated c-Src, which is necessary for carbachol-mediated inhibition of NHE3 activity in Caco-2/BBe cells.

PubMed

Zachos, Nicholas C; Lee, Luke J; Kovbasnjuk, Olga; Li, Xuhang; Donowitz, Mark

2013-08-01

Elevated levels of intracellular Ca(2+) ([Ca(2+)]i) inhibit Na(+)/H(+) exchanger 3 (NHE3) activity in the intact intestine. We previously demonstrated that PLC-γ directly binds NHE3, an interaction that is necessary for [Ca(2+)]i inhibition of NHE3 activity, and that PLC-γ Src homology 2 (SH2) domains may scaffold Ca(2+) signaling proteins necessary for regulation of NHE3 activity. [Ca(2+)]i regulation of NHE3 activity is also c-Src dependent; however, the mechanism by which c-Src is involved is undetermined. We hypothesized that the SH2 domains of PLC-γ might link c-Src to NHE3-containing complexes to mediate [Ca(2+)]i inhibition of NHE3 activity. In Caco-2/BBe cells, carbachol (CCh) decreased NHE3 activity by ∼40%, an effect abolished with the c-Src inhibitor PP2. CCh treatment increased the amount of active c-Src as early as 1 min through increased Y(416) phosphorylation. Coimmunoprecipitation demonstrated that c-Src associated with PLC-γ, but not NHE3, under basal conditions, an interaction that increased rapidly after CCh treatment and occurred before the dissociation of PLC-γ and NHE3 that occurred 10 min after CCh treatment. Finally, direct binding to c-Src only occurred through the PLC-γ SH2 domains, an interaction that was prevented by blocking the PLC-γ SH2 domain. This study demonstrated that c-Src 1) activity is necessary for [Ca(2+)]i inhibition of NHE3 activity, 2) activation occurs rapidly (∼1 min) after CCh treatment, 3) directly binds PLC-γ SH2 domains and associates dynamically with PLC-γ under elevated [Ca(2+)]i conditions, and 4) does not directly bind NHE3. Under elevated [Ca(2+)]i conditions, PLC-γ scaffolds c-Src into NHE3-containing multiprotein complexes before dissociation of PLC-γ from NHE3 and subsequent endocytosis of NHE3.

The American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator Does Not Accurately Predict Risk of 30-Day Complications Among Patients Undergoing Microvascular Head and Neck Reconstruction.

PubMed

Arce, Kevin; Moore, Eric J; Lohse, Christine M; Reiland, Matthew D; Yetzer, Jacob G; Ettinger, Kyle S

2016-09-01

The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) Surgical Risk Calculator (SRC) is a novel universal risk calculator designed to aid in risk stratification of patients undergoing various types of major surgery. The purpose of this study was to assess the validity of the ACS NSQIP SRC in predicting postoperative complications in patients undergoing microvascular head and neck reconstruction. A retrospective cohort study of patients undergoing head and neck microvascular reconstruction with fibular free flaps at a single institution was completed. The NSQIP SRC was used to compute complication risk estimates and length of stay (LOS) estimates for all patients under study. Associations between complication risk estimates generated by the SRC and actual rates of observed complications were evaluated using logistic regression models. Logistic regression models also were used to evaluate the SRC estimates for LOS duration compared with the actual observed LOS after surgery. Of 153 patients under study, 46 (30%) developed a postoperative complication corresponding to those defined by NSQIP SRC. Thirty-eight patients (25%) developed a postoperative complication categorized as severe in the parameters of the NSQIP SRC. None of the SRC complication estimates showed a statistically relevant association with the corresponding observed rates of complications. The mean LOS predicted by the SRC was 8.0 days (median, 7.5 days; interquartile range [IQR], 6.5 to 9; range, 5.0 to 18.5 days). The mean observed LOS for the study group was 9.6 days (median, 7.0 days; IQR, 6 to 9; range, 5 to 67 days). Lin's (Biometrics 45:255, 1989) concordance correlation coefficient to measure agreement between observed and predicted LOS was 0.10, indicating only slight agreement between the 2 values. The ACS NSQIP SRC is not a useful risk-stratifying metric for patients undergoing major head and neck reconstruction with microvascular fibular free flaps. The SRC also does not accurately predict hospital LOS for this same patient cohort. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Sexual attraction to others: a comparison of two models of alloerotic responding in men.

