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Sample records for negative regulatory feedback

  1. Interlinking positive and negative feedback loops creates a tunable motif in gene regulatory networks.

    PubMed

    Tian, Xiao-Jun; Zhang, Xiao-Peng; Liu, Feng; Wang, Wei

    2009-07-01

    Positive and negative feedback loops are often coupled to perform various functions in gene regulatory networks, acting as bistable switches, oscillators, and excitable devices. It is implied that such a system with interlinked positive and negative feedback loops is a flexible motif that can modulate itself among various functions. Here, we developed a minimal model for the system and systematically explored its dynamics and performance advantage in response to stimuli in a unifying framework. The system indeed displays diverse behaviors when the strength of feedback loops is changed. First, the system can be tunable from monostability to bistability by increasing the strength of positive feedback, and the bistability regime is modulated by the strength of negative feedback. Second, the system undergoes transitions from bistability to excitability and to oscillation with increasing the strength of negative feedback, and the reverse conversion occurs by enhancing the strength of positive feedback. Third, the system is more flexible than a single feedback loop; it can produce robust larger-amplitude oscillations over a wider stimulus regime compared with a single time-delayed negative feedback loop. Furthermore, the tunability of the system depends mainly on the topology of coupled feedback loops but less on the exact parameter values or the mode of interactions between model components. Thus, our results interpret why such a system represents a tunable motif and can accomplish various functions. These also suggest that coupled feedback loops can act as toolboxes for engineering diverse functional circuits in synthetic biology.

  2. Messenger RNA fluctuations and regulatory RNAs shape the dynamics of a negative feedback loop

    NASA Astrophysics Data System (ADS)

    Rodríguez Martínez, María; Soriano, Jordi; Tlusty, Tsvi; Pilpel, Yitzhak; Furman, Itay

    2010-03-01

    Single-cell experiments of simple regulatory networks can markedly differ from cell population experiments. Such differences arise from stochastic events in individual cells that are averaged out in cell populations. For instance, while individual cells may show sustained oscillations in the concentrations of some proteins, such oscillations may appear damped in the population average. In this paper we investigate the role of RNA stochastic fluctuations as a leading force to produce a sustained excitatory behavior at the single-cell level. As opposed to some previous models, we build a fully stochastic model of a negative feedback loop that explicitly takes into account the RNA stochastic dynamics. We find that messenger RNA random fluctuations can be amplified during translation and produce sustained pulses of protein expression. Motivated by the recent appreciation of the importance of noncoding regulatory RNAs in post-transcription regulation, we also consider the possibility that a regulatory RNA transcript could bind to the messenger RNA and repress translation. Our findings show that the regulatory transcript helps reducing gene expression variability both at the single-cell level and at the cell population level.

  3. Effects of delay and noise in a negative feedback regulatory motif

    NASA Astrophysics Data System (ADS)

    Palassini, Matteo; Dies, Marta

    2009-03-01

    The small copy number of the molecules involved in gene regulation can induce nontrivial stochastic phenomena such as noise-induced oscillations. An often neglected aspect of regulation dynamics are the delays involved in transcription and translation. Delays introduce analytical and computational complications because the dynamics is non-Markovian. We study the interplay of noise and delays in a negative feedback model of the p53 core regulatory network. Recent experiments have found pronounced oscillations in the concentrations of proteins p53 and Mdm2 in individual cells subjected to DNA damage. Similar oscillations occur in the Hes-1 and NK-kB systems, and in circadian rhythms. Several mechanisms have been proposed to explain this oscillatory behaviour, such as deterministic limit cycles, with and without delay, or noise-induced excursions in excitable models. We consider a generic delayed Master Equation incorporating the activation of Mdm2 by p53 and the Mdm2-promoted degradation of p53. In the deterministic limit and for large delays, the model shows a Hopf bifurcation. Via exact stochastic simulations, we find strong noise-induced oscillations well outside the limit-cycle region. We propose that this may be a generic mechanism for oscillations in gene regulatory systems.

  4. Two different modes of oscillation in a gene transcription regulatory network with interlinked positive and negative feedback loops

    NASA Astrophysics Data System (ADS)

    Karmakar, Rajesh

    2016-12-01

    We study the oscillatory behavior of a gene regulatory network with interlinked positive and negative feedback loop. The frequency and amplitude are two important properties of oscillation. The studied network produces two different modes of oscillation. In one mode (mode-I), frequency of oscillation remains constant over a wide range of amplitude and in the other mode (mode-II) the amplitude of oscillation remains constant over a wide range of frequency. Our study reproduces both features of oscillations in a single gene regulatory network and shows that the negative plus positive feedback loops in gene regulatory network offer additional advantage. We identified the key parameters/variables responsible for different modes of oscillation. The network is flexible in switching between different modes by choosing appropriately the required parameters/variables.

  5. Novel Sinorhizobium meliloti quorum sensing positive and negative regulatory feedback mechanisms respond to phosphate availability.

    PubMed

    McIntosh, Matthew; Meyer, Stefan; Becker, Anke

    2009-12-01

    The Sin quorum sensing system of Sinorhizobium meliloti depends upon at least three genes, sinR, sinI and expR, and N-acyl homoserine lactones (AHLs) as signals to regulate multiple processes in its free-living state in the rhizosphere and in the development towards symbiosis with its plant host. In this study, we have characterized novel mechanisms of transcription control through which the system regulates itself. At low AHL levels a positive feedback loop activates expression of sinI (AHL synthase), resulting in amplification of AHL levels. At high AHL levels, expression of sinI is reduced by a negative feedback loop. These feedback mechanisms are mediated by the LuxR-type regulators ExpR and SinR. Expression of sinR and expR is regulated by ExpR in the presence of AHLs. A novel ExpR binding site in the promoter of sinR is responsible for the reduction of expression of this gene. In addition, expression of sinR, upon which sinI expression is dependent, is induced by phoB during growth under phosphate-limiting conditions. This indicates that this response ensures quorum sensing in phosphate-restricted growth.

  6. Intrinsic Negative Feedback Governs Activation Surge in Two-Component Regulatory Systems

    PubMed Central

    Yeo, Won-Sik; Zwir, Igor; Huang, Henry V.; Shin, Dongwoo; Kato, Akinori; Groisman, Eduardo A.

    2013-01-01

    SUMMARY PhoP and PhoQ comprise a two-component system in the bacterium Salmonella enterica. PhoQ is the sensor kinase/phosphatase that modifies the phosphorylation state of the regulator PhoP in response to stimuli. The amount of phosphorylated PhoP surges after activation, then declines to reach a steady-state level. We now recapitulate this surge in vitro by incubating PhoP and PhoQ with ATP and ADP. Mathematical modeling identified PhoQ’s affinity for ADP as the key parameter dictating phosphorylated PhoP levels, as ADP promotes PhoQ’s phosphatase activity toward phosphorylated PhoP. The lid covering the nucleotide-binding pocket of PhoQ governs the kinase to phosphatase switch because a lid mutation that decreased ADP binding compromised PhoQ’s phosphatase activity in vitro and resulted in sustained expression of PhoP-dependent mRNAs in vivo. This feedback mechanism may curtail futile ATP consumption because ADP not only stimulates PhoQ’s phosphatase activity but also inhibits ATP binding necessary for the kinase reaction. PMID:22325356

  7. Acute heat stress brings down milk secretion in dairy cows by up-regulating the activity of the milk-borne negative feedback regulatory system

    PubMed Central

    Silanikove, Nissim; Shapiro, Fira; Shinder, Dima

    2009-01-01

    Background The objective of this study was to determine if acute heat stress (HS) decreases milk secretion by activating the milk-borne negative feedback system, as an emergency physiological response to prevent a life-threatening situation. To induce HS, summer acclimatized dairy cows were exposed to full sun under mid-summer Mediterranean conditions, with and without conventional cooling procedures. Results Exposure to HS induced a rapid and acute (within 24 h) reduction in milk yield in proportion to the heat load. This decrease was moderated by cooler night-time ambient temperature. The reduction in milk yield was associated with corresponding responses in plasminogen activator/plasminogen-plasmin activities, and with increased activity (concentration) of the (1–28) N-terminal fragment peptide that is released by plasmin from β-casein (β-CN (1–28)). These metabolites constitute the regulatory negative feedback system. Previously, it has been shown that β-CN (1–28) down-regulated milk secretion by blocking potassium channels on the apical aspects of the mammary epithelial cells. Conclusion Here we demonstrate that the potassium channels in mammary tissue became more susceptible to β-CN (1–28) activity under HS. Thus, the present study highlighted two previously unreported features of this regulatory system: (i) that it modulates rapidly in response to stressor impact variations; and (ii) that the regulations of the mammary epithelial potassium channel sensitivity to the inhibitory effect of β-CN (1–28) is part of the regulatory system. PMID:19563620

  8. Positive feedback promotes oscillations in negative feedback loops.

    PubMed

    Ananthasubramaniam, Bharath; Herzel, Hanspeter

    2014-01-01

    A simple three-component negative feedback loop is a recurring motif in biochemical oscillators. This motif oscillates as it has the three necessary ingredients for oscillations: a three-step delay, negative feedback, and nonlinearity in the loop. However, to oscillate, this motif under the common Goodwin formulation requires a high degree of cooperativity (a measure of nonlinearity) in the feedback that is biologically "unlikely." Moreover, this recurring negative feedback motif is commonly observed augmented by positive feedback interactions. Here we show that these positive feedback interactions promote oscillation at lower degrees of cooperativity, and we can thus unify several common kinetic mechanisms that facilitate oscillations, such as self-activation and Michaelis-Menten degradation. The positive feedback loops are most beneficial when acting on the shortest lived component, where they function by balancing the lifetimes of the different components. The benefits of multiple positive feedback interactions are cumulative for a majority of situations considered, when benefits are measured by the reduction in the cooperativity required to oscillate. These positive feedback motifs also allow oscillations with longer periods than that determined by the lifetimes of the components alone. We can therefore conjecture that these positive feedback loops have evolved to facilitate oscillations at lower, kinetically achievable, degrees of cooperativity. Finally, we discuss the implications of our conclusions on the mammalian molecular clock, a system modeled extensively based on the three-component negative feedback loop.

  9. Positive Feedback Promotes Oscillations in Negative Feedback Loops

    PubMed Central

    Ananthasubramaniam, Bharath; Herzel, Hanspeter

    2014-01-01

    A simple three-component negative feedback loop is a recurring motif in biochemical oscillators. This motif oscillates as it has the three necessary ingredients for oscillations: a three-step delay, negative feedback, and nonlinearity in the loop. However, to oscillate, this motif under the common Goodwin formulation requires a high degree of cooperativity (a measure of nonlinearity) in the feedback that is biologically “unlikely.” Moreover, this recurring negative feedback motif is commonly observed augmented by positive feedback interactions. Here we show that these positive feedback interactions promote oscillation at lower degrees of cooperativity, and we can thus unify several common kinetic mechanisms that facilitate oscillations, such as self-activation and Michaelis-Menten degradation. The positive feedback loops are most beneficial when acting on the shortest lived component, where they function by balancing the lifetimes of the different components. The benefits of multiple positive feedback interactions are cumulative for a majority of situations considered, when benefits are measured by the reduction in the cooperativity required to oscillate. These positive feedback motifs also allow oscillations with longer periods than that determined by the lifetimes of the components alone. We can therefore conjecture that these positive feedback loops have evolved to facilitate oscillations at lower, kinetically achievable, degrees of cooperativity. Finally, we discuss the implications of our conclusions on the mammalian molecular clock, a system modeled extensively based on the three-component negative feedback loop. PMID:25126951

  10. Negative feedback system reduces pump oscillations

    NASA Technical Reports Server (NTRS)

    Rosenmann, W.

    1967-01-01

    External negative feedback system counteracts low frequency oscillations in rocket engine propellant pumps. The system uses a control piston to sense pump discharge fluid on one side and a gas pocket on the other.

  11. Understanding responses to feedback: the potential and limitations of regulatory focus theory.

    PubMed

    Watling, Christopher; Driessen, Erik; van der Vleuten, Cees P M; Vanstone, Meredith; Lingard, Lorelei

    2012-06-01

    Regulatory focus theory posits the existence of two systems of self-regulation underlying human motivation: promotion focus, which is concerned with aspirations and accomplishments, and prevention focus, which is concerned with obligations and responsibilities. It has been proposed that regulatory focus theory may help to explain learners' variable responses to feedback, predicting that positive feedback is motivating under promotion focus, whereas negative feedback is motivating under prevention focus. We aimed to explore this link between regulatory focus theory and response to feedback using data collected in a naturalistic setting. In a constructivist grounded theory study, we interviewed 22 early-career academic doctors about experiences they perceived as influential in their learning. Although feedback emerged as important, responses to feedback were highly variable. To better understand how feedback becomes (or fails to become) influential, we used the theoretical framework of regulatory focus to re-examine all descriptions of experiences of receiving and responding to feedback. Feedback could be influential or non-influential, regardless of its sign (positive or negative). In circumstances in which the individual's regulatory focus was readily determined, such as in choosing a career (promotion) or preparing for a high-stakes examination (prevention), the apparent influence of feedback was consistent with the prediction of regulatory focus theory. However, we encountered many challenges in applying regulatory focus theory to real feedback scenarios, including the frequent presence of a mixed regulatory focus, the potential for regulatory focus to change over time, and the competing influences of other factors, such as the perceived credibility of the source or content of the feedback. Regulatory focus theory offers a useful, if limited, construct for exploring learners' responses to feedback in the clinical setting. The insights and predictions it offers

  12. Growth factor TGF-β induces intestinal epithelial cell (IEC-6) differentiation: miR-146b as a regulatory component in the negative feedback loop.

    PubMed

    Liao, Yalin; Zhang, Man; Lönnerdal, Bo

    2013-01-01

    TGF-β is a potent pleiotropic factor that promotes small intestinal cell differentiation. The role of microRNAs in the TGF-β induction of intestinal epithelial phenotype is largely unknown. We hypothesized that microRNAs are functionally involved in TGF-β-induced intestinal cell growth. In this study, TGF-β caused a morphological change of IEC-6 cells and stimulated expression of the epithelial cell markers alkaline phosphatase, villin, and aminopeptidase N. By global microRNA profiling during TGF-β-induced intestinal crypt cell (IEC-6) differentiation, we identified 19 differentially expressed microRNAs. We showed by real-time Q-PCR that miR-146b expression increased rapidly after TGF-β treatment; sequence analysis and in vitro assays revealed that miR-146b targets SIAH2, an E3 ubiquitin ligase, with decreased protein expression upon IEC-6 cell differentiation. Transfection of miR-146b inhibitor before TGF-β treatment blocked the down-regulation of SIAH2 in response to TGF-β. Moreover, SIAH2 over-expression during TGF-β treatment caused a significant decrease in Smad7 protein expression in IEC-6 cells. Furthermore, activation of the ERK1/2 pathway is active in the up-regulation of miR-146b by TGF-β. These findings suggest a novel mechanism whereby TGF-β signaling during IEC-6 cell differentiation may be modulated in part by microRNAs, and we propose a key role for miR-146b in the homeostasis of growth factor TGF-β signaling through a negative feedback regulation involving down-regulation of SIAH2 repressed Smad7 activities.

  13. Anomalous feedback and negative domain wall resistance

    NASA Astrophysics Data System (ADS)

    Cheng, Ran; Zhu, Jian-Gang; Xiao, Di

    2016-11-01

    Magnetic induction can be regarded as a negative feedback effect, where the motive-force opposes the change of magnetic flux that generates the motive-force. In artificial electromagnetics emerging from spintronics, however, this is not necessarily the case. By studying the current-induced domain wall dynamics in a cylindrical nanowire, we show that the spin motive-force exerting on electrons can either oppose or support the applied current that drives the domain wall. The switching into the anomalous feedback regime occurs when the strength of the dissipative torque β is about twice the value of the Gilbert damping constant α. The anomalous feedback manifests as a negative domain wall resistance, which has an analogy with the water turbine.

  14. Project Echo: FM Demodulators with Negative Feedback

    NASA Technical Reports Server (NTRS)

    Ruthroff, Clyde L.

    1961-01-01

    The primary experimental objective of Project Echo was the transmission of radio communications between points on the earth by reflection from the balloon satellite. Owing to the large path losses from transmitter to receiver via the satellite, a wide-band frequency modulation technique was used in which bandwidth was traded for signal-to-noise ratio. This paper describes the FM receiving demodulators employed. Negative feedback applied to the local oscillator reduces the FM modulation index in the receiver IF amplifiers, resulting in threshold performance superior to that of conventional FM receivers.

  15. Stress reduces use of negative feedback in a feedback-based learning task.

    PubMed

    Petzold, Antje; Plessow, Franziska; Goschke, Thomas; Kirschbaum, Clemens

    2010-04-01

    In contrast to the well-established effects of stress on learning of declarative material, much less is known about stress effects on reward- or feedback-based learning. Differential effects on positive and negative feedback especially have received little attention. The objective of this study, thus, was to investigate effects of psychosocial stress on feedback-based learning with a particular focus on the use of negative and positive feedback during learning. Participants completed a probabilistic selection task in both a stress and a control condition. The task allowed quantification of how much participants relied on positive and negative feedback during learning. Although stress had no effect on general acquisition of the task, results indicate that participants used negative feedback significantly less during learning after stress compared with the control condition. An enhancing effect of stress on use of positive feedback failed to reach significance. These findings suggest that stress acts differentially on the use of positive and negative feedback during learning.

  16. The feedback-related negativity is modulated by feedback probability in observational learning.

    PubMed

    Kobza, Stefan; Thoma, Patrizia; Daum, Irene; Bellebaum, Christian

    2011-12-01

    The feedback-related negativity (FRN), an event-related potentials (ERPs) component reflecting activity of the anterior cingulate cortex (ACC), has been shown to be modulated by feedback expectancy following active choices in feedback-based learning tasks. A general reduction of FRN amplitude has been described in observational feedback learning, raising the question whether FRN amplitude is modulated in a similar way in this type of learning. The present study investigated whether the FRN and the P300 - a second ERP component related to feedback processing - are modulated by feedback probability in observational learning. Thirty-two subjects participated in the experiment. They observed a virtual person choosing between two symbols and receiving positive or negative feedback. Learning about stimulus-specific feedback probabilities was assessed in active test trials without feedback. In addition, the bias to learn from positive or negative feedback and - in a subsample of 17 subjects - empathy scores were obtained. General FRN and P300 modulations by feedback probability were found across all subjects. Only for the FRN in learners, an interaction between probability and valence was observed. Larger FRN amplitudes for negative relative to positive feedback only emerged for the lowest outcome probability. The results show that feedback expectancy modulates FRN amplitude also in observational learning, suggesting a similar ACC function as in active learning. On the other hand, the modulation is only seen for very low feedback expectancy, which suggests that brain regions other than those of the reward system contribute to feedback processing in an observation setting.

  17. Noise propagation in gene regulation networks involving interlinked positive and negative feedback loops.

    PubMed

    Zhang, Hui; Chen, Yueling; Chen, Yong

    2012-01-01

    It is well known that noise is inevitable in gene regulatory networks due to the low-copy numbers of molecules and local environmental fluctuations. The prediction of noise effects is a key issue in ensuring reliable transmission of information. Interlinked positive and negative feedback loops are essential signal transduction motifs in biological networks. Positive feedback loops are generally believed to induce a switch-like behavior, whereas negative feedback loops are thought to suppress noise effects. Here, by using the signal sensitivity (susceptibility) and noise amplification to quantify noise propagation, we analyze an abstract model of the Myc/E2F/MiR-17-92 network that is composed of a coupling between the E2F/Myc positive feedback loop and the E2F/Myc/miR-17-92 negative feedback loop. The role of the feedback loop on noise effects is found to depend on the dynamic properties of the system. When the system is in monostability or bistability with high protein concentrations, noise is consistently suppressed. However, the negative feedback loop reduces this suppression ability (or improves the noise propagation) and enhances signal sensitivity. In the case of excitability, bistability, or monostability, noise is enhanced at low protein concentrations. The negative feedback loop reduces this noise enhancement as well as the signal sensitivity. In all cases, the positive feedback loop acts contrary to the negative feedback loop. We also found that increasing the time scale of the protein module or decreasing the noise autocorrelation time can enhance noise suppression; however, the systems sensitivity remains unchanged. Taken together, our results suggest that the negative/positive feedback mechanisms in coupled feedback loop dynamically buffer noise effects rather than only suppressing or amplifying the noise.

  18. Expectancy affects the feedback-related negativity (FRN) for delayed feedback in probabilistic learning.

    PubMed

    Weismüller, Benjamin; Bellebaum, Christian

    2016-11-01

    Learning from feedback is a prerequisite for adapting to the environment. Prediction error signals coded by midbrain dopamine (DA) neurons are projected to the basal ganglia and anterior cingulate cortex (ACC). It has been suggested that neuronal activity shifts away from the DA system when feedback is delayed. The feedback-related negativity (FRN), an ERP that is generated in the ACC and has been shown to be sensitive to feedback valence and prediction error magnitude, was found to be reduced for delayed feedback. It has, however, not yet been investigated if the FRN for delayed feedback reflects a reward prediction error. In this study, effects of feedback delay (1 s vs. 7 s) on the processing of expected and unexpected positive and negative feedback were investigated in a between-subjects design in healthy human participants conducting a probabilistic feedback learning task. FRN and P300 amplitudes were decreased for subjects learning from delayed compared to immediate feedback. Importantly, the FRN, extracted from the negative-positive feedback difference wave, was significantly smaller for expected compared to unexpected feedback for both the immediate and delayed feedback conditions. Expectancy effects for the P300 were also seen, but did not interact with feedback valence. These results demonstrate an influence of feedback expectancy, and thus the prediction error, on early feedback processing even for delayed feedback, suggesting that neuronal structures underlying feedback processing are comparable for immediate and delayed feedback, at least to some extent. Modulations of the P300 by feedback delay may be linked to feedback salience. © 2016 Society for Psychophysiological Research.

  19. The Positive Impact of Negative Feedback

    DTIC Science & Technology

    2011-03-01

    additional research focused on determining 360-degree feedback’s ability to improve individual and organizational effectiveness. Unfortunately, this area of...feedback and managerial effectiveness. He first studied 2,056 managers enrolled in leadership development programs (Fleenor, McCauley, & Brutus, 1996...their abilities such as “leading people, managing job challenges, starting a project from scratch, negotiating a major contract, taking on

  20. Regulatory dynamics of synthetic gene networks with positive feedback.

    PubMed

    Maeda, Yusuke T; Sano, Masaki

    2006-06-16

    Biological processes are governed by complex networks ranging from gene regulation to signal transduction. Positive feedback is a key element in such networks. The regulation enables cells to adopt multiple internal expression states in response to a single external input signal. However, past works lacked a dynamical aspect of this system. To address the dynamical property of the positive feedback system, we employ synthetic gene circuits in Escherichia coli to measure the rise-time of both the no-feedback system and the positive feedback system. We show that the kinetics of gene expression is slowed down if the gene regulatory system includes positive feedback. We also report that the transition of gene switching behaviors from the hysteretic one to the graded one occurs. A mathematical model based on the chemical reactions shows that the response delay is an inherited property of the positive feedback system. Furthermore, with the aid of the phase diagram, we demonstrate the decline of the feedback activation causes the transition of switching behaviors. Our findings provide a further understanding of a positive feedback system in a living cell from a dynamical point of view.

  1. Affect Matters: When Writing Feedback Leads to Negative Feeling

    ERIC Educational Resources Information Center

    Taggart, Amy Rupiper; Laughlin, Mary

    2017-01-01

    A continuous challenge in the writing classroom is maintaining openness and positivity around feedback. There are myriad factors that influence the felt experience of the feedback process, and the researchers wanted to understand better how students experience and perceive negative moments, as well as what factors remain salient in their minds…

  2. Seeing ghosts: negative body evaluation predicts overestimation of negative social feedback.

    PubMed

    Alleva, Jessica M; Lange, Wolf-Gero; Jansen, Anita; Martijn, Carolien

    2014-06-01

    The current study investigated whether negative body evaluation predicts women's overestimation of negative social feedback related to their own body (i.e., covariation bias). Sixty-five female university students completed a computer task where photos of their own body, of a control woman's body, and of a neutral object, were followed by nonverbal social feedback (i.e., facial crowds with equal numbers of negative, positive, and neutral faces). Afterward, women estimated the percentage of negative, positive, and neutral social feedback that followed their own body, the control woman's body, and the neutral object. The findings provided evidence for a covariation bias: negative body evaluation predicted higher estimates of negative social feedback for women's own body, but not for the other stimuli. Additionally, the covariation bias was not explained by differences in how women interpreted the social feedback (the facial stimuli). Clinical implications of the covariation bias to body image are discussed.

  3. A multiple relevance feedback strategy with positive and negative models.

    PubMed

    Ma, Yunlong; Lin, Hongfei

    2014-01-01

    A commonly used strategy to improve search accuracy is through feedback techniques. Most existing work on feedback relies on positive information, and has been extensively studied in information retrieval. However, when a query topic is difficult and the results from the first-pass retrieval are very poor, it is impossible to extract enough useful terms from a few positive documents. Therefore, the positive feedback strategy is incapable to improve retrieval in this situation. Contrarily, there is a relatively large number of negative documents in the top of the result list, and it has been confirmed that negative feedback strategy is an important and useful way for adapting this scenario by several recent studies. In this paper, we consider a scenario when the search results are so poor that there are at most three relevant documents in the top twenty documents. Then, we conduct a novel study of multiple strategies for relevance feedback using both positive and negative examples from the first-pass retrieval to improve retrieval accuracy for such difficult queries. Experimental results on these TREC collections show that the proposed language model based multiple model feedback method which is generally more effective than both the baseline method and the methods using only positive or negative model.

  4. Adaptive disengagement buffers self-esteem from negative social feedback.

    PubMed

    Leitner, Jordan B; Hehman, Eric; Deegan, Matthew P; Jones, James M

    2014-11-01

    The degree to which self-esteem hinges on feedback in a domain is known as a contingency of self-worth, or engagement. Although previous research has conceptualized engagement as stable, it would be advantageous for individuals to dynamically regulate engagement. The current research examined whether the tendency to disengage from negative feedback accounts for variability in self-esteem. We created the Adaptive Disengagement Scale (ADS) to capture individual differences in the tendency to disengage self-esteem from negative outcomes. Results demonstrated that the ADS is reliable and valid (Studies 1 and 2). Furthermore, in response to negative social feedback, higher scores on the ADS predicted greater state self-esteem (Study 3), and this relationship was mediated by disengagement (Study 4). These findings demonstrate that adaptive disengagement protects self-esteem from negative outcomes and that the ADS is a valid measure of individual differences in the implementation of this process.

  5. The regulation of positive and negative social feedback: A psychophysiological study.

    PubMed

    Vanderhasselt, Marie-Anne; Remue, Jonathan; Ng, Kwun Kei; Mueller, Sven C; De Raedt, Rudi

    2015-09-01

    Everyday social evaluations are psychologically potent and trigger self-reflective thoughts and feelings. The present study sought to examine the psychophysiological impact of such evaluations using eye tracking, pupillometry, and heart-rate variability. Fifty-nine healthy adult volunteers received rigged social feedback (criticism and praise) based on their photograph. Gaze data were collected to investigate processes of attentional deployment/allocation toward the self or the evaluator expressing criticism or praise. Whereas voluntary attention was directed to evaluators who expressed praise, attention was drawn to one's own picture after criticism. Pupil dilation and heart-rate variability were larger in response to criticism as compared to praise, suggesting a flexible and adaptive emotion regulatory effort in response to social information that triggers an affective response. Altogether, healthy individuals recruited more regulatory resources to cope with negative (as compared to positive) social feedback, and this processing of social feedback was associated with adjustments in self-focused attention.

  6. A biopsychosocial model based on negative feedback and control

    PubMed Central

    Carey, Timothy A.; Mansell, Warren; Tai, Sara J.

    2014-01-01

    Although the biopsychosocial model has been a popular topic of discussion for over four decades it has not had the traction in fields of research that might be expected of such an intuitively appealing idea. One reason for this might be the absence of an identified mechanism or a functional architecture that is authentically biopsychosocial. What is needed is a robust mechanism that is equally important to biochemical processes as it is to psychological and social processes. Negative feedback may be the mechanism that is required. Negative feedback has been implicated in the regulation of neurotransmitters as well as important psychological and social processes such as emotional regulation and the relationship between a psychotherapist and a client. Moreover, negative feedback is purported to also govern the activity of all other organisms as well as humans. Perceptual Control Theory (PCT) describes the way in which negative feedback establishes control at increasing levels of perceptual complexity. Thus, PCT may be the first biopsychosocial model to be articulated in functional terms. In this paper we outline the working model of PCT and explain how PCT provides an embodied hierarchical neural architecture that utilizes negative feedback to control physiological, psychological, and social variables. PCT has major implications for both research and practice and, importantly, provides a guide by which fields of research that are currently separated may be integrated to bring about substantial progress in understanding the way in which the brain alters, and is altered by, its behavioral and environmental context. PMID:24616685

  7. Oscillations in MAPK cascade triggered by two distinct designs of coupled positive and negative feedback loops

    PubMed Central

    2012-01-01

    robustness of the oscillations in presence or absence of nuclear compartmentalization were differentially determined by two designs of coupled positive and negative feedback loops. A positive feedback from an oscillating MAPK cascade was shown to induce oscillations in an external signal processing module, uncovering a novel regulatory aspect of MAPK signal processing. PMID:22694947

  8. Oscillations in MAPK cascade triggered by two distinct designs of coupled positive and negative feedback loops.

    PubMed

    Sarma, Uddipan; Ghosh, Indira

    2012-06-13

    presence or absence of nuclear compartmentalization were differentially determined by two designs of coupled positive and negative feedback loops. A positive feedback from an oscillating MAPK cascade was shown to induce oscillations in an external signal processing module, uncovering a novel regulatory aspect of MAPK signal processing.

  9. Negative feedback in genetic circuits confers evolutionary resilience and capacitance.

    PubMed

    Marciano, David C; Lua, Rhonald C; Katsonis, Panagiotis; Amin, Shivas R; Herman, Christophe; Lichtarge, Olivier

    2014-06-26

    Natural selection for specific functions places limits upon the amino acid substitutions a protein can accept. Mechanisms that expand the range of tolerable amino acid substitutions include chaperones that can rescue destabilized proteins and additional stability-enhancing substitutions. Here, we present an alternative mechanism that is simple and uses a frequently encountered network motif. Computational and experimental evidence shows that the self-correcting, negative-feedback gene regulation motif increases repressor expression in response to deleterious mutations and thereby precisely restores repression of a target gene. Furthermore, this ability to rescue repressor function is observable across the Eubacteria kingdom through the greater accumulation of amino acid substitutions in negative-feedback transcription factors compared to genes they control. We propose that negative feedback represents a self-contained genetic canalization mechanism that preserves phenotype while permitting access to a wider range of functional genotypes.

  10. Impact of negative feedback in metabolic noise propagation.

    PubMed

    Borri, Alessandro; Palumbo, Pasquale; Singh, Abhyudai

    2016-10-01

    Synthetic biology combines different branches of biology and engineering aimed at designing synthetic biological circuits able to replicate emergent properties useful for the biotechnology industry, human health and environment. The role of negative feedback in noise propagation for a basic enzymatic reaction scheme is investigated. Two feedback control schemes on enzyme expression are considered: one from the final product of the pathway activity, the other from the enzyme accumulation. Both schemes are designed to provide the same steady-state average values of the involved players, in order to evaluate the feedback performances according to the same working mode. Computations are carried out numerically and analytically, the latter allowing to infer information on which model parameter setting leads to a more efficient noise attenuation, according to the chosen scheme. In addition to highlighting the role of the feedback in providing a substantial noise reduction, our investigation concludes that the effect of feedback is enhanced by increasing the promoter sensitivity for both schemes. A further interesting biological insight is that an increase in the promoter sensitivity provides more benefits to the feedback from the product with respect to the feedback from the enzyme, in terms of enlarging the parameter design space.

  11. Negative Feedback Enhances Robustness in the Yeast Polarity Establishment Circuit

    PubMed Central

    Howell, Audrey S.; Jin, Meng; Wu, Chi-Fang; Zyla, Trevin R.; Elston, Timothy C.; Lew, Daniel J.

    2013-01-01

    SUMMARY Many cells undergo symmetry-breaking polarization toward a randomly oriented “front” in the absence of spatial cues. In budding yeast, such polarization involves a positive feedback loop that enables amplification of stochastically arising clusters of polarity factors. Previous mathematical modeling suggested that, if more than one cluster were amplified, the clusters would compete for limiting resources and the largest would “win,” explaining why yeast cells always make one and only one bud. Here, using imaging with improved spatiotemporal resolution, we show the transient coexistence of multiple clusters during polarity establishment, as predicted by the model. Unexpectedly, we also find that initial polarity factor clustering is oscillatory, revealing the presence of a negative feedback loop that disperses the factors. Mathematical modeling predicts that negative feedback would confer robustness to the polarity circuit and make the kinetics of competition between polarity factor clusters relatively insensitive to polarity factor concentration. These predictions are confirmed experimentally. PMID:22500799

  12. Negative feedback enhances robustness in the yeast polarity establishment circuit.

    PubMed

    Howell, Audrey S; Jin, Meng; Wu, Chi-Fang; Zyla, Trevin R; Elston, Timothy C; Lew, Daniel J

    2012-04-13

    Many cells undergo symmetry-breaking polarization toward a randomly oriented "front" in the absence of spatial cues. In budding yeast, such polarization involves a positive feedback loop that enables amplification of stochastically arising clusters of polarity factors. Previous mathematical modeling suggested that, if more than one cluster were amplified, the clusters would compete for limiting resources and the largest would "win," explaining why yeast cells always make one and only one bud. Here, using imaging with improved spatiotemporal resolution, we show the transient coexistence of multiple clusters during polarity establishment, as predicted by the model. Unexpectedly, we also find that initial polarity factor clustering is oscillatory, revealing the presence of a negative feedback loop that disperses the factors. Mathematical modeling predicts that negative feedback would confer robustness to the polarity circuit and make the kinetics of competition between polarity factor clusters relatively insensitive to polarity factor concentration. These predictions are confirmed experimentally. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Osteoclasts and CD8 T cells form a negative feedback loop that contributes to homeostasis of both the skeletal and immune systems.

    PubMed

    Buchwald, Zachary S; Aurora, Rajeev

    2013-01-01

    There are a number of dynamic regulatory loops that maintain homeostasis of the immune and skeletal systems. In this review, we highlight a number of these regulatory interactions that contribute to maintaining homeostasis. In addition, we review data on a negative regulatory feedback loop between osteoclasts and CD8 T cells that contributes to homeostasis of both the skeletal and immune systems.

  14. A computational model clarifies the roles of positive and negative feedback loops in the Drosophila circadian clock

    NASA Astrophysics Data System (ADS)

    Wang, Junwei; Zhou, Tianshou

    2010-06-01

    Previous studies showed that a single negative feedback structure should be sufficient for robust circadian oscillations. It is thus pertinent to ask why current cellular clock models almost universally have interlocked negative feedback loop (NFL) and positive feedback loop (PFL). Here, we propose a molecular model that reflects the essential features of the Drosophila circadian clock to clarify the different roles of negative and positive feedback loops. In agreement with experimental observations, the model can simulate circadian oscillations in constant darkness, entrainment by light-dark cycles, as well as phenotypes of per and clk mutants. Moreover, sustained oscillations persist when the PFL is removed, implying the crucial role of NFL for rhythm generation. Through parameter sensitivity analysis, it is revealed that incorporation of PFL increases the robustness of the system to regulatory processes in PFL itself. Such reduced models can aid understanding of the design principles of circadian clocks in Drosophila and other organisms with complex transcriptional feedback structures.

  15. Delays induce novel stochastic effects in negative feedback gene circuits.

    PubMed

    Zavala, Eder; Marquez-Lago, Tatiana T

    2014-01-21

    Stochastic models of reaction networks are widely used to depict gene expression dynamics. However, stochastic does not necessarily imply accurate, as subtle assumptions can yield erroneous results, masking key discrete effects. For instance, transcription and translation are not instantaneous processes-explicit delays separate their initiation from the appearance of their functional products. However, delays are often ignored in stochastic, single-gene expression models. By consequence, effects such as delay-induced stochastic oscillations at the single-cell level have remained relatively unexplored. Here, we present a systematic study of periodicity and multimodality in a simple gene circuit with negative feedback, analyzing the influence of negative feedback strength and transcriptional/translational delays on expression dynamics. We demonstrate that an oscillatory regime emerges through a Hopf bifurcation in both deterministic and stochastic frameworks. Of importance, a shift in the stochastic Hopf bifurcation evidences inaccuracies of the deterministic bifurcation analysis. Furthermore, noise fluctuations within stochastic oscillations decrease alongside increasing values of transcriptional delays and within a specific range of negative feedback strengths, whereas a strong feedback is associated with oscillations triggered by bursts. Finally, we demonstrate that explicitly accounting for delays increases the number of accessible states in the multimodal regime, and also introduces features typical of excitable systems.

  16. Delays Induce Novel Stochastic Effects in Negative Feedback Gene Circuits

    PubMed Central

    Zavala, Eder; Marquez-Lago, Tatiana T.

    2014-01-01

    Stochastic models of reaction networks are widely used to depict gene expression dynamics. However, stochastic does not necessarily imply accurate, as subtle assumptions can yield erroneous results, masking key discrete effects. For instance, transcription and translation are not instantaneous processes—explicit delays separate their initiation from the appearance of their functional products. However, delays are often ignored in stochastic, single-gene expression models. By consequence, effects such as delay-induced stochastic oscillations at the single-cell level have remained relatively unexplored. Here, we present a systematic study of periodicity and multimodality in a simple gene circuit with negative feedback, analyzing the influence of negative feedback strength and transcriptional/translational delays on expression dynamics. We demonstrate that an oscillatory regime emerges through a Hopf bifurcation in both deterministic and stochastic frameworks. Of importance, a shift in the stochastic Hopf bifurcation evidences inaccuracies of the deterministic bifurcation analysis. Furthermore, noise fluctuations within stochastic oscillations decrease alongside increasing values of transcriptional delays and within a specific range of negative feedback strengths, whereas a strong feedback is associated with oscillations triggered by bursts. Finally, we demonstrate that explicitly accounting for delays increases the number of accessible states in the multimodal regime, and also introduces features typical of excitable systems. PMID:24461022

  17. Feedback-induced glutamate spillover enhances negative feedback from horizontal cells to cones

    PubMed Central

    Vroman, Rozan; Kamermans, Maarten

    2015-01-01

    Key points In the retina, horizontal cells feed back negatively to cone photoreceptors. Glutamate released from cones can spill over to neighbouring cones. Here we show that cone glutamate release induced by negative feedback can also spill over to neighbouring cones. This glutamate activates the glutamate transporter-associated chloride current in these neighbouring cones, which leads to a change in their membrane potential and thus modulates their output. In this way, feedback-induced glutamate spillover enhances negative feedback from horizontal cells to cones, thus forming an additional feedback pathway. This effect will be particularly prominent in cones that are strongly hyperpolarized by light. Abstract Inhibition in the outer retina functions via an unusual mechanism. When horizontal cells hyperpolarize the activation potential of the Ca2+ current of cones shifts to more negative potentials. The underlying mechanism consists of an ephaptic component and a Panx1/ATP-mediated component. Here we identified a third feedback component, which remains active outside the operating range of the Ca2+ current. We show that the glutamate transporters of cones can be activated by glutamate released from their neighbours. This pathway can be triggered by negative feedback from horizontal cells to cones, thus providing an additional feedback pathway. This additional pathway is mediated by a Cl− current, can be blocked by either removing the gradient of K+ or by adding the glutamate transporter blocker TBOA, or low concentrations of Zn2+. These features point to a glutamate transporter-associated Cl− current. The pathway has a delay of 4.7 ± 1.7 ms. The effectiveness of this pathway in modulating the cone output depends on the equilibrium potential of Cl− (ECl) and the membrane potential of the cone. Because estimates of ECl show that it is around the dark resting membrane potential of cones, the activation of the glutamate transporter-associated Cl− current

  18. Expression Optimization and Inducible Negative Feedback in Cell-Free Systems

    SciTech Connect

    Karig, David K; Iyer, Sukanya; Simpson, Michael L; Doktycz, Mitchel John

    2012-01-01

    Synthetic biology offers great promise to a variety of applications through the forward engineering of biological function. Most efforts in this field have focused on employing living cells. Cell-free approaches, on the other hand, offer simpler and more flexible contexts, but few synthetic systems based on cell-free protein expression have been constructed. Here, we evaluate cell-free regulatory systems based on T7 promoter driven expression, and we demonstrate negative feedback, an essential motif in many natural and engineered systems. First, we characterize variants of TetR and LacI repressible T7 promoters in a cell-free context and examine sequence elements that determine expression efficiency. Then, we explore different approaches for composing regulatory systems, leading to the implementation of inducible negative feedback in E. coli extracts and in the minimal PURE system, which consists of purified proteins necessary for transcription and translation. Our quantitative cell-free component characterizations and demonstration of negative feedback embody important steps on the path to harnessing biological function in a bottom up fashion.

  19. Identity Change in Newly Married Couples: Effects of Positive and Negative Feedback

    ERIC Educational Resources Information Center

    Cast, Alicia D.; Cantwell, Allison M.

    2007-01-01

    Previous research has examined individuals' relative preference for consistent and enhancing feedback by examining reactions to negative and positive feedback. Recent research shows that, in general, individuals prefer feedback that is consistent with self-views, even if feedback is negative. It is unclear, however, whether negative and positive…

  20. Interplay between stochasticity and negative feedback leads to pulsed dynamics and distinct gene activity patterns.

    PubMed

    Zambrano, Samuel; Bianchi, Marco E; Agresti, Alessandra; Molina, Nacho

    2015-08-01

    Gene expression is an inherently stochastic process that depends on the structure of the biochemical regulatory network in which the gene is embedded. Here we study the dynamical consequences of the interplay between stochastic gene switching and the widespread negative feedback regulatory loop in a simple model of a biochemical regulatory network. Using a simplified hybrid simulation approach, in which only the gene activation is modeled stochastically, we find that stochasticity in gene switching by itself can induce pulses in the system, providing also analytical insights into their origin. Furthermore, we find that this simple network is able to reproduce both exponential and peaked distributions of gene active and inactive times similar to those that have been observed experimentally. This simplified hybrid simulation approach also allows us to link these patterns to the dynamics of the system for each gene state.

  1. AGN feedback and star formation in ETGs: negative and positive feedback

    NASA Astrophysics Data System (ADS)

    Ciotti, Luca; Ostriker, Jeremiah P.; Negri, Andrea; Pellegrini, Silvia; Posacki, Silvia; Novak, Greg

    AGN feedback from supermassive black holes (SMBHs) at the center of early type galaxies is commonly invoked as the explanation for the quenching of star formation in these systems. The situation is complicated by the significant amount of mass injected in the galaxy by the evolving stellar population over cosmological times. In absence of feedback, this mass would lead to unobserved galactic cooling flows, and to SMBHs two orders of magnitude more massive than observed. By using high-resolution 2D hydrodynamical simulations with radiative transport and star formation in state-of-the-art galaxy models, we show how the intermittent AGN feedback is highly structured on spatial and temporal scales, and how its effects are not only negative (shutting down the recurrent cooling episodes of the ISM), but also positive, inducing star formation in the inner regions of the host galaxy.

  2. AGN feedback and star formation in ETGs: negative and positive feedback

    NASA Astrophysics Data System (ADS)

    Ciotti, Luca; Ostriker, Jeremiah P.; Novak, Greg; Negri, Andrea; Pellegrini, Silvia; Posacki, Silvia

    2015-08-01

    AGN feedback from supermassive black holes at the center of Early Type Galaxies is commonly invoked as the explanation for the quenching of star formation in these systems, that after this phase are considered “red and dead”. The situation is by far more complicated, due to the significant amount of mass injected in the galaxy by the evolving stellar population over cosmological times. In absence of feedback, this mass would lead to unobserved galactic cooling flows, and to central black holes two orders of magnitude more massive than observed. I will present the results of state-of-the-art hydrodynamical simulations with radiative transport and star formation of the “passive” evolution of ETGs, focusing in particular on highly structured spatial and temporal nature of the intermittent AGN feedback, that is not only negative (shutting down the cooling episodes of the ISM), but also positive, inducing star formation in the inner regions of the host galaxy.

  3. Control and regulation of pathways via negative feedback

    PubMed Central

    2017-01-01

    The biochemical networks found in living organisms include a huge variety of control mechanisms at multiple levels of organization. While the mechanistic and molecular details of many of these control mechanisms are understood, their exact role in driving cellular behaviour is not. For example, yeast glycolysis has been studied for almost 80 years but it is only recently that we have come to understand the systemic role of the multitude of feedback and feed-forward controls that exist in this pathway. In this article, control theory is discussed as an approach to dissect the control logic of complex pathways. One of the key issues is distinguishing between the terms control and regulation and how these concepts are applied to regulated enzymes such as phosphofructokinase. In doing so, one of the paradoxes in metabolic regulation can be resolved where enzymes such as phosphofructokinase have little control but, nevertheless, possess significant regulatory influence. PMID:28202588

  4. Negative avalanche feedback detectors for photon-counting optical communications

    NASA Astrophysics Data System (ADS)

    Farr, William H.

    2009-02-01

    Negative Avalanche Feedback photon counting detectors with near-infrared spectral sensitivity offer an alternative to conventional Geiger mode avalanche photodiode or phototube detectors for free space communications links at 1 and 1.55 microns. These devices demonstrate linear mode photon counting without requiring any external reset circuitry and may even be operated at room temperature. We have now characterized the detection efficiency, dark count rate, after-pulsing, and single photon jitter for three variants of this new detector class, as well as operated these uniquely simple to use devices in actual photon starved free space optical communications links.

  5. Negative Avalanche Feedback Detectors for Photon-Counting Optical Communications

    NASA Technical Reports Server (NTRS)

    Farr, William H.

    2009-01-01

    Negative Avalanche Feedback photon counting detectors with near-infrared spectral sensitivity offer an alternative to conventional Geiger mode avalanche photodiode or phototube detectors for free space communications links at 1 and 1.55 microns. These devices demonstrate linear mode photon counting without requiring any external reset circuitry and may even be operated at room temperature. We have now characterized the detection efficiency, dark count rate, after-pulsing, and single photon jitter for three variants of this new detector class, as well as operated these uniquely simple to use devices in actual photon starved free space optical communications links.

  6. Negative Avalanche Feedback Detectors for Photon-Counting Optical Communications

    NASA Technical Reports Server (NTRS)

    Farr, William H.

    2009-01-01

    Negative Avalanche Feedback photon counting detectors with near-infrared spectral sensitivity offer an alternative to conventional Geiger mode avalanche photodiode or phototube detectors for free space communications links at 1 and 1.55 microns. These devices demonstrate linear mode photon counting without requiring any external reset circuitry and may even be operated at room temperature. We have now characterized the detection efficiency, dark count rate, after-pulsing, and single photon jitter for three variants of this new detector class, as well as operated these uniquely simple to use devices in actual photon starved free space optical communications links.

  7. Context-sensitivity of the feedback-related negativity for zero-value feedback outcomes.

    PubMed

    Pfabigan, Daniela M; Seidel, Eva-Maria; Paul, Katharina; Grahl, Arvina; Sailer, Uta; Lanzenberger, Rupert; Windischberger, Christian; Lamm, Claus

    2015-01-01

    The present study investigated whether the same visual stimulus indicating zero-value feedback (€0) elicits feedback-related negativity (FRN) variation, depending on whether the outcomes correspond with expectations or not. Thirty-one volunteers performed a monetary incentive delay (MID) task while EEG was recorded. FRN amplitudes were comparable and more negative when zero-value outcome deviated from expectations than with expected gain or loss, supporting theories emphasising the impact of unexpectedness and salience on FRN amplitudes. Surprisingly, expected zero-value outcomes elicited the most negative FRNs. However, source localisation showed that such outcomes evoked less activation in cingulate areas than unexpected zero-value outcomes. Our study illustrates the context dependency of identical zero-value feedback stimuli. Moreover, the results indicate that the incentive cues in the MID task evoke different reward prediction error signals. These prediction signals differ in FRN amplitude and neuronal sources, and have to be considered in the design and interpretation of future studies.

  8. Bringing in the negative reinforcements: the avoidance feedback-related negativity.

    PubMed

    Crowley, Michael J; Wu, Jia; Bailey, Christopher A; Mayes, Linda C

    2009-11-25

    The feedback-related negativity (FRN) is an event-related potential thought to reflect a reward prediction error, when an outcome is worse than expected. Behavior motivated by the avoidance of negative outcomes is sustained through negative reinforcement processes. Escaping or avoiding a negative outcome may be successful or not, resulting in an analogous situation to that which elicits the FRN. We observed that when expected avoidance of an aversive outcome fails to occur, there occurs a negative deflection in the frontocentral event-related potential at approximately 350 ms, but with a slow wave following. We suggest that the FRN may be considered an index of a broader class of reward-based learning that also includes avoiding negative outcomes as well as expecting positive ones.

  9. Altered emotional and BOLD responses to negative, positive and ambiguous performance feedback in OCD.

    PubMed

    Becker, Michael P I; Nitsch, Alexander M; Schlösser, Ralf; Koch, Kathrin; Schachtzabel, Claudia; Wagner, Gerd; Miltner, Wolfgang H R; Straube, Thomas

    2014-08-01

    While abnormal processing of performance feedback has been associated with obsessive-compulsive disorder (OCD), neural responses to different kinds of feedback information, especially to ambiguous feedback are widely unknown. Using fMRI and a performance adaptive time-estimation task, we acquired blood oxygenation level-dependant responses and emotional ratings to positive, negative and ambiguous performance feedback in patients and healthy controls. Negative and ambiguous feedback led to increased levels of anxiety, guilt and shame in patients. Both negative and ambiguous feedback, as compared to positive feedback, induced increased activation of the insular cortex in patients. Furthermore, patients showed no differential activation to negative feedback in the putamen and to ambiguous feedback in the ventromedial prefrontal cortex (VMPFC). Finally, negative feedback induced increased activation in the midcingulate cortex in patients compared to controls. Findings indicate that both negative and ambiguous performance feedbacks are associated with abnormal negative emotions and altered brain activation, in particular increased insula activation, while activation in the putamen and VMPFC does not differentiate between feedback types in OCD patients. This suggests a parallel pattern of increased and decreased neural sensitivity to different kinds of feedback information and a general emotional hyperresponsivity to negative and ambiguous performance feedback in OCD. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  10. Negative feedback regulation of fatty acid production based on a malonyl-CoA sensor-actuator.

    PubMed

    Liu, Di; Xiao, Yi; Evans, Bradley S; Zhang, Fuzhong

    2015-02-20

    Engineering metabolic biosynthetic pathways has enabled the microbial production of many useful chemicals. However, pathway productivities and yields are often limited by metabolic imbalances. Synthetic regulatory circuits have been shown to be able to balance engineered pathways, improving titers and productivities. Here we developed a negative feedback regulatory circuit based on a malonyl-CoA-based sensor-actuator. Malonyl-CoA is biosynthesized from acetyl-CoA by the acetyl-CoA carboxylase, which is the rate-limiting step for fatty acid biosynthesis. Overexpression of acetyl-CoA carboxylase improves fatty acid production, but slows down cell growth. We have devised a malonyl-CoA sensor-actuator that controls gene expression levels based on intracellular malonyl-CoA concentrations. This sensor-actuator is used to construct a negative feedback circuit to regulate the expression of acetyl-CoA carboxylase. The negative feedback circuit is able to up-regulate acetyl-CoA carboxylase expression when the malonyl-CoA concentration is low and down-regulate acetyl-CoA carboxylase expression when excess amounts of malonyl-CoA have accumulated. We show that the regulatory circuit effectively alleviates the toxicity associated with acetyl-CoA carboxylase overexpression. When used to regulate the fatty acid pathway, the feedback circuit increases fatty acid titer and productivity by 34% and 33%, respectively.

  11. Brain activity elicited by positive and negative feedback in preschool-aged children.

    PubMed

    Mai, Xiaoqin; Tardif, Twila; Doan, Stacey N; Liu, Chao; Gehring, William J; Luo, Yue-Jia

    2011-04-19

    To investigate the processing of positive vs. negative feedback in children aged 4-5 years, we devised a prize-guessing game that is analogous to gambling tasks used to measure feedback-related brain responses in adult studies. Unlike adult studies, the feedback-related negativity (FRN) elicited by positive feedback was as large as that elicited by negative feedback, suggesting that the neural system underlying the FRN may not process feedback valence in early childhood. In addition, positive feedback, compared with negative feedback, evoked a larger P1 over the occipital scalp area and a larger positive slow wave (PSW) over the right central-parietal scalp area. We believe that the PSW is related to emotional arousal and the intensive focus on positive feedback that is present in the preschool and early school years has adaptive significance for both cognitive and emotional development during this period.

  12. Positive and Negative Assessment Center Feedback in Relation to Development Self-Efficacy, Feedback Seeking, and Promotion.

    PubMed

    Dimotakis, Nikolaos; Mitchell, Deb; Maurer, Todd

    2017-07-27

    In this field study we examined both positive and negative developmental feedback given in managerial assessment centers in relation to employees' self-efficacy for their ability to improve their relevant skills assessed in the centers, the extent to which they sought subsequent feedback from others at work, and the career outcome of being promoted to a higher level position within the organization. We found that feedback was related to self-efficacy for improvement which was in turn positively related to feedback seeking, which was positively linked to the career outcome of promotion (e.g., feedback leads to self-efficacy for improvement leads to feedback seeking leads to promotion). In addition, we tested boundary variables for the effects of feedback in this model. Both social support for development and implicit theory of ability moderated the effects of negative feedback on self-efficacy. Having more support and believing that abilities can be improved buffered the detrimental impact of negative feedback on self-efficacy. We discuss implications for theory, future research and practical implications drawing upon literature on assessment centers, feedback and feedback seeking, employee development and career success. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  13. Fetal pituitary negative feedback at early gestational age.

    PubMed

    Rakover, Y; Weiner, E; Mosh, N; Shalev, E

    1999-06-01

    We describe an early prenatal diagnosis and the successful treatment of fetal Graves' disease from transplacental transfer of maternal thyroid stimulating autoantibodies (TSAb). The diagnosis of fetal thyrotoxicosis was made by umbilical cord sampling (UBS) at 20 weeks gestation, based on suppressed TSH with elevated FT4 levels. Therapy with propylthiouracil (PTU) improved fetal thyroid function tests as well as the clinical signs of fetal Graves' disease. Three more UBS were conducted before delivery indicating persisting mild fetal hyperthyroidism. Undetectable concentrations of thyrotrophin in fetal serum in the presence of markedly elevated FT4, suggests pituitary negative feedback at as early as 20 weeks gestation. Amniotic fluid thyrotrophin levels were measured at 20,24 and 26 weeks and were shown to correlate better with (elevated) maternal rather than (suppressed) fetal TSH values; therefore, we believe that amniotic fluid thyrotrophin measurement is unreliable for prediction of fetal thyroid status. Our observation is the first documentation of an intact feedback mechanism so early in fetal development and it suggests that pituitary maturation occurs earlier than previously believed.

  14. Negative derivative feedback for vibration control of flexible structures

    NASA Astrophysics Data System (ADS)

    Cazzulani, G.; Resta, F.; Ripamonti, F.; Zanzi, R.

    2012-07-01

    In this paper a resonant control technique, called negative derivative feedback (NDF), for structural vibration control is presented. Resonant control is a class of control logics, based on the modal approach, which calculates the control action through a dynamic compensator in order to achieve a damping increase on a certain number of system modes. The NDF compensator is designed to work as a band-pass filter, cutting off the control action far from the natural frequencies associated with the controlled modes and reducing the so-called spillover effect. In the paper the proposed control logic is compared both theoretically and experimentally with the most common state-of-the-art resonant control techniques.

  15. Adaptive learning by extremal dynamics and negative feedback

    SciTech Connect

    Bak, Per; Chialvo, Dante R.

    2001-03-01

    We describe a mechanism for biological learning and adaptation based on two simple principles: (i) Neuronal activity propagates only through the network's strongest synaptic connections (extremal dynamics), and (ii) the strengths of active synapses are reduced if mistakes are made, otherwise no changes occur (negative feedback). The balancing of those two tendencies typically shapes a synaptic landscape with configurations which are barely stable, and therefore highly flexible. This allows for swift adaptation to new situations. Recollection of past successes is achieved by punishing synapses which have once participated in activity associated with successful outputs much less than neurons that have never been successful. Despite its simplicity, the model can readily learn to solve complicated nonlinear tasks, even in the presence of noise. In particular, the learning time for the benchmark parity problem scales algebraically with the problem size N, with an exponent k{approx}1.4.

  16. Oscillator frequency stability improvement by means of negative feedback.

    PubMed

    Goryachev, Maxim; Galliou, Serge; Abbé, Philippe; Komine, Vadim

    2011-11-01

    A novel, simple method is proposed to increase the frequency stability of an oscillator. An additional negative feedback is used in combination with the positive loop of the harmonic oscillator to decrease the phase sensitivity to fluctuations of parameters other than the resonator. The main advantage of the proposed correction approach is that it does not require expensive external elements such as mixers or resonators. The validity of the method is theoretically demonstrated on a Colpitts oscillator using the control system theory approach and numerical simulations, and is experimentally verified with phase noise measurements of an actual oscillator-mockup. It is shown that the medium-term frequency stability can be easily improved by a factor of ten.

  17. Negative plant soil feedback explaining ring formation in clonal plants.

    PubMed

    Cartenì, Fabrizio; Marasco, Addolorata; Bonanomi, Giuliano; Mazzoleni, Stefano; Rietkerk, Max; Giannino, Francesco

    2012-11-21

    Ring shaped patches of clonal plants have been reported in different environments, but the mechanisms underlying such pattern formation are still poorly explained. Water depletion in the inner tussocks zone has been proposed as a possible cause, although ring patterns have been also observed in ecosystems without limiting water conditions. In this work, a spatially explicit model is presented in order to investigate the role of negative plant-soil feedback as an additional explanation for ring formation. The model describes the dynamics of the plant biomass in the presence of toxicity produced by the decomposition of accumulated litter in the soil. Our model qualitatively reproduces the emergence of ring patterns of a single clonal plant species during colonisation of a bare substrate. The model admits two homogeneous stationary solutions representing bare soil and uniform vegetation cover which depend only on the ratio between the biomass death and growth rates. Moreover, differently from other plant spatial patterns models, but in agreement with real field observations of vegetation dynamics, we demonstrated that the pattern dynamics always lead to spatially homogeneous vegetation covers without creation of stable Turing patterns. Analytical results show that ring formation is a function of two main components, the plant specific susceptibility to toxic compounds released in the soil by the accumulated litter and the decay rate of these same compounds, depending on environmental conditions. These components act at the same time and their respective intensities can give rise to the different ring structures observed in nature, ranging from slight reductions of biomass in patch centres, to the appearance of marked rings with bare inner zones, as well as the occurrence of ephemeral waves of plant cover. Our results highlight the potential role of plant-soil negative feedback depending on decomposition processes for the development of transient vegetation patterns

  18. Developmental and Gender Related Differences in Response Switches after Nonrepresentative Negative Feedback

    ERIC Educational Resources Information Center

    Jansen, Brenda R. J.; van Duijvenvoorde, Anna C. K.; Huizenga, Hilde M.

    2014-01-01

    In many decision making tasks negative feedback is probabilistic and, as a consequence, may be given when the decision is actually correct. This feedback can be referred to as nonrepresentative negative feedback. In the current study, we investigated developmental and gender related differences in such switching after nonrepresentative negative…

  19. Developmental and Gender Related Differences in Response Switches after Nonrepresentative Negative Feedback

    ERIC Educational Resources Information Center

    Jansen, Brenda R. J.; van Duijvenvoorde, Anna C. K.; Huizenga, Hilde M.

    2014-01-01

    In many decision making tasks negative feedback is probabilistic and, as a consequence, may be given when the decision is actually correct. This feedback can be referred to as nonrepresentative negative feedback. In the current study, we investigated developmental and gender related differences in such switching after nonrepresentative negative…

  20. Relationship between Counseling Students' Childhood Memories and Current Negative Self-Evaluations When Receiving Corrective Feedback

    ERIC Educational Resources Information Center

    Stroud, Daniel; Olguin, David; Marley, Scott

    2016-01-01

    This article entails a study focused on the relationship between counseling students' negative childhood memories of receiving corrective feedback and current negative self-evaluations when receiving similar feedback in counselor education programs. Participants (N = 186) completed the Corrective Feedback Instrument-Revised (CFI-R; Hulse-Killacky…

  1. Relationship between Counseling Students' Childhood Memories and Current Negative Self-Evaluations When Receiving Corrective Feedback

    ERIC Educational Resources Information Center

    Stroud, Daniel; Olguin, David; Marley, Scott

    2016-01-01

    This article entails a study focused on the relationship between counseling students' negative childhood memories of receiving corrective feedback and current negative self-evaluations when receiving similar feedback in counselor education programs. Participants (N = 186) completed the Corrective Feedback Instrument-Revised (CFI-R; Hulse-Killacky…

  2. Comparing the effects of positive and negative feedback in information-integration category learning.

    PubMed

    Freedberg, Michael; Glass, Brian; Filoteo, J Vincent; Hazeltine, Eliot; Maddox, W Todd

    2017-01-01

    Categorical learning is dependent on feedback. Here, we compare how positive and negative feedback affect information-integration (II) category learning. Ashby and O'Brien (2007) demonstrated that both positive and negative feedback are required to solve II category problems when feedback was not guaranteed on each trial, and reported no differences between positive-only and negative-only feedback in terms of their effectiveness. We followed up on these findings and conducted 3 experiments in which participants completed 2,400 II categorization trials across three days under 1 of 3 conditions: positive feedback only (PFB), negative feedback only (NFB), or both types of feedback (CP; control partial). An adaptive algorithm controlled the amount of feedback given to each group so that feedback was nearly equated. Using different feedback control procedures, Experiments 1 and 2 demonstrated that participants in the NFB and CP group were able to engage II learning strategies, whereas the PFB group was not. Additionally, the NFB group was able to achieve significantly higher accuracy than the PFB group by Day 3. Experiment 3 revealed that these differences remained even when we equated the information received on feedback trials. Thus, negative feedback appears significantly more effective for learning II category structures. This suggests that the human implicit learning system may be capable of learning in the absence of positive feedback.

  3. The interaction of positive and negative sensory feedback loops in dynamic regulation of a motor pattern.

    PubMed

    Ausborn, Jessica; Wolf, Harald; Stein, Wolfgang

    2009-10-01

    In many rhythmic behaviors, phasic sensory feedback modifies the motor pattern. This modification is assumed to depend on feedback sign (positive vs. negative). While on a phenomenological level feedback sign is well defined, many sensory pathways also process antagonistic, and possibly contradictory, sensory information. We here model the locust flight pattern generator and proprioceptive feedback provided by the tegula wing receptor to test the functional significance of sensory pathways processing antagonistic information. We demonstrate that the tegula provides delayed positive feedback via interneuron 301, while all other pathways provide negative feedback. Contradictory to previous assumptions, the increase of wing beat frequency when the tegula is activated during flight is due to the positive feedback. By use of an abstract model we reveal that the regulation of motor pattern frequency by sensory feedback critically depends on the interaction of positive and negative feedback, and thus on the weighting of antagonistic pathways.

  4. Potentiated processing of negative feedback in depression is attenuated by anhedonia

    PubMed Central

    Mueller, E. M.; Pechtel, P.; Cohen, A.L.; Douglas, S.R.; Pizzagalli, D.A.

    2014-01-01

    Background Although cognitive theories of depression have postulated enhanced processing of negatively valenced information, previous EEG studies have shown both increased and reduced sensitivity for negative performance feedback in MDD. To reconcile these paradoxical findings, it has been speculated that sensitivity for negative feedback is potentiated in moderate MDD but reduced in highly anhedonic subjects. The goal of this study was to test this hypothesis by analyzing the feedback-related negativity (FRN), frontomedial theta power (FMT), and source-localized anterior midcingulate cortex (aMCC) activity after negative feedback. Methods Fourteen unmedicated participants with MDD and 15 control participants performed a reinforcement learning task while 128-channel EEG was recorded. FRN, FMT and LORETA source-localized aMCC activity after negative and positive feedback were compared between groups. Results The MDD group showed higher FRN amplitudes and aMCC activation to negative feedback than controls. Moreover, aMCC activation to negative feedback was inversely related to self-reported anhedonia. In contrast, self-reported anxiety correlated with feedback-evoked frontomedial theta (FMT) within the depression group. Conclusions The present findings suggest that, among depressed and anxious individuals, enhanced processing of negative feedback occurs relatively early in the information processing stream. These results extend prior work and indicate that although moderate depression is associated with elevated sensitivity for negative feedback, high levels of anhedonia may attenuate this effect. PMID:25620272

  5. From Positivity to Negativity Bias: Ambiguity Affects the Neurophysiological Signatures of Feedback Processing.

    PubMed

    Gibbons, Henning; Schnuerch, Robert; Stahl, Jutta

    2016-04-01

    Previous studies on the neurophysiological underpinnings of feedback processing almost exclusively used low-ambiguity feedback, which does not fully address the diversity of situations in everyday life. We therefore used a pseudo trial-and-error learning task to investigate ERPs of low- versus high-ambiguity feedback. Twenty-eight participants tried to deduce the rule governing visual feedback to their button presses in response to visual stimuli. In the blocked condition, the same two feedback words were presented across several consecutive trials, whereas in the random condition feedback was randomly drawn on each trial from sets of five positive and five negative words. The feedback-related negativity (FRN-D), a frontocentral ERP difference between negative and positive feedback, was significantly larger in the blocked condition, whereas the centroparietal late positive complex indicating controlled attention was enhanced for negative feedback irrespective of condition. Moreover, FRN-D in the blocked condition was due to increased reward positivity (Rew-P) for positive feedback, rather than increased (raw) FRN for negative feedback. Our findings strongly support recent lines of evidence that the FRN-D, one of the most widely studied signatures of reinforcement learning in the human brain, critically depends on feedback discriminability and is primarily driven by the Rew-P. A novel finding concerned larger frontocentral P2 for negative feedback in the random but not the blocked condition. Although Rew-P points to a positivity bias in feedback processing under conditions of low feedback ambiguity, P2 suggests a specific adaptation of information processing in case of highly ambiguous feedback, involving an early negativity bias. Generalizability of the P2 findings was demonstrated in a second experiment using explicit valence categorization of highly emotional positive and negative adjectives.

  6. The organization of plant communities: negative plant-soil feedbacks and semiarid grasslands.

    PubMed

    Reinhart, Kurt O

    2012-11-01

    Understanding how plant communities are organized requires uncovering the mechanism(s) regulating plant species coexistence and relative abundance. Negative soil feedbacks may affect plant communities by suppressing dominant species, causing rarity of most plants, or reducing the competitive abilities of all species. Here, three soil feedback experiments were used to differentiate the effects of soil feedbacks on mid- to late-successional and semiarid grasslands. Then I tested whether the direction and degree of soil feedback accounts for variation in relative abundance among species that coexist within each plant community. Negative soil feedbacks predominated across all species and sites and were individually discernible for 40% of plant species. Negative soil feedbacks affected rare to dominant plant species. Negative soil feedbacks, capable of having negative frequency-dependent effects, have the potential to act as a fundamental driver of species coexistence.

  7. EFA6 controls Arf1 and Arf6 activation through a negative feedback loop.

    PubMed

    Padovani, Dominique; Folly-Klan, Marcia; Labarde, Audrey; Boulakirba, Sonia; Campanacci, Valérie; Franco, Michel; Zeghouf, Mahel; Cherfils, Jacqueline

    2014-08-26

    Guanine nucleotide exchange factors (GEFs) of the exchange factor for Arf6 (EFA6), brefeldin A-resistant Arf guanine nucleotide exchange factor (BRAG), and cytohesin subfamilies activate small GTPases of the Arf family in endocytic events. These ArfGEFs carry a pleckstrin homology (PH) domain in tandem with their catalytic Sec7 domain, which is autoinhibitory and supports a positive feedback loop in cytohesins but not in BRAGs, and has an as-yet unknown role in EFA6 regulation. In this study, we analyzed how EFA6A is regulated by its PH and C terminus (Ct) domains by reconstituting its GDP/GTP exchange activity on membranes. We found that EFA6 has a previously unappreciated high efficiency toward Arf1 on membranes and that, similar to BRAGs, its PH domain is not autoinhibitory and strongly potentiates nucleotide exchange on anionic liposomes. However, in striking contrast to both cytohesins and BRAGs, EFA6 is regulated by a negative feedback loop, which is mediated by an allosteric interaction of Arf6-GTP with the PH-Ct domain of EFA6 and monitors the activation of Arf1 and Arf6 differentially. These observations reveal that EFA6, BRAG, and cytohesins have unanticipated commonalities associated with divergent regulatory regimes. An important implication is that EFA6 and cytohesins may combine in a mixed negative-positive feedback loop. By allowing EFA6 to sustain a pool of dormant Arf6-GTP, such a circuit would fulfill the absolute requirement of cytohesins for activation by Arf-GTP before amplification of their GEF activity by their positive feedback loop.

  8. EFA6 controls Arf1 and Arf6 activation through a negative feedback loop

    PubMed Central

    Padovani, Dominique; Folly-Klan, Marcia; Labarde, Audrey; Boulakirba, Sonia; Campanacci, Valérie; Franco, Michel; Zeghouf, Mahel; Cherfils, Jacqueline

    2014-01-01

    Guanine nucleotide exchange factors (GEFs) of the exchange factor for Arf6 (EFA6), brefeldin A-resistant Arf guanine nucleotide exchange factor (BRAG), and cytohesin subfamilies activate small GTPases of the Arf family in endocytic events. These ArfGEFs carry a pleckstrin homology (PH) domain in tandem with their catalytic Sec7 domain, which is autoinhibitory and supports a positive feedback loop in cytohesins but not in BRAGs, and has an as-yet unknown role in EFA6 regulation. In this study, we analyzed how EFA6A is regulated by its PH and C terminus (Ct) domains by reconstituting its GDP/GTP exchange activity on membranes. We found that EFA6 has a previously unappreciated high efficiency toward Arf1 on membranes and that, similar to BRAGs, its PH domain is not autoinhibitory and strongly potentiates nucleotide exchange on anionic liposomes. However, in striking contrast to both cytohesins and BRAGs, EFA6 is regulated by a negative feedback loop, which is mediated by an allosteric interaction of Arf6-GTP with the PH-Ct domain of EFA6 and monitors the activation of Arf1 and Arf6 differentially. These observations reveal that EFA6, BRAG, and cytohesins have unanticipated commonalities associated with divergent regulatory regimes. An important implication is that EFA6 and cytohesins may combine in a mixed negative-positive feedback loop. By allowing EFA6 to sustain a pool of dormant Arf6-GTP, such a circuit would fulfill the absolute requirement of cytohesins for activation by Arf-GTP before amplification of their GEF activity by their positive feedback loop. PMID:25114232

  9. Development of negative feedback during successive growth cycles of black cherry.

    PubMed Central

    Packer, Alissa; Clay, Keith

    2004-01-01

    Negative feedback between plant and soil microbial communities can be a key determinant of vegetation structure and dynamics. Previous research has shown that negative feedback between black cherry (Prunus serotina) and soil pathogens is strongly distance dependent. Here, we investigate the temporal dynamics of negative feedback. To examine short-term changes, we planted successive cycles of seedlings in the same soil. We found that seedling mortality increased steadily with growth cycle when sterile background soil was inoculated with living field soil but not in controls inoculated with sterilized field soil. To examine long-term changes, we quantified negative feedback across successive growth cycles in soil inoculated with living field soil from a mature forest system (more than 70 years old) versus a younger successional site (ca. 25 years old). In both cases negative feedback developed similarly. Our results suggest that negative feedback can develop very quickly in forest systems, at the spatial scale of a single seedling. PMID:15058444

  10. Control your anger! The neural basis of aggression regulation in response to negative social feedback.

    PubMed

    Achterberg, Michelle; van Duijvenvoorde, Anna C K; Bakermans-Kranenburg, Marian J; Crone, Eveline A

    2016-05-01

    Negative social feedback often generates aggressive feelings and behavior. Prior studies have investigated the neural basis of negative social feedback, but the underlying neural mechanisms of aggression regulation following negative social feedback remain largely undiscovered. In the current study, participants viewed pictures of peers with feedback (positive, neutral or negative) to the participant's personal profile. Next, participants responded to the peer feedback by pressing a button, thereby producing a loud noise toward the peer, as an index of aggression. Behavioral analyses showed that negative feedback led to more aggression (longer noise blasts). Conjunction neuroimaging analyses revealed that both positive and negative feedback were associated with increased activity in the medial prefrontal cortex (PFC) and bilateral insula. In addition, more activation in the right dorsal lateral PFC (dlPFC) during negative feedback vs neutral feedback was associated with shorter noise blasts in response to negative social feedback, suggesting a potential role of dlPFC in aggression regulation, or top-down control over affective impulsive actions. This study demonstrates a role of the dlPFC in the regulation of aggressive social behavior.

