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Sample records for negative regulatory feedback

  1. Negative feedback buffers effects of regulatory variants

    PubMed Central

    Bader, Daniel M; Wilkening, Stefan; Lin, Gen; Tekkedil, Manu M; Dietrich, Kim; Steinmetz, Lars M; Gagneur, Julien

    2015-01-01

    Mechanisms conferring robustness against regulatory variants have been controversial. Previous studies suggested widespread buffering of RNA misexpression on protein levels during translation. We do not find evidence that translational buffering is common. Instead, we find extensive buffering at the level of RNA expression, exerted through negative feedback regulation acting in trans, which reduces the effect of regulatory variants on gene expression. Our approach is based on a novel experimental design in which allelic differential expression in a yeast hybrid strain is compared to allelic differential expression in a pool of its spores. Allelic differential expression in the hybrid is due to cis-regulatory differences only. Instead, in the pool of spores allelic differential expression is not only due to cis-regulatory differences but also due to local trans effects that include negative feedback. We found that buffering through such local trans regulation is widespread, typically compensating for about 15% of cis-regulatory effects on individual genes. Negative feedback is stronger not only for essential genes, indicating its functional relevance, but also for genes with low to middle levels of expression, for which tight regulation matters most. We suggest that negative feedback is one mechanism of Waddington's canalization, facilitating the accumulation of genetic variants that might give selective advantage in different environments. PMID:25634765

  2. Noise Control in Gene Regulatory Networks with Negative Feedback.

    PubMed

    Hinczewski, Michael; Thirumalai, D

    2016-07-01

    Genes and proteins regulate cellular functions through complex circuits of biochemical reactions. Fluctuations in the components of these regulatory networks result in noise that invariably corrupts the signal, possibly compromising function. Here, we create a practical formalism based on ideas introduced by Wiener and Kolmogorov (WK) for filtering noise in engineered communications systems to quantitatively assess the extent to which noise can be controlled in biological processes involving negative feedback. Application of the theory, which reproduces the previously proven scaling of the lower bound for noise suppression in terms of the number of signaling events, shows that a tetracycline repressor-based negative-regulatory gene circuit behaves as a WK filter. For the class of Hill-like nonlinear regulatory functions, this type of filter provides the optimal reduction in noise. Our theoretical approach can be readily combined with experimental measurements of response functions in a wide variety of genetic circuits, to elucidate the general principles by which biological networks minimize noise.

  3. Negative Feedback and Transcriptional Overshooting in a Regulatory Network for Horizontal Gene Transfer

    PubMed Central

    Fernandez-Lopez, Raul; del Campo, Irene; Revilla, Carlos; Cuevas, Ana; de la Cruz, Fernando

    2014-01-01

    Horizontal gene transfer (HGT) is a major force driving bacterial evolution. Because of their ability to cross inter-species barriers, bacterial plasmids are essential agents for HGT. This ability, however, poses specific requisites on plasmid physiology, in particular the need to overcome a multilevel selection process with opposing demands. We analyzed the transcriptional network of plasmid R388, one of the most promiscuous plasmids in Proteobacteria. Transcriptional analysis by fluorescence expression profiling and quantitative PCR revealed a regulatory network controlled by six transcriptional repressors. The regulatory network relied on strong promoters, which were tightly repressed in negative feedback loops. Computational simulations and theoretical analysis indicated that this architecture would show a transcriptional burst after plasmid conjugation, linking the magnitude of the feedback gain with the intensity of the transcriptional burst. Experimental analysis showed that transcriptional overshooting occurred when the plasmid invaded a new population of susceptible cells. We propose that transcriptional overshooting allows genome rebooting after horizontal gene transfer, and might have an adaptive role in overcoming the opposing demands of multilevel selection. PMID:24586200

  4. 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.

  5. Anxiety and feedback negativity.

    PubMed

    Gu, Ruolei; Huang, Yu-Xia; Luo, Yue-Jia

    2010-09-01

    It has been suggested that anxious individuals are more prone to feel that negative outcomes are particularly extreme and to interpret ambiguous outcomes as negative compared to nonanxious individuals. Previous studies have demonstrated that the feedback negativity (FN) component of event-related brain potential (ERP) is sensitive to outcome evaluation and outcome expectancy. Hence, we predicted that the FN should be different between high trait-anxiety (HTA) and low trait-anxiety (LTA) individuals. To test our hypothesis, the ERPs were recorded during a simple monetary gambling task. The FN was measured as a difference wave created across conditions. We found that the amplitude of the FN indicating negative versus positive outcomes was significantly larger for LTA individuals compared to HTA individuals. However, there was no significant difference in the FN between groups in response to ambiguous versus positive outcomes. The results indicate that there is a relationship between the FN and individual differences in anxiety. We suggest that these results reflect the impact of anxiety on outcome expectation. Our results challenge the reinforcement learning theory of error-related negativity, which proposes that ERN and FN reflect the same cognitive process.

  6. Chat-Line Interaction and Negative Feedback.

    ERIC Educational Resources Information Center

    Iwasaki, Junko; Oliver, Rhonda

    2003-01-01

    Examines communicative interactions between native speakers (NSs) and nonnative speakers (NNSs) of Japanese on Internet relay chat, with a special focus on implicit negative feedback in the interactions. Reports that NSs of Japanese gave implicit negative feedback to their NNS partners and NNSs used the feedback in their subsequent production, but…

  7. Enhanced Negative Feedback Responses in Remitted Depression

    PubMed Central

    Santesso, Diane L.; Steele, Katherine T.; Bogdan, Ryan; Holmes, Avram J.; Deveney, Christen M.; Meites, Tiffany M.; Pizzagalli, Diego A.

    2011-01-01

    Major depressive disorder (MDD) is characterized by hypersensitivity to negative feedback that might involve frontocingulate dysfunction. MDD subjects exhibit enhanced electrophysiological responses to negative internal (errors) and external (feedback) cues. Whether this dysfunction extends to remitted depressed (RD) subjects with a history of MDD is currently unknown. To address this issue, we examined the feedback-related negativity (FRN) in RD and control subjects using a probabilistic punishment learning task. Despite equivalent behavioral performance, RD subjects showed larger FRNs to negative feedback relative to controls; group differences remained after accounting for residual anxiety and depressive symptoms. The present findings suggest that abnormal responses to negative feedback extend to samples at increased risk for depressive episodes in the absence of current symptoms. PMID:18580576

  8. 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.

  9. 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.

  10. Negative Feedback in the Vibrio harveyi Quorum-Sensing Circuit

    NASA Astrophysics Data System (ADS)

    Teng, Shu-Wen; Schaffer, Jessie; Wingreen, Ned; Bassler, Bonnie; Phuan Ong, Nai

    2010-03-01

    Quorum sensing is the mechanism by which bacteria communicate and synchronize group behaviors. Multiple feedbacks have been identified in the model quorum-sensing bacterium Vibrio harveyi, but it has been unclear how these feedbacks interact in individual cells to control the fidelity of signal transduction. We measured the copy number distribution of the master regulators to quantify the activity of the signaling network. We find that the feedbacks affect the production rate, level, and noise of the core quorum-sensing components. Using fluorescence time-lapse microscopy, we directly observed the master regulator in individual cells, and analyzed the persistence of heterogeneity in terms of the normalized time-delayed direct correlation. Our findings suggest that feedback from small regulatory RNAs regulates a receptor to control the noise level in signal transduction. We further tested this model by re-engineering the gene circuit to specifically diminish this feedback. We conclude that negative feedbacks mediated by sRNAs permit fine-tuning of gene regulation, thereby increasing the fidelity of signal transduction.

  11. 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.

  12. 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.

  13. 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.

  14. Effects of informative and confirmatory feedback on brain activation during negative feedback processing

    PubMed Central

    Woo, Yeon-kyoung; Song, Juyeon; Jiang, Yi; Cho, Catherine; Bong, Mimi; Kim, Sung-il

    2015-01-01

    The current study compared the effects of informative and confirmatory feedback on brain activation during negative feedback processing. For confirmatory feedback trials, participants were informed that they had failed the task, whereas informative feedback trials presented task relevant information along with the notification of their failure. Fourteen male undergraduates performed a series of spatial-perceptual tasks and received feedback while their brain activity was recorded. During confirmatory feedback trials, greater activations in the amygdala, dorsal anterior cingulate cortex, and the thalamus (including the habenular) were observed in response to incorrect responses. These results suggest that confirmatory feedback induces negative emotional reactions to failure. In contrast, informative feedback trials elicited greater activity in the dorsolateral prefrontal cortex (DLPFC) when participants experienced failure. Further psychophysiological interaction (PPI) analysis revealed a negative coupling between the DLPFC and the amygdala during informative feedback relative to confirmatory feedback trials. These findings suggest that providing task-relevant information could facilitate implicit down-regulation of negative emotions following failure. PMID:26175679

  15. Voluntary modulation of anterior cingulate response to negative feedback.

    PubMed

    Shane, Matthew S; Weywadt, Christina R

    2014-01-01

    Anterior cingulate and medial frontal cortex (dACC/mFC) response to negative feedback represents the actions of a generalized error-monitoring system critical for the management of goal-directed behavior. Magnitude of dACC/mFC response to negative feedback correlates with levels of post-feedback behavioral change, and with proficiency of operant learning processes. With this in mind, it follows that an ability to alter dACC/mFC response to negative feedback may lead to representative changes in operant learning proficiency. To this end, the present study investigated the extent to which healthy individuals would show modulation of their dACC/mFC response when instructed to try to either maximize or minimize their neural response to the presentation of contingent negative feedback. Participants performed multiple runs of a standard time-estimation task, during which they received feedback regarding their ability to accurately estimate a one-second duration. On Watch runs, participants were simply instructed to try to estimate as closely as possible the one second duration. On Increase and Decrease runs, participants performed the same task, but were instructed to "try to increase [decrease] their brain's response every time they received negative feedback". Results indicated that participants showed changes in dACC/mFC response under these differing instructional conditions: dACC/mFC activity following negative feedback was higher in the Increase condition, and dACC activity trended lower in the Decrease condition, compared to the Watch condition. Moreover, dACC activity correlated with post-feedback performance adjustments, and these adjustments were highest in the Increase condition. Potential implications for neuromodulation and facilitated learning are discussed. PMID:25376010

  16. Distinct noise-controlling roles of multiple negative feedback mechanisms in a prokaryotic operon system.

    PubMed

    Nguyen, L K; Kulasiri, D

    2011-03-01

    Molecular fluctuations are known to affect dynamics of cellular systems in important ways. Studies aimed at understanding how molecular systems of certain regulatory architectures control noise therefore become essential. The interplay between feedback regulation and noise has been previously explored for cellular networks governed by a single negative feedback loop. However, similar issues within networks consisting of more complex regulatory structures remain elusive. The authors investigate how negative feedback loops manage noise within a biochemical cascade concurrently governed by multiple negative feedback loops, using the prokaryotic tryptophan (trp) operon system in Escherechia coli as the model system. To the authors knowledge, this is the first study of noise in the trp operon system. They show that the loops in the trp operon system possess distinct, even opposing, noise-controlling effects despite their seemingly analogous feedback structures. The enzyme inhibition loop, although controlling the last reaction of the cascade, was found to suppress noise not only for the tryptophan output but also for other upstream components. In contrast, the Repression (Rep) loop enhances noise for all systems components. Attenuation (Att) poses intermediate effects by attenuating noise for the upstream components but promoting noise for components downstream of its target. Regarding noise at the output tryptophan, Rep and Att can be categorised as noise-enhancing loops whereas Enzyme Inhibition as a noise-reducing loop. These findings suggest novel implications in how cellular systems with multiple feedback mechanisms control noise. [Includes supplementary material]. PMID:21405203

  17. The combination of positive and negative feedback loops confers exquisite flexibility to biochemical switches

    NASA Astrophysics Data System (ADS)

    Pfeuty, Benjamin; Kaneko, Kunihiko

    2009-12-01

    A wide range of cellular processes require molecular regulatory pathways to convert a graded signal into a discrete response. One prevalent switching mechanism relies on the coexistence of two stable states (bistability) caused by positive feedback regulations. Intriguingly, positive feedback is often supplemented with negative feedback, raising the question of whether and how these two types of feedback can cooperate to control discrete cellular responses. To address this issue, we formulate a canonical model of a protein-protein interaction network and analyze the dynamics of a prototypical two-component circuit. The appropriate combination of negative and positive feedback loops can bring a bistable circuit close to the oscillatory regime. Notably, sharply activated negative feedback can give rise to a bistable regime wherein two stable fixed points coexist and may collide pairwise with two saddle points. This specific type of bistability is found to allow for separate and flexible control of switch-on and switch-off events, for example (i) to combine fast and reversible transitions, (ii) to enable transient switching responses and (iii) to display tunable noise-induced transition rates. Finally, we discuss the relevance of such bistable switching behavior, and the circuit topologies considered, to specific biological processes such as adaptive metabolic responses, stochastic fate decisions and cell-cycle transitions. Taken together, our results suggest an efficient mechanism by which positive and negative feedback loops cooperate to drive the flexible and multifaceted switching behaviors arising in biological systems.

  18. 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.

  19. 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. PMID:25189323

  20. 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

  1. A biopsychosocial model based on negative feedback and control.

    PubMed

    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.

  2. Transcriptional up-regulation of inhibitory PAS domain protein gene expression by hypoxia-inducible factor 1 (HIF-1): a negative feedback regulatory circuit in HIF-1-mediated signaling in hypoxic cells.

    PubMed

    Makino, Yuichi; Uenishi, Rie; Okamoto, Kensaku; Isoe, Tsubasa; Hosono, Osamu; Tanaka, Hirotoshi; Kanopka, Arvydas; Poellinger, Lorenz; Haneda, Masakazu; Morimoto, Chikao

    2007-05-11

    The inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS), a dominant negative regulator of hypoxia-inducible transcription factors (HIFs), is potentially implicated in negative regulation of angiogenesis in such tissues as the avascular cornea of the eye. We have previously shown IPAS mRNA expression is up-regulated in hypoxic tissues, which at least in part involves hypoxia-dependent alternative splicing of the transcripts from the IPAS/HIF-3alpha locus. In the present study, we demonstrate that a hypoxia-driven transcriptional mechanism also plays a role in augmentation of IPAS gene expression. Isolation and analyses of the promoter region flanking to the first exon of IPAS gene revealed a functional hypoxia response element at position -834 to -799, whereas the sequence upstream of the HIF-3alpha first exon scarcely responded to hypoxic stimuli. A transient transfection experiment demonstrated that HIF-1alpha mediates IPAS promoter activation via the functional hypoxia response element under hypoxic conditions and that a constitutively active form of HIF-1alpha is sufficient for induction of the promoter in normoxic cells. Moreover, chromatin immunoprecipitation and electrophoretic mobility shift assays showed binding of the HIF-1 complex to the element in a hypoxia-dependent manner. Taken together, HIF-1 directly up-regulates IPAS gene expression through a mechanism distinct from RNA splicing, providing a further level of negative feedback gene regulation in adaptive responses to hypoxic/ischemic conditions. PMID:17355974

  3. Anatomy of a negative feedback loop: the case of IκBα.

    PubMed

    Fagerlund, Riku; Behar, Marcelo; Fortmann, Karen T; Lin, Y Eason; Vargas, Jesse D; Hoffmann, Alexander

    2015-09-01

    The magnitude, duration and oscillation of cellular signalling pathway responses are often limited by negative feedback loops, defined as an 'activator-induced inhibitor' regulatory motif. Within the NFκB signalling pathway, a key negative feedback regulator is IκBα. We show here that, contrary to current understanding, NFκB-inducible expression is not sufficient for providing effective negative feedback. We then employ computational simulations of NFκB signalling to identify IκBα molecular properties that are critical for proper negative feedback control and test the resulting predictions in biochemical and single-cell live-imaging studies. We identified nuclear import and nuclear export of IκBα and the IκBα-NFκB complex, as well as the free IκBα half-life, as key determinants of post-induction repression of NFκB and the potential for subsequent reactivation. Our work emphasizes that negative feedback is an emergent systems property determined by multiple molecular and biophysical properties in addition to the required 'activator-induced inhibitor' relationship. PMID:26311312

  4. Dynamic Switch of Negative Feedback Regulation in Drosophila Akt–TOR Signaling

    PubMed Central

    Kockel, Lutz; Kerr, Kimberly S.; Melnick, Michael; Brückner, Katja; Hebrok, Matthias; Perrimon, Norbert

    2010-01-01

    Akt represents a nodal point between the Insulin receptor and TOR signaling, and its activation by phosphorylation controls cell proliferation, cell size, and metabolism. The activity of Akt must be carefully balanced, as increased Akt signaling is frequently associated with cancer and as insufficient Akt signaling is linked to metabolic disease and diabetes mellitus. Using a genome-wide RNAi screen in Drosophila cells in culture, and in vivo analyses in the third instar wing imaginal disc, we studied the regulatory circuitries that define dAkt activation. We provide evidence that negative feedback regulation of dAkt occurs during normal Drosophila development in vivo. Whereas in cell culture dAkt is regulated by S6 Kinase (S6K)–dependent negative feedback, this feedback inhibition only plays a minor role in vivo. In contrast, dAkt activation under wild-type conditions is defined by feedback inhibition that depends on TOR Complex 1 (TORC1), but is S6K–independent. This feedback inhibition is switched from TORC1 to S6K only in the context of enhanced TORC1 activity, as triggered by mutations in tsc2. These results illustrate how the Akt–TOR pathway dynamically adapts the routing of negative feedback in response to the activity load of its signaling circuit in vivo. PMID:20585550

  5. Phase noise reduction in semiconductor lasers by optical negative feedback

    NASA Astrophysics Data System (ADS)

    Yasaka, Hiroshi; Aoyama, Konosuke; Yokota, Nobuhide

    2016-04-01

    Phase noise of a single mode semiconductor laser is reduced drastically by introducing a newly proposed optical negative feedback scheme. Proof-of-concept experiment confirms that the spectral linewidth of a semiconductor laser can be reduced to 1/1,000 successfully by applying the scheme.

  6. Neural responses to negative feedback are related to negative emotionality in healthy adults

    PubMed Central

    Santesso, Diane L.; Bogdan, Ryan; Birk, Jeffrey L.; Goetz, Elena L.; Holmes, Avram J.

    2012-01-01

    Prior neuroimaging and electrophysiological evidence suggests that potentiated responses in the anterior cingulate cortex (ACC), particularly the rostral ACC, may contribute to abnormal responses to negative feedback in individuals with elevated negative affect and depressive symptoms. The feedback-related negativity (FRN) represents an electrophysiological index of ACC-related activation in response to performance feedback. The purpose of the present study was to examine the FRN and underlying ACC activation using low resolution electromagnetic tomography source estimation techniques in relation to negative emotionality (a composite index including negative affect and subclinical depressive symptoms). To this end, 29 healthy adults performed a monetary incentive delay task while 128-channel event-related potentials were recorded. We found that enhanced FRNs and increased rostral ACC activation in response to negative—but not positive—feedback was related to greater negative emotionality. These results indicate that individual differences in negative emotionality—a putative risk factor for emotional disorders—modulate ACC-related processes critically implicated in assessing the motivational impact and/or salience of environmental feedback. PMID:21917847

  7. Coupled Positive and Negative Feedbacks Produce Diverse Gene Expression Patterns in Colonies

    PubMed Central

    Mitarai, Namiko; Jensen, Mogens Høgh

    2015-01-01

    ABSTRACT Formation of patterns is a common feature in the development of multicellular organism as well as of microbial communities. To investigate the formation of gene expression patterns in colonies, we build a mathematical model of two-dimensional colony growth, where cells carry a coupled positive-and-negative-feedback circuit. We demonstrate that the model can produce sectored, target (concentric), uniform, and scattered expression patterns of regulators, depending on gene expression dynamics and nutrient diffusion. We reconstructed the same regulatory structure in Escherichia coli cells and found gene expression patterns on the surface of colonies similar to the ones produced by the computer simulations. By comparing computer simulations and experimental results, we observed that very simple rules of gene expression can yield a spectrum of well-defined patterns in a growing colony. Our results suggest that variations of the protein content among cells lead to a high level of heterogeneity in colonies. Importance Formation of patterns is a common feature in the development of microbial communities. In this work, we show that a simple genetic circuit composed of a positive-feedback loop and a negative-feedback loop can produce diverse expression patterns in colonies. We obtained similar sets of gene expression patterns in the simulations and in the experiments. Because the combination of positive feedback and negative feedback is common in intracellular molecular networks, our results suggest that the protein content of cells is highly diversified in colonies. PMID:25852158

  8. 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.

  9. 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…

  10. 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.

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

    NASA Astrophysics Data System (ADS)

    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.

  12. 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.

  13. 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.

  14. 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. PMID:19829164

  15. Negative feedback between stress and erosion: origin of sandstone landforms

    NASA Astrophysics Data System (ADS)

    Bruthans, Jiri; Soukup, Jan; Vaculikova, Jana; Filippi, Michal; Schweigstillova, Jana; Mayo, Alan; Masin, David; Kletetschka, Gunther; Rihosek, Jaroslav

    2015-04-01

    Weathering and erosion of sandstone produces spectacular landforms such as arches, alcoves, pedestal rocks and pillars. The effect of gravity loading stress has been overlooked or assumed to increase the landform's weathering rate. Here we show by physical and numerical modeling, and field observations of locked sands and sandstones that an increase in stress within the landform reduces weathering and erosion. Material with insufficient loading is rapidly removed by weathering process and the remaining load bearing landform structure is protected by the fabric interlocking mechanism. As the landform evolves the increased stress inhibits erosion from raindrop impact, flowing water and slaking, and retards surface retreat caused by salt and frost weathering. Planar discontinuities in sandstone and negative feedback between stress and weathering/erosion processes are sufficient conditions to create above-mentioned landforms. Our experiments are able to reproduce natural shapes including arches, alcoves, pedestal rocks and pillars using landform material and mimicking natural processes. The proposed negative feedback mechanism is supported by a numerical model of stress pattern in landforms. We conclude that stress field is the primary control of the shape evolution of sandstone landforms.

  16. Modeling negative feedback in single-photon avalanche diodes

    NASA Astrophysics Data System (ADS)

    Hayat, Majeed M.; Ramirez, David A.; Rees, Graham J.; Itzler, Mark A.

    2010-04-01

    Recently, considerable attention has been placed upon exploiting the negative-feedback effect in accelerating the quenching time of the avalanche current in passively quenched single-photon avalanche-diode (SPAD) circuits. Reducing the quenching time results in a reduction in the total charge generated in the SPAD, thereby reducing the number of trapped carries; this, in turn, can lead to improved after-pulsing characteristics. A passively quenched SPAD circuit consists of a DC source connected to the SPAD, to provide the reverse bias, and a series load resistor. Upon a photon-generated electron-hole pair triggering an avalanche breakdown, current through the diode and the load resistor rises quickly reaching a steady state value, after which it can collapse (quench) at a stochastic time. In this paper we review recent analytical and Monte-Carlo based models for the quenching time. In addition, results on the statistics of the quenching time and the avalanche pulse duration of SPADs with arbitrary time-variant field across the multiplication region are presented. The calculations of the statistics of the avalanche pulse duration use the dead-space multiplication theory (DSMT) to determine the probability of the avalanche pulse to quench by time t after the instant s at which the electron-hole pair that triggers the avalanche was created. In the analytical and Monte-Carlo based models for the quenching time, the dynamic negative feedback, which is due to the dynamic voltage drop across the load resistor, is taken into account. In addition, in the Monte-Carlo simulations the stochastic nature of the avalanche current is also considered.