PubMed

Blanchard, Ray; Kuban, Michael E; Blak, Thomas; Klassen, Philip E; Dickey, Robert; Cantor, James M

2012-02-01

The penile response profiles of homosexual and heterosexual pedophiles, hebephiles, and teleiophiles to laboratory stimuli depicting male and female children and adults may be conceptualized as a series of overlapping stimulus generalization gradients. This study used such profile data to compare two models of alloerotic responding (sexual responding to other people) in men. The first model was based on the notion that men respond to a potential sexual object as a compound stimulus made up of an age component and a gender component. The second model was based on the notion that men respond to a potential sexual object as a gestalt, which they evaluate in terms of global similarity to other potential sexual objects. The analytic strategy was to compare the accuracy of these models in predicting a man's penile response to each of his less arousing (nonpreferred) stimulus categories from his response to his most arousing (preferred) stimulus category. Both models based their predictions on the degree of dissimilarity between the preferred stimulus category and a given nonpreferred stimulus category, but each model used its own measure of dissimilarity. According to the first model ("summation model"), penile response should vary inversely as the sum of stimulus differences on separate dimensions of age and gender. According to the second model ("bipolar model"), penile response should vary inversely as the distance between stimulus categories on a single, bipolar dimension of morphological similarity-a dimension on which children are located near the middle, and adult men and women are located at opposite ends. The subjects were 2,278 male patients referred to a specialty clinic for phallometric assessment of their erotic preferences. Comparisons of goodness of fit to the observed data favored the unidimensional bipolar model.

Different responses of spontaneous and stimulus-related alpha activity to ambient luminance changes.

PubMed

Benedetto, Alessandro; Lozano-Soldevilla, Diego; VanRullen, Rufin

2017-12-04

Alpha oscillations are particularly important in determining our percepts and have been implicated in fundamental brain functions. Oscillatory activity can be spontaneous or stimulus-related. Furthermore, stimulus-related responses can be phase- or non-phase-locked to the stimulus. Non-phase-locked (induced) activity can be identified as the average amplitude changes in response to a stimulation, while phase-locked activity can be measured via reverse-correlation techniques (echo function). However, the mechanisms and the functional roles of these oscillations are far from clear. Here, we investigated the effect of ambient luminance changes, known to dramatically modulate neural oscillations, on spontaneous and stimulus-related alpha. We investigated the effect of ambient luminance on EEG alpha during spontaneous human brain activity at rest (experiment 1) and during visual stimulation (experiment 2). Results show that spontaneous alpha amplitude increased by decreasing ambient luminance, while alpha frequency remained unaffected. In the second experiment, we found that under low-luminance viewing, the stimulus-related alpha amplitude was lower, and its frequency was slightly faster. These effects were evident in the phase-locked part of the alpha response (echo function), but weaker or absent in the induced (non-phase-locked) alpha responses. Finally, we explored the possible behavioural correlates of these modulations in a monocular critical flicker frequency task (experiment 3), finding that dark adaptation in the left eye decreased the temporal threshold of the right eye. Overall, we found that ambient luminance changes impact differently on spontaneous and stimulus-related alpha expression. We suggest that stimulus-related alpha activity is crucial in determining human temporal segmentation abilities. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

[Analysis of electrically evoked response (EER) in relation to the central visual pathway of the cat (1). Wave shape of the cat EER].

PubMed

Fukatsu, Y; Miyake, Y; Sugita, S; Saito, A; Watanabe, S

1990-11-01

To analyze the Electrically evoked response (EER) in relation to the central visual pathway, the authors studied the properties of wave patterns and peak latencies of EER in 35 anesthetized adult cats. The cat EER showed two early positive waves on outward current (cornea cathode) stimulus and three or four early positive waves on inward current (cornea anode) stimulus. These waves were recorded within 50 ms after stimulus onset, and were the most consistent components in cat EER. The stimulus threshold for EER showed a less individual variation than amplitude. The difference of stimulus threshold between outward and inward current stimulus was also essentially negligible. The stimulus threshold was higher in early components than in late components. The peak latency of EER became shorter and the amplitude became higher, as the stimulus intensity was increased. However, this tendency was reversed and some wavelets started to appear when the stimulus was extremely strong. The recording using short stimulus duration and bipolar electrodes enabled us to reduce the electrical artifact of EER. These results obtained from cats were compared with those of humans and rabbits.

Modulation of focal adhesion constituents and their down-stream events by EGF: On the cross-talk of integrins and growth factor receptors.