  11. The Effect of Negative Feedback Loops on the Dynamics of Boolean Networks

    PubMed Central

    Sontag, Eduardo; Veliz-Cuba, Alan; Laubenbacher, Reinhard; Jarrah, Abdul Salam

    2008-01-01

    Feedback loops play an important role in determining the dynamics of biological networks. To study the role of negative feedback loops, this article introduces the notion of distance-to-positive-feedback which, in essence, captures the number of independent negative feedback loops in the network, a property inherent in the network topology. Through a computational study using Boolean networks, it is shown that distance-to-positive-feedback has a strong influence on network dynamics and correlates very well with the number and length of limit cycles in the phase space of the network. To be precise, it is shown that, as the number of independent negative feedback loops increases, the number (length) of limit cycles tends to decrease (increase). These conclusions are consistent with the fact that certain natural biological networks exhibit generally regular behavior and have fewer negative feedback loops than randomized networks with the same number of nodes and same connectivity. PMID:18375509

  12. Threshold sensitivity of quartz variometers with negative feedback

    NASA Astrophysics Data System (ADS)

    Odintsov, V. I.; Petrov, V. G.

    2017-05-01

    The maximum achievable parameters of magnetometers based on optomechanical quartz variometers are studied in connection with the planned transition of the international network Intermagnet to 1-s recording and the need to provide the network of Russian geomagnetic observatories with domestic magnetometers that satisfy Intermagnet requirements. The mechanism of negative feedback effect on the sensitivity threshold of a variometer with an optoelectronic angle transducer is shown. The optimization criterion for the size and shape of the magnets made of different magnetic materials is defined by the maximum ratio of the magnetic moment to the inertial moment. Theoretical and experimental evaluation of the variometer noise level is based on vicalloy and samarium-cobalt. It is shown that the frequency range of magnetometers with variometers based on vicalloy and samarium-cobalt will be bounded from above by frequencies of 1.6 and 6.4 Hz, respectively, at a threshold sensitivity of about 1 pT. These ratios of the frequency and threshold sensitivity for the given magnetic materials are probably limited for quartz variometers with an optoelectronic angle transducer.

  13. Homeostatic signaling: the positive side of negative feedback.

    PubMed

    Turrigiano, Gina

    2007-06-01

    Synaptic homeostasis provides a means for neurons and circuits to maintain stable function in the face of perturbations such as developmental or activity-dependent changes in synapse number or strength. These forms of plasticity are thought to utilize negative feedback signaling to sense some aspect of activity, compare this with an internal set point, and then adjust synaptic properties to keep activity close to this set point. However, the molecular identity of these signaling components has not been firmly established. Recent work suggests that there are likely to be multiple forms of synaptic homeostasis, mediated by distinct signaling pathways and with distinct expression mechanisms. These include presynaptic forms that depend on retrograde signaling to presynaptic Ca(2+) channels, and postsynaptic forms influenced by BDNF, TNFalpha and Arc signaling. Current challenges include matching signaling elements to their functions (i.e. as detectors of activity, as part of the set-point mechanism and/or as effectors of synaptic change), and fitting these molecular candidates into a unified view of the signaling pathways that underlie synaptic homeostasis.

  14. Crystal structure of rat GTP cyclohydrolase I feedback regulatory protein, GFRP.

    PubMed

    Bader, G; Schiffmann, S; Herrmann, A; Fischer, M; Gütlich, M; Auerbach, G; Ploom, T; Bacher, A; Huber, R; Lemm, T

    2001-10-05

    Tetrahydrobiopterin, the cofactor required for hydroxylation of aromatic amino acids regulates its own synthesis in mammals through feedback inhibition of GTP cyclohydrolase I. This mechanism is mediated by a regulatory subunit called GTP cyclohydrolase I feedback regulatory protein (GFRP). The 2.6 A resolution crystal structure of rat GFRP shows that the protein forms a pentamer. This indicates a model for the interaction of mammalian GTP cyclohydrolase I with its regulator, GFRP. Kinetic investigations of human GTP cyclohydrolase I in complex with rat and human GFRP showed similar regulatory effects of both GFRP proteins.

  15. Career Goal Revision in Response to Negative Feedback: Testing a Longitudinal Cross-Lagged Model.

    PubMed

    Hu, Shi; Creed, Peter A; Hood, Michelle

    2017-02-06

    We tested a model based on goal-setting and self-regulation theories of the cross-lagged relationships among negative career-related feedback, negative affect (career-related stress), and career goal revision (downward goal revision and goal disengagement). Participants were 409 Chinese university/college students (Mage 19 years; 58% female), who completed a survey at 2 time points approximately 6 months apart. Consistent with our hypotheses, negative career-related feedback at T1 was related to more career goal disengagement and greater downward goal revision at T2. Career-related stress partially mediated the relationship between negative career-related feedback and downward goal revision. In addition, there were reverse relationships between negative career-related feedback and career-related stress, and between career-related stress and goal disengagement. These findings highlight important roles for negative career-related feedback and negative affect in young peoples' career goal pursuit. (PsycINFO Database Record

  16. Want More? Learn Less: Motivation Affects Adolescents Learning from Negative Feedback

    PubMed Central

    Zhuang, Yun; Feng, Wenfeng; Liao, Yu

    2017-01-01

    The primary goal of the present study was to investigate how positive and negative feedback may differently facilitate learning throughout development. In addition, the role of motivation as a modulating factor was examined. Participants (children, adolescents, and adults) completed two forms of the guess and application task (GAT). Feedback from the Cool-GAT task has low motivational salience because there are no consequences, while feedback from the Hot-GAT task has high motivational salience as it pertains to receiving a reward. The results indicated that negative feedback leads to a reduction in learning compared to positive feedback. The effect of negative feedback was greater in adolescent participants compared to children and adults in the Hot-GAT task, suggesting an interaction between age and motivation level on learning. Further analysis indicated that greater risk was associated with a greater reduction in learning from negative feedback and again, the reduction was greatest in adolescents. In summary, the current study supports the idea that learning from positive feedback and negative feedback differs throughout development. In a rule-based learning task, when associative learning is primarily in practice, participants learned less from negative feedback. This reduction is amplified during adolescence when task-elicited motivation is high. PMID:28191003

  17. Dissociation between Active and Observational Learning from Positive and Negative Feedback in Parkinsonism

    PubMed Central

    Kobza, Stefan; Ferrea, Stefano; Schnitzler, Alfons; Pollok, Bettina

    2012-01-01

    Feedback to both actively performed and observed behaviour allows adaptation of future actions. Positive feedback leads to increased activity of dopamine neurons in the substantia nigra, whereas dopamine neuron activity is decreased following negative feedback. Dopamine level reduction in unmedicated Parkinson’s Disease patients has been shown to lead to a negative learning bias, i.e. enhanced learning from negative feedback. Recent findings suggest that the neural mechanisms of active and observational learning from feedback might differ, with the striatum playing a less prominent role in observational learning. Therefore, it was hypothesized that unmedicated Parkinson’s Disease patients would show a negative learning bias only in active but not in observational learning. In a between-group design, 19 Parkinson’s Disease patients and 40 healthy controls engaged in either an active or an observational probabilistic feedback-learning task. For both tasks, transfer phases aimed to assess the bias to learn better from positive or negative feedback. As expected, actively learning patients showed a negative learning bias, whereas controls learned better from positive feedback. In contrast, no difference between patients and controls emerged for observational learning, with both groups showing better learning from positive feedback. These findings add to neural models of reinforcement-learning by suggesting that dopamine-modulated input to the striatum plays a minor role in observational learning from feedback. Future research will have to elucidate the specific neural underpinnings of observational learning. PMID:23185586

  18. Dissociation between active and observational learning from positive and negative feedback in Parkinsonism.

    PubMed

    Kobza, Stefan; Ferrea, Stefano; Schnitzler, Alfons; Pollok, Bettina; Südmeyer, Martin; Bellebaum, Christian

    2012-01-01

    Feedback to both actively performed and observed behaviour allows adaptation of future actions. Positive feedback leads to increased activity of dopamine neurons in the substantia nigra, whereas dopamine neuron activity is decreased following negative feedback. Dopamine level reduction in unmedicated Parkinson's Disease patients has been shown to lead to a negative learning bias, i.e. enhanced learning from negative feedback. Recent findings suggest that the neural mechanisms of active and observational learning from feedback might differ, with the striatum playing a less prominent role in observational learning. Therefore, it was hypothesized that unmedicated Parkinson's Disease patients would show a negative learning bias only in active but not in observational learning. In a between-group design, 19 Parkinson's Disease patients and 40 healthy controls engaged in either an active or an observational probabilistic feedback-learning task. For both tasks, transfer phases aimed to assess the bias to learn better from positive or negative feedback. As expected, actively learning patients showed a negative learning bias, whereas controls learned better from positive feedback. In contrast, no difference between patients and controls emerged for observational learning, with both groups showing better learning from positive feedback. These findings add to neural models of reinforcement-learning by suggesting that dopamine-modulated input to the striatum plays a minor role in observational learning from feedback. Future research will have to elucidate the specific neural underpinnings of observational learning.

  19. Want More? Learn Less: Motivation Affects Adolescents Learning from Negative Feedback.

    PubMed

    Zhuang, Yun; Feng, Wenfeng; Liao, Yu

    2017-01-01

    The primary goal of the present study was to investigate how positive and negative feedback may differently facilitate learning throughout development. In addition, the role of motivation as a modulating factor was examined. Participants (children, adolescents, and adults) completed two forms of the guess and application task (GAT). Feedback from the Cool-GAT task has low motivational salience because there are no consequences, while feedback from the Hot-GAT task has high motivational salience as it pertains to receiving a reward. The results indicated that negative feedback leads to a reduction in learning compared to positive feedback. The effect of negative feedback was greater in adolescent participants compared to children and adults in the Hot-GAT task, suggesting an interaction between age and motivation level on learning. Further analysis indicated that greater risk was associated with a greater reduction in learning from negative feedback and again, the reduction was greatest in adolescents. In summary, the current study supports the idea that learning from positive feedback and negative feedback differs throughout development. In a rule-based learning task, when associative learning is primarily in practice, participants learned less from negative feedback. This reduction is amplified during adolescence when task-elicited motivation is high.

  20. Loss of Nuclear Receptor SHP Impairs but Does Not Eliminate Negative Feedback Regulation of Bile Acid Synthesis

    PubMed Central

    Kerr, Thomas A.; Saeki, Shigeru; Schneider, Manfred; Schaefer, Karen; Berdy, Sara; Redder, Thadd; Shan, Bei; Russell, David W.; Schwarz, Margrit

    2014-01-01

    Summary The in vivo role of the nuclear receptor SHP in feedback regulation of bile acid synthesis was examined. Loss of SHP in mice caused abnormal accumulation and increased synthesis of bile acids due to derepression of rate-limiting CYP7A1 and CYP8B1 hydroxylase enzymes in the biosynthetic pathway. Dietary bile acids induced liver damage and restored feedback regulation. A synthetic agonist of the nuclear receptor FXR was not hepatotoxic and had no regulatory effects. Reduction of the bile acid pool with cholestyramine enhanced CYP7A1 and CYP8B1 expression. We conclude that input from three negative regulatory pathways controls bile acid synthesis. One is mediated by SHP, and two are SHP independent and invoked by liver damage and changes in bile acid pool size. PMID:12062084

  1. Feedback Control of Two-Component Regulatory Systems.

    PubMed

    Groisman, Eduardo A

    2016-09-08

    Two-component systems are a dominant form of bacterial signal transduction. The prototypical two-component system consists of a sensor that responds to a specific input(s) by modifying the output of a cognate regulator. Because the output of a two-component system is the amount of phosphorylated regulator, feedback mechanisms may alter the amount of regulator, and/or modify the ability of a sensor or other proteins to alter the phosphorylation state of the regulator. Two-component systems may display intrinsic feedback whereby the amount of phosphorylated regulator changes under constant inducing conditions and without the participation of additional proteins. Feedback control allows a two-component system to achieve particular steady-state levels, to reach a given steady state with distinct dynamics, to express coregulated genes in a given order, and to activate a regulator to different extents, depending on the signal acting on the sensor.

  2. Evaluating the negative or valuing the positive? Neural mechanisms supporting feedback-based learning across development.

    PubMed

    van Duijvenvoorde, Anna C K; Zanolie, Kiki; Rombouts, Serge A R B; Raijmakers, Maartje E J; Crone, Eveline A

    2008-09-17

    How children learn from positive and negative performance feedback lies at the foundation of successful learning and is therefore of great importance for educational practice. In this study, we used functional magnetic resonance imaging (fMRI) to examine the neural developmental changes related to feedback-based learning when performing a rule search and application task. Behavioral results from three age groups (8-9, 11-13, and 18-25 years of age) demonstrated that, compared with adults, 8- to 9-year-old children performed disproportionally more inaccurately after receiving negative feedback relative to positive feedback. Additionally, imaging data pointed toward a qualitative difference in how children and adults use performance feedback. That is, dorsolateral prefrontal cortex and superior parietal cortex were more active after negative feedback for adults, but after positive feedback for children (8-9 years of age). For 11- to 13-year-olds, these regions did not show differential feedback sensitivity, suggesting that the transition occurs around this age. Pre-supplementary motor area/anterior cingulate cortex, in contrast, was more active after negative feedback in both 11- to 13-year-olds and adults, but not 8- to 9-year-olds. Together, the current data show that cognitive control areas are differentially engaged during feedback-based learning across development. Adults engage these regions after signals of response adjustment (i.e., negative feedback). Young children engage these regions after signals of response continuation (i.e., positive feedback). The neural activation patterns found in 11- to 13-year-olds indicate a transition around this age toward an increased influence of negative feedback on performance adjustment. This is the first developmental fMRI study to compare qualitative changes in brain activation during feedback learning across distinct stages of development.

  3. Experimental effects of receiving negative weight-related feedback: a weight guessing study.

    PubMed

    Mills, Jennifer S; Miller, Jessie L

    2007-09-01

    The effects of receiving negative verbal weight-related feedback on the mood, self-esteem, and body image of restrained and unrestrained eaters were investigated. Female undergraduate students either reported their current weight (no feedback) or had their weight guessed as 15 lb higher than their actual weight (negative feedback) by an experimenter who presented herself as either an undergraduate (peer) or graduate student (non-peer). Participants overall had higher anxiety and felt "fatter" in the negative feedback condition. When this feedback came from a peer they felt fatter, more dissatisfied with their bodies, and, for restrained eaters, more depressed, as compared to when it came from a non-peer. These results provide empirical evidence that negative weight-related feedback produces adverse psychological consequences for young women, especially restrained eaters, and suggest the importance of peers' perceptions of weight.

  4. Tuning the range and stability of multiple phenotypic states with coupled positive-negative feedback loops.

    PubMed

    Avendaño, Maier S; Leidy, Chad; Pedraza, Juan M

    2013-01-01

    Positive feedback loops can produce multistability, resulting in different phenotypic states. However, many transcription networks contain counteracting positive and negative feedbacks. Here we explore the dynamics of an interlinked positive and negative feedback motif based on the galactose-uptake control system of Saccharomyces cerevisiae modified to make the strength of each feedback externally controllable. Our results show that although the positive feedback loop determines the range of bistability and the width of the regions where intermediate activation is possible, the transition rates between states are mostly sensitive to the negative feedback strength. Thus, our results suggest that the function of the negative loop in this motif is to allow separate tuning of the range and transition rates between phenotypic states. This could enhance fitness by allowing improved matching of the stochastic switching to the frequency of environmental changes.

  5. A feedback regulatory loop between methyltransferase PRMT1 and orphan receptor TR3

    PubMed Central

    Lei, Na-zi; Zhang, Xiao-yan; Chen, Hang-zi; Wang, Yuan; Zhan, Yan-yan; Zheng, Zhong-hui; Shen, Yue-mao; Wu, Qiao

    2009-01-01

    PRMT1, an arginine methyltransferase, plays an important role in numerous cellular processes. In this study, we demonstrate a feedback regulatory loop between PRMT1 and the orphan receptor TR3. Unlike another orphan receptor HNF4, TR3 is not methylated by PRMT1 although they physically interact with each other. By delaying the TR3 protein degradation, PRMT1 binding leads to the elevation of TR3 cellular protein level, thereby enhances the DNA binding and transactivation activity of TR3 in a non-methyltransferase manner. Another coactivator SRC-2 acts synergistically with PRMT1 to regulate TR3 functions. In turn, TR3 binding to the catalytic domain of PRMT1 causes an inhibition of the PRMT1 methyltransferase activity. This repression results in the functional changes in some of PRMT1 substrates, including STAT3 and Sam68. The negative regulation of PRMT1 by TR3 was further confirmed in both TR3-knockdown cells and TR3-knockout mice with the use of an agonist for TR3. Taken together, our study not only identifies a regulatory role of PRMT1, independent on methyltransferase activity, in TR3 transactivation, but also characterizes a novel function of TR3 in the repression of PRMT1 methyltransferase activity. PMID:19095693

  6. Tyrosol exhibits negative regulatory effects on LPS response and endotoxemia.

    PubMed

    Lu, Jing; Huang, Guoren; Wang, Zhenning; Zhuang, Shuang; Xu, Linli; Song, Bocui; Xiong, Ying; Guan, Shuang

    2013-12-01

    Tyrosol, a phenolic compound, was isolated from wine, olive oil and other plant-derived products. In the present study, we first investigated the negative regulatory effects of tyrosol on cytokine production by lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in vitro, and the results showed that tyrosol reduced tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) secretion. This inspired us to further study the effects of tyrosol in vivo. Tyrosol significantly attenuated TNF-α, IL-1β and IL-6 production in serum from mice challenged with LPS, and consistent with the results in vitro. In the murine model of endotoxemia, mice were treated with tyrosol prior to or after LPS challenge. The results showed that tyrosol significantly increased mice survival. We further investigated signal transduction ways to determine how tyrosol works. The data revealed that tyrosol shocked LPS-induced mitogen activated protein kinases (MAPKs) and nuclear transcription factor-κB (NF-κB) signal transduction pathways in RAW 264.7 macrophages. These observations indicated that tyrosol exerted negative regulatory effects on LPS response in vitro and in vivo through suppressing NF-κB and p38/ERK MAPK signaling pathways.

  7. Oscillatory profiles of positive, negative and neutral feedback stimuli during adaptive decision making.

    PubMed

    Li, Peng; Baker, Travis E; Warren, Chris; Li, Hong

    2016-09-01

    The electrophysiological response to positive and negative feedback during reinforcement learning has been well documented over the past two decades, yet, little is known about the neural response to uninformative events that often follow our actions. To address this issue, we recorded the electroencephalograph (EEG) during a time-estimation task using both informative (positive and negative) and uninformative (neutral) feedback. In the time-frequency domain, uninformative feedback elicited significantly less induced beta-gamma activity than informative feedback. This result suggests that beta-gamma activity is particularly sensitive to feedback that can guide behavioral adjustments, consistent with other work. In contrast, neither theta nor delta activity were sensitive to the difference between negative and neutral feedback, though both frequencies discriminated between positive, and non-positive (neutral or negative) feedback. Interestingly, in the time domain, we observed a linear relationship in the amplitude of the feedback-related negativity (neutral>negative>positive), a component of the event-related brain potential thought to index a specific kind of reinforcement learning signal called a reward prediction error. Taken together, these results suggest that the reinforcement learning system treats neutral feedback as a special case, providing valuable information about the electrophysiological measures used to index the cognitive function of frontal midline cortex. Copyright © 2016. Published by Elsevier B.V.

  8. The linkage between infant negative temperament and parenting self-efficacy: the role of resilience against negative performance feedback.

    PubMed

    Verhage, Marije L; Oosterman, Mirjam; Schuengel, Carlo

    2015-11-01

    Caring for infants with negative reactive temperament may tax parents' confidence in their caregiving ability, or parenting self-efficacy (PSE). This may happen in particular in parents who interpret these signals as negative feedback on their performance. To test this hypothesis, 179 first-time pregnant women were presented a caregiving simulation that provided positive and negative feedback on their attempts to comfort a crying baby. According to their PSE resilience to negative feedback during the task, they were grouped in a high resilient and low resilient group. PSE was followed up at 32 weeks of pregnancy and 3 and 12 months after birth, while perceived temperament of the child was assessed at 3 and 12 months after birth. Results showed that among women with low resilience against negative feedback, perceived negative temperament was negatively associated with PSE at 3 months, whereas no such association was observed among women with high resilience against negative feedback. Implications of the concept of resilience for the study of PSE are discussed.

  9. A Theory of Circular Organization and Negative Feedback: Defining Life in a Cybernetic Context

    NASA Astrophysics Data System (ADS)

    Tsokolov, Sergey

    2010-12-01

    All life today incorporates a variety of systems controlled by negative feedback loops and sometimes amplified by positive feedback loops. The first forms of life necessarily also required primitive versions of feedback, yet surprisingly little emphasis has been given to the question of how feedback emerged out of primarily chemical systems. One chemical system has been established that spontaneously develops autocatalytic feedback, the Belousov-Zhabotinsky (BZ) reaction. In this essay, I discuss the BZ reaction as a possible model for similar reactions that could have occurred under prebiotic Earth conditions. The main point is that the metabolism of contemporary life evolved from primitive homeostatic networks regulated by negative feedback. Because life could not exist in their absence, feedback loops should be included in definitions of life.

  10. A theory of circular organization and negative feedback: defining life in a cybernetic context.

    PubMed

    Tsokolov, Sergey

    2010-12-01

    All life today incorporates a variety of systems controlled by negative feedback loops and sometimes amplified by positive feedback loops. The first forms of life necessarily also required primitive versions of feedback, yet surprisingly little emphasis has been given to the question of how feedback emerged out of primarily chemical systems. One chemical system has been established that spontaneously develops autocatalytic feedback, the Belousov-Zhabotinsky (BZ) reaction. In this essay, I discuss the BZ reaction as a possible model for similar reactions that could have occurred under prebiotic Earth conditions. The main point is that the metabolism of contemporary life evolved from primitive homeostatic networks regulated by negative feedback. Because life could not exist in their absence, feedback loops should be included in definitions of life.

  11. A comparison of resonance tuning with positive versus negative sensory feedback.

    PubMed

    Williams, Carrie A; DeWeerth, Stephen P

    2007-06-01

    We used a computational model of rhythmic movement to analyze how the connectivity of sensory feedback affects the tuning of a closed-loop neuromechanical system to the mechanical resonant frequency (omega(r)). Our model includes a Matsuoka half-center oscillator for a central pattern generator (CPG) and a linear, one-degree-of-freedom system for a mechanical component. Using both an open-loop frequency response analysis and closed-loop simulations, we compared resonance tuning with four different feedback configurations as the mechanical resonant frequency, feedback gain, and mechanical damping varied. The feedback configurations consisted of two negative and two positive feedback connectivity schemes. We found that with negative feedback, resonance tuning predominantly occurred when omega(r) was higher than the CPG's endogenous frequency (omega(CPG)). In contrast, with the two positive feedback configurations, resonance tuning only occurred if omega(r) was lower than omega(CPG). Moreover, the differences in resonance tuning between the two positive (negative) feedback configurations increased with increasing feedback gain and with decreasing mechanical damping. Our results indicate that resonance tuning can be achieved with positive feedback. Furthermore, we have shown that the feedback configuration affects the parameter space over which the endogenous frequency of the CPG or resonant frequency the mechanical dynamics dominates the frequency of a rhythmic movement.

  12. Boys, don't cry: Gender and reactions to negative performance feedback.

    PubMed

    Motro, Daphna; Ellis, Aleksander P J

    2017-02-01

    Our experiment is aimed at understanding how employee reactions to negative feedback are received by the feedback provider and how employee gender may play a role in the process. We focus specifically on the act of crying and, based on role congruity theory, argue that a male employee crying in response to negative performance feedback will be seen as atypical behavior by the feedback provider, which will bias evaluations of the employee on a number of different outcome variables, including performance evaluations, assessments of leadership capability, and written recommendations. That is, we expect an interactive effect between gender and crying on our outcomes, an effect that will be mediated by perceived typicality. We find support for our moderated mediation model in a sample of 169 adults, indicating that men who cry in response to negative performance feedback will experience biased evaluations from the feedback provider. Theoretical and practical implications are discussed. (PsycINFO Database Record

  13. The Transmission of Positive and Negative Feedback to Subordinates

    DTIC Science & Technology

    1984-02-01

    responsible for giving financial aid to the disabled. Data were collected on the difference between the time a decision was made to give or deny aid...in procedure was to make the experimental setting more similar to a real job setting by convincing the manager that feedback on performnce would be

  14. Processing of Positive and Negative Feedback in Patients with Cerebellar Lesions.

    PubMed

    Rustemeier, Martina; Koch, Benno; Schwarz, Michael; Bellebaum, Christian

    2016-08-01

    It is well accepted that the cerebellum plays a crucial role in the prediction of the sensory consequences of movements. Recent findings of altered error processing in patients with selective cerebellar lesions led to the hypothesis that feedback processing and feedback-based learning might be affected by cerebellar damage as well. Thus, the present study investigated learning from and processing of positive and negative feedback in 12 patients with selective cerebellar lesions and healthy control subjects. Participants performed a monetary feedback learning task. The processing of positive and negative feedback was assessed by means of event-related potentials (ERPs) during the learning task and during a separate task in which the frequencies of positive and negative feedback were balanced. Patients did not show a general learning deficit compared to controls. Relative to the control group, however, patients with cerebellar lesions showed significantly higher ERP difference wave amplitudes (rewards-losses) in a time window between 250 and 450 ms after feedback presentation, possibly indicating impaired outcome prediction. The analysis of the original waveforms suggested that patients and controls primarily differed in their pattern of feedback-related negativity and P300 amplitudes. Our results add to recent findings on altered performance monitoring associated with cerebellar damage and demonstrate, for the first time, alterations of feedback processing in patients with cerebellar damage. Unaffected learning performance appears to suggest that chronic cerebellar lesions can be compensated in behaviour.

  15. Failure to retreat: Blunted sensitivity to negative feedback supports risky behavior in adolescents.

    PubMed

    McCormick, Ethan M; Telzer, Eva H

    2017-02-15

    Decision-making processes rarely occur in isolation. Rather, representations are updated constantly based on feedback to past decisions and actions. However, previous research has focused on the reaction to feedback receipt itself, instead of examining how feedback information is integrated into future decisions. In the current study, we examined differential neural sensitivity during risk decisions following positive versus negative feedback in a risk-taking context, and how this differential sensitivity is linked to adolescent risk behavior. Fifty-eight adolescents (ages 13-17 years) completed the Balloon Analogue Risk Task (BART) during an fMRI session and reported on their levels of risk-taking behavior. Results show that reduced medial PFC (mPFC) response following negative versus positive feedback is associated with fewer reductions in task-based risky decisions following negative feedback, as well as increased self-reported risk-taking behavior. These results suggest that reduced neural integration of negative feedback into during future decisions supports risky behavior, perhaps by discounting negative relative to positive feedback information when making subsequent risky decisions.

  16. Negative feedback regulation of UV-B-induced photomorphogenesis and stress acclimation in Arabidopsis.

    PubMed

    Gruber, Henriette; Heijde, Marc; Heller, Werner; Albert, Andreas; Seidlitz, Harald K; Ulm, Roman

    2010-11-16

    Plants respond to low levels of UV-B radiation with a coordinated photomorphogenic response that allows acclimation to this environmental stress factor. The key players in this UV-B response are COP1 (an E3 ubiquitin ligase), UVR8 (a β-propeller protein), and HY5 (a bZIP transcription factor). We have shown previously that an elevated UV-B-specific response is associated with dwarf growth, indicating the importance of balancing UV-B-specific signaling. Negative regulators of this pathway are not known, however. Here, we describe two highly related WD40-repeat proteins, REPRESSOR OF UV-B PHOTOMORPHOGENESIS 1 (RUP1) and RUP2, that interact directly with UVR8 as potent repressors of UV-B signaling. Both genes were transcriptionally activated by UV-B in a COP1-, UVR8-, and HY5-dependent manner. rup1 rup2 double mutants showed an enhanced response to UV-B and elevated UV-B tolerance after acclimation. Overexpression of RUP2 resulted in reduced UV-B-induced photomorphogenesis and impaired acclimation, leading to hypersensitivity to UV-B stress. These results are consistent with an important regulatory role for RUP1 and RUP2, which act downstream of UVR8-COP1 in a negative feedback loop impinging on UVR8 function, balancing UV-B defense measures and plant growth.

  17. The Impact of Positive, Negative and Topical Relevance Feedback

    DTIC Science & Technology

    2008-11-01

    REPORT NUMBER(S) 12. DISTRIBUTION/AVAILABILITY STATEMENT Approved for public release; distribution unlimited 13 . SUPPLEMENTARY NOTES Seventeenth...lead to significant improvements over the baseline on the 13 test topics, for MAP no improvement at all is achieved. We do achieve more than 8...improvement in P10. Since the effect of using topical feedback varies a lot over differ- ent queries, the test set of 13 topics is a bit small to draw

  18. Are Success and Failure Experiences Equally Motivational? An Investigation of Regulatory Focus and Feedback

    ERIC Educational Resources Information Center

    Shu, Tse-Mei; Lam, Shui-fong

    2011-01-01

    The present study extended regulatory focus theory (Idson & Higgins, 2000) to an educational setting and attempted to identify individuals with high motivation after both success and failure feedback. College students in Hong Kong (N = 180) participated in an experiment with a 2 promotion focus (high vs. low) x 2 prevention focus (high vs.…

  19. Commentary on: Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis.

    PubMed

    Ramot, Yuval; Vardy, Leah A

    2013-11-01

    Polyamines are cationic amines essential for cellular proliferation. Recently, their role in hair follicle (HF) growth has started to be explored, but their exact function is still obscure. In the October issue of Experimental Dermatology, Luke et al. follow the observation that putrescine overproducing mice and hairless (HR) mutant mice show a similar clinical phenotype of hair loss and dermal cyst formation. They show that HR and putrescine form a negative regulatory feedback mechanism, which might regulate hair cycling and therefore control hair growth. This study clearly demonstrates that a strong connection exists between HR and polyamines although there are probably additional molecular pathways involved in the polyamine regulation of hair growth which remain to be discovered.

  20. Reciprocal, longitudinal associations among adolescents' negative feedback-seeking, depressive symptoms, and peer relations.

    PubMed

    Borelli, Jessica L; Prinstein, Mitchell J

    2006-04-01

    This study examined reciprocal associations among adolescents' negative feedback-seeking, depressive symptoms, perceptions of friendship quality, and peer-reported social preference over an 11-month period. A total of 478 adolescents in grades 6-8 completed measures of negative feedback-seeking, depressive symptoms, friendship quality, global-self-esteem, and social anxiety at two time points. Peer-reported measures of peer status were collected using a sociometric procedure. Consistent with hypotheses, path analyses results suggested that negative feedback-seeking was associated longitudinally with depressive symptoms and perceptions of friendship criticism in girls and with lower social preference scores in boys; however, depressive symptoms were not associated longitudinally with negative feedback-seeking. Implications for interpersonal models of adolescent depression are discussed.

  1. A feedback regulatory module formed by LITTLE ZIPPER and HD-ZIPIII genes.

    PubMed

    Wenkel, Stephan; Emery, John; Hou, Bi-Huei; Evans, Matthew M S; Barton, M K

    2007-11-01

    The Arabidopsis thaliana REVOLUTA (REV) protein is a member of the class III homeodomain-leucine zipper (HD-ZIPIII) proteins. REV is a potent regulator of leaf polarity and vascular development. Here, we report the identification of a gene family that encodes small leucine zipper-containing proteins (LITTLE ZIPPER [ZPR] proteins) where the leucine zipper is similar to that found in REV, PHABULOSA, and PHAVOLUTA proteins. The transcript levels of the ZPR genes increase in response to activation of a steroid-inducible REV protein. We show that the ZPR proteins interact with REV in vitro and that ZPR3 prevents DNA binding by REV in vitro. Overexpression of ZPR proteins in Arabidopsis results in phenotypes similar to those seen when HD-ZIPIII function is reduced. We propose a negative feedback model in which REV promotes transcription of the ZPR genes. The ZPR proteins in turn form heterodimers with the REV protein, preventing it from binding DNA. The HD-ZIPIII/ZPR regulatory module would serve not only to dampen the effect of fluctuations in HD-ZIPIII protein levels but more importantly would provide a potential point of regulation (control over the ratio of inactive heterodimers to active homodimers) that could be influenced by other components of the pathway governing leaf polarity.

  2. DSulfatase-1 fine-tunes Hedgehog patterning activity through a novel regulatory feedback loop

    PubMed Central

    Wojcinski, Alexandre; Nakato, Hiroshi; Soula, Cathy; Glise, Bruno

    2012-01-01

    Summary Sulfs are secreted sulfatases that catalyse removal of sulfate from Heparan Sulfate Proteoglycans (HSPGs) in the extracellular space. These enzymes are well known to regulate a number of crucial signalling pathways during development. In this study, we report that DSulfatase-1 (DSulf1), the unique Drosophila Sulf protein, is a regulator of Hedgehog (Hh) signalling during wing development. DSulf1 activity is required in both Hh source and Hh receiving cells for proper positioning of Hh target gene expression boundaries. As assessed by loss- and gain-of-function experiments in specific compartments, DSulf1 displays dual functions with respect to Hh signalling, acting as a positive regulator in Hh producing cells and a negative regulator in Hh receiving cells. In either domain, DSulf1 modulates Hh distribution by locally lowering the concentration of the morphogen at the apical pole of wing disc cells. Thus, we propose that DSulf1, by its desulfation catalytic activity, lowers Hh/HSPG interaction in both Hh source and target fields, thereby enhancing Hh release from its source of production and reducing Hh signalling activity in responding cells. Finally, we show that Dsulf1 pattern of expression is temporally regulated and depends on EGFR signalling, a Hh-dependent secondary signal in this tissue. Our data reveal a novel Hh regulatory feedback loop, involving DSulf1, which contributes to maintain and stabilize expression domains of Hh target genes during wing disc development. PMID:21806980

  3. The effect of positive and negative verbal feedback on surgical skills performance and motivation.

    PubMed

    Kannappan, Aarthy; Yip, Dana T; Lodhia, Nayna A; Morton, John; Lau, James N

    2012-01-01

    There is considerable effort and time invested in providing feedback to medical students and residents during their time in training. However, little effort has been made to measure the effects of positive and negative verbal feedback on skills performance and motivation to learn and practice. To probe these questions, first-year medical students (n = 25) were recruited to perform a peg transfer task on Fundamentals of Laparoscopic Surgery box trainers. Time to completion and number of errors were recorded. The students were then randomized to receive either positive or negative verbal feedback from an expert in the field of laparoscopic surgery. After this delivery of feedback, the students repeated the peg transfer task. Differences in performance pre- and post-feedback and also between the groups who received positive feedback (PF) vs negative feedback (NF) were analyzed. A survey was then completed by all the participants. Baseline task times were similar between groups (PF 209.3 seconds; NF 203 seconds, p = 0.58). The PF group averaged 1.83 first-time errors while the NF group 1 (p = 0.84). Post-feedback task times were significantly decreased for both groups (PF 159.75 seconds, p = 0.05; NF 132.08 seconds, p = 0.002). While the NF group demonstrated a greater improvement in mean time than the PF group, this was not statistically significant. Both groups also made fewer errors (PF 0.33 errors, p = 0.04; NF 0.38 errors, p = 0.23). When surveyed about their responses to standardized feedback scenarios, the students stated that both positive and negative verbal feedback could be potent stimulants for improved performance and motivation. Further research is required to better understand the effects of feedback on learner motivation and the interpersonal dynamic between mentors and their trainees.

  4. Blocked versus randomized presentation modes differentially modulate feedback-related negativity and P3b amplitudes

    PubMed Central

    Pfabigan, Daniela M.; Zeiler, Michael; Lamm, Claus; Sailer, Uta

    2014-01-01

    Objective Electrophysiological studies on feedback processing typically use a wide range of feedback stimuli which might not always be comparable. The current study investigated whether two indicators of feedback processing – feedback-related negativity (FRN) and P3b – differ for feedback stimuli with explicit (facial expressions) or assigned valence information (symbols). In addition, we assessed whether presenting feedback in either a trial-by-trial or a block-wise fashion affected these ERPs. Methods EEG was recorded in three experiments while participants performed a time estimation task and received two different types of performance feedback. Results Only P3b amplitudes varied consistently in response to feedback type for both presentation types. Moreover, the blocked feedback type presentation yielded more distinct FRN peaks, higher effect sizes, and a significant relation between FRN amplitudes and behavioral task performance measures. Conclusion Both stimulus type and presentation mode may provoke systematic changes in feedback-related ERPs. The current findings point at important potential confounds that need to be controlled for when designing FRN or P3b studies. Significance Studies investigating P3b amplitudes using mixed types of stimuli have to be interpreted with caution. Furthermore, we suggest implementing a blocked presentation format when presenting different feedback types within the same experiment. PMID:24144779

  5. Modeling the effects of positive and negative feedback in kidney blood flow control.

    PubMed

    Liu, Runjing; Layton, Anita T

    2016-06-01

    Blood flow in the mammalian kidney is tightly autoregulated. One of the important autoregulation mechanisms is the myogenic response, which is activated by perturbations in blood pressure along the afferent arteriole. Another is the tubuloglomerular feedback, which is a negative feedback that responds to variations in tubular fluid [Cl(-)] at the macula densa.(1) When initiated, both the myogenic response and the tubuloglomerular feedback adjust the afferent arteriole muscle tone. A third mechanism is the connecting tubule glomerular feedback, which is a positive feedback mechanism located at the connecting tubule, downstream of the macula densa. The connecting tubule glomerular feedback is much less well studied. The goal of this study is to investigate the interactions among these feedback mechanisms and to better understand the effects of their interactions. To that end, we have developed a mathematical model of solute transport and blood flow control in the rat kidney. The model represents the myogenic response, tubuloglomerular feedback, and connecting tubule glomerular feedback. By conducting a bifurcation analysis, we studied the stability of the system under a range of physiologically-relevant parameters. The bifurcation results were confirmed by means of a comparison with numerical simulations. Additionally, we conducted numerical simulations to test the hypothesis that the interactions between the tubuloglomerular feedback and the connecting tubule glomerular feedback may give rise to a yet-to-be-explained low-frequency oscillation that has been observed in experimental records. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Modeling the Effects of Positive and Negative Feedback in Kidney Blood Flow Control

    PubMed Central

    Liu, Runjing; Layton, Anita T.

    2016-01-01

    Blood flow in the mammalian kidney is tightly autoregulated. One of the important autoregulation mechanisms is the myogenic response, which is activated by perturbations in blood pressure along the afferent arteriole. Another is the tubuloglomerular feedback, which is a negative feedback that responds to variations in tubular fluid [Cl−] at the macula densa1. When initiated, both the myogenic response and the tubuloglomerular feedback adjust the afferent arteriole muscle tone. A third mechanism is the connecting tubule glomerular feedback, which is a positive feedback mechanism located at the connecting tubule, downstream of the macula densa. The connecting tubule glomerular feedback is much less well studied. The goal of this study is to investigate the interactions among these feedback mechanisms and to better understand the effects of their interactions. To that end, we have developed a mathematical model of solute transport and blood flow control in the rat kidney. The model represents the myogenic response, tubuloglomerular feedback, and connecting tubule glomerular feedback. By conducting a bifurcation analysis, we studied the stability of the system under a range of physiologically-relevant parameters. The bifurcation results were confirmed by means of a comparison with numerical simulations. Additionally, we conducted numerical simulations to test the hypothesis that the interactions between the tubuloglomerular feedback and the connecting tubule glomerular feedback may give rise to a yet-to-be-explained low-frequency oscillation that has been observed in experimental records. PMID:26972744

  7. Negative Feedback for Small Capacitive Touchscreen Interfaces: A Usability Study for Data Entry Tasks.

    PubMed

    Parikh, S P; Esposito, J M

    2012-01-01

    Touchscreen technology has become pervasive in the consumer product arena over the last decade, offering some distinct advantages such as software reconfigurable interfaces and the removal of space consuming mice and keyboards. However, there are significant drawbacks to these devices that have limited their adoption by some users. Most notably, standard touchscreens demand the user's visual attention and require them to look at the input device to avoid pressing the wrong button. This issue is particularly important for mobile, capacitive sensing, nonstylus devices, such as the iPhone where small button sizes can generate high error rates. While previous work has shown the benefits of augmenting such interfaces with audio or vibrotactile feedback, only positive feedback (confirmation of button presses) has been considered. In this paper, we present a simple prototype interface that provides negative vibrotactile feedback. By negative, we mean feedback is generated when an inactive or ambiguous part of the screen, such as the area between two buttons, is touched. First, we present a usability study comparing positive and negative vibrotactile feedback for a benchmark numerical data entry task. The difference in performance is not statistically significant, implying negative feedback provides comparable benefits. Next, based on the experimenter's observations and the users comments, we introduce a multimodal feedback strategy-combining complementary positive audio and negative vibrotactile signals. User tests on a text entry experiment show that, with multimodal feedback, users exhibit a (statistically significant) 24 percent reduction in corrective key presses, as compared to positive audio feedback alone. Exit survey comments indicate that users favor multimodal feedback.

  8. Negative transcriptional regulatory element that functions in embryonal carcinoma cells.

    PubMed Central

    Ariizumi, K; Takahashi, H; Nakamura, M; Ariga, H

    1989-01-01

    We have cloned the polyomavirus mutant fPyF9, which persists in an episomal state in F9 embryonal carcinoma cells (K. Ariizumi and H. Ariga, Mol. Cell. Biol. 6:3920-3927, 1986). fPyF9 carries three copies of exogenous sequences, the prototype of which is a 21-base-pair repeat (box DNA), in the region of the enhancer B domain of wild-type polyomavirus DNA. The consensus sequence, GCATTCCATTGTT, is 13 base pairs long. The box DNA inserted into fPyF9 appeared to come from a cellular sequence and was present in many kinds of DNAs, including F9 chromosomal DNA. The biological function of box DNA was analyzed by chloramphenicol acetyltransferase expression assays, using chimeric plasmids containing box DNA conjugated with simian virus 40 promoter elements. The results showed that box DNA repressed the activities both of the simian virus 40 promoter and enhancer only in transfected undifferentiated F9 cells and not in differentiated LTK- cells. Box DNA functioned independently of orientation and position with respect to the promoter in an enhancerlike manner, although the effect of box DNA was opposite that of the enhancer. The XhoI linker insertion into the consensus sequences of box DNA abolished the repression activity, and the protein(s) recognizing the consensus sequences was identified only in F9 cells, not in L cells. These analyses suggest that box DNA may be a negative regulatory element that functions in undifferentiated cells. Images PMID:2550812

  9. Interrogative pressure in simulated forensic interviews: the effects of negative feedback.

    PubMed

    McGroarty, Allan; Baxter, James S

    2007-08-01

    Much experimental research on interrogative pressure has concentrated on the effects of leading questions, and the role of feedback in influencing responses in the absence of leading questions has been neglected by comparison. This study assessed the effect of negative feedback and the presence of a second interviewer on interviewee responding in simulated forensic interviews. Participants viewed a videotape of a crime, answered questions about the clip and were requestioned after receiving feedback. Compared with neutral feedback, negative feedback resulted in more response changes, higher reported state anxiety and higher ratings of interview difficulty. These results are consistent with Gudjonsson and Clark's (1986) model of interrogative suggestibility. The presence and involvement of a second interviewer did not significantly affect interviewee responding, although trait anxiety scores were elevated when a second interviewer was present. The theoretical and applied implications of these findings are considered.

  10. Negative plant-soil feedback predicts tree-species relative abundance in a tropical forest.

    PubMed

    Mangan, Scott A; Schnitzer, Stefan A; Herre, Edward A; Mack, Keenan M L; Valencia, Mariana C; Sanchez, Evelyn I; Bever, James D

    2010-08-05

    The accumulation of species-specific enemies around adults is hypothesized to maintain plant diversity by limiting the recruitment of conspecific seedlings relative to heterospecific seedlings. Although previous studies in forested ecosystems have documented patterns consistent with the process of negative feedback, these studies are unable to address which classes of enemies (for example, pathogens, invertebrates, mammals) exhibit species-specific effects strong enough to generate negative feedback, and whether negative feedback at the level of the individual tree is sufficient to influence community-wide forest composition. Here we use fully reciprocal shade-house and field experiments to test whether the performance of conspecific tree seedlings (relative to heterospecific seedlings) is reduced when grown in the presence of enemies associated with adult trees. Both experiments provide strong evidence for negative plant-soil feedback mediated by soil biota. In contrast, above-ground enemies (mammals, foliar herbivores and foliar pathogens) contributed little to negative feedback observed in the field. In both experiments, we found that tree species that showed stronger negative feedback were less common as adults in the forest community, indicating that susceptibility to soil biota may determine species relative abundance in these tropical forests. Finally, our simulation models confirm that the strength of local negative feedback that we measured is sufficient to produce the observed community-wide patterns in tree-species relative abundance. Our findings indicate that plant-soil feedback is an important mechanism that can maintain species diversity and explain patterns of tree-species relative abundance in tropical forests.

  11. On the utility of positive and negative feedback in a paired-associate learning task.

    PubMed

    Arbel, Yael; Murphy, Anthony; Donchin, Emanuel

    2014-07-01

    This study offers a neurophysiological examination of the relationship between feedback processing and learning. A two-choice paired-associate learning task borrowed and modified from Tricomi and Fiez [Tricomi, E., & Fiez, J. A. Feedback signals in the caudate reflect goal achievement on a declarative memory task. Neuroimage, 41, 1154-1167, 2008] was employed to examine the mediofrontal electrophysiological brain activity associated with the processing of performance feedback in a learning task and to elucidate the extent to which the processing of the initial informative feedback is related to learning outcomes. Twenty participants were tasked with learning to correctly pair 60 novel objects with their names by choosing on a trial-by-trial basis between two possible names and receiving feedback about the accuracy of their selection. The novel objects were presented in three blocks of trials (rounds), each of which presented the same set of 60 objects once. The rounds allowed the separation of the initial informative feedback in Round 1 from the other feedback stimuli in Rounds 2 and 3. The results indicated differences in the processing of initial informative and proceeding feedback stimuli. More specifically, the difference appeared to be driven by the change in the processing of positive feedback. Moreover, very first positive feedback provided in association with a particular new object was found associated with learning outcomes. The results imply that signs of successful and unsuccessful learning may be detected as early as the initial positive feedback provided in a learning task. The results suggest that the process giving rise to the feedback-related negativity is sensitive to the utility of the feedback and that the processing of the first informative positive feedback is associated with learning outcomes.

  12. Relatedness is a poor predictor of negative plant–soil feedbacks

    PubMed Central

    Mehrabi, Zia; Tuck, Sean L

    2015-01-01

    Understanding the mechanisms underlying negative plant–soil feedbacks remains a critical challenge in plant ecology. If closely related species are more similar, then phylogeny could be used as a predictor for plant species interactions, simplifying our understanding of how plant–soil feedbacks structure plant communities, underlie invasive species dynamics, or reduce agricultural productivity. Here, we test the utility of phylogeny for predicting plant–soil feedbacks by undertaking a hierarchical Bayesian meta-analysis on all available pairwise plant–soil feedback experiments conducted over the last two decades, including 133 plant species in 329 pairwise interactions. We found that the sign and magnitude of plant–soil feedback effects were not explained by the phylogenetic distance separating interacting species. This result was consistent across different life forms, life cycles, provenances, and phylogenetic scales. Our analysis shows that, contrary to widespread assumption, relatedness is a poor predictor of plant–soil feedback effects. PMID:25557183

  13. Neural correlates of positive and negative performance feedback in younger and older adults.

    PubMed

    Drueke, Barbara; Weichert, Lydia; Forkmann, Thomas; Mainz, Verena; Gauggel, Siegfried; Boecker, Maren

    2015-04-16

    Recent studies with younger adults have shown that performance feedback can serve as a reward, and it elicits reward-related brain activations. This study investigated whether performance feedback is processed similarly in younger and older adults and whether there are differential aging effects for positive and negative performance feedback. We used event-related fMRI in a choice reaction-time task and provided performance feedback after each trial. Although younger and older adults differed in task-related activation, they showed comparable reward-related activation. Positive performance feedback elicited the strongest striatal and amygdala activation, which was reflected behaviorally in slightly faster reaction times. These results suggest that performance feedback serves as a reward in both younger and older adults.

  14. IL-17/miR-192/IL-17Rs Regulatory Feedback Loop Facilitates Multiple Myeloma Progression

    PubMed Central

    Sun, Yuanyuan; Pan, Jing; Mao, Shudan; Jin, Jieping

    2014-01-01

    Multiple myeloma (MM) is a clonal plasma cell disorder which constitutes the second most common hematological malignancy, and remains an incurable tumor with poor survival. Recently, interleukin-17 (IL-17), produced locally in the tumor microenvironment, has been reported to play a crucial role in tumor immunity. In this study, we determined that exposure of MM cells to IL-17 had various promotive influences on different aspects of tumor progression. IL-17 significantly induced cell proliferation, inhibited cellular apoptosis, repressed cell adhesion to fibronectin and collagen I, and facilitated cell migration. Exposure to IL-17 also resulted in epithelial-mesenchymal transition (EMT), as evidenced by repression of the epithelial marker E-cadherin, and induction of the mesenchymal marker Vimentin, and EMT transcription factors Snail and Slug. Further experiments showed that IL-17 activated the oncogenic p65 transcription factor, which directly repressed the miR-192 gene via binding to the miR-192 promoter. Loss of miR-192 in MM cells can mimic the effects of IL-17, and was required for the above oncogenic effects of IL-17 on MM. Furthermore, we found that miR-192, and its homologous miR-215 directly targeted the 3′-untranslated regions of IL-17Rs, including IL-17RA and RE mRNA. By examining bone marrow specimens derived from MM patients, a negative correlation between miR-192 expression and IL-17 or IL-17RA expression was observed. Also, IL-17 was negatively correlated with E-cadherin and positively with Vimentin. Taken together, our study provides evidence that the IL-17/miR-192/IL-17Rs regulatory feedback loop is manifest in MM and might represent a promising and efficient prognostic marker and therapeutic target for MM. PMID:25489847

  15. Positive and negative feedback learning and associated dopamine and serotonin transporter binding after methamphetamine

    PubMed Central

    Stolyarova, Alexandra; O’Dell, Steve J.; Marshall, John F.; Izquierdo, Alicia

    2014-01-01

    Learning from mistakes and prospectively adjusting behavior in response to reward feedback is an important facet of performance monitoring. Dopamine (DA) pathways play an important role in feedback learning and a growing literature has also emerged on the importance of serotonin (5HT) in reward learning, particularly during punishment or reward omission (negative feedback). Cognitive impairments resulting from psychostimulant exposure may arise from altered patterns in feedback learning, which in turn may be modulated by DA and 5HT transmission. We analyzed long-term, off-drug changes in learning from positive and negative feedback and associated striatal DA transporter (DAT) and frontocortical 5HT transporter (SERT) binding in rats pretreated with methamphetamine (mAMPH). Specifically, we assessed the reversal phase of pairwise visual discrimination learning in rats receiving single dose- (mAMPHsingle) vs. escalating-dose exposure (mAMPHescal). Using fine-grained trial-by-trial analyses, we found increased sensitivity to and reliance on positive feedback in mAMPH-pretreated animals, with the mAMPHsingle group showing more pronounced use of this type of feedback. In contrast, overall negative feedback sensitivity was not altered following any mAMPH treatment. In addition to validating the enduring effects of mAMPH on early reversal learning, we found more consecutive error commissions before the first correct response in mAMPH-pretreated rats. This behavioral rigidity was negatively correlated with subregional frontocortical SERT whereas positive feedback sensitivity negatively correlated with striatal DAT binding. These results provide new evidence for the overlapping, yet dissociable roles of DA and 5HT systems in overcoming perseveration and in learning new reward rules. PMID:24959862

  16. Positive and negative feedback learning and associated dopamine and serotonin transporter binding after methamphetamine.

    PubMed

    Stolyarova, Alexandra; O'Dell, Steve J; Marshall, John F; Izquierdo, Alicia

    2014-09-01

    Learning from mistakes and prospectively adjusting behavior in response to reward feedback is an important facet of performance monitoring. Dopamine (DA) pathways play an important role in feedback learning and a growing literature has also emerged on the importance of serotonin (5HT) in reward learning, particularly during punishment or reward omission (negative feedback). Cognitive impairments resulting from psychostimulant exposure may arise from altered patterns in feedback learning, which in turn may be modulated by DA and 5HT transmission. We analyzed long-term, off-drug changes in learning from positive and negative feedback and associated striatal DA transporter (DAT) and frontocortical 5HT transporter (SERT) binding in rats pretreated with methamphetamine (mAMPH). Specifically, we assessed the reversal phase of pairwise visual discrimination learning in rats receiving single dose- (mAMPHsingle) vs. escalating-dose exposure (mAMPHescal). Using fine-grained trial-by-trial analyses, we found increased sensitivity to and reliance on positive feedback in mAMPH-pretreated animals, with the mAMPHsingle group showing more pronounced use of this type of feedback. In contrast, overall negative feedback sensitivity was not altered following any mAMPH treatment. In addition to validating the enduring effects of mAMPH on early reversal learning, we found more consecutive error commissions before the first correct response in mAMPH-pretreated rats. This behavioral rigidity was negatively correlated with subregional frontocortical SERT whereas positive feedback sensitivity negatively correlated with striatal DAT binding. These results provide new evidence for the overlapping, yet dissociable roles of DA and 5HT systems in overcoming perseveration and in learning new reward rules.

  17. sfrp1 promotes cardiomyocyte differentiation in Xenopus via negative-feedback regulation of Wnt signalling

    PubMed Central

    Gibb, Natalie; Lavery, Danielle L.; Hoppler, Stefan

    2013-01-01

    Wnt signalling is a key regulator of vertebrate heart development, yet it is unclear which specific Wnt signalling components are required to regulate which aspect of cardiogenesis. Previously, we identified Wnt6 as an endogenous Wnt ligand required for controlling heart muscle differentiation via canonical Wnt/β-catenin signalling. Here we show for the first time a requirement for an endogenous Wnt signalling inhibitor for normal heart muscle differentiation. Expression of sfrp1 is strongly induced in differentiating heart muscle. We show that sfrp1 is not only able to promote heart muscle differentiation but is also required for the formation of normal size heart muscle in the embryo. sfrp1 is functionally able to inhibit Wnt6 signalling and its requirement during heart development relates to relieving the cardiogenesis-restricting function of endogenous wnt6. In turn, we discover that sfrp1 expression in the heart is regulated by Wnt6 signalling, which for the first time indicates that sfrp genes can function as part of a Wnt negative-feedback regulatory loop. Our experiments indicate that sfrp1 controls the size of the differentiating heart muscle primarily by regulating cell fate within the cardiac mesoderm between muscular and non-muscular cell lineages. The cardiac mesoderm is therefore not passively patterned by signals from the surrounding tissue, but regulates its differentiation into muscular and non-muscular tissue using positional information from the surrounding tissue. This regulatory network might ensure that Wnt activation enables expansion and migration of cardiac progenitors, followed by Wnt inhibition permitting cardiomyocyte differentiation. PMID:23482489

  18. Counter-Intuitive Stochastic Behavior of Simple Gene Circuits with Negative Feedback

    PubMed Central

    Marquez-Lago, Tatiana T.; Stelling, Jörg

    2010-01-01

    Abstract It has often been taken for granted that negative feedback loops in gene regulation work as homeostatic control mechanisms. If one increases the regulation strength a less noisy signal is to be expected. However, recent theoretical studies have reported the exact contrary, counter-intuitive observation, which has left a question mark over the relationship between negative feedback loops and noise. We explore and systematically analyze several minimal models of gene regulation, where a transcriptional repressor negatively regulates its own expression. For models including a quasi-steady-state assumption, we identify processes that buffer noise change (RNA polymerase binding) or accentuate it (repressor dimerization) alongside increasing feedback strength. Moreover, we show that lumping together transcription and translation in simplified models clearly underestimates the impact of negative feedback strength on the system's noise. In contrast, in systems without a quasi-steady-state assumption, noise always increases with negative feedback strength. Hence, subtle mathematical properties and model assumptions yield different types of noise profiles and, by consequence, previous studies have simultaneously reported decrease, increase or persistence of noise levels with increasing feedback. We discuss our findings in terms of separation of timescales and time correlations between molecular species distributions, extending current theoretical findings on the topic and allowing us to propose what we believe new ways to better characterize noise. PMID:20441737

  19. Stereotype threat engenders neural attentional bias toward negative feedback to undermine performance.

    PubMed

    Forbes, Chad E; Leitner, Jordan B

    2014-10-01

    Stereotype threat, a situational pressure individuals experience when they fear confirming a negative group stereotype, engenders a cascade of physiological stress responses, negative appraisals, and performance monitoring processes that tax working memory resources necessary for optimal performance. Less is known, however, about how stereotype threat biases attentional processing in response to performance feedback, and how such attentional biases may undermine performance. Women received feedback on math problems in stereotype threatening compared to stereotype-neutral contexts while continuous EEG activity was recorded. Findings revealed that stereotype threatened women elicited larger midline P100 ERPs, increased phase locking between anterior cingulate cortex and dorsolateral prefrontal cortex (two regions integral for attentional processes), and increased power in left fusiform gyrus in response to negative feedback compared to positive feedback and women in stereotype-neutral contexts. Increased power in left fusiform gyrus in response to negative feedback predicted underperformance on the math task among stereotype threatened women only. Women in stereotype-neutral contexts exhibited the opposite trend. Findings suggest that in stereotype threatening contexts, neural networks integral for attention and working memory are biased toward negative, stereotype confirming feedback at very early speeds of information processing. This bias, in turn, plays a role in undermining performance.

  20. A Program That Acquires Language Using Positive and Negative Feedback.

    ERIC Educational Resources Information Center

    Brand, James

    1987-01-01

    Describes the language learning program "Acquire," which is a sample of grammar induction. It is a learning algorithm based on a pattern-matching scheme, using both a positive and negative network to reduce overgeneration. Language learning programs may be useful as tutorials for learning the syntax of a foreign language. (Author/LMO)

  1. A Program That Acquires Language Using Positive and Negative Feedback.

    ERIC Educational Resources Information Center

    Brand, James

    1987-01-01

    Describes the language learning program "Acquire," which is a sample of grammar induction. It is a learning algorithm based on a pattern-matching scheme, using both a positive and negative network to reduce overgeneration. Language learning programs may be useful as tutorials for learning the syntax of a foreign language. (Author/LMO)

  2. Caspase-1 activity affects AIM2 speck formation/stability through a negative feedback loop

    PubMed Central

    Juruj, C.; Lelogeais, V.; Pierini, R.; Perret, M.; Py, B. F.; Jamilloux, Y.; Broz, P.; Ader, F.; Faure, M.; Henry, T.

    2013-01-01

    The inflammasome is an innate immune signaling platform leading to caspase-1 activation, maturation of pro-inflammatory cytokines and cell death. Recognition of DNA within the host cytosol induces the formation of a large complex composed of the AIM2 receptor, the ASC adaptor and the caspase-1 effector. Francisella tularensis, the agent of tularemia, replicates within the host cytosol. The macrophage cytosolic surveillance system detects Francisella through the AIM2 inflammasome. Upon Francisella novicida infection, we observed a faster kinetics of AIM2 speck formation in ASCKO and Casp1KO as compared to WT macrophages. This observation was validated by a biochemical approach thus demonstrating for the first time the existence of a negative feedback loop controlled by ASC/caspase-1 that regulates AIM2 complex formation/stability. This regulatory mechanism acted before pyroptosis and required caspase-1 catalytic activity. Our data suggest that sublytic caspase-1 activity could delay the formation of stable AIM2 speck, an inflammasome complex associated with cell death. PMID:23630667

  3. A MicroRNA-Mediated Positive Feedback Regulatory Loop of the NF-κB Pathway in Litopenaeus vannamei.

    PubMed

    Zuo, Hongliang; Yuan, Jia; Chen, Yonggui; Li, Sedong; Su, Ziqi; Wei, Erman; Li, Chaozheng; Weng, Shaoping; Xu, Xiaopeng; He, Jianguo

    2016-05-01

    In the evolutionarily conserved canonical NF-κB pathway, degradation of the NF-κB inhibitor IκB in the cytoplasmic NF-κB/IκB complex allows the liberated NF-κB to translocate into the nucleus to activate various target genes. The regulatory mechanism governing this process needs further investigation. In this study, a novel microRNA, temporarily named miR-1959, was first identified from an invertebrate Litopenaeus vannamei miR-1959 targets the 3'-untranslated region of the IκB homolog Cactus gene and reduces the protein level of Cactus in vivo, whereas the NF-κB homolog Dorsal directly binds the miR-1959 promoter to activate its transcription. Therefore, miR-1959 mediates a positive feedback regulatory loop, in that Dorsal activates miR-1959 expression, and in turn, miR-1959 inhibits the expression of Cactus, further leading to enhanced activation of Dorsal. Moreover, miR-1959 regulates the expression of many antimicrobial peptides in vivo and is involved in antibacterial immunity. To our knowledge, it is the first discovery of a microRNA-mediated feedback loop that directly regulates the NF-κB/IκB complex. This positive feedback loop could collaborate with the known NF-κB/IκB negative loop to generate a dynamic balance to regulate the activity of NF-κB, thus constituting an effective regulatory mechanism at the critical node of the NF-κB pathway. Copyright © 2016 by The American Association of Immunologists, Inc.

  4. Quantifying negative feedback regulation by micro-RNAs

    NASA Astrophysics Data System (ADS)

    Wang, Shangying; Raghavachari, Sridhar

    2011-10-01

    Micro-RNAs (miRNAs) play a crucial role in post-transcriptional gene regulation by pairing with target mRNAs to repress protein production. It has been shown that over one-third of human genes are targeted by miRNA. Although hundreds of miRNAs have been identified in mammalian genomes, the function of miRNA-based repression in the context of gene regulation networks still remains unclear. In this study, we explore the functional roles of feedback regulation by miRNAs. In a model where repression of translation occurs by sequestration of mRNA by miRNA, we find that miRNA and mRNA levels are anti-correlated, resulting in larger fluctuation in protein levels than theoretically expected assuming no correlation between miRNA and mRNA levels. If miRNA repression is due to a catalytic suppression of translation rates, we analytically show that the protein fluctuations can be strongly repressed with miRNA regulation. We also discuss how either of these modes may be relevant for cell function.

  5. The feedback-related negativity reflects the binary evaluation of good versus bad outcomes.

    PubMed

    Hajcak, Greg; Moser, Jason S; Holroyd, Clay B; Simons, Robert F

    2006-02-01

    Electrophysiological studies have utilized event-related brain potentials to study neural processes related to the evaluation of environmental feedback. In particular, the feedback-related negativity (FRN) has been shown to reflect the evaluation of monetary losses and negative performance feedback. Two experiments were conducted to examine whether or not the FRN is sensitive to the magnitude of negative feedback. In both experiments, participants performed simple gambling tasks in which they could receive a range of potential outcomes on each trial. Relative to feedback indicating monetary gain, feedback indicating non-rewards was associated with a FRN in both experiments; however, the magnitude of the FRN did not demonstrate sensitivity to the magnitude of non-reward in either experiment. These data suggest that the FRN reflects the early appraisal of feedback based on a binary classification of good versus bad outcomes. These data are discussed in terms of contemporary theories of the FRN, as well as appraisal processes implicated in emotional processing.

  6. Learning from negative feedback in patients with major depressive disorder is attenuated by SSRI antidepressants.

    PubMed

    Herzallah, Mohammad M; Moustafa, Ahmed A; Natsheh, Joman Y; Abdellatif, Salam M; Taha, Mohamad B; Tayem, Yasin I; Sehwail, Mahmud A; Amleh, Ivona; Petrides, Georgios; Myers, Catherine E; Gluck, Mark A

    2013-01-01

    One barrier to interpreting past studies of cognition and major depressive disorder (MDD) has been the failure in many studies to adequately dissociate the effects of MDD from the potential cognitive side effects of selective serotonin reuptake inhibitors (SSRIs) use. To better understand how remediation of depressive symptoms affects cognitive function in MDD, we evaluated three groups of subjects: medication-naïve patients with MDD, medicated patients with MDD receiving the SSRI paroxetine, and healthy control (HC) subjects. All were administered a category-learning task that allows for dissociation between learning from positive feedback (reward) vs. learning from negative feedback (punishment). Healthy subjects learned significantly better from positive feedback than medication-naïve and medicated MDD groups, whose learning accuracy did not differ significantly. In contrast, medicated patients with MDD learned significantly less from negative feedback than medication-naïve patients with MDD and healthy subjects, whose learning accuracy was comparable. A comparison of subject's relative sensitivity to positive vs. negative feedback showed that both the medicated MDD and HC groups conform to Kahneman and Tversky's (1979) Prospect Theory, which expects losses (negative feedback) to loom psychologically slightly larger than gains (positive feedback). However, medicated MDD and HC profiles are not similar, which indicates that the state of medicated MDD is not "normal" when compared to HC, but rather balanced with less learning from both positive and negative feedback. On the other hand, medication-naïve patients with MDD violate Prospect Theory by having significantly exaggerated learning from negative feedback. This suggests that SSRI antidepressants impair learning from negative feedback, while having negligible effect on learning from positive feedback. Overall, these findings shed light on the importance of dissociating the cognitive consequences of MDD

  7. Negative Feedback Enables Fast and Flexible Collective Decision-Making in Ants

    PubMed Central

    Grüter, Christoph; Schürch, Roger; Czaczkes, Tomer J.; Taylor, Keeley; Durance, Thomas; Jones, Sam M.; Ratnieks, Francis L. W.

    2012-01-01

    Positive feedback plays a major role in the emergence of many collective animal behaviours. In many ants pheromone trails recruit and direct nestmate foragers to food sources. The strong positive feedback caused by trail pheromones allows fast collective responses but can compromise flexibility. Previous laboratory experiments have shown that when the environment changes, colonies are often unable to reallocate their foragers to a more rewarding food source. Here we show both experimentally, using colonies of Lasius niger, and with an agent-based simulation model, that negative feedback caused by crowding at feeding sites allows ant colonies to maintain foraging flexibility even with strong recruitment to food sources. In a constant environment, negative feedback prevents the frequently found bias towards one feeder (symmetry breaking) and leads to equal distribution of foragers. In a changing environment, negative feedback allows a colony to quickly reallocate the majority of its foragers to a superior food patch that becomes available when foraging at an inferior patch is already well underway. The model confirms these experimental findings and shows that the ability of colonies to switch to a superior food source does not require the decay of trail pheromones. Our results help to resolve inconsistencies between collective foraging patterns seen in laboratory studies and observations in the wild, and show that the simultaneous action of negative and positive feedback is important for efficient foraging in mass-recruiting insect colonies. PMID:22984518

  8. The human ventromedial frontal lobe is critical for learning from negative feedback.

    PubMed

    Wheeler, Elizabeth Z; Fellows, Lesley K

    2008-05-01

    Are positive and negative feedback weighed in a common balance in the brain, or do they influence behaviour through distinct neural mechanisms? Recent neuroeconomic studies in both human and non-human primates indicate that the ventromedial frontal lobe carries information about both losses and gains, suggesting that this region may encode value across the continuum from absolute negative to absolute positive outcomes. However, such work does not specify whether or how this value information is applied during behaviour. Observations of patients with ventromedial frontal damage indicate that this region is critical for certain forms of reinforcement learning and value-based decision-making, but the underlying processes remain unclear. We disentangled the influence of cumulative positive and negative feedback on subsequent behaviour with a probabilistic reinforcement learning task in 11 patients with ventromedial frontal damage, 9 lesioned controls and 24 healthy controls, and found that ventromedial frontal damage selectively disrupted the ability to learn from negative feedback.

  9. Identification of a negative feedback loop in biological oxidant formation fegulated by 4-hydroxy-2-(E)-nonenal

    PubMed Central

    Gatbonton-Schwager, Tonibelle N.; Sadhukhan, Sushabhan; Zhang, Guo-Fang; Letterio, John J.; Tochtrop, Gregory P.

    2014-01-01

    4-Hydroxy-2-(E)-nonenal (4-HNE) is one of the major lipid peroxidation product formed during oxidative stress. At high concentrations, 4-HNE is cytotoxic and exerts deleterious effects that are often associated with the pathology of oxidative stress-driven disease. Alternatively, at low concentrations it functions as a signaling molecule that can activate protective pathways including the antioxidant Nrf2-Keap1 pathway. Although these biphasic signaling properties have been enumerated in many diseases and pathways, it has yet to be addressed whether 4-HNE has the capacity to modulate oxidative stress-driven lipid peroxidation. Here we report an auto-regulatory mechanism of 4-HNE via modulation of the biological oxidant nitric oxide (NO). Utilizing LPS-activated macrophages to induce biological oxidant production, we demonstrate that 4-HNE modulates NO levels via inhibition of iNOS expression. We illustrate a proposed model of control of NO formation whereby at low concentrations of 4-HNE a negative feedback loop maintains a constant level of NO production with an observed inflection at approximately 1 µM, while at higher 4-HNE concentrations positive feedback is observed. Further, we demonstrate that this negative feedback loop of NO production control is dependent on the Nrf2-Keap1 signaling pathway. Taken together, the careful regulation of NO production by 4-HNE argues for a more fundamental role of this lipid peroxidation product in normal physiology. PMID:25009777

  10. Ultrasensitive Negative Feedback Control: A Natural Approach for the Design of Synthetic Controllers

    PubMed Central

    Montefusco, Francesco; Akman, Ozgur E.; Soyer, Orkun S.; Bates, Declan G.

    2016-01-01

    Many of the most important potential applications of Synthetic Biology will require the ability to design and implement high performance feedback control systems that can accurately regulate the dynamics of multiple molecular species within the cell. Here, we argue that the use of design strategies based on combining ultrasensitive response dynamics with negative feedback represents a natural approach to this problem that fully exploits the strongly nonlinear nature of cellular information processing. We propose that such feedback mechanisms can explain the adaptive responses observed in one of the most widely studied biomolecular feedback systems—the yeast osmoregulatory response network. Based on our analysis of such system, we identify strong links with a well-known branch of mathematical systems theory from the field of Control Engineering, known as Sliding Mode Control. These insights allow us to develop design guidelines that can inform the construction of feedback controllers for synthetic biological systems. PMID:27537373

  11. A negative group delay model for feedback-delayed manual tracking performance.

    PubMed

    Voss, Henning U; Stepp, Nigel

    2016-12-01

    We propose that feedback-delayed manual tracking performance is limited by fundamental constraints imposed by the physics of negative group delay. To test this hypothesis, the results of an experiment in which subjects demonstrate both reactive and predictive dynamics are modeled by a linear system with delay-induced negative group delay. Although one of the simplest real-time predictors conceivable, this model explains key components of experimental observations. Most notably, it explains the observation that prediction time linearly increases with feedback delay, up to a certain point when tracking performance deteriorates. It also explains the transition from reactive to predictive behavior with increasing feedback delay. The model contains only one free parameter, the feedback gain, which has been fixed by comparison with one set of experimental observations for the reactive case. Our model provides quantitative predictions that can be tested in further experiments.

  12. Punishment sensitivity modulates the processing of negative feedback but not error-induced learning

    PubMed Central

    Unger, Kerstin; Heintz, Sonja; Kray, Jutta

    2012-01-01

    Accumulating evidence suggests that individual differences in punishment and reward sensitivity are associated with functional alterations in neural systems underlying error and feedback processing. In particular, individuals highly sensitive to punishment have been found to be characterized by larger mediofrontal error signals as reflected in the error negativity/error-related negativity (Ne/ERN) and the feedback-related negativity (FRN). By contrast, reward sensitivity has been shown to relate to the error positivity (Pe). Given that Ne/ERN, FRN, and Pe have been functionally linked to flexible behavioral adaptation, the aim of the present research was to examine how these electrophysiological reflections of error and feedback processing vary as a function of punishment and reward sensitivity during reinforcement learning. We applied a probabilistic learning task that involved three different conditions of feedback validity (100%, 80%, and 50%). In contrast to prior studies using response competition tasks, we did not find reliable correlations between punishment sensitivity and the Ne/ERN. Instead, higher punishment sensitivity predicted larger FRN amplitudes, irrespective of feedback validity. Moreover, higher reward sensitivity was associated with a larger Pe. However, only reward sensitivity was related to better overall learning performance and higher post-error accuracy, whereas highly punishment sensitive participants showed impaired learning performance, suggesting that larger negative feedback-related error signals were not beneficial for learning or even reflected maladaptive information processing in these individuals. Thus, although our findings indicate that individual differences in reward and punishment sensitivity are related to electrophysiological correlates of error and feedback processing, we found less evidence for influences of these personality characteristics on the relation between performance monitoring and feedback-based learning. PMID

  13. The effect of negative feedback on noise propagation in transcriptional gene networks

    NASA Astrophysics Data System (ADS)

    Hooshangi, Sara; Weiss, Ron

    2006-06-01

    This paper analyzes how the delay and repression strength of negative feedback in single-gene and multigene transcriptional networks influences intrinsic noise propagation and oscillatory behavior. We simulate a variety of transcriptional networks using a stochastic model and report two main findings. First, intrinsic noise is not attenuated by the addition of negative or positive feedback to transcriptional cascades. Second, for multigene negative feedback networks, synchrony in oscillations among a cell population can be improved by increasing network depth and tightening the regulation at one of the repression stages. Our long term goal is to understand how the noise characteristics of complex networks can be derived from the properties of modules that are used to compose these networks.