  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. 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. PMID:26765948

  20. 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.

  1. Effects of positive and negative feedback on behavior control in hyperactive and normal boys.

    PubMed

    Worland, J

    1976-01-01

    The hypothesis that hyperactive boys have relatively less response to negative feedback than to positive feedback was studied. Sixteen hyperactive boys and 16 controls were compared on two tasks under different feedback conditions. Feedback conditions were no feedback, positive feedback, and negative feedback. Tasks were symbol encoding and correcting spelling words. Hyperactives and controls were compared in amount of time on-task and amount of work correctly completed. Hyperactives were on-task significantly more under conditions of negative feedback than under positive feedback, but negative feedback significantly increased errors on the spelling correction task. Controls were equally responsive to positive, negative, or no feedback. Hyperactives accomplished significantly less than controls on the coding task, but performed as well as controls on the spelling correction task, which was administered to each boy at his own level of spelling ability. The results imply that while consistent negative feedback can reduce off-task behavior for hyperactives, it can also decrease the accuracy of the work they are doing.

  2. Reduced sensitivity to neutral feedback versus negative feedback in subjects with mild depression: Evidence from event-related potentials study.

    PubMed

    Li, Peng; Song, Xinxin; Wang, Jing; Zhou, Xiaoran; Li, Jiayi; Lin, Fengtong; Hu, Zhonghua; Zhang, Xinxin; Cui, Hewei; Wang, Wenmiao; Li, Hong; Cong, Fengyu; Roberson, Debi

    2015-11-01

    Many previous event-related potential (ERP) studies have linked the feedback related negativity (FRN) component with medial frontal cortex processing and associated this component with depression. Few if any studies have investigated the processing of neutral feedback in mildly depressive subjects in the normal population. Two experiments compared brain responses to neutral feedback with behavioral performance in mildly depressed subjects who scored highly on the Beck Depression Inventory (high BDI) and a control group with lower BDI scores (low BDI). In the first study, the FRN component was recorded when neutral, negative or positive feedback was pseudo-randomly delivered to the two groups in a time estimation task. In the second study, real feedback was provided to the two groups in the same task in order to measure their actual accuracy of performance. The results of experiment one (Exp. 1) revealed that a larger FRN effect was elicited by neutral feedback than by negative feedback in the low BDI group, but no significant difference was found between neutral condition and negative condition in the High BDI group. The present findings demonstrated that depressive tendencies influence the processing of neutral feedback in medial frontal cortex. The FRN effect may work as a helpful index for investigating cognitive bias in depression in future studies. PMID:26432379

  3. 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

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

    PubMed

    Packer, Alissa; Clay, Keith

    2004-02-01

    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

  5. 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.

  6. Spatial patterns in the tropical forest reveal connections between negative feedback, aggregation and abundance.

    PubMed

    Seri, Efrat; Shnerb, Nadav

    2015-09-01

    The spatial arrangement of trees in a tropical forest reflects the interplay between aggregating processes, like dispersal limitation, and negative feedback that induces effective repulsion among individuals. Monitoring the variance-mean ratio for conspecific individuals along length-scales, we show that the effect of negative feedback is dominant at short scales, while aggregation characterizes the large-scale patterns. A comparison of different species indicates, surprisingly, that both aggregation and negative feedback scales are related to the overall abundance of the species. This suggests a bottom-up control mechanism, in which the negative feedback dictates the dispersal kernel and the overall abundance.

  7. It's worse than you thought: the feedback negativity and violations of reward prediction in gambling tasks.

    PubMed

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

    2007-11-01

    The reinforcement learning theory suggests that the feedback negativity should be larger when feedback is unexpected. Two recent studies found, however, that the feedback negativity was unaffected by outcome probability. To further examine this issue, participants in the present studies made reward predictions on each trial of a gambling task where objective reward probability was indicated by a cue. In Study 1, participants made reward predictions following the cue, but prior to their gambling choice; in Study 2, predictions were made following their gambling choice. Predicted and unpredicted outcomes were associated with equivalent feedback negativities in Study 1. In Study 2, however, the feedback negativity was larger for unpredicted outcomes. These data suggest that the magnitude of the feedback negativity is sensitive to violations of reward prediction, but that this effect may depend on the close coupling of prediction and outcome.

  8. Negative feedback influences auditory recognition: behavioral and event-related potential evidence.

    PubMed

    Kuelzow, Nadine; Nessler, Doreen; Saenger, Jessica; Schneider, Till R; Debener, Stefan

    2010-08-01

    Stress induced by negative feedback is known to impair recognition memory, although little is known about its neural correlates. Immediately before an auditory recognition test, a negative- and positive-feedback group received different, faked scores about their performance in a Tower-of-Hanoi task. Negative feedback increased reaction times for correct rejections of new sounds. Although the positive-feedback group showed frontally and parietally more positive-going event-related potentials for correctly recognized old items than correct rejections (OLD/NEW effect) between 400 and 700 ms, suggesting the presence of familiarity and recollection-related recognition processes, the negative-feedback group showed late (>1100 ms) sustained right-frontal OLD/NEW effects possibly reflecting postmemory monitoring. Hence, negative feedback might change recognition memory by disabling recollection in favor of postmemory monitoring processes. PMID:20531235

  9. Brain Activation of Negative Feedback in Rule Acquisition Revealed in a Segmented Wisconsin Card Sorting Test

    PubMed Central

    Wang, Jing; Cao, Bihua; Cai, Xueli; Gao, Heming; Li, Fuhong

    2015-01-01

    The present study is to investigate the brain activation associated with the informative value of negative feedback in rule acquisition. In each trial of a segmented Wisconsin Card Sorting Test, participants were provided with three reference cards and one target card, and were asked to match one of three reference cards to the target card based on a classification rule. Participants received feedback after each match. Participants would acquire the rule after one negative feedback (1-NF condition) or two successive negative feedbacks (2-NF condition). The functional magnetic resonance imaging (fMRI) results indicated that lateral prefrontal-to-parietal cortices were more active in the 2-NF condition than in the 1-NF condition. The activation in the right lateral prefrontal cortex and left posterior parietal cortex increased gradually with the amount of negative feedback. These results demonstrate that the informative value of negative feedback in rule acquisition might be modulated by the lateral prefronto-parietal loop. PMID:26469519

  10. 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.

  11. Reciprocal, Longitudinal Associations among Adolescents' Negative Feedback-Seeking, Depressive Symptoms, and Peer Relations

    ERIC Educational Resources Information Center

    Borelli, Jessica L.; Prinstein, Mitchell J.

    2006-01-01

    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,…

  12. 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.

  13. 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. PMID:27378537

  14. 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.

  15. 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.

  16. Don't Count on It: Reasons to Doubt a Strong Negative Cloud Feedback

    NASA Astrophysics Data System (ADS)

    Zelinka, M. D.; Terai, C.; Zhou, C.; Klein, S. A.

    2015-12-01

    In CMIP3 and CMIP5 climate models, positive global mean cloud amount and altitude feedbacks are opposed by negative cloud optical depth feedbacks, resulting in a net positive cloud feedback in nearly every model. Is it possible that the relative strengths of these feedbacks are incorrect, such that the net cloud feedback is overestimated in models? In this study we quantify the individual components that govern the magnitude of the LW high cloud altitude feedback and the SW low cloud optical depth feedback. The feedbacks are shown to depend on both mean-state cloud properties and the response of cloud properties to warming. Comparing with observations and exploiting relationships between forced and unforced cloud changes, we demonstrate that models likely underestimate the positive LW high cloud altitude feedback and likely overestimate the magnitude of the negative SW low cloud optical depth feedback. We conclude that it is unlikely that the net cloud feedback is strongly negative. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. It is supported by the Regional and Global Climate Modeling Program of the Office of Science at the DOE. IM release #: LLNL-ABS-669552

  17. Loss feedback negativity elicited by single- versus conjoined-feature stimuli.

    PubMed

    Liu, Yanni; Gehring, William J

    2009-04-22

    Event-related brain potential studies show that negative feedback in guessing tasks elicits a medial frontal negativity. Most theory and experimentation concerning this feedback-related negativity (FRN) has assumed that the FRN has little relationship to the perceptual characteristics of the feedback. This study challenges this assumption. We used a single visual feature or a conjunction of features to indicate reward feedback in a gambling task. In the single-feature condition, losses elicited a larger FRN than gains; in the conjoined-feature condition, that difference was not observed. The results are consistent with the proposal that the FRN is modulated by the deviation of feedback stimuli from a perceptual template. Future studies must not confound the perceptual properties and the valence of reward feedback.

  18. Feedback Control of Two-Component Regulatory Systems.

    PubMed

    Groisman, Eduardo A

    2016-09-01

    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. PMID:27607549

  19. Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression.

    PubMed

    Decherf, Stéphanie; Seugnet, Isabelle; Kouidhi, Soumaya; Lopez-Juarez, Alejandra; Clerget-Froidevaux, Marie-Stéphanie; Demeneix, Barbara A

    2010-03-01

    The type 4 melanocortin receptor MC4R, a key relay in leptin signaling, links central energy control to peripheral reserve status. MC4R activation in different brain areas reduces food intake and increases energy expenditure. Mice lacking Mc4r are obese. Mc4r is expressed by hypothalamic paraventricular Thyrotropin-releasing hormone (TRH) neurons and increases energy usage through activation of Trh and production of the thyroid hormone tri-iodothyronine (T(3)). These facts led us to test the hypothesis that energy homeostasis should require negative feedback by T(3) on Mc4r expression. Quantitative PCR and in situ hybridization showed hyperthyroidism reduces Mc4r mRNA levels in the paraventricular nucleus. Comparative in silico analysis of Mc4r regulatory regions revealed two evolutionarily conserved potential negative thyroid hormone-response elements (nTREs). In vivo ChIP assays on mouse hypothalamus demonstrated association of thyroid hormone receptors (TRs) with a region spanning one nTRE. Further, in vivo gene reporter assays revealed dose-dependent T(3) repression of transcription from the Mc4r promoter in mouse hypothalamus, in parallel with T(3)-dependent Trh repression. Mutagenesis of the nTREs in the Mc4r promoter demonstrated direct regulation by T(3), consolidating the ChIP results. In vivo shRNA knockdown, TR over-expression approaches and use of mutant mice lacking specific TRs showed that both TRalpha and TRbeta contribute to Mc4r regulation. T(3) repression of Mc4r transcription ensures that the energy-saving effects of T(3) feedback on Trh are not overridden by MC4R activation of Trh. Thus parallel repression by T(3) on hypothalamic Mc4r and Trh contributes to energy homeostasis.

  20. Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression

    PubMed Central

    Decherf, Stéphanie; Seugnet, Isabelle; Kouidhi, Soumaya; Lopez-Juarez, Alejandra; Clerget-Froidevaux, Marie-Stéphanie; Demeneix, Barbara A.

    2010-01-01

    The type 4 melanocortin receptor MC4R, a key relay in leptin signaling, links central energy control to peripheral reserve status. MC4R activation in different brain areas reduces food intake and increases energy expenditure. Mice lacking Mc4r are obese. Mc4r is expressed by hypothalamic paraventricular Thyrotropin-releasing hormone (TRH) neurons and increases energy usage through activation of Trh and production of the thyroid hormone tri-iodothyronine (T3). These facts led us to test the hypothesis that energy homeostasis should require negative feedback by T3 on Mc4r expression. Quantitative PCR and in situ hybridization showed hyperthyroidism reduces Mc4r mRNA levels in the paraventricular nucleus. Comparative in silico analysis of Mc4r regulatory regions revealed two evolutionarily conserved potential negative thyroid hormone-response elements (nTREs). In vivo ChIP assays on mouse hypothalamus demonstrated association of thyroid hormone receptors (TRs) with a region spanning one nTRE. Further, in vivo gene reporter assays revealed dose-dependent T3 repression of transcription from the Mc4r promoter in mouse hypothalamus, in parallel with T3-dependent Trh repression. Mutagenesis of the nTREs in the Mc4r promoter demonstrated direct regulation by T3, consolidating the ChIP results. In vivo shRNA knockdown, TR over-expression approaches and use of mutant mice lacking specific TRs showed that both TRα and TRβ contribute to Mc4r regulation. T3 repression of Mc4r transcription ensures that the energy-saving effects of T3 feedback on Trh are not overridden by MC4R activation of Trh. Thus parallel repression by T3 on hypothalamic Mc4r and Trh contributes to energy homeostasis. PMID:20160073

  1. 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.

  2. Managing Written and Oral Negative Feedback in a Synchronous Online Teaching Situation

    ERIC Educational Resources Information Center

    Guichon, Nicolas; Betrancourt, Mireille; Prie, Yannick

    2012-01-01

    This case study focuses on the feedback that is provided by tutors to learners in the course of synchronous online teaching. More specifically, we study how trainee tutors used the affordances of Visu, an experimental web videoconferencing system, to provide negative feedback. Visu features classical functionalities such as video and chat, and it…

  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. 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. PMID:23111049

  5. 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.

  6. 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

  7. Prolonged negative feedback suppression after estradiol administration: proposed mechanism of eugonadal secondary amenorrhea.

    PubMed

    Santen, R J; Friend, J N; Trojanowski, D; Davis, B; Samojlik, E; Bardin, C W

    1978-12-01

    The finding of normal gonadotropin and estradiol levels in eugonadal women with secondary amenorrhea suggests a disordered feedback relationship of the hypothalamic-pituitary-ovarian axis. To identify possible defects in negative and positive feedback, we compared the effects of five daily injections of 17 beta-estradiol (E2) in 13 normal women and 11 eugonadal patients with absent cyclic menses. The suppression phase of negative feedback was normal, as LH and FSH were similarly lowered in both groups on day 3. Continued LH (P less than 0.01) and FSH (P less than 0.02) inhibition on day 10 of the protocol, 5 days after the last E2 injection, indicated a defect in the recovery phase of negative feedback in the 11 amenorrheic women. In the 4 patients studied gonadotropin suppression persisted for 3 weeks, E2 did not blunt pituitary responsiveness to GnRH in the amenorrheic women, suggesting a central nervous system site for prolonged gonadotropin inhibition. Nine normal but only 2 amenorrheic women X2 = 4.15; P less than 0.05) exhibited a positive feedback increase in LH on days 4-6. We propose that a defect in the recovery phase of negative feedback to E2 rather than absent positive feedback may be the dominant physiological abnormality which causes secondary amenorrhea by preventing early follicular phase gonadotropin increments and follicular maturation.

  8. Relatedness is a poor predictor of negative plant-soil feedbacks.

    PubMed

    Mehrabi, Zia; Tuck, Sean L

    2015-02-01

    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.

  9. 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.

  10. 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. PMID:24959862

  11. Negative feedback within a mutualism: host-specific growth of mycorrhizal fungi reduces plant benefit.

    PubMed Central

    Bever, James D

    2002-01-01

    A basic tenet of ecology is that negative feedback on abundance plays an important part in the coexistence of species within guilds. Mutualistic interactions generate positive feedbacks on abundance and therefore are not thought to contribute to the maintenance of diversity. Here, I report evidence of negative feedback on plant growth through changes in the composition of their mutualistic fungal symbionts, arbuscular mycorrhizal (AM) fungi. Negative feedback results from asymmetries in the delivery of benefit between plant and AM fungal species in which the AM fungus that grows best with the plant Plantago lanceolata is a poor growth promoter for Plantago. Growth of Plantago is, instead, best promoted by the AM fungal species that accumulate with a second plant species, Panicum sphaerocarpon. The resulting community dynamic leads to a decline in mutualistic benefit received by Plantago, and can contribute to the coexistence of these two competing plant species. PMID:12573075

  12. 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.

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

    PubMed Central

    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

  14. Responses to formal performance appraisal feedback: the role of negative affectivity.

    PubMed

    Lam, Simon S K; Yik, Michelle S M; Schaubroeck, John

    2002-02-01

    This study examined the effects of performance appraisal feedback on job and organizational attitudes of tellers (N = 329) in a large international bank. Negative affectivity moderated the link between favorable appraisal feedback and job attitudes. Among the higher rated performers, attitudes were improved 1 month after being notified of favorable appraisal results (Time 2). Improved attitudes persisted 6 months after the performance appraisal (Time 3) among tellers with low negative affectivity but not among those with high negative affectivity. Among the lower rated performers, mean levels of attitudes did not change significantly during the study. PMID:11924542

  15. 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

  16. Negative feedback enables fast and flexible collective decision-making in ants.

    PubMed

    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.

  17. Negative feedback enables fast and flexible collective decision-making in ants.

    PubMed

    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

  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. low) x…

  19. 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

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

    PubMed

    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

  1. Nonclassical estrogen receptor alpha signaling mediates negative feedback in the female mouse reproductive axis.

    PubMed

    Glidewell-Kenney, C; Hurley, L A; Pfaff, L; Weiss, J; Levine, J E; Jameson, J L

    2007-05-01

    Ovarian estrogen exerts both positive and negative feedback control over luteinizing hormone (LH) secretion during the ovulatory cycle. Estrogen receptor (ER) alpha but not ERbeta knockout mice lack estrogen feedback. Thus, estrogen feedback appears to be primarily mediated by ERalpha. However, it is now recognized that, in addition to binding to estrogen response elements (EREs) in DNA to alter target gene transcription, ERalpha signals through ERE-independent or nonclassical pathways, and the relative contributions of these pathways in conveying estrogen feedback remain unknown. Previously we created a knockin mouse model expressing a mutant form of ERalpha (AA) with ablated ERE-dependent but intact ERE-independent activity. Breeding this allele onto the ERalpha-null (-/-) background, we examine the ability of ERE-independent ERalpha signaling pathways to convey estrogen feedback regulation of the female hypothalamic-pituitary axis in vivo. ERalpha-/AA exhibited 69.9% lower serum LH levels compared with ERalpha-/- mice. Additionally, like wild type, ERalpha-/AA mice exhibited elevated LH after ovariectomy (OVX). Furthermore, the post-OVX rise in serum LH was significantly suppressed by estrogen treatment in OVX ERalpha-/AA mice. However, unlike wild type, both ERalpha-/AA and ERalpha-/- mice failed to exhibit estrous cyclicity, spontaneous ovulation, or an afternoon LH surge response to estrogen. These results indicate that ERE-independent ERalpha signaling is sufficient to convey a major portion of estrogen's negative feedback actions, whereas positive feedback and spontaneous ovulatory cyclicity require ERE-dependent ERalpha signaling.

  2. MK3 controls Polycomb target gene expression via negative feedback on ERK

    PubMed Central

    2012-01-01

    Background Gene-environment interactions are mediated by epigenetic mechanisms. Polycomb Group proteins constitute part of an epigenetic cellular transcriptional memory system that is subject to dynamic modulation during differentiation. Molecular insight in processes that control dynamic chromatin association and dissociation of Polycomb repressive complexes during and beyond development is limited. We recently showed that MK3 interacts with Polycomb repressive complex 1 (PRC1). The functional relevance of this interaction, however, remained poorly understood. MK3 is activated downstream of mitogen- and stress-activated protein kinases (M/SAPKs), all of which fulfill crucial roles during development. We here use activation of the immediate-early response gene ATF3, a bona fide PRC1 target gene, as a model to study how MK3 and its effector kinases MAPK/ERK and SAPK/P38 are involved in regulation of PRC1-dependent ATF3 transcription. Results Our current data show that mitogenic signaling through ERK, P38 and MK3 regulates ATF3 expression by PRC1/chromatin dissociation and epigenetic modulation. Mitogenic stimulation results in transient P38-dependent H3S28 phosphorylation and ERK-driven PRC1/chromatin dissociation at PRC1 targets. H3S28 phosphorylation by itself appears not sufficient to induce PRC1/chromatin dissociation, nor ATF3 transcription, as inhibition of MEK/ERK signaling blocks BMI1/chromatin dissociation and ATF3 expression, despite induced H3S28 phosphorylation. In addition, we establish that concomitant loss of local H3K27me3 promoter marking is not required for ATF3 activation. We identify pERK as a novel signaling-induced binding partner of PRC1, and provide evidence that MK3 controls ATF3 expression in cultured cells via negative regulatory feedback on M/SAPKs. Dramatically increased ectopic wing vein formation in the absence of Drosophila MK in a Drosophila ERK gain-of-function wing vein patterning model, supports the existence of MK

  3. 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

  4. 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.

  5. Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation.

    PubMed

    Akiyama, Nobuko; Shinzawa, Miho; Miyauchi, Maki; Yanai, Hiromi; Tateishi, Ryosuke; Shimo, Yusuke; Ohshima, Daisuke; Matsuo, Koichi; Sasaki, Izumi; Hoshino, Katsuaki; Wu, Guoying; Yagi, Shintaro; Inoue, Jun-ichiro; Kaisho, Tsuneyasu; Akiyama, Taishin

    2014-11-17

    Medullary thymic epithelial cells (mTECs) expressing the autoimmune regulator AIRE and various tissue-specific antigens (TSAs) are critical for preventing the onset of autoimmunity and may attenuate tumor immunity. However, molecular mechanisms controlling mTEC development remain elusive. Here, we describe the roles of the transcription factor Spi-B in mTEC development. Spi-B is rapidly up-regulated by receptor activator of NF-κB ligand (RANKL) cytokine signaling, which triggers mTEC differentiation, and in turn up-regulates CD80, CD86, some TSAs, and the natural inhibitor of RANKL signaling, osteoprotegerin (OPG). Spi-B-mediated OPG expression limits mTEC development in neonates but not in embryos, suggesting developmental stage-specific negative feedback regulation. OPG-mediated negative regulation attenuates cellularity of thymic regulatory T cells and tumor development in vivo. Hence, these data suggest that this negative RANKL-Spi-B-OPG feedback mechanism finely tunes mTEC development and function and may optimize the trade-off between prevention of autoimmunity and induction of antitumor immunity.

  6. Limitation of immune tolerance–inducing thymic epithelial cell development by Spi-B–mediated negative feedback regulation

    PubMed Central

    Akiyama, Nobuko; Shinzawa, Miho; Miyauchi, Maki; Yanai, Hiromi; Tateishi, Ryosuke; Shimo, Yusuke; Ohshima, Daisuke; Matsuo, Koichi; Sasaki, Izumi; Hoshino, Katsuaki; Wu, Guoying; Yagi, Shintaro; Inoue, Jun-ichiro

    2014-01-01

    Medullary thymic epithelial cells (mTECs) expressing the autoimmune regulator AIRE and various tissue-specific antigens (TSAs) are critical for preventing the onset of autoimmunity and may attenuate tumor immunity. However, molecular mechanisms controlling mTEC development remain elusive. Here, we describe the roles of the transcription factor Spi-B in mTEC development. Spi-B is rapidly up-regulated by receptor activator of NF-κB ligand (RANKL) cytokine signaling, which triggers mTEC differentiation, and in turn up-regulates CD80, CD86, some TSAs, and the natural inhibitor of RANKL signaling, osteoprotegerin (OPG). Spi-B–mediated OPG expression limits mTEC development in neonates but not in embryos, suggesting developmental stage–specific negative feedback regulation. OPG-mediated negative regulation attenuates cellularity of thymic regulatory T cells and tumor development in vivo. Hence, these data suggest that this negative RANKL–Spi-B–OPG feedback mechanism finely tunes mTEC development and function and may optimize the trade-off between prevention of autoimmunity and induction of antitumor immunity. PMID:25385757

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

    PubMed

    Czaczkes, Tomer J

    2014-11-01

    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.