PubMed

Eberwein, Philipp; Laird, Dougal; Schulz, Simon; Reinhard, Thomas; Steinberg, Thorsten; Tomakidi, Pascal

2015-10-01

Within the concept of integrin growth factor receptor (GFR) cross-talk, little is known about the effects of GFRs on focal adhesions (FAs). Therefore, we tested the hypothesis whether EGF can modulate constituents of FAs and subsequent down-stream events. To this end, EGF-treated keratinocytes were subjected to combined fluorescence imaging and western blotting, to quantify expression and/or activation of molecules, involved in integrin GFR cross-talk, and receptor proximal and distal signaling events. Generally, EGF response revealed an amplified redistribution or activation of molecules under study, which will be explained in detail from the plasma membrane to the cell interior. In addition to significant activation of EGF receptor (EGFR) at tyrosine Tyr845, a remarkable redistribution was detectable for the focal adhesion constituents, integrin ß1 and ß3, and zyxin. Increased activation also applied to focal adhesion kinase (FAK) by phosphorylation at Tyr397, Tyr576, and Src at Tyr418, while total FAK remained unchanged. Risen activity was seen as well for the analyzed distal down-stream events, p190RhoGAP and MAP kinases p42/44. Intriguingly, Src-specific inhibitor Herbimycin A abrogated the entire EGF response except FAK Tyr397 phosphorylation, independent of EGF presence. Mechanistically, our results show that EGF modulates adhesion in a dual fashion, by firstly redistributing focal adhesion constituents to adhesion sites, but also by amplifying levels of activated RhoA antagonist p190RhoGAP, important for cell motility. Further, the findings suggest that the observed EGF response underlies an EGFR integrin cross-talk under recruitment of receptor proximal FAK and Src, and MAP kinase and p190RhoGAP as receptor distal events. Copyright © 2015 Elsevier B.V. All rights reserved.

Adults' age-related differences in strategy perseveration are modulated by response-stimulus intervals and problem features.

PubMed

Lemaire, Patrick; Brun, Fleur

2014-10-01

Ageing results in the tendency of older adults to repeat the same strategy across consecutive problems more often than young adults, even when such strategy perseveration is not appropriate. Here, we examined how these age-related differences in strategy perseveration are modulated by response-stimulus intervals and problem characteristics. We asked participants to select the best strategy while accomplishing a computational estimation task (i.e., provide approximate sums to two-digit addition problems like 38 + 74). We found that participants repeated the same strategy across consecutive problems more often when the duration between their response and next problem display was short (300 ms) than when it was long (1300 ms). We also found more strategy perseverations in older than in young adults under short Response-Stimulus Intervals, but not under long Response-Stimulus Intervals. Finally, age-related differences in strategy perseveration decreased when problem features helped participants to select the best strategy. These modulations of age-related differences in strategy perseveration by response-stimulus intervals and characteristics of target problems are important for furthering our understanding of mechanisms underlying strategy perseveration and, more generally, ageing effects on strategy selection.

Corticospinal excitability is dependent on the parameters of peripheral electric stimulation: a preliminary study.

PubMed

Chipchase, Lucy S; Schabrun, Siobhan M; Hodges, Paul W

2011-09-01

To evaluate the effect of 6 electric stimulation paradigms on corticospinal excitability. Using a same subject pre-post test design, transcranial magnetic stimulation (TMS) was used to measure the responsiveness of corticomotor pathway to biceps and triceps brachii muscles before and after 30 minutes of electric stimulation over the biceps brachii. Six different electric stimulation paradigms were applied in random order, at least 3 days apart. Motor control research laboratory. Healthy subjects (N=10; 5 women, 5 men; mean age ± SD, 26 ± 3.6y). Six different electric stimulation paradigms with varied stimulus amplitude, frequency, and ramp settings. Amplitudes of TMS-induced motor evoked potentials at biceps and triceps brachii normalized to maximal M-wave amplitudes. Electric stimulation delivered at stimulus amplitude sufficient to evoke a sensory response at both 10 Hz and 100 Hz, and stimulus amplitude to create a noxious response at 10 Hz decreased corticomotor responsiveness (all P<0.01). Stimulation sufficient to induce a motor contraction (30 Hz) applied in a ramped pattern to mimic a voluntary activation increased corticomotor responsiveness (P=0.002), whereas constant low- and high-intensity motor stimulation at 10 Hz did not. Corticomotor excitability changes were similar for both the stimulated muscle and its antagonist. Stimulus amplitude (intensity) and the nature (muscle flicker vs contraction) of motor stimulation have a significant impact on changes in corticospinal excitability induced by electric stimulation. Here, we demonstrate that peripheral electric stimulation at stimulus amplitude to create a sensory response reduces corticomotor responsiveness. Conversely, stimulus amplitude to create a motor response increases corticomotor responsiveness, but only the parameters that create a motor response that mimics a voluntary muscle contraction. Copyright © 2011 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.