  14. miR-285-Yki/Mask double-negative feedback loop mediates blood-brain barrier integrity in Drosophila.

    PubMed

    Li, Dong; Liu, Yanling; Pei, Chunli; Zhang, Peng; Pan, Linqing; Xiao, Jing; Meng, Songshu; Yuan, Zengqiang; Bi, Xiaolin

    2017-03-21

    The Hippo signaling pathway is highly conserved from Drosophila to mammals and plays a central role in maintaining organ size and tissue homeostasis. The blood-brain barrier (BBB) physiologically isolates the brain from circulating blood or the hemolymph system, and its integrity is strictly maintained to perform sophisticated neuronal functions. Until now, the underlying mechanisms of subperineurial glia (SPG) growth and BBB maintenance during development are not clear. Here, we report an miR-285-Yorkie (Yki)/Multiple Ankyrin repeats Single KH domain (Mask) double-negative feedback loop that regulates SPG growth and BBB integrity. Flies with a loss of miR-285 have a defective BBB with increased SPG ploidy and disruptive septate junctions. Mechanistically, miR-285 directly targets the Yki cofactor Mask to suppress Yki activity and down-regulates the expression of its downstream target cyclin E, a key regulator of cell cycle. Disturbance of cyclin E expression in SPG causes abnormal endoreplication, which leads to aberrant DNA ploidy and defective septate junctions. Moreover, the expression of miR-285 is increased by knockdown of yki or mask and is decreased with yki overexpression, thus forming a double-negative feedback loop. This regulatory loop is crucial for sustaining an appropriate Yki/Mask activity and cyclin E level to maintain SPG ploidy and BBB integrity. Perturbation of this signaling loop, either by dysregulated miR-285 expression or Yki activity, causes irregular SPG ploidy and BBB disruption. Furthermore, ectopic expression of miR-285 promotes canonical Hippo pathway-mediated apoptosis independent of the p53 or JNK pathway. Collectively, these results reveal an exquisite regulatory mechanism for BBB maintenance through an miR-285-Yki/Mask regulatory circuit.

  15. Study of positive and negative feedback sensitivity in psychosis using the Wisconsin Card Sorting Test.

    PubMed

    Farreny, Aida; Del Rey-Mejías, Ángel; Escartin, Gemma; Usall, Judith; Tous, Núria; Haro, Josep Maria; Ochoa, Susana

    2016-07-01

    Schizophrenia involves marked motivational and learning deficits that may reflect abnormalities in reward processing. The purpose of this study was to examine positive and negative feedback sensitivity in schizophrenia using computational modeling derived from the Wisconsin Card Sorting Test (WCST). We also aimed to explore feedback sensitivity in a sample with bipolar disorder. Eighty-three individuals with schizophrenia and 27 with bipolar disorder were included. Demographic, clinical and cognitive outcomes, together with the WCST, were considered in both samples. Computational modeling was performed using the R syntax to calculate 3 parameters based on trial-by-trial execution on the WCST: reward sensitivity (R), punishment sensitivity (P), and choice consistency (D). The associations between outcome variables and the parameters were investigated. Positive and negative sensitivity showed deficits, but P parameter was clearly diminished in schizophrenia. Cognitive variables, age, and symptoms were associated with R, P, and D parameters in schizophrenia. The sample with bipolar disorder would show cognitive deficits and feedback abnormalities to a lesser extent than individuals with schizophrenia. Negative feedback sensitivity demonstrated greater deficit in both samples. Idiosyncratic cognitive requirements in the WCST might introduce confusion when supposing model-free reinforcement learning. Negative symptoms of schizophrenia were related to lower feedback sensitivity and less goal-directed patterns of choice. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Fear of negative evaluation modulates electrocortical and behavioral responses when anticipating social evaluative feedback

    PubMed Central

    Van der Molen, Melle J. W.; Poppelaars, Eefje S.; Van Hartingsveldt, Caroline T. A.; Harrewijn, Anita; Gunther Moor, Bregtje; Westenberg, P. Michiel

    2014-01-01

    Cognitive models posit that the fear of negative evaluation (FNE) is a hallmark feature of social anxiety. As such, individuals with high FNE may show biased information processing when faced with social evaluation. The aim of the current study was to examine the neural underpinnings of anticipating and processing social-evaluative feedback, and its correlates with FNE. We used a social judgment paradigm in which female participants (N = 31) were asked to indicate whether they believed to be socially accepted or rejected by their peers. Anticipatory attention was indexed by the stimulus preceding negativity (SPN), while the feedback-related negativity and P3 were used to index the processing of social-evaluative feedback. Results provided evidence of an optimism bias in social peer evaluation, as participants more often predicted to be socially accepted than rejected. Participants with high levels of FNE needed more time to provide their judgments about the social-evaluative outcome. While anticipating social-evaluative feedback, SPN amplitudes were larger for anticipated social acceptance than for social rejection feedback. Interestingly, the SPN during anticipated social acceptance was larger in participants with high levels of FNE. None of the feedback-related brain potentials correlated with the FNE. Together, the results provided evidence of biased information processing in individuals with high levels of FNE when anticipating (rather than processing) social-evaluative feedback. The delayed response times in high FNE individuals were interpreted to reflect augmented vigilance imposed by the upcoming social-evaluative threat. Possibly, the SPN constitutes a neural marker of this vigilance in females with higher FNE levels, particularly when anticipating social acceptance feedback. PMID:24478667

  17. Flat-response spin-exchange relaxation free atomic magnetometer under negative feedback.

    PubMed

    Lee, Hyun Joon; Shim, Jeong Hyun; Moon, Han Seb; Kim, Kiwoong

    2014-08-25

    We demonstrate that the use of negative feedback extends the detection bandwidth of an atomic magnetometer in a spin-exchange relaxation free (SERF) regime. A flat-frequency response from zero to 190 Hz was achieved, which is nearly a three-fold enhancement while maintaining sensitivity, 3 fT/Hz1/2 at 100 Hz. With the extension of the bandwidth, the linear correlation between measured signals and a magne-tocardiographic field synthesized for comparison was increased from 0.21 to 0.74. This result supports the feasibility of measuring weak biomagnetic signals containing multiple frequency components using a SERF atomic magnetometer under negative feedback.

  18. Negative plant-soil feedbacks increase with plant abundance, and are unchanged by competition.

    PubMed

    Maron, John L; Laney Smith, Alyssa; Ortega, Yvette K; Pearson, Dean E; Callaway, Ragan M

    2016-08-01

    Plant-soil feedbacks and interspecific competition are ubiquitous interactions that strongly influence the performance of plants. Yet few studies have examined whether the strength of these interactions corresponds with the abundance of plant species in the field, or whether feedbacks and competition interact in ways that either ameliorate or exacerbate their effects in isolation. We sampled soil from two intermountain grassland communities where we also measured the relative abundance of plant species. In greenhouse experiments, we quantified the direction and magnitude of plant-soil feedbacks for 10 target species that spanned a range of abundances in the field. In soil from both sites, plant-soil feedbacks were mostly negative, with more abundant species suffering greater negative feedbacks than rare species. In contrast, the average response to competition for each species was unrelated with its abundance in the field. We also determined how competitive response varied among our target species when plants competed in live vs. sterile soil. Interspecific competition reduced plant size, but the strength of this negative effect was unchanged by plant-soil feedbacks. Finally, when plants competed interspecifically, we asked how conspecific-trained, heterospecific-trained, and sterile soil influenced the competitive responses of our target species and how this varied depending on whether target species were abundant or rare in the field. Here, we found that both abundant and rare species were not as harmed by competition when they grew in heterospecific-trained soil compared to when they grew in conspecific-cultured soil. Abundant species were also not as harmed by competition when growing in sterile vs. conspecific-trained soil, but this was not the case for rare species. Our results suggest that abundant plants accrue species-specific soil pathogens to a greater extent than rare species. Thus, negative feedbacks may be critical for preventing abundant species from

  19. Interlocked positive and negative feedback network motifs regulate β-catenin activity in the adherens junction pathway

    PubMed Central

    Klinke, David J.; Horvath, Nicholas; Cuppett, Vanessa; Wu, Yueting; Deng, Wentao; Kanj, Rania

    2015-01-01

    The integrity of epithelial tissue architecture is maintained through adherens junctions that are created through extracellular homotypic protein–protein interactions between cadherin molecules. Cadherins also provide an intracellular scaffold for the formation of a multiprotein complex that contains signaling proteins, including β-catenin. Environmental factors and controlled tissue reorganization disrupt adherens junctions by cleaving the extracellular binding domain and initiating a series of transcriptional events that aim to restore tissue homeostasis. However, it remains unclear how alterations in cell adhesion coordinate transcriptional events, including those mediated by β-catenin in this pathway. Here were used quantitative single-cell and population-level in vitro assays to quantify the endogenous pathway dynamics after the proteolytic disruption of the adherens junctions. Using prior knowledge of isolated elements of the overall network, we interpreted these data using in silico model-based inference to identify the topology of the regulatory network. Collectively the data suggest that the regulatory network contains interlocked network motifs consisting of a positive feedback loop, which is used to restore the integrity of adherens junctions, and a negative feedback loop, which is used to limit β-catenin–induced gene expression. PMID:26224311

  20. Switching between colors and shapes on the basis of positive and negative feedback: an fMRI and EEG study on feedback-based learning.

    PubMed

    Zanolie, Kiki; Teng, Santani; Donohue, Sarah E; van Duijvenvoorde, Anna C K; Band, Guido P H; Rombouts, Serge A R B; Crone, Eveline A

    2008-05-01

    A crucial element of testing hypotheses about rules for behavior is the use of performance feedback. In this study, we used fMRI and EEG to test the role of medial prefrontal cortex (PFC) and dorsolateral (DL) PFC in hypothesis testing using a modified intradimensional/extradimensional rule shift task. Eighteen adults were asked to infer rules about color or shape on the basis of positive and negative feedback in sets of two trials. Half of the trials involved color-to-color or shape-to-shape trials (intradimensional switches; ID) and the other half involved color-to-shape or shape-to-color trials (extradimensional switches; ED). Participants performed the task in separate fMRI and EEG sessions. ED trials were associated with reduced accuracy relative to ID trials. In addition, accuracy was reduced and response latencies increased following negative relative to positive feedback. Negative feedback resulted in increased activation in medial PFC and DLPFC, but more so for ED than ID shifts. Reduced accuracy following negative feedback correlated with increased activation in DLPFC, and increased response latencies following negative feedback correlated with increased activation in medial PFC. Additionally, around 250msec following negative performance feedback participants showed a feedback-related negative scalp potential, but this potential did not differ between ID and ED shifts. These results indicate that both medial PFC and DLPFC signal the need for performance adjustment, and both regions are sensitive to the increased demands of set shifting in hypothesis testing.

  1. Age-related changes in deterministic learning from positive versus negative performance feedback.

    PubMed

    van de Vijver, Irene; Ridderinkhof, K Richard; de Wit, Sanne

    2015-01-01

    Feedback-based learning declines with age. Because older adults are generally biased toward positive information ("positivity effect"), learning from positive feedback may be less impaired than learning from negative outcomes. The literature documents mixed results, due possibly to variability between studies in task design. In the current series of studies, we investigated the influence of feedback valence on reinforcement learning in young and older adults. We used nonprobabilistic learning tasks, to more systematically study the effects of feedback magnitude, learning of stimulus-response (S-R) versus stimulus-outcome (S-O) associations, and working-memory capacity. In most experiments, older adults benefitted more from positive than negative feedback, but only with large feedback magnitudes. Positivity effects were pronounced for S-O learning, whereas S-R learning correlated with working-memory capacity in both age groups. These results underline the context dependence of positivity effects in learning and suggest that older adults focus on high gains when these are informative for behavior.

  2. Photoperiod-dependent negative feedback effects of thyroid hormones in Fundulus heteroclitus

    SciTech Connect

    Brown, C.L.; Stetson, M.H.

    1985-05-01

    In Fundulus heteroclitus, an annual cycle in the response of the thyroid to ovine thyroid-stimulating hormone (oTSH) is characterized by maximal thyroxin (T4) secretion in mid-winter and minimal T4 secretion in summer. Four daily injections of oTSH, given in winter caused serum T4 to plateau at elevated levels for several days, while in summer fish similar treatment resulted in far more fluctuating titers of serum T4; maximum levels were similar in both groups. The difference in sustenance rather than magnitude of Peak T4 led to an examination of the negative feedback effects of thyroid hormones as they might relate to these seasonal changes. Radioiodine uptake by thyroid follicles served as a simple, but effective bioassay for endogenous TSH. Fish collected in summer were more sensitive to negative feedback of T3 than those collected in winter; feedback effects of T4 in the two groups were not significantly different. The effects of specific photoperiods on negative feedback sensitivity to T3 and T4 were also tested. Exposure of winter fish for one month to long days (LD 14:10) enhanced the degree of reduction of iodine uptake caused by T4 in the aquarium water (10 micrograms/100 ml). Negative feedback in short-day (LD 8:16) winter fish was not demonstrated. It is concluded that long days increase and short days diminish the negative feedback sensitivity of the hypothalamus-pituitary axis to thyroid hormones in F. heteroclitus. Such photoperiodically induced changes may act to aid in the year-round maintenance of T4 levels necessary for seasonal adaptation and survival.

  3. Inhibitory GEF phosphorylation provides negative feedback in the yeast polarity circuit.

    PubMed

    Kuo, Chun-Chen; Savage, Natasha S; Chen, Hsin; Wu, Chi-Fang; Zyla, Trevin R; Lew, Daniel J

    2014-03-31

    Cell polarity is critical for the form and function of many cell types. During polarity establishment, cells define a cortical "front" that behaves differently from the rest of the cortex. The front accumulates high levels of the active form of a polarity-determining Rho-family GTPase (Cdc42, Rac, or Rop) that then orients cytoskeletal elements through various effectors to generate the polarized morphology appropriate to the particular cell type [1, 2]. GTPase accumulation is thought to involve positive feedback, such that active GTPase promotes further delivery and/or activation of more GTPase in its vicinity [3]. Recent studies suggest that once a front forms, the concentration of polarity factors at the front can increase and decrease periodically, first clustering the factors at the cortex and then dispersing them back to the cytoplasm [4-7]. Such oscillatory behavior implies the presence of negative feedback in the polarity circuit [8], but the mechanism of negative feedback was not known. Here we show that, in the budding yeast Saccharomyces cerevisiae, the catalytic activity of the Cdc42-directed GEF is inhibited by Cdc42-stimulated effector kinases, thus providing negative feedback. We further show that replacing the GEF with a phosphosite mutant GEF abolishes oscillations and leads to the accumulation of excess GTP-Cdc42 and other polarity factors at the front. These findings reveal a mechanism for negative feedback and suggest that the function of negative feedback via GEF inhibition is to buffer the level of Cdc42 at the polarity site. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Range-expanding populations of a globally introduced weed experience negative plant-soil feedbacks.

    PubMed

    Andonian, Krikor; Hierro, José L; Khetsuriani, Liana; Becerra, Pablo; Janoyan, Grigor; Villarreal, Diego; Cavieres, Lohengrin; Fox, Laurel R; Callaway, Ragan M

    2011-01-01

    Biological invasions are fundamentally biogeographic processes that occur over large spatial scales. Interactions with soil microbes can have strong impacts on plant invasions, but how these interactions vary among areas where introduced species are highly invasive vs. naturalized is still unknown. In this study, we examined biogeographic variation in plant-soil microbe interactions of a globally invasive weed, Centaurea solstitialis (yellow starthistle). We addressed the following questions (1) Is Centaurea released from natural enemy pressure from soil microbes in introduced regions? and (2) Is variation in plant-soil feedbacks associated with variation in Centaurea's invasive success? We conducted greenhouse experiments using soils and seeds collected from native Eurasian populations and introduced populations spanning North and South America where Centaurea is highly invasive and noninvasive. Soil microbes had pervasive negative effects in all regions, although the magnitude of their effect varied among regions. These patterns were not unequivocally congruent with the enemy release hypothesis. Surprisingly, we also found that Centaurea generated strong negative feedbacks in regions where it is the most invasive, while it generated neutral plant-soil feedbacks where it is noninvasive. Recent studies have found reduced below-ground enemy attack and more positive plant-soil feedbacks in range-expanding plant populations, but we found increased negative effects of soil microbes in range-expanding Centaurea populations. While such negative feedbacks may limit the long-term persistence of invasive plants, such feedbacks may also contribute to the success of invasions, either by having disproportionately negative impacts on competing species, or by yielding relatively better growth in uncolonized areas that would encourage lateral spread. Enemy release from soil-borne pathogens is not sufficient to explain the success of this weed in such different regions. The

  5. How to not get stuck-negative feedback due to crowding maintains flexibility in ant foraging.

    PubMed

    Czaczkes, Tomer J

    2014-11-07

    Ant foraging is an important model system in the study of adaptive complex systems. Many ants use trail pheromones to recruit nestmates to resources. Differential recruitment depending on resource quality coupled with positive feedback allows ant colonies to make rapid and accurate collective decisions about how best to allocate their work-force. However, ant colonies can become trapped in sub-optimal foraging decisions if recruitment to a poor resource becomes too strong before a better resource is discovered. Genetic algorithms and Ant Colony Optimisation heuristics can also suffer from being trapped in such local optima. Recently, two negative feedback effects were described, in which an increase in crowding (crowding negative feedback-CNF) or trail pheromones (pheromone negative feedback-PNF) caused a decrease in subsequent pheromone deposition. Using agent based simulations with realistic parameters I test whether these negative feedback effects can prevent simulated ant colonies from becoming trapped in sub-optimal foraging decisions. Colonies are presented with two food sources of different qualities, and these qualities switch part way through the experiment. When either no negative feedback effects are implemented or only PNF is implemented colonies are completely unable to refocus their foraging effort to the high quality feeder. However, when CNF alone is implemented at a realistic level 97% of colonies successfully refocus their foraging effort. This ability to refocus colony foraging efforts is due to the strong reduction of pheromone deposition caused by CNF. This suggests that CNF is an important behaviour enabling ant colonies to maintain foraging flexibility. However, CNF comes at a slight cost to colonies when making their initial foraging decision.

  6. The negative shortwave cloud feedback at high latitudes: mechanisms and observational constraints

    NASA Astrophysics Data System (ADS)

    Ceppi, Paulo; McCoy, Daniel; Hartmann, Dennis; Webb, Mark

    2016-04-01

    Climate models agree on a negative shortwave cloud feedback at high latitudes, driven by increases in cloud optical depth and liquid water path (LWP), but the mechanisms remain uncertain. We assess the importance of microphysical processes for the negative optical depth feedback by perturbing temperature in the microphysics schemes of two aquaplanet models, both of which have separate prognostic equations for liquid water and ice. We find that most of the LWP increase with warming is caused by a suppression of ice microphysical processes in mixed-phase clouds, resulting in reduced conversion efficiencies of liquid water to ice and precipitation, and yielding an enhanced reservoir of cloud liquid water. Hence, in climate models, the suppression of ice-phase microphysics that deplete cloud liquid water is a key mechanism of the LWP increase with warming and of the associated negative shortwave cloud feedback in cold clouds. In support of these findings, we show the existence of a very robust positive relationship between monthly-mean LWP and temperature in CMIP5 models and observations in mixed-phase cloud regions only. In models, the historical LWP sensitivity to temperature is a good predictor of the forced global warming response poleward of about 45°, although models appear to overestimate the LWP response to warming compared to observations. Historical cloud optical depth-temperature relationships are shown to provide an observational constraint on the modeled cloud feedback, and support the prediction of a negative cloud feedback at high latitudes. Because optical thickening with warming is supported by simple temperature-dependent mechanisms and dominates over cloud amount changes, we conclude that the shortwave cloud feedback is very likely negative in mid to high latitudes.

  7. Repression of Essential Chloroplast Genes Reveals New Signaling Pathways and Regulatory Feedback Loops in Chlamydomonas[W

    PubMed Central

    Ramundo, Silvia; Rahire, Michèle; Schaad, Olivier; Rochaix, Jean-David

    2013-01-01

    Although reverse genetics has been used to elucidate the function of numerous chloroplast proteins, the characterization of essential plastid genes and their role in chloroplast biogenesis and cell survival has not yet been achieved. Therefore, we developed a robust repressible chloroplast gene expression system in the unicellular alga Chlamydomonas reinhardtii based mainly on a vitamin-repressible riboswitch, and we used this system to study the role of two essential chloroplast genes: ribosomal protein S12 (rps12), encoding a plastid ribosomal protein, and rpoA, encoding the α-subunit of chloroplast bacterial-like RNA polymerase. Repression of either of these two genes leads to the arrest of cell growth, and it induces a response that involves changes in expression of nuclear genes implicated in chloroplast biogenesis, protein turnover, and stress. This response also leads to the overaccumulation of several plastid transcripts and reveals the existence of multiple negative regulatory feedback loops in the chloroplast gene circuitry. PMID:23292734

  8. Learning from clients: A qualitative investigation of psychotherapists' reactions to negative verbal feedback.

    PubMed

    Brattland, Heidi; Høiseth, Juni R; Burkeland, Olav; Inderhaug, Tryggve S; Binder, Per E; Iversen, Valentina C

    2016-11-09

    To explore how therapists experience, react to, and learn from negative feedback from their clients. Eighteen experienced therapists' written descriptions of episodes where they had received negative verbal feedback from clients were analyzed according to the Consensual Qualitative Research methodology. Receiving feedback was experienced as challenging, but educational. Learning was manifested in different ways: (a) Immediately Applied Learning-therapists improved the following therapy process by changing their behavior with the client, (b) Retrospectively Applied Learning-therapists made changes in their way of working with subsequent clients, and (c) Non-Applied Learning-new ideas generated by the experience had not been translated into behavior. We compared cases describing these manifestations of learning and found differences in the nature of the feedback and how therapists understood, reacted, and responded to it. The therapists benefitted from obtaining and being open to specific feedback from their clients, regulating their own emotional reactions, accommodating dissatisfied clients, and considering how they themselves contributed to negative therapy processes.

  9. Positive And Negative Feedback Loops Coupled By Common Transcription Activator And Repressor

    NASA Astrophysics Data System (ADS)

    Sielewiesiuk, Jan; Łopaciuk, Agata

    2015-03-01

    Dynamical systems consisting of two interlocked loops with negative and positive feedback have been studied using the linear analysis of stability and numerical solutions. Conditions for saddle-node bifurcation were formulated in a general form. Conditions for Hopf bifurcations were found in a few symmetrical cases. Auto-oscillations, when they exist, are generated by the negative feedback repressive loop. This loop determines the frequency and amplitude of oscillations. The positive feedback loop of activation slightly modifies the oscillations. Oscillations are possible when the difference between Hilll's coefficients of the repression and activation is sufficiently high. The highly cooperative activation loop with a fast turnover slows down or even makes the oscillations impossible. The system under consideration can constitute a component of epigenetic or enzymatic regulation network.

  10. Positive And Negative Feedback Loops Coupled By Common Transcription Activator And Repressor

    NASA Astrophysics Data System (ADS)

    Sielewiesiuk, Jan; Łopaciuk, Agata

    2015-03-01

    Dynamical systems consisting of two interlocked loops with negative and positive feedback have been studied using the linear analysis of stability and numerical solutions. Conditions for saddle-node bifurcation were formulated in a general form. Conditions for Hopf bifurcations were found in a few symmetrical cases. Auto-oscillations, when they exist, are generated by the negative feedback repressive loop. This loop determines the frequency and amplitude of oscillations. The positive feedback loop of activation slightly modifies the oscillations. Oscillations are possible when the difference between Hilll's coefficients of the repression and activation is sufficiently high. The highly cooperative activation loop with a fast turnover slows down or even makes the oscillations impossible. The system under consideration can constitute a component of epigenetic or enzymatic regulation network.

  11. Removal of Negative Feedback Enhances WCST Performance for Individuals with ASD

    ERIC Educational Resources Information Center

    Broadbent, Jaclyn; Stokes, Mark A.

    2013-01-01

    Negative feedback was explored as a potential mechanism that may exacerbate perseverative behaviours in individuals with Asperger's syndrome (AS). The current study compared 50 individuals with AS and 50 typically developing (TD) individuals for their abilities to successfully complete the Wisconsin Card Sorting Task (WCST) in the presence or…

  12. Effects of Concurrent Negative Feedback On Performance of Two Motor Tasks. Working Paper Number Six.

    ERIC Educational Resources Information Center

    Kieffer, Leigh F.; Tennyson, Robert D.

    1973-01-01

    The effects of stress on state anxiety and heart rate of male high school subjects were investigated. Two psychomotor tasks were used. In the stress condition, subjects received negative feedback about performance; the subjects in the nonstress condition were given rest intervals. Subjects in both conditions showed differing regression lines. The…

  13. Evidence that the Arcuate Nucleus Is an Important Site of Progesterone Negative Feedback in the Ewe

    PubMed Central

    Holaskova, Ida; Nestor, Casey C.; Connors, John M.; Billings, Heather J.; Valent, Miro; Lehman, Michael N.; Hileman, Stanley M.

    2011-01-01

    There is now considerable evidence that dynorphin neurons mediate the negative feedback actions of progesterone to inhibit GnRH and LH pulse frequency, but the specific neurons have yet to be identified. In ewes, dynorphin neurons in the arcuate nucleus (ARC) and preoptic area (POA) are likely candidates based on colocalization with progesterone receptors. These studies tested the hypothesis that progesterone negative feedback occurs in either the ARC or POA by determining whether microimplants of progesterone into either site would inhibit LH pulse frequency (study 1) and whether microimplants of the progesterone receptor antagonist, RU486, would disrupt the inhibitory effects of peripheral progesterone (study 2). Both studies were done in ovariectomized (OVX) and estradiol-treated OVX ewes. In study 1, no inhibitory effects of progesterone were observed during treatment in either area. In study 2, microimplants of RU486 into the ARC disrupted the negative-feedback actions of peripheral progesterone treatments on LH pulse frequency in both OVX and OVX+estradiol ewes. In contrast, microimplants of RU486 into the POA had no effect on the ability of systemic progesterone to inhibit LH pulse frequency. We thus conclude that the ARC is one important site of progesterone-negative feedback in the ewe. These data, which are the first evidence on the neural sites in which progesterone inhibits GnRH pulse frequency in any species, are consistent with the hypothesis that ARC dynorphin neurons mediate this action of progesterone. PMID:21693677

  14. The Human Ventromedial Frontal Lobe Is Critical for Learning from Negative Feedback

    ERIC Educational Resources Information Center

    Wheeler, Elizabeth Z.; Fellows, Lesley K.

    2008-01-01

    Are positive and negative feedback weighed in a common balance in the brain, or do they influence behaviour through distinct neural mechanisms? Recent neuroeconomic studies in both human and non-human primates indicate that the ventromedial frontal lobe carries information about both losses and gains, suggesting that this region may encode value…

  15. Negative feedback from maternal signals reduces false alarms by collectively signalling offspring.

    PubMed

    Hamel, Jennifer A; Cocroft, Reginald B

    2012-09-22

    Within animal groups, individuals can learn of a predator's approach by attending to the behaviour of others. This use of social information increases an individual's perceptual range, but can also lead to the propagation of false alarms. Error copying is especially likely in species that signal collectively, because the coordination required for collective displays relies heavily on social information. Recent evidence suggests that collective behaviour in animals is, in part, regulated by negative feedback. Negative feedback may reduce false alarms by collectively signalling animals, but this possibility has not yet been tested. We tested the hypothesis that negative feedback increases the accuracy of collective signalling by reducing the production of false alarms. In the treehopper Umbonia crassicornis, clustered offspring produce collective signals during predator attacks, advertising the predator's location to the defending mother. Mothers signal after evicting the predator, and we show that this maternal communication reduces false alarms by offspring. We suggest that maternal signals elevate offspring signalling thresholds. This is, to our knowledge, the first study to show that negative feedback can reduce false alarms by collectively behaving groups.

  16. Early Detection of Online Auction Opportunistic Sellers through the Use of Negative-Positive Feedback

    ERIC Educational Resources Information Center

    Reinert, Gregory J.

    2010-01-01

    Apparently fraud is a growth industry. The monetary losses from Internet fraud have increased every year since first officially reported by the Internet Crime Complaint Center (IC3) in 2000. Prior research studies and third-party reports of fraud show rates substantially higher than eBay's reported negative feedback rate of less than 1%. The…

  17. The Human Ventromedial Frontal Lobe Is Critical for Learning from Negative Feedback

    ERIC Educational Resources Information Center

    Wheeler, Elizabeth Z.; Fellows, Lesley K.

    2008-01-01

    Are positive and negative feedback weighed in a common balance in the brain, or do they influence behaviour through distinct neural mechanisms? Recent neuroeconomic studies in both human and non-human primates indicate that the ventromedial frontal lobe carries information about both losses and gains, suggesting that this region may encode value…

  18. Early Detection of Online Auction Opportunistic Sellers through the Use of Negative-Positive Feedback

    ERIC Educational Resources Information Center

    Reinert, Gregory J.

    2010-01-01

    Apparently fraud is a growth industry. The monetary losses from Internet fraud have increased every year since first officially reported by the Internet Crime Complaint Center (IC3) in 2000. Prior research studies and third-party reports of fraud show rates substantially higher than eBay's reported negative feedback rate of less than 1%. The…

  19. Removal of Negative Feedback Enhances WCST Performance for Individuals with ASD

    ERIC Educational Resources Information Center

    Broadbent, Jaclyn; Stokes, Mark A.

    2013-01-01

    Negative feedback was explored as a potential mechanism that may exacerbate perseverative behaviours in individuals with Asperger's syndrome (AS). The current study compared 50 individuals with AS and 50 typically developing (TD) individuals for their abilities to successfully complete the Wisconsin Card Sorting Task (WCST) in the presence or…

  20. Negative Feedback and Positive Evidence in Task-Based Interaction: Differential Effects on L2 Development

    ERIC Educational Resources Information Center

    Iwashita, Noriko

    2003-01-01

    This study examines the role of task-based conversation in second language (L2) grammatical development, focusing on the short-term effects of both negative feedback and positive evidence on the acquisition of two Japanese structures. The data are drawn from 55 L2 learners of Japanese at a beginning level of proficiency in an Australian tertiary…

  1. Changes in Intrinsic Motivation as a Function of Negative Feedback and Threats.

    ERIC Educational Resources Information Center

    Deci, Edward L.; Cascio, Wayne F.

    Recent studies have demonstrated that external rewards can affect intrinsic motivation to perform an activity. Money tends to decrease intrinsic motivation, whereas positive verbal reinforcements tend to increase intrinsic motivation. This paper presents evidence that negative feedback and threats of punishment also decrease intrinsic motivation.…

  2. Why do some therapists not deal with outcome monitoring feedback? A feasibility study on the effect of regulatory focus and person-organization fit on attitude and outcome.

    PubMed

    de Jong, Kim; de Goede, Marije

    2015-01-01

    Despite research on its effectiveness, many therapists still have negative attitudes toward using outcome monitoring feedback. The current study aims to investigate how the perceived match between values of an individual and those of the organization (Person-Organization fit; PO fit), and motivation to prevent failure or to achieve success (regulatory focus) are related to therapists' attitude, attitude changes over time, and outcomes. Therapists (n = 20) filled out a feedback attitude questionnaire at two points in time: before the start of outcome monitoring, and after six months. In addition, they completed measures on PO fit and regulatory focus. PO fit was predictive of outcomes, when feedback was provided, but did not predict therapists' attitude. Therapists with a strong prevention focus (prevent failures), had a more positive attitude toward feedback, but achieved slower symptom reduction in their at risk cases. A strong promotion focus (achieve success) was not predictive of attitude, but did result in faster symptom reduction in at risk patients when feedback was provided. Therapists motivational approach to work and the perceived match with the organization they work for, can influence both their attitude toward outcome monitoring and their outcomes.

  3. Novel feedback loop between M2 macrophages/microglia and regulatory B cells in estrogen-protected EAE mice.

    PubMed

    Benedek, Gil; Zhang, Jun; Nguyen, Ha; Kent, Gail; Seifert, Hilary; Vandenbark, Arthur A; Offner, Halina

    2017-04-15

    Immunoregulatory sex hormones, including estrogen and estriol, may prevent relapses in multiple sclerosis during pregnancy. Our previous studies have demonstrated that regulatory B cells are crucial for estrogen-mediated protection against experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate an estrogen-dependent induction of alternatively activated (M2) macrophages/microglia that results in an increased frequency of regulatory B cells in the spinal cord of estrogen treated mice with EAE. We further demonstrate that cultured M2-polarized microglia promote the induction of regulatory B cells. Our study suggests that estrogen neuroprotection induces a regulatory feedback loop between M2 macrophages/microglia and regulatory B cells.

  4. Negative feedback mechanisms surpass the effect of intrinsic EGFR activation during skin chemical carcinogenesis.

    PubMed

    Dahlhoff, Maik; Rose, Christian; de Angelis, Martin Hrabé; Wolf, Eckhard; Schneider, Marlon R

    2012-04-01

    The negative feedback regulation of epidermal growth factor receptor (EGFR) and other tyrosine kinase receptors, including receptor dephosphorylation and endocytosis followed by degradation, is becoming recognized as a major determinant of receptor function. To evaluate the significance of the negative regulation of EGFR during carcinogenesis in vivo, we subjected the mutant mouse line Dsk5, in which the intrinsic activation of the receptor due to a point mutation is normally counterbalanced by increased posttranslational receptor down-regulation, to skin chemical carcinogenesis. Dsk5 mice showed reduced tumor numbers and tumor burden compared with control littermates, and Dsk5-derived tumors showed a reduction in the activation and total levels of EGFR. Furthermore, the transcript levels of several molecules known to act as negative regulators of EGFR were significantly increased in Dsk5-derived tumors. Another intriguing observation was the appearance of tumors with sebaceous differentiation in the ears of Dsk5 mice after chemical carcinogenesis. Further studies are necessary to reveal whether these tumors represent a cell type-specific evasion from EGFR negative feedback machinery. In conclusion, this study reveals that several negative feedback regulators contribute to suppression of the intrinsic activation of mutant EGFR during skin carcinogenesis, stressing the potential exploitation of negative regulators as either therapeutic targets or diagnostic tools in cancer and other diseases. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. Crystal structure of the stimulatory complex of GTP cyclohydrolase I and its feedback regulatory protein GFRP.

    PubMed

    Maita, Nobuo; Okada, Kengo; Hatakeyama, Kazuyuki; Hakoshima, Toshio

    2002-02-05

    In the presence of phenylalanine, GTP cyclohydrolase I feedback regulatory protein (GFRP) forms a stimulatory 360-kDa complex with GTP cyclohydrolase I (GTPCHI), which is the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin. The crystal structure of the stimulatory complex reveals that the GTPCHI decamer is sandwiched by two GFRP homopentamers. Each GFRP pentamer forms a symmetrical five-membered ring similar to beta-propeller. Five phenylalanine molecules are buried inside each interface between GFRP and GTPCHI, thus enhancing the binding of these proteins. The complex structure suggests that phenylalanine-induced GTPCHI x GFRP complex formation enhances GTPCHI activity by locking the enzyme in the active state.

  6. Negative feedback regulation of thyrotropin subunits and pituitary deiodinases in red drum, Sciaenops ocellatus.

    PubMed

    Jones, R A; Cohn, W B; Wilkes, A A; MacKenzie, D S

    2017-01-01

    Thyroxine (T4) undergoes dynamic daily cycles in the perciform fish the red drum, Sciaenops ocellatus, that are inversely timed to cycles of thyrotropin (TSH) subunit mRNA expression in the pituitary gland. We have proposed that these daily cycles are regulated by negative feedback of circulating T4 on expression of pituitary thyroid hormone deiodinase type 3 (Dio3), such that elevated circulating T4 results in diminished pituitary thyroid hormone catabolism and consequent increased negative feedback on expression of TSH subunits during the day. To determine whether thyroid hormones function to modulate expression of pituitary deiodinase enzymes we developed an immersion technique to administer physiological doses of T3 and T4in vivo. Immersion in T4 or T3 significantly inhibited the mRNA expression of the TSH α and β subunits from 4 to 66h of immersion. Pituitary Dio3 expression was significantly diminished by T3 and T4 at 22h. These results indicate that both T4 and T3 are capable of negative feedback regulation of TSH subunit expression in red drum at physiological concentrations and on a time scale consistent with the T4 daily cycle. Furthermore, thyroid hormones negatively regulate Dio3 expression in the pituitary in a manner suggesting that negative thyroxine feedback on Dio3 promotes the release of TSH subunits from TH inhibition and may be an important mechanism for generating daily thyroid hormone cycles. These results highlight a potentially important role for D3 in mediating thyroid hormone feedback on TSH expression, not previously described in other species.

  7. Periodic solutions of piecewise affine gene network models with non uniform decay rates: the case of a negative feedback loop.

    PubMed

    Farcot, Etienne; Gouzé, Jean-Luc

    2009-12-01

    This paper concerns periodic solutions of a class of equations that model gene regulatory networks. Unlike the vast majority of previous studies, it is not assumed that all decay rates are identical. To handle this more general situation, we rely on monotonicity properties of these systems. Under an alternative assumption, it is shown that a classical fixed point theorem for monotone, concave operators can be applied to these systems. The required assumption is expressed in geometrical terms as an alignment condition on so-called focal points. As an application, we show the existence and uniqueness of a stable periodic orbit for negative feedback loop systems in dimension 3 or more, and of a unique stable equilibrium point in dimension 2. This extends a theorem of Snoussi, which showed the existence of these orbits only.

  8. The facilitatory effect of negative feedback on the emergence of analogical reasoning abilities.

    PubMed

    Ball, Linden J; Hoyle, Alison M; Towse, Andrea S

    2010-09-01

    This paper focuses on the development of analogical reasoning abilities in 5- and 6-year-old children. Our particular interest relates to the way in which analogizing is influenced by the provision of task-based feedback coupled with a self-explanation requirement. Both feedback and self-explanation provide children with opportunities to engage in self-reflective thinking about the process of analogical reasoning. To examine the role of such metacognitive factors in analogical strategy development the reported study combined a proportional analogy paradigm with a small-scale microgenetic approach involving multiple testing sessions over a restricted time period. The key manipulation involved exposing participants either to the correct or incorrect analogy completions of another reasoner that they were then asked to explain. The data revealed that the development of an effective analogizing strategy embodying a 'relational shift' from superficial to relational responding was modulated by the feedback condition that the child was placed in, with a negative feedback intervention providing the greatest developmental benefit. We suggest that the value of negative feedback for the acquisition of analogical reasoning abilities derives from the way in which a self-reflective analysis of the reasons for erroneous responses sensitizes the child to a deeper understanding of how to make effective relational mappings.

  9. Observational evidence for a negative shortwave cloud feedback in middle to high latitudes

    NASA Astrophysics Data System (ADS)

    Ceppi, Paulo; McCoy, Daniel T.; Hartmann, Dennis L.

    2016-02-01

    Exploiting the observed robust relationships between temperature and optical depth in extratropical clouds, we calculate the shortwave cloud feedback from historical data, by regressing observed and modeled cloud property histograms onto local temperature in middle to high southern latitudes. In this region, all CMIP5 models and observational data sets predict a negative cloud feedback, mainly driven by optical thickening. Between 45° and 60°S, the mean observed shortwave feedback (-0.91 ± 0.82 W m-2 K-1, relative to local rather than global mean warming) is very close to the multimodel mean feedback in RCP8.5 (-0.98 W m-2 K-1), despite differences in the meridional structure. In models, historical temperature-cloud property relationships reliably predict the forced RCP8.5 response. Because simple theory predicts this optical thickening with warming, and cloud amount changes are relatively small, we conclude that the shortwave cloud feedback is very likely negative in the real world at middle to high latitudes.

  10. Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst

    PubMed Central

    Graham, Daniel B.; Becker, Christine E.; Doan, Aivi; Goel, Gautam; Villablanca, Eduardo J.; Knights, Dan; Mok, Amanda; Ng, Aylwin C.Y.; Doench, John G.; Root, David E.; Clish, Clary B.; Xavier, Ramnik J.

    2015-01-01

    The phagocyte oxidative burst, mediated by Nox2 NADPH oxidase-derived reactive oxygen species, confers host defense against a broad spectrum of bacterial and fungal pathogens. Loss-of-function mutations that impair function of the Nox2 complex result in a life-threatening immunodeficiency, and genetic variants of Nox2 subunits have been implicated in pathogenesis of inflammatory bowel disease (IBD). Thus, alterations in the oxidative burst can profoundly impact host defense, yet little is known about regulatory mechanisms that fine-tune this response. Here we report the discovery of regulatory nodes controlling oxidative burst by functional screening of genes within loci linked to human inflammatory disease. Implementing a multi-omics approach, we define transcriptional, metabolic and ubiquitin-cycling nodes controlled by Rbpj, Pfkl and Rnf145, respectively. Furthermore, we implicate Rnf145 in proteostasis of the Nox2 complex by endoplasmic reticulum-associated degradation. Consequently, ablation of Rnf145 in murine macrophages enhances bacterial clearance, and rescues the oxidative burst defects associated with Ncf4 haploinsufficiency. PMID:26194095

  11. Global stability of a population dynamics model with inhibition and negative feedback.

    PubMed

    Vargas-De-Leóon, Cruz; Korobeinikov, Andrei

    2013-03-01

    Reactions or interactions with the rate which is inhibited by the product or a by-product of the reaction are fairly common in biology and chemical kinetics. Biological examples of such interactions include selfpoisoning of bacteria, the non-lytic immune response and the antiviral (and in particular antiretroviral) therapy. As a case study, in this notice, we consider global asymptotic properties for a simple model with negative feedback (the Wodarz model) where the interaction is inhibited by a by-product of the reaction. The objective of this notice is an extending of a technique that was developed during last decade for the global analysis of models with positive feedback to the systems, where the feedback is negative. Using the direct Lyapunov method with Volterra type Lyapunov functions, we establish conditions for the global stability of this model. This result enables us to evaluate the comparative impacts of the lytic and nonlytic components, the efficiency of the antiviral therapy and the possibility of self-poisoning for bacteria. The same approach can be successfully applied to more complex models with negative feedback.

  12. Feedback-reactivity time-dependencies for a negative reactivity insertion in EBR-II

    SciTech Connect

    Grimm, K.N.; Meneghetti, D.

    1987-01-01

    Knowledge of time-dependencies (and magnitudes) of feedback components is necessary for interpretation and understanding of transient behaviors. Described herein is one analysis of negative insertion (approx. 36 cents) of a control rod from full power during Experimental Breeder Reactor-II (EBR-II) run 93a. The time-dependencies of the component feedbacks have been analyzed using 24 channels in the EROS computer code. Seventy distinct temperature coefficients of reactivity were used in conjunction with this 24-channel EBR-II model. These temperature coefficients of reactivity were obtained using an addition (TEMCO) to the EBRPOCO code.

  13. Genome-Wide Negative Feedback Drives Transgenerational DNA Methylation Dynamics in Arabidopsis

    PubMed Central

    Kassam, Mohamed; Duvernois-Berthet, Evelyne; Cortijo, Sandra; Takashima, Kazuya; Saze, Hidetoshi; Toyoda, Atsushi; Fujiyama, Asao; Colot, Vincent; Kakutani, Tetsuji

    2015-01-01

    Epigenetic variations of phenotypes, especially those associated with DNA methylation, are often inherited over multiple generations in plants. The active and inactive chromatin states are heritable and can be maintained or even be amplified by positive feedback in a transgenerational manner. However, mechanisms controlling the transgenerational DNA methylation dynamics are largely unknown. As an approach to understand the transgenerational dynamics, we examined long-term effect of impaired DNA methylation in Arabidopsis mutants of the chromatin remodeler gene DDM1 (Decrease in DNA Methylation 1) through whole genome DNA methylation sequencing. The ddm1 mutation induces a drastic decrease in DNA methylation of transposable elements (TEs) and repeats in the initial generation, while also inducing ectopic DNA methylation at hundreds of loci. Unexpectedly, this ectopic methylation can only be seen after repeated self-pollination. The ectopic cytosine methylation is found primarily in the non-CG context and starts from 3’ regions within transcription units and spreads upstream. Remarkably, when chromosomes with reduced DNA methylation were introduced from a ddm1 mutant into a DDM1 wild-type background, the ddm1-derived chromosomes also induced analogous de novo accumulation of DNA methylation in trans. These results lead us to propose a model to explain the transgenerational DNA methylation redistribution by genome-wide negative feedback. The global negative feedback, together with local positive feedback, would ensure robust and balanced differentiation of chromatin states within the genome. PMID:25902052

  14. Genome-wide negative feedback drives transgenerational DNA methylation dynamics in Arabidopsis.

    PubMed

    Ito, Tasuku; Tarutani, Yoshiaki; To, Taiko Kim; Kassam, Mohamed; Duvernois-Berthet, Evelyne; Cortijo, Sandra; Takashima, Kazuya; Saze, Hidetoshi; Toyoda, Atsushi; Fujiyama, Asao; Colot, Vincent; Kakutani, Tetsuji

    2015-04-01

    Epigenetic variations of phenotypes, especially those associated with DNA methylation, are often inherited over multiple generations in plants. The active and inactive chromatin states are heritable and can be maintained or even be amplified by positive feedback in a transgenerational manner. However, mechanisms controlling the transgenerational DNA methylation dynamics are largely unknown. As an approach to understand the transgenerational dynamics, we examined long-term effect of impaired DNA methylation in Arabidopsis mutants of the chromatin remodeler gene DDM1 (Decrease in DNA Methylation 1) through whole genome DNA methylation sequencing. The ddm1 mutation induces a drastic decrease in DNA methylation of transposable elements (TEs) and repeats in the initial generation, while also inducing ectopic DNA methylation at hundreds of loci. Unexpectedly, this ectopic methylation can only be seen after repeated self-pollination. The ectopic cytosine methylation is found primarily in the non-CG context and starts from 3' regions within transcription units and spreads upstream. Remarkably, when chromosomes with reduced DNA methylation were introduced from a ddm1 mutant into a DDM1 wild-type background, the ddm1-derived chromosomes also induced analogous de novo accumulation of DNA methylation in trans. These results lead us to propose a model to explain the transgenerational DNA methylation redistribution by genome-wide negative feedback. The global negative feedback, together with local positive feedback, would ensure robust and balanced differentiation of chromatin states within the genome.

  15. High trait anxiety is associated with attenuated feedback-related negativity in risky decision making.

    PubMed

    Takács, Ádám; Kóbor, Andrea; Janacsek, Karolina; Honbolygó, Ferenc; Csépe, Valéria; Németh, Dezső

    2015-07-23

    Expectation biases could affect decision making in trait anxiety. Studying the alterations of feedback processing in real-life risk-taking tasks could reveal the presence of expectation biases at the neural level. A functional relevance of the feedback-related negativity (FRN) is the expression of outcome expectation errors. The aim of the study was to investigate whether nonclinical adults with high trait anxiety show smaller FRN for negative feedback than those with low trait anxiety. Participants (N=26) were assigned to low and high trait anxiety groups by a median split on the state-trait anxiety inventory trait score. They performed a balloon analogue risk task (BART) where they pumped a balloon on a screen. Each pump yielded either a reward or a balloon pop. If the balloon popped, the accumulated reward was lost. Participants were matched on their behavioral performance. We measured event-related brain potentials time-locked to the presentation of the feedback (balloon increase or pop). Our results showed that the FRN for balloon pops was decreased in the high anxiety group compared to the low anxiety group. We propose that pessimistic expectations triggered by the ambiguity in the BART decreased outcome expectation errors in the high anxiety group indicated by the smaller FRN. Our results highlight the importance of expectation biases at the neural level of decision making in anxiety.

  16. Range-Expanding Populations of a Globally Introduced Weed Experience Negative Plant-Soil Feedbacks

    PubMed Central

    Andonian, Krikor; Hierro, José L.; Khetsuriani, Liana; Becerra, Pablo; Janoyan, Grigor; Villarreal, Diego; Cavieres, Lohengrin; Fox, Laurel R.; Callaway, Ragan M.

    2011-01-01

    Background Biological invasions are fundamentally biogeographic processes that occur over large spatial scales. Interactions with soil microbes can have strong impacts on plant invasions, but how these interactions vary among areas where introduced species are highly invasive vs. naturalized is still unknown. In this study, we examined biogeographic variation in plant-soil microbe interactions of a globally invasive weed, Centaurea solstitialis (yellow starthistle). We addressed the following questions (1) Is Centaurea released from natural enemy pressure from soil microbes in introduced regions? and (2) Is variation in plant-soil feedbacks associated with variation in Centaurea's invasive success? Methodology/Principal Findings We conducted greenhouse experiments using soils and seeds collected from native Eurasian populations and introduced populations spanning North and South America where Centaurea is highly invasive and noninvasive. Soil microbes had pervasive negative effects in all regions, although the magnitude of their effect varied among regions. These patterns were not unequivocally congruent with the enemy release hypothesis. Surprisingly, we also found that Centaurea generated strong negative feedbacks in regions where it is the most invasive, while it generated neutral plant-soil feedbacks where it is noninvasive. Conclusions/Significance Recent studies have found reduced below-ground enemy attack and more positive plant-soil feedbacks in range-expanding plant populations, but we found increased negative effects of soil microbes in range-expanding Centaurea populations. While such negative feedbacks may limit the long-term persistence of invasive plants, such feedbacks may also contribute to the success of invasions, either by having disproportionately negative impacts on competing species, or by yielding relatively better growth in uncolonized areas that would encourage lateral spread. Enemy release from soil-borne pathogens is not sufficient to

  17. Negative ocean--atmosphere feedback in the South Atlantic Convergence Zone

    NASA Astrophysics Data System (ADS)

    de Almeida, R. F.; Nobre, P.; Haarsma, R. J.; Campos, E. J.

    2007-05-01

    The temporal evolution of the coupled variability between the South Atlantic Convergence Zone (SACZ) and the underlying sea surface temperature (SST) during austral summer is investigated using monthly data from the NCEP/NCAR reanalysis. A maximum covariance analysis shows that the SACZ is intensified [weakened] by warm [cold] SST anomalies in the beginning of summer, drifting northward. This migration is accompanied by the cooling [warming] of the underlying oceanic anomalies. The results confirm earlier analyses using numerical models, and suggest the existence of a negative feedback between the SACZ and the underlying South Atlantic SST field. A linear regression of daily anomalies of SST and omega at 500 hPa to the equations of a stochastic oscillator reveals a negative ocean--atmosphere feedback in the western South Atlantic, stronger during January and February and directly underneath the oceanic band of the SACZ.

  18. Negative ocean-atmosphere feedback in the South Atlantic Convergence Zone

    NASA Astrophysics Data System (ADS)

    De Almeida, R. A. F.; Nobre, P.; Haarsma, R. J.; Campos, E. J. D.

    2007-09-01

    The temporal evolution of the coupled variability between the South Atlantic Convergence Zone (SACZ) and the underlying sea surface temperature (SST) during austral summer is investigated using monthly data from the NCEP/NCAR reanalysis. A maximum covariance analysis shows that the SACZ is intensified [weakened] by warm [cold] SST anomalies in the beginning of summer, drifting northward. This migration is accompanied by the cooling [warming] of the original oceanic anomalies. The results confirm earlier analyses using numerical models that suggest the existence of a negative feedback between the SACZ and the underlying South Atlantic SST field. A linear regression of daily anomalies of SST and omega at 500 hPa to the equations of a stochastic oscillator reveals a negative ocean-atmosphere feedback in the western South Atlantic, stronger during January and February directly underneath the oceanic band of the SACZ.

  19. Coherently amplified negative feedback loop as a model for NF-kappaB oscillations

    NASA Astrophysics Data System (ADS)

    Joo, Jaewook

    2010-03-01

    The cells secrets various signaling molecules as a response to an external signal and modulate its own signaling processes. The precise role of this autocrine and/or paracrine signaling on cell information processing is mostly unknown. We will present the effect of TNF alpha autocrine signaling on NF-kappaB oscillations, using a simplified model of coherently amplified negative feedback loop. We will discuss the bifurcation diagram (i.e., dose-response curve), especially the robustness and the tenability of the period of NF-kappaB oscillations. Finally, we will compare the results from the above model with those from a previous model of time-delayed negative feedback alone.

  20. Prospect theory does not describe the feedback-related negativity value function.

    PubMed

    Sambrook, Thomas D; Roser, Matthew; Goslin, Jeremy

    2012-12-01

    Humans handle uncertainty poorly. Prospect theory accounts for this with a value function in which possible losses are overweighted compared to possible gains, and the marginal utility of rewards decreases with size. fMRI studies have explored the neural basis of this value function. A separate body of research claims that prediction errors are calculated by midbrain dopamine neurons. We investigated whether the prospect theoretic effects shown in behavioral and fMRI studies were present in midbrain prediction error coding by using the feedback-related negativity, an ERP component believed to reflect midbrain prediction errors. Participants' stated satisfaction with outcomes followed prospect theory but their feedback-related negativity did not, instead showing no effect of marginal utility and greater sensitivity to potential gains than losses.

  1. A Self-regulatory System of Interlinked Signaling Feedback Loops Controls Mouse Limb Patterning

    NASA Astrophysics Data System (ADS)

    Benazet, Jean-Denis; Bischofberger, Mirko; Tiecke, Eva; Gonalves, Alexandre; Martin, James F.; Zuniga, Aime; Naef, Felix; Zeller, Rolf

    Developmental pathways need to be robust against environmental and genetic variation to enable reliable morphogenesis. Here, we take a systems biology approach to explain how robustness is achieved in the developing mouse limb, a classical model of organogenesis. By combining quantitative genetics with computational modeling we established a computational model of multiple interlocked feedback modules, involving sonic hedgehog (SHH) morphogen, fibroblast growth factor (FGFs) signaling, bone morphogenetic protein (BMP) and its antagonist GREM1. Earlier modeling work had emphasized the versatile kinetic characteristics of interlocked feedback loops operating at different time scales. Here we develop and then validate a similar computational model to show how BMP4 first initiates and SHH then propagates feedback in the network through differential transcriptional regulation of Grem1 to control digit specification. This switch occurs by linking a fast BMP4/GREM1 module to a slower SHH/GREM1/FGF feedback loop. Simulated gene expression profiles modeled normal limb development as well those of single-gene knockouts. Sensitivity analysis showed how the model was robust and insensitive to variability in parameters. A surprising prediction of the model was that an early Bmp4 signal is essential to kick-start Grem1 expression and the digit specification system. We experimentally validated the prediction using inducible alleles and showed that early, but not late, removal of Bmp4 dramatically disrupted limb development. Sensitivity analysis showed how robustness emerges from this circuitry. This study shows how modeling and computation can help us understand how self-regulatory signaling networks achieve robust regulation of limb development, by exploiting interconnectivity among the three signaling pathways. We expect that similar computational analyses will shed light on the origins of robustness in other developmental systems, and I will discuss some recent examples from

  2. Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling

    PubMed Central

    Nemazanyy, Ivan; Montagnac, Guillaume; Russell, Ryan C.; Morzyglod, Lucille; Burnol, Anne-Françoise; Guan, Kun-Liang; Pende, Mario; Panasyuk, Ganna

    2015-01-01

    Defective hepatic insulin receptor (IR) signalling is a pathogenic manifestation of metabolic disorders including obesity and diabetes. The endo/lysosomal trafficking system may coordinate insulin action and nutrient homeostasis by endocytosis of IR and the autophagic control of intracellular nutrient levels. Here we show that class III PI3K—a master regulator of endocytosis, endosomal sorting and autophagy—provides negative feedback on hepatic insulin signalling. The ultraviolet radiation resistance-associated gene protein (UVRAG)-associated class III PI3K complex interacts with IR and is stimulated by insulin treatment. Acute and chronic depletion of hepatic Vps15, the regulatory subunit of class III PI3K, increases insulin sensitivity and Akt signalling, an effect that requires functional IR. This is reflected by FoxO1-dependent transcriptional defects and blunted gluconeogenesis in Vps15 mutant cells. On depletion of Vps15, the metabolic syndrome in genetic and diet-induced models of insulin resistance and diabetes is alleviated. Thus, feedback regulation of IR trafficking and function by class III PI3K may be a therapeutic target in metabolic conditions of insulin resistance. PMID:26387534

  3. Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women.

    PubMed

    Shaw, N D; Histed, S N; Srouji, S S; Yang, J; Lee, H; Hall, J E

    2010-04-01

    Studies in humans and animals indicate that estrogen negative feedback occurs at the level of the hypothalamus, but it is unclear whether estrogen also exerts an inhibitory effect directly at the pituitary. The aim of the study was to determine whether estrogen has a direct negative feedback effect at the pituitary and whether this varies with aging. A GnRH antagonist and graded doses of GnRH were used to isolate pituitary responsiveness before and after estrogen administration in Clinical Research Center studies at an academic medical center. Subjects were healthy postmenopausal women aged 48-56 yr (n = 8) or 70-75 yr (n= 8). A suppressive dose of the NAL-GLU GnRH antagonist was administered, followed by graded doses of GnRH before and after 1 month of estrogen administration. LH and FSH responses to GnRH decreased after estrogen administration (P = 0.01 and P = 0.0001, respectively). The ratio of FSH to LH amplitudes decreased in response to estrogen (P = 0.04) indicating a greater sensitivity of FSH than LH to inhibition by estrogen. The inhibitory effect of estrogen on FSH was attenuated with aging (P = 0.02), but was maintained for LH (P = 0.4). Studies that control for endogenous GnRH and estradiol demonstrate a direct pituitary site of estrogen negative feedback on LH and FSH responsiveness to GnRH in women. The effect of estrogen on FSH responsiveness is greater than on LH and is attenuated with aging. These studies indicate that estrogen negative feedback occurs directly at the pituitary and contributes to the differential regulation of FSH and LH secretion.

  4. Risky Decision-making from Childhood through Adulthood: Contributions of Learning and Sensitivity to Negative Feedback

    PubMed Central

    Humphreys, Kathryn L.; Telzer, Eva; Flannery, Jessica; Goff, Bonnie; Gabard-Durnam, Laurel; Gee, Dylan G.; Lee, Steve S.; Tottenham, Nim

    2015-01-01

    Decision-making in the context of risk is a complex and dynamic process that changes across development. Here, we assess the influence of learning and sensitivity to negative feedback (i.e., loss) on age-related changes in risky decision-making, both of which can show unique developmental trajectories. The present study examined risky decision-making in 216 individuals, ranging in age from 3–26 years, using the Balloon Emotional Learning Task (BELT), a computerized task in which participants pump up a series of virtual balloons in order to earn points, but risk balloon explosion on each trial which results in no points. Importantly, there were three balloon conditions, signified by different balloon colors, ranging from quick- to slow-to-explode, and participants could learn the color–condition pairings via task experience. Overall, we found age-related increases in pumps made and points earned. However, in the quick-to-explode condition, there was a nonlinear adolescent peak for points earned. Follow-up analyses indicated that this adolescent phenotype occurred at the developmental intersection of linear age-related increases in learning and decreases in sensitivity to negative feedback. Adolescence was marked by intermediate values on both these processes. These findings show that a combination of linearly changing processes can result in non-linear changes in risky decision-making, where adolescent-specific risky decision-making is associated with developmental improvements in learning and reduced sensitivity to negative feedback. PMID:26389647

  5. GTP cyclohydrolase I feedback regulatory protein is expressed in serotonin neurons and regulates tetrahydrobiopterin biosynthesis.

    PubMed

    Kapatos, G; Hirayama, K; Shimoji, M; Milstien, S

    1999-02-01

    Tetrahydrobiopterin, the coenzyme required for hydroxylation of phenylalanine, tyrosine, and tryptophan, regulates its own synthesis through feedback inhibition of GTP cyclohydrolase I (GTPCH) mediated by a regulatory subunit, the GTP cyclohydrolase feedback regulatory protein (GFRP). In the liver, L-phenylalanine specifically stimulates tetrahydrobiopterin synthesis by displacing tetrahydrobiopterin from the GTPCH-GFRP complex. To explore the role of this regulatory system in rat brain, we examined the localization of GFRP mRNA using double-label in situ hybridization. GFRP mRNA expression was abundant in serotonin neurons of the dorsal raphe nucleus but was undetectable in dopamine neurons of the midbrain or norepinephrine neurons of the locus coeruleus. Simultaneous nuclease protection assays for GFRP and GTPCH mRNAs showed that GFRP mRNA is most abundant within the brainstem and that the ratio of GFRP to GTPCH mRNA is much higher than in the ventral midbrain. Two species of GFRP mRNA differing by approximately 20 nucleotides in length were detected in brainstem but not in other tissues, with the longer, more abundant form being common to other brain regions. It is interesting that the pineal and adrenal glands did not contain detectable levels of GFRP mRNA, although GTPCH mRNA was abundant in both. Primary neuronal cultures were used to examine the role of GFRP-mediated regulation of GTPCH on tetrahydrobiopterin synthesis within brainstem serotonin neurons and midbrain dopamine neurons. L-Phenylalanine increased tetrahydrobiopterin levels in serotonin neurons to a maximum of twofold in a concentration-dependent manner, whereas D-phenylalanine and L-tryptophan were without effect. In contrast, tetrahydrobiopterin levels within cultured dopamine neurons were not altered by L-phenylalanine. The time course of this effect was very rapid, with a maximal response observed within 60 min. Inhibitors of tetrahydrobiopterin biosynthesis prevented the L

  6. A double-negative feedback loop between E2F3b and miR- 200b regulates docetaxel chemosensitivity of human lung adenocarcinoma cells

    PubMed Central

    Gao, Yanping; Chen, Longbang; Song, Haizhu; Chen, Yitian; Wang, Rui; Feng, Bing

    2016-01-01

    MicroRNAs (miRNAs) are non-coding small RNAs which negatively regulate gene expressions mainly through 3′-untranslated region (3′-UTR) binding of target mRNAs. Recent studies have highlighted the feedback loops between miRNAs and their target genes in physiological and pathological processes including chemoresistance of cancers. Our previous study identified miR-200b/E2F3 axis as a chemosensitivity restorer of human lung adenocarcinoma (LAD) cells. Moreover, E2F3b was bioinformatically proved to be a potential transcriptional regulator of pre-miR-200b gene promoter. The existance of this double-negative feedback minicircuitry comprising E2F3b and miR-200b was confirmed by chromatin immunoprecipitation (ChIP) assay, site-specific mutation and luciferase reporter assay. And the underlying regulatory mechanisms of this feedback loop on docetaxel resistance of LAD cells were further investigated by applying in vitro chemosensitivity assay, colony formation assay, flow cytometric analysis of cell cycle and apoptosis, as well as mice xenograft model. In conclusion, our results suggest that the double-negative feedback loop between E2F3b and miR-200b regulates docetaxel chemosensitivity of human LAD cells mainly through cell proliferation, cell cycle distribution and apoptosis. PMID:27027446

  7. The feedback-related negativity reflects “more or less” prediction error in appetitive and aversive conditions

    PubMed Central

    Huang, Yi; Yu, Rongjun

    2014-01-01

    Humans make predictions and use feedback to update their subsequent predictions. The feedback-related negativity (FRN) has been found to be sensitive to negative feedback as well as negative prediction error, such that the FRN is larger for outcomes that are worse than expected. The present study examined prediction errors in both appetitive and aversive conditions. We found that the FRN was more negative for reward omission vs. wins and for loss omission vs. losses, suggesting that the FRN might classify outcomes in a “more-or-less than expected” fashion rather than in the “better-or-worse than expected” dimension. Our findings challenge the previous notion that the FRN only encodes negative feedback and “worse than expected” negative prediction error. PMID:24904254

  8. BLOWIN' IN THE WIND: BOTH ''NEGATIVE'' AND ''POSITIVE'' FEEDBACK IN AN OBSCURED HIGH-z QUASAR

    SciTech Connect

    Cresci, G.; Mannucci, F.; Mainieri, V.; Brusa, M.; Perna, M.; Lanzuisi, G.; Piconcelli, E.; Feruglio, C.; Fiore, F.; Bongiorno, A.; Maiolino, R.; Merloni, A; Schramm, M.; Silverman, J. D.; Civano, F.

    2015-01-20

    Quasar feedback in the form of powerful outflows is invoked as a key mechanism to quench star formation in galaxies, preventing massive galaxies to overgrow and producing the red colors of ellipticals. On the other hand, some models are also requiring ''positive'' active galactic nucleus feedback, inducing star formation in the host galaxy through enhanced gas pressure in the interstellar medium. However, finding observational evidence of the effects of both types of feedback is still one of the main challenges of extragalactic astronomy, as few observations of energetic and extended radiatively driven winds are available. Here we present SINFONI near infrared integral field spectroscopy of XID2028, an obscured, radio-quiet z = 1.59 QSO detected in the XMM-COSMOS survey, in which we clearly resolve a fast (1500 km s{sup –1}) and extended (up to 13 kpc from the black hole) outflow in the [O III] lines emitting gas, whose large velocity and outflow rate are not sustainable by star formation only. The narrow component of Hα emission and the rest frame U-band flux from Hubble Space Telescope/Advanced Camera for Surveys imaging enable to map the current star formation in the host galaxy: both tracers independently show that the outflow position lies in the center of an empty cavity surrounded by star forming regions on its edge. The outflow is therefore removing the gas from the host galaxy (''negative feedback''), but also triggering star formation by outflow induced pressure at the edges (''positive feedback''). XID2028 represents the first example of a host galaxy showing both types of feedback simultaneously at work.

  9. REVEILLE8 and PSEUDO-REPONSE REGULATOR5 Form a Negative Feedback Loop within the Arabidopsis Circadian Clock

    PubMed Central

    Rawat, Reetika; Jones, Matthew A.; Schwartz, Jacob; Salemi, Michelle R.; Phinney, Brett S.; Harmer, Stacey L.

    2011-01-01

    Circadian rhythms provide organisms with an adaptive advantage, allowing them to regulate physiological and developmental events so that they occur at the most appropriate time of day. In plants, as in other eukaryotes, multiple transcriptional feedback loops are central to clock function. In one such feedback loop, the Myb-like transcription factors CCA1 and LHY directly repress expression of the pseudoresponse regulator TOC1 by binding to an evening element (EE) in the TOC1 promoter. Another key regulatory circuit involves CCA1 and LHY and the TOC1 homologs PRR5, PRR7, and PRR9. Purification of EE–binding proteins from plant extracts followed by mass spectrometry led to the identification of RVE8, a homolog of CCA1 and LHY. Similar to these well-known clock genes, expression of RVE8 is circadian-regulated with a dawn phase of expression, and RVE8 binds specifically to the EE. However, whereas cca1 and lhy mutants have short period phenotypes and overexpression of either gene causes arrhythmia, rve8 mutants have long-period and RVE8-OX plants have short-period phenotypes. Light input to the clock is normal in rve8, but temperature compensation (a hallmark of circadian rhythms) is perturbed. RVE8 binds to the promoters of both TOC1 and PRR5 in the subjective afternoon, but surprisingly only PRR5 expression is perturbed by overexpression of RVE8. Together, our data indicate that RVE8 promotes expression of a subset of EE–containing clock genes towards the end of the subjective day and forms a negative feedback loop with PRR5. Thus RVE8 and its homologs CCA1 and LHY function close to the circadian oscillator but act via distinct molecular mechanisms. PMID:21483796

  10. Multiple feedback loop design in the tryptophan regulatory network of Escherichia coli suggests a paradigm for robust regulation of processes in series

    PubMed Central

    Bhartiya, Sharad; Chaudhary, Nikhil; Venkatesh, K.V; Doyle, Francis J

    2005-01-01

    Biological networks have evolved through adaptation in uncertain environments. Of the different possible design paradigms, some may offer functional advantages over others. These designs can be quantified by the structure of the network resulting from molecular interactions and the parameter values. One may, therefore, like to identify the design motif present in the evolved network that makes it preferable over other alternatives. In this work, we focus on the regulatory networks characterized by serially arranged processes, which are regulated by multiple feedback loops. Specifically, we consider the tryptophan system present in Escherichia coli, which may be conceptualized as three processes in series, namely transcription, translation and tryptophan synthesis. The multiple feedback loop motif results from three distinct negative feedback loops, namely genetic repression, mRNA attenuation and enzyme inhibition. A framework is introduced to identify the key design components of this network responsible for its physiological performance. We demonstrate that the multiple feedback loop motif, as seen in the tryptophan system, enables robust performance to variations in system parameters while maintaining a rapid response to achieve homeostasis. Superior performance, if arising from a design principle, is intrinsic and, therefore, inherent to any similarly designed system, either natural or engineered. An experimental engineering implementation of the multiple feedback loop design on a two-tank system supports the generality of the robust attributes offered by the design. PMID:16849267

  11. The association of positive and negative feedback with clinical performance, self-evaluation and practice contribution of nursing students.

    PubMed

    Plakht, Ygal; Shiyovich, Arthur; Nusbaum, Lika; Raizer, Haya

    2013-10-01

    Providing consistent and high-quality feedback is a crucial component of clinical instruction. Such feedback can improve the students' ability to reflect themselves more accurately. However, giving feedback, especially negative is intricate. To evaluate the level of feedback provided to nursing students during clinical practice and investigate their association with related outcomes, such us clinical performance, self-evaluation of achievements and contribution of the practice to the professional skills. Cross-sectional study. 124 third-year nursing students during their "Emergency Nursing" (EN) clinical practice were instructed, criticized and graded by three teachers from the university staff. Following their clinical practice the students filled-out a questionnaire, in which they evaluated the feedback provided by their teachers, the contribution of the practice to their professional skills and their personal performance. Additionally, the teachers' grades of students' achievements were collected. Accuracy of students' self-evaluation was calculated as the arithmetical difference between the students' grades and the teachers' grades. The mean grades of positive and negative feedback were 74.5/100 and 70.7/100, respectively. Higher-quality positive feedback was associated with higher teachers' grade (p=0.027) and with "very high" evaluation of the contribution of the practice (p=0.022). Higher-quality positive feedback was associated with student's over-self-evaluation (p=0.02), whereas higher-quality negative feedback was associated with more accurate self-evaluation (p=0.015). High-quality positive feedback is associated with higher grades, higher contribution of the clinical practice to the student and over-self-evaluation whereas high-quality negative feedback is related to an accurate self evaluation of the students' performance. Teachers should pay more attention to administering high-quality positive and negative feedback. Copyright © 2012 Elsevier Ltd

  12. Feeling Better About Self After Receiving Negative Feedback: When the Sense That Ability Can Be Improved Is Activated.

    PubMed

    Hu, Xinyi; Chen, Yinghe; Tian, Baowei

    2016-01-01

    Past studies suggest that managers and educators often consider negative feedback as a motivator for individuals to think about their shortcomings and improve their work, but delivering negative feedback does not always achieve desired results. The present study, based on incremental theory, employed an intervention method to activate the belief that a particular ability could be improved after negative feedback. Three experiments tested the intervention effect on negative self-relevant emotion. Study 1 indicated conveying suggestions for improving ability reduced negative self-relevant emotion after negative feedback. Study 2 tested whether activating the sense of possible improvement in the ability could reduce negative self-relevant emotion. Results indicated activating the belief that ability could be improved reduced negative self-relevant emotion after failure, but delivering emotion management information alone did not yield the same effect. Study 3 extended the results by affirming the effort participants made in doing the test, and found the affirmation reduced negative self-relevant emotion. Collectively, the findings indicated focusing on the belief that the ability could be improved in the future can reduce negative self-relevant emotion after negative feedback.

  13. The Role of Outcome Expectations in the Generation of the Feedback-related Negativity

    PubMed Central

    Bismark, Andrew W.; Hajcak, Greg; Whitworth, Nicole M.; Allen, John J.B.

    2012-01-01

    The Feedback-related Negativity (FRN) is thought to index activity within the midbrain dopaminergic reward-learning system, with larger FRN magnitudes observed when outcomes are worse than expected. This view holds that the FRN is an index of neural activity coding for prediction errors, and reflects activity that can be used to adaptively alter future performance. Untested to date, however, is a key prediction of this view: the FRN should not appear in response to negative outcomes when outcome expectations are not allowed to develop. The current study tests this assumption by eliciting FRNs to win and loss feedback in conditions of participant choice, participant observation of computer choice, and critically, simple presentation of win or loss feedback in the absence of a predictive choice cue. Whereas FRNs were observed in each of the conditions in which there was time for an expectation to develop, no FRN was observed in conditions without sufficient time for the development of an expectation. These results provide empirical support for an untested but central tenet of the reinforcement learning account of the genesis of the FRN. PMID:23153354

  14. Negative feedback in ants: crowding results in less trail pheromone deposition.

    PubMed

    Czaczkes, Tomer J; Grüter, Christoph; Ratnieks, Francis L W

    2013-04-06

    Crowding in human transport networks reduces efficiency. Efficiency can be increased by appropriate control mechanisms, which are often imposed externally. Ant colonies also have distribution networks to feeding sites outside the nest and can experience crowding. However, ants do not have external controllers or leaders. Here, we report a self-organized negative feedback mechanism, based on local information, which downregulates the production of recruitment signals in crowded parts of a network by Lasius niger ants. We controlled crowding by manipulating trail width and the number of ants on a trail, and observed a 5.6-fold reduction in the number of ants depositing trail pheromone from least to most crowded conditions. We also simulated crowding by placing glass beads covered in nest-mate cuticular hydrocarbons on the trail. After 10 bead encounters over 20 cm, forager ants were 45 per cent less likely to deposit pheromone. The mechanism of negative feedback reported here is unusual in that it acts by downregulating the production of a positive feedback signal, rather than by direct inhibition or the production of an inhibitory signal.