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

    PubMed

    Czaczkes, Tomer J

    2014-11-01

    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. PMID:25034339

  9. 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.

  10. 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.

  11. Nonlinear dynamics in semiconductor ring lasers with negative optoelectronic and incoherent optical feedback

    NASA Astrophysics Data System (ADS)

    Kingni, S. T.; Van der Sande, G.; Ermakov, Ilya V.; Danckaert, J.

    2014-05-01

    In this work, we study theoretically the dynamical behavior of two semiconductor ring lasers (SRLs). One is subject to negative optoelectronic feedback and the other laser is subject to incoherent optical feedback. Relying on asymptotic methods, we are able to reduce the original set of five equations used to describe the dynamical behavior of SRLs with negative optoelectronic feedback (SRL-NOEF) or incoherent optical feedback (SRL-IOF) to two equations and one map with time delay valid on time-scales longer than the relaxation oscillations (ROs). The equations of the reduced models turn out to be the same for both systems. As we vary the feedback strength, the devices under consideration in this work display both continuous wave operation and a period-doubling route to chaos. The two counter-propagating intensities of both systems exhibit in-phase chaotic behavior for small delay times comparable to the period of relaxation oscillations. For delay times significantly longer than the period of ROs, the two counter-propagating modes show in anti-phase chaotic oscillations. Moreover, for long delay times, we find that the counter-propagating intensities of both systems depict the same dynamical behaviors when their feedback strengths are increased.

  12. 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. PMID:26994223

  13. 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.

  14. 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

  15. 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.

  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. 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…

  18. 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. PMID:22787019

  19. 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…

  20. 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.…

  1. 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.

  2. 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…

  3. Feedback-Related Negativity in Children with Two Subtypes of Attention Deficit Hyperactivity Disorder

    PubMed Central

    Gong, Jingbo; Yuan, Jiajin; Wang, Suhong; Shi, Lijuan; Cui, Xilong; Luo, Xuerong

    2014-01-01

    Objective The current model of ADHD suggests abnormal reward and punishment sensitivity, although differences in ADHD subgroups are unclear. This study aimed to investigate the effect of feedback valence (reward or punishment) and punishment magnitude (small or large) on Feedback-Related Negativity (FRN) and Late Positive Potential (LPP) in two subtypes of ADHD (ADHD-C and ADHD-I) compared to typically developing children (TD) during a children's gambling task. Methods Children with ADHD-C (n = 16), children with ADHD-I (n = 15) and typically developing children (n = 15) performed a children's gambling task under three feedback conditions: large losses, small losses and gains. FRN and LPP components in brain potentials were recorded and analyzed. Results In TD children and children with ADHD-C, large loss feedback evoked more negative FRN amplitudes than small loss feedback, suggesting that brain sensitivity to the punishment and its magnitude is not impaired in children with ADHD-C. In contrast to these two groups, the FRN effect was absent in children with ADHD-I. The LPP amplitudes were larger in children with ADHD-C in comparison with those with ADHD-I, regardless of feedback valence and magnitude. Conclusion Children with ADHD-C exhibit intact brain sensitivity to punishment similar to TD children. In contrast, children with ADHD-I are significantly impaired in neural sensitivity to the feedback stimuli and in particular, to punishment, compared to TD and ADHD-C children. Thus, FRN, rather than LPP, is a reliable index of the difference in reward and punishment sensitivity across different ADHD-subcategories. PMID:24932610

  4. Show me the Money: the impact of actual rewards and losses on the feedback negativity.

    PubMed

    Weinberg, Anna; Riesel, Anja; Proudfit, Greg Hajcak

    2014-06-01

    The feedback negativity (FN) is an event-related potential component which is typically conceptualized as a negativity in response to losses that is absent in response to gains. However, there is also evidence that variation in the FN reflects the neural response to gains. The present study sought to explore these possibilities by manipulating the context in which loss and gain feedback was presented in a straightforward gambling task. In half the blocks, participants could win or lose money (Value condition), and in half the blocks, participants could not win or lose any money (No Value condition). The degree to which losses and gains were differentiated from one another (i.e., the ΔFN) was greater in the Value condition than in the No Value condition. Furthermore, though the responses to loss feedback and gain feedback were each enhanced in the Value condition relative to the No-Value condition, the effect of the monetary manipulation was substantially larger for the positivity to gains than the negativity to losses. This is consistent with the notion that the FN might reflect two independent processes, but that variation in the FN depends more upon the response to rewards than losses.

  5. Show me the Money: the impact of actual rewards and losses on the feedback negativity.

    PubMed

    Weinberg, Anna; Riesel, Anja; Proudfit, Greg Hajcak

    2014-06-01

    The feedback negativity (FN) is an event-related potential component which is typically conceptualized as a negativity in response to losses that is absent in response to gains. However, there is also evidence that variation in the FN reflects the neural response to gains. The present study sought to explore these possibilities by manipulating the context in which loss and gain feedback was presented in a straightforward gambling task. In half the blocks, participants could win or lose money (Value condition), and in half the blocks, participants could not win or lose any money (No Value condition). The degree to which losses and gains were differentiated from one another (i.e., the ΔFN) was greater in the Value condition than in the No Value condition. Furthermore, though the responses to loss feedback and gain feedback were each enhanced in the Value condition relative to the No-Value condition, the effect of the monetary manipulation was substantially larger for the positivity to gains than the negativity to losses. This is consistent with the notion that the FN might reflect two independent processes, but that variation in the FN depends more upon the response to rewards than losses. PMID:24735733

  6. Modelling and analysis of gene regulatory network using feedback control theory

    NASA Astrophysics Data System (ADS)

    El-Samad, H.; Khammash, M.

    2010-01-01

    Molecular pathways are a part of a remarkable hierarchy of regulatory networks that operate at all levels of organisation. These regulatory networks are responsible for much of the biological complexity within the cell. The dynamic character of these pathways and the prevalence of feedback regulation strategies in their operation make them amenable to systematic mathematical analysis using the same tools that have been used with success in analysing and designing engineering control systems. In this article, we aim at establishing this strong connection through various examples where the behaviour exhibited by gene networks is explained in terms of their underlying control strategies. We complement our analysis by a survey of mathematical techniques commonly used to model gene regulatory networks and analyse their dynamic behaviour.

  7. The feedback related negativity encodes both social rejection and explicit social expectancy violation

    PubMed Central

    Sun, Sai; Yu, Rongjun

    2014-01-01

    Humans consistently make predictions about the valence of future events and use feedback to validate initial predictions. While the valence of outcomes provides utilitarian information, the accuracy of predictions is crucial for future performance adjustment. The feedback related negativity (FRN), identified as a marker of reward prediction error, possibly encodes social rejection and social prediction error. To test this possibility, we used event related potential (ERP) techniques combined with social tasks in which participants were required to make explicit predictions (whether others will accept their “friend request” or not, Experiment 1) or implicit predictions (whether they would like this person or not, Experiment 2) respectively, and then received social feedback. We found that the FRN is sensitive to social rejection and explicit social prediction error in Experiment 1 but not implicit social prediction error in Experiment 2. We conclude that the FRN encodes social rejection and explicit social expectancy violation. PMID:25120457

  8. 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

  9. 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. PMID:26093064

  10. Plant-soil feedbacks shift from negative to positive with decreasing light in forest understory species.

    PubMed

    Smith, Lauren M; Reynolds, Heather L

    2015-09-01

    Net pairwise plant-soil feedbacks (PSF) may be an important factor structuring plant communities, yet the influence of abiotic context on PSF is not yet understood. Abiotic factors such as light availability can alter plant-soil interactions, potentially resulting in strong context dependence of PSF. Here, we present an experiment in which we measured whole-soil net pairwise feedbacks amongst six common forest understory species across a gradient of light availability. Light treatments were imposed throughout both phases (the conditioning phase and the response phase) of the feedback experiment. Across the plant community, PSF shifted from negative at high light availability to weakly positive under low light (P = 0.0 13). Differences in the biomass of plants during the conditioning phase did not fully explain light-imposed differences in feedbacks, indicating that reduced light availability qualitatively changes the nature of PSF rather than simply weakening feedbacks by reducing plant growth. Results indicate that abiotic context can fundamentally alter the role of PSF in structuring plant communities.

  11. 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.

  12. Spatio-temporal dynamcis of a cell signal cascade with negative feedback

    NASA Astrophysics Data System (ADS)

    Maya Bernal, Jose Luis; Ramirez-Santiago, Guillermo

    2014-03-01

    We studied the spatio-temporal dynamics of a system of reactio-diffusion equations that models a cell signal transduction pathway with six cycles and negative feedback. The basic cycle consists of the phosphorylation-dephosphorylation of two antagonic proteins. We found two regimes of saturation of the enzimatic reaction in the kinetic parameters space and determined the conditions for the signal propagation in the steady state. The trajectories for which transduction occurs are defined in terms of the ratio of the enzimatic activities. We found that in spite of the negative feedback the cell signal cascade behaves as an amplifier and produces phosphoprotein concentration gradients within the cell. This model behaves also as a noise filter and as a switch. Supported by DGAPA-UNAM Contract IN118410-3.

  13. Exposure to an Inflammatory Challenge Enhances Neural Sensitivity to Negative and Positive Social Feedback

    PubMed Central

    Muscatell, Keely A.; Moieni, Mona; Inagaki, Tristen K.; Dutcher, Janine M.; Jevtic, Ivana; Breen, Elizabeth C.; Irwin, Michael R.; Eisenberger, Naomi I.

    2016-01-01

    Inflammation, part of the body’s innate immune response, can lead to “sickness behaviors,” as well as alterations in social and affective experiences. Elevated levels of pro-inflammatory cytokines have been associated with increased neural sensitivity to social rejection and social threat, but also decreased neural sensitivity to rewards. However, recent evidence suggests that inflammation may actually enhance sensitivity to certain social rewards, such as those that signal support and care. Despite a growing interest in how inflammation influences neural reactivity to positive and negative social experiences, no known studies have investigated these processes in the same participants, using a similar task. To examine this issue, 107 participants were randomly assigned to receive either placebo or low-dose endotoxin, which safely triggers an inflammatory response. When levels of pro-inflammatory cytokines were at their peak, participants were scanned using fMRI while they received positive, negative, and neutral feedback from an “evaluator” (actually a confederate) about how they came across in an audio-recorded interview. In response to negative feedback (vs. neutral), participants in the endotoxin condition showed heightened neural activity in a number of threat-related neural regions (i.e., bilateral amygdala, dorsal anterior cingulate cortex) and a key mentalizing-related region (i.e., dorsomedial PFC), compared to placebo participants. Interestingly, when receiving positive feedback (vs. neutral), endotoxin led to greater neural activity in the ventral striatum and ventromedial PFC, regions often implicated in processing reward, compared to placebo. Together, these results reveal that individuals exposed to an inflammatory challenge are more “neurally sensitive” to both negative and positive social feedback, suggesting that inflammation may lead to a greater vigilance for both social threats and social rewards. PMID:27032568

  14. Exposure to an inflammatory challenge enhances neural sensitivity to negative and positive social feedback.

    PubMed

    Muscatell, Keely A; Moieni, Mona; Inagaki, Tristen K; Dutcher, Janine M; Jevtic, Ivana; Breen, Elizabeth C; Irwin, Michael R; Eisenberger, Naomi I

    2016-10-01

    Inflammation, part of the body's innate immune response, can lead to "sickness behaviors," as well as alterations in social and affective experiences. Elevated levels of pro-inflammatory cytokines have been associated with increased neural sensitivity to social rejection and social threat, but also decreased neural sensitivity to rewards. However, recent evidence suggests that inflammation may actually enhance sensitivity to certain social rewards, such as those that signal support and care. Despite a growing interest in how inflammation influences neural reactivity to positive and negative social experiences, no known studies have investigated these processes in the same participants, using a similar task. To examine this issue, 107 participants were randomly assigned to receive either placebo or low-dose endotoxin, which safely triggers an inflammatory response. When levels of pro-inflammatory cytokines were at their peak, participants were scanned using fMRI while they received positive, negative, and neutral feedback from an "evaluator" (actually a confederate) about how they came across in an audio-recorded interview. In response to negative feedback (vs. neutral), participants in the endotoxin condition showed heightened neural activity in a number of threat-related neural regions (i.e., bilateral amygdala, dorsal anterior cingulate cortex) and a key mentalizing-related region (i.e., dorsomedial PFC), compared to placebo participants. Interestingly, when receiving positive feedback (vs. neutral), endotoxin (vs. placebo) led to greater neural activity in the ventral striatum and ventromedial PFC, regions often implicated in processing reward, as well as greater activity in dorsomedial PFC. Together, these results reveal that individuals exposed to an inflammatory challenge are more "neurally sensitive" to both negative and positive social feedback, suggesting that inflammation may lead to a greater vigilance for both social threats and social rewards.

  15. Protein kinase A and casein kinases mediate sequential phosphorylation events in the circadian negative feedback loop.

    PubMed

    Huang, Guocun; Chen, She; Li, Shaojie; Cha, Joonseok; Long, Chengzu; Li, Lily; He, Qiyang; Liu, Yi

    2007-12-15

    Regulation of circadian clock components by phosphorylation plays essential roles in clock functions and is conserved from fungi to mammals. In the Neurospora circadian negative feedback loop, FREQUENCY (FRQ) protein inhibits WHITE COLLAR (WC) complex activity by recruiting the casein kinases CKI and CKII to phosphorylate the WC proteins, resulting in the repression of frq transcription. On the other hand, CKI and CKII progressively phosphorylate FRQ to promote FRQ degradation, a process that is a major determinant of circadian period length. Here, by using whole-cell isotope labeling and quantitative mass spectrometry methods, we show that the WC-1 phosphorylation events critical for the negative feedback process occur sequentially-first by a priming kinase, then by the FRQ-recruited casein kinases. We further show that the cyclic AMP-dependent protein kinase A (PKA) is essential for clock function and inhibits WC activity by serving as a priming kinase for the casein kinases. In addition, PKA also regulates FRQ phosphorylation, but unlike CKI and CKII, PKA stabilizes FRQ, similar to the stabilization of human PERIOD2 (hPER2) due to the phosphorylation at the familial advanced sleep phase syndrome (FASPS) site. Thus, PKA is a key clock component that regulates several critical processes in the circadian negative feedback loop. PMID:18079175

  16. Risky decision making from childhood through adulthood: Contributions of learning and sensitivity to negative feedback.

    PubMed

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

    2016-02-01

    Decision making in the context of risk is a complex and dynamic process that changes across development. Here, we assessed the influence of sensitivity to negative feedback (e.g., loss) and learning on age-related changes in risky decision making, both of which show unique developmental trajectories. In the present study, we 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 to earn points, but risk balloon explosion on each trial, which results in no points. It is important to note that there were 3 balloon conditions, signified by different balloon colors, ranging from quick- to slow-to-explode, and participants could learn the color-condition pairings through 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 nonlinear changes in risky decision making, the adolescent-specific nature of which is associated with developmental improvements in learning and reduced sensitivity to negative feedback. PMID:26389647

  17. The role of time delay in adaptive cellular negative feedback systems.

    PubMed

    Lapytsko, Anastasiya; Schaber, Jörg

    2016-06-01

    Adaptation in cellular systems is often mediated by negative feedbacks, which usually come with certain time delays causing several characteristic response patterns including an overdamped response, damped or sustained oscillations. Here, we analyse generic two-dimensional delay differential equations with delayed negative feedback describing the dynamics of biochemical adaptive signal-response networks. We derive explicit thresholds and boundaries showing how time delay determines characteristic response patterns of these networks. Applying our theoretical analyses to concrete data we show that adaptation to osmotic stress in yeast is optimal in the sense of minimizing adaptation time without causing oscillatory behaviour, i.e., a critically damped response. In addition, our framework demonstrates that a slight increase of time delay in the NF-κB system might induce a switch from damped to sustained oscillatory behaviour. Thus, we demonstrate how delay differential equations can be used to explicitly study the delay in biochemical negative feedback systems. Our analysis also provides insight into how time delay may tune biological signal-response patterns and control the systems behaviour.

  18. 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

  19. Blowin' in the Wind: Both "Negative" and "Positive" Feedback in an Obscured High-z Quasar

    NASA Astrophysics Data System (ADS)

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

    2015-01-01

    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-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.

  20. 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.

  1. Shortwave infrared negative feedback avalanche diodes and solid-state photomultipliers

    NASA Astrophysics Data System (ADS)

    Jiang, Xudong; Itzler, Mark A.; O'Donnell, Kevin; Entwistle, Mark; Slomkowski, Krystyna

    2014-08-01

    In recent years, significant progress has been made in InP-based Geiger-mode single photon avalanche diodes (SPADs), and a variety of circuits for enabling Geiger-mode operation have been proposed and demonstrated. However, due to the inherent positive feedback of the impact ionization avalanche process, Geiger-mode SPADs are constrained by certain performance limitations, particularly with regard to counting rate and the inability to resolve photon number. To overcome some of the performance limitations of regular SPADs, we have developed negative feedback avalanche diodes (NFADs) that employ a negative feedback mechanism to regulate the avalanche process. The NFAD fabrication process is based on the design platform we use to achieve state-of-the-art performance SPADs and is very flexible. The operation of NFAD devices is also very simple, with only a direct current (DC) bias being required. Various discrete devices and matrices composed of different elements have been designed, fabricated, and characterized. For discrete devices, ˜10% photon detection efficiency has been realized consistent with acceptable afterpulsing probability. The negative feedback mechanism significantly improves the uniformity of the output pulse heights and avalanche charge per detection event, resulting in a low "charge excess noise" factor. When configured in a matrix format, the NFAD devices were demonstrated to have the ability to resolve photon number and work effectively as solid-state photomultipliers (SSPMs) in the shortwave infrared (SWIR) region. The InGaAs/InP NFAD SSPMs have the potential to replace photomultiplier tubes and provide a solid-state solution in applications where the requirement for single-photon sensitivity in the SWIR region beyond ˜0.9 μm cannot be met by silicon photomultipliers. The NFAD devices have been used in various quantum optics and quantum key distribution applications and demonstrated an excellent performance.

  2. 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

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

    PubMed

    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

    2015-07-21

    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.

  4. 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

  5. A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus

    PubMed Central

    Menon, Madhvi; Blair, Paul A.; Isenberg, David A.; Mauri, Claudia

    2016-01-01

    Summary Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an “auto”-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24+CD38hi Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24+CD38hi Breg cells conversely restrained IFN-α production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α. Defective pDC-mediated expansion of CD24+CD38hi Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24+CD38hi Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24+CD38hi Breg cell interaction contributes to the pathogenesis of SLE. PMID:26968426

  6. 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.

  7. 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. PMID:25699420

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

    PubMed

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

    2013-04-01

    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

  9. An Epigenetic Feedback Regulatory Loop Involving MicroRNA-195 and MBD1 Governs Neural Stem Cell Differentiation

    PubMed Central

    Liu, Changmei; Teng, Zhao-Qian; McQuate, Andrea L.; Jobe, Emily M.; Christ, Christa C.; von Hoyningen-Huene, Sergei J.; Reyes, Marie D.; Polich, Eric D.; Xing, Yina; Li, Yue; Guo, Weixiang; Zhao, Xinyu

    2013-01-01

    Background Epigenetic mechanisms, including DNA methylation, histone modification, and microRNAs, play pivotal roles in stem cell biology. Methyl-CpG binding protein 1 (MBD1), an important epigenetic regulator of adult neurogenesis, controls the proliferation and differentiation of adult neural stem/progenitor cells (aNSCs). We recently demonstrated that MBD1 deficiency in aNSCs leads to altered expression of several noncoding microRNAs (miRNAs). Methodology/Principal Findings Here we show that one of these miRNAs, miR-195, and MBD1 form a negative feedback loop. While MBD1 directly represses the expression of miR-195 in aNSCs, high levels of miR-195 in turn repress the expression of MBD1. Both gain-of-function and loss-of-function investigations show that alterations of the MBD1–miR-195 feedback loop tip the balance between aNSC proliferation and differentiation. Conclusions/Significance Therefore the regulatory loop formed by MBD1 and miR-195 is an important component of the epigenetic network that controls aNSC fate. PMID:23349673

  10. 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. PMID:22208135

  11. 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.

  12. 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.

  13. The feedback negativity reflects favorable compared to nonfavorable outcomes based on global, not local, alternatives.

    PubMed

    Kujawa, Autumn; Smith, Ezra; Luhmann, Christian; Hajcak, Greg

    2013-02-01

    The feedback negativity (FN) has been shown to reflect the binary evaluation of possible outcomes in a context-dependent manner, but it is unclear whether context dependence is based on global or local alternatives. A cued gambling task was used to examine whether the FN is sensitive to possible outcomes on a given trial, or the range of outcomes across trials. On 50% of trials, participants could break even or lose money; on remaining trials, participants could win or break even. Breaking even was an unfavorable outcome relative to all possibilities in the current task, but the best possible outcome on 50% of trials. Results indicated that breaking even elicited an FN in both contexts, and reward feedback was uniquely associated with an enhanced positivity. Results suggest that the magnitude of the FN depends on all possible outcomes within the current task and are consistent with the view that the FN reflects reward-related neural activity. PMID:23241216

  14. 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. PMID:25665164

  15. A Novel TGFβ Modulator that Uncouples R-Smad/I-Smad-Mediated Negative Feedback from R-Smad/Ligand-Driven Positive Feedback

    PubMed Central

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

    2015-01-01

    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. PMID:25665164

  16. Soil moisture-precipitation feedback: reconciling negative spatial coupling with a positive temporal feedback via moisture recycling

    NASA Astrophysics Data System (ADS)

    Guillod, Benoît; Orlowsky, Boris; Miralles, Diego G.; Teuling, Adriaan J.; Seneviratne, Sonia I.

    2015-04-01

    Soil moisture-precipitation coupling, i.e., the impact of soil moisture on precipitation, conveys some of the largest uncertainties in land-atmosphere interactions. In addition to a direct positive effect via moisture recycling, a number of indirect effects have been identified, where surface turbulent fluxes impact temperature and humidity in the boundary layer, its growth and thereby indirectly many variables that can support or inhibit convection triggering, such as atmospheric stability, entrainment, or mesoscale circulations. Due to the complexity of the involved interactions, the sign and strength of this feedback remains heavily debated in the literature, despite important advances in recent years. Traditional "temporal" perspectives often highlight positive relationships, i.e. rain falling more often over wet soils [e.g., 1], albeit with difficulties in attributing these relationships to a coupling due to atmospheric persistence [e.g., 2]. On the other hand, recent studies focusing on the impacts of spatial differences in soil moisture have highlighted that rain falls preferentially over soils that are drier than their surrounding [3]. This is likely due to negative indirect effects, such as mesoscale circulations that are induced by the underlying spatial soil moisture patterns [4]. These results from "temporal" and "spatial" perspectives may first appear contradictory and dependent on the underlying datasets. However, they could also refer to different processes that determine when and where it rains. In other words, the presence of negative spatial coupling may not necessarily be incompatible with the concept of positive temporal coupling. Using global satellite-based data, we compare spatial and temporal perspectives using metrics that relate precipitation events to prior spatial and temporal soil moisture patterns. We find that relationships between soil moisture and subsequent precipitation can be spatially negative while temporally positive, with

  17. [Phenotypic switching of Escherichia coli cells containing cyclic digenic systems with negative feedback upon changes in cultivation conditions].

    PubMed

    Stupak, E E; Stupak, I V

    2010-05-01

    One of the mechanisms for the epigenetic control of cell phenotypes is based on switching the functioning regimes of bistable gene networks, which can maintain the two alternative levels of gene expression under the same conditions. Cyclic digenic systems with negative feedback represent an example of a simple bistable gene network. Cells carrying artificial cyclic digenic systems on plasmids inherit each alternative phenotype upon exponential growth on rich medium during several cell generations. The action of specific inducers is necessary for switching. In this work, the impact of changes in cell cultivation conditions on the phenotypic composition of the clonal Escherichia coli cell population containing artificial cyclic digenic systems with negative feedback was studied. Phenotypes differ with respect to the expression level of marker proteins: beta-galactosidase and GFP. Slow growth on a medium containing little-available carbon sources was shown to cause the transition from the phenotype Lac- to Lac+ in the absence of inducers. Phenotypic switching cannot be explained by transcriptional activation of the lactose operon, because 80 +/- 15% of cells inherit the acquired phenotype after replating bacteria on rich medium. Inheritance of the phenotype Lac- in batch culture depends on the medium and duration of cultivation. Dynamics of changes in the activity of beta-galactosidase and culture fluorescence suggests that a decrease in the level of metabolism resulted in the switch of these cyclic systems from bistable to monostable functioning regime, which corresponds to the Lac+ phenotype with respect to the ratio of regulatory proteins. Thus, the instability of growth conditions may cause phenotypic heterogeneity in the clonal population of cells containing bistable gene networks. PMID:20583595

  18. 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

  19. Negative Feedback of Glycolysis and Oxidative Phosphorylation: Mechanisms of and Reasons for It.

    PubMed

    Sokolov, S S; Balakireva, A V; Markova, O V; Severin, F F

    2015-05-01

    There are two main pathways of ATP biosynthesis: glycolysis and oxidative phosphorylation. As a rule, the two pathways are not fully active in a single cell. In this review, we discuss mechanisms of glycolytic inhibition of respiration (Warburg and Crabtree effects). What are the reasons for the existence of this negative feedback? It is known that maximal activation of both processes can cause generation of reactive oxygen species. Oxidative phosphorylation is more efficient from the energy point of view, while glycolysis is safer and favors biomass synthesis. This might be the reason why quiescent cells are mainly using oxidative phosphorylation, while the quickly proliferating ones - glycolysis. PMID:26071773

  20. Negative Feedback of Glycolysis and Oxidative Phosphorylation: Mechanisms of and Reasons for It.

    PubMed

    Sokolov, S S; Balakireva, A V; Markova, O V; Severin, F F

    2015-05-01

    There are two main pathways of ATP biosynthesis: glycolysis and oxidative phosphorylation. As a rule, the two pathways are not fully active in a single cell. In this review, we discuss mechanisms of glycolytic inhibition of respiration (Warburg and Crabtree effects). What are the reasons for the existence of this negative feedback? It is known that maximal activation of both processes can cause generation of reactive oxygen species. Oxidative phosphorylation is more efficient from the energy point of view, while glycolysis is safer and favors biomass synthesis. This might be the reason why quiescent cells are mainly using oxidative phosphorylation, while the quickly proliferating ones - glycolysis.

  1. A negative feedback mechanism for the long-term stabilization of the earth's surface temperature

    NASA Technical Reports Server (NTRS)

    Walker, J. C. G.; Hays, P. B.; Kasting, J. F.

    1981-01-01

    It is suggested that the partial pressure of carbon dioxide in the atmosphere is buffered, over geological time scales, by a negative feedback mechanism, in which the rate of weathering of silicate minerals (followed by deposition of carbonate minerals) depends on surface temperature, which in turn depends on the carbon dioxide partial pressure through the greenhouse effect. Although the quantitative details of this mechanism are speculative, it appears able to partially stabilize the earth's surface temperature against the steady increase of solar luminosity, believed to have occurred since the origin of the solar system.

  2. Working memory capacity and spontaneous emotion regulation: high capacity predicts self-enhancement in response to negative feedback.

    PubMed

    Schmeichel, Brandon J; Demaree, Heath A

    2010-10-01

    Although previous evidence suggests that working memory capacity (WMC) is important for success at emotion regulation, that evidence may reveal simply that people with higher WMC follow instructions better than those with lower WMC. The present study tested the hypothesis that people with higher WMC more effectively engage in spontaneous emotion regulation following negative feedback, relative to those with lower WMC. Participants were randomly assigned to receive either no feedback or negative feedback about their emotional intelligence. They then completed a disguised measure of self-enhancement and a self-report measure of affect. Experimental condition and WMC interacted such that higher WMC predicted more self-enhancement and less negative affect following negative feedback. This research provides novel insight into the consequences of individual differences in WMC and illustrates that cognitive capacity may facilitate the spontaneous self-regulation of emotion. PMID:21038959

  3. 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

  4. 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.

  5. The feedback-related negativity signals salience prediction errors, not reward prediction errors.

    PubMed

    Talmi, Deborah; Atkinson, Ryan; El-Deredy, Wael

    2013-05-01

    Modulations of the feedback-related negativity (FRN) event-related potential (ERP) have been suggested as a potential biomarker in psychopathology. A dominant theory about this signal contends that it reflects the operation of the neural system underlying reinforcement learning in humans. The theory suggests that this frontocentral negative deflection in the ERP 230-270 ms after the delivery of a probabilistic reward expresses a prediction error signal derived from midbrain dopaminergic projections to the anterior cingulate cortex. We tested this theory by investigating whether FRN will also be observed for an inherently aversive outcome: physical pain. In another session, the outcome was monetary reward instead of pain. As predicted, unexpected reward omissions (a negative reward prediction error) yielded a more negative deflection relative to unexpected reward delivery. Surprisingly, unexpected pain omission (a positive reward prediction error) also yielded a negative deflection relative to unexpected pain delivery. Our data challenge the theory by showing that the FRN expresses aversive prediction errors with the same sign as reward prediction errors. Both FRNs were spatiotemporally and functionally equivalent. We suggest that FRN expresses salience prediction errors rather than reward prediction errors. PMID:23658166

  6. The feedback-related negativity signals salience prediction errors, not reward prediction errors.

    PubMed

    Talmi, Deborah; Atkinson, Ryan; El-Deredy, Wael

    2013-05-01

    Modulations of the feedback-related negativity (FRN) event-related potential (ERP) have been suggested as a potential biomarker in psychopathology. A dominant theory about this signal contends that it reflects the operation of the neural system underlying reinforcement learning in humans. The theory suggests that this frontocentral negative deflection in the ERP 230-270 ms after the delivery of a probabilistic reward expresses a prediction error signal derived from midbrain dopaminergic projections to the anterior cingulate cortex. We tested this theory by investigating whether FRN will also be observed for an inherently aversive outcome: physical pain. In another session, the outcome was monetary reward instead of pain. As predicted, unexpected reward omissions (a negative reward prediction error) yielded a more negative deflection relative to unexpected reward delivery. Surprisingly, unexpected pain omission (a positive reward prediction error) also yielded a negative deflection relative to unexpected pain delivery. Our data challenge the theory by showing that the FRN expresses aversive prediction errors with the same sign as reward prediction errors. Both FRNs were spatiotemporally and functionally equivalent. We suggest that FRN expresses salience prediction errors rather than reward prediction errors.

  7. Robust stability analysis and design under consideration of multiple feedback loops of the tryptophan regulatory network of Escherichia coli.

    PubMed

    Meyer-Baese, A; Theis, F; Emmett, M R

    2010-01-01

    The tryptophan system present in Escherichia coli represents an important regulatory unit described by multiple feedback loops. The role of these feedback loops is crucial for the analysis of the dynamical behavior of the tryptophan synthesis. We analyze the robust stability of this system which models the dynamics of both fast state, such as transcription and synthesis of free operator, and slow state, such as translation and tryptophan synthesis under consideration of nonlinear uncertainties. In addition, we analyze the role of these feedback loops as key design components of this regulatory unit responsible for its physiological performance. The range of allowed parameter perturbations and the conditions that ensure the existence of asymptotically stable equilibria of the perturbed system are determined. We also analyze two important alternate regulatory designs for the tryptophan synthesis pathway and derive the stability conditions. PMID:20865501

  8. Simplified phase noise model for negative-resistance oscillators and a comparison with feedback oscillator models.

    PubMed

    Everard, Jeremy; Xu, Min; Bale, Simon

    2012-03-01

    This paper describes a greatly simplified model for the prediction of phase noise in oscillators which use a negative resistance as the active element. It is based on a simple circuit consisting of the parallel addition of a noise current, a negative admittance/resistance, and a parallel (Qlimited) resonant circuit. The transfer function is calculated as a forward trans-resistance (VOUT/IIN) and then converted to power. The effect of limiting is incorporated by assuming that the phase noise element of the noise floor is kT/2, i.e., -177 dBm/Hz at room temperature. The result is the same as more complex analyses, but enables a simple, clear insight into the operation of oscillators. The phase noise for a given power in the resonator appears to be lower than in feedback oscillators. The reasons for this are explained. Simulation and experimental results are included.

  9. 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. PMID:26407298

  10. 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

  11. 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. PMID:27466448

  12. 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.

  13. Feedback.

    ERIC Educational Resources Information Center

    Stenstrom, Anna-Brita

    A study of feedback in conversational question-response exchanges focused on the questioner's feedback to the respondent. It examined three types of "followup" moves: the ordinary type revealing the questioner's attitude to the response and closing the exchange; the type signaling the questioner's reaction to the response and inviting further…

  14. 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.

  15. Corp Regulates P53 in Drosophila melanogaster via a Negative Feedback Loop.

    PubMed

    Chakraborty, Riddhita; Li, Ying; Zhou, Lei; Golic, Kent G

    2015-07-01

    The tumor suppressor P53 is a critical mediator of the apoptotic response to DNA double-strand breaks through the transcriptional activation of pro-apoptotic genes. This mechanism is evolutionarily conserved from mammals to lower invertebrates, including Drosophila melanogaster. P53 also transcriptionally induces its primary negative regulator, Mdm2, which has not been found in Drosophila. In this study we identified the Drosophila gene companion of reaper (corp) as a gene whose overexpression promotes survival of cells with DNA damage in the soma but reduces their survival in the germline. These disparate effects are shared by p53 mutants, suggesting that Corp may be a negative regulator of P53. Confirming this supposition, we found that corp negatively regulates P53 protein level. It has been previously shown that P53 transcriptionally activates corp; thus, Corp produces a negative feedback loop on P53. We further found that Drosophila Corp shares a protein motif with vertebrate Mdm2 in a region that mediates the Mdm2:P53 physical interaction. In Corp, this motif mediates physical interaction with Drosophila P53. Our findings implicate Corp as a functional analog of vertebrate Mdm2 in flies.

  16. 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.

  17. 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. PMID:22205920

  18. 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

  19. Grassland establishment under varying resource availability: a test of positive and negative feedback.

    PubMed

    Baer, Sara G; Blair, John M

    2008-07-01

    The traditional logic of carbon (C) and nitrogen (N) interactions in ecosystems predicts further increases or decreases in productivity (positive feedback) in response to high and low fertility in the soil, respectively; but the potential for development of feedback in ecosystems recovering from disturbance is less well understood. Furthermore, this logic has been challenged in grassland ecosystems where frequent fires or grazing may reduce the contribution of aboveground litter inputs to soil organic matter pools and nutrient supply for plant growth, relative to forest ecosystems. Further, if increases in plant productivity increase soil C content more than soil N content, negative feedback may result from increased microbial demand for N making less available for plant growth. We used a field experiment to test for feedback in an establishing grassland by comparing aboveground net primary productivity (ANPP) and belowground pools and fluxes of C and N in soil with enriched, ambient, and reduced N availability. For eight years annual N enrichment increased ANPP, root N, and root tissue quality, but root C:N ratios remained well above the threshold for net mineralization of N. There was no evidence that N enrichment increased root biomass, soil C or N accrual rates, or storage of C in total, microbial, or mineralizable pools within this time frame. However, the net nitrogen mineralization potential (NMP) rate was greater following eight years of N enrichment, and we attributed this to N saturation of the microbial biomass. Grassland developing under experimentally imposed N limitation through C addition to the soil exhibited ANPP, root biomass and quality, and net NMP rate similar to the ambient soil. Similarity in productivity and roots in the reduced and ambient N treatments was attributed to the potentially high nitrogen-use efficiency (NUE) of the dominant C4 grasses, and increasing cover of legumes over time in the C-amended soil. Thus, in a developing

  20. 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

  1. Negative feedback regulation of gonadotropin secretion by androgens in fetal rhesus macaques.

    PubMed

    Resko, J A; Ellinwood, W E

    1985-09-01

    Previously we described sex differences in circulating gonadotropin concentrations (greater in females) in fetal rhesus macaques, and demonstrated that these sex differences relate, at least in part, to the negative feedback actions of testicular secretions. A fully functional gonadal-hypothalamic-pituitary feedback relationship is present as early as Day 100 of gestation in fetal males because castration at this time results in a dramatic increase (greater than 10-fold) in fetal luteinizing hormone (LH) concentrations. Although short-term (6-h) treatment of fetuses with testosterone (T) 3 wk after gonadectomy (GX) does not lower LH levels in males, it is completely effective in females. These data suggest that either T is not the primary testicular factor responsible for feedback suppression of LH in fetal males, or the hypothalamic-pituitary axis becomes insensitive to T after GX. To determine if immediate treatment with T after GX is effective in maintaining LH levels, we gonadectomized five fetal rhesus males on Days 98-104 of gestation and immediately implanted crystalline-T-containing intraabdominal Silastic capsules. An additional five fetuses were treated with the nonaromatizable androgen dihydrotestosterone (DHT). Umbilical arterial samples for hormone analysis were obtained prior to GX and again approximately 3 wk later. Serum from control males (n = 11) castrated in utero on Day 100 of gestation contained significantly greater concentrations of LH and follicle-stimulating hormone (FSH) 3 wk after the operation than before GX. Five sham-operated male fetuses did not have elevated levels of either LH or FSH in their serum on Day 120 of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. 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.

  3. Construction of an Oscillator Gene Circuit by Negative and Positive Feedbacks.

    PubMed

    Shen, Shihui; Ma, Yushu; Ren, Yuhong; Wei, Dongzhi

    2016-01-01

    Synthetic oscillators are gene circuits in which the protein expression will change over time. The delay of transcription, translation, and protein folding is used to form this kind of behavior. Here, we tried to design a synthetic oscillator by a negative feedback combined with a positive feedback. With the mutant promoter PLacC repressed by LacIq and PLux activated by AHL-bound LuxR, two gene circuits, Os-LAA and Os-ASV, were constructed and introduced into LacI-deleted E. coli DH5α cells. When glucose was used as the carbon source, a low level of fluorescence was detected in the culture, and the bacteria with Os-ASV showed no oscillation, whereas a small portion of those carrying Os-LAA demonstrated oscillation behavior with a period of about 68.3 ± 20 min. When glycerol was used as the carbon source, bacteria with Os-ASV demonstrated high fluorescence value and oscillation behavior with the period of about 121 ± 21 min. PMID:26387818

  4. Construction of an Oscillator Gene Circuit by Negative and Positive Feedbacks.

    PubMed

    Shen, Shihui; Ma, Yushu; Ren, Yuhong; Wei, Dongzhi

    2016-01-01

    Synthetic oscillators are gene circuits in which the protein expression will change over time. The delay of transcription, translation, and protein folding is used to form this kind of behavior. Here, we tried to design a synthetic oscillator by a negative feedback combined with a positive feedback. With the mutant promoter PLacC repressed by LacIq and PLux activated by AHL-bound LuxR, two gene circuits, Os-LAA and Os-ASV, were constructed and introduced into LacI-deleted E. coli DH5α cells. When glucose was used as the carbon source, a low level of fluorescence was detected in the culture, and the bacteria with Os-ASV showed no oscillation, whereas a small portion of those carrying Os-LAA demonstrated oscillation behavior with a period of about 68.3 ± 20 min. When glycerol was used as the carbon source, bacteria with Os-ASV demonstrated high fluorescence value and oscillation behavior with the period of about 121 ± 21 min.

  5. Better Bet-Hedging with coupled positive and negative feedback loops

    NASA Astrophysics Data System (ADS)

    Narula, Jatin; Igoshin, Oleg

    2011-03-01

    Bacteria use the phenotypic heterogeneity associated with bistable switches to distribute the risk of activating stress response strategies like sporulation and persistence. However bistable switches offer little control over the timing of phenotype switching and first passage times (FPT) for individual cells are found to be exponentially distributed. We show that a genetic circuit consisting of interlinked positive and negative feedback loops allows cells to control the timing of phenotypic switching. Using a mathematical model we find that in this system a stable high expression state and stable low expression limit cycle coexist and the FPT distribution for stochastic transitions between them shows multiple peaks at regular intervals. A multimodal FPT distribution allows cells to detect the persistence of stress and control the rate of phenotype transition of the population. We further show that extracellular signals from cell-cell communication that change the strength of the feedback loops can modulate the FPT distribution and allow cells even greater control in a bet-hedging strategy.

  6. 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.

  7. 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.

  8. NOS1-dependent negative feedback regulation of the epithelial sodium channel in the collecting duct.

    PubMed

    Hyndman, Kelly A; Bugaj, Vladislav; Mironova, Elena; Stockand, James D; Pollock, Jennifer S

    2015-02-01

    With an increase in urine flow there is a significant increase in shear stress against the renal epithelium including the inner medullary collecting duct, resulting in an increase in nitric oxide (NO) production. The mechanisms of the shear stress-mediated increases in NO are undetermined. Previous studies found that shear stress increases epithelial sodium channel (ENaC) open probability and endothelin (ET)-1 production in an ENaC-dependent mechanism in the collecting duct (CD). Given that ET-1 stimulates NO production in the CD, we hypothesized that shear stress-induced NO production is downstream of shear stress-induced ENaC activation and ET-1 production in a negative feedback loop. We determined that nitric oxide synthase 1 (NOS1) and NOS3 contribute to shear stress-mediated NO production in the CD, that is attenuated by low doses of the ENaC inhibitors amiloride and benzamil. Moreover, ETB receptor blockade significantly blunted the shear stress-mediated NO production. We further elucidated whether mice lacking NOS1 in the collecting duct (CDNOS1KO) have an impaired renal ET-1 system in the CD. Although urinary ET-1 production and inner medullary ET receptor expression were similar between flox control and CDNOS1KO mice, acute ET-1 treatment significantly reduced ENaC open probability in CDs from flox mice but not CDNOS1KO mice compared with basal. Basal ENaC activity in CDs was similar between the genotypes. We conclude that during acute shear stress across the CD, ENaC acts in a negative feedback loop to stimulate NO production in an ETB/NOS1-dependent manner resulting in a decrease in ENaC open probability and promoting natriuresis.

  9. 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

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. Bayesian non-negative factor analysis for reconstructing transcription factor mediated regulatory networks

    PubMed Central

    2011-01-01

    Background Transcriptional regulation by transcription factor (TF) controls the time and abundance of mRNA transcription. Due to the limitation of current proteomics technologies, large scale measurements of protein level activities of TFs is usually infeasible, making computational reconstruction of transcriptional regulatory network a difficult task. Results We proposed here a novel Bayesian non-negative factor model for TF mediated regulatory networks. Particularly, the non-negative TF activities and sample clustering effect are modeled as the factors from a Dirichlet process mixture of rectified Gaussian distributions, and the sparse regulatory coefficients are modeled as the loadings from a sparse distribution that constrains its sparsity using knowledge from database; meantime, a Gibbs sampling solution was developed to infer the underlying network structure and the unknown TF activities simultaneously. The developed approach has been applied to simulated system and breast cancer gene expression data. Result shows that, the proposed method was able to systematically uncover TF mediated transcriptional regulatory network structure, the regulatory coefficients, the TF protein level activities and the sample clustering effect. The regulation target prediction result is highly coordinated with the prior knowledge, and sample clustering result shows superior performance over previous molecular based clustering method. Conclusions The results demonstrated the validity and effectiveness of the proposed approach in reconstructing transcriptional networks mediated by TFs through simulated systems and real data. PMID:22166063

  15. 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.

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

    PubMed

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

    2015-12-01

    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. PMID:26609065

  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. A regulatory role for the memory B cell as suppressor-inducer of feedback control

    SciTech Connect

    Kennedy, M.W.; Thomas, D.B.

    1983-02-01

    A regulatory role is proposed for the antigen-responsive B cell, as suppressor-inducer of feedback control during the secondary response in vivo. In a double adoptive transfer of memory cells primed to a thymus-dependent antigen from one irradiated host to another, antigen-specific suppressors are generated after a critical time in the primary recipient, able to entirely ablate a secondary anti-hapten response. Positive cell selection in the fluorescence-activated cell sorter confirmed that suppression was mediated by an Lyt-2+ T cell; however, positively selected B cells were also inhibitory and able to induce suppressors in a carrier-specific manner: Bhapten induced suppressors in a carrier-primed population, and Bcarrier induced suppressors in a hapten-carrier population. At the peak of the antibody response in the primary host, memory B cells and their progeny were unable to differentiate further to plasma cells due to their intrinsic suppressor-inducer activity, but this autoregulatory circuit could be severed by adoptive transfer to carrier-primed, X-irradiated recipients.

  19. Phytochrome signaling in green Arabidopsis seedlings: impact assessment of a mutually negative phyB-PIF feedback loop.

    PubMed

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

    2012-05-01

    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

  20. 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

  1. 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.

  2. 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.

  3. 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+). PMID:25977473

  4. The stability of the feedback negativity and its relationship with depression during childhood and adolescence.

    PubMed

    Bress, Jennifer N; Meyer, Alexandria; Proudfit, Greg Hajcak

    2015-11-01

    Feedback negativity (FN) is an event-related potential elicited by monetary reward and loss; it is thought to relate to reward-related neural activity and has been linked to depression in children and adults. In the current study, we examined the stability of FN, and its relationship with depression in adolescents, over 2 years in 45 8- to 13-year-old children. From Time 1 to Time 2, FN in response to monetary loss and in response to monetary gain showed moderate to strong reliability (rs = .64 and .67, respectively); these relationships remained significant even when accounting for related variables. FN also demonstrated high within-session reliability. Moreover, the relationship between a blunted FN and greater depression observed at Time 1 was reproduced at Time 2, and the magnitude of FN at Time 1 predicted depressive symptomatology at Time 2. These findings are consistent with the hypothesis that FN and its relationship with depression remain consistent over the course of development, and that FN may prospectively predict later depressive symptomatology. The current results suggest that FN may be suitable as a biomarker of depressive symptoms during adolescence. PMID:26439074

  5. 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

  6. 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. PMID:26076035

  7. 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

  8. A Negative Feedback Between Anthropogenic Ozone Pollution and Enhanced Ocean Emissions of Iodine

    NASA Astrophysics Data System (ADS)

    Saiz-Lopez, A.; Prados-Roman, C.; Cuevas, C.; Fernandez, R.; Lamarque, J. F.; Kinnison, D. E.