  15. Negative feedback in ants: crowding results in less trail pheromone deposition

    PubMed Central

    Czaczkes, Tomer J.; Grüter, Christoph; Ratnieks, Francis L. W.

    2013-01-01

    Crowding in human transport networks reduces efficiency. Efficiency can be increased by appropriate control mechanisms, which are often imposed externally. Ant colonies also have distribution networks to feeding sites outside the nest and can experience crowding. However, ants do not have external controllers or leaders. Here, we report a self-organized negative feedback mechanism, based on local information, which downregulates the production of recruitment signals in crowded parts of a network by Lasius niger ants. We controlled crowding by manipulating trail width and the number of ants on a trail, and observed a 5.6-fold reduction in the number of ants depositing trail pheromone from least to most crowded conditions. We also simulated crowding by placing glass beads covered in nest-mate cuticular hydrocarbons on the trail. After 10 bead encounters over 20 cm, forager ants were 45 per cent less likely to deposit pheromone. The mechanism of negative feedback reported here is unusual in that it acts by downregulating the production of a positive feedback signal, rather than by direct inhibition or the production of an inhibitory signal. PMID:23365196

  16. Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein.

    PubMed

    Werner, Ernst R; Bahrami, Soheyl; Heller, Regine; Werner-Felmayer, Gabriele

    2002-03-22

    GTP cyclohydrolase I feedback regulatory protein (GFRP) is a 9.7-kDa protein regulating GTP cyclohydrolase I activity in dependence of tetrahydrobiopterin and phenylalanine concentrations, thus enabling stimulation of tetrahydrobiopterin biosynthesis by phenylalanine to ensure its efficient metabolism by phenylalanine hydroxylase. Here, we were interested in regulation of GFRP expression by proinflammatory cytokines and stimuli, which are known to induce GTP cyclohydrolase I expression. Recombinant human GFRP stimulated recombinant human GTP cyclohydrolase I in the presence of phenylalanine and mediated feedback inhibition by tetrahydrobiopterin. Levels of GFRP mRNA in human myelomonocytoma (THP-1) cells remained unaltered by treatment of cells with interferon-gamma or interleukin-1beta, but were significantly down-regulated by bacterial lipopolysaccharide (LPS, 1 microg/ml), without or with cotreatment by interferon-gamma, which strongly up-regulated GTP cyclohydrolase I expression and activity. GFRP expression was also suppressed in human umbilical vein endothelial cells treated with 1 microg/ml LPS, as well as in rat tissues 7 h post intraperitoneal injection of 10 mg/kg LPS. THP-1 cells stimulated with interferon-gamma alone showed increased pteridine synthesis by addition of phenylalanine to the culture medium. Cells stimulated with interferon-gamma plus LPS, in contrast, showed phenylalanine-independent pteridine synthesis. These results demonstrate that LPS down-regulates expression of GFRP, thus rendering pteridine synthesis independent of metabolic control by phenylalanine.

  17. GTP cyclohydrolase I feedback regulatory protein-dependent and -independent inhibitors of GTP cyclohydrolase I.

    PubMed

    Yoneyama, T; Wilson, L M; Hatakeyama, K

    2001-04-01

    GTP cyclohydrolase I feedback regulatory protein (GFRP) mediates the feedback inhibition of GTP cyclohydrolase I activity by (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) through protein complex formation. Since guanine and BH4 have a common pyrimidine ring structure, we examined the inhibitory effect of guanine and its analogs on the enzyme activity. Guanine, 8-hydroxyguanine, 8-methylguanine, and 8-bromoguanine inhibited the enzyme activity in a GFRP-dependent and pH-dependent manner and induced complex formation between GTP cyclohydrolase I and GFRP. The type of inhibition by this group is a mixed type. All these properties were shared with BH4. In striking contrast, inhibition by 8-azaguanine and 8-mercaptoguanine was GFRP-independent and pH-independent. The type of inhibition by 8-azaguanine and 8-mercaptoguanine was a competitive type. The two compounds did not induce complex formation between the enzyme and GFRP. These results demonstrate that guanine compounds of the first group bind to the BH4-binding site of the GTP cyclohydrolase I/GFRP complex, whereas 8-azaguanine and 8-mercaptoguanine bind to the active site of the enzyme. Finally, the possible implications in Lesch-Nyhan syndrome and Parkinson diseases of the inhibition of GTP cyclohydrolase I by guanine and 8-hydroxyguanine are discussed.

  18. A Cell-Regulatory Mechanism Involving Feedback between Contraction and Tissue Formation Guides Wound Healing Progression

    PubMed Central

    Valero, Clara; Javierre, Etelvina; García-Aznar, José Manuel; Gómez-Benito, María José

    2014-01-01

    Wound healing is a process driven by cells. The ability of cells to sense mechanical stimuli from the extracellular matrix that surrounds them is used to regulate the forces that cells exert on the tissue. Stresses exerted by cells play a central role in wound contraction and have been broadly modelled. Traditionally, these stresses are assumed to be dependent on variables such as the extracellular matrix and cell or collagen densities. However, we postulate that cells are able to regulate the healing process through a mechanosensing mechanism regulated by the contraction that they exert. We propose that cells adjust the contraction level to determine the tissue functions regulating all main activities, such as proliferation, differentiation and matrix production. Hence, a closed-regulatory feedback loop is proposed between contraction and tissue formation. The model consists of a system of partial differential equations that simulates the evolution of fibroblasts, myofibroblasts, collagen and a generic growth factor, as well as the deformation of the extracellular matrix. This model is able to predict the wound healing outcome without requiring the addition of phenomenological laws to describe the time-dependent contraction evolution. We have reproduced two in vivo experiments to evaluate the predictive capacity of the model, and we conclude that there is feedback between the level of cell contraction and the tissue regenerated in the wound. PMID:24681636

  19. HIC1 and miR-23~27~24 clusters form a double-negative feedback loop in breast cancer

    PubMed Central

    Wang, Yanbo; Liang, Hongwei; Zhou, Geyu; Hu, Xiuting; Liu, Zhengya; Jin, Fangfang; Yu, Mengchao; Sang, Jianfeng; Zhou, Yong; Fu, Zheng; Zhang, Chen-Yu; Zhang, Weijie; Zen, Ke; Chen, Xi

    2017-01-01

    MicroRNAs (miRNAs) have emerged as a major regulator of the initiation and progression of human cancers, including breast cancer. However, the cooperative effects and transcriptional regulation of multiple miRNAs, especially miRNAs that are present in clusters, remain largely undiscovered. Here we showed that all members of the miR-23~27~24 clusters are upregulated and function as oncogenes in breast cancer and simultaneously target HIC1. Furthermore, we found that HIC1 functions as a transcriptional repressor to negatively control the expression of miR-23~27~24 clusters and forms a double-negative (overall positive) feedback loop. This feedback regulatory pathway is important because overexpression of miR-23~27~24 clusters can remarkably accelerate tumor growth, whereas restoration of HIC1 significantly blocks tumor growth in vivo. A mathematical model was created to quantitatively illustrate the regulatory circuit. Our finding highlights the cooperative effects of miRNAs in a cluster and adds another layer of complexity to the miRNA regulatory network. This study may also provide insight into the molecular mechanisms of breast cancer progression. PMID:28009350

  20. Learning from positive and negative monetary feedback in patients with alcohol dependence.

    PubMed

    Rustemeier, Martina; Römling, Juliane; Czybulka, Christine; Reymann, Gerhard; Daum, Irene; Bellebaum, Christian

    2012-06-01

    Chronic and excessive consumption of alcohol is associated with structural, physiological, and functional changes in multiple regions of the human brain including the prefrontal cortex, the medial temporal lobe, and the structures of the reward system. The present study aimed to assess the ability of alcohol-dependent patients (ADP) to learn probabilistic stimulus-reward contingencies and to transfer the acquired knowledge to new contexts. During transfer, the relative preference to learn from positive or negative feedback was also assessed. Twenty-four recently detoxified ADP and 20 healthy controls engaged in a feedback learning task with monetary rewards. The learning performance per se and transfer performance including positive versus negative learning were examined, as well as the relationship between different learning variables and variables comprising alcohol and nicotine consumption patterns, depression, and personality traits (harm avoidance and impulsivity). Patients did not show a significant general learning deficit in the acquisition of stimulus-response-outcome associations. Fifteen healthy subjects and 13 patients reached the transfer phase, in which ADP showed generally lower performance than healthy controls. There was no specific deficit with regard to learning from positive or negative feedback. The only near-significant (negative) correlation between learning variables and drug consumption patterns, depression, and personality traits emerged for harm avoidance and positive learning in controls. Impaired transfer performance suggests that ADP had problems applying their acquired knowledge in a new context. Potential relations to dysfunctions of specific brain structures and implications of the finding for therapy are discussed. Copyright © 2012 by the Research Society on Alcoholism.

  1. Autoregulatory feedback controls sequential action of cis-regulatory modules at the brinker locus.

    PubMed

    Dunipace, Leslie; Saunders, Abbie; Ashe, Hilary L; Stathopoulos, Angelike

    2013-09-16

    cis-regulatory modules (CRMs) act sequentially to regulate temporal expression of genes, but how the switch from one to the next is accomplished is not well understood. To provide insight, here we investigate the cis-regulatory system controlling brinker (brk) expression in the Drosophila embryo. Two distally located CRMs support expression at different times, while a promoter-proximal element (PPE) is required to support their action. In the absence of Brk protein itself or upon mutagenesis of Brk binding sites within the PPE, the late-acting CRM, specifically, is delayed. This block to late-acting CRM function appears to be removed when the early-acting CRM is also deleted. These results demonstrate that autoregulatory feedback is necessary for the early-acting CRM to disengage from the promoter so that the late-acting CRM may act. Autoregulation may be a commonly used mechanism to control sequential CRM action necessary for dynamic gene expression throughout the course of development. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Autoregulatory Feedback Controls Sequential Action of cis-Regulatory Modules at the brinker Locus

    PubMed Central

    Dunipace, Leslie; Saunders, Abbie; Ashe, Hilary L.; Stathopoulos, Angelike

    2013-01-01

    Summary cis-regulatory modules (CRMs) act sequentially to regulate temporal expression of genes, but how the switch from one to the next is accomplished is not well understood. To provide insight, here we investigate the cis-regulatory system controlling brinker (brk) expression in the Drosophila embryo. Two distally located CRMs support expression at different times, while a promoter-proximal element (PPE) is required to support their action. In the absence of Brk protein itself or upon mutagenesis of Brk binding sites within the PPE, the late-acting CRM, specifically, is delayed. This block to late-acting CRM function appears to be removed when the early-acting CRM is also deleted. These results demonstrate that autoregulatory feedback is necessary for the early-acting CRM to disengage from the promoter so that the late-acting CRM may act. Autoregulation may be a commonly used mechanism to control sequential CRM action necessary for dynamic gene expression throughout the course of development. PMID:24044892

  3. Universal attenuators and their interactions with feedback loops in gene regulatory networks

    PubMed Central

    Liu, Dianbo; Albergante, Luca

    2017-01-01

    Abstract Using a combination of mathematical modelling, statistical simulation and large-scale data analysis we study the properties of linear regulatory chains (LRCs) within gene regulatory networks (GRNs). Our modelling indicates that downstream genes embedded within LRCs are highly insulated from the variation in expression of upstream genes, and thus LRCs act as attenuators. This observation implies a progressively weaker functionality of LRCs as their length increases. When analyzing the preponderance of LRCs in the GRNs of Escherichia coli K12 and several other organisms, we find that very long LRCs are essentially absent. In both E. coli and M. tuberculosis we find that four-gene LRCs are intimately linked to identical feedback loops that are involved in potentially chaotic stress response, indicating that the dynamics of these potentially destabilising motifs are strongly restrained under homeostatic conditions. The same relationship is observed in a human cancer cell line (K562), and we postulate that four-gene LRCs act as ‘universal attenuators’. These findings suggest a role for long LRCs in dampening variation in gene expression, thereby protecting cell identity, and in controlling dramatic shifts in cell-wide gene expression through inhibiting chaos-generating motifs. PMID:28575450

  4. Evidence for a negative cloud longwave radiative feedback that weakens the annular mode variability

    NASA Astrophysics Data System (ADS)

    Li, Y.; Thompson, D. W. J.

    2016-12-01

    Southern and northern annular modes are prominent modes of large-scale interannual variability in the extratropics. The variability of annular modes has been widely examined in the context of dry atmospheric dynamics but less so in the context of two-way interactions with clouds. Previous results suggest that cloud radiative effect (CRE) have impact on the long-term mean circulation in both troposphere and stratosphere, and CRE may short the time scale of the North Atlantic Oscillation. Here we use numerical expriments which disable the cloud radiative feedbacks on the circulation to support the idea that cloud may regulate unforced climate variability. We found that cloud longwave radiative effects have a negative feedback that weakens the annular mode variability by 30-50% on month-to-month timescales. The possible physical processes by which cloud radiative effects impact the variability are investigated. Implications for trends in the large-scale atmospheric circulation in a warmer climate are discussed.

  5. Response to "The Iris Hypothesis: A Negative or Positive Cloud Feedback?"

    NASA Technical Reports Server (NTRS)

    Chou, Ming-Dah; Lindzen, Richard S.; Hou, Arthur Y.; Lau, William K. M. (Technical Monitor)

    2001-01-01

    Based on radiance measurements of Japan's Geostationary Meteorological Satellite, Lindzen et al. found that the high-level cloud cover averaged over the tropical western Pacific decreases with increasing sea surface temperature. They further found that the response of high-level clouds to the sea surface temperature had an effect of reducing the magnitude of climate change, which is referred as a negative climate feedback. Lin et al. reassessed the results found by Lindzen et al. by analyzing the radiation and clouds derived from the Tropical Rainfall Measuring Mission Clouds and the Earth's Radiant Energy System measurements. They found a weak positive feedback between high-level clouds and the surface temperature. We have found that the approach taken by Lin et al. to estimating the albedo and the outgoing longwave radiation is incorrect and that the inferred climate sensitivity is unreliable.

  6. Withholding negative feedback: is it about protecting the self or protecting others?

    PubMed

    Jeffries, Carla H; Hornsey, Matthew J

    2012-12-01

    The reluctance to deliver negative feedback to someone's face is widely documented. This research disentangles the extent to which this reluctance is motivated by a desire to protect the self as opposed to others. Participants assessed an essay written by someone with high, medium, or low self-esteem. Assessment of the essay was most positive when the feedback was to be provided face-to-face, less positive when delivered anonymously, and least positive when it was not required to be delivered at all. This effect only emerged among participants low in self-liking (but was unrelated to self-competency). The self-esteem of the essay writer had no effect on evaluations. The data lend support for a self-protection motive and modest support for an other-protection motive. ©2012 The British Psychological Society.

  7. Examination of a perceived cost model of employees' negative feedback-seeking behavior.

    PubMed

    Lu, Kuo-Ming; Pan, Su-Ying; Cheng, Jen-Wei

    2011-01-01

    The present study extends the feedback-seeking behavior literature by investigating how supervisor-related antecedents (i.e., supervisors' expert power, reflected appraisals of supervisors, and supervisors' emotional intelligence) influence subordinates' negative feedback-seeking behavior (NFSB) through different cost/value perceptions (i.e., expectancy value, self-presentation cost, and ego cost). Using data collected from 216 supervisor-subordinate dyads from various industries in Taiwan, we employ structural equation modeling analysis to test our hypotheses. The results show that expectancy value mediates the relationship between supervisor expert power and subordinates' NFSB. Moreover, self-presentation cost mediates the relationship between reflected appraisals of supervisors' and subordinates' NFSB. Theoretical and practical implications of this study are also discussed.

  8. A novel TGFβ modulator that uncouples R-Smad/I-Smad-mediated negative feedback from R-Smad/ligand-driven positive feedback.

    PubMed

    Gu, Wenchao; Monteiro, Rui; Zuo, Jie; Simões, Filipa Costa; Martella, Andrea; Andrieu-Soler, Charlotte; Grosveld, Frank; Sauka-Spengler, Tatjana; Patient, Roger

    2015-02-01

    As some of the most widely utilised intercellular signalling molecules, transforming growth factor β (TGFβ) superfamily members play critical roles in normal development and become disrupted in human disease. Establishing appropriate levels of TGFβ signalling involves positive and negative feedback, which are coupled and driven by the same signal transduction components (R-Smad transcription factor complexes), but whether and how the regulation of the two can be distinguished are unknown. Genome-wide comparison of published ChIP-seq datasets suggests that LIM domain binding proteins (Ldbs) co-localise with R-Smads at a substantial subset of R-Smad target genes including the locus of inhibitory Smad7 (I-Smad7), which mediates negative feedback for TGFβ signalling. We present evidence suggesting that zebrafish Ldb2a binds and directly activates the I-Smad7 gene, whereas it binds and represses the ligand gene, Squint (Sqt), which drives positive feedback. Thus, the fine tuning of TGFβ signalling derives from positive and negative control by Ldb2a. Expression of ldb2a is itself activated by TGFβ signals, suggesting potential feed-forward loops that might delay the negative input of Ldb2a to the positive feedback, as well as the positive input of Ldb2a to the negative feedback. In this way, precise gene expression control by Ldb2a enables an initial build-up of signalling via a fully active positive feedback in the absence of buffering by the negative feedback. In Ldb2a-deficient zebrafish embryos, homeostasis of TGFβ signalling is perturbed and signalling is stably enhanced, giving rise to excess mesoderm and endoderm, an effect that can be rescued by reducing signalling by the TGFβ family members, Nodal and BMP. Thus, Ldb2a is critical to the homeostatic control of TGFβ signalling and thereby embryonic patterning.

  9. Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

    PubMed Central

    van Staveren, Wilma C. G.; Solís, David Weiss; Delys, Laurent; Venet, David; Cappello, Matteo; Andry, Guy; Dumont, Jacques E.; Libert, Frédérick; Detours, Vincent; Maenhaut, Carine

    2006-01-01

    The cAMP signaling pathway regulates growth of many cell types, including somatotrophs, thyrocytes, melanocytes, ovarian follicular granulosa cells, adrenocortical cells, and keratinocytes. Mutations of partners from the cAMP signaling cascade are involved in tumor formation. Thyroid-stimulating hormone (TSH) receptor and Gsα activating mutations have been detected in thyroid autonomous adenomas, Gsα mutations in growth hormone-secreting pituitary adenomas, and PKAR1A mutations in Carney complex, a multiple neoplasia syndrome. To gain more insight into the role of cAMP signaling in tumor formation, human primary cultures of thyrocytes were treated for different times (1.5, 3, 16, 24, and 48 h) with TSH to characterize modulations in gene expression using cDNA microarrays. This kinetic study showed a clear difference in expression, early (1.5 and 3 h) and late (16–48 h) after the onset of TSH stimulation. This result suggests a progressive sequential process leading to a change of cell program. The gene expression profile of the long-term stimulated cultures resembled the autonomous adenomas, but not papillary carcinomas. The molecular phenotype of the adenomas thus confirms the role of long-term stimulation of the TSH–cAMP cascade in the pathology. TSH induced a striking up-regulation of different negative feedback modulators of the cAMP cascade, presumably insuring the one-shot effect of the stimulus. Some were down- or nonregulated in adenomas, suggesting a loss of negative feedback control in the tumors. These results suggest that in tumorigenesis, activation of proliferation pathways may be complemented by suppression of multiple corresponding negative feedbacks, i.e., specific tumor suppressors. PMID:16381821

  10. Negative plant-soil feedbacks may limit persistence of an invasive tree due to rapid accumulation of soil pathogens.

    PubMed

    Nijjer, Somereet; Rogers, William E; Siemann, Evan

    2007-10-22

    Soil organisms influence plant species coexistence and invasion potential. Plant-soil feedbacks occur when plants change soil community composition such that interactions with that soil community in turn may positively or negatively affect the performance of conspecifics. Theories predict and studies show that invasions may be promoted by stronger negative soil feedbacks for native compared with exotic species. We present a counter-example of a successful invader with strong negative soil feedbacks apparently caused by host-specific, pathogenic soil fungi. Using a feedback experiment in pots, we investigated whether the relative strength of plant-soil feedbacks experienced by a non-native woody invader, Sapium sebiferum, differed from several native tree species by examining their performance in soils collected near conspecifics ('home soils') or heterospecifics ('away soils') in the introduced range. Sapium seedlings, but no native seedlings, had lower survival and biomass in its home soils compared with soils of other species (negative feedback'). To investigate biotic agents potentially responsible for the observed negative feedbacks, we conducted two additional experiments designed to eliminate different soil taxa ('rescue experiments'). We found that soil sterilization (pot experiment ) or soil fungicide applications (pot and field experiments) restored Sapium performance in home soil thereby eliminating the negative feedbacks we observed in the original experiment. Such negative feedbacks apparently mediated by soil fungi could have important effects on persistence of this invader by limiting Sapium seedling success in Sapium dominated forests (home soils) though their weak effects in heterospecific (away) soils suggest a weak role in limiting initial establishment.

  11. Conditions for Global Stability of Monotone Tridiagonal Systems with Negative Feedback

    PubMed Central

    Wang, Liming; Leenheer, Patrick De; Sontag, Eduardo D.

    2010-01-01

    This paper studies monotone tridiagonal systems with negative feedback. These systems possess the Poincaré-Bendixson property, which implies that, if orbits are bounded, if there is a unique steady state and this unique steady state is asymptotically stable, and if one can rule out periodic orbits, then the steady state is globally asymptotically stable. Two different approaches are discussed to rule out period orbits, one based on direct linearization and another one based on the theory of second additive compound matrices. Among the examples that illustrate the theoretical results is the classical Goldbeter model of the circadian rhythm. PMID:20711508

  12. Acute Stress Modulates Feedback Processing in Men and Women: Differential Effects on the Feedback-Related Negativity and Theta and Beta Power

    PubMed Central

    Banis, Stella; Geerligs, Linda; Lorist, Monicque M.

    2014-01-01

    Sex-specific prevalence rates in mental and physical disorders may be partly explained by sex differences in physiological stress responses. Neural networks that might be involved are those underlying feedback processing. Aim of the present EEG study was to investigate whether acute stress alters feedback processing, and whether stress effects differ between men and women. Male and female participants performed a gambling task, in a control and a stress condition. Stress was induced by exposing participants to a noise stressor. Brain activity was analyzed using both event-related potential and time-frequency analyses, measuring the feedback-related negativity (FRN) and feedback-related changes in theta and beta oscillatory power, respectively. While the FRN and feedback-related theta power were similarly affected by stress induction in both sexes, feedback-related beta power depended on the combination of stress induction condition and sex. FRN amplitude and theta power increases were smaller in the stress relative to the control condition in both sexes, demonstrating that acute noise stress impairs performance monitoring irrespective of sex. However, in the stress but not in the control condition, early lower beta-band power increases were larger for men than women, indicating that stress effects on feedback processing are partly sex-dependent. Our findings suggest that sex-specific effects on feedback processing may comprise a factor underlying sex-specific stress responses. PMID:24755943

  13. [On efficiency of biomanagement with negative feedback from patient's EEG in correction of functional disorders, caused by stress].

    PubMed

    Fedotchev, A I

    2010-01-01

    The perspective approach to non-pharmacological correction of the stress induced functional disorders in humans, based on the double negative feedback from patient's EEG was validated and experimentally tested. The approach implies a simultaneous use of narrow frequency EEG-oscillators, characteristic for each patient and recorded in real time span, in two independent contours of negative feedback--traditional contour of adaptive biomanagement and additional contour of resonance stimulation. In the last the signals of negative feedback from individual narrow frequency EEG oscillators are not recognized by the subject, but serve for an automatic modulation of the parameters of the sensory impact. Was shown that due to combination of active (conscious perception) and passive (automatic modulation) use of signals of negative feedback from narrow frequency EEG components of the patient, opens a possibility of considerable increase of efficiency of the procedures of EEG biomanagement.

  14. Impact of time delays on oscillatory dynamics of interlinked positive and negative feedback loops

    NASA Astrophysics Data System (ADS)

    Huang, Bo; Tian, Xinyu; Liu, Feng; Wang, Wei

    2016-11-01

    Interlinking a positive feedback loop (PFL) with a negative feedback loop (NFL) constitutes a typical motif in genetic networks, performing various functions in cell signaling. How time delay in feedback regulation affects the dynamics of such systems still remains unclear. Here, we investigate three systems of interlinked PFL and NFL with time delays: a synthetic genetic oscillator, a three-node circuit, and a simplified single-node model. The stability of steady states and the routes to oscillation in the single-node model are analyzed in detail. The amplitude and period of oscillations vary with a pointwise periodicity over a range of time delay. Larger-amplitude oscillations can be induced when the PFL has an appropriately long delay, in comparison with the PFL with no delay or short delay; this conclusion holds true for all the three systems. We unravel the underlying mechanism for the above effects via analytical derivation under a limiting condition. We also develop a stochastic algorithm for simulating a single reaction with two delays and show that robust oscillations can be maintained by the PFL with a properly long delay in the single-node system. This work presents an effective method for constructing robust large-amplitude oscillators and interprets why similar circuit architectures are engaged in timekeeping systems such as circadian clocks.

  15. Global negative vegetation feedback to climate warming responses of leaf litter decomposition rates in cold biomes.

    PubMed

    Cornelissen, Johannes H C; van Bodegom, Peter M; Aerts, Rien; Callaghan, Terry V; van Logtestijn, Richard S P; Alatalo, Juha; Chapin, F Stuart; Gerdol, Renato; Gudmundsson, Jon; Gwynn-Jones, Dylan; Hartley, Anne E; Hik, David S; Hofgaard, Annika; Jónsdóttir, Ingibjörg S; Karlsson, Staffan; Klein, Julia A; Laundre, Jim; Magnusson, Borgthor; Michelsen, Anders; Molau, Ulf; Onipchenko, Vladimir G; Quested, Helen M; Sandvik, Sylvi M; Schmidt, Inger K; Shaver, Gus R; Solheim, Bjørn; Soudzilovskaia, Nadejda A; Stenström, Anna; Tolvanen, Anne; Totland, Ørjan; Wada, Naoya; Welker, Jeffrey M; Zhao, Xinquan

    2007-07-01

    Whether climate change will turn cold biomes from large long-term carbon sinks into sources is hotly debated because of the great potential for ecosystem-mediated feedbacks to global climate. Critical are the direction, magnitude and generality of climate responses of plant litter decomposition. Here, we present the first quantitative analysis of the major climate-change-related drivers of litter decomposition rates in cold northern biomes worldwide. Leaf litters collected from the predominant species in 33 global change manipulation experiments in circum-arctic-alpine ecosystems were incubated simultaneously in two contrasting arctic life zones. We demonstrate that longer-term, large-scale changes to leaf litter decomposition will be driven primarily by both direct warming effects and concomitant shifts in plant growth form composition, with a much smaller role for changes in litter quality within species. Specifically, the ongoing warming-induced expansion of shrubs with recalcitrant leaf litter across cold biomes would constitute a negative feedback to global warming. Depending on the strength of other (previously reported) positive feedbacks of shrub expansion on soil carbon turnover, this may partly counteract direct warming enhancement of litter decomposition.

  16. The Effect of Positive and Negative Feedback on Risk-Taking across Different Contexts

    PubMed Central

    Losecaat Vermeer, Annabel B.; Sanfey, Alan G.

    2015-01-01

    Preferences for risky choices have often been shown to be unstable and context-dependent. Though people generally avoid gambles with mixed outcomes, a phenomenon often attributed to loss aversion, contextual factors can impact this dramatically. For example, people typically prefer risky options after a financial loss, while generally choosing safer options after a monetary gain. However, it is unclear what exactly contributes to these preference shifts as a function of prior outcomes, as these gain/loss outcomes are usually confounded with participant performance, and therefore it is unclear whether these effects are driven purely by the monetary gains or losses, or rather by success or failure at the actual task. Here, we experimentally separated the effects of monetary gains/losses from performance success/failure prior to a standard risky choice. Participants performed a task in which they experienced contextual effects: 1) monetary gain or loss based directly on performance, 2) monetary gain or loss that was randomly awarded and was, crucially, independent from performance, and 3) success or failure feedback based on performance, but without any monetary incentive. Immediately following these positive/negative contexts, participants were presented with a gain-loss gamble that they had to decide to either play or pass. We found that risk preferences for identical sets of gambles were biased by positive and negative contexts containing monetary gains and losses, but not by contexts containing performance feedback. This data suggests that the observed framing effects are driven by aversion for monetary losses and not simply by the positive or negative valence of the context, or by potential moods resulting from positive or negative contexts. These results highlight the specific context dependence of risk preferences. PMID:26407298

  17. The Effect of Positive and Negative Feedback on Risk-Taking across Different Contexts.

    PubMed

    Losecaat Vermeer, Annabel B; Sanfey, Alan G

    2015-01-01

    Preferences for risky choices have often been shown to be unstable and context-dependent. Though people generally avoid gambles with mixed outcomes, a phenomenon often attributed to loss aversion, contextual factors can impact this dramatically. For example, people typically prefer risky options after a financial loss, while generally choosing safer options after a monetary gain. However, it is unclear what exactly contributes to these preference shifts as a function of prior outcomes, as these gain/loss outcomes are usually confounded with participant performance, and therefore it is unclear whether these effects are driven purely by the monetary gains or losses, or rather by success or failure at the actual task. Here, we experimentally separated the effects of monetary gains/losses from performance success/failure prior to a standard risky choice. Participants performed a task in which they experienced contextual effects: 1) monetary gain or loss based directly on performance, 2) monetary gain or loss that was randomly awarded and was, crucially, independent from performance, and 3) success or failure feedback based on performance, but without any monetary incentive. Immediately following these positive/negative contexts, participants were presented with a gain-loss gamble that they had to decide to either play or pass. We found that risk preferences for identical sets of gambles were biased by positive and negative contexts containing monetary gains and losses, but not by contexts containing performance feedback. This data suggests that the observed framing effects are driven by aversion for monetary losses and not simply by the positive or negative valence of the context, or by potential moods resulting from positive or negative contexts. These results highlight the specific context dependence of risk preferences.

  18. Negative feedback between TAp63 and Mir-133b mediates colorectal cancer suppression

    PubMed Central

    Zhang, Yi; Gao, Kai; Hu, Gui; guo, Yihang; Lin, Changwei; Li, Xiaorong

    2016-01-01

    Background TAp63 is known as the most potent transcription activator and tumor suppressor. microRNAs (miRNAs) are increasingly recognized as essential components of the p63 pathway, mediating downstream post-transcriptional gene repression. The aim of present study was to investigate a negative feedback loop between TAp63 and miR-133b. Results Overexpression of TAp63 inhibited HCT-116 cell proliferation, apoptosis and invasion via miR-133b. Accordingly, miR-133b inhibited TAp63 expression through RhoA and its downstream pathways. Moreover, we demonstrated that TAp63/miR-133b could inhibit colorectal cancer proliferation and metastasis in vivo and vitro. Materials and Methods We evaluated the correlation between TAp63 and miR-133b in HCT-116 cells and investigated the roles of the TAp63/miR-133b feedback loop in cell proliferation, apoptosis and metastasis via MTT, flow cytometry, Transwell, and nude mouse xenograft experiments. The expression of TAp63, miR-133b, RhoA, α-tubulin and Akt was assessed via qRT-PCR, western blot and immunofluorescence analyses. miR-133b target genes were identified through luciferase reporter assays. Conclusions miR-133b plays an important role in the anti-tumor effects of TAp63 in colorectal cancer. miR-133b may represent a tiemolecule between TAp63 and RhoA, forming a TAp63/miR-133b/RhoA negative feedback loop, which could significantly inhibit proliferation, apoptosis and metastasis. PMID:27894087

  19. Quantifying the Negative Feedback of Vegetation to Greenhouse Warming: A Modeling Approach

    NASA Technical Reports Server (NTRS)

    Bounous, L.; Hall, F. G.; Sellers, P. J.; Kumar, A.; Collatz, G. J.; Tucker, C. J.; Imhoff, M. L.

    2010-01-01

    Several climate models indicate that in a 2 x CO2 environment, temperature and precipitation would increase and runoff would increase faster than precipitation. These models, however, did not allow the vegetation to increase its leaf density as a response to the physiological effects of increased CO2 and consequent changes in climate. Other assessments included these interactions but did not account for the vegetation down-regulation to reduce plant's photosynthetic activity and as such resulted in a weak vegetation negative response. When we combine these interactions in climate simulations with 2 x CO2, the associated increase in precipitation contributes primarily to increase evapotranspiration rather than surface runoff, consistent with observations, and results in an additional cooling effect not fully accounted for in previous simulations with elevated CO2. By accelerating the water cycle, this feedback slows but does not alleviate the projected warming, reducing the land surface warming by 0.6 C. Compared to previous studies, these results imply that long term negative feedback from CO2-induced increases in vegetation density could reduce temperature following a stabilization of CO2 concentration.

  20. Basolateral amygdala lesions facilitate reward choices after negative feedback in rats.

    PubMed

    Izquierdo, Alicia; Darling, Chelsi; Manos, Nic; Pozos, Hilda; Kim, Charissa; Ostrander, Serena; Cazares, Victor; Stepp, Haley; Rudebeck, Peter H

    2013-02-27

    The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) constitute part of a neural circuit important for adaptive, goal-directed learning. One task measuring flexibility of response to changes in reward is discrimination reversal learning. Damage to OFC produces well documented impairments on various forms of reversal learning in rodents, monkeys, and humans. Recent reports show that BLA, though highly interconnected with OFC, may be differentially involved in reversal learning. In the present experiment, we compared the effects of bilateral, ibotenic acid lesions of OFC or BLA (or SHAM) on visual discrimination and reversal learning. Specifically, we used pairwise visual discrimination methods, as is commonly administered in non-human primate studies, and analyzed how animals use positive and negative trial-by-trial feedback, domains not previously explored in a rat study. As expected, OFC lesions displayed significantly slower reversal learning than SHAM and BLA rats across sessions. Rats with BLA lesions, conversely, showed facilitated reversal learning relative to SHAM and OFC groups. Furthermore, a trial-by-trial analysis of the errors committed showed the BLA group benefited more from incorrectly performed trials (or negative feedback) on future choices than either SHAM or OFC rats. This provides evidence that BLA and OFC are involved in updating responses to changes in reward contingency and that the roles are distinct. Our results are discussed in relation to a competitive framework model for OFC and BLA in reward processing.

  1. Near infrared single photon avalanche detector with negative feedback and self quenching

    NASA Astrophysics Data System (ADS)

    Linga, Krishna; Yevtukhov, Yuriy; Liang, Bing

    2009-08-01

    We present the design and development of a negative feedback devices using the internal discrete amplifier approach used for the development of a single photon avalanche photodetector in the near infrared wavelength region. This new family of photodetectors with negative feedback, requiring no quenching mechanism using Internal Discrete Amplification (IDA) mechanism for the realization of very high gain and low excess noise factor in the visible and near infrared spectral regions, operates in the non-gated mode under a constant bias voltage. The demonstrated device performance far exceeds any available solid state Photodetectors in the near infrared wavelength range. The measured devices have Gain > 2×105, Excess noise factor < 1.05, Rise time < 350ps, Fall time < 500ps, Dark current < 2×106 cps at room temperature, and Operating Voltage < 60V. These devices are ideal for researchers in the field of Ladar/Lidar, free space optical communication, 3D imaging, industrial and scientific instrumentation, night vision, quantum cryptography, and other military, defence and aerospace applications.

  2. Plant-soil feedbacks promote negative frequency dependence in the coexistence of two aridland grasses.

    PubMed

    Chung, Y Anny; Rudgers, Jennifer A

    2016-07-27

    Understanding the mechanisms of species coexistence is key to predicting patterns of species diversity. Historically, the ecological paradigm has been that species coexist by partitioning resources: as a species increases in abundance, self-limitation kicks in, because species-specific resources decline. However, determining coexistence mechanisms has been a particular puzzle for sedentary organisms with high overlap in their resource requirements, such as plants. Recent evidence suggests that plant-associated microbes could generate the stabilizing self-limitation (negative frequency dependence) that is required for species coexistence. Here, we test the key assumption that plant-microbe feedbacks cause such self-limitation. We used competition experiments and modelling to evaluate how two common groups of soil microbes (rhizospheric microbes and biological soil crusts) influenced the self-limitation of two competing desert grass species. Negative feedbacks between the dominant plant competitor and its rhizospheric microbes magnified self-limitation, whereas beneficial interactions between both plant species and biological soil crusts partly counteracted this stabilizing effect. Plant-microbe interactions have received relatively little attention as drivers of vegetation dynamics in dry land ecosystems. Our results suggest that microbial mechanisms can contribute to patterns of plant coexistence in arid grasslands.

  3. Negative plant–soil feedbacks may limit persistence of an invasive tree due to rapid accumulation of soil pathogens

    PubMed Central

    Nijjer, Somereet; Rogers, William E; Siemann, Evan

    2007-01-01

    Soil organisms influence plant species coexistence and invasion potential. Plant–soil feedbacks occur when plants change soil community composition such that interactions with that soil community in turn may positively or negatively affect the performance of conspecifics. Theories predict and studies show that invasions may be promoted by stronger negative soil feedbacks for native compared with exotic species. We present a counter-example of a successful invader with strong negative soil feedbacks apparently caused by host-specific, pathogenic soil fungi. Using a feedback experiment in pots, we investigated whether the relative strength of plant–soil feedbacks experienced by a non-native woody invader, Sapium sebiferum, differed from several native tree species by examining their performance in soils collected near conspecifics (‘home soils’) or heterospecifics (‘away soils’) in the introduced range. Sapium seedlings, but no native seedlings, had lower survival and biomass in its home soils compared with soils of other species (‘negative feedback’). To investigate biotic agents potentially responsible for the observed negative feedbacks, we conducted two additional experiments designed to eliminate different soil taxa (‘rescue experiments’). We found that soil sterilization (pot experiment) or soil fungicide applications (pot and field experiments) restored Sapium performance in home soil thereby eliminating the negative feedbacks we observed in the original experiment. Such negative feedbacks apparently mediated by soil fungi could have important effects on persistence of this invader by limiting Sapium seedling success in Sapium dominated forests (home soils) though their weak effects in heterospecific (away) soils suggest a weak role in limiting initial establishment. PMID:17711837

  4. Motor imagery based brain-computer interface: a study of the effect of positive and negative feedback.

    PubMed

    González-Franco, Mar; Yuan, Peng; Zhang, Dan; Hong, Bo; Gao, Shangkai

    2011-01-01

    Co-adaptation between the human brain and computers is an important issue in brain-computer interface (BCI) research. However, most of the research has focused on the computer side of BCI, such as developing powerful machine-learning algorithms, while less research has focused on investigating how BCI users may optimally adapt. This paper assesses the influences of positive and negative visual feedback on motor imagery (MI) skills by evaluating the performance. More precisely, a MI based BCI paradigm was employed with fake visual feedback, regardless of subjects' real performance. Subjects were exposed to two experimental conditions--one positive and one negative, in which 80% or 30% of the trials were associated with positive feedback, respectively. The main EEG feature for MI-BCI classification--the asymmetry of mu-rhythm between hemispheres--was more prominent only after the negative feedback session. In addition, the negative feedback condition was accompanied by larger heart rate variability compared to the positive feedback condition. Our results suggest that visual feedback is an important aspect to take into account when designing BCI skill acquisition sessions.

  5. Using negative feedback to guide behavior: impairments on the first 4 cards of the Wisconsin Card Sorting Test predict negative symptoms of schizophrenia.

    PubMed

    Vogel, Sally J; Strauss, Gregory P; Allen, Daniel N

    2013-12-01

    Research has demonstrated that individuals with schizophrenia fail to appropriately use negative feedback to guide learning. These learning deficits are thought to arise from abnormalities in midbrain dopamine activity. Primary and enduring negative symptoms are also associated with abnormal dopamine activity and are expected to produce more severe deficits in learning when they present in individuals with schizophrenia. The current study examines this matter by comparing individuals with deficit syndrome schizophrenia, which is characterized by primary and enduring negative symptoms, to individuals with nondeficit syndrome schizophrenia and to normal controls in their use of positive feedback and negative feedback to guide learning on the first four cards of the WCST. Participants included 67 individuals with schizophrenia (15 deficit; 52 nondeficit syndrome) and 51 healthy controls. Accuracy data from the first 4 cards of the WCST and measures of global test performance were examined. Individuals with schizophrenia were significantly less accurate than controls in their performance on early (pre-shift) WCST trials, and this impairment was significantly greater in patients with deficit than nondeficit schizophrenia. Additionally, accuracy across the first 4 WCST cards significantly predicted the number of categories completed and percentage of perseverative errors across the entire test. These findings suggest that negative symptoms of schizophrenia are associated with difficulty using negative feedback to adaptively guide behavior, and are consistent with the notion that abnormal DA signaling contributes to the higher-order executive functioning impairments seen in schizophrenia with severe negative symptoms.

  6. The effect of negative feedback on tension and subsequent performance: the main and interactive effects of goal content and conscientiousness.

    PubMed

    Cianci, Anna M; Klein, Howard J; Seijts, Gerard H

    2010-07-01

    The purpose of this experiment was to examine the interplay of goal content, conscientiousness, and tension on performance following negative feedback. Undergraduate students were assigned either a learning or performance goal and then were provided with false feedback indicating very poor performance on the task they performed. After assessing tension, participants performed the task again with the same learning or performance goal. A mediated moderation model was tested, and results were supportive of our hypotheses. Specifically, individuals assigned a learning goal experienced less tension and performed better following negative feedback than individuals assigned a performance goal. Individuals high in conscientiousness experienced greater tension than individuals low in conscientiousness. Conscientiousness and goal content interacted in relating to both tension and performance, with tension as a mediator, such that high conscientiousness amplified the detrimental effect of a performance goal on tension following negative feedback leading to lower performance. High conscientiousness facilitated performance for participants with a learning goal.

  7. Individual differences in reward–prediction–error: extraversion and feedback-related negativity

    PubMed Central

    Cooper, Andrew J.; Pickering, Alan D.

    2011-01-01

    Medial frontal scalp-recorded negativity occurring ∼200–300 ms post-stimulus [known as feedback-related negativity (FRN)] is attenuated following unpredicted reward and potentiated following unpredicted non-reward. This encourages the view that FRN may partly reflect dopaminergic ‘reward–prediction–error’ signalling. We examined the influence of a putatively dopamine-based personality trait, extraversion (N = 30), and a dopamine-related gene polymorphism, DRD2/ANKK1 (N = 24), on FRN during an associative reward-learning paradigm. FRN was most negative following unpredicted non-reward and least-negative following unpredicted reward. A difference wave contrasting these conditions was significantly more pronounced for extraverted participants than for introverts, with a similar but non-significant trend for participants carrying at least one copy of the A1 allele of the DRD2/ANKK1 gene compared with those without the allele. Extraversion was also significantly higher in A1 allele carriers. Results have broad relevance to neuroscience and personality research concerning reward processing and dopamine function. PMID:20855297

  8. Individual differences in reward-prediction-error: extraversion and feedback-related negativity.

    PubMed

    Smillie, Luke D; Cooper, Andrew J; Pickering, Alan D

    2011-10-01

    Medial frontal scalp-recorded negativity occurring ∼200-300 ms post-stimulus [known as feedback-related negativity (FRN)] is attenuated following unpredicted reward and potentiated following unpredicted non-reward. This encourages the view that FRN may partly reflect dopaminergic 'reward-prediction-error' signalling. We examined the influence of a putatively dopamine-based personality trait, extraversion (N = 30), and a dopamine-related gene polymorphism, DRD2/ANKK1 (N = 24), on FRN during an associative reward-learning paradigm. FRN was most negative following unpredicted non-reward and least-negative following unpredicted reward. A difference wave contrasting these conditions was significantly more pronounced for extraverted participants than for introverts, with a similar but non-significant trend for participants carrying at least one copy of the A1 allele of the DRD2/ANKK1 gene compared with those without the allele. Extraversion was also significantly higher in A1 allele carriers. Results have broad relevance to neuroscience and personality research concerning reward processing and dopamine function.

  9. MicroRNA-138 and SIRT1 form a mutual negative feedback loop to regulate mammalian axon regeneration.

    PubMed

    Liu, Chang-Mei; Wang, Rui-Ying; Saijilafu; Jiao, Zhong-Xian; Zhang, Bo-Yin; Zhou, Feng-Quan

    2013-07-01

    Regulated gene expression determines the intrinsic ability of neurons to extend axons, and loss of such ability is the major reason for the failed axon regeneration in the mature mammalian CNS. MicroRNAs and histone modifications are key epigenetic regulators of gene expression, but their roles in mammalian axon regeneration are not well explored. Here we report microRNA-138 (miR-138) as a novel suppressor of axon regeneration and show that SIRT1, the NAD-dependent histone deacetylase, is the functional target of miR-138. Importantly, we provide the first evidence that miR-138 and SIRT1 regulate mammalian axon regeneration in vivo. Moreover, we found that SIRT1 also acts as a transcriptional repressor to suppress the expression of miR-138 in adult sensory neurons in response to peripheral nerve injury. Therefore, miR-138 and SIRT1 form a mutual negative feedback regulatory loop, which provides a novel mechanism for controlling intrinsic axon regeneration ability.

  10. Proximal human FOXP3 promoter transactivated by NF-kappaB and negatively controlled by feedback loop and SP3.

    PubMed

    Eckerstorfer, Paul; Novy, Michael; Burgstaller-Muehlbacher, Sebastian; Paster, Wolfgang; Schiller, Herbert B; Mayer, Herbert; Stockinger, Hannes

    2010-07-01

    Forkhead box protein 3 (Foxp3) is indispensable for the development of CD4(+)CD25(+) regulatory T cells (Tregs). Here we analyzed three prominent evolutionary conserved regions (ECRs) upstream of the transcription start site of the human FOXP3 gene. We show that ECR2 and ECR3 fragments derived from positions -1.3 to -2.0 kb and -5.0 to -6.0 kb, respectively, display basal transcriptional activity. Reporter constructs derived from ECR1, located between -0.6 and +0.23 kb and thus the most proximal ECR in respect of transcription initiation, remained almost inactive. However, ECR1 was transactivated by the NF-kappaB subunit p65 in HEK 293 cells. In Jurkat and primary T cells, in addition to p65, a second stimulus delivered by either T-cell receptor stimulation or addition of PMA was needed. Co-expression of I kappaB alpha inhibited p65-mediated FOXP3 proximal promoter transactivation, and the NF-kappaB inhibitor curcumin reduced Foxp3 neoexpression in IL-2/CD3/CD28/TGF-beta stimulated PBMCs. Moreover, proximal FOXP3 promoter transactivation was inhibited by Foxp3 and the SP transcription factor family member SP3. Thus, the human proximal FOXP3 promoter is controlled by activation through the TCR involving PKC and the NF-kappaB subunit p65 and by inhibition through a negative feedback loop and SP3. (c) 2010 Elsevier Ltd. All rights reserved.

  11. A Simple Negative Interaction in the Positive Transcriptional Feedback of a Single Gene Is Sufficient to Produce Reliable Oscillations

    PubMed Central

    Miró-Bueno, Jesús M.; Rodríguez-Patón, Alfonso

    2011-01-01

    Negative and positive transcriptional feedback loops are present in natural and synthetic genetic oscillators. A single gene with negative transcriptional feedback needs a time delay and sufficiently strong nonlinearity in the transmission of the feedback signal in order to produce biochemical rhythms. A single gene with only positive transcriptional feedback does not produce oscillations. Here, we demonstrate that this single-gene network in conjunction with a simple negative interaction can also easily produce rhythms. We examine a model comprised of two well-differentiated parts. The first is a positive feedback created by a protein that binds to the promoter of its own gene and activates the transcription. The second is a negative interaction in which a repressor molecule prevents this protein from binding to its promoter. A stochastic study shows that the system is robust to noise. A deterministic study identifies that the dynamics of the oscillator are mainly driven by two types of biomolecules: the protein, and the complex formed by the repressor and this protein. The main conclusion of this paper is that a simple and usual negative interaction, such as degradation, sequestration or inhibition, acting on the positive transcriptional feedback of a single gene is a sufficient condition to produce reliable oscillations. One gene is enough and the positive transcriptional feedback signal does not need to activate a second repressor gene. This means that at the genetic level an explicit negative feedback loop is not necessary. The model needs neither cooperative binding reactions nor the formation of protein multimers. Therefore, our findings could help to clarify the design principles of cellular clocks and constitute a new efficient tool for engineering synthetic genetic oscillators. PMID:22205920

  12. A simple negative interaction in the positive transcriptional feedback of a single gene is sufficient to produce reliable oscillations.

    PubMed

    Miró-Bueno, Jesús M; Rodríguez-Patón, Alfonso

    2011-01-01

    Negative and positive transcriptional feedback loops are present in natural and synthetic genetic oscillators. A single gene with negative transcriptional feedback needs a time delay and sufficiently strong nonlinearity in the transmission of the feedback signal in order to produce biochemical rhythms. A single gene with only positive transcriptional feedback does not produce oscillations. Here, we demonstrate that this single-gene network in conjunction with a simple negative interaction can also easily produce rhythms. We examine a model comprised of two well-differentiated parts. The first is a positive feedback created by a protein that binds to the promoter of its own gene and activates the transcription. The second is a negative interaction in which a repressor molecule prevents this protein from binding to its promoter. A stochastic study shows that the system is robust to noise. A deterministic study identifies that the dynamics of the oscillator are mainly driven by two types of biomolecules: the protein, and the complex formed by the repressor and this protein. The main conclusion of this paper is that a simple and usual negative interaction, such as degradation, sequestration or inhibition, acting on the positive transcriptional feedback of a single gene is a sufficient condition to produce reliable oscillations. One gene is enough and the positive transcriptional feedback signal does not need to activate a second repressor gene. This means that at the genetic level an explicit negative feedback loop is not necessary. The model needs neither cooperative binding reactions nor the formation of protein multimers. Therefore, our findings could help to clarify the design principles of cellular clocks and constitute a new efficient tool for engineering synthetic genetic oscillators.

  13. Elevated atmospheric CO2 negatively impacts photosynthesis through radiative forcing and physiology-mediated climate feedback

    NASA Astrophysics Data System (ADS)

    Zhu, Peng; Zhuang, Qianlai; Ciais, Philippe; Welp, Lisa; Li, Wenyu; Xin, Qinchuan

    2017-02-01

    Increasing atmospheric CO2 affects photosynthesis involving directly increasing leaf carboxylation rates, stomatal closure, and climatic effects. The direct effects are generally thought to be positive leading to increased photosynthesis, while its climatic effects can be regionally positive or negative. These effects are usually considered to be independent from each other, but they are in fact coupled through interactions between land surface exchanges of gases and heat and the physical climate system. In particular, stomatal closure reduces evapotranspiration and increases sensible heat emissions from ecosystems, leading to decreased atmospheric moisture and precipitation and local warming. We use a coupled earth system model to attribute the influence of the increase in CO2 on gross primary productivity (GPP) during the period of 1930-2011. In our model, CO2 radiative effects cause climate change that has only a negligible effect on global GPP (a reduction of 0.9 ± 2% during the last 80 years) because of opposite responses between tropical and northern biomes. On the other hand, CO2 physiological effects on GPP are both positive, by increased carboxylation rates and water use efficiency (7.1 ± 0.48% increase), and negative, by vegetation-climate feedback reducing precipitation, as a consequence of decreased transpiration and increased sensible heat in areas without water limitation (2.7 ± 1.76% reduction).When considering the coupled atmosphere-vegetation system, negative climate feedback on photosynthesis and plant growth due to the current level of CO2 opposes 29-38% of the gains from direct fertilization effects.

  14. Modeling of a negative feedback mechanism explains antagonistic pleiotropy in reproduction in domesticated Caenorhabditis elegans strains

    PubMed Central

    Large, Edward E.; Padmanabhan, Raghavendra; Watkins, Kathie L.

    2017-01-01

    Most biological traits and common diseases have a strong but complex genetic basis, controlled by large numbers of genetic variants with small contributions to a trait or disease risk. The effect-size of most genetic variants is not absolute and is instead dependent upon multiple factors such as the age and genetic background of an organism. In order to understand the mechanistic basis of these changes, we characterized heritable trait differences between two domesticated strains of C. elegans. We previously identified a major effect locus, caused in part by a mutation in a component of the NURF chromatin remodeling complex, that regulates reproductive output in an age-dependent manner. The effect-size of this locus changes from positive to negative over the course of an animal’s reproductive lifespan. Here, we use a previously published macroscale model of the egg-laying rate in C. elegans to show that time-dependent effect-size is explained by an unequal use of sperm combined with negative feedback between sperm and ovulation rate. We validate key predictions of this model with controlled mating experiments and quantification of oogenesis and sperm use. Incorporation of this model into QTL mapping allows us to identify and partition new QTLs into specific aspects of the egg-laying process. Finally, we show how epistasis between two genetic variants is predicted by this modeling as a consequence of the unequal use of sperm. This work demonstrates how modeling of multicellular communication systems can improve our ability to predict and understand the role of genetic variation on a complex phenotype. Negative autoregulatory feedback loops, common in transcriptional regulation, could play an important role in modifying genetic architecture in other traits. PMID:28493873

  15. Age disrupts androgen receptor-modulated negative feedback in the gonadal axis in healthy men

    PubMed Central

    Takahashi, Paul Y.; Keenan, Daniel M.; Liu, Peter Y.; Mielke, Kristi L.; Weist, Suanne M.

    2010-01-01

    Testosterone (T) exerts negative feedback on the hypothalamo-pituitary (GnRH-LH) unit, but the relative roles of the CNS and pituitary are not established. We postulated that relatively greater LH responses to flutamide (brain-permeant antiandrogen) than bicalutamide (brain-impermeant antiandrogen) should reflect greater feedback via CNS than pituitary/peripheral androgen receptor-dependent pathways. To this end, 24 healthy men ages 20–73 yr, BMI 21–32 kg/m2, participated in a prospective, placebo-controlled, randomized, double-blind crossover study of the effects of antiandrogen control of pulsatile, basal, and entropic (pattern regularity) measurements of LH secretion. Analysis of covariance revealed that flutamide but not bicalutamide 1) increased pulsatile LH secretion (P = 0.003), 2) potentiated the age-related abbreviation of LH secretory bursts (P = 0.025), 3) suppressed incremental GnRH-induced LH release (P = 0.015), and 4) decreased the regularity of GnRH-stimulated LH release (P = 0.012). Furthermore, the effect of flutamide exceeded that of bicalutamide in 1) raising mean LH (P = 0.002) and T (P = 0.017) concentrations, 2) accelerating LH pulse frequency (P = 0.013), 3) amplifying total (basal plus pulsatile) LH (P = 0.002) and T (P < 0.001) secretion, 4) shortening LH secretory bursts (P = 0.032), and 5) reducing LH secretory regularity (P < 0.001). Both flutamide and bicalutamide elevated basal (nonpulsatile) LH secretion (P < 0.001). These data suggest the hypothesis that topographically selective androgen receptor pathways mediate brain-predominant and pituitary-dependent feedback mechanisms in healthy men. PMID:20682842

  16. The time scale of the silicate weathering negative feedback on atmospheric CO2

    NASA Astrophysics Data System (ADS)

    Colbourn, G.; Ridgwell, A.; Lenton, T. M.

    2015-05-01

    The ultimate fate of CO2 added to the ocean-atmosphere system is chemical reaction with silicate minerals and burial as marine carbonates. The time scale of this silicate weathering negative feedback on atmospheric pCO2 will determine the duration of perturbations to the carbon cycle, be they geological release events or the current anthropogenic perturbation. However, there has been little previous work on quantifying the time scale of the silicate weathering feedback, with the primary estimate of 300-400 kyr being traceable to an early box model study by Sundquist (1991). Here we employ a representation of terrestrial rock weathering in conjunction with the "GENIE" (Grid ENabled Integrated Earth system) model to elucidate the different time scales of atmospheric CO2 regulation while including the main climate feedbacks on CO2 uptake by the ocean. In this coupled model, the main dependencies of weathering—runoff, temperature, and biological productivity—were driven from an energy-moisture balance atmosphere model and parameterized plant productivity. Long-term projections (1 Myr) were conducted for idealized scenarios of 1000 and 5000 PgC fossil fuel emissions and their sensitivity to different model parameters was tested. By fitting model output to a series of exponentials we determined the e-folding time scale for atmospheric CO2 drawdown by silicate weathering to be ˜240 kyr (range 170-380 kyr), significantly less than existing quantifications. Although the time scales for reequilibration of global surface temperature and surface ocean pH are similar to that for CO2, a much greater proportion of the peak temperature anomaly persists on this longest time scale; ˜21% compared to ˜10% for CO2.

  17. Experimental Comparison of two Active Vibration Control Approaches: Velocity Feedback and Negative Capacitance Shunt Damping

    NASA Technical Reports Server (NTRS)

    Beck, Benjamin; Schiller, Noah

    2013-01-01

    This paper outlines a direct, experimental comparison between two established active vibration control techniques. Active vibration control methods, many of which rely upon piezoelectric patches as actuators and/or sensors, have been widely studied, showing many advantages over passive techniques. However, few direct comparisons between different active vibration control methods have been made to determine the performance benefit of one method over another. For the comparison here, the first control method, velocity feedback, is implemented using four accelerometers that act as sensors along with an analog control circuit which drives a piezoelectric actuator. The second method, negative capacitance shunt damping, consists of a basic analog circuit which utilizes a single piezoelectric patch as both a sensor and actuator. Both of these control methods are implemented individually using the same piezoelectric actuator attached to a clamped Plexiglas window. To assess the performance of each control method, the spatially averaged velocity of the window is compared to an uncontrolled response.

  18. Antennally mediated negative feedback regulation of pheromone production in the pine engraver beetle, Ips pini

    NASA Astrophysics Data System (ADS)

    Ginzel, Matthew D.; Bearfield, Jeremy C.; Keeling, Christopher I.; McCormack, Colin C.; Blomquist, Gary J.; Tittiger, Claus

    2007-01-01

    Bark beetles use monoterpenoid aggregation pheromones to coordinate host colonization and mating. These chemical signals are produced de novo in midgut cells via the mevalonate pathway, and pheromone production may be regulated by a negative feedback system mediated through the antennae. In this study, we explored the effect of antennectomy on pheromone production and transcript levels of key mevalonate pathway genes in juvenile hormone III-treated male pine engraver beetles, Ips pini (Say). Antennectomized males produced significantly greater amounts of pheromone than podectomized males and those with intact antennae. Likewise, mRNA levels of three mevalonate pathway genes important in pheromone biosynthesis were measured by quantitative real-time PCR and found to be induced to a greater extent with antennectomy, suggesting a transcriptional regulation of pheromone production.

  19. Purification and cloning of the GTP cyclohydrolase I feedback regulatory protein, GFRP.

    PubMed

    Milstien, S; Jaffe, H; Kowlessur, D; Bonner, T I

    1996-08-16

    The activity of GTP cyclohydrolase I, the initial enzyme of the de novo pathway for biosynthesis of tetrahydrobiopterin, the cofactor required for aromatic amino acid hydroxylations and nitric oxide synthesis, is sensitive to end-product feedback inhibition by tetrahydrobiopterin. This inhibition by tetrahydrobiopterin is mediated by the GTP cyclohydrolase I feedback regulatory protein GFRP, previously named p35 (Harada, T., Kagamiyama, H., and Hatakeyama, K. (1993) Science 260, 1507-1510), and -phenylalanine specifically reverses the tetrahydrobiopterin-dependent inhibition. As a first step in the investigation of the physiological role of this unique mechanism of regulation, a convenient procedure has been developed to co-purify to homogeneity both GTP cyclohydrolase I and GFRP from rat liver. GTP cyclohydrolase I and GFRP exist in a complex which can be bound to a GTP-affinity column from which GTP cyclohydrolase I and GFRP are separately and selectively eluted. GFRP is dissociated from the GTP agarose-bound complex with 0.2 NaCl, a concentration of salt which also effectively blocks the tetrahydrobiopterin-dependent inhibitory activity of GFRP. GTP cyclohydrolase I is then eluted from the GTP-agarose column with GTP. Both GFRP and GTP cyclohydrolase I were then purified separately to near homogeneity by sequential high performance anion exchange and gel filtration chromatography. GFRP was found to have a native molecular mass of 20 kDa and consist of a homodimer of 9.5-kDa subunits. Based on peptide sequences obtained from purified GFRP, oligonucleotides were synthesized and used to clone a cDNA from a rat liver cDNA library by polymerase chain reaction-based methods. The cDNA contained an open reading frame that encoded a novel protein of 84 amino acids (calculated molecular mass 9665 daltons). This protein when expressed in Escherichia coli as a thioredoxin fusion protein had tetrahydrobiopterin-dependent GTP cyclohydrolase I inhibitory activity. Northern

  20. Smart conjugated polymer nanocarrier for healthy weight loss by negative feedback regulation of lipase activity

    NASA Astrophysics Data System (ADS)

    Chen, Yu-Lei; Zhu, Sha; Zhang, Lei; Feng, Pei-Jian; Yao, Xi-Kuang; Qian, Cheng-Gen; Zhang, Can; Jiang, Xi-Qun; Shen, Qun-Dong

    2016-02-01

    Healthy weight loss represents a real challenge when obesity is increasing in prevalence. Herein, we report a conjugated polymer nanocarrier for smart deactivation of lipase and thus balancing calorie intake. After oral administration, the nanocarrier is sensitive to lipase in the digestive tract and releases orlistat, which deactivates the enzyme and inhibits fat digestion. It also creates negative feedback to control the release of itself. The nanocarrier smartly regulates activity of the lipase cyclically varied between high and low levels. In spite of high fat diet intervention, obese mice receiving a single dose of the nanocarrier lose weight over eight days, whereas a control group continues the tendency to gain weight. Daily intragastric administration of the nanocarrier leads to lower weight of livers or fat pads, smaller adipocyte size, and lower total cholesterol level than that of the control group. Near-infrared fluorescence of the nanocarrier reveals its biodistribution.Healthy weight loss represents a real challenge when obesity is increasing in prevalence. Herein, we report a conjugated polymer nanocarrier for smart deactivation of lipase and thus balancing calorie intake. After oral administration, the nanocarrier is sensitive to lipase in the digestive tract and releases orlistat, which deactivates the enzyme and inhibits fat digestion. It also creates negative feedback to control the release of itself. The nanocarrier smartly regulates activity of the lipase cyclically varied between high and low levels. In spite of high fat diet intervention, obese mice receiving a single dose of the nanocarrier lose weight over eight days, whereas a control group continues the tendency to gain weight. Daily intragastric administration of the nanocarrier leads to lower weight of livers or fat pads, smaller adipocyte size, and lower total cholesterol level than that of the control group. Near-infrared fluorescence of the nanocarrier reveals its biodistribution

  1. Negative feedback regulation of Homer 1a on norepinephrine-dependent cardiac hypertrophy

    SciTech Connect

    Chiarello, Carmelina; Bortoloso, Elena; Carpi, Andrea; Furlan, Sandra; Volpe, Pompeo

    2013-07-15

    Homers are scaffolding proteins that modulate diverse cell functions being able to assemble signalling complexes. In this study, the presence, sub-cellular distribution and function of Homer 1 was investigated. Homer 1a and Homer 1b/c are constitutively expressed in cardiac muscle of both mouse and rat and in HL-1 cells, a cardiac cell line. As judged by confocal immunofluorescence microscopy, Homer 1a displays sarcomeric and peri-nuclear localization. In cardiomyocytes and cultured HL-1 cells, the hypertrophic agonist norepinephrine (NE) induces α{sub 1}-adrenergic specific Homer 1a over-expression, with a two-to-three-fold increase within 1 h, and no up-regulation of Homer 1b/c, as judged by Western blot and qPCR. In HL-1 cells, plasmid-driven over-expression of Homer 1a partially antagonizes activation of ERK phosphorylation and ANF up-regulation, two well-established, early markers of hypertrophy. At the morphometric level, NE-induced increase of cell size is likewise and partially counteracted by exogenous Homer 1a. Under the same experimental conditions, Homer 1b/c does not have any effect on ANF up-regulation nor on cell hypertrophy. Thus, Homer 1a up-regulation is associated to early stages of cardiac hypertrophy and appears to play a negative feedback regulation on molecular transducers of hypertrophy. -- Highlights: • Homer 1a is constitutively expressed in cardiac tissue. • In HL-1 cells, norepinephrine activates signaling pathways leading to hypertrophy. • Homer 1a up-regulation is an early event of norepinephrine-induced hypertrophy. • Homer 1a plays a negative feedback regulation modulating pathological hypertrophy. • Over-expression of Homer 1a per se does not induce hypertrophy.

  2. Evidence that Orphanin FQ Mediates Progesterone Negative Feedback in the Ewe

    PubMed Central

    Nestor, Casey C; Coolen, Lique M.; Nesselrod, Gail L.; Valent, Miro; Connors, John M.; Hileman, Stanley M.; Cheng, Guanliang; Lehman, Michael N.

    2013-01-01

    Orphanin FQ (OFQ), a member of the opioid family, is found in many areas of the hypothalamus and, when given centrally OFQ inhibits episodic LH secretion in rodents and sheep. Because GnRH neurons are devoid of the appropriate receptors to mediate steroid negative feedback directly, neurons that release OFQ may be involved. Using immunocytochemistry, we first determined that most OFQ neurons in the arcuate nucleus (ARC) and other hypothalamic regions of luteal phase ewes contained both estrogen receptor α and progesterone (P) receptor. Given a similar high degree of steroid receptor colocalization in other ARC subpopulations, we examined whether OFQ neurons of the ARC contained those other neuropeptides and neurotransmitters. OFQ did not colocalize with kisspeptin, tyrosine hydroxylase, or agouti-related peptide, but all ARC OFQ neurons coexpressed proopiomelanocortin. To test for a role for endogenous OFQ, we examined the effects of an OFQ receptor antagonist, [Nphe1,Arg14,Lys15]Nociceptin-NH2 (UFP-101) (30 nmol intracerebroventricular/h), on LH secretion in steroid-treated ewes in the breeding season and ovary-intact ewes in anestrus. Ovariectomized ewes with luteal phase concentrations of P and estradiol showed a significant increase in LH pulse frequency during infusion of UFP-101 (4.5 ± 0.5 pulses/6 h) compared with saline infusion (2.6 ± 0.4 pulses/6 h), whereas ewes implanted with only estradiol did not. Ovary-intact anestrous ewes displayed no significant differences in LH pulse amplitude or frequency during infusion of UFP-101. Therefore, we conclude that OFQ mediates, at least in part, the negative feedback action of P on GnRH/LH pulse frequency in sheep. PMID:23928375

  3. Evidence that orphanin FQ mediates progesterone negative feedback in the ewe.

    PubMed

    Nestor, Casey C; Coolen, Lique M; Nesselrod, Gail L; Valent, Miro; Connors, John M; Hileman, Stanley M; Cheng, Guanliang; Lehman, Michael N; Goodman, Robert L

    2013-11-01

    Orphanin FQ (OFQ), a member of the opioid family, is found in many areas of the hypothalamus and, when given centrally OFQ inhibits episodic LH secretion in rodents and sheep. Because GnRH neurons are devoid of the appropriate receptors to mediate steroid negative feedback directly, neurons that release OFQ may be involved. Using immunocytochemistry, we first determined that most OFQ neurons in the arcuate nucleus (ARC) and other hypothalamic regions of luteal phase ewes contained both estrogen receptor α and progesterone (P) receptor. Given a similar high degree of steroid receptor colocalization in other ARC subpopulations, we examined whether OFQ neurons of the ARC contained those other neuropeptides and neurotransmitters. OFQ did not colocalize with kisspeptin, tyrosine hydroxylase, or agouti-related peptide, but all ARC OFQ neurons coexpressed proopiomelanocortin. To test for a role for endogenous OFQ, we examined the effects of an OFQ receptor antagonist, [Nphe1,Arg14,Lys15]Nociceptin-NH2 (UFP-101) (30 nmol intracerebroventricular/h), on LH secretion in steroid-treated ewes in the breeding season and ovary-intact ewes in anestrus. Ovariectomized ewes with luteal phase concentrations of P and estradiol showed a significant increase in LH pulse frequency during infusion of UFP-101 (4.5 ± 0.5 pulses/6 h) compared with saline infusion (2.6 ± 0.4 pulses/6 h), whereas ewes implanted with only estradiol did not. Ovary-intact anestrous ewes displayed no significant differences in LH pulse amplitude or frequency during infusion of UFP-101. Therefore, we conclude that OFQ mediates, at least in part, the negative feedback action of P on GnRH/LH pulse frequency in sheep.

  4. Age-related changes in processing positive and negative feedback: is there a positivity effect for older adults?

    PubMed

    Ferdinand, Nicola K; Kray, Jutta

    2013-10-01

    Older people sometimes show a bias toward the processing of positive information. In this study, we used an event-related potential approach to examine whether such a positivity bias is also present during feedback processing in older adults. Our results suggest that a fast initial monitoring process, as reflected in the feedback-related negativity (FRN), is sensitive to the expectancy of events irrespective of their valence for older (aged 70-77 years) as well as younger (aged 20-27 years) adults. In contrast, in a later evaluation process, associated with memory updating and indexed by the P300, both age groups preferably processed unexpected positive feedback. However, younger adults additionally differentiated between unexpected negative and expected feedback while older adults did not, probably due to a lower working memory capacity. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. An evolutionarily conserved negative feedback mechanism in the Hippo pathway reflects functional difference between LATS1 and LATS2

    PubMed Central

    Park, Gun-Soo; Oh, Hyangyee; Kim, Minchul; Kim, Tackhoon; Johnson, Randy L.; Irvine, Kenneth D.; Lim, Dae-Sik

    2016-01-01

    The Hippo pathway represses YAP oncoprotein activity through phosphorylation by LATS kinases. Although variety of upstream components has been found to participate in the Hippo pathway, the existence and function of negative feedback has remained uncertain. We found that activated YAP, together with TEAD transcription factors, directly induces transcription of LATS2, but not LATS1, to form a negative feedback loop. We also observed increased mRNA levels of Hippo upstream components upon YAP activation. To reveal the physiological role of this negative feedback regulation, we deleted Lats2 or Lats1 in the liver-specific Sav1-knockout mouse model which develops a YAP-induced tumor. Additional deletion of Lats2 severely enhanced YAP-induced tumorigenic phenotypes in a liver specific Sav1 knock-out mouse model while additional deletion of Lats1 mildly affected the phenotype. Only Sav1 and Lats2 double knock-down cells formed larger colonies in soft agar assay, thereby recapitulating accelerated tumorigenesis seen in vivo. Importantly, this negative feedback is evolutionarily conserved, as Drosophila Yorkie (YAP ortholog) induces transcription of Warts (LATS2 ortholog) with Scalloped (TEAD ortholog). Collectively, we demonstrated the existence and function of an evolutionarily conserved negative feedback mechanism in the Hippo pathway, as well as the functional difference between LATS1 and LATS2 in regulation of YAP. PMID:27006470

  6. An evolutionarily conserved negative feedback mechanism in the Hippo pathway reflects functional difference between LATS1 and LATS2.

    PubMed

    Park, Gun-Soo; Oh, Hyangyee; Kim, Minchul; Kim, Tackhoon; Johnson, Randy L; Irvine, Kenneth D; Lim, Dae-Sik

    2016-04-26

    The Hippo pathway represses YAP oncoprotein activity through phosphorylation by LATS kinases. Although variety of upstream components has been found to participate in the Hippo pathway, the existence and function of negative feedback has remained uncertain. We found that activated YAP, together with TEAD transcription factors, directly induces transcription of LATS2, but not LATS1, to form a negative feedback loop. We also observed increased mRNA levels of Hippo upstream components upon YAP activation. To reveal the physiological role of this negative feedback regulation, we deleted Lats2 or Lats1 in the liver-specific Sav1-knockout mouse model which develops a YAP-induced tumor. Additional deletion of Lats2 severely enhanced YAP-induced tumorigenic phenotypes in a liver specific Sav1 knock-out mouse model while additional deletion of Lats1 mildly affected the phenotype. Only Sav1 and Lats2 double knock-down cells formed larger colonies in soft agar assay, thereby recapitulating accelerated tumorigenesis seen in vivo. Importantly, this negative feedback is evolutionarily conserved, as Drosophila Yorkie (YAP ortholog) induces transcription of Warts (LATS2 ortholog) with Scalloped (TEAD ortholog). Collectively, we demonstrated the existence and function of an evolutionarily conserved negative feedback mechanism in the Hippo pathway, as well as the functional difference between LATS1 and LATS2 in regulation of YAP.

  7. Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory Smad7 by a negative feedback mechanism.