    2014-12-01

    Naturally emitted from the oceans, iodine compounds efficiently destroy atmospheric ozone and reduce 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 since 1850 as a result of human activities. A chemistry-climate model is used to quantify the current ocean emissions of inorganic iodine and assess 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. Results included in this communication 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.

  9. 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...

  10. 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.

  11. Identification of cis-acting repressive sequences within the negative regulatory element of human immunodeficiency virus type 1.

    PubMed Central

    Lu, Y C; Touzjian, N; Stenzel, M; Dorfman, T; Sodroski, J G; Haseltine, W A

    1990-01-01

    The negative regulatory element of human immunodeficiency virus type 1 is a 260-nucleotide-long sequence that decreases the rate of RNA transcription initiation specified by the long terminal repeat. This region has the potential to bind several cellular transcription factors. Here it is shown that sequences which recognize the NFAT-1 and USF cellular transcription factors contribute to this negative regulatory effect. The sequences within the negative regulatory element which resemble the AP-1 site and the URS do not negatively regulate human immunodeficiency virus long terminal repeat transcription initiation. PMID:2398545

  12. 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

  13. 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.

  14. 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

  15. 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

  16. Blowin' in the wind: both `negative' and `positive' feedback in an outflowing quasar at z~1.6

    NASA Astrophysics Data System (ADS)

    Cresci, Giovanni

    2015-02-01

    Quasar feedback in the form of powerful outflows is invoked as a key mechanism to quench star formation, preventing massive galaxies to over-grow and producing the red colors of ellipticals. On the other hand, some models are also requiring `positive' AGN 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. We present SINFONI near infrared integral field spectroscopy of XID2028, an obscured, radio-quiet z=1.59 QSO, in which we clearly resolve a fast (1500 km/s) and extended (up to 13 kpc from the black hole) outflow in the [OIII] 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 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.

  17. 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. PMID:26269614

  18. 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.

  19. Positive and negative regulatory regions control the spatial distribution of polygalacturonase transcription in tomato fruit pericarp.

    PubMed Central

    Montgomery, J; Pollard, V; Deikman, J; Fischer, R L

    1993-01-01

    The tomato fruit consists of a thick, fleshy pericarp composed predominantly of highly vacuolated parenchymatous cells, which surrounds the seeds. During ripening, the activation of gene expression results in dramatic biochemical and physiological changes in the pericarp. The polygalacturonase (PG) gene, unlike many fruit ripening-induced genes, is not activated by the increase in ethylene hormone concentration associated with the onset of ripening. To investigate ethylene concentration-independent gene transcription in ripe tomato fruit, we analyzed the expression of chimeric PG promoter-beta-glucuronidase (GUS) reporter gene fusions in transgenic tomato plants. We determined that a 1.4-kb PG promoter directs ripening-regulated transcription in outer pericarp but not in inner pericarp cells, with a sharp boundary of PG promoter activity located midway through the pericarp. Promoter deletion analysis indicated that a minimum of three promoter regions influence the spatial regulation of PG transcription. A positive regulatory region from -231 to -134 promotes gene transcription in the outer pericarp of ripe fruit. A second positive regulatory region from -806 to -443 extends gene activity to the inner pericarp. However, a negative regulatory region from -1411 to -1150 inhibits gene transcription in the inner pericarp. DNase I footprint analysis showed that nuclear proteins in unripe and ripe fruit interact with DNA sequences within each of these three regulatory regions. Thus, temporal and spatial control of PG transcription is mediated by the interaction of negative and positive regulatory promoter elements, resulting in gene activity in the outer pericarp but not the inner pericarp of ripe tomato fruit. The expression pattern of PG suggests that, although they are morphologically similar, there is a fundamental difference between the parenchymatous cells within the inner and outer pericarp. PMID:8400876

  20. 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…

  1. Dorsomedial hypothalamic lesions block Syrian hamster testicular regression in short day lengths without diminishing increased testosterone negative-feedback sensitivity.

    PubMed

    Jarjisian, Stephan G; Piekarski, David J; Place, Ned J; Driscoll, Joseph R; Paxton, Eve G; Kriegsfeld, Lance J; Zucker, Irving

    2013-08-01

    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.

  2. A CaMKII/PDE4D negative feedback regulates cAMP signaling

    PubMed Central

    Mika, Delphine; Richter, Wito; Conti, Marco

    2015-01-01

    cAMP production and protein kinase A (PKA) are the most widely studied steps in β-adrenergic receptor (βAR) signaling in the heart; however, the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is also activated in response to βAR stimulation and is involved in the regulation of cardiac excitation-contraction coupling. Its activity and expression are increased during cardiac hypertrophy, in heart failure, and under conditions that promote arrhythmias both in animal models and in the human heart, underscoring the clinical relevance of CaMKII in cardiac pathophysiology. Both CaMKII and PKA phosphorylate a number of protein targets critical for Ca2+ handling and contraction with similar, but not always identical, functional consequences. How these two pathways communicate with each other remains incompletely understood, however. To maintain homeostasis, cyclic nucleotide levels are regulated by phosphodiesterases (PDEs), with PDE4s predominantly responsible for cAMP degradation in the rodent heart. Here we have reassessed the interaction between cAMP/PKA and Ca2+/CaMKII signaling. We demonstrate that CaMKII activity constrains basal and βAR-activated cAMP levels. Moreover, we show that these effects are mediated, at least in part, by CaMKII regulation of PDE4D. This regulation establishes a negative feedback loop necessary to maintain cAMP/CaMKII homeostasis, revealing a previously unidentified function for PDE4D as a critical integrator of cAMP/PKA and Ca2+/CaMKII signaling. PMID:25646485

  3. Ventral tegmental area orexin 1 receptors promote palatable food intake and oppose postingestive negative feedback.

    PubMed

    Terrill, Sarah J; Hyde, Kellie M; Kay, Kristen E; Greene, Hayden E; Maske, Calyn B; Knierim, Amanda E; Davis, Jon F; Williams, Diana L

    2016-09-01

    Hypothalamic orexin neurons project to numerous brain areas, including the ventral tegmental area (VTA), which is involved in motivation and food-seeking behavior. Here we address how exogenously administered orexin-A and endogenous orexin 1 receptor (OX1R) activation in the VTA affects feeding behavior. We hypothesized that orexin-A and OX1R antagonist SB334867 delivered to the VTA, at doses that were subthreshold for effect when injected into the ventricle, would affect intake of palatable foods in multiple test situations. We first used a hedonic feeding model in which satiated rats selectively consume a high-fat diet (HFD). Intra-VTA orexin-A stimulated additional consumption of chow and increased HFD intake in this model. In ad libitum-fed rats given daily 30-min test sessions, intra-VTA orexin-A also increased intake of HFD and 0.1 M sucrose. Further analysis of licking patterns revealed that that VTA orexin-A increased meal size and licking burst size only toward the end of the meal. Consistent with this finding, a subthreshold dose of VTA orexin-A prevented intake suppression induced by gastrointestinal nutrient infusion. Surprisingly, intra-VTA orexin-A had no effect on operant responding for sucrose pellets on a progressive ratio schedule of reinforcement. A role for endogenous VTA OX1R stimulation is supported by our finding that bilateral VTA injection of the selective OX1R antagonist SB334867 suppressed 0.1 M sucrose intake. Together, our data suggest that OX1R activity in the VTA facilitates food intake, potentially by counteracting postingestive negative feedback that would normally suppress feeding later in a meal. PMID:27385732

  4. 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.

  5. ANXA1 inhibits miRNA-196a in a negative feedback loop through NF-kB and c-Myc to reduce breast cancer proliferation

    PubMed Central

    Yuan, Yi; Anbalagan, Durkeshwari; Lee, Lay Hoon; Samy, Ramar Perumal; Shanmugam, Muthu K.; Kumar, Alan Prem; Sethi, Gautam; Lobie, Peter E.; Lim, Lina H.K.

    2016-01-01

    MiRNAs are endogenous ~22 nt RNAs which play critical regulatory roles in a wide range of biological and pathological processes, which can act as oncogenes or tumor suppressor genes depending on their target genes. We have recently shown that ANXA1 inhibits the expression of miRNAs including miR196a. Here, we show that miR196a was highly expressed in ER+ MCF-7 breast cancer cells when compared to normal mammary gland cells, with expression levels negatively correlating to ANXA1. ANXA1 inhibits the biogenesis of oncogenic miR-196a by suppressing primary-miR196a indirectly through the stimulation of c-myc and NFkB expression and activity in breast cancer cells. In a negative feedback loop, miR-196a directly inhibits ANXA1 and enhances breast cancer cell proliferation in vitro. Finally, miR196a promotes breast tumor growth in vivo. This study reports a novel regulatory circuit between ANXA1, NF-kB, c-myc and miR-196a which regulates breast cancer cell proliferation and tumor growth. PMID:27105503

  6. 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.

  7. 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

  8. Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition.

    PubMed

    Weist, Brian M; Kurd, Nadia; Boussier, Jeremy; Chan, Shiao Wei; Robey, Ellen A

    2015-06-01

    The thymic production of regulatory T cells (Treg cells) requires interleukin 2 (IL-2) and agonist T cell antigen receptor (TCR) ligands and is controlled by competition for a limited developmental niche, but the thymic sources of IL-2 and the factors that limit access to the niche are poorly understood. Here we found that IL-2 produced by antigen-bearing dendritic cells (DCs) had a key role in Treg cell development and that existing Treg cells limited new development of Treg cells by competing for IL-2. Our data suggest that antigen-presenting cells (APCs) that can provide both IL-2 and a TCR ligand constitute the thymic niche and that competition by existing Treg cells for a limited supply of IL-2 provides negative feedback for new production of Treg cells. PMID:25939026

  9. Erk negative feedback control enables pre-B cell transformation and represents a therapeutic target in acute lymphoblastic leukemia

    PubMed Central

    Shojaee, Seyedmehdi; Caeser, Rebecca; Buchner, Maike; Park, Eugen; Swaminathan, Srividya; Hurtz, Christian; Geng, Huimin; Chan, Lai N; Klemm, Lars; Hofmann, Wolf-Karsten; Qiu, Yi Hua; Zhang, Nianxiang; Coombes, Kevin R.; Paietta, Elisabeth; Molkentin, Jeffery; Koeffler, H Phillip; Willman, Cheryl L; Hunger, Stephen P.; Melnick, Ari; Kornblau, Steven M.; Müschen, Markus

    2015-01-01

    Summary Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation of Erk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels, we found that Spry2, Dusp6 and Etv5 were essential for oncogenic transformation in mouse models for pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance. PMID:26073130

  10. The feedback-related negativity (FRN) revisited: new insights into the localization, meaning and network organization.

    PubMed

    Hauser, Tobias U; Iannaccone, Reto; Stämpfli, Philipp; Drechsler, Renate; Brandeis, Daniel; Walitza, Susanne; Brem, Silvia

    2014-01-01

    Changes in response contingencies require adjusting ones assumptions about outcomes of behaviors. Such adaptation processes are driven by reward prediction error (RPE) signals which reflect the inadequacy of expectations. Signals resembling RPEs are known to be encoded by mesencephalic dopamine neurons projecting to the striatum and frontal regions. Although regions that process RPEs, such as the dorsal anterior cingulate cortex (dACC), have been identified, only indirect evidence links timing and network organization of RPE processing in humans. In electroencephalography (EEG), which is well known for its high temporal resolution, the feedback-related negativity (FRN) has been suggested to reflect RPE processing. Recent studies, however, suggested that the FRN might reflect surprise, which would correspond to the absolute, rather than the signed RPE signals. Furthermore, the localization of the FRN remains a matter of debate. In this simultaneous EEG-functional magnetic resonance imaging (fMRI) study, we localized the FRN directly using the superior spatial resolution of fMRI without relying on any spatial constraint or other assumption. Using two different single-trial approaches, we consistently found a cluster within the dACC. One analysis revealed additional activations of the salience network. Furthermore, we evaluated the effect of signed RPEs and surprise signals on the FRN amplitude. We considered that both signals are usually correlated and found that only surprise signals modulate the FRN amplitude. Last, we explored the pathway of RPE signals using dynamic causal modeling (DCM). We found that the surprise signals are directly projected to the source region of the FRN. This finding contradicts earlier theories about the network organization of the FRN, but is in line with a recent theory stating that dopamine neurons also encode surprise-like saliency signals. Our findings crucially advance the understanding of the FRN. We found compelling evidence that

  11. The feedback-related negativity (FRN) revisited: new insights into the localization, meaning and network organization.

    PubMed

    Hauser, Tobias U; Iannaccone, Reto; Stämpfli, Philipp; Drechsler, Renate; Brandeis, Daniel; Walitza, Susanne; Brem, Silvia

    2014-01-01

    Changes in response contingencies require adjusting ones assumptions about outcomes of behaviors. Such adaptation processes are driven by reward prediction error (RPE) signals which reflect the inadequacy of expectations. Signals resembling RPEs are known to be encoded by mesencephalic dopamine neurons projecting to the striatum and frontal regions. Although regions that process RPEs, such as the dorsal anterior cingulate cortex (dACC), have been identified, only indirect evidence links timing and network organization of RPE processing in humans. In electroencephalography (EEG), which is well known for its high temporal resolution, the feedback-related negativity (FRN) has been suggested to reflect RPE processing. Recent studies, however, suggested that the FRN might reflect surprise, which would correspond to the absolute, rather than the signed RPE signals. Furthermore, the localization of the FRN remains a matter of debate. In this simultaneous EEG-functional magnetic resonance imaging (fMRI) study, we localized the FRN directly using the superior spatial resolution of fMRI without relying on any spatial constraint or other assumption. Using two different single-trial approaches, we consistently found a cluster within the dACC. One analysis revealed additional activations of the salience network. Furthermore, we evaluated the effect of signed RPEs and surprise signals on the FRN amplitude. We considered that both signals are usually correlated and found that only surprise signals modulate the FRN amplitude. Last, we explored the pathway of RPE signals using dynamic causal modeling (DCM). We found that the surprise signals are directly projected to the source region of the FRN. This finding contradicts earlier theories about the network organization of the FRN, but is in line with a recent theory stating that dopamine neurons also encode surprise-like saliency signals. Our findings crucially advance the understanding of the FRN. We found compelling evidence that

  12. Increased Thyroid Hormone Activation Accompanies the Formation of Thyroid Hormone-Dependent Negative Feedback in Developing Chicken Hypothalamus.

    PubMed

    Mohácsik, P; Füzesi, T; Doleschall, M; Szilvásy-Szabó, A; Vancamp, P; Hadadi, É; Darras, V M; Fekete, C; Gereben, B

    2016-03-01

    The hypothalamic-pituitary-thyroid axis is governed by hypophysiotropic TRH-synthesizing neurons located in the hypothalamic paraventricular nucleus under control of the negative feedback of thyroid hormones. The mechanisms underlying the ontogeny of this phenomenon are poorly understood. We aimed to determine the onset of thyroid hormone-mediated hypothalamic-negative feedback and studied how local hypothalamic metabolism of thyroid hormones could contribute to this process in developing chicken. In situ hybridization revealed that whereas exogenous T4 did not induce a statistically significant inhibition of TRH expression in the paraventricular nucleus at embryonic day (E)19, T4 treatment was effective at 2 days after hatching (P2). In contrast, TRH expression responded to T3 treatment in both age groups. TSHβ mRNA expression in the pituitary responded to T4 in a similar age-dependent manner. Type 2 deiodinase (D2) was expressed from E13 in tanycytes of the mediobasal hypothalamus, and its activity increased between E15 and P2 both in the mediobasal hypothalamus and in tanycyte-lacking hypothalamic regions. Nkx2.1 was coexpressed with D2 in E13 and P2 tanycytes and transcription of the cdio2 gene responded to Nkx2.1 in U87 glioma cells, indicating its potential role in the developmental regulation of D2 activity. The T3-degrading D3 enzyme was also detected in tanycytes, but its level was not markedly changed before and after the period of negative feedback acquisition. These findings suggest that increasing the D2-mediated T3 generation during E18-P2 could provide the sufficient local T3 concentration required for the onset of T3-dependent negative feedback in the developing chicken hypothalamus. PMID:26779746

  13. Increased Thyroid Hormone Activation Accompanies the Formation of Thyroid Hormone-Dependent Negative Feedback in Developing Chicken Hypothalamus.

    PubMed

    Mohácsik, P; Füzesi, T; Doleschall, M; Szilvásy-Szabó, A; Vancamp, P; Hadadi, É; Darras, V M; Fekete, C; Gereben, B

    2016-03-01

    The hypothalamic-pituitary-thyroid axis is governed by hypophysiotropic TRH-synthesizing neurons located in the hypothalamic paraventricular nucleus under control of the negative feedback of thyroid hormones. The mechanisms underlying the ontogeny of this phenomenon are poorly understood. We aimed to determine the onset of thyroid hormone-mediated hypothalamic-negative feedback and studied how local hypothalamic metabolism of thyroid hormones could contribute to this process in developing chicken. In situ hybridization revealed that whereas exogenous T4 did not induce a statistically significant inhibition of TRH expression in the paraventricular nucleus at embryonic day (E)19, T4 treatment was effective at 2 days after hatching (P2). In contrast, TRH expression responded to T3 treatment in both age groups. TSHβ mRNA expression in the pituitary responded to T4 in a similar age-dependent manner. Type 2 deiodinase (D2) was expressed from E13 in tanycytes of the mediobasal hypothalamus, and its activity increased between E15 and P2 both in the mediobasal hypothalamus and in tanycyte-lacking hypothalamic regions. Nkx2.1 was coexpressed with D2 in E13 and P2 tanycytes and transcription of the cdio2 gene responded to Nkx2.1 in U87 glioma cells, indicating its potential role in the developmental regulation of D2 activity. The T3-degrading D3 enzyme was also detected in tanycytes, but its level was not markedly changed before and after the period of negative feedback acquisition. These findings suggest that increasing the D2-mediated T3 generation during E18-P2 could provide the sufficient local T3 concentration required for the onset of T3-dependent negative feedback in the developing chicken hypothalamus.

  14. Frequency modulation noise and linewidth reduction in a semiconductor laser by means of negative frequency feedback technique

    SciTech Connect

    Saito, S.; Nilsson, O.; Yamamoto, Y.

    1985-01-01

    Electrical negative frequency feedback control has been shown to reduce frequency modulation (FM) noise linewidth in semiconductor lasers. The method is based on the direct frequency modulation capability of a semiconductor laser. An error signal is extracted through optical heterodyne frequency discrimination detection using a stable master laser. FM noise is reduced by more than 20 dB and linewidth is reduced by one order of magnitude.

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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…

  3. 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.

  4. 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. PMID:27250444

  5. Type One Protein Phosphatase 1 and Its Regulatory Protein Inhibitor 2 Negatively Regulate ABA Signaling

    PubMed Central

    Zhao, Yang; Xie, Shaojun; Batelli, Giorgia; Wang, Bangshing; Duan, Cheng-Guo; Wang, Xingang; Xing, Lu; Lei, Mingguang; Yan, Jun; Zhu, Xiaohong; Zhu, Jian-Kang

    2016-01-01

    The phytohormone abscisic acid (ABA) regulates plant growth, development and responses to biotic and abiotic stresses. The core ABA signaling pathway consists of three major components: ABA receptor (PYR1/PYLs), type 2C Protein Phosphatase (PP2C) and SNF1-related protein kinase 2 (SnRK2). Nevertheless, the complexity of ABA signaling remains to be explored. To uncover new components of ABA signal transduction pathways, we performed a yeast two-hybrid screen for SnRK2-interacting proteins. We found that Type One Protein Phosphatase 1 (TOPP1) and its regulatory protein, At Inhibitor-2 (AtI-2), physically interact with SnRK2s and also with PYLs. TOPP1 inhibited the kinase activity of SnRK2.6, and this inhibition could be enhanced by AtI-2. Transactivation assays showed that TOPP1 and AtI-2 negatively regulated the SnRK2.2/3/6-mediated activation of the ABA responsive reporter gene RD29B, supporting a negative role of TOPP1 and AtI-2 in ABA signaling. Consistent with these findings, topp1 and ati-2 mutant plants displayed hypersensitivities to ABA and salt treatments, and transcriptome analysis of TOPP1 and AtI-2 knockout plants revealed an increased expression of multiple ABA-responsive genes in the mutants. Taken together, our results uncover TOPP1 and AtI-2 as negative regulators of ABA signaling. PMID:26943172

  6. A regulatory feedback loop between HIF-1α and PIM2 in HepG2 cells.

    PubMed

    Yu, Zhenhai; Zhao, Xiaoping; Ge, Yingying; Zhang, Teng; Huang, Liangqian; Zhou, Xiang; Xie, Lei; Liu, Jianjun; Huang, Gang

    2014-01-01

    To survive under hypoxic conditions, cancer cells remodel glucose metabolism to support tumor progression. HIF transcription factor is essential for cellular response to hypoxia. The underlying mechanism how HIF is constitutively activated in cancer cells remains elusive. In the present study, we characterized a regulatory feedback loop between HIF-1α and PIM2 in HepG2 cells. Serine/threonine kinase proto-oncogene PIM2 level was induced upon hypoxia in a HIF-1α-mediated manner in cancer cells. HIF-1α induced PIM2 expression via binding to the hypoxia-responsive elements (HREs) of the PIM2 promoter. In turn, PIM2 interacted with HIF-1α, especially a transactivation domain of HIF-1α. PIM2 as a co-factor but not an upstream kinase of HIF-1α, enhanced HIF-1α effect in response to hypoxia. The positive feedback loop between PIM2 and HIF-1α was correlated with glucose metabolism as well as cell survival in HepG2 cells. Such a regulatory mode may be important for the adaptive responses of cancer cells in antagonizing hypoxia during cancer progression. PMID:24505470

  7. Molecular cloning and analysis of the scon-2 negative regulatory gene of Neurospora crassa.

    PubMed Central

    Paietta, J V

    1990-01-01

    The sulfur regulatory system of Neurospora crassa is composed of a group of highly regulated structural genes (e.g., the gene encoding arylsulfatase) that are under coordinate control of scon+ (sulfur controller) negative and cys-3+ positive regulatory genes. In scon-1 (previously designated sconC) and scon-2 mutants, there is constitutive expression of sulfur structural genes regardless of the sulfur level available to the cells. The scon-2+ gene was cloned by sib selection screening of a cosmid-based gene library. The screening was based on the use of chromate, a toxic sulfate analog, which is transported into scon-2 cells grown on high sulfur but is not transported into cells that have regained normal sulfur regulation. Restriction fragment length polymorphism analysis was used to confirm that the cloned segment mapped to the proper chromosomal location. In wild-type cells, Northern (RNA) blot analysis showed that a 2.6-kilobase scon-2+ transcript was present at a substantial level only under sulfur-derepressing conditions. Kinetic analysis showed that scon-2+ mRNA content increased as the cells became sulfur starved. Further, scon-2+ RNA was detectable in a nuclear transcription assay only under derepressing conditions. In scon-1, the levels of scon-2+ mRNA were found to be constitutive. In the cys-3 regulatory mutant, there was a reduced level of scon-2+ transcript. cys-3+ and ars-1+ mRNAs were present under both derepressing and repressing conditions in the scon-2 mutant. Repeat-induced point mutation-generated scon-2 mutants were identical in phenotype to the known mutant. Images PMID:1975945

  8. 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.

  9. AMAP1 as a negative-feedback regulator of nuclear factor-κB under inflammatory conditions.

    PubMed

    Tien, Dat Nguyen; Kishihata, Masako; Yoshikawa, Ayumu; Hashimoto, Ari; Sabe, Hisataka; Nishi, Eiichiro; Kamei, Kaeko; Arai, Hidenori; Kita, Toru; Kimura, Takeshi; Yokode, Masayuki; Ashida, Noboru

    2014-05-28

    NF-κB is a major transcriptional factor regulating many cellular functions including inflammation; therefore, its appropriate control is of high importance. The detailed mechanism of its activation has been well characterized, but that of negative regulation is poorly understood. In this study, we showed AMAP1, an Arf-GTPase activating protein, as a negative feedback regulator for NF-κB by binding with IKKβ, an essential kinase in NF-κB signaling. Proteomics analysis identified AMAP1 as a binding protein with IKKβ. Overexpression of AMAP1 suppressed NF-κB activity by interfering the binding of IKKβ and NEMO, and deletion of AMAP1 augmented NF-κB activity. The activation of NF-κB induced translocation of AMAP1 to cytoplasm from cell membrane and nucleus, which resulted in augmented interaction of AMAP1 and IKKβ. These results demonstrated a novel role of AMAP1 as a negative feedback regulator of NF-κB, and presented it as a possible target for anti-inflammatory treatments.

  10. COMPONENTS OF LASER SYSTEMS AND STABILITY PROBLEMS: Highly stable subpicosecond neodymium (Nd3+) glass laser with passive mode locking and negative feedback

    NASA Astrophysics Data System (ADS)

    Burneĭka, K.; Grigonis, R.; Piskarskas, A.; Sinkyavichyus, G.; Sirutkaĭtis, V.

    1988-08-01

    An electrically controlled feedback loop was used in a phosphate glass laser with passive mode locking to ensure stable generation of 500-600 fs pulses. This negative feedback loop ensured a high reproducibility of the energy and time characteristics of the pulses. The product of the spectral width of the pulses and their duration was 0.44.

  11. Glucocorticoid negative feedback in methadone-maintained former heroin addicts with ongoing cocaine dependence: dose-response to dexamethasone suppression.

    PubMed

    Aouizerate, Bruno; Ho, Ann; Schluger, James H; Perret, Guillaume; Borg, Lisa; Le Moal, Michel; Piazza, Pier V; Kreek, Mary Jeanne

    2006-03-01

    Combined cocaine and illicit opiate use is common. This study aimed to test the hypothesis that cocaine dependence in former heroin-addicted patients maintained on methadone treatment is associated with enhanced glucocorticoid negative feedback. Multiple dose dexamethasone suppression tests, using a conventional 2.0 mg dose, and two lower doses, 0.5 mg and 0.125 mg, were performed in 10 methadone-maintained former heroin addicts with ongoing cocaine dependence (C-MM), 10 stabilized methadone-maintained former heroin addicts with no ongoing drug or alcohol use (MM), and 22 normal volunteers (NV). At 9 hours, there was no difference in plasma adrenocorticotropin hormone (ACTH) and/or cortisol levels among groups on the baseline day, as well as after the two lower doses of dexamethasone. At 17 hours, C-MM and MM had significantly lower plasma ACTH and/or cortisol levels than NV. However, C-MM did not significantly differ from MM in their hormonal levels. When the hormonal responses to dexamethasone are expressed as magnitude of lowering from baseline, there was no significant difference at any dose among groups. Therefore, C-MM exhibited a normal glucocorticoid negative feedback in the morning. Using the standard interpretation of dexamethasone suppression testing based on the examination of the actual hormonal levels rather than the difference from baseline condition, C-MM appear to have glucocorticoid effects similar to MM, yet were both greater than NV in the late afternoon. Thus, further studies are needed to know whether altered glucocorticoid negative feedback is related to chronic cocaine exposure, or is the result of former heroin addiction and/or its long-term treatment with methadone.

  12. 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

  13. A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network.

    PubMed

    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

  14. 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.

  15. 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

  16. 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

    2007-03-01

    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.

  17. Evidence for epidermal growth factor receptor as negative-feedback control in aldosterone-induced Na+ reabsorption.

    PubMed

    Grossmann, Claudia; Freudinger, Ruth; Mildenberger, Sigrid; Krug, Alexander W; Gekle, Michael

    2004-06-01

    Aldosterone enhances Na(+) reabsorption via epithelial Na(+) channels (ENaC). Aldosterone also stimulates the protein kinase ERK1/2- and the epidermal growth factor (EGF) receptor (EGFR)-signaling pathway. Yet EGF and ERK1/2 are known inhibitors of ENaC-mediated Na(+) reabsorption. In the present study, using the well-established Madin-Darby canine kidney C7 cell line, we tested the hypothesis that EGFR represents a negative-feedback control for chronic aldosterone-induced Na(+) reabsorption [amiloride-inhibitable short-circuit current (I(sc))]. Mineralocorticoid receptor expression was confirmed by RT-PCR and Western blot analysis. Aldosterone enhanced ERK1/2 phosphorylation in an EGFR-dependent way. Furthermore, aldosterone stimulated EGFR expression. Aldosterone (10 nmol/l) induced a small transient increase in I(sc) under control conditions. Inhibition of ERK1/2 phosphorylation with U-0126 (10 micromol/l) stimulated I(sc), indicating constitutive ENaC inhibition. Aldosterone exerted a significantly larger effect in the presence of U-0126 than without U-0126. EGF (10 microg/l) inhibited I(sc), whereas inhibition of EGFR kinase by tyrphostin AG-1478 (100 nmol/l) enhanced I(sc). Aldosterone was more effective in the presence of AG-1478 than without AG-1478. In summary, we propose that the EGFR-signaling cascade can serve as a negative-feedback control to limit the effect of aldosterone-induced Na(+) reabsorption. PMID:14749256

  18. 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.

  19. 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. PMID:26783525

  20. 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

  1. 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

  2. Noise Enhanced Persistence in a Biochemical Regulatory Network with Feedback Control

    NASA Astrophysics Data System (ADS)

    Assaf, Michael; Meerson, Baruch

    2008-02-01

    We find that discrete noise of inhibiting (signal) molecules can greatly delay the extinction of plasmids in a plasmid replication system: a prototypical biochemical regulatory network. We calculate the probability distribution of the metastable state of the plasmids and show in this example that the reaction rate equations may fail in predicting the average number of regulated molecules even when this number is large, and the time is much shorter than the mean extinction time.

  3. 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…

  4. The Circadian System: A Regulatory Feedback Network of Periphery and Brain.

    PubMed

    Buijs, Frederik N; León-Mercado, Luis; Guzmán-Ruiz, Mara; Guerrero-Vargas, Natali N; Romo-Nava, Francisco; Buijs, Ruud M

    2016-05-01

    Circadian rhythms are generated by the autonomous circadian clock, the suprachiasmatic nucleus (SCN), and clock genes that are present in all tissues. The SCN times these peripheral clocks, as well as behavioral and physiological processes. Recent studies show that frequent violations of conditions set by our biological clock, such as shift work, jet lag, sleep deprivation, or simply eating at the wrong time of the day, may have deleterious effects on health. This infringement, also known as circadian desynchronization, is associated with chronic diseases like diabetes, hypertension, cancer, and psychiatric disorders. In this review, we will evaluate evidence that these diseases stem from the need of the SCN for peripheral feedback to fine-tune its output and adjust physiological processes to the requirements of the moment. This feedback can vary from neuronal or hormonal signals from the liver to changes in blood pressure. Desynchronization renders the circadian network dysfunctional, resulting in a breakdown of many functions driven by the SCN, disrupting core clock rhythms in the periphery and disorganizing cellular processes that are normally driven by the synchrony between behavior and peripheral signals with neuronal and humoral output of the hypothalamus. Consequently, we propose that the loss of synchrony between the different elements of this circadian network as may occur during shiftwork and jet lag is the reason for the occurrence of health problems. PMID:27053731

  5. 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.

  6. 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. PMID:22178442

  7. MASSIVE MOLECULAR OUTFLOWS AND NEGATIVE FEEDBACK IN ULIRGs OBSERVED BY HERSCHEL-PACS

    SciTech Connect

    Sturm, E.; Gracia-Carpio, J.; Hailey-Dunsheath, S.; Contursi, A.; Poglitsch, A.; Davies, R.; Genzel, R.; Lutz, D.; Tacconi, L.; De Jong, J. A.; Gonzalez-Alfonso, E.; Veilleux, S.; Fischer, J.; Sternberg, A.; Verma, A.; Maiolino, R.

    2011-05-20

    Mass outflows driven by stars and active galactic nuclei (AGNs) are a key element in many current models of galaxy evolution. They may produce the observed black-hole-galaxy mass relation and regulate and quench both star formation in the host galaxy and black hole accretion. However, observational evidence of such feedback processes through outflows of the bulk of the star-forming molecular gas is still scarce. Here we report the detection of massive molecular outflows, traced by the hydroxyl molecule (OH), in far-infrared spectra of ULIRGs obtained with Herschel-PACS as part of the SHINING key project. In some of these objects the (terminal) outflow velocities exceed 1000 km s{sup -1}, and their outflow rates (up to {approx}1200 M{sub sun} yr{sup -1}) are several times larger than their star formation rates. We compare the outflow signatures in different types of ULIRGs and in starburst galaxies to address the issue of the energy source (AGN or starburst) of these outflows. We report preliminary evidence that ULIRGs with a higher AGN luminosity (and higher AGN contribution to L{sub IR}) have higher terminal velocities and shorter gas depletion timescales. The outflows in the observed ULIRGs are able to expel the cold gas reservoirs from the centers of these objects within {approx}10{sup 6}-10{sup 8} years.

  8. 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

  9. Detection of miRNA regulatory effect on triple negative breast cancer transcriptome.

    PubMed

    Martignetti, Loredana; Tesson, Bruno; Almeida, Anna; Zinovyev, Andrei; Tucker, Gordon C; Dubois, Thierry; Barillot, Emmanuel

    2015-01-01

    Identifying key microRNAs (miRNAs) contributing to the genesis and development of a particular disease is a focus of many recent studies. We introduce here a rank-based algorithm to detect miRNA regulatory activity in cancer-derived tissue samples which combines measurements of gene and miRNA expression levels and sequence-based target predictions. The method is designed to detect modest but coordinated changes in the expression of sequence-based predicted target genes. We applied our algorithm to a cohort of 129 tumour and healthy breast tissues and showed its effectiveness in identifying functional miRNAs possibly involved in the disease. These observations have been validated using an independent publicly available breast cancer dataset from The Cancer Genome Atlas. We focused on the triple negative breast cancer subtype to highlight potentially relevant miRNAs in this tumour subtype. For those miRNAs identified as potential regulators, we characterize the function of affected target genes by enrichment analysis. In the two independent datasets, the affected targets are not necessarily the same, but display similar enriched categories, including breast cancer related processes like cell substrate adherens junction, regulation of cell migration, nuclear pore complex and integrin pathway. The R script implementing our method together with the datasets used in the study can be downloaded here (http://bioinfo-out.curie.fr/projects/targetrunningsum).

  10. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3.

    PubMed

    Li, Kang; Li, Yucheng; Wu, Wenjuan; Gordon, Wendy R; Chang, David W; Lu, Mason; Scoggin, Shane; Fu, Tihui; Vien, Long; Histen, Gavin; Zheng, Ji; Martin-Hollister, Rachel; Duensing, Thomas; Singh, Sanjaya; Blacklow, Stephen C; Yao, Zhengbin; Aster, Jon C; Zhou, Bin-Bing S

    2008-03-21

    The Notch pathway regulates the development of many tissues and cell types and is involved in a variety of human diseases, making it an attractive potential therapeutic target. This promise has been limited by the absence of potent inhibitors or agonists that are specific for individual human Notch receptors (NOTCH1-4). Using an unbiased functional screening, we identified monoclonal antibodies that specifically inhibit or induce activating proteolytic cleavages in NOTCH3. Remarkably, the most potent inhibitory and activating antibodies bind to overlapping epitopes within a juxtamembrane negative regulatory region that protects NOTCH3 from proteolysis and activation in its resting autoinhibited state. The inhibitory antibodies revert phenotypes conveyed on 293T cells by NOTCH3 signaling, such as increased cellular proliferation, survival, and motility, whereas the activating antibody mimics some of the effects of ligand-induced Notch activation. These findings provide insights into the mechanisms of Notch autoinhibition and activation and pave the way for the further development of specific antibody-based modulators of the Notch receptors, which are likely to be of utility in a wide range of experimental and therapeutic settings. PMID:18182388

  11. The inhibitory effects of AR/miR-190a/YB-1 negative feedback loop on prostate cancer and underlying mechanism.

    PubMed

    Xu, Shaohua; Wang, Tao; Song, Wen; Jiang, Tao; Zhang, Feng; Yin, Yu; Jiang, Shi-Wen; Wu, Kongming; Yu, Zuoren; Wang, Chenguang; Chen, Ke

    2015-08-28

    Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. MiR-190a belongs to the small noncoding RNA family and has an important role in breast cancer metastasis. However, it is still unknown whether miR-190a plays a role in prostate cancer development. Herein, we first observed AR/miR-190a/YB-1 forms an auto-regulatory negative feedback loop in prostate cancer: miR-190a expression was down-regulated by AR activation; YB-1 functions are as an AR activator; miR-190a inhibited AR expression and transactivation through direct binding to 3'UTR of YB-1 gene. MiR-190a contributes the human prostate cancer cell growth through AR-dependent signaling. Moreover, we examined the expression of miR-190a and observed a significant decrease in human prostate cancers. Reduced expression of miR-190a was inversely correlated to AR levels of prostate cancer patients, and patients with higher miR-190a expression in their tumor have improved tumor-free survival. Taken together, our findings identified a biochemical and functional link between miR-190a with reduced expression in advanced prostate cancer, YB-1 and AR signaling in prostate cancer.

  12. Negative feedback regulation and desensitization of insulin- and epidermal growth factor-stimulated p21ras activation.

    PubMed

    Langlois, W J; Sasaoka, T; Saltiel, A R; Olefsky, J M

    1995-10-27

    Insulin and epidermal growth factor receptors transmit signals for cell proliferation and gene regulation through formation of active GTP-bound p21ras mediated by the guanine nucleotide exchange factor Sos. Sos is constitutively bound to the adaptor protein Grb2 and growth factor stimulation induces association of the Grb2/Sos complex with Shc and movement of Sos to the plasma membrane location of p21ras. Insulin or epidermal growth factor stimulation induces a rapid increase in p21ras levels, but after several minutes levels decline toward basal despite ongoing hormone stimulation. Here we show that deactivation of p21ras correlates closely with phosphorylation of Sos and dissociation of Sos from Grb2, and that inhibition of mitogen-activated protein (MAP) kinase kinase (also known as extracellular signal-related kinase (ERK) kinase, or MEK) blocks both events, resulting in prolonged p21ras activation. These data suggest that a negative feedback loop exists whereby activation of the Raf/MEK/MAP kinase cascade by p21ras causes Sos phosphorylation and, therefore, Sos/Grb2 dissociation, limiting the duration of p21ras activation by growth factors. A serine/threonine kinase downstream of MEK (probably MAP kinase) mediates this desensitization feedback pathway.

  13. miR-340 and ZEB1 negative feedback loop regulates TGF-β- mediated breast cancer progression

    PubMed Central

    Xie, Ye-Gong; Wang, Jie; Mao, Jie-Fei; Zhang, Bin; Wang, Xin; Cao, Xu-Chen

    2016-01-01

    MicroRNAs act as key regulators in carcinogenesis and progression in various cancers. In present study, we explored the role of miR-340 in the breast cancer progression. Our results showed that overexpression of miR-340 inhibits breast cancer cell proliferation and invasion, whereas depletion of miR-340 promotes breast cancer progression. Molecularly, ZEB1 was identified as a target gene of miR-340 and miR-340 suppressed the expression of ZEB1 by directly binding to the 3′-UTR of ZEB1. Furthermore, ZEB1 transcriptionally suppresses miR-340 expression. The negative feedback loop regulated TGF-β-mediated breast cancer progression. In conclusion, our data suggested that miR-340 acted as a tumor suppressor in breast cancer progression. PMID:27036021

  14. 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. PMID:25224177

  15. 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.

  16. Increased sensitivity to the negative feedback effects of testosterone induced by hyperprolactinemia in the adult male rat.

    PubMed

    McNeilly, A S; Sharpe, R M; Fraser, H M

    1983-01-01

    High plasma levels of PRL induced by transplants of two donor pituitaries under the kidney capsule of adult male rats resulted in a prolonged suppression of plasma levels of LH and FSH although testosterone levels were maintained within normal limits. Castration of rats with pituitary transplants resulted in a normal though delayed rise in serum levels of both LH and FSH to levels equivalent to those in normal castrated controls. This increase in gonadotropin levels occurred in spite of maintenance of elevated PRL levels. Two experiments were carried out in which testosterone was restored after castration by Silastic testosterone-containing implants of various lengths (Exp 1:60, 30, and 10 mm; Exp 2: 30, 20, 10, 5, and 2 mm). In both experiments 60- and 30-mm testosterone implants prevented the postcastration rise in LH and FSH in both control and hyperprolactinemic rats. However, although the shorter testosterone implants delayed this rise in control rats, levels of LH and FSH increased by 4 days and were not significantly different from castrated rats without testosterone implants by 15 days after castration. In contrast, this rise in gonadotropins was abolished or considerably delayed by the shorter implants in hyperprolactinemic rats, demonstrating an increase in sensitivity of the hypothalamic pituitary axis to the negative feedback effects of testosterone in these animals. These results suggest that 1) to maintain suppression of gonadotropin secretion in hyperprolactinemia high levels of PRL alone are insufficient and gonadal steroids are required, and 2) high levels of PRL appear to sensitize the hypothalamic-pituitary axis to the negative feedback effects of gonadal steroids.

  17. Negative feedback effects of chlormadinone acetate and ethynylestradiol on gonadotropin secretion in patients with prostatic cancer and male rats.

    PubMed

    Noguchi, K; Nishimura, R; Takai, S; Arita, J; Higuchi, T; Kawakami, M

    1980-06-01

    Serum LH and FSH levels were determined before and after LH-RH injection (100 micrograms, i.m.) in patients with prostatic cancer who were chronically treated with either chlormadinone acetate (CMA, 100 mg/day) or ethynylestradiol (EE, 1 mg/day). In patients treated with EE, the levels of serum LH and FSH before and after injection of LH-RH were significantly lower than those in controls. On the other hand in patients treated with CMA, the basal levels of serum gonadotropins did not differ from those in controls, and the increase in gonadotropin after LH-RH injection was comparable to that in controls. To examine the effects of these steroids on the hypothalamo-hypophysial axis in the regulation of gonadotropin secretion, CMA or EE was implanted in castrated male rats. CMA, EE or cholesterol (control) was implanted in the hypothalamic median eminence-arcuate nucleus region through a stainless doublecannula. EE implantation resulted in a 75% decrease in serum LH (p < 0.001) and a 38% decrease in serum FSH (p < 0.05) from the control levels on day 5 of implantation. On the other hand, CMA implantation induced a 33% decrease in serum LH (p < 0.05) from the control level on day 3 of implantation, but no significant change in serum FSH levels. The injection of 2 micrograms/kg of LH-RH on day 7 of implantation induced significant lowering of LH and FSH levels. There was no significant difference between serum levels of the hormones 20 min after LH-RH injection for these two groups and those for the control group. These studies suggest that EE has a potent negative feedback effect on both LH and FSH secretion, and that CMA has a mild negative feedback effect on LH secretion.

  18. 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. PMID:25344870

  19. MicroRNA-7/NF-κB signaling regulatory feedback circuit regulates gastric carcinogenesis

    PubMed Central

    Zhao, Xiao-Di; Lu, Yuan-Yuan; Guo, Hao; Xie, Hua-Hong; He, Li-Jie; Shen, Gao-Fei; Zhou, Jin-Feng; Li, Ting; Hu, Si-Jun; Zhou, Lin; Han, Ya-Nan; Liang, Shu-Li; Wang, Xin; Wu, Kai-Chun; Shi, Yong-Quan; Nie, Yong-Zhan

    2015-01-01

    MicroRNAs play essential roles in gene expression regulation during carcinogenesis. Here, we investigated the role of miR-7 and the mechanism by which it is dysregulated in gastric cancer (GC). We used genome-wide screenings and identified RELA and FOS as novel targets of miR-7. Overexpression of miR-7 repressed RELA and FOS expression and prevented GC cell proliferation and tumorigenesis. These effects were clinically relevant, as low miR-7 expression was correlated with high RELA and FOS expression and poor survival in GC patients. Intriguingly, we found that miR-7 indirectly regulated RELA activation by targeting the IκB kinase IKKε. Furthermore, IKKε and RELA can repress miR-7 transcription, which forms a feedback circuit between miR-7 and nuclear factor κB (NF-κB) signaling. Additionally, we demonstrate that down-regulation of miR-7 may occur as a result of the aberrant activation of NF-κB signaling by Helicobacter pylori infection. These findings suggest that miR-7 may serve as an important regulator in GC development and progression. PMID:26261179

  20. Genetic analysis of yeast strains lacking negative feedback control: a one-step method for positive selection and cloning of carbamoylphosphate synthetase-aspartate transcarbamoylase mutants unable to respond to UTP.

    PubMed

    Jaquet, L; Lollier, M; Souciet, J L; Potier, S

    1993-10-01

    We have undertaken an in vivo genetic approach to the analysis of negative feedback control by uridine triphosphate (UTP) of the yeast carbamoylphosphate synthetase-aspartate transcarbamoylase multifunctional protein (CPSase-ATCase). Using an analog of uracil, 5-fluorouracil, we have constructed a screening system leading, in one step, to selection and cloning of a functional aspartate transcarbamoylase that is defective in negative feedback control by UTP. Due to the nature of the screen, spontaneous or UV-induced mutants could be recovered. Well-characterized cloned mutants have been sequenced and reveal one or two modifications in single codons leading to single amino acid replacements. These amino acid changes occurred either in the CPSase or ATCase domains, abolishing their sensitivity to regulation but not their catalytic activities. Hence the regulatory and catalytic sites are distinct. With the same screening system, it may also be possible to enlarge the scope of the molecular study of the feedback processes to include equivalent proteins in fungi as well as higher eukaryotes. PMID:8232215

  1. Threat ≠ prevention, challenge ≠ promotion: the impact of threat, challenge and regulatory focus on attention to negative stimuli.

    PubMed

    Sassenberg, Kai; Sassenrath, Claudia; Fetterman, Adam K

    2015-01-01

    The purpose of the current experiment was to distinguish between the impact of strategic and affective forms of gain- and loss-related motivational states on the attention to negative stimuli. On the basis of the counter-regulation principle and regulatory focus theory, we predicted that individuals would attend more to negative than to neutral stimuli in a prevention focus and when experiencing challenge, but not in a promotion focus and under threat. In one experiment (N = 88) promotion, prevention, threat, or challenge states were activated through a memory task, and a subsequent dot probe task was administered. As predicted, those in the prevention focus and challenge conditions had an attentional bias towards negative words, but those in promotion and threat conditions did not. These findings provide support for the idea that strategic mindsets (e.g., regulatory focus) and hot emotional states (e.g., threat vs. challenge) differently affect the processing of affective stimuli.

  2. Fulfilling desire: evidence for negative feedback between men's testosterone, sociosexual psychology, and sexual partner number.