    PubMed

    Zhu, Xiangyang; Topouzis, Stavros; Liang, Li-Fang; Stotish, Ronald L

    2004-06-21

    As a member of the TGF-beta superfamily, myostatin is a specific negative regulator of skeletal muscle mass. To identify the downstream components in the myostatin signal transduction pathway, we used a luciferase reporter assay to elucidate myostatin-induced activity. The myostatin-induced transcription requires the participation of regulatory Smads (Smad2/3) and Co-Smads (Smad4). Conversely, inhibitory Smad7, but not Smad6, dramatically reduces the myostatin-induced transcription. This Smad7 inhibition is enhanced by co-expression of Smurf1. We have also shown that Smad7 expression is stimulated by myostatin via the interaction between Smad2, Smad3, Smad4 and the SBE (Smad binding element) in the Smad7 promoter. These results suggest that the myostatin signal transduction pathway is regulated by Smad7 through a negative feedback mechanism.

  8. Coordination of the arc regulatory system and pheromone-mediated positive feedback in controlling the Vibrio fischeri lux operon.

    PubMed

    Septer, Alecia N; Stabb, Eric V

    2012-01-01

    Bacterial pheromone signaling is often governed both by environmentally responsive regulators and by positive feedback. This regulatory combination has the potential to coordinate a group response among distinct subpopulations that perceive key environmental stimuli differently. We have explored the interplay between an environmentally responsive regulator and pheromone-mediated positive feedback in intercellular signaling by Vibrio fischeri ES114, a bioluminescent bacterium that colonizes the squid Euprymna scolopes. Bioluminescence in ES114 is controlled in part by N-(3-oxohexanoyl)-L-homoserine lactone (3OC6), a pheromone produced by LuxI that together with LuxR activates transcription of the luxICDABEG operon, initiating a positive feedback loop and inducing luminescence. The lux operon is also regulated by environmentally responsive regulators, including the redox-responsive ArcA/ArcB system, which directly represses lux in culture. Here we show that inactivating arcA leads to increased 3OC6 accumulation to initiate positive feedback. In the absence of positive feedback, arcA-mediated control of luminescence was only ∼2-fold, but luxI-dependent positive feedback contributed more than 100 fold to the net induction of luminescence in the arcA mutant. Consistent with this overriding importance of positive feedback, 3OC6 produced by the arcA mutant induced luminescence in nearby wild-type cells, overcoming their ArcA repression of lux. Similarly, we found that artificially inducing ArcA could effectively repress luminescence before, but not after, positive feedback was initiated. Finally, we show that 3OC6 produced by a subpopulation of symbiotic cells can induce luminescence in other cells co-colonizing the host. Our results suggest that even transient loss of ArcA-mediated regulation in a sub-population of cells can induce luminescence in a wider community. Moreover, they indicate that 3OC6 can communicate information about both cell density and the state of

  9. A feedback regulatory pathway between LDL and alpha-1 proteinase inhibitor in chronic inflammation and infection.

    PubMed

    Bristow, Cynthia L; Modarresi, Rozbeh; Babayeva, Mariya A; LaBrunda, Michelle; Mukhtarzad, Roya; Trucy, Maylis; Franklin, Aaron; Reeves, Rudy E R; Long, Allegra; Mullen, Michael P; Cortes, Jose; Winston, Ronald

    2013-11-01

    Dietary lipids are transported via lymph to the liver and transformed to lipoproteins which bind to members of the low density lipoprotein receptor family (LDL-RFMs). Certain LDL-RFMs, e.g., very low density lipoprotein receptor (VLDLR), are also bound by inactivated proteinase inhibitors, the most abundant being α1proteinase inhibitor (α1PI, α1antitrypsin). Inflammation/infection, including HIV-1 infection, is accompanied by low levels of CD4+ T cells and active α1PI and high levels of inactivated α1PI. By inducing LDL-RFMs-mediated cellular locomotion, active α1PI regulates the number of CD4+ T cells. We sought to investigate whether CD4+ T cells and α1PI directly impact lipoprotein levels. At the cellular level, we show that active α1PI is required for VLDLR-mediated uptake of receptor-associated cargo, specifically CD4-bound HIV-1. We show that active α1PI levels linearly correlate with LDL levels in HIV-1 infected individuals (P<0.001) and that therapeutic, weekly infusions of active α1PI elevate the number of CD4+ T cells and HDL levels while lowering LDL levels in patients on antiretroviral therapy with controlled HIV-1. Based on the unusual combination of lipodystrophy and low levels of α1PI and CD4+ T cells in HIV-1 disease, we reveal that LDL and α1PI participate in a feedback regulatory pathway. We demonstrate integral roles for sequentially acting active and inactive α1PI in the uptake and recycling of receptors and cargo aggregated with VLDLR including CD4 and chemokine receptors. Evidence supports a role for α1PI as a primary sentinel to deploy the immune system as a consequence of its role in lipoprotein transport.

  10. Where and why soil moisture - precipitation feedback is negative: observational perspective over the African Sahel

    NASA Astrophysics Data System (ADS)

    Petrova, Irina; van Heerwaarden, Chiel; Guichard, Françoise

    2016-04-01

    Soil moisture affects initiation of convective rain storms and related precipitation variability. Yet, the physical mechanisms, strength and even the sign of the soil moisture - precipitation coupling remains uncertain, owning largely to a lack of extensive long-term observational products. Recent studies, built on global remote sensing data and probability statistics at 5° grid resolution, suggest the co-existence of a positive temporal (rain over temporally wetter soils) and a negative spatial (rain over spatially drier soils) coupling. However, the physical interpretation of the obtained statistical relationships remains subtle. Our present study revisits the physical nature of the observed spatial and temporal soil moisture - precipitation coupling (SMPC) at 1° grid resolution over the Sahelian domain (5-20°N, 20°W-40°E). Analysis of a 10-yr (2002-2011) satellite remote sensing data set of daily AMSR-E soil moisture and 3-hourly TMPA precipitation reveals a dipole pattern in the spatial SMPC over the region. In the S-W of the domain (Ghana, Benin), rainfall events indicate higher probability to occur over spatially drier soils, while they happen preferably over spatially wetter soils in the East (South Sudan). The dominant spatially negative coupling in the Sahel shows coherence with a negative temporal feedback. The latter contrasts with previous global findings and gives rise to additional questions on the atmospheric moisture origin in the event locations. The identified land surface factors contributing to the negative SMPC on the S-W include the presence of statistical extremes and higher relative to the rest of the domain drying rates of the upper surface layer prior events. In contrast, seasonal flooding of the territories in the East and an overall moister land surface and boundary layer characterize the locations of positive coupling in the South Sudan region. The contribution of atmospheric factors to the observed coupling relationships and

  11. Negative feedback regulation of auxin signaling by ATHB8/ACL5-BUD2 transcription module.

    PubMed

    Baima, Simona; Forte, Valentina; Possenti, Marco; Peñalosa, Andrés; Leoni, Guido; Salvi, Sergio; Felici, Barbara; Ruberti, Ida; Morelli, Giorgio

    2014-06-01

    The role of auxin as main regulator of vascular differentiation is well established, and a direct correlation between the rate of xylem differentiation and the amount of auxin reaching the (pro)cambial cells has been proposed. It has been suggested that thermospermine produced by ACAULIS5 (ACL5) and bushy and dwarf2 (BUD2) is one of the factors downstream to auxin contributing to the regulation of this process in Arabidopsis. Here, we provide an in-depth characterization of the mechanism through which ACL5 modulates xylem differentiation. We show that an increased level of ACL5 slows down xylem differentiation by negatively affecting the expression of homeodomain-leucine zipper (HD-ZIP) III and key auxin signaling genes. This mechanism involves the positive regulation of thermospermine biosynthesis by the HD-ZIP III protein Arabidopsis thaliana homeobox8 tightly controlling the expression of ACL5 and BUD2. In addition, we show that the HD-ZIP III protein REVOLUTA contributes to the increased leaf vascularization and long hypocotyl phenotype of acl5 likely by a direct regulation of auxin signaling genes such as like auxin resistant2 (LAX2) and LAX3. We propose that proper formation and differentiation of xylem depend on a balance between positive and negative feedback loops operating through HD-ZIP III genes.

  12. Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing.

    PubMed

    Watanabe, Reiko; Kanno, Shin-Ichiro; Mohammadi Roushandeh, Amaneh; Ui, Ayako; Yasui, Akira

    2017-10-05

    Nucleosome remodelling (NR) regulates transcription in an ATP-dependent manner, and influences gene expression required for development and cellular functions, including those involved in anti-cancer and anti-ageing processes. ATP-utilizing chromatin assembly and remodelling factor (ACF) and Brahma-associated factor (BAF) complexes, belonging to the ISWI and SWI/SNF families, respectively, are involved in various types of DNA repair. Suppression of several BAF factors makes U2OS cells significantly sensitive to X-rays, UV and especially to cisplatin, and these BAF factors contribute to the accumulation of repair proteins at various types of DNA damage and to DNA repair. Recent cancer genome sequencing and expression analysis has shown that BAF factors are frequently mutated or, more frequently, silenced in various types of cancer cells. Thus, those cancer cells are potentially X-ray- and especially cisplatin-sensitive, suggesting a way of optimizing current cancer therapy. Recent single-stem cell analysis suggests that mutations and epigenetic changes influence stem cell functionality leading to cellular ageing. Genetic and epigenetic changes in the BAF factors diminish DNA repair as well as transcriptional regulation activities, and DNA repair defects in turn negatively influence NR and transcriptional regulation. Thus, they build negative feedback loops, which accelerate both cellular senescence and transformation as common and rare cellular events, respectively, causing cellular ageing.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. © 2017 The Author(s).

  13. A CRY-BIC negative-feedback circuitry regulating blue light sensitivity of Arabidopsis.

    PubMed

    Wang, Xu; Wang, Qin; Han, Yun-Jeong; Liu, Qing; Gu, Lianfeng; Yang, Zhaohe; Su, Jun; Liu, Bobin; Zuo, Zecheng; He, Wenjin; Wang, Jian; Liu, Bin; Matsui, Minami; Kim, Jeong-Il; Oka, Yoshito; Lin, Chentao

    2017-08-22

    Cryptochromes are blue light receptors that regulate various light responses in plants. Arabidopsis cryptochrome 1 (CRY1) and cryptochrome 2 (CRY2) mediate blue light inhibition of hypocotyl elongation and long-day (LD) promotion of floral initiation. It has been reported recently that two negative regulators of Arabidopsis cryptochromes, Blue light Inhibitors of Cryptochromes 1 and 2 (BIC1 and BIC2), inhibit cryptochrome function by blocking blue light-dependent cryptochrome dimerization. However, it remained unclear how cryptochromes regulate the BIC gene activity. Here we show that cryptochromes mediate light activation of transcription of the BIC genes, by suppressing the activity of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), resulting in activation of the transcription activator ELONGATED HYPOCOTYL 5 (HY5) that is associated with chromatins of the BIC promoters. These results demonstrate a CRY-BIC negative-feedback circuitry that regulates the activity of each other. Surprisingly, phytochromes also mediate light activation of BIC transcription, suggesting a novel photoreceptor co-action mechanism to sustain blue light sensitivity of plants under the broad spectra of solar radiation in nature. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  14. Modulation of feedback-related negativity during trial-and-error exploration and encoding of behavioral shifts

    PubMed Central

    Sallet, Jérôme; Camille, Nathalie; Procyk, Emmanuel

    2013-01-01

    The feedback-related negativity (FRN) is a mid-frontal event-related potential (ERP) recorded in various cognitive tasks and associated with the onset of sensory feedback signaling decision outcome. Some properties of the FRN are still debated, notably its sensitivity to positive and negative reward prediction error (RPE)—i.e., the discrepancy between the expectation and the actual occurrence of a particular feedback,—and its role in triggering the post-feedback adjustment. In the present study we tested whether the FRN is modulated by both positive and negative RPE. We also tested whether an instruction cue indicating the need for behavioral adjustment elicited the FRN. We asked 12 human subjects to perform a problem-solving task where they had to search by trial and error which of five visual targets, presented on a screen, was associated with a correct feedback. After exploration and discovery of the correct target, subjects could repeat their correct choice until the onset of a visual signal to change (SC) indicative of a new search. Analyses showed that the FRN was modulated by both negative and positive prediction error (RPE). Finally, we found that the SC elicited an FRN-like potential on the frontal midline electrodes that was not modulated by the probability of that event. Collectively, these results suggest the FRN may reflect a mechanism that evaluates any event (outcome, instruction cue) signaling the need to engage adaptive actions. PMID:24294190

  15. Regulatory Forum Opinion Piece*: The Value of Publishing Negative Scientific Study Data.

    PubMed

    Boorman, Gary A; Foster, John R; Laast, Victoria A; Francke, Sabine

    2015-10-01

    Historically it has been easier to publish positive scientific results than negative data not supporting the research hypothesis. This appears to be increasing, with fewer negative studies appearing in the literature across many disciplines. Failure to recognize the value of negative results has important implications for the toxicology community. Implications include perpetuating scientific fields based upon selective or occasionally erroneous, positive results. One example is decreased vaccination rates and increased measles infections that can lead to childhood mortality following one erroneous positive study linking vaccination to adverse effects despite multiple negative studies. Publication of negative data that challenges existing paradigms enhances progress by stopping further investment in scientifically barren topics, decreases the use of animals, and focuses research in more fruitful areas. The National Toxicology Program (NTP) publishes both positive and negative rodent data. Retrospective analysis of the NTP database has provided insights on the carcinogenic process and in the gradual acceptance of using fewer animals in safety studies. This article proposes that careful publication of both positive and negative data can enhance product safety assessment, add robustness to safety determinations in the regulatory decision-making process, and should be actively encouraged by those determining journal editorial policy. © 2015 by The Author(s).

  16. Stochastic focusing coupled with negative feedback enables robust regulation in biochemical reaction networks.

    PubMed

    Milias-Argeitis, Andreas; Engblom, Stefan; Bauer, Pavol; Khammash, Mustafa

    2015-12-06

    Nature presents multiple intriguing examples of processes that proceed with high precision and regularity. This remarkable stability is frequently counter to modellers' experience with the inherent stochasticity of chemical reactions in the regime of low-copy numbers. Moreover, the effects of noise and nonlinearities can lead to 'counterintuitive' behaviour, as demonstrated for a basic enzymatic reaction scheme that can display stochastic focusing (SF). Under the assumption of rapid signal fluctuations, SF has been shown to convert a graded response into a threshold mechanism, thus attenuating the detrimental effects of signal noise. However, when the rapid fluctuation assumption is violated, this gain in sensitivity is generally obtained at the cost of very large product variance, and this unpredictable behaviour may be one possible explanation of why, more than a decade after its introduction, SF has still not been observed in real biochemical systems. In this work, we explore the noise properties of a simple enzymatic reaction mechanism with a small and fluctuating number of active enzymes that behaves as a high-gain, noisy amplifier due to SF caused by slow enzyme fluctuations. We then show that the inclusion of a plausible negative feedback mechanism turns the system from a noisy signal detector to a strong homeostatic mechanism by exchanging high gain with strong attenuation in output noise and robustness to parameter variations. Moreover, we observe that the discrepancy between deterministic and stochastic descriptions of stochastically focused systems in the evolution of the means almost completely disappears, despite very low molecule counts and the additional nonlinearity due to feedback. The reaction mechanism considered here can provide a possible resolution to the apparent conflict between intrinsic noise and high precision in critical intracellular processes.

  17. The negative feedback between anthropogenic ozone pollution and enhanced ocean emissions of iodine

    NASA Astrophysics Data System (ADS)

    Cuevas, Carlos A.; Prados-Roman, Cristina; Fernandez, Rafael P.; Kinnison, Douglas E.; Lamarque, Jean-Francois; Saiz-Lopez, Alfonso

    2015-04-01

    Natural emissions of iodine compounds from the oceans efficiently destroy atmospheric ozone reducing its positive radiative forcing effects in the troposphere. Emissions of inorganic iodine have been experimentally shown to depend on the deposition to the oceans of tropospheric ozone, whose concentrations have significantly increased (40%) since 1850 as a result of human activities. In this work a chemistry-climate model is used to quantify the current ocean emissions of inorganic iodine and evaluate the impact that the anthropogenic increase of tropospheric ozone has had on the natural cycle of iodine in the marine environment since pre-industrial times. Our results indicate that the human driven enhancement of tropospheric ozone has doubled the oceanic inorganic iodine emissions following the reaction of ozone with iodide at the sea surface. The consequent build-up of atmospheric iodine, with maximum enhancements of up to 70% with respect to preindustrial times in continental pollution outflow regions, has in turn accelerated the ozone chemical loss over the oceans with strong spatial patterns. We suggest that this ocean-atmosphere interaction represents a negative geochemical feedback loop by which current ocean emissions of iodine act as a natural buffer for ozone pollution and its radiative forcing in the global marine environment. This feedback represents a potentially important link between climate change and tropospheric O3 since the oceanic emissions of iodine are not only linked to surface O3, but also to SST and wind speed and might also be linked to climatically driven changes in the state of the world oceans.

  18. Negative feedback of extracellular ADP on ATP release in goldfish hepatocytes: a theoretical study.

    PubMed

    Chara, Osvaldo; Pafundo, Diego E; Schwarzbaum, Pablo J

    2010-06-21

    A mathematical model was built to account for the kinetic of extracellular ATP (ATPe) and extracellular ADP (ADPe) concentrations from goldfish hepatocytes exposed to hypotonicity. The model was based on previous experimental results on the time course of ATPe accumulation, ectoATPase activity, and cell viability [Pafundo et al., 2008]. The kinetic of ATPe is controlled by a lytic ATP flux, a non-lytic ATP flux, and ecto-ATPase activity, whereas ADPe kinetic is governed by a lytic ADP flux and both ecto-ATPase and ecto-ADPase activities. Non-lytic ATPe efflux was included as a diffusion equation modulated by ATPe activation (positive feedback) and ADPe inhibition (negative feedback). The model yielded physically meaningful and stable steady-state solutions, was able to fit the experimental time evolution of ATPe and simulated the concomitant kinetic of ADPe. According to the model during the first minute of hypotonicity the concentration of ATPe is mainly governed by both lytic and non-lytic ATP efflux, with almost no contribution from ecto-ATPase activity. Later on, ecto-ATPase activity becomes important in defining the time dependent decay of ATPe levels. ADPe inhibition of the non-lytic ATP efflux was strong, whereas ATPe activation was minimal. Finally, the model was able to predict the consequences of partial inhibition of ecto-ATPase activity on the ATPe kinetic, thus emulating the exposure of goldfish cells to hypotonic medium in the presence of the ATP analog AMP-PCP. The model predicts this analog to both inhibit ectoATPase activity and increase non-lytic ATP release.

  19. Chaos and hyperchaos in simple gene network with negative feedback and time delays.

    PubMed

    Khlebodarova, Tamara M; Kogai, Vladislav V; Fadeev, Stanislav I; Likhoshvai, Vitaly A

    2016-11-29

    Today there are examples that prove the existence of chaotic dynamics at all levels of organization of living systems, except intracellular, although such a possibility has been theoretically predicted. The lack of experimental evidence of chaos generation at the intracellular level in vivo may indicate that during evolution the cell got rid of chaos. This work allows the hypothesis that one of the possible mechanisms for avoiding chaos in gene networks can be a negative evolutionary selection, which prevents fixation or realization of regulatory circuits, creating too mild, from the biological point of view, conditions for the emergence of chaos. It has been shown that one of such circuits may be a combination of negative autoregulation of expression of transcription factors at the level of their synthesis and degradation. The presence of such a circuit results in formation of multiple branches of chaotic solutions as well as formation of hyperchaos with equal and sufficiently low values of the delayed argument that can be implemented not only in eukaryotic, but in prokaryotic cells.

  20. Phytochrome Signaling in Green Arabidopsis Seedlings: Impact Assessment of a Mutually Negative phyB–PIF Feedback Loop

    PubMed Central

    Leivar, Pablo; Monte, Elena; Cohn, Megan M.; Quail, Peter H.

    2012-01-01

    The reversibly red (R)/far-red (FR)-light-responsive phytochrome (phy) photosensory system initiates both the deetiolation process in dark-germinated seedlings upon first exposure to light, and the shade-avoidance process in fully deetiolated seedlings upon exposure to vegetational shade. The intracellular signaling pathway from the light-activated photoreceptor conformer (Pfr) to the transcriptional network that drives these responses involves direct, physical interaction of Pfr with a small subfamily of bHLH transcription factors, termed Phy-Interacting Factors (PIFs), which induces rapid PIF proteolytic degradation. In addition, there is evidence of further complexity in light-grown seedlings, whereby phyB–PIF interaction reciprocally induces phyB degradation, in a mutually-negative, feedback-loop configuration. Here, to assess the relative contributions of these antagonistic activities to the net phenotypic readout in light-grown seedlings, we have examined the magnitude of the light- and simulated-shade-induced responses of a pentuple phyBpif1pif3pif4pif5 (phyBpifq) mutant and various multiple pif-mutant combinations. The data (1) reaffirm that phyB is the predominant, if not exclusive, photoreceptor imposing the inhibition of hypocotyl elongation in deetiolating seedlings in response to prolonged continuous R irradiation and (2) show that the PIF quartet (PIF1, PIF3, PIF4, and PIF5) retain and exert a dual capacity to modulate hypocotyl elongation under these conditions, by concomitantly promoting cell elongation through intrinsic transcriptional-regulatory activity, and reducing phyB-inhibitory capacity through feedback-loop-induced phyB degradation. In shade-exposed seedlings, immunoblot analysis shows that the shade-imposed reduction in Pfr levels induces increases in the abundance of PIF3, and mutant analysis indicates that PIF3 acts, in conjunction with PIF4 and PIF5, to promote the known shade-induced acceleration of hypocotyl elongation. Conversely

  1. Spatio-temporal dynamics of a cell signal pathway with negative feedbacks: the MAPK/ERK pathway.

    PubMed

    Maya-Bernal, José Luis; Ramírez-Santiago, Guillermo

    2016-03-01

    We studied the spatio-temporal dynamics of a cell signal cascade with negative feedback that quantitatively emulates the regulative process that occurs in the Mitogen Activated Protein Kinase/Extracellular Regulated Kinase (MAPK/ERK) pathway. The model consists of a set of six coupled reaction-diffusion equations that describes the dynamics of the six-module pathway. In the basic module the active form of the protein transmits the signal to the next pathway’s module. As suggested by experiments, the model considers that the fifth module's kinase down-regulates the first and third modules. The feedback parameter is defined as, μ(r)( j)= k(kin)5/k(kin)(j), (j = 1, 3). We analysed the pathway's dynamics for μ(r)( j) = 0.10, 1.0, and 10 in the kinetic regimes: i) saturation of both kinases and phosphatases, ii) saturation of the phosphatases and iii) saturation of the kinases. For a regulated pathway the Total Activated Protein Profiles (TAPPs) as a function of time develop a maximum during the transient stage in the three kinetic regimes. These maxima become higher and their positions shift to longer times downstream. This scenario also applies to the TAPP's regulatory kinase that sums up its inhibitory action to that of the phosphatases leading to a maximum. Nevertheless, when μ(r)(j)= 1.0 , the TAPPs develop two maxima, with the second maximum being almost imperceptible. These results are in qualitative agreement with experimental data obtained from NIH 3T3 mouse fibroblasts. In addition, analyses of the stationary states as a function of position indicate that in the kinetic regime i) which is of physiological interest, signal transduction occurs with a relatively large propagation length for the three values of the regulative parameter. However, for μ(r)(j)= 0.10 , the sixth module concentration profile is transmitted with approximately 45% of its full value. The results obtained for μ(r)(j) = 10 , indicate that the first five concentration profiles are

  2. Negative-feedback regulation of excitation-contraction coupling in gastric smooth muscle.

    PubMed

    Ozaki, H; Zhang, L; Buxton, I L; Sanders, K M; Publicover, N G

    1992-12-01

    The role of phosphatidylinositol (PI) turnover in excitation-contraction coupling was investigated in canine antral smooth muscle. Acetylcholine (ACh; 0.1-1 microM) transiently increased tissue levels of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and increased the amplitudes of the plateau phase of slow waves and associated Ca2+ transients and phasic contractions. ACh also increased basal concentrations of cytosolic Ca2+ ([Ca2+]c), but these changes were not associated with an increase in resting tension. ATP (0.3 mM) had similar effects on Ins(1,4,5)P3 levels, basal [Ca2+]c, and resting tension. However, in contrast to the effects of ACh, ATP transiently reduced the amplitude of the plateau phase of slow waves and reduced the amplitudes of associated Ca2+ transients and phasic contractions. We investigated the possibility that two products of PI turnover, diacylglycerol (DAG) and Ins(1,4,5)P3, might provide negative feedback to regulate Ca2+ entry during slow waves. 1) DAG is known to activate protein kinase C (PKC). Activation of PKC by phorbol 12,13-dibutyrate (PDBu, 0.5 microM) reduced the amplitude of the plateau phase of slow waves and corresponding Ca2+ transients and phasic contractions. Assay of PKC showed that ACh, ATP, and PDBu stimulated enzyme activity. 2) Ins(1,4,5)P3 is known to increase [Ca2+]c by release of Ca2+ from internal stores. Basal [Ca2+]c was also increased by elevated external K+, ionomycin, thapsigargin, or caffeine. Each of these compounds reduced the amplitude and duration of slow waves. Results suggest that products of PI turnover may provide negative-feedback control of Ca2+ influx during slow waves, tending to reduce the amplitude of phasic contractile activity in gastric muscles. Differences in responses to ACh and ATP can be explained by a G protein-dependent mechanism in which ACh suppresses the voltage dependence of Ca(2+)-activated K+ channels.

  3. Dopaminergic Medication Modulates Learning from Feedback and Error-Related Negativity in Parkinson’s Disease: A Pilot Study

    PubMed Central

    Volpato, Chiara; Schiff, Sami; Facchini, Silvia; Silvoni, Stefano; Cavinato, Marianna; Piccione, Francesco; Antonini, Angelo; Birbaumer, Niels

    2016-01-01

    Dopamine systems mediate key aspects of reward learning. Parkinson’s disease (PD) represents a valuable model to study reward mechanisms because both the disease process and the anti-Parkinson medications influence dopamine neurotransmission. The aim of this pilot study was to investigate whether the level of levodopa differently modulates learning from positive and negative feedback and its electrophysiological correlate, the error related negativity (ERN), in PD. Ten PD patients and ten healthy participants performed a two-stage reinforcement learning task. In the Learning Phase, they had to learn the correct stimulus within a stimulus pair on the basis of a probabilistic positive or negative feedback. Three sets of stimulus pairs were used. In the Testing Phase, the participants were tested with novel combinations of the stimuli previously experienced to evaluate whether they learned more from positive or negative feedback. PD patients performed the task both ON- and OFF-levodopa in two separate sessions while they remained on stable therapy with dopamine agonists. The electroencephalogram (EEG) was recorded during the task. PD patients were less accurate in negative than positive learning both OFF- and ON-levodopa. In the OFF-levodopa state they were less accurate than controls in negative learning. PD patients had a smaller ERN amplitude OFF- than ON-levodopa only in negative learning. In the OFF-levodopa state they had a smaller ERN amplitude than controls in negative learning. We hypothesize that high tonic dopaminergic stimulation due to the dopamine agonist medication, combined to the low level of phasic dopamine due to the OFF-levodopa state, could prevent phasic “dopamine dips” indicated by the ERN needed for learning from negative feedback. PMID:27822182

  4. Cell Shape and Negative Links in Regulatory Motifs Together Control Spatial Information Flow in Signaling Networks

    PubMed Central

    Neves, Susana R.; Tsokas, Panayiotis; Sarkar, Anamika; Grace, Elizabeth A.; Rangamani, Padmini; Taubenfeld, Stephen M.; Alberini, Cristina M.; Schaff, James C.; Blitzer, Robert D.; Moraru, Ion I.; Iyengar, Ravi

    2009-01-01

    Summary The role of cell size and shape in controlling local intracellular signaling reactions, and how this spatial information originates and is propagated, is not well understood. We have used partial differential equations to model the flow of spatial information from the β-adrenergic receptor to MAPK1,2 through the cAMP/PKA/B-Raf/MAPK1,2 network in neurons using real geometries. The numerical simulations indicated that cell shape controls the dynamics of local biochemical activity of signal-modulated negative regulators, such as phosphodiesterases and protein phosphatases within regulatory loops to determine the size of microdomains of activated signaling components. The model prediction that negative regulators control the flow of spatial information to downstream components was verified experimentally in rat hippocampal slices. These results suggest a mechanism by which cellular geometry, the presence of regulatory loops with negative regulators, and key reaction rates all together control spatial information transfer and microdomain characteristics within cells. PMID:18485874

  5. Self-verification and social anxiety: preference for negative social feedback and low social self-esteem.

    PubMed

    Valentiner, David P; Skowronski, John J; McGrath, Patrick B; Smith, Sarah A; Renner, Kerry A

    2011-10-01

    A self-verification model of social anxiety views negative social self-esteem as a core feature of social anxiety. This core feature is proposed to be maintained through self-verification processes, such as by leading individuals with negative social self-esteem to prefer negative social feedback. This model is tested in two studies. In Study 1, questionnaires were administered to a college sample (N = 317). In Study 2, questionnaires were administered to anxiety disordered patients (N = 62) before and after treatment. Study 1 developed measures of preference for negative social feedback and social self-esteem, and provided evidence of their incremental validity in a college sample. Study 2 found that these two variables are not strongly related to fears of evaluation, are relatively unaffected by a treatment that targets such fears, and predict residual social anxiety following treatment. Overall, these studies provide preliminary evidence for a self-verification model of social anxiety.

  6. Distributions for negative-feedback-regulated stochastic gene expression: dimension reduction and numerical solution of the chemical master equation.

    PubMed

    Zeron, Eduardo S; Santillán, Moisés

    2010-05-21

    In this work we introduce a novel approach to study biochemical noise. It comprises a simplification of the master equation of complex reaction schemes (via an adiabatic approximation) and the numerical solution of the reduced master equation. The accuracy of this procedure is tested by comparing its results with analytic solutions (when available) and with Gillespie stochastic simulations. We further employ our approach to study the stochastic expression of a simple gene network, which is subject to negative feedback regulation at the transcriptional level. Special attention is paid to the influence of negative feedback on the amplitude of intrinsic noise, as well as on the relaxation rate of the system probability distribution function to the steady solution. Our results suggest the existence of an optimal feedback strength that maximizes this relaxation rate.

  7. Negative feedback regulation is responsible for the non-linear modulation of photosynthetic activity in plants and cyanobacteria exposed to a dynamic light environment.

    PubMed

    Nedbal, Ladislav; Brezina, Vítezslav; Adamec, Frantisek; Stys, Dalibor; Oja, Vello; Laisk, Agu; Govindjee

    2003-10-17

    Photosynthetic organisms exposed to a dynamic light environment exhibit complex transients of photosynthetic activities that are strongly dependent on the temporal pattern of the incident irradiance. In a harmonically modulated light of intensity I approximately const.+sin(omegat), chlorophyll fluorescence response consists of a steady-state component, a component modulated with the angular frequency of the irradiance omega and several upper harmonic components (2omega, 3omega and higher). Our earlier reverse engineering analysis suggests that the non-linear response can be caused by a negative feedback regulation of photosynthesis. Here, we present experimental evidence that the negative feedback regulation of the energetic coupling between phycobilisome and Photosystem II (PSII) in the cyanobacterium Synechocystis sp. PCC6803 indeed results in the appearance of upper harmonic modes in the chlorophyll fluorescence emission. Dynamic changes in the coupling of the phycobilisome to PSII are not accompanied by corresponding antiparallel changes in the Photosystem I (PSI) excitation, suggesting a regulation limited to PSII. Strong upper harmonic modes were also found in the kinetics of the non-photochemical quenching (NPQ) of chlorophyll fluorescence, of the P700 redox state and of the CO(2) assimilation in tobacco (Nicotiana tabaccum) exposed to harmonically modulated light. They are ascribed to negative feedback regulation of the reactions of the Calvin-Benson cycle limiting the photosynthetic electron transport. We propose that the observed non-linear response of photosynthesis may also be relevant in a natural light environment that is modulated, e.g., by ocean waves, moving canopy or by varying cloud cover. Under controlled laboratory conditions, the non-linear photosynthetic response provides a new insight into dynamics of the regulatory processes.

  8. A dynamical negative climate feedback: Surface cooling of the SE Pacific

    NASA Astrophysics Data System (ADS)

    Garreaud, R. D.; Van den Hoof, C.

    2014-12-01

    The Southeast (SE) Pacific has experienced a marked cooling since the late 70's, as detected in stations along the west coast of South America and satellite derived SST observations. The observed cooling further extends into the tropical Pacific where it has been mostly interpreted as natural variability and related to the negative phase of the PDO. While the CMIP-5 historical simulations in general fail to detect the cooling over the Pacific during the last few decades, the multi-model trend does shows a minimum warming over the SE Pacific and a few models do show a cooling there, suggesting that some of this trend can be a interpreted as a forced response to increase greenhouse gas concentrations. Considering the CMIP5 historical runs and reanalysis data we show that the cooling trend over the SE Pacific is related with the enhanced anticyclonic circulation in this region but exhibits no correlation with the trends of the trade winds. The reinforced SE Pacific anticyclone -seen both in the reanalysis and models- drives stronger low-level southeasterly winds which can cool the ocean surface through enhanced latent heat flux (evaporation), particularly over the extremely dry SE Pacific. We finally show that the increase in sea-level-pressure over the southern fringe of the SE Pacific can be associated with the expansion of the Hadley Cell, a trend that has been observed and projected to continue in the future in concert with the increase of greenhouse gas concentrations. Therefore, the resulting cooling over a vast region of the SE Pacific can in turn act as a negative dynamical feedback on global warming. Indeed, the regional anomaly cooling off the west coast of South America appears as a robust feature in future climate prediction that also scale with the greenhouse gas concentrations.

  9. The interplay between feedback-related negativity and individual differences in altruistic punishment: An EEG study.

    PubMed

    Mothes, Hendrik; Enge, Sören; Strobel, Alexander

    2016-04-01

    To date, the interplay betwexen neurophysiological and individual difference factors in altruistic punishment has been little understood. To examine this issue, 45 individuals participated in a Dictator Game with punishment option while the feedback-related negativity (FRN) was derived from the electroencephalogram (EEG). Unlike previous EEG studies on the Dictator Game, we introduced a third party condition to study the effect of fairness norm violations in addition to employing a first person perspective. For the first time, we also examined the role of individual differences, specifically fairness concerns, positive/negative affectivity, and altruism/empathy as well as recipients' financial situation during altruistic punishment. The main results show that FRN amplitudes were more pronounced for unfair than for fair assignments in both the first person and third party perspectives. These findings suggest that FRN amplitudes are sensitive to fairness norm violations and play a crucial role in the recipients' evaluation of dictator assignments. With respect to individual difference factors, recipients' current financial situation affected the FRN fairness effect in the first person perspective, indicating that when being directly affected by the assignments, more affluent participants experienced stronger violations of expectations in altruistic punishment decisions. Regarding individual differences in trait empathy, in the third party condition FRN amplitudes were more pronounced for those who scored lower in empathy. This may suggest empathy as another motive in third party punishment. Independent of the perspective taken, higher positive affect was associated with more punishment behavior, suggesting that positive emotions may play an important role in restoring violated fairness norms.

  10. Protein kinase Calpha activation by RET: evidence for a negative feedback mechanism controlling RET tyrosine kinase.

    PubMed

    Andreozzi, Francesco; Melillo, Rosa Marina; Carlomagno, Francesca; Oriente, Francesco; Miele, Claudia; Fiory, Francesca; Santopietro, Stefania; Castellone, Maria Domenica; Beguinot, Francesco; Santoro, Massimo; Formisano, Pietro

    2003-05-15

    We have studied the role of protein kinase C (PKC) in signaling of the RET tyrosine kinase receptor. By using a chimeric receptor (E/R) in which RET kinase can be tightly controlled by the addition of epidermal growth factor (EGF), we have found that RET triggering induces a strong increase of PKCalpha, PKCdelta and PKCzeta activity and that PKCalpha, not PKCdelta and PKCzeta, forms a ligand-dependent protein complex with E/R. We have identified tyrosine 1062 in the RET carboxyl-terminal tail as the docking site for PKCalpha. Block of PKC activity by bisindolylmaleimide or chronic phorbol esters treatment decreased EGF-induced serine/threonine phosphorylation of E/R, while it caused a similarly sized increase of EGF-induced E/R tyrosine kinase activity and mitogenic signaling. Conversely, acute phorbol esters treatment, which promotes PKC activity, increased the levels of E/R serine/threonine phosphorylation and significantly decreased its phosphotyrosine content. A threefold reduction of tyrosine phosphorylation levels of the constitutively active RET/MEN2A oncoprotein was observed upon coexpression with PKCalpha. We conclude that RET binds to and activates PKCalpha. PKCalpha, in turn, causes RET phosphorylation and downregulates RET tyrosine kinase and downstream signaling, thus functioning as a negative feedback loop to modulate RET activity.

  11. Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion

    PubMed Central

    van der Meulen, Talitha; Donaldson, Cynthia J.; Cáceres, Elena; Hunter, Anna E.; Cowing–Zitron, Christopher; Pound, Lynley D.; Adams, Michael W.; Zembrzycki, Andreas; Grove, Kevin L.; Huising, Mark O.

    2015-01-01

    The peptide hormone Urocortin3 (Ucn3) is abundantly expressed by mature beta cells, yet its physiological role is unknown. Here we demonstrate that Ucn3 is stored and co–released with insulin and potentiates glucose–stimulated somatostatin secretion via cognate receptor on delta cells. Further, we found that islets lacking endogenous Ucn3 demonstrate fewer delta cells, reduced somatostatin content, impaired somatostatin secretion and exaggerated insulin release, and that these defects are rectified by synthetic Ucn3 in vitro. Our observations indicate that the paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. Moreover, Ucn3 is markedly depleted from beta cells in mouse and macaque diabetes models and in human diabetic islets. This suggests that Ucn3 is a key contributor to stable glycemic control whose reduction during diabetes aggravates glycemic volatility and contributes to the pathophysiology of this disease. PMID:26076035

  12. Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion.

    PubMed

    van der Meulen, Talitha; Donaldson, Cynthia J; Cáceres, Elena; Hunter, Anna E; Cowing-Zitron, Christopher; Pound, Lynley D; Adams, Michael W; Zembrzycki, Andreas; Grove, Kevin L; Huising, Mark O

    2015-07-01

    The peptide hormone urocortin3 (Ucn3) is abundantly expressed by mature beta cells, yet its physiological role is unknown. Here we demonstrate that Ucn3 is stored and co-released with insulin and potentiates glucose-stimulated somatostatin secretion via cognate receptors on delta cells. Further, we found that islets lacking endogenous Ucn3 have fewer delta cells, reduced somatostatin content, impaired somatostatin secretion, and exaggerated insulin release, and that these defects are rectified by treatment with synthetic Ucn3 in vitro. Our observations indicate that the paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. Moreover, Ucn3 is markedly depleted from beta cells in mouse and macaque models of diabetes and in human diabetic islets. This suggests that Ucn3 is a key contributor to stable glycemic control, whose reduction during diabetes aggravates glycemic volatility and contributes to the pathophysiology of this disease.

  13. Who Deserves My Trust? Cue-Elicited Feedback Negativity Tracks Reputation Learning in Repeated Social Interactions.

    PubMed

    Li, Diandian; Meng, Liang; Ma, Qingguo

    2017-01-01

    Trust and trustworthiness contribute to reciprocal behavior and social relationship development. To make better decisions, people need to evaluate others' trustworthiness. They often assess this kind of reputation by learning through repeated social interactions. The present event-related potential (ERP) study explored the reputation learning process in a repeated trust game where subjects made multi-round decisions of investment to different partners. We found that subjects gradually learned to discriminate trustworthy partners from untrustworthy ones based on how often their partners reciprocated the investment, which was indicated by their own investment decisions. Besides, electrophysiological data showed that the faces of the untrustworthy partners induced larger feedback negativity (FN) amplitude than those of the trustworthy partners, but only in the late phase of the game. The ERP results corresponded with the behavioral pattern and revealed that the learned trustworthiness differentiation was coded by the cue-elicited FN component. Consistent with previous research, our findings suggest that the anterior cue-elicited FN reflects the reputation appraisal and tracks the reputation learning process in social interactions.

  14. A Negative Feedback Loop Between Autophagy and Immune Responses in Mycobacterium leprae Infection.

    PubMed

    Ma, Yuelong; Zhang, Li; Lu, Jie; Shui, Tiejun; Chen, Jia; Yang, Jun; Yuan, Joanna; Liu, Yeqiang; Yang, Degang

    2017-01-01

    The obligate intracellular bacterium Mycobacterium leprae is the causative agent of leprosy and primarily infects macrophages, leading to irreversible nerve damage and deformities. So far, the underlying reasons allowing M. leprae to persist and propagate in macrophages, despite the presence of cellular immunity, are still a mystery. Here, we investigated the role of autophagy, a cellular process that degrades cytosolic materials and intracellular pathogens, in M. leprae infection. We found that live M. leprae infection of macrophages resulted in significantly elevated autophagy level. However, macrophages with high autophagy levels preferentially expressed lower levels of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-12, and tumor necrosis factor-α, and preferentially primed anti-inflammatory T cells responses, characterized by high IL-10 and low interferon-γ, granzyme B, and perforin responses. These anti-inflammatory T cells could suppress further induction of autophagy, leading to improved survival of intracellular M. leprae in infected macrophages. Therefore, these data demonstrated that although autophagy had a role in eliminating intracellular pathogens, the induction of autophagy resulted in anti-inflammatory immune responses, which suppressed autophagy in a negative feedback loop and allowed the persistence of M. leprae.

  15. Dorsal horn convergent neurones: negative feedback triggered by spatial summation of nociceptive afferents.

    PubMed

    Bouhassira, D; Gall, O; Chitour, D; Le Bars, D

    1995-08-01

    In order to investigate the effects of spatial summation on the spinal transmission of nociceptive information, we compared in intact and spinal anaesthetized rats, responses of lumbar convergent neurones elicited by noxious heat stimuli applied to areas of the body much greater in size than their individual excitatory receptive fields, located distally on the hindpaw. Twenty-four neurones were recorded in each group of animals. For each neurone, 4 successive immersions of increasing areas (1.9-18 cm2) of the ipsilateral hindpaw in a 48 degrees C water bath (15-sec duration) were performed with 10-min intervals in a randomized and balanced order. In intact animals, the responses of convergent neurones progressively decreased when the area of noxious thermal stimulation reached and then exceeded approximately twice the area of their individual excitatory receptive fields. This decrease was highly significant for 18 cm2 which represents approximately 10-fold the mean of the receptive field areas. Such a phenomenon was not observed for neurones recorded in spinal animals although their excitatory receptive field areas were not significantly different. These results suggest that the activation of a large population of nociceptive afferents triggers supraspinally mediated negative feed-back loop modulating the responses of convergent neurones.

  16. NF-κB regulates neuronal ankyrin-G via a negative feedback loop

    PubMed Central

    König, Hans-Georg; Schwamborn, Robert; Andresen, Silke; Kinsella, Sinéad; Watters, Orla; Fenner, Beau; Prehn, Jochen H. M.

    2017-01-01

    The axon initial segment (AIS) is a neuronal compartment defined by ankyrin-G expression. We here demonstrate that the IKK-complex co-localizes and interacts with the cytoskeletal anchor protein ankyrin-G in immunoprecipitation and proximity-ligation experiments in cortical neurons. Overexpression of the 270 kDa variant of ankyrin-G suppressed, while gene-silencing of ankyrin-G expression increased nuclear factor-κB (NF-κB) activity in primary neurons, suggesting that ankyrin-G sequesters the transcription factor in the AIS. We also found that p65 bound to the ank3 (ankyrin-G) promoter sequence in chromatin immunoprecipitation analyses thereby increasing ank3 expression and ankyrin-G levels at the AIS. Gene-silencing of p65 or ankyrin-G overexpression suppressed ank3 reporter activity. Collectively these data demonstrate that p65/NF-κB controls ankyrin-G levels via a negative feedback loop, thereby linking NF-κB signaling with neuronal polarity and axonal plasticity. PMID:28181483

  17. Chronic Psychosocial Stress and Negative Feedback Inhibition: Enhanced Hippocampal Glucocorticoid Signaling despite Lower Cytoplasmic GR Expression.

    PubMed

    Füchsl, Andrea M; Reber, Stefan O

    2016-01-01

    Chronic subordinate colony housing (CSC), a pre-clinically validated mouse model for chronic psychosocial stress, results in increased basal and acute stress-induced plasma adrenocorticotropic hormone (ACTH) levels. We assessed CSC effects on hippocampal glucocorticoid (GC) receptor (GR), mineralocorticoid receptor (MR), and FK506 binding protein (FKBP51) expression, acute heterotypic stressor-induced GR translocation, as well as GC effects on gene expression and cell viability in isolated hippocampal cells. CSC mice showed decreased GR mRNA and cytoplasmic protein levels compared with single-housed control (SHC) mice. Basal and acute stress-induced nuclear GR protein expression were comparable between CSC and SHC mice, as were MR and FKBP51 mRNA and/or cytoplasmic protein levels. In vitro the effect of corticosterone (CORT) on hippocampal cell viability and gene transcription was more pronounced in CSC versus SHC mice. In summary, CSC mice show an, if at all, increased hippocampal GC signaling capacity despite lower cytoplasmic GR protein expression, making negative feedback deficits in the hippocampus unlikely to contribute to the increased ACTH drive following CSC.

  18. A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory

    PubMed Central

    Mathew, Rebecca S; Tatarakis, Antonis; Rudenko, Andrii; Johnson-Venkatesh, Erin M; Yang, Yawei J; Murphy, Elisabeth A; Todd, Travis P; Schepers, Scott T; Siuti, Nertila; Martorell, Anthony J; Falls, William A; Hammack, Sayamwong E; Walsh, Christopher A; Tsai, Li-Huei; Umemori, Hisashi; Bouton, Mark E; Moazed, Danesh

    2016-01-01

    The SNARE-mediated vesicular transport pathway plays major roles in synaptic remodeling associated with formation of long-term memories, but the mechanisms that regulate this pathway during memory acquisition are not fully understood. Here we identify miRNAs that are up-regulated in the rodent hippocampus upon contextual fear-conditioning and identify the vesicular transport and synaptogenesis pathways as the major targets of the fear-induced miRNAs. We demonstrate that miR-153, a member of this group, inhibits the expression of key components of the vesicular transport machinery, and down-regulates Glutamate receptor A1 trafficking and neurotransmitter release. MiR-153 expression is specifically induced during LTP induction in hippocampal slices and its knockdown in the hippocampus of adult mice results in enhanced fear memory. Our results suggest that miR-153, and possibly other fear-induced miRNAs, act as components of a negative feedback loop that blocks neuronal hyperactivity at least partly through the inhibition of the vesicular transport pathway. DOI: http://dx.doi.org/10.7554/eLife.22467.001 PMID:28001126

  19. Negative feedback from CaSR signaling to aquaporin-2 sensitizes vasopressin to extracellular Ca2.

    PubMed

    Ranieri, Marianna; Tamma, Grazia; Di Mise, Annarita; Russo, Annamaria; Centrone, Mariangela; Svelto, Maria; Calamita, Giuseppe; Valenti, Giovanna

    2015-07-01

    We previously described that high luminal Ca(2+) in the renal collecting duct attenuates short-term vasopressin-induced aquaporin-2 (AQP2) trafficking through activation of the Ca(2+)-sensing receptor (CaSR). Here, we evaluated AQP2 phosphorylation and permeability, in both renal HEK-293 cells and in the dissected inner medullary collecting duct, in response to specific activation of CaSR with NPS-R568. In CaSR-transfected cells, CaSR activation drastically reduced the basal levels of AQP2 phosphorylation at S256 (AQP2-pS256), thus having an opposite effect to vasopressin action. When forskolin stimulation was performed in the presence of NPS-R568, the increase in AQP2-pS256 and in the osmotic water permeability were prevented. In the freshly isolated inner mouse medullar collecting duct, stimulation with forskolin in the presence of NPS-R568 prevented the increase in AQP2-pS256 and osmotic water permeability. Our data demonstrate that the activation of CaSR in the collecting duct prevents the cAMP-dependent increase in AQP2-pS256 and water permeability, counteracting the short-term vasopressin response. By extension, our results suggest the attractive concept that CaSR expressed in distinct nephron segments exerts a negative feedback on hormones acting through cAMP, conferring high sensitivity of hormone to extracellular Ca(2+).

  20. Chronic Psychosocial Stress and Negative Feedback Inhibition: Enhanced Hippocampal Glucocorticoid Signaling despite Lower Cytoplasmic GR Expression

    PubMed Central

    Füchsl, Andrea M.; Reber, Stefan O.

    2016-01-01

    Chronic subordinate colony housing (CSC), a pre-clinically validated mouse model for chronic psychosocial stress, results in increased basal and acute stress-induced plasma adrenocorticotropic hormone (ACTH) levels. We assessed CSC effects on hippocampal glucocorticoid (GC) receptor (GR), mineralocorticoid receptor (MR), and FK506 binding protein (FKBP51) expression, acute heterotypic stressor-induced GR translocation, as well as GC effects on gene expression and cell viability in isolated hippocampal cells. CSC mice showed decreased GR mRNA and cytoplasmic protein levels compared with single-housed control (SHC) mice. Basal and acute stress-induced nuclear GR protein expression were comparable between CSC and SHC mice, as were MR and FKBP51 mRNA and/or cytoplasmic protein levels. In vitro the effect of corticosterone (CORT) on hippocampal cell viability and gene transcription was more pronounced in CSC versus SHC mice. In summary, CSC mice show an, if at all, increased hippocampal GC signaling capacity despite lower cytoplasmic GR protein expression, making negative feedback deficits in the hippocampus unlikely to contribute to the increased ACTH drive following CSC. PMID:27057751

  1. Who Deserves My Trust? Cue-Elicited Feedback Negativity Tracks Reputation Learning in Repeated Social Interactions

    PubMed Central

    Li, Diandian; Meng, Liang; Ma, Qingguo

    2017-01-01

    Trust and trustworthiness contribute to reciprocal behavior and social relationship development. To make better decisions, people need to evaluate others’ trustworthiness. They often assess this kind of reputation by learning through repeated social interactions. The present event-related potential (ERP) study explored the reputation learning process in a repeated trust game where subjects made multi-round decisions of investment to different partners. We found that subjects gradually learned to discriminate trustworthy partners from untrustworthy ones based on how often their partners reciprocated the investment, which was indicated by their own investment decisions. Besides, electrophysiological data showed that the faces of the untrustworthy partners induced larger feedback negativity (FN) amplitude than those of the trustworthy partners, but only in the late phase of the game. The ERP results corresponded with the behavioral pattern and revealed that the learned trustworthiness differentiation was coded by the cue-elicited FN component. Consistent with previous research, our findings suggest that the anterior cue-elicited FN reflects the reputation appraisal and tracks the reputation learning process in social interactions. PMID:28663727

  2. Negative feedback regulation of Homer 1a on norepinephrine-dependent cardiac hypertrophy.

    PubMed

    Chiarello, Carmelina; Bortoloso, Elena; Carpi, Andrea; Furlan, Sandra; Volpe, Pompeo

    2013-07-15

    Homers are scaffolding proteins that modulate diverse cell functions being able to assemble signalling complexes. In this study, the presence, sub-cellular distribution and function of Homer 1 was investigated. Homer 1a and Homer 1b/c are constitutively expressed in cardiac muscle of both mouse and rat and in HL-1 cells, a cardiac cell line. As judged by confocal immunofluorescence microscopy, Homer 1a displays sarcomeric and peri-nuclear localization. In cardiomyocytes and cultured HL-1 cells, the hypertrophic agonist norepinephrine (NE) induces α1-adrenergic specific Homer 1a over-expression, with a two-to-three-fold increase within 1h, and no up-regulation of Homer 1b/c, as judged by Western blot and qPCR. In HL-1 cells, plasmid-driven over-expression of Homer 1a partially antagonizes activation of ERK phosphorylation and ANF up-regulation, two well-established, early markers of hypertrophy. At the morphometric level, NE-induced increase of cell size is likewise and partially counteracted by exogenous Homer 1a. Under the same experimental conditions, Homer 1b/c does not have any effect on ANF up-regulation nor on cell hypertrophy. Thus, Homer 1a up-regulation is associated to early stages of cardiac hypertrophy and appears to play a negative feedback regulation on molecular transducers of hypertrophy. Copyright © 2013. Published by Elsevier Inc.

  3. Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons.

    PubMed

    Dubois, Sharon L; Acosta-Martínez, Maricedes; DeJoseph, Mary R; Wolfe, Andrew; Radovick, Sally; Boehm, Ulrich; Urban, Janice H; Levine, Jon E

    2015-03-01

    Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor α (ERα) and exert control over GnRH/LH secretion in female rodents. It has been proposed that estradiol (E2) activation of ERα in kisspeptin neurons in the arcuate nucleus (ARC) suppresses GnRH/LH secretion (negative feedback), whereas E2 activation of ERα in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback). To test these hypotheses, we generated mice bearing kisspeptin cell-specific deletion of ERα (KERαKO) and treated them with E2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion. Using negative feedback regimens, as expected, E2 effectively suppressed LH levels in ovariectomized (OVX) wild-type (WT) mice to the levels seen in ovary-intact mice. Surprisingly, however, despite the fact that E2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KERαKO mice, E2 also effectively decreased LH levels in OVX KERαKO mice to the levels seen in ovary-intact mice. Conversely, using a positive feedback regimen, E2 stimulated LH surges in WT mice, but had no effect in KERαKO mice. These experiments clearly demonstrate that ERα in kisspeptin neurons is required for the positive, but not negative feedback actions of E2 on GnRH/LH secretion in adult female mice. It remains to be determined whether the failure of KERαKO mice to exhibit GnRH/LH surges reflects the role of ERα in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both.

  4. Feedback-related negativity is enhanced in adolescence during a gambling task with and without probabilistic reinforcement learning.

    PubMed

    Martínez-Velázquez, Eduardo S; Ramos-Loyo, Julieta; González-Garrido, Andrés A; Sequeira, Henrique

    2015-01-21

    Feedback-related negativity (FRN) is a negative deflection that appears around 250 ms after the gain or loss of feedback to chosen alternatives in a gambling task in frontocentral regions following outcomes. Few studies have reported FRN enhancement in adolescents compared with adults in a gambling task without probabilistic reinforcement learning, despite the fact that learning from positive or negative consequences is crucial for decision-making during adolescence. Therefore, the aim of the present research was to identify differences in FRN amplitude and latency between adolescents and adults on a gambling task with favorable and unfavorable probabilistic reinforcement learning conditions, in addition to a nonlearning condition with monetary gains and losses. Higher rate scores of high-magnitude choices during the final 30 trials compared with the first 30 trials were observed during the favorable condition, whereas lower rates were observed during the unfavorable condition in both groups. Higher FRN amplitude in all conditions and longer latency in the nonlearning condition were observed in adolescents compared with adults and in relation to losses. Results indicate that both the adolescents and the adults improved their performance in relation to positive and negative feedback. However, the FRN findings suggest an increased sensitivity to external feedback to losses in adolescents compared with adults, irrespective of the presence or absence of probabilistic reinforcement learning. These results reflect processing differences on the neural monitoring system and provide new perspectives on the dynamic development of an adolescent's brain.

  5. Negative Feedback Control of Pituitary Thyroid-stimulating Hormone Synthesis and Secretion by Thyroid Hormones during Metamorphosis in Xenopus laevis

    EPA Science Inventory

    A basic understanding of the endocrinology of the hypothalamic-pituitary-thyroid (HPT) axis of anuran larvae is necessary for predicting the consequences of HPT perturbation by thyroid-disrupting chemicals (TDCs) on the whole organism. This project examined negative feedback con...

  6. Negative Feedback Control of Pituitary Thyroid-stimulating Hormone Synthesis and Secretion by Thyroid Hormones during Metamorphosis in Xenopus laevis

    EPA Science Inventory

    A basic understanding of the endocrinology of the hypothalamic-pituitary-thyroid (HPT) axis of anuran larvae is necessary for predicting the consequences of HPT perturbation by thyroid-disrupting chemicals (TDCs) on the whole organism. This project examined negative feedback con...

  7. PATZ1 induces PP4R2 to form a negative feedback loop on IKK/NF-κB signaling in lung cancer

    PubMed Central

    Ho, Ming-Yi; Liang, Chi-Ming; Liang, Shu-Mei

    2016-01-01

    Activation of IKK enhances NF-κB signaling to facilitate cancer cell migration, invasion and metastasis. Here, we uncover the existence of a negative feedback loop of IKK. The transcription factor PATZ1 induces protein phosphatase-4 (PP4) regulatory subunit 2 (PP4R2) in an IKK-dependent manner. PP4R2 enhances the binding of PP4 to phosphorylated IKK to inactivate IKK/NF-κB signaling during sustained stimulation by cellular stimuli such as growth factors and inflammatory mediators. Matched pair studies reveal that primary lung cancers express more PATZ1 and PP4R2 than lymph node metastases in patients. Ectopic PATZ1 decreases invasion/colonization of lung cancers and prolongs the survival of xenograft mice. These effects of PATZ1 are reversed by downregulating PP4R2. Our results suggest that PATZ1 and PP4R2 provide negative feedback on IKK/NF-κB signaling to prevent cancer cells from over-stimulation from cellular stimuli; a decline in PATZ1 and PP4R2 is functionally associated with cancer migration/invasion and agents enhancing PATZ1 and PP4R2 are worth exploring to prevent invasion/metastasis of lung cancers. PMID:27391343

  8. Dictyostelium discoideum Nucleoside Diphosphate Kinase C Plays a Negative Regulatory Role in Phagocytosis, Macropinocytosis and Exocytosis

    PubMed Central

    Annesley, Sarah J.; Bago, Ruzica; Bosnar, Maja Herak; Filic, Vedrana; Marinović, Maja; Weber, Igor; Mehta, Anil; Fisher, Paul R.

    2011-01-01

    Nucleoside diphosphate kinases (NDPKs) are ubiquitous phosphotransfer enzymes responsible for producing most of the nucleoside triphosphates except for ATP. This role is important for the synthesis of nucleic acids and proteins and the metabolism of sugars and lipids. Apart from this housekeeping role NDPKs have been shown to have many regulatory functions in diverse cellular processes including proliferation and endocytosis. Although the protein has been shown to have a positive regulatory role in clathrin- and dynamin-mediated micropinocytosis, its roles in macropinocytosis and phagocytosis have not been studied. The additional non-housekeeping roles of NDPK are often independent of enzyme activity but dependent on the expression level of the protein. In this study we altered the expression level of NDPK in the model eukaryotic organism Dictyostelium discoideum through antisense inhibition and overexpression. We demonstrate that NDPK levels affect growth, endocytosis and exocytosis. In particular we find that Dictyostelium NDPK negatively regulates endocytosis in contrast to the positive regulatory role identified in higher eukaryotes. This can be explained by the differences in types of endocytosis that have been studied in the different systems - phagocytosis and macropinocytosis in Dictyostelium compared with micropinocytosis in mammalian cells. This is the first report of a role for NDPK in regulating macropinocytosis and phagocytosis, the former being the major fluid phase uptake mechanism for macrophages, dendritic cells and other (non dendritic) cells exposed to growth factors. PMID:21991393

  9. Dictyostelium discoideum nucleoside diphosphate kinase C plays a negative regulatory role in phagocytosis, macropinocytosis and exocytosis.

    PubMed

    Annesley, Sarah J; Bago, Ruzica; Bosnar, Maja Herak; Filic, Vedrana; Marinović, Maja; Weber, Igor; Mehta, Anil; Fisher, Paul R

    2011-01-01

    Nucleoside diphosphate kinases (NDPKs) are ubiquitous phosphotransfer enzymes responsible for producing most of the nucleoside triphosphates except for ATP. This role is important for the synthesis of nucleic acids and proteins and the metabolism of sugars and lipids. Apart from this housekeeping role NDPKs have been shown to have many regulatory functions in diverse cellular processes including proliferation and endocytosis. Although the protein has been shown to have a positive regulatory role in clathrin- and dynamin-mediated micropinocytosis, its roles in macropinocytosis and phagocytosis have not been studied. The additional non-housekeeping roles of NDPK are often independent of enzyme activity but dependent on the expression level of the protein. In this study we altered the expression level of NDPK in the model eukaryotic organism Dictyostelium discoideum through antisense inhibition and overexpression. We demonstrate that NDPK levels affect growth, endocytosis and exocytosis. In particular we find that Dictyostelium NDPK negatively regulates endocytosis in contrast to the positive regulatory role identified in higher eukaryotes. This can be explained by the differences in types of endocytosis that have been studied in the different systems - phagocytosis and macropinocytosis in Dictyostelium compared with micropinocytosis in mammalian cells. This is the first report of a role for NDPK in regulating macropinocytosis and phagocytosis, the former being the major fluid phase uptake mechanism for macrophages, dendritic cells and other (non dendritic) cells exposed to growth factors.

  10. Clustering and Negative Feedback by Endocytosis in Planar Cell Polarity Signaling Is Modulated by Ubiquitinylation of Prickle

    PubMed Central

    Cho, Bomsoo; Pierre-Louis, Gandhy; Sagner, Andreas; Eaton, Suzanne; Axelrod, Jeffrey D.

    2015-01-01

    The core components of the planar cell polarity (PCP) signaling system, including both transmembrane and peripheral membrane associated proteins, form asymmetric complexes that bridge apical intercellular junctions. While these can assemble in either orientation, coordinated cell polarization requires the enrichment of complexes of a given orientation at specific junctions. This might occur by both positive and negative feedback between oppositely oriented complexes, and requires the peripheral membrane associated PCP components. However, the molecular mechanisms underlying feedback are not understood. We find that the E3 ubiquitin ligase complex Cullin1(Cul1)/SkpA/Supernumerary limbs(Slimb) regulates the stability of one of the peripheral membrane components, Prickle (Pk). Excess Pk disrupts PCP feedback and prevents asymmetry. We show that Pk participates in negative feedback by mediating internalization of PCP complexes containing the transmembrane components Van Gogh (Vang) and Flamingo (Fmi), and that internalization is activated by oppositely oriented complexes within clusters. Pk also participates in positive feedback through an unknown mechanism promoting clustering. Our results therefore identify a molecular mechanism underlying generation of asymmetry in PCP signaling. PMID:25996914

  11. Clustering and negative feedback by endocytosis in planar cell polarity signaling is modulated by ubiquitinylation of prickle.

    PubMed

    Cho, Bomsoo; Pierre-Louis, Gandhy; Sagner, Andreas; Eaton, Suzanne; Axelrod, Jeffrey D

    2015-05-01

    The core components of the planar cell polarity (PCP) signaling system, including both transmembrane and peripheral membrane associated proteins, form asymmetric complexes that bridge apical intercellular junctions. While these can assemble in either orientation, coordinated cell polarization requires the enrichment of complexes of a given orientation at specific junctions. This might occur by both positive and negative feedback between oppositely oriented complexes, and requires the peripheral membrane associated PCP components. However, the molecular mechanisms underlying feedback are not understood. We find that the E3 ubiquitin ligase complex Cullin1(Cul1)/SkpA/Supernumerary limbs(Slimb) regulates the stability of one of the peripheral membrane components, Prickle (Pk). Excess Pk disrupts PCP feedback and prevents asymmetry. We show that Pk participates in negative feedback by mediating internalization of PCP complexes containing the transmembrane components Van Gogh (Vang) and Flamingo (Fmi), and that internalization is activated by oppositely oriented complexes within clusters. Pk also participates in positive feedback through an unknown mechanism promoting clustering. Our results therefore identify a molecular mechanism underlying generation of asymmetry in PCP signaling.

  12. Can we bet on negative emissions to achieve the 2°C target even under strong carbon cycle feedbacks?

    NASA Astrophysics Data System (ADS)

    Tanaka, K.; Yamagata, Y.; Yokohata, T.; Emori, S.; Hanaoka, T.

    2015-12-01

    Negative emission technologies such as Bioenergy with Carbon dioxide Capture and Storage (BioCCS) play an ever more crucial role in meeting the 2°C stabilization target. However, such technologies are currently at their infancy and their future penetrations may fall short of the scale required to stabilize the warming. Furthermore, the overshoot in the mid-century prior to a full realization of negative emissions would give rise to a risk because such a temporal but excessive warming above 2°C might amplify itself by strengthening climate-carbon cycle feedbacks. It has not been extensively assessed yet how carbon cycle feedbacks might play out during the overshoot in the context of negative emissions. This study explores how 2°C stabilization pathways, in particular those which undergo overshoot, can be influenced by carbon cycle feedbacks and asks their climatic and economic consequences. We compute 2°C stabilization emissions scenarios under a cost-effectiveness principle, in which the total abatement costs are minimized such that the global warming is capped at 2°C. We employ a reduced-complexity model, the Aggregated Carbon Cycle, Atmospheric Chemistry, and Climate model (ACC2), which comprises a box model of the global carbon cycle, simple parameterizations of the atmospheric chemistry, and a land-ocean energy balance model. The total abatement costs are estimated from the marginal abatement cost functions for CO2, CH4, N2O, and BC.Our preliminary results show that, if carbon cycle feedbacks turn out to be stronger than what is known today, it would incur substantial abatement costs to keep up with the 2°C stabilization goal. Our results also suggest that it would be less expensive in the long run to plan for a 2°C stabilization pathway by considering strong carbon cycle feedbacks because it would cost more if we correct the emission pathway in the mid-century to adjust for unexpectedly large carbon cycle feedbacks during overshoot. Furthermore, our

  13. Identification of a calcium-controlled negative regulatory system affecting Vibrio cholerae biofilm formation.

    PubMed

    Bilecen, Kivanc; Yildiz, Fitnat H

    2009-08-01

    Vibrio cholerae's capacity to cause outbreaks of cholera is linked to its survival and adaptability to changes in aquatic environments. One of the environmental conditions that can vary in V. cholerae's natural aquatic habitats is calcium (Ca(+2)). In this study, we investigated the response of V. cholerae to changes in extracellular Ca(2+) levels. Whole-genome expression profiling revealed that Ca(2+) decreased the expression of genes required for biofilm matrix production. Luria-Bertani (LB) medium supplemented with Ca(2+) (LBCa(2+)) caused V. cholerae to form biofilms with decreased thickness and increased roughness, as compared with biofilms formed in LB. Furthermore, addition of Ca(2+) led to dissolution in biofilms. Transcription of two genes encoding a two-component regulatory system pair, now termed calcium-regulated sensor (carS) and regulator (carR), was decreased in cells grown in LBCa(2+). Analysis of null and overexpression alleles of carS and carR revealed that expression of vps (Vibriopolysaccharide) genes and biofilm formation are negatively regulated by the CarRS two-component regulatory system. Through epistasis analysis we determined that CarR acts in parallel with HapR, the negative regulator of vps gene expression.

  14. Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis.

    PubMed

    Luke, Courtney T; Casta, Alexandre; Kim, Hyunmi; Christiano, Angela M

    2013-10-01

    Hairless (HR) is a nuclear protein with corepressor activity that is highly expressed in the skin and hair follicle. Mutations in Hairless lead to hair loss accompanied by the appearance of papules (atrichia with papular lesions), and similar phenotypes appear when the key polyamine enzymes ornithine decarboxylase (ODC) and spermidine/spermine N(1) -acetyltransferase (SSAT) are overexpressed. Both ODC and SSAT transgenic mice have elevated epidermal levels of putrescine, leading us to investigate the mechanistic link between putrescine and HR. We show here that HR and putrescine form a negative regulatory network, as epidermal ODC expression is elevated when HR is decreased and vice versa. We also show that the regulation of ODC by HR is dependent on the MYC superfamily of proteins, in particular MYC, MXI1 and MXD3. Furthermore, we found that elevated levels of putrescine lead to decreased HR expression, but that the SSAT-TG phenotype is distinct from that found when HR is mutated. Transcriptional microarray analysis of putrescine-treated primary human keratinocytes demonstrated differential regulation of genes involved in protein-protein interactions, nucleotide binding and transcription factor activity, suggesting that the putrescine-HR negative regulatory loop may have a large impact on epidermal homeostasis and hair follicle cycling.

  15. The Fission Yeast Homeodomain Protein Yox1p Binds to MBF and Confines MBF-Dependent Cell-Cycle Transcription to G1-S via Negative Feedback

    PubMed Central

    Aligianni, Sofia; Lackner, Daniel H.; Klier, Steffi; Rustici, Gabriella; Wilhelm, Brian T.; Marguerat, Samuel; Codlin, Sandra; Brazma, Alvis; de Bruin, Robertus A. M.; Bähler, Jürg

    2009-01-01

    The regulation of the G1- to S-phase transition is critical for cell-cycle progression. This transition is driven by a transient transcriptional wave regulated by transcription factor complexes termed MBF/SBF in yeast and E2F-DP in mammals. Here we apply genomic, genetic, and biochemical approaches to show that the Yox1p homeodomain protein of fission yeast plays a critical role in confining MBF-dependent transcription to the G1/S transition of the cell cycle. The yox1 gene is an MBF target, and Yox1p accumulates and preferentially binds to MBF-regulated promoters, via the MBF components Res2p and Nrm1p, when they are transcriptionally repressed during the cell cycle. Deletion of yox1 results in constitutively high transcription of MBF target genes and loss of their cell cycle–regulated expression, similar to deletion of nrm1. Genome-wide location analyses of Yox1p and the MBF component Cdc10p reveal dozens of genes whose promoters are bound by both factors, including their own genes and histone genes. In addition, Cdc10p shows promiscuous binding to other sites, most notably close to replication origins. This study establishes Yox1p as a new regulatory MBF component in fission yeast, which is transcriptionally induced by MBF and in turn inhibits MBF-dependent transcription. Yox1p may function together with Nrm1p to confine MBF-dependent transcription to the G1/S transition of the cell cycle via negative feedback. Compared to the orthologous budding yeast Yox1p, which indirectly functions in a negative feedback loop for cell-cycle transcription, similarities but also notable differences in the wiring of the regulatory circuits are evident. PMID:19714215

  16. Negative plant-soil feedbacks increase with plant abundance, and are unchanged by competition

    Treesearch

    John L. Maron; Alyssa Laney Smith; Yvette K. Ortega; Dean E. Pearson; Ragan M. Callaway

    2016-01-01

    Plant-soil feedbacks and interspecific competition are ubiquitous interactions that strongly influence the performance of plants. Yet few studies have examined whether the strength of these interactions corresponds with the abundance of plant species in the field, or whether feedbacks and competition interact in ways that either ameliorate or exacerbate their...

  17. The Facilitatory Effect of Negative Feedback on the Emergence of Analogical Reasoning Abilities

    ERIC Educational Resources Information Center

    Ball, Linden J.; Hoyle, Alison M.; Towse, Andrea S.

    2010-01-01

    This paper focuses on the development of analogical reasoning abilities in 5- and 6-year-old children. Our particular interest relates to the way in which analogizing is influenced by the provision of task-based feedback coupled with a self-explanation requirement. Both feedback and self-explanation provide children with opportunities to engage in…

  18. Coordination of the Arc Regulatory System and Pheromone-Mediated Positive Feedback in Controlling the Vibrio fischeri lux Operon

    PubMed Central

    Septer, Alecia N.; Stabb, Eric V.

    2012-01-01

    Bacterial pheromone signaling is often governed both by environmentally responsive regulators and by positive feedback. This regulatory combination has the potential to coordinate a group response among distinct subpopulations that perceive key environmental stimuli differently. We have explored the interplay between an environmentally responsive regulator and pheromone-mediated positive feedback in intercellular signaling by Vibrio fischeri ES114, a bioluminescent bacterium that colonizes the squid Euprymna scolopes. Bioluminescence in ES114 is controlled in part by N-(3-oxohexanoyl)-L-homoserine lactone (3OC6), a pheromone produced by LuxI that together with LuxR activates transcription of the luxICDABEG operon, initiating a positive feedback loop and inducing luminescence. The lux operon is also regulated by environmentally responsive regulators, including the redox-responsive ArcA/ArcB system, which directly represses lux in culture. Here we show that inactivating arcA leads to increased 3OC6 accumulation to initiate positive feedback. In the absence of positive feedback, arcA-mediated control of luminescence was only ∼2-fold, but luxI-dependent positive feedback contributed more than 100 fold to the net induction of luminescence in the arcA mutant. Consistent with this overriding importance of positive feedback, 3OC6 produced by the arcA mutant induced luminescence in nearby wild-type cells, overcoming their ArcA repression of lux. Similarly, we found that artificially inducing ArcA could effectively repress luminescence before, but not after, positive feedback was initiated. Finally, we show that 3OC6 produced by a subpopulation of symbiotic cells can induce luminescence in other cells co-colonizing the host. Our results suggest that even transient loss of ArcA-mediated regulation in a sub-population of cells can induce luminescence in a wider community. Moreover, they indicate that 3OC6 can communicate information about both cell density and the state of

  19. Stochasticity and bifurcations in a reduced model with interlinked positive and negative feedback loops of CREB1 and CREB2 stimulated by 5-HT.

    PubMed

    Hao, Lijie; Yang, Zhuoqin; Bi, Yuanhong

    2016-04-01

    The cyclic AMP (cAMP)-response element-binding protein (CREB) family of transcription factors is crucial in regulating gene expression required for long-term memory (LTM) formation. Upon exposure of sensory neurons to the neurotransmitter serotonin (5-HT), CREB1 is activated via activation of the protein kinase A (PKA) intracellular signaling pathways, and CREB2 as a transcriptional repressor is relieved possibly via phosphorylation of CREB2 by mitogen-activated protein kinase (MAPK). Song et al. [18] proposed a minimal model with only interlinked positive and negative feedback loops of transcriptional regulation by the activator CREB1 and the repressor CREB2. Without considering feedbacks between the CREB proteins, Pettigrew et al. [8] developed a computational model characterizing complex dynamics of biochemical pathways downstream of 5-HT receptors. In this work, to describe more simply the biochemical pathways and gene regulation underlying 5-HT-induced LTM, we add the important extracellular sensitizing stimulus 5-HT as well as the product Ap-uch into the Song's minimal model. We also strive to examine dynamical properties of the gene regulatory network under the changing concentration of the stimulus, [5-HT], cooperating with the varying positive feedback strength in inducing a high state of CREB1 for the establishment of long-term memory. Different dynamics including monostability, bistability and multistability due to coexistence of stable steady states and oscillations is investigated by means of codimension-2 bifurcation analysis. At the different positive feedback strengths, comparative analysis of deterministic and stochastic dynamics reveals that codimension-1 bifurcation with respect to [5-HT] as the parameter can predict diverse stochastic behaviors resulted from the finite number of molecules, and the number of CREB1 molecules more and more preferentially resides near the high steady state with increasing [5-HT], which contributes to long

  20. A Negative Feedback Loop Controlling bHLH Complexes Is Involved in Vascular Cell Division and Differentiation in the Root Apical Meristem.

    PubMed

    Katayama, Hirofumi; Iwamoto, Kuninori; Kariya, Yuka; Asakawa, Tomohiro; Kan, Toshiyuki; Fukuda, Hiroo; Ohashi-Ito, Kyoko

    2015-12-07

    Controlling cell division and differentiation in meristems is essential for proper plant growth. Two bHLH heterodimers consisting of LONESOME HIGHWAY (LHW) and TARGET OF MONOPTEROS 5 (TMO5)/TMO5-LIKE1 (T5L1) regulate periclinal cell division in vascular cells in the root apical meristem (RAM). In this study, we further investigated the functions of LHW-T5L1, finding that in addition to controlling cell division, this complex regulates xylem differentiation in the RAM via a novel negative regulatory system. LHW-T5L1 upregulated the thermospermine synthase gene ACAULIS5 (ACL5), as well as SUPPRESSOR OF ACAULIS5 LIKE3 (SACL3), which encodes a bHLH protein, in the RAM. The SACL3 promoter sequence contains a conserved upstream open reading frame (uORF), which blocked translation of the main SACL3 ORF in the absence of thermospermine. Thermospermine eliminated the negative effect of uORF and enhanced SACL3 production. Further genetic and molecular biological analyses indicated that ACL5 and SACL3 suppress the function of LHW-T5L1 through a protein-protein interaction between LHW and SACL3. Finally, we showed that a negative feedback loop consisting of LHW-T5L1, ACL5, SACL3, and LHW-SACL3 contributes to maintain RAM size and proper root growth. These findings suggest that a negative feedback loop regulates the LHW-T5L1 output level to coordinate cell division and differentiation in a cell-autonomous manner. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. The Arcuate Nucleus: A Site of Fast Negative Feedback for Corticosterone Secretion in Male Rats.

    PubMed

    Leon-Mercado, Luis; Herrera Moro Chao, Daniela; Basualdo, María Del Carmen; Kawata, Mitsuhiro; Escobar, Carolina; Buijs, Ruud M

    2017-01-01

    Variations in circulating corticosterone (Cort) are driven by the paraventricular nucleus of the hypothalamus (PVN), mainly via the sympathetic autonomic nervous system (ANS) directly stimulating Cort release from the adrenal gland and via corticotropin-releasing hormone targeting the adenohypophysis to release adrenocorticotropic hormone (ACTH). Cort feeds back through glucocorticoid receptors (GRs). Here we show in male Wistar rats that PVN neurons projecting to the adrenal gland do not express GRs, leaving the question of how the ANS in the PVN gets information about circulating Cort levels to control the adrenal. Since the arcuate nucleus (ARC) shows a less restrictive blood-brain barrier, expresses GRs, and projects to the PVN, we investigated whether the ARC can detect and produce fast adjustments of circulating Cort. In low Cort conditions (morning), local microdialysis in the ARC with type I GR antagonist produced a fast and sustained increase of Cort. This was not observed with a type II antagonist. At the circadian peak levels of Cort (afternoon), a type II GR antagonist, but not a type I antagonist, increased Cort levels but not ACTH levels. Antagonist infusions in the PVN did not modify circulating Cort levels, demonstrating the specificity of the ARC to give Cort negative feedback. Furthermore, type I and II GR agonists in the ARC prevented the increase of Cort after stress, demonstrating the role of the ARC as sensor to modulate Cort release. Our findings show that the ARC may be essential to sense blood levels of Cort and adapt Cort secretion depending on such conditions as stress or time of day.

  2. The Arcuate Nucleus: A Site of Fast Negative Feedback for Corticosterone Secretion in Male Rats

    PubMed Central

    Kawata, Mitsuhiro; Escobar, Carolina

    2017-01-01

    Abstract Variations in circulating corticosterone (Cort) are driven by the paraventricular nucleus of the hypothalamus (PVN), mainly via the sympathetic autonomic nervous system (ANS) directly stimulating Cort release from the adrenal gland and via corticotropin-releasing hormone targeting the adenohypophysis to release adrenocorticotropic hormone (ACTH). Cort feeds back through glucocorticoid receptors (GRs). Here we show in male Wistar rats that PVN neurons projecting to the adrenal gland do not express GRs, leaving the question of how the ANS in the PVN gets information about circulating Cort levels to control the adrenal. Since the arcuate nucleus (ARC) shows a less restrictive blood–brain barrier, expresses GRs, and projects to the PVN, we investigated whether the ARC can detect and produce fast adjustments of circulating Cort. In low Cort conditions (morning), local microdialysis in the ARC with type I GR antagonist produced a fast and sustained increase of Cort. This was not observed with a type II antagonist. At the circadian peak levels of Cort (afternoon), a type II GR antagonist, but not a type I antagonist, increased Cort levels but not ACTH levels. Antagonist infusions in the PVN did not modify circulating Cort levels, demonstrating the specificity of the ARC to give Cort negative feedback. Furthermore, type I and II GR agonists in the ARC prevented the increase of Cort after stress, demonstrating the role of the ARC as sensor to modulate Cort release. Our findings show that the ARC may be essential to sense blood levels of Cort and adapt Cort secretion depending on such conditions as stress or time of day. PMID:28275717

  3. The stress-buffering effect of acute exercise: Evidence for HPA axis negative feedback.

    PubMed

    Zschucke, Elisabeth; Renneberg, Babette; Dimeo, Fernando; Wüstenberg, Torsten; Ströhle, Andreas

    2015-01-01

    According to the cross-stressor adaptation hypothesis, physically trained individuals show lower physiological and psychological responses to stressors other than exercise, e.g. psychosocial stress. Reduced stress reactivity may constitute a mechanism of action for the beneficial effects of exercise in maintaining mental health. With regard to neural and psychoneuroendocrine stress responses, the acute stress-buffering effects of exercise have not been investigated yet. A sample of highly trained (HT) and sedentary (SED) young men was randomized to either exercise on a treadmill at moderate intensity (60-70% VO2max; AER) for 30 min, or to perform 30 min of "placebo" exercise (PLAC). 90 min later, an fMRI experiment was conducted using an adapted version of the Montreal Imaging Stress Task (MIST). The subjective and psychoneuroendocrine (cortisol and α-amylase) changes induced by the exercise intervention and the MIST were assessed, as well as neural activations during the MIST. Finally, associations between the different stress responses were analysed. Participants of the AER group showed a significantly reduced cortisol response to the MIST, which was inversely related to the previous exercise-induced α-amylase and cortisol fluctuations. With regard to the sustained BOLD signal, we found higher bilateral hippocampus (Hipp) activity and lower prefrontal cortex (PFC) activity in the AER group. Participants with a higher aerobic fitness showed lower cortisol responses to the MIST. As the Hipp and PFC are brain structures prominently involved in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, these findings indicate that the acute stress-buffering effect of exercise relies on negative feedback mechanisms. Positive affective changes after exercise appear as important moderators largely accounting for the effects related to physical fitness.

  4. Phasic Firing and Coincidence Detection by Subthreshold Negative Feedback: Divisive or Subtractive or, Better, Both

    PubMed Central

    Huguet, Gemma; Meng, Xiangying; Rinzel, John

    2017-01-01

    Phasic neurons typically fire only for a fast-rising input, say at the onset of a step current, but not for steady or slow inputs, a property associated with type III excitability. Phasic neurons can show extraordinary temporal precision for phase locking and coincidence detection. Exemplars are found in the auditory brain stem where precise timing is used in sound localization. Phasicness at the cellular level arises from a dynamic, voltage-gated, negative feedback that can be recruited subthreshold, preventing the neuron from reaching spike threshold if the voltage does not rise fast enough. We consider two mechanisms for phasicness: a low threshold potassium current (subtractive mechanism) and a sodium current with subthreshold inactivation (divisive mechanism). We develop and analyze three reduced models with either divisive or subtractive mechanisms or both to gain insight into the dynamical mechanisms for the potentially high temporal precision of type III-excitable neurons. We compare their firing properties and performance for a range of stimuli. The models have characteristic non-monotonic input-output relations, firing rate vs. input intensity, for either stochastic current injection or Poisson-timed excitatory synaptic conductance trains. We assess performance according to precision of phase-locking and coincidence detection by the models' responses to repetitive packets of unitary excitatory synaptic inputs with more or less temporal coherence. We find that each mechanism contributes features but best performance is attained if both are present. The subtractive mechanism confers extraordinary precision for phase locking and coincidence detection but only within a restricted parameter range when the divisive mechanism of sodium inactivation is inoperative. The divisive mechanism guarantees robustness of phasic properties, without compromising excitability, although with somewhat less precision. Finally, we demonstrate that brief transient inhibition if

  5. Methylglyoxal in cells elicits a negative feedback loop entailing transglutaminase 2 and glyoxalase 1.

    PubMed

    Lee, Der-Yen; Chang, Geen-Dong

    2014-01-01

    Glyoxalase 1 (GlxI) is the key enzyme that converts the highly reactive α-oxo-aldehydes into the corresponding α-hydroxy acids using l-glutathione as a cofactor. In our preliminary data, GlxI was identified as a substrate of transglutaminase 2 (TG2), a ubiquitous enzyme with multiple functions. According to the catalytic properties of TG2, protein cross-linking, polyamine conjugation, and/or deamidation are potential post-translational modifications. In this article, we have demonstrated that TG2 catalyzes either polyamine conjugation or deamidation to GlxI depending on the presence of polyamines or not. Deamidation leads to activation of GlxI while polyamine conjugation results in activation of GlxI as well as stabilization of GlxI against denaturation treatment. In cultured HeLa cells, methylglyoxal challenge causes increase in intracellular levels of reactive oxygen species (ROS) and calcium leading to TG2 activation and subsequent transamidation and activation of GlxI. The inhibition of TG2 significantly weakens the cell resistance to the methylglyoxal challenge. Thus, GlxI is a novel substrate of TG2 and is activated by TG2 in vitro and in cellulo. Exposure to methylglyoxal elicits a negative feedback loop entailing ROS, calcium, TG2 and GlxI, thus leading to attenuation of the increase in the methylglyoxal level. The results imply that cancer cells highly express TG2 or GlxI can endure the oxidative stress derived from higher glycolytic flux and may gain extra growth advantage from the aerobic glycolysis.

  6. Identification of positive and negative transcriptional regulatory elements of the rabbit angiotensin-converting enzyme gene.

    PubMed Central

    Goraya, T Y; Kessler, S P; Kumar, R S; Douglas, J; Sen, G C

    1994-01-01

    The two tissue-specific mRNAs encoding the isozymes of rabbit angiotensin-converting enzyme (ACE) are generated from the same gene by alternative choice of two transcription initiation sites 5.7 kb apart. In the current study, we have characterized the regulatory sites controlling the transcription of the larger pulmonary isozyme mRNA. For this purpose, reporter genes driven by varying lengths of upstream region of the ACE gene were transfected into ACE-producing cells. Our results demonstrated that the transcription of this gene is primarily driven by positive elements within the first 274 bp DNA upstream of the transcription initiation site. The reporter gene driven by this region was expressed in two ACE-producing cells but not in two ACE-non-producing cells thereby establishing its tissue specificity. Our experiments also revealed the existence of a strong negative element located between -692 and -610 positions. This element suppressed the expression of the reporter gene in a dose-dependent and position and orientation-independent fashion thus suggesting that it is a true silencer element. It could also repress the expression of a reporter gene driven by the heterologous strong promoter of the beta-actin gene. The repressing effects of the negative element could be partially overcome by cotransfecting the isolated negative element along with the reporter gene containing the negative element. This result was possibly due to the functional removal of a limiting trans-acting factor which binds to this element. Electrophoretic mobility shift assays revealed that the negative element can form several complexes with proteins present in the nuclear extract of an ACE-producing cell line. At least part of the negative element is strongly conserved in the upstream regions of the human and mouse ACE genes. Images PMID:8165133

  7. H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance

    PubMed Central

    Peng, Fei; Li, Ting-Ting; Wang, Kai-Li; Xiao, Guo-Qing; Wang, Ju-Hong; Zhao, Hai-Dong; Kang, Zhi-Jie; Fan, Wen-Jun; Zhu, Li-Li; Li, Mei; Cui, Bai; Zheng, Fei-Meng; Wang, Hong-Jiang; Lam, Eric W-F; Wang, Bo; Xu, Jie; Liu, Quentin

    2017-01-01

    Long noncoding RNA-H19 (H19), an imprinted oncofetal gene, has a central role in carcinogenesis. Hitherto, the mechanism by which H19 regulates cancer stem cells, remains elusive. Here we show that breast cancer stem cells (BCSCs) express high levels of H19, and ectopic overexpression of H19 significantly promotes breast cancer cell clonogenicity, migration and mammosphere-forming ability. Conversely, silencing of H19 represses these BCSC properties. In concordance, knockdown of H19 markedly inhibits tumor growth and suppresses tumorigenesis in nude mice. Mechanistically, we found that H19 functions as a competing endogenous RNA to sponge miRNA let-7, leading to an increase in expression of a let-7 target, the core pluripotency factor LIN28, which is enriched in BCSC populations and breast patient samples. Intriguingly, this gain of LIN28 expression can also feedback to reverse the H19 loss-mediated suppression of BCSC properties. Our data also reveal that LIN28 blocks mature let-7 production and, thereby, de-represses H19 expression in breast cancer cells. Appropriately, H19 and LIN28 expression exhibits strong correlations in primary breast carcinomas. Collectively, these findings reveal that lncRNA H19, miRNA let-7 and transcriptional factor LIN28 form a double-negative feedback loop, which has a critical role in the maintenance of BCSCs. Consequently, disrupting this pathway provides a novel therapeutic strategy for breast cancer. PMID:28102845

  8. H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance.

    PubMed

    Peng, Fei; Li, Ting-Ting; Wang, Kai-Li; Xiao, Guo-Qing; Wang, Ju-Hong; Zhao, Hai-Dong; Kang, Zhi-Jie; Fan, Wen-Jun; Zhu, Li-Li; Li, Mei; Cui, Bai; Zheng, Fei-Meng; Wang, Hong-Jiang; Lam, Eric W-F; Wang, Bo; Xu, Jie; Liu, Quentin

    2017-01-19

    Long noncoding RNA-H19 (H19), an imprinted oncofetal gene, has a central role in carcinogenesis. Hitherto, the mechanism by which H19 regulates cancer stem cells, remains elusive. Here we show that breast cancer stem cells (BCSCs) express high levels of H19, and ectopic overexpression of H19 significantly promotes breast cancer cell clonogenicity, migration and mammosphere-forming ability. Conversely, silencing of H19 represses these BCSC properties. In concordance, knockdown of H19 markedly inhibits tumor growth and suppresses tumorigenesis in nude mice. Mechanistically, we found that H19 functions as a competing endogenous RNA to sponge miRNA let-7, leading to an increase in expression of a let-7 target, the core pluripotency factor LIN28, which is enriched in BCSC populations and breast patient samples. Intriguingly, this gain of LIN28 expression can also feedback to reverse the H19 loss-mediated suppression of BCSC properties. Our data also reveal that LIN28 blocks mature let-7 production and, thereby, de-represses H19 expression in breast cancer cells. Appropriately, H19 and LIN28 expression exhibits strong correlations in primary breast carcinomas. Collectively, these findings reveal that lncRNA H19, miRNA let-7 and transcriptional factor LIN28 form a double-negative feedback loop, which has a critical role in the maintenance of BCSCs. Consequently, disrupting this pathway provides a novel therapeutic strategy for breast cancer.

  9. IKBKE promotes glioblastoma progression by establishing the regulatory feedback loop of IKBKE/YAP1/miR-Let-7b/i.

    PubMed

    Zhang, Zhimeng; Lu, Jie; Guo, Gaochao; Yang, Yi; Dong, Shicai; Liu, Yang; Nan, Yang; Zhong, Yue; Yu, Kai; Huang, Qiang

    2017-07-01

    Recently, we have demonstrated that IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon) is overexpressed in human glioblastoma and that inhibition of IKBKE remarkably suppresses the proliferative and invasive behaviour of glioblastoma cells. However, the specific pathogenic molecular mechanism remains to be elucidated. In this study, we verified that IKBKE promotes YAP1 expression via posttranslational modification and accelerates YAP1 translocation to the nucleus for the development of glioblastoma. We then determined that YAP1 negatively regulates miR-let-7b/i by overexpressing and silencing YAP1 expression. In addition, miR-let-7b/i feedback decreases the expression of IKBKE and YAP1 and suppresses the transportation of YAP1 located in the nucleus. Therefore, the regulatory feedback circuit of IKBKE↑→YAP1↑→miR-let-7b/i↓→IKBKE↑ dictates glioblastoma progression. Thus, we propose that blocking the circuit may be a new therapeutic strategy for the treatment of glioblastoma.

  10. The Office of Land and Emergency Management is Seeking Feedback on Reducing Regulatory Burden

    EPA Pesticide Factsheets

    This page contains information about the comments the Office of Land and Emergency Management is collecting and the public meeting they are holding in response to Executive Order 13777 Regulatory Reform Review

  11. Effects of spike-triggered negative feedback on receptive-field properties.

    PubMed

    Urdapilleta, Eugenio; Samengo, Inés

    2015-04-01

    Sensory neurons are often described in terms of a receptive field, that is, a linear kernel through which stimuli are filtered before they are further processed. If information transmission is assumed to proceed in a feedforward cascade, the receptive field may be interpreted as the external stimulus' profile maximizing neuronal output. The nervous system, however, contains many feedback loops, and sensory neurons filter more currents than the ones representing the transduced external stimulus. Some of the additional currents are generated by the output activity of the neuron itself, and therefore constitute feedback signals. By means of a time-frequency analysis of the input/output transformation, here we show how feedback modifies the receptive field. The model is applicable to various types of feedback processes, from spike-triggered intrinsic conductances to inhibitory synaptic inputs from nearby neurons. We distinguish between the intrinsic receptive field (filtering all input currents) and the effective receptive field (filtering only external stimuli). Whereas the intrinsic receptive field summarizes the biophysical properties of the neuron associated to subthreshold integration and spike generation, only the effective receptive field can be interpreted as the external stimulus' profile maximizing neuronal output. We demonstrate that spike-triggered feedback shifts low-pass filtering towards band-pass processing, transforming integrator neurons into resonators. For strong feedback, a sharp resonance in the spectral neuronal selectivity may appear. Our results provide a unified framework to interpret a collection of previous experimental studies where specific feedback mechanisms were shown to modify the filtering properties of neurons.

  12. Understanding the dynamics of sustainable social-ecological systems: human behavior, institutions, and regulatory feedback networks.

    PubMed

    Anderies, John M

    2015-02-01

    I present a general mathematical modeling framework that can provide a foundation for the study of sustainability in social- ecological systems (SESs). Using basic principles from feedback control and a sequence of specific models from bioeconomics and economic growth, I outline several mathematical and empirical challenges associated with the study of sustainability of SESs. These challenges are categorized into three classes: (1) the social choice of performance measures, (2) uncertainty, and (3) collective action. Finally, I present some opportunities for combining stylized dynamical systems models with empirical data on human behavior and biophysical systems to address practical challenges for the design of effective governance regimes (policy feedbacks) for highly uncertain natural resource systems.

  13. A general non-equilibrium framework for the parameterization of positive and negative feedbacks in atmospheric systems

    NASA Astrophysics Data System (ADS)

    Garrett, T. J.

    2012-12-01

    For any identifiable system, regardless of its complexity or scale, evolution can be treated as a spontaneous thermodynamic response to a local convergence of down-gradient material flows. In climate studies, examples of identifiable systems might include cloud cover or the global incidence of temperatures warmer than a certain threshold. Here it is shown how the time-dependent evolution of such systems is constrained by positive and negative feedbacks that fall into a few mathematically distinct modes. In general, evolution depends on the time integral of past flows and the current availability of material and energetic resources. More specifically, negative feedbacks arise from the depletion or predation of the material and potential energy reservoirs that supply the system. Positive feedbacks are due to either new reservoir "discovery" or system expansion into existing reservoirs. When positive feedbacks dominate, the time dependent response of system growth falls into a few clearly identifiable behaviors that include a law of diminishing returns, logistic behavior, and, if reservoirs are expanding very rapidly, unstable super-exponential or explosive growth. For open systems (e.g. radiative flows in our atmosphere) that have a resolved sink as well as a source, oscillatory behavior emerges and can be characterized in terms of a slightly modified form of the predator-prey equations commonly employed in ecology. The perturbation formulation of these equations is equivalent to a damped simple harmonic oscillator. Specific examples of non-equilibrium positive and negative feedback response can be described for the sudden development of rain and the oscillatory evolution of open-celled stratocumulus cloud decks.

  14. High diatom production and export in stratified waters - A potential negative feedback to global warming

    NASA Astrophysics Data System (ADS)

    Kemp, Alan E. S.; Villareal, Tracy A.

    2013-12-01

    chlorophyll maxima in highly stratified waters dominated by rhizosolenid diatoms but also including H. hauckii. In the Cretaceous when CO2 levels were higher than present, laminated sediments reveal dominant flux also including Hemiaulus and rhizosolenid species. Nitrogen isotope and biomarker studies suggest that, analogous to modern DDA blooms within the subtropical gyres, Hemiaulus blooms in the ancient Mediterranean and within the Cretaceous seas were aided by nitrogen-fixing cyanobacterial symbionts. These lines of evidence suggest that diatom production and associated export of organic carbon, may not decrease, as is widely predicted, but may actually increase with greater ocean stratification, and potentially act as a negative feedback to global warming. However, the key genera involved in such potential feedbacks are underrepresented in both laboratory and field studies and are poorly represented in models. Our findings suggest that a reappraisal is necessary of the way diatoms are represented as plankton functional types (PFTs) in ocean biogeochemical models and that new observing and sampling strategies are also required to study these processes.

  15. A proximal tissue-specific module and a distal negative regulatory module control apolipoprotein(a) gene transcription.

    PubMed Central

    Negi, Sarita; Singh, Saurabh K; Pati, Nirupma; Handa, Vikas; Chauhan, Ruchi; Pati, Uttam

    2004-01-01

    The apo(a) [apolipoprotein(a)] gene is responsible for variations in plasma lipoprotein(a), high levels of which are a risk factor for atherosclerosis and myocardial infarction. The apo(a) promoter stimulates the expression of reporter genes in HepG2 cells, but not in HeLa cells. In the present study, we demonstrate that the 1.4 kb apo(a) promoter comprises two composite regulatory regions: a distal negative regulatory module (positions -1432 to -716) and a proximal tissue-specific module (-716 to -616). The distal negative regulatory module contains two strong negative regulatory regions [polymorphic PNR (pentanucleotide repeat region) and NREbeta (negative regulatory element beta)], which sandwich the postive regulatory region PREbeta (positive regulatory element beta). The PNR was shown to bind to transcription factors in a tissue-specific manner, whereas the ubiquitous transcription factors hepatocyte nuclear factor 3alpha and GATA binding protein 4 bound to NREbeta to repress gene transcription. The proximal tissue-specific module contains two regulatory elements: an activating region (PREalpha) that activates transcription in HepG2 cells, and NREalpha, which is responsible for repressing the apo(a) gene in HeLa cells. NREalpha binds to a HeLa-specific repressor. These multiple regulatory elements might work co-operatively to finely regulate apo(a) gene expression. Although the tissue-specific module is required for apo(a) gene activation and repression in a tissue-specific manner, the combinatorial interplay of the distal and proximal regulators might define the complex pathway(s) of apo(a) gene regulation. PMID:14680477

  16. Autocrine IFNγ Controls the Regulatory Function of Lymphoproliferative Double Negative T Cells

    PubMed Central

    Juvet, Stephen C.; Han, Mei; Vanama, Ramesh; Joe, Betty; Kim, Edward Y.; Zhao, Fei Linda; Jeon, Caroline; Adeyi, Oyedele; Zhang, Li

    2012-01-01

    TCRαβ+ CD4−CD8−NK− double negative T cells (DN T cells) can act as regulatory T cells to inhibit allograft rejection and autoimmunity. Their role in graft-versus-host disease and mechanisms of suppression remain elusive. In this study, we demonstrate that DN T cells can inhibit CD4+ T cell-mediated GVHD in a semi-allogeneic model of bone marrow transplantation. Furthermore, we present evidence of a novel autocrine IFNγ signaling pathway in Fas-deficient C57BL/6.lpr (B6.lpr) DN T cells. B6.lpr DN T cells lacking IFNγ or its receptor were impaired in their ability to suppress syngeneic CD4+ T cells responding to alloantigen stimulation both in vitro and in vivo. Autocrine IFNγ signaling was required for sustained B6.lpr DN T cell IFNγ secretion in vivo and for upregulation of surface Fas ligand expression during TCR stimulation. Fas ligand (FasL) expression by B6.lpr DN T cells permitted lysis of activated CD4+ T cells and was required for suppression of GVHD. Collectively, our data indicate that DN T cells can inhibit GVHD and that IFNγ plays a critical autocrine role in controlling the regulatory function of B6.lpr DN T cells. PMID:23077665

  17. Cardiovascular regulatory response to lower body negative pressure following blood volume loss

    NASA Technical Reports Server (NTRS)

    Shimizu, M.; Ghista, D. N.; Sandler, H.

    1979-01-01

    An attempt is made to explain the cardiovascular regulatory responses to lower body negative pressure (LBNP) stress, both in the absence of and following blood or plasma volume loss, the latter being factors regularly observed with short- or long-term recumbency or weightlessness and associated with resulting cardiovascular deconditioning. Analytical expressions are derived for the responses of mean venous pressure and blood volume pooled in the lower body due to LBNP. An analysis is presented for determining the HR change due to LBNP stress following blood volume loss. It is concluded that the reduced orthostatic tolerance following long-term space flight or recumbency can be mainly attributed to blood volume loss, and that the associated cardiovascular responses characterizing this orthostatic intolerance is elicited by the associated central venous pressure response.

  18. Cardiovascular regulatory response to lower body negative pressure following blood volume loss

    NASA Technical Reports Server (NTRS)

    Shimizu, M.; Ghista, D. N.; Sandler, H.

    1979-01-01

    An attempt is made to explain the cardiovascular regulatory responses to lower body negative pressure (LBNP) stress, both in the absence of and following blood or plasma volume loss, the latter being factors regularly observed with short- or long-term recumbency or weightlessness and associated with resulting cardiovascular deconditioning. Analytical expressions are derived for the responses of mean venous pressure and blood volume pooled in the lower body due to LBNP. An analysis is presented for determining the HR change due to LBNP stress following blood volume loss. It is concluded that the reduced orthostatic tolerance following long-term space flight or recumbency can be mainly attributed to blood volume loss, and that the associated cardiovascular responses characterizing this orthostatic intolerance is elicited by the associated central venous pressure response.

  19. CaV3.2 Channels and the Induction of Negative Feedback in Cerebral Arteries

    PubMed Central

    Harraz, Osama F.; Abd El-Rahman, Rasha R.; Bigdely-Shamloo, Kamran; Wilson, Sean M.; Brett, Suzanne E.; Romero, Monica; Gonzales, Albert L.; Earley, Scott; Vigmond, Edward J.; Nygren, Anders; Menon, Bijoy K.; Mufti, Rania E.; Watson, Tim; Starreveld, Yves; Furstenhaupt, Tobias; Muellerleile, Philip R.; Kurjiaka, David T.; Kyle, Barry D.; Braun, Andrew P.; Welsh, Donald G.

    2015-01-01

    Rationale T-type (CaV3.1/CaV3.2) Ca2+ channels are expressed in rat cerebral arterial smooth muscle. Although present, their functional significance remains uncertain with findings pointing to a variety of roles. Objective This study tested whether CaV3.2 channels mediate a negative feedback response by triggering Ca2+ sparks, discrete events that initiate arterial hyperpolarization by activating large-conductance Ca2+-activated K+ channels. Methods and Results Micromolar Ni2+, an agent that selectively blocks CaV3.2 but not CaV1.2/CaV3.1, was first shown to depolarize/constrict pressurized rat cerebral arteries; no effect was observed in CaV3.2−/− arteries. Structural analysis using 3-dimensional tomography, immunolabeling, and a proximity ligation assay next revealed the existence of microdomains in cerebral arterial smooth muscle which comprised sarcoplasmic reticulum and caveolae. Within these discrete structures, CaV3.2 and ryanodine receptor resided in close apposition to one another. Computational modeling revealed that Ca2+ influx through CaV3.2 could repetitively activate ryanodine receptor, inducing discrete Ca2+-induced Ca2+ release events in a voltage-dependent manner. In keeping with theoretical observations, rapid Ca2+ imaging and perforated patch clamp electrophysiology demonstrated that Ni2+ suppressed Ca2+ sparks and consequently spontaneous transient outward K+ currents, large-conductance Ca2+-activated K+ channel mediated events. Additional functional work on pressurized arteries noted that paxilline, a large-conductance Ca2+-activated K+ channel inhibitor, elicited arterial constriction equivalent, and not additive, to Ni2+. Key experiments on human cerebral arteries indicate that CaV3.2 is present and drives a comparable response to moderate constriction. Conclusions These findings indicate for the first time that CaV3.2 channels localize to discrete microdomains and drive ryanodine receptor–mediated Ca2+ sparks, enabling large

  20. An ultra low noise telecom wavelength free running single photon detector using negative feedback avalanche diode.

    PubMed

    Yan, Zhizhong; Hamel, Deny R; Heinrichs, Aimee K; Jiang, Xudong; Itzler, Mark A; Jennewein, Thomas

    2012-07-01

    It is challenging to implement genuine free running single-photon detectors for the 1550 nm wavelength range with simultaneously high detection efficiency (DE), low dark noise, and good time resolution. We report a novel read out system for the signals from a negative feedback avalanche diode (NFAD) [M. A. Itzler, X. Jiang, B. Nyman, and K. Slomkowski, "Quantum sensing and nanophotonic devices VI," Proc. SPIE 7222, 72221K (2009); X. Jiang, M. A. Itzler, K. ODonnell, M. Entwistle, and K. Slomkowski, "Advanced photon counting techniques V," Proc. SPIE 8033, 80330K (2011); M. A. Itzler, X. Jiang, B. M. Onat, and K. Slomkowski, "Quantum sensing and nanophotonic devices VII," Proc. SPIE 7608, 760829 (2010)], which allows useful operation of these devices at a temperature of 193 K and results in very low darkcounts (∼100 counts per second (CPS)), good time jitter (∼30 ps), and good DE (∼10%). We characterized two NFADs with a time-correlation method using photons generated from weak coherent pulses and photon pairs produced by spontaneous parametric down conversion. The inferred detector efficiencies for both types of photon sources agree with each other. The best noise equivalent power of the device is estimated to be 8.1 × 10(-18) W Hz(-1/2), more than 10 times better than typical InP/InGaAs single photon avalanche diodes (SPADs) show in free running mode. The afterpulsing probability was found to be less than 0.1% per ns at the optimized operating point. In addition, we studied the performance of an entanglement-based quantum key distribution (QKD) using these detectors and develop a model for the quantum bit error rate that incorporates the afterpulsing coefficients. We verified experimentally that using these NFADs it is feasible to implement QKD over 400 km of telecom fiber. Our NFAD photon detector system is very simple, and is well suited for single-photon applications where ultra-low noise and free-running operation is required, and some afterpulsing

  1. A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias.

    PubMed

    Moretti, Francesca; Marinari, Barbara; Lo Iacono, Nadia; Botti, Elisabetta; Giunta, Alessandro; Spallone, Giulia; Garaffo, Giulia; Vernersson-Lindahl, Emma; Merlo, Giorgio; Mills, Alea A; Ballarò, Costanza; Alemà, Stefano; Chimenti, Sergio; Guerrini, Luisa; Costanzo, Antonio

    2010-05-01

    The human congenital syndromes ectrodactyly ectodermal dysplasia-cleft lip/palate syndrome, ankyloblepharon ectodermal dysplasia clefting, and split-hand/foot malformation are all characterized by ectodermal dysplasia, limb malformations, and cleft lip/palate. These phenotypic features are a result of an imbalance between the proliferation and differentiation of precursor cells during development of ectoderm-derived structures. Mutations in the p63 and interferon regulatory factor 6 (IRF6) genes have been found in human patients with these syndromes, consistent with phenotypes. Here, we used human and mouse primary keratinocytes and mouse models to investigate the role of p63 and IRF6 in proliferation and differentiation. We report that the DeltaNp63 isoform of p63 activated transcription of IRF6, and this, in turn, induced proteasome-mediated DeltaNp63 degradation. This feedback regulatory loop allowed keratinocytes to exit the cell cycle, thereby limiting their ability to proliferate. Importantly, mutations in either p63 or IRF6 resulted in disruption of this regulatory loop: p63 mutations causing ectodermal dysplasias were unable to activate IRF6 transcription, and mice with mutated or null p63 showed reduced Irf6 expression in their palate and ectoderm. These results identify what we believe to be a novel mechanism that regulates the proliferation-differentiation balance of keratinocytes essential for palate fusion and skin differentiation and links the pathogenesis of 2 genetically different groups of ectodermal dysplasia syndromes into a common molecular pathway.

  2. Neural Response to Action and Reward Prediction Errors: Comparing the Error Related Negativity to Behavioral Errors and the Feedback Related Negativity to Reward Prediction Violations

    PubMed Central

    Potts, Geoffrey F.; Martin, Laura E.; Kamp, Siri-Maria; Donchin, Emanuel

    2010-01-01

    The error-related negativity (ERN) is thought to index an anterior cingulate (ACC) behavioral monitoring system. The feedback ERN (FRN) is elicited to error feedback when the correct response is not known, but also when a choice outcome is suboptimal and to passive reward prediction violation, suggesting that the monitoring system may not be restricted to actions. This study used principal components analysis to show that the ERN consists of a single central component while the reward prediction violation FRN is comprised of central and prefrontal components. A prefrontal component is also present in action monitoring but occurs later, at the Error Positivity latency. This suggests that ACC monitors both actions and events for reward prediction error. Prefrontal cortex may update reward expectation based on the prediction violation with the latency difference due to differential processing time for motor and perceptual information. PMID:20557487

  3. The Effects of Positive and Negative Feedback on Maximal Voluntary Contraction Level of the Biceps Brachii Muscle: Moderating Roles of Gender and Conscientiousness.

    PubMed

    Sarıkabak, Murat; Yaman, Çetin; Tok, Serdar; Binboga, Erdal

    2016-11-02

    We investigated the effect of positive and negative feedback on maximal voluntary contraction (MVC) of the biceps brachii muscle and explored the mediating effects of gender and conscientiousness. During elbow flexion, MVCs were measured in positive, negative, and no-feedback conditions. Participants were divided into high- and low-conscientiousness groups based on the median split of their scores on Tatar's five-factor personality inventory. Considering all participants 46 college student athletes (21 female, 28 male), positive feedback led to a greater MVC percentage change (-5.76%) than did negative feedback (2.2%). MVC percentage change in the positive feedback condition differed significantly by gender, but the negative feedback condition did not. Thus, positive feedback increased female athletes' MVC level by 3.49%, but decreased male athletes' MVC level by 15.6%. For conscientiousness, MVC percentage change in the positive feedback condition did not differ according to high and low conscientiousness. However, conscientiousness interacted with gender in the positive feedback condition, increasing MVC in high-conscientiousness female athletes and decreasing MVC in low-conscientiousness female athletes. Positive feedback decreased MVC in both high- and low-conscientiousness male athletes.

  4. Leader-member exchange and member performance: a new look at individual-level negative feedback-seeking behavior and team-level empowerment climate.

    PubMed

    Chen, Ziguang; Lam, Wing; Zhong, Jian An

    2007-01-01

    From a basis in social exchange theory, the authors investigated whether, and how, negative feedback-seeking behavior and a team empowerment climate affect the relationship between leader-member exchange (LMX) and member performance. Results showed that subordinates' negative feedback-seeking behavior mediated the relationship between LMX and both objective and subjective in-role performance. In addition, the level of a team's empowerment climate was positively related to subordinates' own sense of empowerment, which in turn negatively moderated the effects of LMX on negative feedback-seeking behavior. 2007 APA, all rights reserved

  5. A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation

    SciTech Connect

    Ren, Jinqi; Cook, Aaron A.; Bergmeier, Wolfgang; Sondek, John

    2016-05-20

    The dynamic regulation of ERK1 and -2 (ERK1/2) is required for precise signal transduction controlling cell proliferation, differentiation, and survival. However, the underlying mechanisms regulating the activation of ERK1/2 are not completely understood. In this study, we show that phosphorylation of RasGRP2, a guanine nucleotide exchange factor (GEF), inhibits its ability to activate the small GTPase Rap1 that ultimately leads to decreased activation of ERK1/2 in cells. ERK2 phosphorylates RasGRP2 at Ser394 located in the linker region implicated in its autoinhibition. These studies identify RasGRP2 as a novel substrate of ERK1/2 and define a negative-feedback loop that regulates the BRaf–MEK–ERK signaling cascade. This negative-feedback loop determines the amplitude and duration of active ERK1/2. -- Highlights: •ERK2 phosphorylates the guanine nucleotide exchange factor RasGRP2 at Ser394. •Phosphorylated RasGRP2 has decreased capacity to active Rap1b in vitro and in cells. •Phosphorylation of RasGRP2 by ERK1/2 introduces a negative-feedback loop into the BRaf-MEK-ERK pathway.

  6. Estradiol negative and positive feedback in a prenatal androgen-induced mouse model of polycystic ovarian syndrome.

    PubMed

    Moore, Aleisha M; Prescott, Melanie; Campbell, Rebecca E

    2013-02-01

    Gonadal steroid hormone feedback is impaired in polycystic ovarian syndrome (PCOS), a common endocrine disorder characterized by hyperandrogenism and an associated increase in LH pulse frequency. Using a prenatal androgen (PNA)-treated mouse model of PCOS, we aimed to investigate negative and positive feedback effects of estrogens on the hypothalamic-pituitary axis regulation of LH. PNA-treated mice exhibited severely disrupted estrous cycles, hyperandrogenism, significantly reduced fertility, and altered ovarian morphology. To assess the negative feedback effects of estrogens, LH was measured before and after ovariectomy and after estradiol (E2) administration. Compared with controls, PNA-treated mice exhibited a blunted postcastration rise in LH (P < .001) and an absence of LH suppression after E2 administration. To assess E2-positive feedback, control and PNA-treated GnRH-green fluorescent protein transgenic mice were subjected to a standard ovariectomy with E2-replacement regimen, and both plasma and perfusion-fixed brains were collected at the time of the expected GnRH/LH surge. Immunocytochemistry and confocal imaging of cFos and green fluorescent protein were used to assess GnRH neuron activation and spine density. In the surged group, both control and PNA-treated mice had significantly increased LH and cFos activation in GnRH neurons (P < .05) compared with nonsurged animals. Spine density was quantified in cFos-positive and -negative GnRH neurons to examine whether there was an increase in spine density in cFos-expressing GnRH neurons of surged mice as expected. A significant increase in spine density in cFos-expressing GnRH neurons was evident in control animals; however, no significant increase was observed in the PNA-treated mice because spine density was elevated across all GnRH neurons. These data support that PNA treatment results in a PCOS-like phenotype that includes impaired E2-negative feedback. Additionally, although E2-positive feedback

  7. Positive or negative? The impact of X-ray feedback on the formation of direct collapse black hole seeds

    NASA Astrophysics Data System (ADS)

    Regan, John A.; Johansson, Peter H.; Wise, John H.

    2016-09-01

    A nearby source of Lyman-Werner (LW) photons is thought to be a central component in dissociating H2 and allowing for the formation of a direct collapse black hole seed. Nearby sources are also expected to produce copious amounts of hydrogen ionizing photons and X-ray photons. We study here the feedback effects of the X-ray photons by including a spectrum due to high-mass X-ray binaries on top of a galaxy with a stellar spectrum. We explicitly trace photon packages emerging from the nearby source and track the radiative and chemical effects of the multifrequency source (Ephoton = 0.76 eV → 7500 eV). We find that X-rays have a strongly negative feedback effect, compared to a stellar only source, when the radiative source is placed at a separation greater than ≳ 1 kpc. The X-rays heat the low and medium density gas in the envelope surrounding the collapsing halo suppressing the mass inflow. The result is a smaller enclosed mass compared to the stellar only case. However, for separations of ≲ 1 kpc, the feedback effects of the X-rays becomes somewhat neutral. The enhanced LW intensity at close separations dissociates more H2 and this gas is heated due to stellar photons alone, the addition of X-rays is then not significant. This distance dependence of X-ray feedback suggests that a Goldilocks zone exists close to a forming galaxy where X-ray photons have a much smaller negative feedback effect and ideal conditions exist for creating massive black hole seeds.

  8. Positive and negative regulatory elements mediating transcription from the Drosophila melanogaster actin 5C distal promoter.

    PubMed Central

    Chung, Y T; Keller, E B

    1990-01-01

    The major cytoskeletal actin gene of Drosophila melanogaster, the actin 5C gene, has two promoters, the distal one of which controls synthesis of actin in a tissue- and developmental stage-specific manner. This very strong promoter has widely been used for expression of heterologous genes in cultured cells. To locate functional regulatory elements in this distal promoter, mutants of the promoter were fused to the bacterial chloramphenicol acetyltransferase gene and assayed for transient expression activity in cultured Drosophila embryonic Schneider line 2 cells. The results showed that the upstream end of the promoter extends to 522 bp from the transcription start site. In addition, there are two remote activating regions about 2 kb upstream. Between -522 and -379 are two regions that exert a strong negative effect. Downstream from these negative regions are at least six positive regions and a TATA element. The strongest positive determinant of the promoter was identified at -320 as AAAATGTG by footprinting and by a replacement experiment. When the relevant region was replaced by a synthetic sequence containing this element in a random context, the transient expression activity was restored. The sequence TGTATG located at -355 was also identified as a positive element by a similar replacement approach. Apparently the very high activity of this promoter is the result of the combined activities of multiple factors. Images PMID:2123290

  9. Fearless Dominance and reduced feedback-related negativity amplitudes in a time-estimation task – Further neuroscientific evidence for dual-process models of psychopathy☆

    PubMed Central

    Schulreich, Stefan; Pfabigan, Daniela M.; Derntl, Birgit; Sailer, Uta

    2013-01-01

    Dual-process models of psychopathy postulate two etiologically relevant processes. Their involvement in feedback processing and its neural correlates has not been investigated so far. Multi-channel EEG was collected while healthy female volunteers performed a time-estimation task and received negative or positive feedback in form of signs or emotional faces. The affective-interpersonal factor Fearless Dominance, but not Self-Centered Impulsivity, was associated with reduced feedback-related negativity (FRN) amplitudes. This neural dissociation extends previous findings on the impact of psychopathy on feedback processing and further highlights the importance of distinguishing psychopathic traits and extending previous (neuroscientific) models of psychopathy. PMID:23607997

  10. Influences of State and Trait Affect on Behavior, Feedback-Related Negativity, and P3b in the Ultimatum Game

    PubMed Central

    Riepl, Korbinian; Mussel, Patrick; Osinsky, Roman; Hewig, Johannes

    2016-01-01

    The present study investigates how different emotions can alter social bargaining behavior. An important paradigm to study social bargaining is the Ultimatum Game. There, a proposer gets a pot of money and has to offer part of it to a responder. If the responder accepts, both players get the money as proposed by the proposer. If he rejects, none of the players gets anything. Rational choice models would predict that responders accept all offers above 0. However, evidence shows that responders typically reject a large proportion of all unfair offers. We analyzed participants’ behavior when they played the Ultimatum Game as responders and simultaneously collected electroencephalogram data in order to quantify the feedback-related negativity and P3b components. We induced state affect (momentarily emotions unrelated to the task) via short movie clips and measured trait affect (longer-lasting emotional dispositions) via questionnaires. State happiness led to increased acceptance rates of very unfair offers. Regarding neurophysiology, we found that unfair offers elicited larger feedback-related negativity amplitudes than fair offers. Additionally, an interaction of state and trait affect occurred: high trait negative affect (subsuming a variety of aversive mood states) led to increased feedback-related negativity amplitudes when participants were in an angry mood, but not if they currently experienced fear or happiness. We discuss that increased rumination might be responsible for this result, which might not occur, however, when people experience happiness or fear. Apart from that, we found that fair offers elicited larger P3b components than unfair offers, which might reflect increased pleasure in response to fair offers. Moreover, high trait negative affect was associated with decreased P3b amplitudes, potentially reflecting decreased motivation to engage in activities. We discuss implications of our results in the light of theories and research on depression and

  11. Influences of State and Trait Affect on Behavior, Feedback-Related Negativity, and P3b in the Ultimatum Game.

    PubMed

    Riepl, Korbinian; Mussel, Patrick; Osinsky, Roman; Hewig, Johannes

    2016-01-01

    The present study investigates how different emotions can alter social bargaining behavior. An important paradigm to study social bargaining is the Ultimatum Game. There, a proposer gets a pot of money and has to offer part of it to a responder. If the responder accepts, both players get the money as proposed by the proposer. If he rejects, none of the players gets anything. Rational choice models would predict that responders accept all offers above 0. However, evidence shows that responders typically reject a large proportion of all unfair offers. We analyzed participants' behavior when they played the Ultimatum Game as responders and simultaneously collected electroencephalogram data in order to quantify the feedback-related negativity and P3b components. We induced state affect (momentarily emotions unrelated to the task) via short movie clips and measured trait affect (longer-lasting emotional dispositions) via questionnaires. State happiness led to increased acceptance rates of very unfair offers. Regarding neurophysiology, we found that unfair offers elicited larger feedback-related negativity amplitudes than fair offers. Additionally, an interaction of state and trait affect occurred: high trait negative affect (subsuming a variety of aversive mood states) led to increased feedback-related negativity amplitudes when participants were in an angry mood, but not if they currently experienced fear or happiness. We discuss that increased rumination might be responsible for this result, which might not occur, however, when people experience happiness or fear. Apart from that, we found that fair offers elicited larger P3b components than unfair offers, which might reflect increased pleasure in response to fair offers. Moreover, high trait negative affect was associated with decreased P3b amplitudes, potentially reflecting decreased motivation to engage in activities. We discuss implications of our results in the light of theories and research on depression and

  12. Regulatory mechanisms differ in UMP kinases from gram-negative and gram-positive bacteria.

    PubMed

    Evrin, Cécile; Straut, Monica; Slavova-Azmanova, Neli; Bucurenci, Nadia; Onu, Adrian; Assairi, Liliane; Ionescu, Mihaela; Palibroda, Nicolae; Bârzu, Octavian; Gilles, Anne-Marie

    2007-03-09

    In this work, we examined the regulation by GTP and UTP of the UMP kinases from eight bacterial species. The enzyme from Gram-positive organisms exhibited cooperative kinetics with ATP as substrate. GTP decreased this cooperativity and increased the affinity for ATP. UTP had the opposite effect, as it decreased the enzyme affinity for ATP. The nucleotide analogs 5-bromo-UTP and 5-iodo-UTP were 5-10 times stronger inhibitors than the parent compound. On the other hand, UMP kinases from the Gram-negative organisms did not show cooperativity in substrate binding and catalysis. Activation by GTP resulted mainly from the reversal of inhibition caused by excess UMP, and inhibition by UTP was accompanied by a strong increase in the apparent K(m) for UMP. Altogether, these results indicate that, depending on the bacteria considered, GTP and UTP interact with different enzyme recognition sites. In Gram-positive bacteria, GTP and UTP bind to a single site or largely overlapping sites, shifting the T R equilibrium to either the R or T form, a scenario corresponding to almost all regulatory proteins, commonly called K systems. In Gram-negative organisms, the GTP-binding site corresponds to the unique allosteric site of the Gram-positive bacteria. In contrast, UTP interacts cooperatively with a site that overlaps the catalytic center, i.e. the UMP-binding site and part of the ATP-binding site. These characteristics make UTP an original regulator of UMP kinases from Gram-negative organisms, beyond the common scheme of allosteric control.

  13. The organization of plant communities: negative plant-soil feedbacks and semiarid grasslands

    USDA-ARS?s Scientific Manuscript database

    Estimates of species losses and evidence of positive plant diversity-productivity relationships have spurred interest in understanding the mechanism(s) regulating species coexistence and relative abundance. Plant-soil biota feedbacks appear to affect plant diversity and community structure by eithe...

  14. The Effects of a Local Negative Feedback Function between Choice and Relative Reinforcer Rate

    ERIC Educational Resources Information Center

    Davison, Michael; Elliffe, Douglas; Marr, M. Jackson

    2010-01-01

    Four pigeons were trained on two-key concurrent variable-interval schedules with no changeover delay. In Phase 1, relative reinforcers on the two alternatives were varied over five conditions from 0.1 to 0.9. In Phases 2 and 3, we instituted a molar feedback function between relative choice in an interreinforcer interval and the probability of…

  15. Development of a low noise induction magnetic sensor using magnetic flux negative feedback in the time domain.

    PubMed

    Wang, X G; Shang, X L; Lin, J

    2016-05-01

    Time-domain electromagnetic system can implement great depth detection. As for the electromagnetic system, the receiver utilized an air coil sensor, and the matching mode of the sensor employed the resistance matching method. By using the resistance matching method, the vibration of the coil in the time domain can be effectively controlled. However, the noise of the sensor, especially the noise at the resonance frequency, will be increased as well. In this paper, a novel design of a low noise induction coil sensor is proposed, and the experimental data and noise characteristics are provided. The sensor is designed based on the principle that the amplified voltage will be converted to current under the influence of the feedback resistance of the coil. The feedback loop around the induction coil exerts a magnetic field and sends the negative feedback signal to the sensor. The paper analyses the influence of the closed magnetic feedback loop on both the bandwidth and the noise of the sensor. The signal-to-noise ratio is improved dramatically.

  16. Time-dependent characteristic of negative feedback optical amplifier at bit rates 10-Gbit/s based on an optical triode

    NASA Astrophysics Data System (ADS)

    Harada, Yuki; Azmi, Mohamad Syafiq; Azizan, Siti Aisyah; Matsutani, Takaomi; Maeda, Yoshinobu

    2015-01-01

    We proposed and demonstrated an all-optical triode based on a tandem wavelength converter using cross-gain modulation (XGM) in semiconductor optical amplifiers (SOAs). Negative feedback optical amplification scheme, which has the key advantages of reducing bit error rate and waveform reshaping at the output, was employed in this optical triode. This scheme utilizes an input signal and a negative feedback signal (a signal with reverse intensity to the input) and they were fed together into the optical amplifier. Manipulating the intensity of negative feedback signal enabled the noise suppression effect to be optimized and the outputs recorded improvements in bit error rate (BER) and also undergone waveform reshaping shown by the eye-pattern. In negative feedback optical amplifier, the negative feedback signal and input signal were fed into the SOA. However, due to XGM mechanism, there is a setback in which both signals could not be simultaneously fed. Therefore, by using an optical delay, negative feedback timing was manipulated and we investigate timing characteristics of negative feedback optical amplifier with BER and eye-pattern waveforms at 10 Gb/s.

  17. Preparation and crystallization of the stimulatory and inhibitory complexes of GTP cyclohydrolase I and its feedback regulatory protein GFRP.

    PubMed

    Maita, N; Okada, K; Hirotsu, S; Hatakeyama, K; Hakoshima, T

    2001-08-01

    Mammalian GTP cyclohydrolase I is a decameric enzyme in the first and rate-limiting step in the biosynthesis of tetrahydrobiopterin, which is an essential cofactor for enzymes producing neurotransmitters such as catecholamines and for nitric oxide synthases. The enzyme is dually regulated by its feedback regulatory protein GFRP in the presence of its stimulatory effector phenylalanine and its inhibitory effector biopterin. Here, both the stimulatory and inhibitory complexes of rat GTP cyclohydrolase I bound to GFRP were crystallized by vapour diffusion. Diffraction data sets at resolutions of 3.0 and 2.64 A were collected for the stimulatory and inhibitory complexes, respectively. Each complex consists of two GTPCHI pentamer rings and two GFRP pentamer rings, with pseudo-52 point-group symmetry.

  18. GTP cyclohydrolase I feedback regulatory protein is a pentamer of identical subunits. Purification, cDNA cloning, and bacterial expression.

    PubMed

    Yoneyama, T; Brewer, J M; Hatakeyama, K

    1997-04-11

    GTP cyclohydrolase I feedback regulatory protein (GFRP) mediates feedback inhibition of GTP cyclohydrolase I activity by tetrahydrobiopterin and also mediates the stimulatory effect of phenylalanine on the enzyme activity. To characterize the molecular structure of GFRP, we have purified it from rat liver using an efficient step of affinity chromatography and isolated cDNA clones, based on partial amino acid sequences of peptides derived from purified GFRP. Comparison between the amino acid sequence deduced from the cDNA and the N-terminal amino acid sequence of purified GFRP showed that the mature form of GFRP consists of 83 amino acid residues with a calculated Mr of 9,542. The isolated GFRP cDNA was expressed in Escherichia coli as a fusion protein with six consecutive histidine residues at its N terminus. The fusion protein was affinity-purified and digested with thrombin to remove the histidine tag. The resulting recombinant GFRP showed kinetic properties similar to those of GFRP purified from rat liver. Cross-linking experiments using dimethyl suberimidate indicated that GFRP was a pentamer of 52 kDa. Sedimentation equilibrium measurements confirmed the pentameric structure of GFRP by giving an average Mr of 49,734, which is 5 times the calculated molecular weight of the recombinant GFRP polypeptide. Based on the pentameric structure of GFRP, we have proposed a model for the quaternary structure of GFRP and GTP cyclohydrolase I complexes.

  19. Structural basis of biopterin-induced inhibition of GTP cyclohydrolase I by GFRP, its feedback regulatory protein.

    PubMed

    Maita, Nobuo; Hatakeyama, Kazuyuki; Okada, Kengo; Hakoshima, Toshio

    2004-12-03

    GTP cyclohydrolase I (GTPCHI) is the rate-limiting enzyme involved in the biosynthesis of tetrahydrobiopterin, a key cofactor necessary for nitric oxide synthase and for the hydroxylases that are involved in the production of catecholamines and serotonin. In animals, the GTPCHI feedback regulatory protein (GFRP) binds GTPCHI to mediate feed-forward activation of GTPCHI activity in the presence of phenylalanine, whereas it induces feedback inhibition of enzyme activity in the presence of biopterin. Here, we have reported the crystal structure of the biopterin-induced inhibitory complex of GTPCHI and GFRP and compared it with the previously reported phenylalanine-induced stimulatory complex. The structure reveals five biopterin molecules located at each interface between GTPCHI and GFRP. Induced fitting structural changes by the biopterin binding expand large conformational changes in GTPCHI peptide segments forming the active site, resulting in inhibition of the activity. By locating 3,4-dihydroxy-phenylalanine-responsive dystonia mutations in the complex structure, we found mutations that may possibly disturb the GFRP-mediated regulation of GTPCHI.

  20. Double negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells

    PubMed Central

    Yang, Xiaojun; Lin, Xiaojuan; Zhong, Xiaomin; Kaur, Sippy; Li, Ning; Liang, Shun; Lassus, Heini; Wang, Liping; Katsaros, Dionyssios; Montone, Kathleen; Zhao, Xia; Zhang, Youcheng; Bützow, Ralf; Coukos, George; Zhang, Lin

    2010-01-01

    A relatively rare aldehyde dehydrogenase 1 (ALDH1) positive “stem cell-like” subpopulation of tumor cells has the unique ability to initiate and perpetuate tumor growth; moreover it is highly resistant to chemotherapy and significantly associated with poor clinical outcomes. The development of more effective therapies for cancer requires targeting of this cell population. Using cDNA microarray analysis, we identified that the expression of the C. elegans lin-28 homolog (LIN28) was positively correlated with the percentage of ALDH1+ tumor cells; this was further validated in an independent set of tissue arrays (n=197). Both lose-of-function and gain-of-function studies demonstrated that LIN28 plays a critical role in the maintenance of ALDH1+ tumor cells. In addition, we found that there is a double negative feedback loop between LIN28 and let-7 in tumor cells, and that let-7 negatively regulates ALDH1+ tumor cells. Finally, we report that a LIN28/let-7 loop modulates self renewal and differentiation of mammary gland epithelial progenitor cells. Our data provide evidence that cancer stem cells may arise through a “reprogramming-like” mechanism. A rebalancing of the LIN28/let-7 regulatory loop could be a novel therapeutic strategy to target ALDH1+ cancer stem cells. PMID:21045151

  1. The Rice Transcription Factor WRKY53 Suppresses Herbivore-Induced Defenses by Acting as a Negative Feedback Modulator of Mitogen-Activated Protein Kinase Activity1

    PubMed Central

    Hu, Lingfei; Ye, Meng; Zhang, Tongfang; Zhou, Guoxin; Wang, Qi; Lu, Jing

    2015-01-01

    The mechanisms by which herbivore-attacked plants activate their defenses are well studied. By contrast, little is known about the regulatory mechanisms that allow them to control their defensive investment and avoid a defensive overshoot. We characterized a rice (Oryza sativa) WRKY gene, OsWRKY53, whose expression is rapidly induced upon wounding and induced in a delayed fashion upon attack by the striped stem borer (SSB) Chilo suppressalis. The transcript levels of OsWRKY53 are independent of endogenous jasmonic acid but positively regulated by the mitogen-activated protein kinases OsMPK3/OsMPK6. OsWRKY53 physically interacts with OsMPK3/OsMPK6 and suppresses their activity in vitro. By consequence, it modulates the expression of defensive, MPK-regulated WRKYs and thereby reduces jasmonic acid, jasmonoyl-isoleucine, and ethylene induction. This phytohormonal reconfiguration is associated with a reduction in trypsin protease inhibitor activity and improved SSB performance. OsWRKY53 is also shown to be a negative regulator of plant growth. Taken together, these results show that OsWRKY53 functions as a negative feedback modulator of MPK3/MPK6 and thereby acts as an early suppressor of induced defenses. OsWRKY53 therefore enables rice plants to control the magnitude of their defensive investment during early signaling. PMID:26453434

  2. Depression-related difficulties disengaging from negative faces are associated with sustained attention to negative feedback during social evaluation and predict stress recovery

    PubMed Central

    Romero, Nuria; De Raedt, Rudi

    2017-01-01

    The present study aimed to clarify: 1) the presence of depression-related attention bias related to a social stressor, 2) its association with depression-related attention biases as measured under standard conditions, and 3) their association with impaired stress recovery in depression. A sample of 39 participants reporting a broad range of depression levels completed a standard eye-tracking paradigm in which they had to engage/disengage their gaze with/from emotional faces. Participants then underwent a stress induction (i.e., giving a speech), in which their eye movements to false emotional feedback were measured, and stress reactivity and recovery were assessed. Depression level was associated with longer times to engage/disengage attention with/from negative faces under standard conditions and with sustained attention to negative feedback during the speech. These depression-related biases were associated and mediated the association between depression level and self-reported stress recovery, predicting lower recovery from stress after giving the speech. PMID:28362826

  3. Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy.

    PubMed

    Jiang, Ding-Sheng; Liu, Yu; Zhou, Heng; Zhang, Yan; Zhang, Xiao-Dong; Zhang, Xiao-Fei; Chen, Ke; Gao, Lu; Peng, Juan; Gong, Hui; Chen, Yingjie; Yang, Qinglin; Liu, Peter P; Fan, Guo-Chang; Zou, Yunzeng; Li, Hongliang

    2014-04-01

    Cardiac hypertrophy is a complex pathological process that involves multiple factors including inflammation and apoptosis. Interferon regulatory factor 7 (IRF7) is a multifunctional regulator that participates in immune regulation, cell differentiation, apoptosis, and oncogenesis. However, the role of IRF7 in cardiac hypertrophy remains unclear. We performed aortic banding in cardiac-specific IRF7 transgenic mice, IRF7 knockout mice, and the wild-type littermates of these mice. Our results demonstrated that IRF7 was downregulated in aortic banding-induced animal hearts and cardiomyocytes that had been treated with angiotensin II or phenylephrine for 48 hours. Accordingly, heart-specific overexpression of IRF7 significantly attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction, whereas loss of IRF7 led to opposite effects. Moreover, IRF7 protected against angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we identified that IRF7-dependent cardioprotection was mediated through IRF7 binding to inhibitor of κB kinase-β, and subsequent nuclear factor-κB inactivation. In fact, blocking nuclear factor-κB signaling with cardiac-specific inhibitors of κBα(S32A/S36A) super-repressor transgene counteracted the adverse effect of IRF7 deficiency. Conversely, activation of nuclear factor-κB signaling via a cardiac-specific conditional inhibitor of κB kinase-β(S177E/S181E) (constitutively active) transgene negated the antihypertrophic effect of IRF7 overexpression. Our data demonstrate that IRF7 acts as a novel negative regulator of pathological cardiac hypertrophy by inhibiting nuclear factor-κB signaling and may constitute a potential therapeutic target for pathological cardiac hypertrophy.

  4. Interferon Regulatory Factor 7 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy

    PubMed Central

    Jiang, Ding-Sheng; Liu, Yu; Zhou, Heng; Zhang, Yan; Zhang, Xiao-Dong; Zhang, Xiao-Fei; Chen, Ke; Gao, Lu; Peng, Juan; Gong, Hui; Chen, Yingjie; Yang, Qinglin; Liu, Peter P.; Fan, Guo-Chang; Zou, Yunzeng; Li, Hongliang

    2017-01-01

    Cardiac hypertrophy is a complex pathological process that involves multiple factors including inflammation and apoptosis. Interferon regulatory factor 7 (IRF7) is a multifunctional regulator that participates in immune regulation, cell differentiation, apoptosis, and oncogenesis. However, the role of IRF7 in cardiac hypertrophy remains unclear. We performed aortic banding in cardiac-specific IRF7 transgenic mice, IRF7 knockout mice, and the wild-type littermates of these mice. Our results demonstrated that IRF7 was downregulated in aortic banding–induced animal hearts and cardiomyocytes that had been treated with angiotensin II or phenylephrine for 48 hours. Accordingly, heart-specific overexpression of IRF7 significantly attenuated pressure overload–induced cardiac hypertrophy, fibrosis, and dysfunction, whereas loss of IRF7 led to opposite effects. Moreover, IRF7 protected against angiotensin II–induced cardiomyocyte hypertrophy in vitro. Mechanistically, we identified that IRF7-dependent cardioprotection was mediated through IRF7 binding to inhibitor of κB kinase-β, and subsequent nuclear factor-κB inactivation. In fact, blocking nuclear factor-κB signaling with cardiac-specific inhibitors of κBαS32A/S36A super-repressor transgene counteracted the adverse effect of IRF7 deficiency. Conversely, activation of nuclear factor-κB signaling via a cardiac-specific conditional inhibitor of κB kinase-βS177E/S181E (constitutively active) transgene negated the antihypertrophic effect of IRF7 overexpression. Our data demonstrate that IRF7 acts as a novel negative regulator of pathological cardiac hypertrophy by inhibiting nuclear factor-κB signaling and may constitute a potential therapeutic target for pathological cardiac hypertrophy. PMID:24396025

  5. Distal regulatory element of the STAT1 gene potentially mediates positive feedback control of STAT1 expression.

    PubMed

    Yuasa, Katsutoshi; Hijikata, Takao

    2016-01-01

    We previously identified a distal regulatory element located approximately 5.5-kb upstream of the signal transducer and activator of transcription 1 (STAT1) gene, thereafter designating it as 5.5-kb upstream regulatory region (5.5URR). In this study, we investigated the functional roles of 5.5URR in the transcriptional regulation of STAT1 gene. A chromosome conformation capture assay indicated physical interaction of 5.5URR with the STAT1 core promoter. In luciferase reporter assays, 5.5URR-combined STAT1 core promoter exhibited significant increase in reporter activity enhanced by forced STAT1 expression or interferon (IFN) treatment, but STAT1 core promoter alone did not. The 5.5URR contained IFN-stimulated response element and GAS sites, which bound STAT1 complexes in electrophoretic mobility shift assays. Consistently, chromatin immunoprecipitation (ChIP) assays of HEK293 cells with Halo-tagged STAT1 expression indicated the association of Halo-tagged STAT1 with 5.5URR. ChIP assays with IFN treatment demonstrated that IFNs promoted the recruitment of Halo-tagged STAT1 to 5.5URR. Forced STAT1 expression or IFN treatment increased the expression of endogenous STAT1 and other IFN signaling pathway components, such as STAT2, IRF9 and IRF1, besides IFN-responsive genes. Collectively, the results suggest that 5.5URR may provide a regulatory platform for positive feedback control of STAT1 expression possibly to amplify or sustain the intracellular IFN signals.

  6. A synthetic gene circuit for measuring autoregulatory feedback control.

    PubMed

    Schikora-Tamarit, Miquel Àngel; Toscano-Ochoa, Carlos; Domingo Espinós, Júlia; Espinar, Lorena; Carey, Lucas B

    2016-04-18

    Autoregulatory feedback loops occur in the regulation of molecules ranging from ATP to MAP kinases to zinc. Negative feedback loops can increase a system's robustness, while positive feedback loops can mediate transitions between cell states. Recent genome-wide experimental and computational studies predict hundreds of novel feedback loops. However, not all physical interactions are regulatory, and many experimental methods cannot detect self-interactions. Our understanding of regulatory feedback loops is therefore hampered by the lack of high-throughput methods to experimentally quantify the presence, strength and temporal dynamics of autoregulatory feedback loops. Here we present a mathematical and experimental framework for high-throughput quantification of feedback regulation and apply it to RNA binding proteins (RBPs) in yeast. Our method is able to determine the existence of both direct and indirect positive and negative feedback loops, and to quantify the strength of these loops. We experimentally validate our model using two RBPs which lack native feedback loops and by the introduction of synthetic feedback loops. We find that RBP Puf3 does not natively participate in any direct or indirect feedback regulation, but that replacing the native 3'UTR with that of COX17 generates an auto-regulatory negative feedback loop which reduces gene expression noise. Likewise, RBP Pub1 does not natively participate in any feedback loops, but a synthetic positive feedback loop involving Pub1 results in increased expression noise. Our results demonstrate a synthetic experimental system for quantifying the existence and strength of feedback loops using a combination of high-throughput experiments and mathematical modeling. This system will be of great use in measuring auto-regulatory feedback by RNA binding proteins, a regulatory motif that is difficult to quantify using existing high-throughput methods.

  7. Alternative Polyadenylation Allows Differential Negative Feedback of Human miRNA miR-579 on Its Host Gene ZFR

    PubMed Central

    Hinske, Ludwig Christian; Galante, Pedro A. F.; Limbeck, Elisabeth; Möhnle, Patrick; Parmigiani, Raphael B.; Ohno-Machado, Lucila; Camargo, Anamaria A.; Kreth, Simone

    2015-01-01

    About half of the known miRNA genes are located within protein-coding host genes, and are thus subject to co-transcription. Accumulating data indicate that this coupling may be an intrinsic mechanism to directly regulate the host gene’s expression, constituting a negative feedback loop. Inevitably, the cell requires a yet largely unknown repertoire of methods to regulate this control mechanism. We propose APA as one possible mechanism by which negative feedback of intronic miRNA on their host genes might be regulated. Using in-silico analyses, we found that host genes that contain seed matching sites for their intronic miRNAs yield longer 32UTRs with more polyadenylation sites. Additionally, the distribution of polyadenylation signals differed significantly between these host genes and host genes of miRNAs that do not contain potential miRNA binding sites. We then transferred these in-silico results to a biological example and investigated the relationship between ZFR and its intronic miRNA miR-579 in a U87 cell line model. We found that ZFR is targeted by its intronic miRNA miR-579 and that alternative polyadenylation allows differential targeting. We additionally used bioinformatics analyses and RNA-Seq to evaluate a potential cross-talk between intronic miRNAs and alternative polyadenylation. CPSF2, a gene previously associated with alternative polyadenylation signal recognition, might be linked to intronic miRNA negative feedback by altering polyadenylation signal utilization. PMID:25799583

  8. Down‐regulation of TIMP2 by HIF‐1α/miR‐210/HIF‐3α regulatory feedback circuit enhances cancer metastasis in hepatocellular carcinoma

    PubMed Central

    Kai, Alan Ka‐Lun; Chan, Lo Kong; Lo, Regina Cheuk‐Lam; Lee, Joyce Man‐Fong; Wong, Carmen Chak‐Lui; Wong, Jack Chun‐Ming

    2016-01-01

    Cancer metastasis is a multistep process that involves a series of tumor‐stromal interaction, including extracellular matrix (ECM) remodeling, which requires a concerted action of multiple proteolytic enzymes and their endogenous inhibitors. This study investigated the role of tissue inhibitor of metalloproteinases (TIMP) 2 in the context of hepatocellular carcinoma (HCC) metastasis. We found that TIMP2 was the most significantly down‐regulated member among the TIMP family in human HCCs. Moreover, TIMP2 underexpression was frequent (41.8%; 23 of 55) in human HCCs and was significantly associated with liver invasion and poorer survival outcomes of HCC patients. Furthermore, stable silencing of TIMP2 in HCC cell lines enhanced cell invasive ability and ECM degradation associated with formation of invadopodia‐like feature, suggesting that TIMP2 is a negative regulator of HCC metastasis. Using an orthotopic tumor xenograft model, we demonstrated that ectopic expression of TIMP2 open reading frame in the highly metastatic HCC cell line, MHCC‐97L, significantly reduced HCC progression as well as pulmonary metastasis. Mechanistically, TIMP2 suppression, in a hypoxic environment, was induced through a regulatory feedback circuit consisting of hypoxia‐inducible factor (HIF) 1 alpha, microRNA‐210 (miR‐210), and HIF‐3α. Conclusion: TIMP2 is frequently down‐regulated in human HCCs and its down‐regulation is associated with aggressive tumor behavior and poorer patient outcome. Its suppression is under the regulation of a novel feedback circuit consisting of HIF‐1α/miR‐210/HIF‐3α. TIMP2 is an important regulator of ECM degradation and HCC metastasis. (Hepatology 2016;64:473‐487) PMID:27018975

  9. Arctic shelf flooding: a negative feedback on climate warming during terminations

    NASA Astrophysics Data System (ADS)

    Blaschek, Michael; Renssen, Hans

    2013-04-01

    heat release and surface warming during the entire year. Our analysis exhibits a surprising connection between increased sea-ice export through Fram Strait and changes in atmospheric winds that result from modifications in the atmospheric circulation, that are forced by changes in differential heating over the East Siberian Shelf and the Nordic Seas. This atmospheric teleconnection clearly shows that regional changes can affect hemispheric changes. In a first comparison with available sea-ice proxy reconstructions our results do not disagree, but show the necessity of increased temporal and spatial coverage of proxy reconstructions for future investigations. Our results indicate that shelf flooding had a significant impact on the climate during the early Holocene, namely reducing sea-ice cover and affecting atmospheric circulation. During terminations this can be considered to be a negative feedback on the progress of the termination, as a shelf area becomes flooded, sea-ice production and extent are likely to increase and reduce high latitude intake of orbitally-forced insolation, slowing down the warming trend. This can be the cause of observed cold reversals during warming phases in the continuous transformation of a glacial to an interglacial climate. This implies that shelf flooding should be taken into account when studying the climate dynamics during all glacial terminations. References Bauch, H.; Mueller-Lupp, T.; Taldenkova, E.; Spielhagen, R.; Kassens, H.; Grootes, P.; Thiede, J.; Heinemeier, J. & Petryashov, V. Chronology of the Holocene transgression at the North Siberian margin, Global and Planetary Change, 2001, 31, 125 - 139 Rigor, I. & Colony, R., Sea-ice production and transport of pollutants in the Laptev Sea, 1979-1993, Science of The Total Environment, Environmental Radioactivity in the Arctic, 1997, 202, 89-110 Tamura, T. & Ohshima, K. I., Mapping of sea ice production in the Arctic coastal polynyas, J. Geophys. Res., AGU, 2011, 116, C07030-

  10. A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network

    PubMed Central

    Park, Sang-Min; Shin, Sung-Young; Cho, Kwang-Hyun

    2016-01-01

    Revealing the hidden mechanism of how cells sense and react to environmental signals has been a central question in cell biology. We focused on the rate of increase of stimulation, or temporal gradient, known to cause different responses of cells. We have investigated all possible three-node enzymatic networks and identified a network motif that robustly generates a transient or sustained response by acute or gradual stimulation, respectively. We also found that a regulated double-negative feedback within the motif is essential for the temporal gradient-sensitive switching. Our analysis highlights the essential structure and mechanism enabling cells to properly respond to dynamic environmental changes. PMID:27584002

  11. French Regulatory practice and experience feedback on steam generator tube integrity

    SciTech Connect

    Sandon, G.