    PubMed

    Puts, David A; Pope, Lauramarie E; Hill, Alexander K; Cárdenas, Rodrigo A; Welling, Lisa L M; Wheatley, John R; Marc Breedlove, S

    2015-04-01

    Across human societies and many nonhuman animals, males have greater interest in uncommitted sex (more unrestricted sociosexuality) than do females. Testosterone shows positive associations with male-typical sociosexual behavior in nonhuman animals. Yet, it remains unclear whether the human sex difference in sociosexual psychology (attitudes and desires) is mediated by testosterone, whether any relationships between testosterone and sociosexuality differ between men and women, and what the nature of these possible relationships might be. In studies to resolve these questions, we examined relationships between salivary testosterone concentrations and sociosexual psychology and behavior in men and women. We measured testosterone in all men in our sample, but only in those women taking oral contraception (OC-using women) in order to reduce the influence of ovulatory cycle variation in ovarian hormone production. We found that OC-using women did not differ from normally-ovulating women in sociosexual psychology or behavior, but that circulating testosterone mediated the sex difference in human sociosexuality and predicted sociosexual psychology in men but not OC-using women. Moreover, when sociosexual psychology was controlled, men's sociosexual behavior (number of sexual partners) was negatively related to testosterone, suggesting that testosterone drives sociosexual psychology in men and is inhibited when those desires are fulfilled. This more complex relationship between androgens and male sexuality may reconcile some conflicting prior reports.

  3. DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop.

    PubMed

    Abdallah, Basem M; Ditzel, Nicholas; Laborda, Jorge; Karsenty, Gerard; Kassem, Moustapha

    2015-09-01

    The endocrine role of the skeleton in regulating energy metabolism is supported by a feed-forward loop between circulating osteoblast (OB)-derived undercarboxylated osteocalcin (Glu-OCN) and pancreatic β-cell insulin; in turn, insulin favors osteocalcin (OCN) bioactivity. These data suggest the existence of a negative regulation of this cross talk between OCN and insulin. Recently, we identified delta like-1 (DLK1) as an endocrine regulator of bone turnover. Because DLK1 is colocalized with insulin in pancreatic β-cells, we examined the role of DLK1 in insulin signaling in OBs and energy metabolism. We show that Glu-OCN specifically stimulates Dlk1 expression by the pancreas. Conversely, Dlk1-deficient (Dlk1(-/-) ) mice exhibited increased circulating Glu-OCN levels and increased insulin sensitivity, whereas mice overexpressing Dlk1 in OB displayed reduced insulin secretion and sensitivity due to impaired insulin signaling in OB and lowered Glu-OCN serum levels. Furthermore, Dlk1(-/-) mice treated with Glu-OC experienced significantly lower blood glucose levels than Glu-OCN-treated wild-type mice. The data suggest that Glu-OCN-controlled production of DLK1 by pancreatic β-cells acts as a negative feedback mechanism to counteract the stimulatory effects of insulin on OB production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia.

  4. 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. PMID:25354164

  5. 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. PMID:24476134

  6. 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.

  7. Binding of cellular repressor protein or the IE2 protein to a cis-acting negative regulatory element upstream of a human cytomegalovirus early promoter.

    PubMed Central

    Huang, L; Stinski, M F

    1995-01-01

    We have previously shown that the human cytomegalovirus early UL4 promoter has upstream negative and positive cis-acting regulatory elements. In the absence of the upstream negative regulatory region, the positive element confers strong transcriptional activity. The positive element contains a CCAAT box dyad symmetry and binds the cellular transcription factor NF-Y. The effect of the negative regulatory element is negated by the viral IE2 protein (L. Huang, C.L. Malone, and M.F. Stinski, J. Virol. 68:2108, 1994). We investigated the binding of cellular or viral IE2 protein to the negative regulatory region. The major cis-acting negative regulatory element was located between -168 and -134 bp relative to the transcription start site. This element could be transferred to a heterologous promoter, and it functioned in either orientation. Mutational analysis demonstrated that a core DNA sequence in the cis-acting negative regulatory element, 5'-GTTTGGAATCGTT-3', was required for the binding of either a cellular repressor protein(s) or the viral IE2 protein. The cellular DNA binding activity was present in both nonpermissive HeLa and permissive human fibroblast cells but more abundant in HeLa cells. Binding of the cellular repressor protein to the upstream cis-acting negative regulatory element correlates with repression of transcription from the early UL4 promoter. Binding of the viral IE2 protein correlates with negation of the repressive effect. PMID:7494269

  8. Carbon Balance and Greenhouse Gas Fluxes in a Thermokarst Bog in Interior Alaska: Positive and Negative Feedbacks from Permafrost Thaw

    NASA Astrophysics Data System (ADS)

    Waldrop, M. P.; McFarland, J.; Euskirchen, E. S.; Turetsky, M. R.; Harden, J. W.; Manies, K.; Jones, M.; McGuire, A. D.

    2012-12-01

    Climate change in northern latitudes is expected to cause widespread permafrost thaw in Interior Alaska over the 21st century. One result of permafrost thaw is land subsidence and the formation of thermokarst bogs. The net result of permafrost thaw on carbon (C) balance depends on the difference between forest floor carbon loss and Sphagnum productivity in the bog. However, greenhouse gas feedbacks including methane (CH4) and nitrous oxide (N2O) can be significant from a thawed saturated permafrost environment, strongly modifying the net climate forcing caused by CO2 exchange. We hypothesized that the saturated conditions in thermokarst bogs would decrease respiration compared to an intact permafrost forest, potentially promoting net CO2 uptake. However, CH4 and N2O production in the thermokarst bog may reduce any potential negative climate feedback. Our field sites are located at the Alaska Peatland Experiment (APEX), part of the Bonanza Creek LTER outside Fairbanks, Alaska. We examined net changes in C storage, greenhouse gas fluxes, and soil nutrients in a lowland black spruce forest with intact permafrost and an adjacent young thermokarst bog that developed 20-40 years ago. Using combined flux towers and autochambers (0.36 m2), we quantified net ecosystem exchange (NEE), ecosystem respiration (ER), and gross primary productivity (GPP). We also quantified semi-continuous CH4 fluxes using an isotopic CH4 analyzer (Picarro Inc) connected in-line to the autochambers, and N2O was measured using static chambers. Chamber measurements suggest that in mid-summer of 2012 the thermokarst bog was a net sink of CO2, while the understory black spruce was a net source. Furthermore, preliminary chamber measurements from 2012 indicate that thermokarst conditions have decreased respiration compared to the black spruce forest, potentially promoting net CO2 uptake in the bog. However, eddy covariance measurements of CO2 in 2011 indicate that the thermokarst bog was a source of CO2

  9. 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.

  10. 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

  11. Computational modelling of Smad-mediated negative feedback and crosstalk in the TGF-β superfamily network

    PubMed Central

    Nicklas, Daniel; Saiz, Leonor

    2013-01-01

    The transforming growth factor-β (TGF-β) signal transduction pathway controls many cellular processes, including differentiation, proliferation and apoptosis. It plays a fundamental role during development and it is dysregulated in many diseases. The factors that control the dynamics of the pathway, however, are not fully elucidated yet and so far computational approaches have been very limited in capturing the distinct types of behaviour observed under different cellular backgrounds and conditions into a single-model description. Here, we develop a detailed computational model for TGF-β signalling that incorporates elements of previous models together with crosstalking between Smad1/5/8 and Smad2/3 channels through a negative feedback loop dependent on Smad7. The resulting model accurately reproduces the diverse behaviour of experimental datasets for human keratinocytes, bovine aortic endothelial cells and mouse mesenchymal cells, capturing the dynamics of activation and nucleocytoplasmic shuttling of both R-Smad channels. The analysis of the model dynamics and its system properties revealed Smad7-mediated crosstalking between Smad1/5/8 and Smad2/3 channels as a major determinant in shaping the distinct responses to single and multiple ligand stimulation for different cell types. PMID:23804438

  12. The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells.

    PubMed

    Gao, Yuan; Wu, Fuju; Zhou, Jichun; Yan, Lei; Jurczak, Michael J; Lee, Hui-Young; Yang, Lihua; Mueller, Martin; Zhou, Xiao-Bo; Dandolo, Luisa; Szendroedi, Julia; Roden, Michael; Flannery, Clare; Taylor, Hugh; Carmichael, Gordon G; Shulman, Gerald I; Huang, Yingqun

    2014-12-16

    The H19 lncRNA has been implicated in development and growth control and is associated with human genetic disorders and cancer. Acting as a molecular sponge, H19 inhibits microRNA (miRNA) let-7. Here we report that H19 is significantly decreased in muscle of human subjects with type-2 diabetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is recapitulated in vitro where H19 depletion results in impaired insulin signaling and decreased glucose uptake. Furthermore, acute hyperinsulinemia downregulates H19, a phenomenon that occurs through PI3K/AKT-dependent phosphorylation of the miRNA processing factor KSRP, which promotes biogenesis of let-7 and its mediated H19 destabilization. Our results reveal a previously undescribed double-negative feedback loop between sponge lncRNA and target miRNA that contributes to glucose regulation in muscle cells. PMID:25399420

  13. 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.

  14. Escalating risk and the moderating effect of resistance to peer influence on the P200 and feedback-related negativity.

    PubMed

    Kiat, John; Straley, Elizabeth; Cheadle, Jacob E

    2016-03-01

    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

  15. Genetic polymorphisms in circadian negative feedback regulation genes predict overall survival and response to chemotherapy in gastric cancer patients.

    PubMed

    Qu, Falin; Qiao, Qing; Wang, Nan; Ji, Gang; Zhao, Huadong; He, Li; Wang, Haichao; Bao, Guoqiang

    2016-01-01

    Circadian negative feedback loop (CNFL) genes play important roles in cancer development and progression. To evaluate the effects of single nucleotide polymorphisms (SNPs) in CNFL genes on the survival of GC patients, 13 functional SNPs from 5 CNFL genes were genotyped in a cohort of 1030 resected GC patients (704 in the training set, 326 in the validation set) to explore the association of SNPs with overall survival (OS). Among the 13 SNPs, three SNPs (rs1056560 in CRY1, rs3027178 in PER1 and rs228729 in PER3) were significantly associated with OS of GC in the training set, and verified in the validation set and pooled analysis. Furthermore, a dose-dependent cumulative effect of these SNPs on GC survival was observed, and survival tree analysis showed higher order interactions between these SNPs. In addition, protective effect conferred by adjuvant chemotherapy (ACT) on GC was observed in patients with variant alleles (TG/GG) of rs1056560, but not in those with homozygous wild (TT) genotype. Functional assay suggested rs1056560 genotypes significantly affect CRY1 expression in cancer cells. Our study presents that SNPs in the CNFL genes may be associated with GC prognosis, and provides the guidance in selecting potential GC patients most likely responsive to ACT. PMID:26927666

  16. Estrogen-negative feedback and estrous cyclicity are critically dependent upon estrogen receptor-α expression in the arcuate nucleus of adult female mice.

    PubMed

    Yeo, Shel-Hwa; Herbison, Allan E

    2014-08-01

    The location and characteristics of cells within the brain that suppress GnRH neuron activity to contribute to the estrogen-negative feedback mechanism are poorly understood. Using adeno-associated virus (AAV)-mediated Cre-LoxP recombination in estrogen receptor-α (ERα) floxed mice (ERα(flox/flox)), we aimed to examine the role of ERα-expressing neurons located in the arcuate nucleus (ARN) in the estrogen-negative feedback mechanism. Bilateral injection of AAV-Cre into the ARN of ERα(flox/flox) mice (n = 14) resulted in the time-dependent ablation of up to 99% of ERα-immunoreactive cell numbers throughout the rostrocaudal length of the ARN. These mice were all acyclic by 5 weeks after AAV-Cre injections with most mice in constant estrous. Control wild-type mice injected with AAV-Cre (n = 13) were normal. Body weight was not altered in ERα(flox/flox) mice. After ovariectomy, a significant increment in LH secretion was observed in all genotypes, although its magnitude was reduced in ERα(flox/flox) mice. Acute and chronic estrogen-negative feedback were assessed by administering 17β-estradiol to mice as a bolus (LH measured 3 h later) or SILASTIC brand capsule implant (LH measured 5 d later). This demonstrated that chronic estrogen feedback was absent in ERα(flox/flox) mice, whereas the acute feedback was normal. These results reveal a critical role for ERα-expressing cells within the ARN in both estrous cyclicity and the chronic estrogen negative feedback mechanism in female mice. This suggests that ARN cells provide a key indirect, transsynpatic route through which estradiol suppresses the activity of GnRH neurons.

  17. Regulation of the Nanog Gene by Both Positive and Negative cis-Regulatory Elements in Embryonal Carcinoma Cells and Embryonic Stem Cells

    PubMed Central

    Boer, Brian; Cox, Jesse L.; Claassen, David; Mallanna, Sunil Kumar; Desler, Michelle; Rizzino, Angie

    2008-01-01

    The transcription factor Nanog is essential for mammalian embryogenesis, as well as the pluripotency of embryonic stem (ES) cells. Work with ES cells and embryonal carcinoma (EC) cells previously identified positive and negative cis-regulatory elements that influence the activity of the Nanog promoter, including adjacent cis-regulatory elements that bind Sox2 and Oct-3/4. Given the importance of Nanog during mammalian development, we examined the cis-regulatory elements required for Nanog promoter activity more closely. In this study, we demonstrate that two positive cis-regulatory elements previously shown to be active in F9 EC cells are also active in ES cells. We also identify a novel negative regulatory region that is located in close proximity to two other positive Nanog cis-regulatory elements. Although this negative regulatory region is active in F9 EC cells and ES cells, it is inactive in P19 EC cells. Furthermore, we demonstrate that one of the positive cis-regulatory elements active in F9 EC cells and ES cells is inactive in P19 EC cells. Together, these and other studies suggest that Nanog transcription is regulated by the interplay of positive and negative cis-regulatory elements. Given that P19 appears to be more closely related to a later developmental stage of mammalian development than F9 and ES cells, differential utilization of cis-regulatory elements may reflect mechanisms used during development to achieve the correct level of Nanog expression as embryogenesis unfolds. PMID:18537119

  18. 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. PMID:27445719

  19. 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

  20. 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

  1. FRET imaging and statistical signal processing reveal positive and negative feedback loops regulating the morphology of randomly migrating HT-1080 cells.

    PubMed

    Kunida, Katsuyuki; Matsuda, Michiyuki; Aoki, Kazuhiro

    2012-05-15

    Cell migration plays an important role in many physiological processes. Rho GTPases (Rac1, Cdc42, RhoA) and phosphatidylinositols have been extensively studied in directional cell migration. However, it remains unclear how Rho GTPases and phosphatidylinositols regulate random cell migration in space and time. We have attempted to address this issue using fluorescence resonance energy transfer (FRET) imaging and statistical signal processing. First, we acquired time-lapse images of random migration of HT-1080 fibrosarcoma cells expressing FRET biosensors of Rho GTPases and phosphatidyl inositols. We developed an image-processing algorithm to extract FRET values and velocities at the leading edge of migrating cells. Auto- and cross-correlation analysis suggested the involvement of feedback regulations among Rac1, phosphatidyl inositols and membrane protrusions. To verify the feedback regulations, we employed an acute inhibition of the signaling pathway with pharmaceutical inhibitors. The inhibition of actin polymerization decreased Rac1 activity, indicating the presence of positive feedback from actin polymerization to Rac1. Furthermore, treatment with PI3-kinase inhibitor induced an adaptation of Rac1 activity, i.e. a transient reduction of Rac1 activity followed by recovery to the basal level. In silico modeling that reproduced the adaptation predicted the existence of a negative feedback loop from Rac1 to actin polymerization. Finally, we identified MLCK as the probable controlling factor in the negative feedback. These findings quantitatively demonstrate positive and negative feedback loops that involve actin, Rac1 and MLCK, and account for the ordered patterns of membrane dynamics observed in randomly migrating cells.

  2. 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

  3. 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.

  4. Suppressor of Cytokine Signalling-6 Promotes Neurite Outgrowth via JAK2/STAT5-Mediated Signalling Pathway, Involving Negative Feedback Inhibition

    PubMed Central

    Gupta, Sakshi; Mishra, Kanchan; Surolia, Avadhesha; Banerjee, Kakoli

    2011-01-01

    Background Suppressors of cytokine signalling (SOCS) protein family are key regulators of cellular responses to cytokines and play an important role in the nervous system. The SOCS6 protein, a less extensively studied SOCS family member, has been shown to induce insulin resistance in the retina and promote survival of the retinal neurons. But no reports are available about the role of SOCS6 in neuritogenesis. In this study, we examined the role of SOCS6 in neurite outgrowth and neuronal cell signalling. Methodology/Principal Findings The effect of SOCS6 in neural stem cells differentiation was studied in neural stem cells and PC12 cell line. Highly elevated levels of SOCS6 were found upon neural cell differentiation both at the mRNA and protein level. Furthermore, SOCS6 over-expression lead to increase in neurite outgrowth and degree of branching, whereas SOCS6 knockdown with specific siRNAs, lead to a significant decrease in neurite initiation and extension. Insulin-like growth factor-1 (IGF-1) stimulation which enhanced neurite outgrowth of neural cells resulted in further enhancement of SOCS6 expression. Jak/Stat (Janus Kinase/Signal Transducer And Activator Of Transcription) pathway was found to be involved in the SOCS6 mediated neurite outgrowth. Bioinformatics study revealed presence of putative Stat binding sites in the SOCS6 promoter region. Transcription factors Stat5a and Stat5b were involved in SOCS6 gene upregulation leading to neuronal differentiation. Following differentiation, SOCS6 was found to form a ternary complex with IGFR (Insulin Like Growth Factor-1 Receptor) and JAK2 which acted in a negative feedback loop to inhibit pStat5 activation. Conclusion/Significance The current paradigm for the first time states that SOCS6, a SOCS family member, plays an important role in the process of neuronal differentiation. These findings define a novel molecular mechanism for Jak2/Stat5 mediated SOCS6 signalling. PMID:22125600

  5. 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.

  6. Dynamics and control at feedback vertex sets. II: a faithful monitor to determine the diversity of molecular activities in regulatory networks.

    PubMed

    Mochizuki, Atsushi; Fiedler, Bernold; Kurosawa, Gen; Saito, Daisuke

    2013-10-21

    Modern biology provides many networks describing regulations between many species of molecules. It is widely believed that the dynamics of molecular activities based on such regulatory networks are the origin of biological functions. However, we currently have a limited understanding of the relationship between the structure of a regulatory network and its dynamics. In this study we develop a new theory to provide an important aspect of dynamics from information of regulatory linkages alone. We show that the "feedback vertex set" (FVS) of a regulatory network is a set of "determining nodes" of the dynamics. The theory is powerful to study real biological systems in practice. It assures that (i) any long-term dynamical behavior of the whole system, such as steady states, periodic oscillations or quasi-periodic oscillations, can be identified by measurements of a subset of molecules in the network, and that (ii) the subset is determined from the regulatory linkage alone. For example, dynamical attractors possibly generated by a signal transduction network with 113 molecules can be identified by measurement of the activity of only 5 molecules, if the information on the network structure is correct. Our theory therefore provides a rational criterion to select key molecules to control a system. We also demonstrate that controlling the dynamics of the FVS is sufficient to switch the dynamics of the whole system from one attractor to others, distinct from the original.

  7. Trauma exposure and cigarette smoking: the impact of negative affect and affect-regulatory smoking motives.

    PubMed

    Farris, Samantha G; Zvolensky, Michael J; Beckham, Jean C; Vujanovic, Anka A; Schmidt, Norman B

    2014-01-01

    Cognitive-affective mechanisms related to the maintenance of smoking among trauma-exposed individuals are largely unknown. Cross-sectional data from trauma-exposed treatment-seeking smokers (n = 283) were utilized to test a series of multiple mediator models of trauma exposure and smoking, as mediated by the sequential effects of negative affect and affect-modulation smoking motives. The sequential effects of both mediators indirectly predicted the effect of greater trauma exposure types on nicotine dependence, a biochemical index of smoking, perceived barriers to smoking cessation, and greater withdrawal-related problems during past quit attempts. Negative affect and affect-modulation motives for smoking may contribute to the trauma-smoking association.

  8. 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

  9. 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

    2015-01-01

    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.

  10. 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

  11. Leptin-inhibited PBN neurons enhance counter-regulatory responses to hypoglycemia in negative energy balance

    PubMed Central

    D’Agostino, Giuseppe; Goforth, Paulette B.; Sutton, Amy K.; Malec, Paige A.; Wong, Jenny-Marie T.; Germani, Mark; Jones, Justin C.; Rajala, Michael; Satin, Leslie; Rhodes, Christopher J.; Olson, David P.; Kennedy, Robert T.; Heisler, Lora K.; Myers, Martin G.

    2014-01-01

    Hypoglycemia initiates the counter regulatory response (CRR), in which the sympathetic nervous system, glucagon, and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin restrains energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here, we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates leptin receptor (LepRb) and cholecystokinin (CCK)-expressing neurons of the parabrachial nucleus (PBN), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells and Cckcre-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, while their activation mimics the CRR in a CCK-dependent manner. PBN LepRbCCK neurons represent a crucial component of the CRR system, and may represent a therapeutic target in hypoglycemia. PMID:25383904

  12. Identification of a negative regulatory role for spi-C in the murine B cell lineage.

    PubMed

    Li, Stephen K H; Solomon, Lauren A; Fulkerson, Patricia C; DeKoter, Rodney P

    2015-04-15

    Spi-C is an E26 transformation-specific family transcription factor that is highly related to PU.1 and Spi-B. Spi-C is expressed in developing B cells, but its function in B cell development and function is not well characterized. To determine whether Spi-C functions as a negative regulator of Spi-B (encoded by Spib), mice were generated that were germline knockout for Spib and heterozygous for Spic (Spib(-/-)Spic(+/-)). Interestingly, loss of one Spic allele substantially rescued B cell frequencies and absolute numbers in Spib(-/-) mouse spleens. Spib(-/-)Spic(+/-) B cells had restored proliferation compared with Spib(-/-) B cells in response to anti-IgM or LPS stimulation. Investigation of a potential mechanism for the Spib(-/-)Spic(+/-) phenotype revealed that steady-state levels of Nfkb1, encoding p50, were elevated in Spib(-/-)Spic(+/-) B cells compared with Spib(-/-) B cells. Spi-B was shown to directly activate the Nfkb1 gene, whereas Spi-C was shown to repress this gene. These results indicate a novel role for Spi-C as a negative regulator of B cell development and function.

  13. The CaM Kinase CMK-1 Mediates a Negative Feedback Mechanism Coupling the C. elegans Glutamate Receptor GLR-1 with Its Own Transcription

    PubMed Central

    Moss, Benjamin J.; Park, Lidia; Dahlberg, Caroline L.; Juo, Peter

    2016-01-01

    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

  14. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival

    PubMed Central

    Wainwright, Derek A.; Balyasnikova, Irina V.; Chang, Alan L.; Ahmed, Atique U.; Moon, Kyung-Sub; Auffinger, Brenda; Tobias, Alex L.; Han, Yu; Lesniak, Maciej S.