    1997-02-01

    This paper summarizes the way the French Safety Authority applies regulatory rules and practices to the problem of steam generator tube cracking in French PWR reactors. There are 54 reactors providing 80% of French electrical consumption. The Safety Authority closely monitors the performance of tubes in steam generators, and requires application of a program which deals with problems prior to the actual development of leakage. The actual rules regarding such performance are flexible, responding to the overall performance of operating steam generators. In addition there is an inservice inspection service to examine tubes during shutdown, and to monitor steam generators for leakage during operation, with guidelines for when generators must be pulled off line.

  12. Resonance tuning of a neuromechanical system with two negative sensory feedback configurations

    PubMed Central

    Williams, Carrie A.; DeWeerth, Stephen P.

    2009-01-01

    Resonance tuning in a model of rhythmic movement is compared when the central pattern generator (CPG) consists of two endogenously bursting or two tonically spiking neurons that are connected with reciprocally inhibitory synapses. The CPG receives inhibitory and/or excitatory position feedback from a linear, one-degree-of-freedom mechanical subsystem. As with previously published results [5, 15], resonance tuning is limited to frequencies that are greater than the intrinsic CPG frequency with endogenously bursting neurons. In contrast, with tonically spiking neurons, the resonance tuning range is expanded to frequencies that are below the intrinsic CPG frequency. PMID:19584947

  13. Microwave oscillator with reduced phase noise by negative feedback incorporating microwave signals with suppressed carrier

    NASA Technical Reports Server (NTRS)

    Dick, G. J.; Saunders, J.

    1989-01-01

    Oscillator configurations which reduce the effect of 1/f noise sources for both direct feedback and stabilized local oscillator (STALO) circuits are developed and analyzed. By appropriate use of carrier suppression, a small signal is generated which suffers no loss of loop phase information or signal-to-noise ratio. This small signal can be amplified without degradation by multiplicative amplifier noise, and can be detected without saturation of the detector. Together with recent advances in microwave resonator Qs, these circuit improvements will make possible lower phase noise than can be presently achieved without the use of cryogenic devices.

  14. Positive and Negative Feedbacks and Free-Scale Pattern Distribution in Rural-Population Dynamics

    PubMed Central

    Alados, Concepción L.; Errea, Paz; Gartzia, Maite; Saiz, Hugo; Escós, Juan

    2014-01-01

    Depopulation of rural areas is a widespread phenomenon that has occurred in most industrialized countries, and has contributed significantly to a reduction in the productivity of agro-ecological resources. In this study, we identified the main trends in the dynamics of rural populations in the Central Pyrenees in the 20th C and early 21st C, and used density independent and density dependent models and identified the main factors that have influenced the dynamics. In addition, we investigated the change in the power law distribution of population size in those periods. Populations exhibited density-dependent positive feedback between 1960 and 2010, and a long-term positive correlation between agricultural activity and population size, which has resulted in a free-scale population distribution that has been disrupted by the collapse of the traditional agricultural society and by emigration to the industrialized cities. We concluded that complex socio-ecological systems that have strong feedback mechanisms can contribute to disruptive population collapses, which can be identified by changes in the pattern of population distribution. PMID:25474704

  15. FcRγ Controls the Fas-Dependent Regulatory Function of Lymphoproliferative Double Negative T Cells

    PubMed Central

    Juvet, Stephen C.; Thomson, Christopher W.; Kim, Edward Y.; Han, Mei; Zhang, Li

    2013-01-01

    Patients with autoimmune lymphoproliferative syndrome (ALPS) and lymphoproliferation (LPR) mice are deficient in Fas, and accumulate large numbers of αβ-TCR+, CD4−, CD8− double negative (DN) T cells. The function of these DN T cells remains largely unknown. The common γ subunit of the activating Fc receptors, FcRγ, plays an important role in mediating innate immune responses. We have shown previously that a significant proportion of DN T cells express FcRγ, and that this molecule is required for TCR transgenic DN T cells to suppress allogeneic immune responses. Whether FcRγ plays a critical role in LPR DN T cell-mediated suppression of immune responses to auto and allo-antigens is not known. Here, we demonstrated that FcRγ+, but not FcRγ− LPR DN T cells could suppress Fas+ CD4+ and CD8+ T cell proliferation in vitro and attenuated CD4+ T cell-mediated graft-versus host disease. Although FcRγ expression did not allow LPR DN T cells to inhibit the expansion of Fas-deficient cells within the LPR context, adoptive transfer of FcRγ+, but not FcRγ−, DN T cells inhibited lymphoproliferation in generalized lymphoproliferative disease (GLD) mice. Furthermore, FcRγ acted in a cell-intrinsic fashion to limit DN T cell accumulation by increasing the rate of apoptosis in proliferated cells. These results indicate that FcRγ can confer Fas-dependent regulatory properties on LPR DN T cells, and suggest that FcRγ may be a novel marker for functional DN Tregs. PMID:23762329

  16. Negative regulatory responses to metabolically triggered inflammation impair renal epithelial immunity in diabetes mellitus.

    PubMed

    Chen, Nelson K F; Chong, Tsung Wen; Loh, Hwai-Liang; Lim, Kiat Hon; Gan, Valerie H L; Wang, Marian; Kon, Oi Lian

    2013-05-01

    Diabetes mellitus is characterized by chronic inflammation and increased risk of infections, particularly of tissues exposed to the external environment. However, the causal molecular mechanisms that affect immune cells and their functions in diabetes are unclear. Here we show, by transcript and protein analyses, signatures of glucose-induced tissue damage, chronic inflammation, oxidative stress, and dysregulated expression of multiple inflammation- and immunity-related molecules in diabetic kidneys compared with non-diabetic controls. Abnormal signaling involving cytokines, G-protein coupled receptors, protein kinase C isoforms, mitogen-activated protein kinases, nuclear factor-κB (NFκB), and Toll-like receptors (TLR) were evident. These were accompanied by overexpression of negative regulators of NFκB, TLR, and other proinflammatory pathways, e.g., A20, SOCS1, IRAK-M, IκBα, Triad3A, Tollip, SIGIRR, and ST2L. Anti-inflammatory and immunomodulatory molecules, e.g., IL-10, IL-4, and TSLP that favor TH2 responses were strongly induced. These molecular indicators of immune dysfunction led us to detect the cryptic presence of bacteria and human cytomegalovirus in more than one third of kidneys of diabetic subjects but none in non-diabetic kidneys. Similar signaling abnormalities could be induced in primary human renal tubular epithelial (but not mesangial) cell cultures exposed to high glucose, proinflammatory cytokines and methylglyoxal, and were reversed by combined pharmacological treatment with an antioxidant and a PKC inhibitor. Our results suggest that diabetes impairs epithelial immunity as a consequence of chronic and inappropriate activation of counter-regulatory immune responses, which are otherwise physiological protective mechanisms against inflammation. The immune abnormalities and cryptic renal infections described here may contribute to progression of diabetic nephropathy.

  17. Heparin affin regulatory peptide/pleiotrophin negatively affects diverse biological activities in C6 glioma cells.

    PubMed

    Parthymou, Anastasia; Lampropoulou, Evgenia; Mikelis, Constantinos; Drosou, Georgia; Papadimitriou, Evangelia

    2008-01-01

    Heparin affin regulatory peptide (HARP) or pleiotrophin seems to be involved in the progression of several tumors of diverse origin. In this study, we tried to determine the role of HARP in rat C6 glioma cells by using an antisense strategy for inhibition of HARP expression. Decrease of the expression of endogenous HARP in C6 cells (AS-C6 cells) significantly increased proliferation, migration, and anchorage-independent growth of cells. Implantation of AS-C6 cells onto chicken embryo chorioallantoic membranes resulted in a significant increase of tumor-induced angiogenesis compared with that induced by non-transfected or C6 cells transfected with the plasmid alone (PC-C6 cells). In the same line, conditioned medium from AS-C6 cells significantly increased endothelial cell proliferation, migration, and tube formation in vitro compared with the effect of conditioned medium from C6 or PC-C6 cells. Interestingly, vascular endothelial growth factor (VEGF) induced C6 cell proliferation and migration, and SU1496, a selective inhibitor of VEGF receptor 2 (VEGFR2), blocked increased glioma cell growth, migration, and angiogenicity observed in AS-C6 cell cultures. The above results seem to be due to a direct interaction between HARP and VEGF in the culture medium of C6 and PC-C6 cells, while AS-C6 cells secreted comparable amounts of VEGF that do not interact with HARP. Collectively, these data suggest that HARP negatively affects diverse biological activities in C6 glioma cells, mainly due to binding of HARP to VEGF, which may sequester secreted VEGF from signalling through VEGFR2.

  18. The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway

    PubMed Central

    Cheng, Debra A; Kadlecek, Theresa A.; Cantor, Aaron J.; Kuriyan, John

    2015-01-01

    T cell activation must be properly regulated to ensure normal T cell development and effective immune responses to pathogens and transformed cells while avoiding autoimmunity. The mechanisms controlling the fine-tuning of T cell receptor (TCR) signaling and T cell activation are unclear. The Syk family kinase ζ chain–associated protein kinase of 70 kD (ZAP-70) is a critical component of the TCR signaling machinery that leads to T cell activation. To elucidate potential feedback targets that are dependent on the kinase activity of ZAP-70, we performed a mass spectrometry–based, phosphoproteomic study to quantify temporal changes in phosphorylation patterns after inhibition of ZAP-70 catalytic activity. Our results provide insights into the fine-tuning of the T cell signaling network before and after TCR engagement. The data indicate that the kinase activity of ZAP-70 stimulates negative feedback pathways that target the Src family kinase Lck and modulate the phosphorylation patterns of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 and ζ-chain components of the TCR, and of downstream signaling molecules, including ZAP-70. We developed a computational model that provides a unified mechanistic explanation for the experimental findings on ITAM phosphorylation in wild-type cells, ZAP-70–deficient cells, and cells with inhibited ZAP-70 catalytic activity. This model incorporates negative feedback regulation of Lck activity by the kinase activity of ZAP-70 and makes unanticipated specific predictions for the order in which tyrosines in the ITAMs of TCR ζ-chains must be phosphorylated to be consistent with the experimental data. PMID:25990959

  19. Tunable Stochastic Pulsing in the Escherichia coli Multiple Antibiotic Resistance Network from Interlinked Positive and Negative Feedback Loops

    PubMed Central

    Garcia-Bernardo, Javier; Dunlop, Mary J.

    2013-01-01

    Cells live in uncertain, dynamic environments and have many mechanisms for sensing and responding to changes in their surroundings. However, sudden fluctuations in the environment can be catastrophic to a population if it relies solely on sensory responses, which have a delay associated with them. Cells can reconcile these effects by using a tunable stochastic response, where in the absence of a stressor they create phenotypic diversity within an isogenic population, but use a deterministic response when stressors are sensed. Here, we develop a stochastic model of the multiple antibiotic resistance network of Escherichia coli and show that it can produce tunable stochastic pulses in the activator MarA. In particular, we show that a combination of interlinked positive and negative feedback loops plays an important role in setting the dynamics of the stochastic pulses. Negative feedback produces a pulsatile response that is tunable, while positive feedback serves to amplify the effect. Our simulations show that the uninduced native network is in a parameter regime that is of low cost to the cell (taxing resistance mechanisms are expressed infrequently) and also elevated noise strength (phenotypic variability is high). The stochastic pulsing can be tuned by MarA induction such that variability is decreased once stresses are sensed, avoiding the detrimental effects of noise when an optimal MarA concentration is needed. We further show that variability in the expression of MarA can act as a bet hedging mechanism, allowing for survival in time-varying stress environments, however this effect is tunable to allow for a fully induced, deterministic response in the presence of a stressor. PMID:24086119

  20. Tunable stochastic pulsing in the Escherichia coli multiple antibiotic resistance network from interlinked positive and negative feedback loops.

    PubMed

    Garcia-Bernardo, Javier; Dunlop, Mary J

    2013-01-01

    Cells live in uncertain, dynamic environments and have many mechanisms for sensing and responding to changes in their surroundings. However, sudden fluctuations in the environment can be catastrophic to a population if it relies solely on sensory responses, which have a delay associated with them. Cells can reconcile these effects by using a tunable stochastic response, where in the absence of a stressor they create phenotypic diversity within an isogenic population, but use a deterministic response when stressors are sensed. Here, we develop a stochastic model of the multiple antibiotic resistance network of Escherichia coli and show that it can produce tunable stochastic pulses in the activator MarA. In particular, we show that a combination of interlinked positive and negative feedback loops plays an important role in setting the dynamics of the stochastic pulses. Negative feedback produces a pulsatile response that is tunable, while positive feedback serves to amplify the effect. Our simulations show that the uninduced native network is in a parameter regime that is of low cost to the cell (taxing resistance mechanisms are expressed infrequently) and also elevated noise strength (phenotypic variability is high). The stochastic pulsing can be tuned by MarA induction such that variability is decreased once stresses are sensed, avoiding the detrimental effects of noise when an optimal MarA concentration is needed. We further show that variability in the expression of MarA can act as a bet hedging mechanism, allowing for survival in time-varying stress environments, however this effect is tunable to allow for a fully induced, deterministic response in the presence of a stressor.

  1. The light cycle controls the hatching rhythm in Bombyx mori via negative feedback loop of the circadian oscillator.

    PubMed

    Tao, Hui; Li, Xue; Qiu, Jian-Feng; Liu, Heng-Jiang; Zhang, Da-Yan; Chu, Feng; Sima, Yanghu; Xu, Shi-Qing

    2017-10-01

    Hatching behavior is a key target in silkworm (Bombyx mori) rearing, especially for the control of Lepidoptera pests. According to previous research, hatching rhythms appear to be controlled by a clock mechanism that restricts or "gates" hatching to a particular time. However, the underlying mechanism remains elusive. Under 12-h light:12-h dark photoperiod (LD) conditions, the transcriptional levels of the chitinase5 (Cht5) and hatching enzyme-like (Hel) genes, as well as the enzymatic activities of their gene products, oscillated in time with ambient light cycles, as did the transcriptional levels of the cryptochrome 1, cryptochrome 2, period (per), and timeless genes, which are key components of the negative feedback loop of the circadian rhythm. These changes were related to the expression profile of the ecdysteroid receptor gene and the hatching behavior of B. mori eggs. However, under continuous light or dark conditions, the hatching behavior, the expression levels of Cht5 and Hel, as well as the enzymatic activities of their gene products, were not synchronized unlike under LD conditions. In addition, immunohistochemistry experiments showed that light promoted the translocation of PER from the cytoplasm to the nucleus. In conclusion, LD cycles regulate the hatching rhythm of B. mori via negative feedback loop of the circadian oscillator. © 2017 Wiley Periodicals, Inc.

  2. Ligand binding to the inhibitory and stimulatory GTP cyclohydrolase I/GTP cyclohydrolase I feedback regulatory protein complexes.

    PubMed

    Yoneyama, T; Hatakeyama, K

    2001-04-01

    GTP cyclohydrolase I feedback regulatory protein (GFRP) mediates feedback inhibition of GTP cyclohydrolase I activity by 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4), which is an essential cofactor for key enzymes producing catecholamines, serotonin, and nitric oxide as well as phenylalanine hydroxylase. GFRP also mediates feed-forward stimulation of GTP cyclohydrolase I activity by phenylalanine at subsaturating GTP levels. These ligands, BH4 and phenylalanine, induce complex formation between one molecule of GTP cyclohydrolase I and two molecules of GFRP. Here, we report the analysis of ligand binding using the gel filtration method of Hummel and Dreyer. BH4 binds to the GTP cyclohydrolase I/GFRP complex with a Kd of 4 microM, and phenylalanine binds to the protein complex with a Kd of 94 microM. The binding of BH4 is enhanced by dGTP. The binding stoichiometrics of BH4 and phenylalanine were estimated to be 10 molecules of each per protein complex, in other words, one molecule per subunit of protein, because GTP cyclohydrolase I is a decamer and GFRP is a pentamer. These findings were corroborated by data from equilibrium dialysis experiments. Regarding ligand binding to free proteins, BH4 binds weakly to GTP cyclohydrolase I but not to GFRP, and phenylalanine binds weakly to GFRP but not to GTP cyclohydrolase I. These results suggest that the overall structure of the protein complex contributes to binding of BH4 and phenylalanine but also that each binding site of BH4 and phenylalanine may be primarily composed of residues of GTP cyclohydrolase I and GFRP, respectively.

  3. The Context Matters: Outcome Probability and Expectation Mismatch Modulate the Feedback Negativity When Self-Evaluation of Response Correctness Is Possible

    PubMed Central

    Leue, Anja; Cano Rodilla, Carmen; Beauducel, André

    2015-01-01

    Individuals typically evaluate whether their performance and the obtained feedback match. Previous research has shown that feedback negativity (FN) depends on outcome probability and feedback valence. It is, however, less clear to what extent previous effects of outcome probability on FN depend on self-evaluations of response correctness. Therefore, we investigated the effects of outcome probability on FN amplitude in a simple go/no-go task that allowed for the self-evaluation of response correctness. We also investigated effects of performance incompatibility and feedback valence. In a sample of N = 22 participants, outcome probability was manipulated by means of precues, feedback valence by means of monetary feedback, and performance incompatibility by means of feedback that induced a match versus mismatch with individuals' performance. We found that the 100% outcome probability condition induced a more negative FN following no-loss than the 50% outcome probability condition. The FN following loss was more negative in the 50% compared to the 100% outcome probability condition. Performance-incompatible loss resulted in a more negative FN than performance-compatible loss. Our results indicate that the self-evaluation of the correctness of responses should be taken into account when the effects of outcome probability and expectation mismatch on FN are investigated. PMID:26783525

  4. The Context Matters: Outcome Probability and Expectation Mismatch Modulate the Feedback Negativity When Self-Evaluation of Response Correctness Is Possible.

    PubMed

    Leue, Anja; Cano Rodilla, Carmen; Beauducel, André

    2015-01-01

    Individuals typically evaluate whether their performance and the obtained feedback match. Previous research has shown that feedback negativity (FN) depends on outcome probability and feedback valence. It is, however, less clear to what extent previous effects of outcome probability on FN depend on self-evaluations of response correctness. Therefore, we investigated the effects of outcome probability on FN amplitude in a simple go/no-go task that allowed for the self-evaluation of response correctness. We also investigated effects of performance incompatibility and feedback valence. In a sample of N = 22 participants, outcome probability was manipulated by means of precues, feedback valence by means of monetary feedback, and performance incompatibility by means of feedback that induced a match versus mismatch with individuals' performance. We found that the 100% outcome probability condition induced a more negative FN following no-loss than the 50% outcome probability condition. The FN following loss was more negative in the 50% compared to the 100% outcome probability condition. Performance-incompatible loss resulted in a more negative FN than performance-compatible loss. Our results indicate that the self-evaluation of the correctness of responses should be taken into account when the effects of outcome probability and expectation mismatch on FN are investigated.

  5. Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL

    PubMed Central

    Li, Benshang; Li, Hui; Bai, Yun; Kirschner-Schwabe, Renate; Yang, Jun J; Chen, Yao; Lu, Gang; Tzoneva, Gannie; Ma, Xiaotu; Wu, Tongmin; Li, Wenjing; Lu, Haisong; Ding, Lixia; Liang, Huanhuan; Huang, Xiaohang; Yang, Minjun; Jin, Lei; Kang, Hui; Chen, Shuting; Du, Alicia; Shen, Shuhong; Ding, Jianping; Chen, Hongzhuan; Chen, Jing; von Stackelberg, Arend; Gu, Longjun; Zhang, Jinghui; Ferrando, Adolfo; Tang, Jingyan; Wang, Shengyue; Zhou, Bin-Bing S.

    2015-01-01

    Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in the backbone of ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in phosphoribosyl pyrophosphate synthetase 1 (PRPS1), a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapse B-ALL cases. All individuals who harbored PRPS1 mutations relapsed early on-treatment, and mutated ALL clones expanded exponentially prior to clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol can effectively abrogate PRPS1 mutant-driven drug resistance. Overall these results highlight the importance of constitutive activation of de novo purine pathway in thiopurine resistance, and offer therapeutic strategies for the treatment of relapsed and resistant ALL. PMID:25962120

  6. Sound shielding by a piezoelectric membrane and a negative capacitor with feedback control.

    PubMed

    Sluka, Tomás; Kodama, Hidekazu; Fukada, Eiichi; Mokrý, Pavel

    2008-08-01

    The design and realization of an adaptive sound-shielding system based on a method to control the effective elastic stiffness of piezoelectric materials are presented in this paper. In this system, the sound-shielding effect is achieved by a sound reflection from the piezoelectric curved membrane fixed in rigid frame and connected to an active analog circuit that behaves as a negative capacitor. The acoustic transmission loss through the curved membrane was measured for the incident sound of frequency 1.6 kHz and of acoustic pressure level 80 dB. When the negative capacitor in the system was properly adjusted, the acoustic pressure level of the transmitted sound was reduced from the initial 60 dB to 15 dB by the action of the negative capacitor. Then the system was exposed to naturally changing operational conditions, and their effect on sound-shielding efficiency was studied. It is shown that the acoustic transmission loss of the system dropped by 35 dB within 30 min from the moment of negative capacitor adjustment. Therefore, a self-adjustment of the system has been implemented by appending an additional digital control circuit to the negative capacitor. It is shown that the aforementioned deteriorating effect has been eliminated by the adjusting action of the control circuit. The long-time sustainable value of 60 dB in the acoustic transmission loss of the adaptive sound shielding system has been achieved.

  7. Observational evidence that positive and negative AGN feedback depends on galaxy mass and jet power

    NASA Astrophysics Data System (ADS)

    Kalfountzou, E.; Stevens, J. A.; Jarvis, M. J.; Hardcastle, M. J.; Wilner, D.; Elvis, M.; Page, M. J.; Trichas, M.; Smith, D. J. B.

    2017-10-01

    Several studies support the existence of a link between the active galactic nucleus (AGN) and star formation activity. Radio jets have been argued to be an ideal mechanism for direct interaction between the AGN and the host galaxy. A drawback of previous surveys of AGN is that they are fundamentally limited by the degeneracy between redshift and luminosity in flux-density limited samples. To overcome this limitation, we present far-infrared Herschel observations of 74 radio-loud quasars (RLQs), 72 radio-quiet quasars (RQQs) and 27 radio galaxies (RGs), selected at 0.9 < z < 1.1, which span over two decades in optical luminosity. By decoupling luminosity from evolutionary effects, we investigate how the star formation rate (SFR) depends on AGN luminosity, radio-loudness and orientation. We find that (1) the SFR shows a weak correlation with the bolometric luminosity for all AGN sub-samples, (2) the RLQs show an SFR excess of about a factor of 1.4 compared to the RQQs, matched in terms of black hole mass and bolometric luminosity, suggesting that either positive radio-jet feedback or radio AGN triggering is linked to star formation triggering, and (3) RGs have lower SFRs by a factor of 2.5 than the RLQ sub-sample with the same BH mass and bolometric luminosity. We suggest that there is some jet power threshold at which radio-jet feedback switches from enhancing star formation (by compressing gas) to suppressing it (by ejecting gas). This threshold depends on both galaxy mass and jet power.

  8. Identifying the Impact of Negative Feedback and Learners' Responses on ESL Question Development

    ERIC Educational Resources Information Center

    McDonough, Kim

    2005-01-01

    Swain's (1985, 1995, 2000) output hypothesis states that language production is facilitative of second language (L2) learning. An important component of the output hypothesis involves "pushing" learners to produce appropriate, accurate, and complex language (Swain, 1993), which may occur when interlocutors provide learners with negative feedback…

  9. Identifying the Impact of Negative Feedback and Learners' Responses on ESL Question Development

    ERIC Educational Resources Information Center

    McDonough, Kim

    2005-01-01

    Swain's (1985, 1995, 2000) output hypothesis states that language production is facilitative of second language (L2) learning. An important component of the output hypothesis involves "pushing" learners to produce appropriate, accurate, and complex language (Swain, 1993), which may occur when interlocutors provide learners with negative feedback…

  10. Negative feedback from a Proteus class II flagellum export defect to the flhDC master operon controlling cell division and flagellum assembly.

    PubMed Central

    Furness, R B; Fraser, G M; Hay, N A; Hughes, C

    1997-01-01

    The Proteus mirabilis flagellum class I flhDC operon was isolated, and its transcript was shown to originate from a sigma70 promoter 244 bp 5' of flhD and 29 bp 3' of a putative cyclic AMP receptor protein-binding site. Expression of this regulatory master operon increased strongly as cells differentiated into elongated hyperflagellated swarm filaments, and cell populations artificially overexpressing flhDC migrated sooner and faster. A class II flhA transposon mutant was reduced in flagellum class III gene expression, as would be expected from the FlgM anti-sigma28 accumulation demonstrated in Salmonella typhimurium, but was unexpectedly also reduced in cell elongation. Here, we show that levels of flhDC transcript were ca. 10-fold lower in this flagellum export mutant, indicating that in cells defective in flagellum assembly, there is additional negative feedback via flhDC. In support of this view, artificial overexpression of flhDC in the flhA mutant restored elongation but not class III flagellum gene transcription. PMID:9287017

  11. Peatland plant communities under global change: negative feedback loops counteract shifts in species composition.

    PubMed

    Hedwall, Per-Ola; Brunet, Jörg; Rydin, Håkan

    2017-01-01

    Mires (bogs and fens) are nutrient-limited peatland ecosystems, the vegetation of which is especially sensitive to nitrogen deposition and climate change. The role of mires in the global carbon cycle, and the delivery of different ecosystem services can be considerably altered by changes in the vegetation, which has a strong impact on peat-formation and hydrology. Mire ecosystems are commonly open with limited canopy cover but both nitrogen deposition and increased temperatures may increase the woody vegetation component. It has been predicted that such an increase in tree cover and the associated effects on light and water regimes would cause a positive feed-back loop with respect to the ground vegetation. None of these effects, however, have so far been confirmed in large-scale spatiotemporal studies. Here we analyzed data pertaining to mire vegetation from the Swedish National Forest Inventory collected from permanent sample plots over a period of 20 yr along a latitudinal gradient covering 14°. We hypothesized that the changes would be larger in the southern parts as a result of higher nitrogen deposition and warmer climate. Our results showed an increase in woody vegetation with increases in most ericaceous dwarf-shrubs and in the basal area of trees. These changes were, in contrast to our expectations, evenly distributed over most of the latitudinal gradient. While nitrogen deposition is elevated in the south, the increase in temperatures during recent decades has been larger in the north. Hence, we suggest that different processes in the north and south have produced similar vegetation changes along the latitudinal gradient. There was, however, a sharp increase in compositional change at high deposition, indicating a threshold effect in the response. Instead of a positive feed-back loop caused by the tree layer, an increase in canopy cover reduced the changes in composition of the ground vegetation, whereas a decrease in canopy cover lead to larger changes

  12. The mouse albumin enhancer contains a negative regulatory element that interacts with a novel DNA-binding protein.

    PubMed Central

    Herbst, R S; Boczko, E M; Darnell, J E; Babiss, L E

    1990-01-01

    The far-upstream mouse albumin enhancer (-10.5 to -8.43 kilobases) has both positive and negative regulatory domains which contribute to the rate and tissue specificity of albumin gene transcription. (R. S. Herbst, N. Friedman, J. E. Darnell, Jr., and L. E. Babiss, Proc. Natl. Acad. Sci. USA 86:1553-1557). In this work, the negative regulatory region has been functionally localized to sequences -8.7 to -8.43 kilobases upstream of the albumin gene cap site. In the absence of the albumin-modulating region (in which there are binding sites for the transcription factor C/EBP), the negative region can suppress a neighboring positive-acting element, thereby interfering with albumin enhancer function. The negative region is also capable of negating the positive action of the heterologous transthyretin enhancer in an orientation-independent fashion. Within this negative-acting region we can detect two DNA-binding sites, both of which are recognized by a protein present in all cell types tested. This DNA-binding activity is not competed for by any of a series of known DNA-binding sites, and hence this new protein is a candidate for a role in suppressing the albumin gene in nonhepatic cells. Images PMID:2370857

  13. Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7.

    PubMed Central

    Marié, I; Durbin, J E; Levy, D E

    1998-01-01

    Interferon (IFN) genes are among the earliest transcriptional responses to virus infection of mammalian cells. Although the regulation of the IFNbeta gene has been well characterized, the induction of the large family of IFNalpha genes has remained obscure. We report that the IFNalpha genes can be divided into two groups: an immediate-early response gene (IFNalpha4) which is induced rapidly and without the need for ongoing protein synthesis; and a set of genes that display delayed induction, consisting of at least IFNalpha2, 5, 6 and 8, which are induced more slowly and require cellular protein synthesis. One protein that must be synthesized for induction of the delayed gene set is IFN itself, presumably IFNalpha4 or IFNbeta, which stimulates the Jak-Stat pathway through the IFN receptor, resulting in activation of the transcription factor interferon-stimulated gene factor 3 (ISGF3). Among the IFN-stimulated genes induced through this positive feedback loop is the IFN regulatory factor (IRF) protein, IRF7. Induction of IRF7 protein in response to IFN and its subsequent activation by phosphorylation in response to virus-specific signals, involving two C-terminal serine residues, are required for induction of the delayed IFNalpha gene set. PMID:9822609

  14. Overexpression of GTP cyclohydrolase 1 feedback regulatory protein is protective in a murine model of septic shock.

    PubMed

    Starr, Anna; Sand, Claire A; Heikal, Lamia; Kelly, Peter D; Spina, Domenico; Crabtree, Mark; Channon, Keith M; Leiper, James M; Nandi, Manasi

    2014-11-01

    Overproduction of nitric oxide (NO) by inducible NO synthase contributes toward refractory hypotension, impaired microvascular perfusion, and end-organ damage in septic shock patients. Tetrahydrobiopterin (BH4) is an essential NOS cofactor. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme for BH4 biosynthesis. Under inflammatory conditions, GCH1 activity and hence BH4 levels are increased, supporting pathological NOS activity. GCH1 activity can be controlled through allosteric interactions with GCH1 feedback regulatory protein (GFRP). We investigated whether overexpression of GFRP can regulate BH4 and NO production and attenuate cardiovascular dysfunction in sepsis. Sepsis was induced in mice conditionally overexpressing GFRP and wild-type littermates by cecal ligation and puncture. Blood pressure was monitored by radiotelemetry, and mesenteric blood flow was quantified by laser speckle contrast imaging. Blood biochemistry data were obtained using an iSTAT analyzer, and BH4 levels were measured in plasma and tissues by high-performance liquid chromatography. Increased BH4 and NO production and hypotension were observed in all mice, but the extents of these pathophysiological changes were attenuated in GFRP OE mice. Perturbations in blood biochemistry were similarly attenuated in GFRP OE compared with wild-type controls. These results suggest that GFRP overexpression regulates GCH1 activity during septic shock, which in turn limits BH4 bioavailability for iNOS. We conclude that the GCH1-GFRP axis is a critical regulator of BH4 and NO production and the cardiovascular derangements that occur in septic shock.

  15. Negative Feedbacks by Isoprenoids on a Mevalonate Kinase Expressed in the Corpora Allata of Mosquitoes

    PubMed Central

    Noriega, Fernando G.

    2015-01-01

    Background Juvenile hormones (JH) regulate development and reproductive maturation in insects. JHs are synthesized through the mevalonate pathway (MVAP), an ancient metabolic pathway present in the three domains of life. Mevalonate kinase (MVK) is a key enzyme in the MVAP. MVK catalyzes the synthesis of phosphomevalonate (PM) by transferring the γ-phosphoryl group from ATP to the C5 hydroxyl oxygen of mevalonic acid (MA). Despite the importance of MVKs, these enzymes have been poorly characterized in insects. Results We functionally characterized an Aedes aegypti MVK (AaMVK) expressed in the corpora allata (CA) of the mosquito. AaMVK displayed its activity in the presence of metal cofactors. Different nucleotides were used by AaMVK as phosphoryl donors. In the presence of Mg2+, the enzyme has higher affinity for MA than ATP. The activity of AaMVK was regulated by feedback inhibition from long-chain isoprenoids, such as geranyl diphosphate (GPP) and farnesyl diphosphate (FPP). Conclusions AaMVK exhibited efficient inhibition by GPP and FPP (Ki less than 1 μM), and none by isopentenyl pyrophosphate (IPP) and dimethyl allyl pyrophosphate (DPPM). These results suggest that GPP and FPP might act as physiological inhibitors in the synthesis of isoprenoids in the CA of mosquitoes. Changing MVK activity can alter the flux of precursors and therefore regulate juvenile hormone biosynthesis. PMID:26566274

  16. Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL.

    PubMed

    Li, Benshang; Li, Hui; Bai, Yun; Kirschner-Schwabe, Renate; Yang, Jun J; Chen, Yao; Lu, Gang; Tzoneva, Gannie; Ma, Xiaotu; Wu, Tongmin; Li, Wenjing; Lu, Haisong; Ding, Lixia; Liang, Huanhuan; Huang, Xiaohang; Yang, Minjun; Jin, Lei; Kang, Hui; Chen, Shuting; Du, Alicia; Shen, Shuhong; Ding, Jianping; Chen, Hongzhuan; Chen, Jing; von Stackelberg, Arend; Gu, Longjun; Zhang, Jinghui; Ferrando, Adolfo; Tang, Jingyan; Wang, Shengyue; Zhou, Bin-Bing S

    2015-06-01

    Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy-resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol effectively abrogated PRPS1 mutant-driven drug resistance. These results highlight the importance of constitutive activation of the de novo purine synthesis pathway in thiopurine resistance, and they offer therapeutic strategies for the treatment of relapsed and thiopurine-resistant ALL.

  17. Behavioral approach and reward processing: results on feedback-related negativity and P3 component.

    PubMed

    Lange, Sebastian; Leue, Anja; Beauducel, André

    2012-02-01

    This study examined the FRN, the P3, and individual differences in trait-BAS and trait-BIS in the context of reward expectation mismatch. A more negative FRN was predicted for higher vs. lower trait-BAS individuals and for higher vs. lower trait-BIS individuals. In the extinction-learning task, participants (N=102) chose between two response buttons to earn a maximum of points. In the acquisition phase, button 1 was continuously rewarded and button 2 was partially rewarded. In the extinction phase, one button was unexpectedly no longer rewarded. The FRN amplitude was more negative for higher vs. lower trait-BAS individuals and for lower vs. higher trait-BIS individuals within the extinction phase. The P3 was more positive in the extinction compared to the acquisition phase. Our results suggest that higher trait-BAS individuals have a more pronounced reward expectation mismatch.

  18. The Effects of Varied Ratios of Positive and Negative Nonverbal Audience Feedback on Selected Attitudes and Behaviors of Normal Speaking College Students.

    ERIC Educational Resources Information Center

    Barwind, Jack Alan

    Based on a theoretical rationale derived from dissonance theory, this study investigated the effects of 80%/20% ratios of positive/negative and negative/positive audience feedback on perceptual, attitudinal, and behavioral responses of normal speaking college students. Twenty-six skilled speakers and 30 unskilled speakers were randomly assigned to…

  19. The vicious cycle towards violence: focus on the negative feedback mechanisms of brain serotonin neurotransmission.

    PubMed

    de Boer, Sietse F; Caramaschi, Doretta; Natarajan, Deepa; Koolhaas, Jaap M

    2009-01-01

    Violence can be defined as a form of escalated aggressive behavior that is expressed out of context and out of inhibitory control, and apparently has lost its adaptive function in social communication. Little is known about the social and environmental factors as well as the underlying neurobiological mechanisms involved in the shift of normal adaptive aggression into violence. In an effort to model the harmful acts of aggression and violence in humans, we recently (re)developed an animal model that is focused on engendering uncontrolled forms of maladaptive aggressive behavior in laboratory-bred feral rats and mice. We show that certain (8-12%) constitutionally aggressive individuals gradually develop, over the course of repetitive exposures to victorious social conflicts, escalated (short-latency, high-frequency and ferocious attacks), persistent (lack of attack inhibition by defeat/submission signals and perseverance of the aggressive attack-biting bout), indiscriminating (attacking female and anesthetized male intruders) and injurious (enhanced vulnerable-body region attacks and inflicted wounding) forms of offensive aggression. Based on the neurobiological results obtained using this model, a revised view is presented on the key role of central serotonergic (auto)regulatory mechanisms in this transition of normal aggression into violence.

  20. An ocean-biology-induced negative feedback on ENSO as derived from a hybrid coupled model of the tropical Pacific

    NASA Astrophysics Data System (ADS)

    Zhang, Rong-Hua

    2015-12-01

    Biological conditions in the tropical Pacific Ocean (e.g., phytoplankton biomass) are strongly regulated by physical changes that are associated with the El Niño-Southern Oscillation (ENSO). The existence and variation of phytoplankton biomass act to modulate the vertical penetration of the incoming sunlight into the upper ocean, which causes an ocean-biology-induced heating (OBH) effect on the climate system. Previously, the penetration depth of solar radiation in the upper ocean (Hp) has been defined to describe the related bioclimate connections. An empirical model for interannual Hp variability that is parameterized in terms of its relationship with the sea surface temperature (SST) in the tropical Pacific was derived from remotely sensed ocean color data and is incorporated into a hybrid coupled model (HCM) to represent the OBH effects. In this paper, several HCM experiments are performed to demonstrate the biofeedback onto the ENSO, including a climatological Hp run (in which Hp is prescribed as only seasonally varying), interannual Hp runs (with different intensities of the interannually varying OBH effects), and a run in which the sign of the OBH effect is reversed. Significant modulating impacts on the interannual variability are found in the HCM and are characterized by a negative feedback between the ocean biology and the climate system in the tropical Pacific; stronger the OBH feedback, weaker the interannual variability. The processes that are involved in the feedback are analyzed. The SST is modulated indirectly by dynamic ocean processes that are induced by OBH. The significance and implication of the OBH effects are discussed in terms of their roles in ENSO variability and the model biases in the tropical Pacific.

  1. An Nkx2-5/Bmp2/Smad1 negative feedback loop controls second heart field progenitor specification and proliferation

    PubMed Central

    Prall, Owen WJ; Menon, Mary K; Solloway, Mark J; Watanabe, Yusuke; Zaffran, Stéphane; Bajolle, Fanny; Biben, Christine; McBride, Jim J; Robertson, Bronwyn R; Chaulet, Hervé; Stennard, Fiona A; Wise, Natalie; Schaft, Daniel; Wolstein, Orit; Furtado, Milena B; Shiratori, Hidetaka; Chien, Kenneth R; Hamada, Hiroshi; Black, Brian L; Saga, Yumiko; Robertson, Elizabeth J; Buckingham, Margaret E; Harvey, Richard P

    2007-01-01

    Summary During heart development the second heart field (SHF) provides progenitor cells for most cardiomyocytes and expresses the homeodomain factor Nkx2-5. We now show that feedback repression of Bmp2/Smad1 signaling by Nkx2-5 critically regulates SHF proliferation and outflow tract (OFT) morphology. In the cardiac fields of Nkx2-5 mutants, genes controlling cardiac specification (including Bmp2) and maintenance of the progenitor state were up-regulated, leading initially to progenitor over-specification, but subsequently to failed SHF proliferation and OFT truncation. In Smad1 mutants, SHF proliferation and deployment to the OFT were increased, while Smad1 deletion in Nkx2-5 mutants rescued SHF proliferation and OFT development. In Nkx2-5 hypomorphic mice, which recapitulate human congenital heart disease (CHD), OFT anomalies were also rescued by Smad1 deletion. Our findings demonstrate that Nkx2-5 orchestrates the transition between periods of cardiac induction, progenitor proliferation and OFT morphogenesis via a Smad1-dependent negative feedback loop, which may be a frequent molecular target in CHD. PMID:17350578

  2. The Feedback-related Negativity Codes Components of Abstract Inference during Reward-based Decision-making.

    PubMed

    Reiter, Andrea M F; Koch, Stefan P; Schröger, Erich; Hinrichs, Hermann; Heinze, Hans-Jochen; Deserno, Lorenz; Schlagenhauf, Florian

    2016-08-01

    Behavioral control is influenced not only by learning from the choices made and the rewards obtained but also by "what might have happened," that is, inference about unchosen options and their fictive outcomes. Substantial progress has been made in understanding the neural signatures of direct learning from choices that are actually made and their associated rewards via reward prediction errors (RPEs). However, electrophysiological correlates of abstract inference in decision-making are less clear. One seminal theory suggests that the so-called feedback-related negativity (FRN), an ERP peaking 200-300 msec after a feedback stimulus at frontocentral sites of the scalp, codes RPEs. Hitherto, the FRN has been predominantly related to a so-called "model-free" RPE: The difference between the observed outcome and what had been expected. Here, by means of computational modeling of choice behavior, we show that individuals employ abstract, "double-update" inference on the task structure by concurrently tracking values of chosen stimuli (associated with observed outcomes) and unchosen stimuli (linked to fictive outcomes). In a parametric analysis, model-free RPEs as well as their modification because of abstract inference were regressed against single-trial FRN amplitudes. We demonstrate that components related to abstract inference uniquely explain variance in the FRN beyond model-free RPEs. These findings advance our understanding of the FRN and its role in behavioral adaptation. This might further the investigation of disturbed abstract inference, as proposed, for example, for psychiatric disorders, and its underlying neural correlates.

  3. The regulatory effect of choice in Situation Selection reduces experiential, exocrine and respiratory arousal for negative emotional stimulations.

    PubMed

    Thuillard, Simon; Dan-Glauser, Elise S

    2017-10-03

    Situation selection is a seldom studied emotion regulation strategy that entails choosing an upcoming emotional situation. Two mechanisms may drive its regulatory effect on emotional responses. One relates to the evaluation of the chosen option, people generally selecting the most positive. The other one implies that having the choice regarding the upcoming emotional situation is already regulatory, independently of what we choose. This research aimed at investigating this latter hypothesis. In a within-subject design, we compared emotional responses of 65 participants when they viewed negative and positive images they could select (use of Situation selection) vs. when they were imposed the exact same images (Situation selection not used). Results show that having the choice in negative contexts decreased negative experience, skin conductance, and respiration reactivity, while enhancing expressivity and cardiovascular reactivity. In positive contexts, choosing generally reinforced the image calming effect. Thus, contrary to other strategies that are efficient for negative but usually impair positive reactions (e.g., distraction), Situation selection may be used widely to reduce negative experience, while avoiding depletion of positive responses. This is particularly notable in emotion experience. Remarkably, these effects are not driven by the content of the situations, but by the act of choosing itself.

  4. Negative feedback control of jasmonate signaling by an alternative splice variant of JAZ10.

    PubMed

    Moreno, Javier E; Shyu, Christine; Campos, Marcelo L; Patel, Lalita C; Chung, Hoo Sun; Yao, Jian; He, Sheng Yang; Howe, Gregg A

    2013-06-01

    The plant hormone jasmonate (JA) activates gene expression by promoting ubiquitin-dependent degradation of jasmonate ZIM domain (JAZ) transcriptional repressor proteins. A key feature of all JAZ proteins is the highly conserved Jas motif, which mediates both JAZ degradation and JAZ binding to the transcription factor MYC2. Rapid expression of JAZ genes in response to JA is thought to attenuate JA responses, but little is known about the mechanisms by which newly synthesized JAZ proteins exert repression in the presence of the hormone. Here, we show in Arabidopsis (Arabidopsis thaliana) that desensitization to JA is mediated by an alternative splice variant (JAZ10.4) of JAZ10 that lacks the Jas motif. Unbiased protein-protein interaction screens identified three related basic helix-loop-helix transcription factors (MYC2, MYC3, and MYC4) and the corepressor NINJA as JAZ10.4-binding partners. We show that the amino-terminal region of JAZ10.4 contains a cryptic MYC2-binding site that resembles the Jas motif and that the ZIM motif of JAZ10.4 functions as a transferable repressor domain whose activity is associated with the recruitment of NINJA. Functional studies showed that the expression of JAZ10.4 from the native JAZ10 promoter complemented the JA-hypersensitive phenotype of a jaz10 mutant. Moreover, treatment of these complemented lines with JA resulted in the rapid accumulation of JAZ10.4 protein. Our results provide an explanation for how the unique domain architecture of JAZ10.4 links transcription factors to a corepressor complex and suggest how JA-induced transcription and alternative splicing of JAZ10 premessenger RNA creates a regulatory circuit to attenuate JA responses.

  5. Different strategies underlying uncertain decision making: higher executive performance is associated with enhanced feedback-related negativity.

    PubMed

    Kóbor, Andrea; Takács, Ádám; Janacsek, Karolina; Németh, Dezső; Honbolygó, Ferenc; Csépe, Valéria

    2015-03-01

    The aim of the present study was to investigate the role of executive functions (EFs) in different strategies underlying risky decision making. Adult participants from a nonclinical sample were assigned to low or high EF groups based on their performance on EF tasks measuring shifting, updating, and inhibition. ERPs were recorded while participants performed the Balloon Analogue Risk Task (BART). In this task, each balloon pump was associated with either a reward or a balloon pop with unknown probability. The BART behavioral measures did not show between-group differences. However, the feedback-related negativity (FRN) associated with undesirable outcomes was larger in the high EF group than in the low EF group. Since the FRN represents salience prediction error, our results suggest that the high EF group formed internal models that were violated by the outcomes. Thus, we provided ERP evidence for EFs influencing risky decision-making processes.

  6. A Application of Feedback Control to Stabilise a Specific Case of the Negative Buoyancy Flow Instability

    NASA Astrophysics Data System (ADS)

    Ffowcs Williams, J. E.; Morgans, A. S.

    2001-10-01

    This paper is one that David Maull would have enjoyed savaging. Firstly, because he always enjoyed lively discussions about hare-brained schemes for using feedback control to produce unnatural states of motion, and secondly, because he was never happier than when probing details of imaginative undergraduate projects. This paper results from such a project in the group where David spent most of his professional life, a project so far-fetched that it would have attracted his most critical attention. It would also have attracted his characteristically encouraging support. The idea that instabilities of inviscid vortex sheets, which prevent them from being naturally steady, might be controlled through suitably excited actuators is being tentatively advanced, and some peculiar features of the controlled state also attract attention. The project that produced this paper addressed one peculiarity that turned out to be an error [see Ffowcs Williams (1982)], the solution to the actively controlled sheet turning out to be different and much simpler; this solution is published in Ffowcs Williams (2001). The project went on to consider whether another planar interface that is naturally unstable might be made stable by the action of an adjustable nearby surface. The situation envisaged is an unstable density stratified arrangement where heavy fluid lies initially at rest above a lighter fluid, the interface between the two fluids being planar. Above the interface is an impervious structural surface, which can be moved by a small amount by actuators designed to induce in the fluid a motion that will prevent the growth of any gravitational mode of instability. We show that it is indeed possible to define a controller with the required performance, but its implementation would be a very demanding task. A finite body of fluid could, on the other hand, be held suspended against gravity by relatively straightforward control arrangements. A particular example is worked out in detail

  7. Functional polymorphisms of circadian negative feedback regulation genes are associated with clinical outcome in hepatocellular carcinoma patients receiving radical resection.

    PubMed

    Zhang, Zhaohui; Ma, Fei; Zhou, Feng; Chen, Yibing; Wang, Xiaoyan; Zhang, Hongxin; Zhu, Yong; Bi, Jianwei; Zhang, Yiguan

    2014-12-01

    Previous studies have demonstrated that circadian negative feedback loop genes play an important role in the development and progression of many cancers. However, the associations between single-nucleotide polymorphisms (SNPs) in these genes and the clinical outcomes of hepatocellular carcinoma (HCC) after surgical resection have not been studied so far. Thirteen functional SNPs in circadian genes were genotyped using the Sequenom iPLEX genotyping system in a cohort of 489 Chinese HCC patients who received radical resection. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis. Cumulative effect analysis and survival tree analysis were used for the multiple SNPs analysis. Four individual SNPs, including rs3027178 in PER1, rs228669 and rs2640908 in PER3 and rs3809236 in CRY1, were significantly associated with overall survival (OS) of HCC patients, and three SNPs, including rs3027178 in PER1, rs228729 in PER3 and rs3809236 in CRY1, were significantly associated with recurrence-free survival (RFS). Moreover, we observed a cumulative effect of significant SNPs on OS and RFS (P for trend < 0.001 for both). Survival tree analysis indicated that wild genotype of rs228729 in PER3 was the primary risk factor contributing to HCC patients' RFS. Our study suggests that the polymorphisms in circadian negative feedback loop genes may serve as independent prognostic biomarkers in predicting clinical outcomes for HCC patients who received radical resection. Further studies with different ethnicities are needed to validate our findings and generalize its clinical utility.

  8. Differential contributions of nitric oxide synthase isoforms at hippocampal formation to negative feedback regulation of penile erection in the rat

    PubMed Central

    Chang, Alice Y W; Chan, Julie Y H; Chan, Samuel H H

    2002-01-01

    We established previously that a novel negative feedback mechanism for the regulation of penile erection, which is triggered by ascending sensory inputs initiated by tumescence of the penis, exists in the hippocampal formation (HF). This study further evaluated the participation of nitric oxide (NO) and the contribution of nitric oxide synthase (NOS) isoforms at the HF in this process.Adult, male Sprague-Dawley rats that were anaesthetized and maintained with chloral hydrate were used, and intracavernous pressure (ICP) recorded from the corpus cavernosum of the penis was employed as our experimental index for penile erection.Microinjection bilaterally of a NO donor, S-nitroso-N-acetylpenicillamine (0.25 or 1 nmoles), or the NO precursor, L-arginine (1 or 5 nmoles), into the hippocampal CA1 or CA3 subfield or dentate gyrus elicited a significant reduction in baseline ICP.Bilateral hippocampal application of a NO trapping agent, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (10 nmoles), significantly potentiated the elevation in ICP induced by intracavernous administration of papaverine (400 μg).Microinjection bilaterally into the HF of equimolar doses (0.5 or 2.5 pmoles) of two selective neuronal NOS inhibitors, 7-nitroindazole or Nω-propyl-L-arginine; or equimolar doses (50 or 250 pmoles) of two selective inducible NOS inhibitors, aminoguanidine or S-methylisothiourea, significantly enhanced the magnitude and/or duration of the papaverine-induced elevation in ICP. In contrast, hippocampal application of a potent endothelial NOS inhibitor, N5-(1-iminoethyl)-L-ornithine (18 or 92 nmoles), was ineffective. Neither of these inhibitors, furthermore, affected baseline ICP.These results suggest that NO generated via both neuronal and inducible NOS at the HF may participate in negative feedback regulation of penile erection. PMID:11976262

  9. Experimental investigation on nonlinear dynamics of 1550 nm VCSEL simultaneously subject to orthogonal optical injection and negative optoelectronic feedback

    NASA Astrophysics Data System (ADS)

    Deng, Tao; Xia, Guang-Qiong; Chen, Jian-Jun; Tang, Xi; Lin, Xiao-Dong; Yang, Xin; Huang, Shou-Wen; Wu, Zheng-Mao

    2017-04-01

    Nonlinear dynamic characteristics of a 1550 nm vertical-cavity surface-emitting laser (1550 nm VCSEL) simultaneously subject to orthogonal optical injection and negative optoelectronic feedback are experimentally investigated. The results show that, under suitable orthogonal optical injection the VCSEL can exhibit rich nonlinear dynamic behaviors such as stable state (S), period-one (P1), period-two (P2), chaos (CO), stable injection locking (SIL) and polarization switching (PS). After further introducing negative optoelectronic feedback with a certain feedback delay time, the dynamic distribution of the orthogonal optical injection 1550 nm VCSEL is significantly affected, and some new phenomena including three-frequency quasiperiodic (Q3) state can be observed. With the increase of optoelectronic feedback strength, the S and SIL regions typically are shrank, while the quasiperiodic (QP) and CO regions are enlarged.

  10. Positive or negative feedback of optokinetic signals: degree of the misrouted optic flow determines system dynamics of human ocular motor behavior.

    PubMed

    Chen, Chien-Cheng; Bockisch, Christopher J; Olasagasti, Itsaso; Weber, Konrad P; Straumann, Dominik; Huang, Melody Ying-Yu

    2014-04-09

    The optokinetic system in healthy humans is a negative-feedback system that stabilizes gaze: slow-phase eye movements (i.e., the output signal) minimize retinal slip (i.e., the error signal). A positive-feedback optokinetic system may exist due to the misrouting of optic fibers. Previous studies have shown that, in a zebrafish mutant with a high degree of the misrouting, the optokinetic response (OKR) is reversed. As a result, slow-phase eye movements amplify retinal slip, forming a positive-feedback optokinetic loop. The positive-feedback optokinetic system cannot stabilize gaze, thus leading to spontaneous eye oscillations (SEOs). Because the misrouting in human patients (e.g., with a condition of albinism or achiasmia) is partial, both positive- and negative-feedback loops co-exist. How this co-existence affects human ocular motor behavior remains unclear. We presented a visual environment consisting of two stimuli in different parts of the visual field to healthy subjects. One mimicked positive-feedback optokinetic signals and the other preserved negative-feedback optokinetic signals. By changing the ratio and position of the visual field of these visual stimuli, various optic nerve misrouting patterns were simulated. Eye-movement responses to stationary and moving stimuli were measured and compared with computer simulations. The SEOs were correlated with the magnitude of the virtual positive-feedback optokinetic effect. We found a correlation among the simulated misrouting, the corresponding OKR, and the SEOs in humans. The proportion of the simulated misrouting needed to be greater than 50% to reverse the OKR and at least greater than or equal to 70% to evoke SEOs. Once the SEOs were evoked, the magnitude positively correlated to the strength of the positive-feedback OKR. This study provides a mechanism of how the misrouting of optic fibers in humans could lead to SEOs, offering a possible explanation for a subtype of infantile nystagmus syndrome (INS).

  11. The hypoxia-inducible miR-429 regulates hypoxia-inducible factor-1α expression in human endothelial cells through a negative feedback loop

    PubMed Central

    Bartoszewska, Sylwia; Kochan, Kinga; Piotrowski, Arkadiusz; Kamysz, Wojciech; Ochocka, Renata J.; Collawn, James F.; Bartoszewski, Rafal

    2015-01-01

    Hypoxia-inducible factors (HIFs) 1 and 2 are dimeric α/β transcription factors that regulate cellular responses to low oxygen. HIF-1 is induced first, whereas HIF-2 is associated with chronic hypoxia. To determine how HIF1A mRNA, the inducible subunit of HIF-1, is regulated during hypoxia, we followed HIF1A mRNA levels in primary HUVECs over 24 hours using quantitative PCR. HIF1A and VEGF A (VEGFA) mRNA, a transcriptional target of HIF-1, increased ∼2.5- and 8-fold at 2–4 hours, respectively. To determine how the mRNAs were regulated, we identified a microRNA (miRNA), miR-429, that destabilized HIF1A message and decreased VEGFA mRNA by inhibiting HIF1A. Target protector analysis, which interferes with miRNA-mRNA complex formation, confirmed that miR-429 targeted HIF1A message. Desferoxamine treatment, which inhibits the hydroxylases that promote HIF-1α protein degradation, stabilized HIF-1 activity during normoxic conditions and elevated miR-429 levels, demonstrating that HIF-1 promotes miR-429 expression. RNA-sequencing-based transcriptome analysis indicated that inhibition of miRNA-429 in HUVECs up-regulated 209 mRNAs, a number of which regulate angiogenesis. The results demonstrate that HIF-1 is in a negative regulatory loop with miR-429, that miR-429 attenuates HIF-1 activity by decreasing HIF1A message during the early stages of hypoxia before HIF-2 is activated, and this regulatory network helps explain the HIF-1 transition to HIF-2 during chronic hypoxia in endothelial cells.—Bartoszewska, S., Kochan, K., Piotrowski, A., Kamysz, W., Ochocka, R. J., Collawn, J. F., Bartoszewski, R. The hypoxia-inducible miR-429 regulates hypoxia hypoxia-inducible factor-1α expression in human endothelial cells through a negative feedback loop. PMID:25550463

  12. GTP cyclohydrolase I expression, protein, and activity determine intracellular tetrahydrobiopterin levels, independent of GTP cyclohydrolase feedback regulatory protein expression.

    PubMed

    Tatham, Amy L; Crabtree, Mark J; Warrick, Nicholas; Cai, Shijie; Alp, Nicholas J; Channon, Keith M

    2009-05-15

    GTP cyclohydrolase I (GTPCH) is a key enzyme in the synthesis of tetrahydrobiopterin (BH4), a required cofactor for nitricoxide synthases and aromatic amino acid hydroxylases. Alterations of GTPCH activity and BH4 availability play an important role in human disease. GTPCH expression is regulated by inflammatory stimuli, in association with reduced expression of GTP cyclohydrolase feedback regulatory protein (GFRP). However, the relative importance of GTPCH expression versus GTPCH activity and the role of GFRP in relation to BH4 bioavailability remain uncertain. We investigated these relationships in a cell line with tet-regulated GTPCH expression and in the hph-1 mouse model of GTPCH deficiency. Doxycycline exposure resulted in a dose-dependent decrease in GTPCH protein and activity, with a strong correlation between GTPCH expression and BH4 levels (r(2) = 0.85, p < 0.0001). These changes in GTPCH and BH4 had no effect on GFRP expression or protein levels. GFRP overexpression and knockdown in tet-GCH cells did not alter GTPCH activity or BH4 levels, and GTPCH-specific knockdown in sEnd.1 endothelial cells had no effect on GFRP protein. In mouse liver we observed a graded reduction of GTPCH expression, protein, and activity, from wild type, heterozygote, to homozygote littermates, with a striking linear correlation between GTPCH expression and BH4 levels (r(2) = 0.82, p < 0.0001). Neither GFRP expression nor protein differed between wild type, heterozygote, nor homozygote mice, despite the substantial differences in BH4. We suggest that GTPCH expression is the primary regulator of BH4 levels, and changes in GTPCH or BH4 are not necessarily accompanied by changes in GFRP expression.

  13. Overexpression of GTP Cyclohydrolase 1 Feedback Regulatory Protein Is Protective in a Murine Model of Septic Shock

    PubMed Central

    Starr, Anna; Sand, Claire A.; Heikal, Lamia; Kelly, Peter D.; Spina, Domenico; Crabtree, Mark; Channon, Keith M.; Leiper, James M.; Nandi, Manasi

    2014-01-01

    ABSTRACT Overproduction of nitric oxide (NO) by inducible NO synthase contributes toward refractory hypotension, impaired microvascular perfusion, and end-organ damage in septic shock patients. Tetrahydrobiopterin (BH4) is an essential NOS cofactor. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme for BH4 biosynthesis. Under inflammatory conditions, GCH1 activity and hence BH4 levels are increased, supporting pathological NOS activity. GCH1 activity can be controlled through allosteric interactions with GCH1 feedback regulatory protein (GFRP). We investigated whether overexpression of GFRP can regulate BH4 and NO production and attenuate cardiovascular dysfunction in sepsis. Sepsis was induced in mice conditionally overexpressing GFRP and wild-type littermates by cecal ligation and puncture. Blood pressure was monitored by radiotelemetry, and mesenteric blood flow was quantified by laser speckle contrast imaging. Blood biochemistry data were obtained using an iSTAT analyzer, and BH4 levels were measured in plasma and tissues by high-performance liquid chromatography. Increased BH4 and NO production and hypotension were observed in all mice, but the extents of these pathophysiological changes were attenuated in GFRP OE mice. Perturbations in blood biochemistry were similarly attenuated in GFRP OE compared with wild-type controls. These results suggest that GFRP overexpression regulates GCH1 activity during septic shock, which in turn limits BH4 bioavailability for iNOS. We conclude that the GCH1-GFRP axis is a critical regulator of BH4 and NO production and the cardiovascular derangements that occur in septic shock. PMID:25046538

  14. Validating the GTP-cyclohydrolase 1-feedback regulatory complex as a therapeutic target using biophysical and in vivo approaches

    PubMed Central

    Hussein, D; Starr, A; Heikal, L; McNeill, E; Channon, K M; Brown, P R; Sutton, B J; McDonnell, J M; Nandi, M

    2015-01-01

    Background and Purpose 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide biosynthesis. Substantial clinical evidence indicates that intravenous BH4 restores vascular function in patients. Unfortunately, oral BH4 has limited efficacy. Therefore, orally bioavailable pharmacological activators of endogenous BH4 biosynthesis hold significant therapeutic potential. GTP-cyclohydrolase 1 (GCH1), the rate limiting enzyme in BH4 synthesis, forms a protein complex with GCH1 feedback regulatory protein (GFRP). This complex is subject to allosteric feed-forward activation by L-phenylalanine (L-phe). We investigated the effects of L-phe on the biophysical interactions of GCH1 and GFRP and its potential to alter BH4 levels in vivo. Experimental Approach Detailed characterization of GCH1–GFRP protein–protein interactions were performed using surface plasmon resonance (SPR) with or without L-phe. Effects on systemic and vascular BH4 biosynthesis in vivo were investigated following L-phe treatment (100 mg·kg−1, p.o.). Key Results GCH1 and GFRP proteins interacted in the absence of known ligands or substrate but the presence of L-phe doubled maximal binding and enhanced binding affinity eightfold. Furthermore, the complex displayed very slow association and dissociation rates. In vivo, L-phe challenge induced a sustained elevation of aortic BH4, an effect absent in GCH1(fl/fl)-Tie2Cre mice. Conclusions and Implications Biophysical data indicate that GCH1 and GFRP are constitutively bound. In vivo, data demonstrated that L-phe elevated vascular BH4 in an endothelial GCH1 dependent manner. Pharmacological agents which mimic the allosteric effects of L-phe on the GCH1–GFRP complex have the potential to elevate endothelial BH4 biosynthesis for numerous cardiovascular disorders. PMID:26014146

  15. Control of mRNA decapping by positive and negative regulatory elements in the Dcp2 C-terminal domain

    PubMed Central

    He, Feng; Jacobson, Allan

    2015-01-01

    Decapping commits an mRNA to complete degradation and promotes general 5′ to 3′ decay, nonsense-mediated decay (NMD), and transcript-specific degradation. In Saccharomyces cerevisiae, a single decapping enzyme composed of a regulatory subunit (Dcp1) and a catalytic subunit (Dcp2) targets thousands of distinct substrate mRNAs. However, the mechanisms controlling this enzyme's in vivo activity and substrate specificity remain elusive. Here, using a genetic approach, we show that the large C-terminal domain of Dcp2 includes a set of conserved negative and positive regulatory elements. A single negative element inhibits enzymatic activity and controls the downstream functions of several positive elements. The positive elements recruit the specific decapping activators Edc3, Pat1, and Upf1 to form distinct decapping complexes and control the enzyme's substrate specificity and final activation. Our results reveal unforeseen regulatory mechanisms that control decapping enzyme activity and function in vivo, and define roles for several decapping activators in the regulation of mRNA decapping. PMID:26184073

  16. Inhibitory and toxic effects of extracellular self-DNA in litter: a mechanism for negative plant-soil feedbacks?

    PubMed

    Mazzoleni, Stefano; Bonanomi, Giuliano; Incerti, Guido; Chiusano, Maria Luisa; Termolino, Pasquale; Mingo, Antonio; Senatore, Mauro; Giannino, Francesco; Cartenì, Fabrizio; Rietkerk, Max; Lanzotti, Virginia

    2015-02-01

    Plant-soil negative feedback (NF) is recognized as an important factor affecting plant communities. The objectives of this work were to assess the effects of litter phytotoxicity and autotoxicity on root proliferation, and to test the hypothesis that DNA is a driver of litter autotoxicity and plant-soil NF. The inhibitory effect of decomposed litter was studied in different bioassays. Litter biochemical changes were evaluated with nuclear magnetic resonance (NMR) spectroscopy. DNA accumulation in litter and soil was measured and DNA toxicity was assessed in laboratory experiments. Undecomposed litter caused nonspecific inhibition of root growth, while autotoxicity was produced by aged litter. The addition of activated carbon (AC) removed phytotoxicity, but was ineffective against autotoxicity. Phytotoxicity was related to known labile allelopathic compounds. Restricted (13) C NMR signals related to nucleic acids were the only ones negatively correlated with root growth on conspecific substrates. DNA accumulation was observed in both litter decomposition and soil history experiments. Extracted total DNA showed evident species-specific toxicity. Results indicate a general occurrence of litter autotoxicity related to the exposure to fragmented self-DNA. The evidence also suggests the involvement of accumulated extracellular DNA in plant-soil NF. Further studies are needed to further investigate this unexpected function of extracellular DNA at the ecosystem level and related cellular and molecular mechanisms. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  17. FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging

    PubMed Central

    Miyamoto, Kana; Kato, Reiko; Yoshimura, Akihiko; Motoyama, Noboru

    2008-01-01

    Stress or aging of tissue-specific stem cells is considered central to the decline of tissue homeostasis in the elderly, although little is known of molecular mechanisms underlying hematopoietic stem cell (HSC) aging and stress resistance. Here, we report that mice lacking the transcription factor forkhead box O3a (FoxO3a) develop neutrophilia associated with inhibition of the up-regulation of negative regulator of cell proliferation, Sprouty-related Ena/VASP homology 1 domain-containing proteins 2 (Spred2) and AKT and ERK activation, in HSCs during hematopoietic recovery following myelosuppressive stress conditions. Compared with aged wild-type mice, more severe neutrophilia was also observed in aged Foxo3a-deficient mice. AKT and ERK activation and inhibition of Spred2 were detected in HSCs from aged FoxO3a-deficient mice. Spred2-deficient mice also developed neutrophilia during hematopoietic recovery following myelosuppressive stress, indicating that FoxO3a plays a pivotal role in maintenance, integrity, and stress resistance of HSCs through negative feedback pathways for proliferation. This will provide new insight into the hematopoietic homeostasis in conditions of aging and stress. PMID:18799725

  18. Effects of neuron-specific estrogen receptor (ER) α and ERβ deletion on the acute estrogen negative feedback mechanism in adult female mice.

    PubMed

    Cheong, Rachel Y; Porteous, Robert; Chambon, Pierre; Abrahám, István; Herbison, Allan E

    2014-04-01

    The negative feedback mechanism through which 17β-estradiol (E2) acts to suppress the activity of the GnRH neurons remains unclear. Using inducible and cell-specific genetic mouse models, we examined the estrogen receptor (ER) isoforms expressed by neurons that mediate acute estrogen negative feedback. Adult female mutant mice in which ERα was deleted from all neurons in the neonatal period failed to exhibit estrous cycles or negative feedback. Adult mutant female mice with neonatal neuronal ERβ deletion exhibited normal estrous cycles, but a failure of E2 to suppress LH secretion was seen in ovariectomized mice. Mutant mice with a GnRH neuron-selective deletion of ERβ exhibited normal cycles and negative feedback, suggesting no critical role for ERβ in GnRH neurons in acute negative feedback. To examine the adult roles of neurons expressing ERα, an inducible tamoxifen-based Cre-LoxP approach was used to ablate ERα from neurons that express calmodulin kinase IIα in adults. This resulted in mice with no estrous cycles, a normal increase in LH after ovariectomy, but an inability of E2 to suppress LH secretion. Finally, acute administration of ERα- and ERβ-selective agonists to adult ovariectomized wild-type mice revealed that activation of ERα suppressed LH secretion, whereas ERβ agonists had no effect. This study highlights the differences in adult reproductive phenotypes that result from neonatal vs adult ablation of ERα in the brain. Together, these experiments expand previous global knockout studies by demonstrating that neurons expressing ERα are essential and probably sufficient for the acute estrogen negative feedback mechanism in female mice.

  19. The miR-101/RUNX1 feedback regulatory loop modulates chemo-sensitivity and invasion in human lung cancer

    PubMed Central

    Wang, Xianghui; Zhao, Yihua; Qian, Haiyun; Huang, Jiangping; Cui, Fenghe; Mao, Zhifu

    2015-01-01

    The deregulation of miR-101 has been implicated in multiple cancer types including lung cancer, but the exact role, mechanisms and how silencing of miR-101 remain elusive. Here we confirmed miR-101 downregulation in lung cancer cell lines and patient tissues. Restored miR-101 expression remarkably sensitized lung cancer cells to chemotherapy and inhibited invasion. Mechanistically, we indicated that miR-101 inversely correlated with RUNX1 expression, and identified RUNX1 as a novel target of miR-101. RUNX1 impaired the effects of miR-101 on chemotherapeutic sensitization and invasion inhibition. Moreover, RUNX1 knockdown resulted into increase of miR-101 expression and elevation of luciferase activity driven by miR-101 promoter in lung cancer cells, suggesting RUNX1 negatively transcriptionally regulated miR-101 expression via physically binding to miR-101 promoter. These findings support that miR-101 downregulation accelerates the progression of lung cancer via RUNX1 dependent manner and suggest that miR-101/RUNX1 feedback axis may have therapeutic value in treating refractory lung cancer. PMID:26628987

  20. A Regulatory Feedback Loop between RpoS and SpoT Supports the Survival of Legionella pneumophila in Water

    PubMed Central

    Trigui, Hana; Dudyk, Paulina; Oh, Jinrok; Hong, Jong-In

    2014-01-01

    Legionella pneumophila is a waterborne pathogen, and survival in the aquatic environment is central to its transmission to humans. Therefore, identifying genes required for its survival in water could help prevent Legionnaires' disease outbreaks. In the present study, we investigate the role of the sigma factor RpoS in promoting survival in water, where L. pneumophila experiences severe nutrient deprivation. The rpoS mutant showed a strong survival defect compared to the wild-type strain in defined water medium. The transcriptome of the rpoS mutant during exposure to water revealed that RpoS represses genes associated with replication, translation, and transcription, suggesting that the mutant fails to shut down major metabolic programs. In addition, the rpoS mutant is transcriptionally more active than the wild-type strain after water exposure. This could be explained by a misregulation of the stringent response in the rpoS mutant. Indeed, the rpoS mutant shows an increased expression of spoT and a corresponding decrease in the level of (p)ppGpp, which is due to the presence of a negative feedback loop between RpoS and SpoT. Therefore, the lack of RpoS causes an aberrant regulation of the stringent response, which prevents the induction of a successful response to starvation. PMID:25416763

  1. Double negative regulatory T cells in transplantation and autoimmunity: recent progress and future directions

    PubMed Central

    Juvet, Stephen C.; Zhang, Li

    2012-01-01

    T lymphocytes bearing the αβ T cell receptor (TCR) but lacking CD4, CD8, and markers of natural killer (NK) cell differentiation are known as ‘double-negative’ (DN) T cells and have been described in both humans and rodent models. We and others have shown that DN T cells can act as regulatory T cells (Tregs) that are able to prevent allograft rejection, graft-versus-host disease, and autoimmune diabetes. In the last few years, new data have revealed evidence of DN Treg function in vivo in rodents and humans. Moreover, significant advances have been made in the mechanisms by which DN Tregs target antigen-specific T cells. One major limitation of the field is the lack of a specific marker that can be used to distinguish truly regulatory DN T cells (DN Tregs) from non-regulatory ones, and this is the central challenge in the coming years. Here, we review recent progress on the role of DN Tregs in transplantation and autoimmunity, and their mechanisms of action. We also provide some perspectives on how DN Tregs compare with Foxp3+ Tregs. PMID:22294241

  2. Participation of both adrenergic and opioidergic systems in the negative feedback of adrenal progesterone on LH secretion.

    PubMed

    Salicioni, A M; Carón, R W; Deis, R P

    1997-08-13

    It has been shown that adrenal progesterone plays an important role in regulating the negative feedback of oestrogen on luteinizing hormone (LH) release in ovariectomized and oestrogen-treated rats. The purpose of the present study was to determine whether adrenal progesterone modulation of LH secretion is mediated by adrenergic and opioidergic systems in ovariectomized and oestrogen-treated rats. Oestradiol benzoate (20 micrograms/rat) was given s.c. to ovariectomized rats on day 0. Control animals were injected with the vehicle alone. The specific adrenoceptor antagonists prazosin (10 mg/kg), idazoxan (100 micrograms/kg), metoprolol (10 mg/kg) or ICI 118,551 (200 micrograms/kg) were injected at 12.00 and 20.00 h on day 2 and at 08.00 h on day 3 to oestrogen-primed rats treated or not with RU486. Control animals were injected with saline. RU486 (10 mg/kg) was administered s.c. at 08.00 h on day 3 to oestradiol-treated animals receiving adrenoceptor antagonists or saline. Naloxone (2 mg/kg) was administered i.p. 30 min before blood-sampling to oestrogen-primed rats treated or not with RU486. All groups were blood-sampled at 13.00 and 18.00 h on day 3, and LH concentration was measured by radioimmunoassay. The administration of oestradiol to ovariectomized rats decreased serum LH levels at 13.00 and 18.00 h on day 3. Prazosin or idazoxan partially prevented the effect of oestradiol at 13.00 h, while metoprolol, ICI 118,551 or naloxone totally blocked the inhibitory effect of oestradiol on LH secretion; both adrenoceptor and opioid receptor antagonists also prevented the effect of oestrogen on LH concentration at 18.00 h. RU486 increased serum LH concentration at 18.00 h in oestrogen-primed rats to values higher than in ovariectomized control rats, with no effect at noon. The administration of prazosin to ovariectomized and oestrogen-primed rats treated with RU486 prevented this increase while the other adrenoceptor antagonists or naloxone increased serum LH

  3. Identification of novel non-coding RNA-based negative feedback regulating the expression of the oncogenic transcription factor GLI1.

    PubMed

    Villegas, Victoria E; Rahman, Mohammed Ferdous-Ur; Fernandez-Barrena, Maite G; Diao, Yumei; Liapi, Eleni; Sonkoly, Enikö; Ståhle, Mona; Pivarcsi, Andor; Annaratone, Laura; Sapino, Anna; Ramírez Clavijo, Sandra; Bürglin, Thomas R; Shimokawa, Takashi; Ramachandran, Saraswathi; Kapranov, Philipp; Fernandez-Zapico, Martin E; Zaphiropoulos, Peter G

    2014-07-01

    Non-coding RNAs are a complex class of nucleic acids, with growing evidence supporting regulatory roles in gene expression. Here we identify a non-coding RNA located head-to-head with the gene encoding the Glioma-associated oncogene 1 (GLI1), a transcriptional effector of multiple cancer-associated signaling pathways. The expression of this three-exon GLI1 antisense (GLI1AS) RNA in cancer cells was concordant with GLI1 levels. siRNAs knockdown of GLI1AS up-regulated GLI1 and increased cellular proliferation and tumor growth in a xenograft model system. Conversely, GLI1AS overexpression decreased the levels of GLI1, its target genes PTCH1 and PTCH2, and cellular proliferation. Additionally, we demonstrate that GLI1 knockdown reduced GLI1AS, while GLI1 overexpression increased GLI1AS, supporting the role of GLI1AS as a target gene of the GLI1 transcription factor. Activation of TGFβ and Hedgehog signaling, two known regulators of GLI1 expression, conferred a concordant up-regulation of GLI1 and GLI1AS in cancer cells. Finally, analysis of the mechanism underlying the interplay between GLI1 and GLI1AS indicates that the non-coding RNA elicits a local alteration of chromatin structure by increasing the silencing mark H3K27me3 and decreasing the recruitment of RNA polymerase II to this locus. Taken together, the data demonstrate the existence of a novel non-coding RNA-based negative feedback loop controlling GLI1 levels, thus expanding the repertoire of mechanisms regulating the expression of this oncogenic transcription factor.

  4. Germline Genetic Variants Disturbing the Let-7/LIN28 Double-Negative Feedback Loop Alter Breast Cancer Susceptibility

    PubMed Central

    Fan, Lei; Li, Ji-Yu; Yang, Chen; Huang, A-Ji; Shao, Zhi-Ming

    2011-01-01

    Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7–induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0×10−5. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk. PMID:21912531

  5. Germline genetic variants disturbing the Let-7/LIN28 double-negative feedback loop alter breast cancer susceptibility.

    PubMed

    Chen, Ao-Xiang; Yu, Ke-Da; Fan, Lei; Li, Ji-Yu; Yang, Chen; Huang, A-Ji; Shao, Zhi-Ming

    2011-09-01

    Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7-induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0 × 10⁻⁵. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk.

  6. Inducible CD4+LAP+ Foxp3 negative Regulatory T cells Suppress Allergic Inflammation

    PubMed Central

    Duan, Wei; So, Takanori; Mehta, Amit K.; Choi, Heonsik; Croft, Michael

    2011-01-01

    Regulatory T cells (Treg cells) play a critical role in the maintenance of airway tolerance. We report here that inhaled soluble antigen induces not only adaptive Foxp3+ Treg but also a regulatory population of CD4+ T cells in the lungs and lung-draining lymph nodes that express latency-associated peptide (LAP) on their cell surface but do not express Foxp3. Blocking the cytokines IL-10 or transforming growth factor-β (TGF-β) prevented the generation of the LAP+ Treg and Foxp3+ Treg cells in vivo, and the LAP+ Treg could also be generated concomitantly with Foxp3+ Treg in vitro by culturing naïve CD4+ T cells with antigen and exogenous TGF-β. The LAP+ Treg cells strongly suppressed naïve CD4+ T cell proliferation, and transfer of sorted OVA-specific LAP+ Treg cells in vivo inhibited allergic eosinophilia and Th2 cytokine expression in the lung, either when present at the time of Th2 sensitization or when injected after Th2 cells were formed. Furthermore, inflammatory innate stimuli from house dust mite (HDM) extract, nucleotide-binding oligomerization domain containing 2 (Nod2) ligand, and lipopolysacchride (LPS), that are sufficient for blocking airway tolerance, strongly decreased the induction of LAP+ Treg cells. Taken together, we conclude that inducible antigen-specific LAP+ Treg cells can suppress asthmatic lung inflammation and constitute a mediator of airway tolerance together with Foxp3+ Treg cells. PMID:22079987

  7. Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulation.

    PubMed

    Håkansson, Petra; Nilsson, Björn; Andersson, Anna; Lassen, Carin; Gullberg, Urban; Fioretos, Thoas

    2008-04-01

    Philadelphia (Ph) chromosome-positive leukemia is characterized by the BCR/ABL1 fusion protein that affects a wide range of signal transduction pathways. The knowledge about its downstream target genes is, however, still quite limited. To identify novel BCR/ABL1-regulated genes we used global gene expression profiling of several Ph-positive and Ph-negative cell lines treated with imatinib. Following imatinib treatment, the Ph-positive cells showed decreased growth, viability, and reduced phosphorylation of BCR/ABL1 and STAT5. In total, 142 genes were identified as being dependent on BCR/ABL1-mediated signaling, mainly including genes involved in signal transduction, e.g. the JAK/STAT, MAPK, TGFB, and insulin signaling pathways, and in regulation of metabolism. Interestingly, BCR/ABL1 was found to activate several genes involved in negative feedback regulation (CISH, SOCS2, SOCS3, PIM1, DUSP6, and TNFAIP3), which may act to indirectly suppress the tumor promoting effects exerted by BCR/ABL1. In addition, several genes identified as deregulated upon BCR/ABL1 expression could be assigned to the TGFB and NFkB signaling pathways, as well as to reflect the metabolic adjustments needed for rapidly growing cells. Apart from providing important pathogenetic insights into BCR/ABL1-mediated leukemogenesis, the present study also provides a number of pathways/individual genes that may provide attractive targets for future development of targeted therapies. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

  8. Negative feedback avalanche diode

    NASA Technical Reports Server (NTRS)

    Itzler, Mark Allen (Inventor)

    2010-01-01

    A single-photon avalanche detector is disclosed that is operable at wavelengths greater than 1000 nm and at operating speeds greater than 10 MHz. The single-photon avalanche detector comprises a thin-film resistor and avalanche photodiode that are monolithically integrated such that little or no additional capacitance is associated with the addition of the resistor.

  9. New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses

    PubMed Central

    Zhang, Dong; Yang, Wei; Degauque, Nicolas; Tian, Yan; Mikita, Allison

    2007-01-01

    Recent studies have demonstrated that in peripheral lymphoid tissues of normal mice and healthy humans, 1% to 5% of αβ T-cell receptor–positive (TCR+) T cells are CD4−CD8− (double-negative [DN]) T cells, capable of down-regulating immune responses. However, the origin and developmental pathway of DN T cells is still not clear. In this study, by monitoring CD4 expression during T-cell proliferation and differentiation, we identified a new differentiation pathway for the conversion of CD4+ T cells to DN regulatory T cells. We showed that the converted DN T cells retained a stable phenotype after restimulation and that furthermore, the disappearance of cell-surface CD4 molecules on converted DN T cells was a result of CD4 gene silencing. The converted DN T cells were resistant to activation-induced cell death (AICD) and expressed a unique set of cell-surface markers and gene profiles. These cells were highly potent in suppressing alloimmune responses both in vitro and in vivo in an antigen-specific manner. Perforin was highly expressed by the converted DN regulatory T cells and played a role in DN T-cell–mediated suppression. Our findings thus identify a new differentiation pathway for DN regulatory T cells and uncover a new intrinsic homeostatic mechanism that regulates the magnitude of immune responses. This pathway provides a novel, cell-based, therapeutic approach for preventing allograft rejection. PMID:17197428

  10. Escalating risk and the moderating effect of resistance to peer influence on the P200 and feedback-related negativity

    PubMed Central

    Straley, Elizabeth; Cheadle, Jacob E.

    2016-01-01

    Young people frequently socialize together in contexts that encourage risky decision making, pointing to a need for research into how susceptibility to peer influence is related to individual differences in the neural processing of decisions during sequentially escalating risk. We applied a novel analytic approach to analyze EEG activity from college-going students while they completed the Balloon Analogue Risk Task (BART), a well-established risk-taking propensity assessment. By modeling outcome-processing-related changes in the P200 and feedback-related negativity (FRN) sequentially within each BART trial as a function of pump order as an index of increasing risk, our results suggest that analyzing the BART in a progressive fashion may provide valuable new insights into the temporal neurophysiological dynamics of risk taking. Our results showed that a P200, localized to the left caudate nucleus, and an FRN, localized to the left dACC, were positively correlated with the level of risk taking and reward. Furthermore, consistent with our hypotheses, the rate of change in the FRN was higher among college students with greater self-reported resistance to peer influence. PMID:26416785

  11. SIRT1 is regulated by a PPARγ–SIRT1 negative feedback loop associated with senescence

    PubMed Central

    Zhou, Rui; Niu, Jing; McNutt, Michael A.; Wang, Pan; Tong, Tanjun

    2010-01-01

    Human Silent Information Regulator Type 1 (SIRT1) is an NAD+-dependent deacetylase protein which is an intermediary of cellular metabolism in gene silencing and aging. SIRT1 has been extensively investigated and shown to delay senescence; however, less is known about the regulation of SIRT1 during aging. In this study, we show that the peroxisome proliferator-activated receptor-γ (PPARγ), which is a ligand-regulated modular nuclear receptor that governs adipocyte differentiation and inhibits cellular proliferation, inhibits SIRT1 expression at the transcriptional level. Moreover, both PPARγ and SIRT1 can bind the SIRT1 promoter. PPARγ directly interacts with SIRT1 and inhibits SIRT1 activity, forming a negative feedback and self-regulation loop. In addition, our data show that acetylation of PPARγ increased with increasing cell passage number. We propose that PPARγ is subject to regulation by acetylation and deacetylation via p300 and SIRT1 in cellular senescence. These results demonstrate a mutual regulation between PPARγ and SIRT1 and identify a new posttranslational modification that affects cellular senescence. PMID:20660480

  12. Active vibration control of structure by Active Mass Damper and Multi-Modal Negative Acceleration Feedback control algorithm

    NASA Astrophysics Data System (ADS)

    Yang, Don-Ho; Shin, Ji-Hwan; Lee, HyunWook; Kim, Seoug-Ki; Kwak, Moon K.

    2017-03-01

    In this study, an Active Mass Damper (AMD) consisting of an AC servo motor, a movable mass connected to the AC servo motor by a ball-screw mechanism, and an accelerometer as a sensor for vibration measurement were considered. Considering the capability of the AC servo motor which can follow the desired displacement accurately, the Negative Acceleration Feedback (NAF) control algorithm which uses the acceleration signal directly and produces the desired displacement for the active mass was proposed. The effectiveness of the NAF control was proved theoretically using a single-degree-of-freedom (SDOF) system. It was found that the stability condition for the NAF control is static and it can effectively increase the damping of the target natural mode without causing instability in the low frequency region. Based on the theoretical results of the SDOF system, the Multi-Modal NAF (MMNAF) control is proposed to suppress the many natural modes of multi-degree-of-freedom (MDOF) systems using a single AMD. It was proved both theoretically and experimentally that the MMNAF control can suppress vibrations of the MDOF system.

  13. SEL-10/Fbw7-dependent negative feedback regulation of LIN-45/Braf signaling in C. elegans via a conserved phosphodegron

    PubMed Central

    de la Cova, Claire; Greenwald, Iva

    2012-01-01

    The conserved E3 ubiquitin ligase component named SEL-10 in Caenorhabditis elegans and Fbw7 in mammals targets substrates for ubiquitin-mediated degradation through a high-affinity binding site called a Cdc4 phosphodegron (CPD). As many known substrates of Fbw7 are oncoproteins, the identification of new substrates may offer insight into cancer biology as well as aspects of proteome regulation. Here, we evaluated whether the presence of an evolutionarily conserved CPD would be a feasible complement to proteomics-based approaches for identifying new potential substrates. For functional assessments, we focused on LIN-45, a component of the signal transduction pathway underlying vulval induction and the ortholog of human Braf, an effector of Ras in numerous cancers. Our analysis demonstrates that LIN-45 behaves as a bona fide substrate of SEL-10, with mutation of the CPD or loss of sel-10 resulting in increased activity and protein stability in vivo. Furthermore, during vulval induction, the downstream kinase MPK-1/ERK is also required for LIN-45 protein degradation in a negative feedback loop, resulting in degradation of LIN-45 where ERK is highly active. As the CPD consensus sequence is conserved in human Braf, we propose that Fbw7 may also regulate Braf stability in some cell contexts. We discuss the implications of our findings for vulval development in C. elegans, the potential applicability to human Braf, and the value of a CPD-based predictive approach for human Fbw7 substrates. PMID:23154983

  14. SEL-10/Fbw7-dependent negative feedback regulation of LIN-45/Braf signaling in C. elegans via a conserved phosphodegron.

    PubMed

    de la Cova, Claire; Greenwald, Iva

    2012-11-15

    The conserved E3 ubiquitin ligase component named SEL-10 in Caenorhabditis elegans and Fbw7 in mammals targets substrates for ubiquitin-mediated degradation through a high-affinity binding site called a Cdc4 phosphodegron (CPD). As many known substrates of Fbw7 are oncoproteins, the identification of new substrates may offer insight into cancer biology as well as aspects of proteome regulation. Here, we evaluated whether the presence of an evolutionarily conserved CPD would be a feasible complement to proteomics-based approaches for identifying new potential substrates. For functional assessments, we focused on LIN-45, a component of the signal transduction pathway underlying vulval induction and the ortholog of human Braf, an effector of Ras in numerous cancers. Our analysis demonstrates that LIN-45 behaves as a bona fide substrate of SEL-10, with mutation of the CPD or loss of sel-10 resulting in increased activity and protein stability in vivo. Furthermore, during vulval induction, the downstream kinase MPK-1/ERK is also required for LIN-45 protein degradation in a negative feedback loop, resulting in degradation of LIN-45 where ERK is highly active. As the CPD consensus sequence is conserved in human Braf, we propose that Fbw7 may also regulate Braf stability in some cell contexts. We discuss the implications of our findings for vulval development in C. elegans, the potential applicability to human Braf, and the value of a CPD-based predictive approach for human Fbw7 substrates.

  15. Coordination of Double Strand Break Repair and Meiotic Progression in Yeast by a Mek1- Ndt80 Negative Feedback Loop.

    PubMed

    Prugar, Evelyn; Burnett, Cameron; Chen, Xiangyu; Hollingsworth, Nancy M

    2017-03-01

    During meiosis, homologous chromosomes are physically connected by crossovers and sister chromatid cohesion. Interhomolog crossovers are generated by the highly regulated repair of programmed double strand breaks (DSBs). The meiosis-specific kinase, Mek1, is critical for this regulation. Mek1 down-regulates the mitotic recombinase Rad51, indirectly promoting interhomolog strand invasion by the meiosis-specific recombinase, Dmc1. Mek1 also promotes the formation of crossovers that are distributed throughout the genome by interference and is the effector kinase for a meiosis-specific checkpoint that delays entry into Meiosis I until DSBs have been repaired. The target of this checkpoint is a meiosis-specific transcription factor, Ndt80, which is necessary to express the polo-like kinase, CDC5, and the cyclin, CLB1, thereby allowing completion of recombination and meiotic progression. This work shows that Mek1 and Ndt80 negatively feedback on each other such that when DSB levels are high, Ndt80 is inactive due to high levels of Mek1 activity. As DSBs are repaired, chromosomes synapse and Mek1 activity is reduced below a threshold that allows activation of Ndt80. Ndt80 transcription of CDC5 results in degradation of Red1, a meiosis-specific protein required for Mek1 activation, thereby abolishing Mek1 activity completely. Elimination of Mek1 kinase activity allows Rad51-mediated repair of any remaining DSBs. In this way, cells do not enter Meiosis I until recombination is complete and all DSBs are repaired.

  16. Dysregulation of SOCS-Mediated Negative Feedback of Cytokine Signaling in Carcinogenesis and Its Significance in Cancer Treatment

    PubMed Central

    Jiang, Mengmeng; Zhang, Wen-wen; Liu, Pengpeng; Yu, Wenwen; Liu, Ting; Yu, Jinpu

    2017-01-01

    Suppressor of cytokine signaling (SOCS) proteins are major negative feedback regulators of cytokine signaling mediated by the Janus kinase (JAK)-signal transducer and activator of transcription signaling pathway. In particular, SOCS1 and SOCS3 are strong inhibitors of JAKs and can play pivotal roles in the development and progression of cancers. The abnormal expression of SOCS1 and SOCS3 in cancer cells is associated with the dysregulation of cell growth, migration, and death induced by multiple cytokines and hormones in human carcinomas. In addition, the mechanisms involved in SOCS1- and SOCS3-regulated abnormal development and activation of immune cells in carcinogenesis, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells, are still unclear. Therefore, this study aims to further discuss the molecules and signal pathways regulating the expression and function of SOCS1 and SOCS3 in various types of cancers and elucidate the feasibility and efficiency of SOCS-based target therapeutic strategy in anticancer treatment. PMID:28228755

  17. Low noise InGaAs/InP single-photon negative feedback avalanche diodes: characterization and applications

    NASA Astrophysics Data System (ADS)

    Boso, Gianluca; Korzh, Boris; Lunghi, Tommaso; Zbinden, Hugo

    2015-05-01

    In recent years, many applications have been proposed that require detection of light signals in the near-infrared range with single-photon sensitivity and time resolution down to few hundreds of picoseconds. InGaAs/InP singlephoton avalanche diodes (SPADs) are a viable choice for these tasks thanks to their compactness and ease-of-use. Unfortunately, their performance is traditionally limited by high dark count rates (DCRs) and afterpulsing effects. However, a recent demonstration of negative feedback avalanche diodes (NFADs), operating in the free-running regime, achieved a DCR down to 1 cps at 10 % photon detection efficiency (PDE) at telecom wavelengths. Here we present our recent results on the characterization of NFAD detectors for temperatures down to approximately 150 K. A FPGA controlled test-bench facilitates the acquisition of all the parameters of interest like PDE, DCR, afterpulsing probability etc. We also demonstrate the performance of the detector in different applications: In particular, with low-temperature NFADs, we achieved high secret key rates with quantum key distribution over fiber links between 100-300 km. But low noise InGaAs/InP SPADs will certainly find applications in yet unexplored fields like photodynamic therapy, near infrared diffuse optical spectroscopy and many more. For example with a large area detector, we made time-resolved measurements of singlet-oxygen luminescence from a standard Rose Bengal dye in aqueous solution.

  18. Anterior cingulate activity to monetary loss and basal ganglia activity to monetary gain uniquely contribute to the feedback negativity

    PubMed Central

    Foti, Dan; Weinberg, Anna; Bernat, Edward M.; Proudfit, Greg H.

    2014-01-01

    Objective The feedback negativity (FN) is an event-related potential that differentiates unfavorable versus favorable outcomes. Although thought to reflect error-related activity within the anterior cingulate cortex, recent work indicates the FN may also reflect reward-related activity that has been linked to the basal ganglia. To date, it remains unclear how to reconcile these conflicting perspectives. Methods We decomposed the FN by applying time-frequency analysis to isolate activity unique to monetary losses and gains. The FN was recorded from 84 individuals during a laboratory gambling task. Results Two signals contributed to the FN elicited by unpredictable outcomes: theta activity (4-7 Hz) was increased following monetary loss, and delta activity (< 3 Hz) was increased following monetary gain. Predictable outcomes elicited delta but not theta activity. Source analysis revealed distinct generators, with loss-related theta localized to the anterior cingulate cortex and gain-related delta to a possible source in the striatum. Symptoms of depression, anxiety, and stress reactivity were specifically associated with blunted gain-related delta. Conclusions The FN may be a composite of loss- and gain-related neural activity, reflecting distinct facets of reward processing. Significance Gain-related delta activity may provide unique information about reward dysfunction in major depression and other internalizing psychopathology. PMID:25454338

  19. A Negative Feedback Loop between PHYTOCHROME INTERACTING FACTORs and HECATE Proteins Fine-Tunes Photomorphogenesis in Arabidopsis

    PubMed Central

    Zhu, Ling; Bu, Qingyun; Shen, Hui; Dang, Jonathan

    2016-01-01

    The phytochrome interacting factors (PIFs), a small group of basic helix-loop-helix transcription factors, repress photomorphogenesis both in the dark and light. Light signals perceived by the phytochrome family of photoreceptors induce rapid degradation of PIFs to promote photomorphogenesis. Here, we show that HECATE (HEC) proteins, another small group of HLH proteins, antagonistically regulate PIFs to promote photomorphogenesis. HEC1 and HEC2 heterodimerize with PIF family members. PIF1, HEC1, and HEC2 genes are spatially and temporally coexpressed, and HEC2 is localized in the nucleus. hec1, hec2, and hec3 single mutants and the hec1 hec2 double mutant showed hyposensitivity to light-induced seed germination and accumulation of chlorophyll and carotenoids, hallmark processes oppositely regulated by PIF1. HEC2 inhibits PIF1 target gene expression by directly heterodimerizing with PIF1 and preventing DNA binding and transcriptional activation activity of PIF1. Conversely, PIFs directly activate the expression of HEC1 and HEC2 in the dark, and light reduces the expression of these HECs possibly by degrading PIFs. HEC2 is partially degraded in the dark through the ubiquitin/26S-proteasome pathway and is stabilized by light. HEC2 overexpression also reduces the light-induced degradation of PIF1. Taken together, these data suggest that PIFs and HECs constitute a negative feedback loop to fine-tune photomorphogenesis in Arabidopsis thaliana. PMID:27073231

  20. [Role of dopamine-dependent negative feedback in the hippocampal--basal ganglia--thalamo---hippocampal loop in response decrement].

    PubMed

    Sil'kis, I G

    2007-03-01

    The mechanism of response decrement in hippocampal and dopaminergic neurons on repeating stimuli based on the dopamine-dependent negative feedback in the hippocampal--basal ganglia--thalamo--hippocampal loop is suggested. Activation of hippocampal neurons caused by new stimulus facilitates occurrence of reaction of dopaminergic cells due to their disinhibition through striatopallidal cells of nucleus accumbens and ventral pallidum. However, increase in dopamine level and activation accumbens and ventral pallidum. However, increase in dopamine level and activation of D2 receptors on the striatopallidal cell, while promoting depression of hippocampal inputs, prevents disinhibition of dopaminergic cells, and their reactions start their decrement. The subsequent decrease in D1 receptor activation leads to reduction of efficiency of neuron excitation in the hippocampal CA1 fields, as well as in striatonigral cells of nucleus accumbens. This leads to a decrease of disinhibition through a direct pathway via the basal ganglia of thalamic nucleus reunions which activates neurons of the CA1 field. This effect causes decrement of reactions of the hippocampal neurons, a subsequent reduction of dopaminergic cell disinhibition, and further decrement of their responses.

  1. Pleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53

    PubMed Central

    Chao, Tengfei; Zhou, Xiang; Cao, Bo; Liao, Peng; Liu, Hongbing; Chen, Yun; Park, Hee-Won; Zeng, Shelya X.; Lu, Hua

    2016-01-01

    The tumour suppressor p53 transactivates the expression of its target genes to exert its functions. Here, we identify a pleckstrin homology domain-containing protein (PHLDB3)-encoding gene as a p53 target. PHLDB3 overexpression increases proliferation and restrains apoptosis of wild-type p53-harboring cancer cells by reducing p53 protein levels. PHLDB3 binds to MDM2 (mouse double minute 2 homolog) and facilitates MDM2-mediated ubiquitination and degradation of p53. Knockdown of PHLDB3 more efficiently inhibits the growth of mouse xenograft tumours derived from human colon cancer HCT116 cells that contain wild type p53 compared with p53-deficient HCT116 cells, and also sensitizes tumour cells to doxorubicin and 5-Fluorouracil. Analysis of cancer genomic databases reveals that PHLDB3 is amplified and/or highly expressed in numerous human cancers. Altogether, these results demonstrate that PHLDB3 promotes tumour growth by inactivating p53 in a negative feedback fashion and suggest PHLDB3 as a potential therapeutic target in various human cancers. PMID:28008906

  2. Negative feedback contributes to the stochastic expression of the interferon-β gene in virus-triggered type I interferon signaling pathways.

    PubMed

    Zhang, Wei; Tian, Tianhai; Zou, Xiufen

    2015-07-01

    Type I interferon (IFN) signaling pathways play an essential role in the defense against early viral infections; however, the diverse and intricate molecular mechanisms of virus-triggered type I IFN responses are still poorly understood. In this study, we analyzed and compared two classes of models i.e., deterministic ordinary differential equations (ODEs) and stochastic models to elucidate the dynamics and stochasticity of type I IFN signaling pathways. Bifurcation analysis based on an ODE model reveals that the system exhibits a bistable switch and a one-way switch at high or low levels when the strengths of the negative and positive feedbacks are tuned. Furthermore, we compared the stochastic simulation results under the Master and Langevin equations. Both of the stochastic equations generate the bistable switch phenomenon, and the distance between two stable states are smaller than normal under the simulation of the Langevin equation. The quantitative computations also show that a moderate ratio between positive and negative feedback strengths is required to ensure a reliable switch between the different IFN concentrations that regulate the immune response. Moreover, we propose a multi-state stochastic model based on the above deterministic model to describe the multi-cellular system coupled with the diffusion of IFNs. The perturbation and inhibition analysis showed that the positive feedback, as well as noises, has little effect on the stochastic expression of IFNs, but the negative feedback of ISG56 on the activation of IRF7 has a great influence on IFN stochastic expression. Together, these results reveal that positive feedback stabilizes IFN gene expression, and negative feedback may be the main contribution to the stochastic expression of the IFN gene in the virus-triggered type I IFN response. These findings will provide new insight into the molecular mechanisms of virus-triggered type I IFN signaling pathways.

  3. Negative feedback adjustment challenges reconstruction study from tree rings: A study case of response of Populus euphratica to river discontinuous flow and ecological water conveyance.

    PubMed

    Ling, Hongbo; Zhang, Pei; Guo, Bin; Xu, Hailiang; Ye, Mao; Deng, Xiaoya

    2017-01-01

    Drought stress changes the relationship between the growth of tree rings and variations in ambient temperature. However, it is not clear how the growth of trees changes in response to drought of varying intensities, especially in arid areas. Therefore, Tree rings were studied for 6years in Populus euphratica to assess the impacts of abrupt changes in environment on tree rings using the theories and methods in dendrohydrology, ecology and phytophysiology. The width of tree rings increased by 8.7% after ecological water conveyance downstream of Tarim River compared to that when the river water had been cut off. However, during intermediate drought, as the depth of the groundwater increases, the downward trend in the tree rings was reversed because of changes in the physiology of the tree. Therefore, the growth of tree rings shows a negative feedback to intermediate drought stress, an observation that challenges the homogenization theory of tree ring reconstruction based on the traditional methods. Owing to the time lag, the cumulative effect and the negative feedback between the growth of tree rings and drought stress, the reconstruction of past environment by studying the patterns of tree rings is often inaccurate. Our research sets out to verify the hypothesis that intermediate drought stress results in a negative feedback adjustment and thus to answers two scientific questions: (1) How does the negative feedback adjustment promote the growth of tree rings as a result of intermediate drought stress? (2) How does the negative feedback adjustment lower the accuracy with which the past is reconstructed based on tree rings? This research not only enriches the connotations of intermediate disturbance hypothesis and reconstruction theory of tree rings, but also provides a scientific basis for the conservation of desert riparian forests worldwide. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Generalized Anxiety Disorder and Social Anxiety Disorder, but Not Panic Anxiety Disorder, Are Associated with Higher Sensitivity to Learning from Negative Feedback: Behavioral and Computational Investigation.

    PubMed

    Khdour, Hussain Y; Abushalbaq, Oday M; Mughrabi, Ibrahim T; Imam, Aya F; Gluck, Mark A; Herzallah, Mohammad M; Moustafa, Ahmed A

    2016-01-01

    Anxiety disorders, including generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic anxiety disorder (PAD), are a group of common psychiatric conditions. They are characterized by excessive worrying, uneasiness, and fear of future events, such that they affect social and occupational functioning. Anxiety disorders can alter behavior and cognition as well, yet little is known about the particular domains they affect. In this study, we tested the cognitive correlates of medication-free patients with GAD, SAD, and PAD, along with matched healthy participants using a probabilistic category-learning task that allows the dissociation between positive and negative feedback learning. We also fitted all participants' data to a Q-learning model and various actor-critic models that examine learning rate parameters from positive and negative feedback to investigate effects of valence vs. action on performance. SAD and GAD patients were more sensitive to negative feedback than either PAD patients or healthy participants. PAD, SAD, and GAD patients did not differ in positive-feedback learning compared to healthy participants. We found that Q-learning models provide the simplest fit of the data in comparison to other models. However, computational analysis revealed that groups did not differ in terms of learning rate or exploration values. These findings argue that (a) not all anxiety spectrum disorders share similar cognitive correlates, but are rather different in ways that do not link them to the hallmark of anxiety (higher sensitivity to negative feedback); and (b) perception of negative consequences is the core feature of GAD and SAD, but not PAD. Further research is needed to examine the similarities and differences between anxiety spectrum disorders in other cognitive domains and potential implementation of behavioral therapy to remediate cognitive deficits.

  5. Generalized Anxiety Disorder and Social Anxiety Disorder, but Not Panic Anxiety Disorder, Are Associated with Higher Sensitivity to Learning from Negative Feedback: Behavioral and Computational Investigation

    PubMed Central

    Khdour, Hussain Y.; Abushalbaq, Oday M.; Mughrabi, Ibrahim T.; Imam, Aya F.; Gluck, Mark A.; Herzallah, Mohammad M.; Moustafa, Ahmed A.

    2016-01-01

    Anxiety disorders, including generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic anxiety disorder (PAD), are a group of common psychiatric conditions. They are characterized by excessive worrying, uneasiness, and fear of future events, such that they affect social and occupational functioning. Anxiety disorders can alter behavior and cognition as well, yet little is known about the particular domains they affect. In this study, we tested the cognitive correlates of medication-free patients with GAD, SAD, and PAD, along with matched healthy participants using a probabilistic category-learning task that allows the dissociation between positive and negative feedback learning. We also fitted all participants' data to a Q-learning model and various actor-critic models that examine learning rate parameters from positive and negative feedback to investigate effects of valence vs. action on performance. SAD and GAD patients were more sensitive to negative feedback than either PAD patients or healthy participants. PAD, SAD, and GAD patients did not differ in positive-feedback learning compared to healthy participants. We found that Q-learning models provide the simplest fit of the data in comparison to other models. However, computational analysis revealed that groups did not differ in terms of learning rate or exploration values. These findings argue that (a) not all anxiety spectrum disorders share similar cognitive correlates, but are rather different in ways that do not link them to the hallmark of anxiety (higher sensitivity to negative feedback); and (b) perception of negative consequences is the core feature of GAD and SAD, but not PAD. Further research is needed to examine the similarities and differences between anxiety spectrum disorders in other cognitive domains and potential implementation of behavioral therapy to remediate cognitive deficits. PMID:27445719

  6. Numerical solution of the chemical master equation uniqueness and stability of the stationary distribution for chemical networks, and mRNA bursting in a gene network with negative feedback regulation.

    PubMed

    Zeron, E S; Santillán, M

    2011-01-01

    In this work, we introduce a couple of algorithms to compute the stationary probability distribution for the chemical master equation (CME) of arbitrary chemical networks. We further find the conditions guaranteeing the algorithms' convergence and the unity and stability of the stationary distribution. Next, we employ these algorithms to study the mRNA and protein probability distributions in a gene regulatory network subject to negative feedback regulation. In particular, we analyze the influence of the promoter activation/deactivation speed on the shape of such distributions. We find that a reduction of the promoter activation/deactivation speed modifies the shape of those distributions in a way consistent with the phenomenon known as mRNA (or transcription) bursting.

  7. Regulatory Feedback Loop of Two phz Gene Clusters through 5′-Untranslated Regions in Pseudomonas sp. M18

    PubMed Central

    Li, Yaqian; Du, Xilin; Lu, Zhi John; Wu, Daqiang; Zhao, Yilei; Ren, Bin; Huang, Jiaofang; Huang, Xianqing; Xu, Yuhong; Xu, Yuquan

    2011-01-01

    Background Phenazines are important compounds produced by pseudomonads and other bacteria. Two phz gene clusters called phzA1-G1 and phzA2-G2, respectively, were found in the genome of Pseudomonas sp. M18, an effective biocontrol agent, which is highly homologous to the opportunistic human pathogen P. aeruginosa PAO1, however little is known about the correlation between the expressions of two phz gene clusters. Methodology/Principal Findings Two chromosomal insertion inactivated mutants for the two gene clusters were constructed respectively and the correlation between the expressions of two phz gene clusters was investigated in strain M18. Phenazine-1-carboxylic acid (PCA) molecules produced from phzA2-G2 gene cluster are able to auto-regulate expression itself and activate the expression of phzA1-G1 gene cluster in a circulated amplification pattern. However, the post-transcriptional expression of phzA1-G1 transcript was blocked principally through 5′-untranslated region (UTR). In contrast, the phzA2-G2 gene cluster was transcribed to a lesser extent and translated efficiently and was negatively regulated by the GacA signal transduction pathway, mainly at a post-transcriptional level. Conclusions/Significance A single molecule, PCA, produced in different quantities by the two phz gene clusters acted as the functional mediator and the two phz gene clusters developed a specific regulatory mechanism which acts through 5′-UTR to transfer a single, but complex bacterial signaling event in Pseudomonas sp. strain M18. PMID:21559370

  8. Dorsomedial Hypothalamic Lesions Block Syrian Hamster Testicular Regression in Short Day Lengths Without Diminishing Increased Testosterone Negative-Feedback Sensitivity1

    PubMed Central

    Jarjisian, Stephan G.; Piekarski, David J.; Place, Ned J.; Driscoll, Joseph R.; Paxton, Eve G.; Kriegsfeld, Lance J.; Zucker, Irving

    2013-01-01

    ABSTRACT The dorsomedial nucleus (DMN) of the hypothalamus, the only site within the mediobasal hypothalamus of Syrian hamsters that both binds melatonin and has abundant concentrations of androgen receptors, has been proposed as a target tissue for induction of seasonal changes in brain sensitivity to steroid negative feedback. We tested whether DMN ablation, which does not interfere with pineal gland secretion of melatonin in short day lengths, prevents testicular regression by altering sensitivity to steroid negative feedback. Hamsters with DMN lesions, unlike control hamsters, failed to undergo testicular regression after transfer from a long (14 h light/day) to a short day length (8 h light/day); however, increased negative-feedback inhibition of follicle-stimulating hormone by testosterone was not compromised by ablation of the DMN, indicating that this tissue is not an essential mediator of seasonal changes in feedback sensitivity. We propose a redundant neural network comprised of multiple structures, each of which contributes to neuroendocrine mechanisms, that determines the effect of short days on gonadal function. PMID:23782839

  9. Negative regulatory roles of DE-ETIOLATED1 in flowering time in Arabidopsis

    PubMed Central

    Kang, Min-Young; Yoo, Soo-Cheul; Kwon, Hye-Young; Lee, Byoung-Doo; Cho, Jung-Nam; Noh, Yoo-Sun; Paek, Nam-Chon

    2015-01-01

    Arabidopsis flowers early under long days (LD) and late under short days (SD). The repressor of photomorphogenesis DE-ETIOLATED1 (DET1) delays flowering; det1-1 mutants flower early, especially under SD, but the molecular mechanism of DET1 regulation remains unknown. Here we examine the regulatory function of DET1 in repression of flowering. Under SD, the det1-1 mutation causes daytime expression of FKF1 and CO; however, their altered expression has only a small effect on early flowering in det1-1 mutants. Notably, DET1 interacts with GI and binding of GI to the FT promoter increases in det1-1 mutants, suggesting that DET1 mainly restricts GI function, directly promoting FT expression independent of CO expression. Moreover, DET1 interacts with MSI4/FVE, which epigenetically inhibits FLC expression, indicating that the lack of FLC expression in det1-1 mutants likely involves altered histone modifications at the FLC locus. These data demonstrate that DET1 acts in both photoperiod and autonomous pathways to inhibit expression of FT and SOC1. Consistent with this, the early flowering of det1-1 mutants disappears completely in the ft-1 soc1-2 double mutant background. Thus, we propose that DET1 is a strong repressor of flowering and has a pivotal role in maintaining photoperiod sensitivity in the regulation of flowering time. PMID:25962685

  10. Interaction between transcriptional activator protein LAC9 and negative regulatory protein GAL80.

    PubMed Central

    Salmeron, J M; Langdon, S D; Johnston, S A

    1989-01-01

    In Saccharomyces cerevisiae, transcriptional activation mediated by the GAL4 regulatory protein is repressed in the absence of galactose by the binding of the GAL80 protein, an interaction that requires the carboxy-terminal 28 amino acids of GAL4. The homolog of GAL4 from Kluyveromyces lactis, LAC9, activates transcription in S. cerevisiae and is highly similar to GAL4 in its carboxyl terminus but is not repressed by wild-type levels of GAL80 protein. Here we show that GAL80 does repress LAC9-activated transcription in S. cerevisiae if overproduced. We sought to determine the molecular basis for the difference in the responses of the LAC9 and GAL4 proteins to GAL80. Our results indicate that this difference is due primarily to the fact that under wild-type conditions, the level of LAC9 protein in S. cerevisiae is much higher than that of GAL4, which suggests that LAC9 escapes GAL80-mediated repression by titration of GAL80 protein in vivo. The difference in response to GAL80 is not due to amino acid sequence differences between the LAC9 and GAL4 carboxyl termini. We discuss the implications of these results for the mechanism of galactose metabolism regulation in S. cerevisiae and K. lactis. Images PMID:2550790

  11. SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex

    PubMed Central

    Park, Yoon; Jin, Hyung-seung; Lopez, Justine; Lee, Jeeho; Liao, Lujian; Elly, Chris; Liu, Yun-Cai

    2016-01-01

    SHARPIN forms a linear-ubiquitin-chain-assembly complex that promotes signaling via the transcription factor NF-κB. SHARPIN deficiency leads to progressive multi-organ inflammation and immune system malfunction, but how SHARPIN regulates T cell responses is unclear. Here we found that SHARPIN deficiency resulted in a substantial reduction in the number of and defective function of regulatory T cells (Treg cells). Transfer of SHARPIN-sufficient Treg cells into SHARPIN-deficient mice considerably alleviated their systemic inflammation. SHARPIN-deficient T cells displayed enhanced proximal signaling via the T cell antigen receptor (TCR) without an effect on the activation of NF-κB. SHARPIN conjugated with Lys63 (K63)-linked ubiquitin chains, which led to inhibition of the association of TCRζ with the signaling kinase Zap70; this affected the generation of Treg cells. Our study therefore identifies a role for SHARPIN in TCR signaling whereby it maintains immunological homeostasis and tolerance by regulating Treg cells. PMID:26829767

  12. A self-adjusting negative feedback joint controller for legs standing on moving substrates of unknown compliance

    NASA Astrophysics Data System (ADS)

    Schneider, Axel; Cruse, Holk; Fischer, Björn; Schmitz, Josef

    2007-05-01

    Some recent robot controllers for hexapod walking have been developed based on investigations of stick insects. These animals live in an unpredictable environment that consists of twigs and leaves. Supports like twigs, leaves and branches induce a considerable amount of movement to the legs and their elastic joints. Earlier studies proposed negative feedback PD-controllers to regulate the angles of the knee joints to handle this situation. Recent studies suggest that the behaviour of the joint controller depends on the compliance of the substrate the insect is standing on. On highly elastic substrates (e.g. leaves) the joint controller exhibits an I-characteristic. Deviations from the original position are compensated completely. On moderately elastic substrates (e.g. twigs) the joint controller comprises a P-characteristic. The leg attains a resting position that differs from the original position through application of a specific compensation force. On stiff substrates the knee joint seems to be controlled by a D-controller. If the leg endpoint is forced away from the original position by an external disturbance (e.g. a moving branch), the controller compensates this deviation by activation of the according muscle which results in a counter force. After some time the controller seems to "give up." The force decreases to zero. To model these results, we propose a self-adjusting joint controller that changes its own setpoint in dependance of the substrate stiffness. The substrate stiffness is determined by means of a correlator circuit that compares (superimposed) movement commands with the actual responses of the leg joint. The new controller can be used for the control of legged robots.

  13. NDRG2 phosphorylation provides negative feedback for SGK1-dependent regulation of a kainate receptor in astrocytes

    PubMed Central

    Matschke, Veronika; Theiss, Carsten; Hollmann, Michael; Schulze-Bahr, Eric; Lang, Florian; Seebohm, Guiscard; Strutz-Seebohm, Nathalie

    2015-01-01

    Glutamate receptors play an important role in the function of astrocytes. Among their tasks is the regulation of gliotransmission, gene expression and exocytosis of the tissue-type plasminogen activator (tPA), which has an enhancing effect on N-methyl-D-aspartate (NMDA) receptors and thus prevent over-excitation of neighboring neurons. The kainate receptor GluK2, which is expressed in neurons and astrocytes, is under tight regulation of the PI3-kinase SGK pathway as shown in neurons. SGK1 targets include N-myc downstream-regulated genes (NDRGs) 1 and 2 (NDRG1, NDRG2), proteins with elusive function. In the present study, we analyzed the effects of SGK1, NDRG1, and NDRG2 on GluK2 current amplitude and plasma membrane localization in astrocytes and heterologous expression. We demonstrate that NDRG1 and NDRG2 themselves have no effect on GluK2 current amplitudes in heterologous expressed ion channels. However, when NDRG2 is coexpressed with GluK2 and SGK1, the stimulating effect of SGK1 on GluK2 is suppressed both in heterologous expression and in astrocytes. Here, we reveal a new negative feedback mechanism, whereby GluK2 stimulation by SGK1 is regulated by parallel phosphorylation of NDRG2. This regulation of GluK2 by SGK1 and NDRG2 in astrocytes may play an important role in gliotransmission, modulation of gene expression and regulation of exocytosis of tPA. PMID:26500492

  14. Advances on Non-CD4 + Foxp3+ T Regulatory Cells: CD8+, Type 1, and Double Negative T Regulatory Cells in Organ Transplantation.

    PubMed

    Ligocki, Ann J; Niederkorn, Jerry Y

    2015-08-01

    The overwhelming body of research on T regulatory cells (Treg) has focused on CD4 + CD25 + Foxp3+ T cells. However, recent years have witnessed a resurgence in interest in CD4 - CD8+, CD4 - CD8- (double negative [DN]), and CD4 + Foxp3- type 1 Treg (Tr1) Treg and their role in controlling autoimmune diseases and in promoting the survival of organ allografts and xenografts. CD8+ and DN Treg can arise spontaneously (natural Treg) or can be induced in situ. Both CD8+ and DN Treg have been shown to enhance the survival of organ allografts and xenografts. Additionally, both can suppress alloimmune responses by contact-dependent mechanisms by either inducing apoptosis or mediating direct cytolysis of effector T cells. CD8+, DN, and Tr1 Treg can also act in a contact-independent manner by elaborating soluble immunosuppressive factors, such as TGF-β and IL-10. Applying CD8+, DN, and Tr1 Treg for enhancing the survival of organ allografts and xenografts is still in its infancy but holds significant potential. Furthermore, there is a need for a more comprehensive understanding of how current immunosuppressive therapies applied to organ transplantations affect the wide array of Treg populations.

  15. Negative regulatory elements upstream of a novel exon of the neuronal nicotinic acetylcholine receptor alpha 2 subunit gene.

    PubMed Central

    Bessis, A; Savatier, N; Devillers-Thiéry, A; Bejanin, S; Changeux, J P

    1993-01-01

    The expression of the nicotinic acetylcholine receptor alpha 2 subunit gene is highly restricted to the Spiriform lateralis nucleus of the Chick diencephalon. As a first step toward understanding the molecular mechanism underlying this regulation, we have investigated the structural and regulatory properties of the 5' sequence of this gene. A strategy based on the ligation of an oligonucleotide to the first strand of the cDNA (SLIC) followed by PCR amplification was used. A new exon was found approximately 3kb upstream from the first coding exon, and multiple transcription start sites of the gene were mapped. Analysis of the flanking region shows many consensus sequences for the binding of nuclear proteins, suggesting that the 1 kb flanking region contains at least a portion of the promoter of the gene. We have analysed the negative regulatory elements present within this region and found that a silencer region located between nucleotide -144 and +76 is active in fibroblasts as well as in neurons. This silencer is composed of six tandem repeat Oct-like motifs (CCCCATGCAAT), but does not bind any member of the Oct family. Moreover these motifs were found to act as a silencer only when they were tandemly repeated. When two, four or five motifs were deleted, the silencer activity of the motifs unexpectedly became an enhancer activity in all cells we have tested. Images PMID:8502560

  16. Mining Specific and General Features in Both Positive and Negative Relevance Feedback. QUT E-Discovery Lab at the TREC󈧍 Relevance Feedback Track

    DTIC Science & Technology

    2009-11-01

    relevance feedback algo- rithm. Four methods, εMap [1], MapA , P10A, and StatAP [2], were used in the track to measure the performance of Phase 2 runs...εMap and StatAP were applied to the runs us- ing the testing set of only ClueWeb09 Category-B, whereas MapA and P10A were applied to those using the...whole ClueWeb09 English set. Because our experiments were based on only ClueWeb09 Category-B, measuring our per- formance by MapA and P10A might not

  17. A negative regulatory role for auxin in sulphate deficiency response in Arabidopsis thaliana.

    PubMed

    Dan, Hanbin; Yang, Guohua; Zheng, Zhi-Liang

    2007-01-01

    Sulphate is a major macronutrient required for the synthesis of the sulphur (S)-containing amino acid cysteine and thus is critical for cellular metabolism, growth and development and response to various abiotic and biotic stresses. A recent genome-wide expression study suggested that several auxin-inducible genes were up-regulated by S deficiency in Arabidopsis. Here, we examined the relationship between auxin signaling and S deficiency. Investigation of DR5::GUS expression patterns indicates that auxin accumulation and/or response is suppressed by S deficiency. Consistently, S deficiency resulted in the suppression of lateral root development, but the axr1-3 mutant was insensitive to this response. Furthermore, the activation of the promoter for the putative thioglucosidase gene (At2g44460) by S deficiency was suppressed by auxin, cytokinin and abscisic acid (ABA). Interestingly, the activation of At2g44460 by S deficiency is regulated by the availability of carbon and nitrogen nutrients in a tissue-specific manner. These results demonstrate that auxin plays a negative role in signaling to S deficiency. Given that activation of the genes encoding the sulphate transporter SULTR1;2 and 5'-adenylylsulphate reductase APR2 are suppressed by cytokinin only, we hypothesize that while cytokinin may play an important role in general S deficiency response, auxin might be only involved in a subset of S deficiency responses such as the release of thiol groups from the S storage sources.

  18. GTP cyclohydrolase I inhibition by the prototypic inhibitor 2, 4-diamino-6-hydroxypyrimidine. Mechanisms and unanticipated role of GTP cyclohydrolase I feedback regulatory protein.

    PubMed

    Xie, L; Smith, J A; Gross, S S

    1998-08-14

    2,4-Diamino-6-hydroxypyrimidine (DAHP) is considered to be a selective and direct-acting inhibitor of GTP cyclohydrolase I (GTPCH), the first and rate-limiting enzyme in the pathway for synthesis of tetrahydrobiopterin (BH4). Accordingly, DAHP has been widely employed to distinguish whether de novo BH4 synthesis is required in a given biological system. Although it has been assumed that DAHP inhibits GTPCH by direct competition with substrate GTP, this has never been formally demonstrated. In view of apparent structural homology between DAHP and BH4, we questioned whether DAHP may mimic BH4 in its inhibition of GTPCH by an indirect mechanism, involving interaction with a recently cloned 9.5-kDa protein termed GTPCH Feedback Regulatory Protein (GFRP). We show by reverse transcription-polymerase chain reaction that GFRP mRNA is constitutively expressed in rat aortic smooth muscle cells and further induced by treatment with immunostimulants. Moreover, functional GFRP is expressed and immunostimulant-induced BH4 accumulates in sufficient quantity to trigger feedback inhibition of GTPCH. Studies with DAHP reveal that GFRP is also essential to achieve potent inhibition of GTPCH. Indeed, DAHP inhibits GTPCH by dual mechanisms. At a relatively low concentration, DAHP emulates BH4 and engages the GFRP-dependent feedback inhibitory system; at higher concentrations, DAHP competes directly for binding with GTP substrate. This knowledge predicts that DAHP would preferably target GTPCH in tissues with abundant GFRP.

  19. MOTHER OF FT AND TFL1 Regulates Seed Germination through a Negative Feedback Loop Modulating ABA Signaling in Arabidopsis[C][W

    PubMed Central

    Xi, Wanyan; Liu, Chang; Hou, Xingliang; Yu, Hao

    2010-01-01

    Abscisic acid (ABA) and gibberellin (GA) are two antagonistic phytohormones that regulate seed germination in response to biotic and abiotic environmental stresses. We demonstrate here that MOTHER OF FT AND TFL1 (MFT), which encodes a phosphatidylethanolamine-binding protein, regulates seed germination via the ABA and GA signaling pathways in Arabidopsis thaliana. MFT is specifically induced in the radical-hypocotyl transition zone of the embryo in response to ABA, and mft loss-of-function mutants show hypersensitivity to ABA in seed germination. In germinating seeds, MFT expression is directly regulated by ABA-INSENSITIVE3 (ABI3) and ABI5, two key transcription factors in ABA signaling pathway. MFT is also upregulated by DELLA proteins in the GA signaling pathway. MFT in turn provides negative feedback regulation of ABA signaling by directly repressing ABI5. We conclude that during seed germination, MFT promotes embryo growth by constituting a negative feedback loop in the ABA signaling pathway. PMID:20551347

  20. Dual Masking of Specific Negative Splicing Regulatory Elements Resulted in Maximal Exon 7 Inclusion of SMN2 Gene

    PubMed Central

    Pao, Peng Wen; Wee, Keng Boon; Yee, Woon Chee; DwiPramono, Zacharias Aloysius

    2014-01-01

    Spinal muscular atrophy (SMA) is a fatal autosomal recessive disease caused by survival motor neuron (SMN) protein insufficiency due to SMN1 mutations. Boosting SMN2 expression is a potential therapy for SMA. SMN2 has identical coding sequence as SMN1 except for a silent C-to-T transition at the 6th nucleotide of exon 7, converting a splicing enhancer to a silencer motif. Consequently, most SMN2 transcripts lack exon 7. More than ten putative splicing regulatory elements (SREs) were reported to regulate exon 7 splicing. To investigate the relative strength of each negative SRE in inhibiting exon 7 inclusion, antisense oligonucleotides (AONs) were used to mask each element, and the fold increase of full-length SMN transcripts containing exon 7 were compared. The most potent negative SREs are at intron 7 (in descending order): ISS-N1, 3′ splice site of exon 8 (ex8 3′ss) and ISS+100. Dual-targeting AONs were subsequently used to mask two nonadjacent SREs simultaneously. Notably, masking of both ISS-N1 and ex8 3′ss induced the highest fold increase of full-length SMN transcripts and proteins. Therefore, efforts should be directed towards the two elements simultaneously for the development of optimal AONs for SMA therapy. PMID:24317636

  1. Disturbance of the let-7/LIN28 double-negative feedback loop is associated with radio- and chemo-resistance in non-small cell lung cancer.

    PubMed

    Yin, Jun; Zhao, Jian; Hu, Weimin; Yang, Guangping; Yu, Hui; Wang, Ruihao; Wang, Linjing; Zhang, Guoqian; Fu, Wenfan; Dai, Lu; Li, Wanzhen; Liao, Boyu; Zhang, Shuxu

    2017-01-01

    Radio- and chemo-resistance represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC) and the underlying molecular mechanisms are not known. In the present study, during induction of radio- or chemo-resistance in NSCLC cells, dynamic analyses revealed that decreased expression of let-7 induced by irradiation or cisplatin resulted in increased expression of its target gene LIN28, and increased expression of LIN28 then contributed to further decreased expression of let-7 by inhibiting its maturation and biogenesis. Moreover, we showed that down-regulation of let-7 and up-regulation of LIN28 expression promoted resistance to irradiation or cisplatin by regulating the single-cell proliferative capability of NSCLC cells. Consequently, in NSCLC cells, let-7 and LIN28 can form a double-negative feedback loop through mutual inhibition, and disturbance of the let-7/LIN28 double-negative feedback loop induced by irradiation or chemotherapeutic drugs can result in radio- and chemo-resistance. In addition, low expression of let-7 and high expression of LIN28 in NSCLC patients was associated significantly with resistance to radiotherapy or chemotherapy. Therefore, our study demonstrated that disturbance of the let-7/LIN28 double-negative feedback loop is involved in the regulation of radio- and chemo-resistance, and that let-7 and LIN28 could be employed as predictive biomarkers of response to radiotherapy or chemotherapy in NSCLC patients.

  2. The role of mRNA and protein stability in the function of coupled positive and negative feedback systems in eukaryotic cells

    PubMed Central

    Moss Bendtsen, Kristian; Jensen, Mogens H.; Krishna, Sandeep; Semsey, Szabolcs

    2015-01-01

    Oscillators and switches are important elements of regulation in biological systems. These are composed of coupling negative feedback loops, which cause oscillations when delayed, and positive feedback loops, which lead to memory formation. Here, we examine the behavior of a coupled feedback system, the Negative Autoregulated Frustrated bistability motif (NAF). This motif is a combination of two previously explored motifs, the frustrated bistability motif (FBM) and the negative auto regulation motif (NAR), which both can produce oscillations. The NAF motif was previously suggested to govern long term memory formation in animals, and was used as a synthetic oscillator in bacteria. We build a mathematical model to analyze the dynamics of the NAF motif. We show analytically that the NAF motif requires an asymmetry in the strengths of activation and repression links in order to produce oscillations. We show that the effect of time delays in eukaryotic cells, originating from mRNA export and protein import, are negligible in this system. Based on the reported protein and mRNA half-lives in eukaryotic cells, we find that even though the NAF motif possesses the ability for oscillations, it mostly promotes constant protein expression at the biologically relevant parameter regimes. PMID:26365394

  3. The role of mRNA and protein stability in the function of coupled positive and negative feedback systems in eukaryotic cells.

    PubMed

    Moss Bendtsen, Kristian; Jensen, Mogens H; Krishna, Sandeep; Semsey, Szabolcs

    2015-09-14

    Oscillators and switches are important elements of regulation in biological systems. These are composed of coupling negative feedback loops, which cause oscillations when delayed, and positive feedback loops, which lead to memory formation. Here, we examine the behavior of a coupled feedback system, the Negative Autoregulated Frustrated bistability motif (NAF). This motif is a combination of two previously explored motifs, the frustrated bistability motif (FBM) and the negative auto regulation motif (NAR), which both can produce oscillations. The NAF motif was previously suggested to govern long term memory formation in animals, and was used as a synthetic oscillator in bacteria. We build a mathematical model to analyze the dynamics of the NAF motif. We show analytically that the NAF motif requires an asymmetry in the strengths of activation and repression links in order to produce oscillations. We show that the effect of time delays in eukaryotic cells, originating from mRNA export and protein import, are negligible in this system. Based on the reported protein and mRNA half-lives in eukaryotic cells, we find that even though the NAF motif possesses the ability for oscillations, it mostly promotes constant protein expression at the biologically relevant parameter regimes.

  4. Disturbance of the let-7/LIN28 double-negative feedback loop is associated with radio- and chemo-resistance in non-small cell lung cancer

    PubMed Central

    Hu, Weimin; Yang, Guangping; Yu, Hui; Wang, Ruihao; Wang, Linjing; Zhang, Guoqian; Fu, Wenfan; Dai, Lu; Li, Wanzhen; Liao, Boyu; Zhang, Shuxu

    2017-01-01

    Radio- and chemo-resistance represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC) and the underlying molecular mechanisms are not known. In the present study, during induction of radio- or chemo-resistance in NSCLC cells, dynamic analyses revealed that decreased expression of let-7 induced by irradiation or cisplatin resulted in increased expression of its target gene LIN28, and increased expression of LIN28 then contributed to further decreased expression of let-7 by inhibiting its maturation and biogenesis. Moreover, we showed that down-regulation of let-7 and up-regulation of LIN28 expression promoted resistance to irradiation or cisplatin by regulating the single-cell proliferative capability of NSCLC cells. Consequently, in NSCLC cells, let-7 and LIN28 can form a double-negative feedback loop through mutual inhibition, and disturbance of the let-7/LIN28 double-negative feedback loop induced by irradiation or chemotherapeutic drugs can result in radio- and chemo-resistance. In addition, low expression of let-7 and high expression of LIN28 in NSCLC patients was associated significantly with resistance to radiotherapy or chemotherapy. Therefore, our study demonstrated that disturbance of the let-7/LIN28 double-negative feedback loop is involved in the regulation of radio- and chemo-resistance, and that let-7 and LIN28 could be employed as predictive biomarkers of response to radiotherapy or chemotherapy in NSCLC patients. PMID:28235063

  5. Negative feedback regulation of ABA biosynthesis in peanut (Arachis hypogaea): a transcription factor complex inhibits AhNCED1 expression during water stress

    PubMed Central

    Liu, Shuai; Li, Meijuan; Su, Liangchen; Ge, Kui; Li, Limei; Li, Xiaoyun; Liu, Xu; Li, Ling

    2016-01-01

    Abscisic acid (ABA), a key plant stress-signaling hormone, is produced in response to drought and counteracts the effects of this stress. The accumulation of ABA is controlled by the enzyme 9-cis-epoxycarotenoid dioxygenase (NCED). In Arabidopsis, NCED3 is regulated by a positive feedback mechanism by ABA. In this study in peanut (Arachis hypogaea), we demonstrate that ABA biosynthesis is also controlled by negative feedback regulation, mediated by the inhibitory effect on AhNCED1 transcription of a protein complex between transcription factors AhNAC2 and AhAREB1. AhNCED1 was significantly down-regulated after PEG treatment for 10 h, at which time ABA content reached a peak. A ChIP-qPCR assay confirmed AhAREB1 and AhNAC2 binding to the AhNCED1 promoter in response to ABA. Moreover, the interaction between AhAREB1 and AhNAC2, and a transient expression assay showed that the protein complex could negatively regulate the expression of AhNCED1. The results also demonstrated that AhAREB1 was the key factor in AhNCED1 feedback regulation, while AhNAC2 played a subsidiary role. ABA reduced the rate of AhAREB1 degradation and enhanced both the synthesis and degradation rate of the AhNAC2 protein. In summary, the AhAREB1/AhNAC2 protein complex functions as a negative feedback regulator of drought-induced ABA biosynthesis in peanut. PMID:27892506

  6. The CaM Kinase CMK-1 Mediates a Negative Feedback Mechanism Coupling the C. elegans Glutamate Receptor GLR-1 with Its Own Transcription.

    PubMed

    Moss, Benjamin J; Park, Lidia; Dahlberg, Caroline L; Juo, Peter

    2016-07-01

    Regulation of synaptic AMPA receptor levels is a major mechanism underlying homeostatic synaptic scaling. While in vitro studies have implicated several molecules in synaptic scaling, the in vivo mechanisms linking chronic changes in synaptic activity to alterations in AMPA receptor expression are not well understood. Here we use a genetic approach in C. elegans to dissect a negative feedback pathway coupling levels of the AMPA receptor GLR-1 with its own transcription. GLR-1 trafficking mutants with decreased synaptic receptors in the ventral nerve cord (VNC) exhibit compensatory increases in glr-1 mRNA, which can be attributed to increased glr-1 transcription. Glutamatergic transmission mutants lacking presynaptic eat-4/VGLUT or postsynaptic glr-1, exhibit compensatory increases in glr-1 transcription, suggesting that loss of GLR-1 activity is sufficient to trigger the feedback pathway. Direct and specific inhibition of GLR-1-expressing neurons using a chemical genetic silencing approach also results in increased glr-1 transcription. Conversely, expression of a constitutively active version of GLR-1 results in decreased glr-1 transcription, suggesting that bidirectional changes in GLR-1 signaling results in reciprocal alterations in glr-1 transcription. We identify the CMK-1/CaMK signaling axis as a mediator of the glr-1 transcriptional feedback mechanism. Loss-of-function mutations in the upstream kinase ckk-1/CaMKK, the CaM kinase cmk-1/CaMK, or a downstream transcription factor crh-1/CREB, result in increased glr-1 transcription, suggesting that the CMK-1 signaling pathway functions to repress glr-1 transcription. Genetic double mutant analyses suggest that CMK-1 signaling is required for the glr-1 transcriptional feedback pathway. Furthermore, alterations in GLR-1 signaling that trigger the feedback mechanism also regulate the nucleocytoplasmic distribution of CMK-1, and activated, nuclear-localized CMK-1 blocks the feedback pathway. We propose a model in

  7. Concise Review: LIN28/let-7 Signaling, a Critical Double-Negative Feedback Loop During Pluripotency, Reprogramming, and Tumorigenicity.

    PubMed

    Farzaneh, Maryam; Attari, Farnoosh; Khoshnam, Seyed Esmaeil

    2017-08-28

    MicroRNAs (miRNAs) with 20-30 nucleotides have recently emerged as the multidimensional regulators of cell fate decisions. Recent improvement in high-throughput sequencing has highlighted the potential role of LIN28/let-7 regulatory network in several developmental events. It was proposed that this pathway might represent a functional signature in cell proliferation, transition between commitment and pluripotency, and regulation of cancer and tumorigenicity. LIN28/let-7 regulatory pathway is one of the excellent examples of the relationship between an miRNA and mRNAs. This review article highlights the potentials of LIN28/let-7 signaling in gene regulatory pathways during pluripotency, reprogramming, and tumorigenicity.

  8. Expression of the CDR1 efflux pump in clinical Candida albicans isolates is controlled by a negative regulatory element

    SciTech Connect

    Gaur, Naseem Akhtar; Manoharlal, Raman; Saini, Preeti; Prasad, Tulika; Mukhopadhyay, Gauranga; Hoefer, Milan; Morschhaeuser, Joachim; Prasad, Rajendra . E-mail: rp47@hotmail.com

    2005-06-24

    Resistance to azole antifungal drugs in clinical isolates of the human fungal pathogen Candida albicans is often caused by constitutive overexpression of the CDR1 gene, which encodes a multidrug efflux pump of the ABC transporter superfamily. To understand the relevance of a recently identified negative regulatory element (NRE) in the CDR1 promoter for the control of CDR1 expression in the clinical scenario, we investigated the effect of mutation or deletion of the NRE on CDR1 expression in two matched pairs of azole-sensitive and resistant clinical isolates of C. albicans. Expression of GFP or lacZ reporter genes from the wild type CDR1 promoter was much higher in the azole-resistant C. albicans isolates than in the azole-susceptible isolates, reflecting the known differences in CDR1 expression in these strains. Deletion or mutation of the NRE resulted in enhanced reporter gene expression in azole-sensitive strains, but did not further increase the already high CDR1 promoter activity in the azole-resistant strains. In agreement with these findings, electrophoretic mobility shift assays showed a reduced binding to the NRE of nuclear extracts from the resistant C. albicans isolates as compared with extracts from the sensitive isolates. These results demonstrate that the NRE is involved in maintaining CDR1 expression at basal levels and that this repression is overcome in azole-resistant clinical C. albicans isolates, resulting in constitutive CDR1 overexpression and concomitant drug resistance.

  9. Two negative cis-regulatory regions involved in fruit-specific promoter activity from watermelon (Citrullus vulgaris S.).

    PubMed

    Yin, Tao; Wu, Hanying; Zhang, Shanglong; Lu, Hongyu; Zhang, Lingxiao; Xu, Yong; Chen, Daming; Liu, Jingmei

    2009-01-01

    A 1.8 kb 5'-flanking region of the large subunit of ADP-glucose pyrophosphorylase, isolated from watermelon (Citrullus vulgaris S.), has fruit-specific promoter activity in transgenic tomato plants. Two negative regulatory regions, from -986 to -959 and from -472 to -424, were identified in this promoter region by fine deletion analyses. Removal of both regions led to constitutive expression in epidermal cells. Gain-of-function experiments showed that these two regions were sufficient to inhibit RFP (red fluorescent protein) expression in transformed epidermal cells when fused to the cauliflower mosaic virus (CaMV) 35S minimal promoter. Gel mobility shift experiments demonstrated the presence of leaf nuclear factors that interact with these two elements. A TCCAAAA motif was identified in these two regions, as well as one in the reverse orientation, which was confirmed to be a novel specific cis-element. A quantitative beta-glucuronidase (GUS) activity assay of stable transgenic tomato plants showed that the activities of chimeric promoters harbouring only one of the two cis-elements, or both, were approximately 10-fold higher in fruits than in leaves. These data confirm that the TCCAAAA motif functions as a fruit-specific element by inhibiting gene expression in leaves.

  10. Two negative cis-regulatory regions involved in fruit-specific promoter activity from watermelon (Citrullus vulgaris S.)

    PubMed Central

    Yin, Tao; Wu, Hanying; Zhang, Shanglong; Liu, Jingmei; Lu, Hongyu; Zhang, Lingxiao; Xu, Yong; Chen, Daming

    2009-01-01

    A 1.8 kb 5′-flanking region of the large subunit of ADP-glucose pyrophosphorylase, isolated from watermelon (Citrullus vulgaris S.), has fruit-specific promoter activity in transgenic tomato plants. Two negative regulatory regions, from –986 to –959 and from –472 to –424, were identified in this promoter region by fine deletion analyses. Removal of both regions led to constitutive expression in epidermal cells. Gain-of-function experiments showed that these two regions were sufficient to inhibit RFP (red fluorescent protein) expression in transformed epidermal cells when fused to the cauliflower mosaic virus (CaMV) 35S minimal promoter. Gel mobility shift experiments demonstrated the presence of leaf nuclear factors that interact with these two elements. A TCCAAAA motif was identified in these two regions, as well as one in the reverse orientation, which was confirmed to be a novel specific cis-element. A quantitative β-glucuronidase (GUS) activity assay of stable transgenic tomato plants showed that the activities of chimeric promoters harbouring only one of the two cis-elements, or both, were ∼10-fold higher in fruits than in leaves. These data confirm that the TCCAAAA motif functions as a fruit-specific element by inhibiting gene expression in leaves. PMID:19073962

  11. CDK5 Regulatory Subunit-Associated Protein 1-like 1 Negatively Regulates Adipocyte Differentiation through Activation of Wnt Signaling Pathway.

    PubMed

    Take, Kazumi; Waki, Hironori; Sun, Wei; Wada, Takahito; Yu, Jing; Nakamura, Masahiro; Aoyama, Tomohisa; Yamauchi, Toshimasa; Kadowaki, Takashi

    2017-08-04

    CDK5 Regulatory Subunit-Associated Protein 1-like 1 (CDKAL1) was identified as a susceptibility gene for type 2 diabetes and body mass index in genome-wide association studies. Although it was reported that CDKAL1 is a methylthiotransferase essential for tRNA(Lys)(UUU) and faithful translation of proinsulin generated in pancreatic β cells, the role of CDKAL1 in adipocytes has not been understood well. In this study, we found that CDKAL1 is expressed in adipose tissue and its expression is increased during differentiation. Stable overexpression of CDKAL1, however, inhibited adipocyte differentiation of 3T3-L1 cells, whereas knockdown of CDKAL1 promoted differentiation. CDKAL1 increased protein levels of β-catenin and its active unphosphorylated form in the nucleus, thereby promoting Wnt target gene expression, suggesting that CDKAL1 activated the Wnt/β-catenin pathway-a well-characterized inhibitory regulator of adipocyte differentiation. Mutant experiments show that conserved cysteine residues of Fe-S clusters of CDKAL1 are essential for its anti-adipogenic action. Our results identify CDKAL1 as novel negative regulator of adipocyte differentiation and provide insights into the link between CDKAL1 and metabolic diseases such as type 2 diabetes and obesity.

  12. Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL

    SciTech Connect

    Gordon, Wendy R.; Roy, Monideepa; Vardar-Ulu, Didem; Garfinkel, Megan; Mansour, Marc R.; Aster, Jon C.; Blacklow, Stephen C.

    2009-09-02

    Proteolytic resistance of Notch prior to ligand binding depends on the structural integrity of a negative regulatory region (NRR) of the receptor that immediately precedes the transmembrane segment. The NRR includes the 3 Lin12/Notch repeats and the juxtamembrane heterodimerization domain, the region of Notch1 most frequently mutated in T-cell acute lymphoblastic leukemia lymphoma (T-ALL). Here, we report the x-ray structure of the Notch1 NRR in its autoinhibited conformation. A key feature of the Notch1 structure that maintains its closed conformation is a conserved hydrophobic plug that sterically occludes the metalloprotease cleavage site. Crystal packing interactions involving a highly conserved, exposed face on the third Lin12/Notch repeat suggest that this site may normally be engaged in intermolecular or intramolecular protein-protein interactions. The majority of known T-ALL-associated point mutations map to residues in the hydrophobic interior of the Notch1 NRR. A novel mutation (H1545P), which alters a residue at the crystal-packing interface, leads to ligand-independent increases in signaling in reporter gene assays despite only mild destabilization of the NRR, suggesting that it releases the autoinhibitory clamp on the heterodimerization domain imposed by the Lin12/Notch repeats. The Notch1 NRR structure should facilitate a search for antibodies or compounds that stabilize the autoinhibited conformation.

  13. Impulsivity and the association between the feedback-related negativity and performance on an inhibitory control task in young at-risk children.

    PubMed

    Roos, Leslie E; Pears, Katherine; Bruce, Jacqueline; Kim, Hyoun K; Fisher, Philip A

    2015-05-01

    Identifying neurocognitive processes associated with effective inhibitory control is particularly relevant for individuals at high risk for disruptive behaviors, such as maltreated children. Performance feedback processing during a flanker task was investigated in maltreated preschool-aged children (N = 67) via an event-related potential component, the feedback-related negativity (FRN). The functionality of the FRN in children with high impulsivity was of interest, as impulsivity was associated with an exaggerated FRN in previous research. Results showed that high impulsivity was associated with an exaggerated FRN and greater post-error slowing. For children with high impulsivity, there was a correlation between the FRN and accuracy, which was not found in children with low impulsivity. This suggests that an exaggerated FRN is particularly important for children with high impulsivity to maintain effective inhibitory control.

  14. GTP cyclohydrolase feedback regulatory protein controls cofactor 6-tetrahydrobiopterin synthesis in the cytosol and in the nucleus of epidermal keratinocytes and melanocytes.

    PubMed

    Chavan, Bhaven; Gillbro, Johanna M; Rokos, Hartmut; Schallreuter, Karin U

    2006-11-01

    (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH4) is crucial in the hydroxylation of L-phenylalanine-, L-tyrosine-, and L-tryptophan-regulating catecholamine and serotonin synthesis as well as tyrosinase in melanogenesis. The rate-limiting step of 6BH4 de novo synthesis is controlled by guanosine triphosphate (GTP) cyclohydrolase I (GTPCHI) and its feedback regulatory protein (GFRP), where binding of L-phenylalanine to GFRP increases enzyme activities, while 6BH4 exerts the opposite effect. Earlier it was demonstrated that the human epidermis holds the full capacity for autocrine 6BH4 de novo synthesis and recycling. However, besides the expression of epidermal mRNA for GFRP, the presence of a functioning GFRP feedback has never been shown. Therefore, it was tempting to investigate whether this important mechanism is present in epidermal cells. Our results identified indeed a functioning GFRP/GTPCHI axis in epidermal keratinocytes and melanocytes in the cytosol, adding the missing link for 6BH4 de novo synthesis which in turn controls cofactor supply for catecholamine and serotonin biosynthesis as well as melanogenesis in the human epidermis. Moreover, GFRP expression and GTPCHI activities have been found in the nucleus of both cell types. The