    2012-01-01

    Purpose Glioblastoma multiforme (GBM) is an aggressive adult brain tumor with a poor prognosis. One hallmark of GBM is the accumulation of immunosuppressive and tumor-promoting CD4+FoxP3+GITR+ regulatory T cells (Tregs). Here, we investigated the role of indoleamine 2,3 dioxygenase (IDO) in brain tumors and the impact on Treg recruitment. Experimental Design To determine the clinical relevance of IDO expression in brain tumors, we first correlated patient survival to the level of IDO expression from resected glioma specimens. We also used novel orthotopic and transgenic models of glioma to study how IDO affects Tregs. The impact of tumor-derived and peripheral IDO expression on Treg recruitment, GITR expression and long-term survival was determined. Results Downregulated IDO expression in glioma predicted a significantly better prognosis in patients. Co-incidently, both IDO -competent and -deficient mice showed a survival advantage bearing IDO-deficient brain tumors, when compared to IDO-competent brain tumors. Moreover, IDO-deficiency was associated with a significant decrease in brain-resident Tregs, both in orthotopic and transgenic mouse glioma models. IDO-deficiency was also associated with lower GITR expression levels on Tregs. Interestingly, the long-term survival advantage conferred by IDO-deficiency was lost in T cell-deficient mice. Conclusions These clinical and pre-clinical data confirm that IDO expression increases the recruitment of immunosuppressive Tregs which leads to tumor outgrowth. In contrast, IDO deficiency decreases Treg recruitment and enhances T cell-mediated tumor rejection. Thus, the data suggest a critical role for IDO-mediated immunosuppression in glioma and supports the continued investigation of IDO-Treg interactions in the context of brain tumors. PMID:22932670

  15. Mouse mammary tumor virus proviruses in T-cell lymphomas lack a negative regulatory element in the long terminal repeat.

    PubMed Central

    Hsu, C L; Fabritius, C; Dudley, J

    1988-01-01

    The nucleotide sequences of long terminal repeats (LTRs) from several mouse mammary tumor virus (MMTV) proviruses acquired in mouse T-cell lymphomas were determined. All MMTV proviruses cloned from a C57BL/6 lymphoma contained an identical LTR deletion of 491 base pairs (approximately -655 to -165), whereas an MMTV provirus from a BALB/c T-cell lymphoma had a 430-base-pair deletion in the same U3 region. MMTV proviruses with LTR deletions were acquired in these tumors 10 times more frequently than proviruses with intact LTRs. Because the deletions removed a portion of the glucocorticoid response element or "regulated" enhancer, the transcriptional activity of the deleted MMTV LTRs was assessed in both transient expression and stable transfection experiments. Plasmids were constructed in which the deleted or full-length MMTV LTRs were placed upstream of the chloramphenicol acetyltransferase gene. Results from transfection experiments with these constructs showed that the basal expression of the deleted MMTV LTR in the absence of glucocorticoids was higher than that of the full-length Mtv-17 or C3H MMTV LTRs under the same conditions. Moreover, the C3H LTR with a similar deletion (-637 to -255) also promoted high basal levels of chloramphenicol acetyltransferase activity. These results, coupled with the observation in lymphomas of high basal levels of transcription from MMTV proviruses with deleted LTRs, suggested that these proviruses lack negative regulatory elements in their LTRs. Loss of the negative regulatory element may contribute to the selective propagation of proviruses with deleted LTRs. Images PMID:2846876

  16. Impulsivity and the Association Between the Feedback-Related Negativity and Performance on an Inhibitory Control Task in Young At-Risk Children

    PubMed Central

    Roos, Leslie E.; Pears, Katherine; Bruce, Jacqueline; Kim, Hyoun K.; Fisher, Philip A.

    2015-01-01

    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. PMID:25424570

  17. Reciprocal relationships between behaviour and parasites suggest that negative feedback may drive flexibility in male reproductive behaviour.

    PubMed

    Ezenwa, Vanessa O; Snider, Matthew H

    2016-05-25

    Parasites are ubiquitous components of the environment that contribute to behavioural and life-history variation among hosts. Although it is well known that host behaviour can affect parasite infection risk and that parasites can alter host behaviour, the potential for dynamic feedback between these processes is poorly characterized. Using Grant's gazelle (Nanger granti) as a model, we tested for reciprocal effects of behaviour on parasites and parasites on behaviour to understand whether behaviour-parasite feedback could play a role in maintaining variation in male reproductive behaviour. Adult male gazelles either defend territories to attract mates or reside in bachelor groups. Territoriality is highly variable both within- and between-individuals, suggesting that territory maintenance is costly. Using a combination of longitudinal and experimental studies, we found that individual males transition frequently between territorial and bachelor reproductive status, and that elevated parasite burdens are a cost of territoriality. Moreover, among territorial males, parasites suppress aspects of behaviour related to territory maintenance and defence. These results suggest that territorial behaviour promotes the accumulation of parasites in males, and these parasites dampen the very behaviours required for territory maintenance. Our findings suggest that reciprocal feedback between host behaviour and parasitism could be a mechanism maintaining variation in male reproductive behaviour in the system. PMID:27194703

  18. Reciprocal relationships between behaviour and parasites suggest that negative feedback may drive flexibility in male reproductive behaviour.

    PubMed

    Ezenwa, Vanessa O; Snider, Matthew H

    2016-05-25

    Parasites are ubiquitous components of the environment that contribute to behavioural and life-history variation among hosts. Although it is well known that host behaviour can affect parasite infection risk and that parasites can alter host behaviour, the potential for dynamic feedback between these processes is poorly characterized. Using Grant's gazelle (Nanger granti) as a model, we tested for reciprocal effects of behaviour on parasites and parasites on behaviour to understand whether behaviour-parasite feedback could play a role in maintaining variation in male reproductive behaviour. Adult male gazelles either defend territories to attract mates or reside in bachelor groups. Territoriality is highly variable both within- and between-individuals, suggesting that territory maintenance is costly. Using a combination of longitudinal and experimental studies, we found that individual males transition frequently between territorial and bachelor reproductive status, and that elevated parasite burdens are a cost of territoriality. Moreover, among territorial males, parasites suppress aspects of behaviour related to territory maintenance and defence. These results suggest that territorial behaviour promotes the accumulation of parasites in males, and these parasites dampen the very behaviours required for territory maintenance. Our findings suggest that reciprocal feedback between host behaviour and parasitism could be a mechanism maintaining variation in male reproductive behaviour in the system.

  19. The FERM Protein Yurt Is a Negative Regulatory Component of the Crumbs Complex that Controls Epithelial Polarity and Apical Membrane Size

    PubMed Central

    Laprise, Patrick; Beronja, Slobodan; Silva-Gagliardi, Nancy F.; Pellikka, Milena; Jensen, Abbie M.; McGlade, C. Jane; Tepass, Ulrich

    2010-01-01

    Summary The Crumbs (Crb) complex is a key regulator of epithelial cell architecture where it promotes apical membrane formation. Here, we show that binding of the FERM protein Yurt to the cytoplasmic domain of Crb is part of a negative-feedback loop that regulates Crb activity. Yurt is predominantly a basolateral protein but is recruited by Crb to apical membranes late during epithelial development. Loss of Yurt causes an expansion of the apical membrane in embryonic epithelia and photoreceptor cells similar to Crb overexpression and in contrast to loss of Crb. Analysis of yurt crb double mutants suggests that these genes function in one pathway and that yurt negatively regulates crb. We also show that the mammalian Yurt orthologs YMO1 and EHM2 bind to mammalian Crb proteins. We propose that Yurt is part of an evolutionary conserved negative-feedback mechanism that restricts Crb complex activity in promoting apical membrane formation. PMID:16950127

  20. Effects of affective arousal on choice behavior, reward prediction errors, and feedback-related negativities in human reward-based decision making.

    PubMed

    Liu, Hong-Hsiang; Hsieh, Ming H; Hsu, Yung-Fong; Lai, Wen-Sung

    2015-01-01

    Emotional experience has a pervasive impact on choice behavior, yet the underlying mechanism remains unclear. Introducing facial-expression primes into a probabilistic learning task, we investigated how affective arousal regulates reward-related choice based on behavioral, model fitting, and feedback-related negativity (FRN) data. Sixty-six paid subjects were randomly assigned to the Neutral-Neutral (NN), Angry-Neutral (AN), and Happy-Neutral (HN) groups. A total of 960 trials were conducted. Subjects in each group were randomly exposed to half trials of the pre-determined emotional faces and another half of the neutral faces before choosing between two cards drawn from two decks with different assigned reward probabilities. Trial-by-trial data were fit with a standard reinforcement learning model using the Bayesian estimation approach. The temporal dynamics of brain activity were simultaneously recorded and analyzed using event-related potentials. Our analyses revealed that subjects in the NN group gained more reward values than those in the other two groups; they also exhibited comparatively differential estimated model-parameter values for reward prediction errors. Computing the difference wave of FRNs in reward vs. non-reward trials, we found that, compared to the NN group, subjects in the AN and HN groups had larger "General" FRNs (i.e., FRNs in no-reward trials minus FRNs in reward trials) and "Expected" FRNs (i.e., FRNs in expected reward-omission trials minus FRNs in expected reward-delivery trials), indicating an interruption in predicting reward. Further, both AN and HN groups appeared to be more sensitive to negative outcomes than the NN group. Collectively, our study suggests that affective arousal negatively regulates reward-related choice, probably through overweighting with negative feedback.

  1. Effects of affective arousal on choice behavior, reward prediction errors, and feedback-related negativities in human reward-based decision making

    PubMed Central

    Liu, Hong-Hsiang; Hsieh, Ming H.; Hsu, Yung-Fong; Lai, Wen-Sung

    2015-01-01

    Emotional experience has a pervasive impact on choice behavior, yet the underlying mechanism remains unclear. Introducing facial-expression primes into a probabilistic learning task, we investigated how affective arousal regulates reward-related choice based on behavioral, model fitting, and feedback-related negativity (FRN) data. Sixty-six paid subjects were randomly assigned to the Neutral-Neutral (NN), Angry-Neutral (AN), and Happy-Neutral (HN) groups. A total of 960 trials were conducted. Subjects in each group were randomly exposed to half trials of the pre-determined emotional faces and another half of the neutral faces before choosing between two cards drawn from two decks with different assigned reward probabilities. Trial-by-trial data were fit with a standard reinforcement learning model using the Bayesian estimation approach. The temporal dynamics of brain activity were simultaneously recorded and analyzed using event-related potentials. Our analyses revealed that subjects in the NN group gained more reward values than those in the other two groups; they also exhibited comparatively differential estimated model-parameter values for reward prediction errors. Computing the difference wave of FRNs in reward vs. non-reward trials, we found that, compared to the NN group, subjects in the AN and HN groups had larger “General” FRNs (i.e., FRNs in no-reward trials minus FRNs in reward trials) and “Expected” FRNs (i.e., FRNs in expected reward-omission trials minus FRNs in expected reward-delivery trials), indicating an interruption in predicting reward. Further, both AN and HN groups appeared to be more sensitive to negative outcomes than the NN group. Collectively, our study suggests that affective arousal negatively regulates reward-related choice, probably through overweighting with negative feedback. PMID:26042057

  2. HMBA Enhances Prostratin-Induced Activation of Latent HIV-1 via Suppressing the Expression of Negative Feedback Regulator A20/TNFAIP3 in NF-κB Signaling

    PubMed Central

    Chen, Duchu; Wang, Huiping; Aweya, Jude Juventus; Chen, Yanheng; Chen, Meihua; Wu, Xiaomeng; Chen, Xiaonan; Lu, Jing

    2016-01-01

    In the past decade, much emphasis has been put on the transcriptional activation of HIV-1, which is proposed as a promised strategy for eradicating latent HIV-1 provirus. Two drugs, prostratin and hexamethylene bisacetamide (HMBA), have shown potent effects as inducers for releasing HIV-1 latency when used alone or in combination, although their cellular target(s) are currently not well understood, especially under drug combination. Here, we have shown that HMBA and prostratin synergistically release HIV-1 latency via different mechanisms. While prostratin strongly stimulates HMBA-induced HIV-1 transcription via improved P-TEFb activation, HMBA is capable of boosting NF-κB-dependent transcription initiation by suppressing prostratin-induced expression of the deubiquitinase A20, a negative feedback regulator in the NF-κB signaling pathway. In addition, HMBA was able to increase prostratin-induced phosphorylation and degradation of NF-κB inhibitor IκBα, thereby enhancing and prolonging prostratin-induced nuclear translocation of NF-κB, a prerequisite for stimulation of transcription initiation. Thus, by blocking the negative feedback circuit, HMBA functions as a signaling enhancer of the NF-κB signaling pathway. PMID:27529070

  3. Identification of positive and negative regulatory elements governing cell-type-specific expression of the neural cell adhesion molecule gene.

    PubMed Central

    Hirsch, M R; Gaugler, L; Deagostini-Bazin, H; Bally-Cuif, L; Goridis, C

    1990-01-01

    The neural cell adhesion molecule (NCAM) is one of the most prevalent cell adhesion molecules in vertebrates. Its expression is subject to complex cell-type- and developmental-stage-dependent regulation. To study this regulation at the level of transcription, we analyzed the promoter region of the mouse NCAM gene. The NCAM promoter did not contain a typical TATA box. Transcription started at several sites that were used indiscriminately by different cell types, implying that the different NCAM isoforms are expressed from a single promoter. Sequences responsible for both promotion and inhibition of transcription resided within 840 base pairs upstream of the main transcriptional start site. The sequence from positions -645 to -37 relative to the translation initiation site directed high levels of expression in NCAM-expressing N2A cells. The same fragment was six times less active but still significantly active in L cells, but this activity was repressed by inclusion of an additional upstream segment. We mapped eight domains of interactions with nuclear proteins within the 840-base-pair region. The segment with maximum promoter activity contained two adjacent footprints, the occupation of which appeared to be mutually exclusive. One of them corresponded to an Sp1-factor-binding consensus site, the other one bound a factor with nuclear factor I activity. The single protected domain in the fragment harboring a repressor activity consisted of a GGA repeat resembling negative regulatory elements in other promoters. Three adjacent binding sites occupied an A + T-rich segment and contained ATTA motifs also found in the recognition elements of homeodomain proteins. These results show that negative and positive elements interact to regulate the tissue-specific patterns of expression of the NCAM gene and indicate that a factor related to nuclear factor I is involved in its transcriptional control. Images PMID:2325642

  4. Overexpression of the Dominant-Negative Form of Interferon Regulatory Factor 1 in Oligodendrocytes Protects against Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Ren, Zhihua; Wang, Yan; Tao, Duan; Liebenson, David; Liggett, Thomas; Goswami, Rajendra; Clarke, Robert; Stefoski, Dusan

    2011-01-01

    Interferon regulatory factor 1 (IRF-1) is a transcription factor that has been implicated in the pathogenesis of the human autoimmune demyelinating disease multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). The goal of the present study was to directly examine the role of IRF-1 in oligodendrocyte injury and inflammatory demyelination. For the purpose of this study, we generated a transgenic mouse line (CNP/dnIRF-1) that overexpresses the dominant-negative form of IRF-1 (dnIRF1) specifically in oligodendrocytes. CNP/dnIRF-1 mice exhibited no phenotypic abnormalities but displayed suppressed IRF-1 signaling in oligodendrocytes. The major finding of our study was that the CNP/dnIRF-1 mice, compared with the wild-type mice, were protected against EAE, a phenomenon associated with significant reduction of inflammatory demyelination and with oligodendrocyte and axonal preservation. The observed protection was related to suppressed IRF-1 signaling and impaired expression of immune and proapoptotic genes in oligodendrocytes. No significant differences in the peripheral immune responses between the wild-type and the CNP/dnIRF-1 mice were identified throughout the experiments. This study indicates that IRF-1 plays a critical role in the pathogenesis of EAE by mediating oligodendrocyte response to inflammation and injury. It also suggests that oligodendrocytes are actively involved in the neuroimmune network, and that exploring oligodendrocyte-related pathogenic mechanisms, in addition to the conventional immune-based ones, may have important therapeutic implications in MS. PMID:21653838

  5. 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.

  6. The LSD1 Family of Histone Demethylases and the Pumilio Posttranscriptional Repressor Function in a Complex Regulatory Feedback Loop

    PubMed Central

    Miles, Wayne O.; Lepesant, Julie M. J.; Bourdeaux, Jessie; Texier, Manuela; Kerenyi, Marc A.; Nakakido, Makoto; Hamamoto, Ryuji; Orkin, Stuart H.; Dyson, Nicholas J.

    2015-01-01

    The lysine (K)-specific demethylase (LSD1) family of histone demethylases regulates chromatin structure and the transcriptional potential of genes. LSD1 is frequently deregulated in tumors, and depletion of LSD1 family members causes developmental defects. Here, we report that reductions in the expression of the Pumilio (PUM) translational repressor complex enhanced phenotypes due to dLsd1 depletion in Drosophila. We show that the PUM complex is a target of LSD1 regulation in fly and mammalian cells and that its expression is inversely correlated with LSD1 levels in human bladder carcinoma. Unexpectedly, we find that PUM posttranscriptionally regulates LSD1 family protein levels in flies and human cells, indicating the existence of feedback loops between the LSD1 family and the PUM complex. Our results highlight a new posttranscriptional mechanism regulating LSD1 activity and suggest that the feedback loop between the LSD1 family and the PUM complex may be functionally important during development and in human malignancies. PMID:26438601

  7. Multisite light-induced phosphorylation of the transcription factor PIF3 is necessary for both its rapid degradation and concomitant negative feedback modulation of photoreceptor phyB levels in Arabidopsis.

    PubMed

    Ni, Weimin; Xu, Shou-Ling; Chalkley, Robert J; Pham, Thao Nguyen D; Guan, Shenheng; Maltby, Dave A; Burlingame, Alma L; Wang, Zhi-Yong; Quail, Peter H

    2013-07-01

    Plants constantly monitor informational light signals using sensory photoreceptors, which include the phytochrome (phy) family (phyA to phyE), and adjust their growth and development accordingly. Following light-induced nuclear translocation, photoactivated phy molecules bind to and induce rapid phosphorylation and degradation of phy-interacting basic Helix Loop Helix (bHLH) transcription factors (PIFs), such as PIF3, thereby regulating the expression of target genes. However, the mechanisms underlying the signal-relay process are still not fully understood. Here, using mass spectrometry, we identify multiple, in vivo, light-induced Ser/Thr phosphorylation sites in PIF3. Using transgenic expression of site-directed mutants of PIF3, we provide evidence that a set of these phosphorylation events acts collectively to trigger rapid degradation of the PIF3 protein in response to initial exposure of dark-grown seedlings to light. In addition, we show that phyB-induced PIF3 phosphorylation is also required for the known negative feedback modulation of phyB levels in prolonged light, potentially through codegradation of phyB and PIF3. This mutually regulatory intermolecular transaction thus provides a mechanism with the dual capacity to promote early, graded, or threshold regulation of the primary, PIF3-controlled transcriptional network in response to initial light exposure, and later, to attenuate global sensitivity to the light signal through reductions in photoreceptor levels upon prolonged exposure. PMID:23903316

  8. Individual differences in reward prediction error: contrasting relations between feedback-related negativity and trait measures of reward sensitivity, impulsivity and extraversion

    PubMed Central

    Cooper, Andrew J.; Duke, Éilish; Pickering, Alan D.; Smillie, Luke D.

    2014-01-01

    Medial-frontal negativity occurring ∼200–300 ms post-stimulus in response to motivationally salient stimuli, usually referred to as feedback-related negativity (FRN), appears to be at least partly modulated by dopaminergic-based reward prediction error (RPE) signaling. Previous research (e.g., Smillie et al., 2011) has shown that higher scores on a putatively dopaminergic-based personality trait, extraversion, were associated with a more pronounced difference wave contrasting unpredicted non-reward and unpredicted reward trials on an associative learning task. In the current study, we sought to extend this research by comparing how trait measures of reward sensitivity, impulsivity and extraversion related to the FRN using the same associative learning task. A sample of healthy adults (N = 38) completed a battery of personality questionnaires, before completing the associative learning task while EEG was recorded. As expected, FRN was most negative following unpredicted non-reward. A difference wave contrasting unpredicted non-reward and unpredicted reward trials was calculated. Extraversion, but not measures of impulsivity, had a significant association with this difference wave. Further, the difference wave was significantly related to a measure of anticipatory pleasure, but not consummatory pleasure. These findings provide support for the existing evidence suggesting that variation in dopaminergic functioning in brain “reward” pathways may partially underpin associations between the FRN and trait measures of extraversion and anticipatory pleasure. PMID:24808845

  9. The Feedback-Related Negativity and the P300 Brain Potential Are Sensitive to Price Expectation Violations in a Virtual Shopping Task

    PubMed Central

    Schaefer, Alexandre; Buratto, Luciano G.; Goto, Nobuhiko; Brotherhood, Emilie V.

    2016-01-01

    A large body of evidence shows that buying behaviour is strongly determined by consumers’ price expectations and the extent to which real prices violate these expectations. Despite the importance of this phenomenon, little is known regarding its neural mechanisms. Here we show that two patterns of electrical brain activity known to index prediction errors–the Feedback-Related Negativity (FRN) and the feedback-related P300 –were sensitive to price offers that were cheaper than participants’ expectations. In addition, we also found that FRN amplitude time-locked to price offers predicted whether a product would be subsequently purchased or not, and further analyses suggest that this result was driven by the sensitivity of the FRN to positive price expectation violations. This finding strongly suggests that ensembles of neurons coding positive prediction errors play a critical role in real-life consumer behaviour. Further, these findings indicate that theoretical models based on the notion of prediction error, such as the Reinforcement Learning Theory, can provide a neurobiologically grounded account of consumer behavior. PMID:27658301

  10. Endogenous opioids participate in the regulation of the hypothalamus-pituitary-luteinizing hormone axis and testosterone's negative feedback control of luteinizing hormone.

    PubMed

    Cicero, T J; Schainker, B A; Meyer, E R

    1979-05-01

    Two narcotic antagonists, naloxone and naltrexone, significantly elevated serum LH levels in male rats within minutes after their sc injection. The peak increase in serum LH occurred 20 min after the injection. Naloxone increased LH levels up to a dose of 1 mg/kg, after which no further increases were found. A dose of 0.35 mg/kg produced a half-maximal response. The exogenous opioid morphine blocked the increase in LH produced by naloxone in a dose-dependent fashion, suggesting that the specific receptor-blocking effects of the antagonist could account for its enhancement of serum LH levels. The locus of action of naloxone within the hypothalamic-pituitary-LH axis appeared to be at the level of the hypothalamus since the drug had no effect on LHRH-stimulated release of LH by the anterior pituitary and did not block dihydrotestosterone's suppression of pituitary LH release in vitro. Naloxone also prevented testosterone's negative feedback inhibition of serum LH in the castrated male rat. The results of these studies suggest that endogenous opioids exist in brain tissue which normally inhibit activity in the hypothalamic-pituitary-LH axis and participate in the androgen-dependent feedback control of LH elaboration by this axis. PMID:374068

  11. Dissociated roles of the anterior cingulate cortex in reward and conflict processing as revealed by the feedback error-related negativity and N200.

    PubMed

    Baker, Travis E; Holroyd, Clay B

    2011-04-01

    The reinforcement learning theory of the error-related negativity (ERN) holds that the impact of reward signals carried by the midbrain dopamine system modulates activity of the anterior cingulate cortex (ACC), alternatively disinhibiting and inhibiting the ACC following unpredicted error and reward events, respectively. According to a recent formulation of the theory, activity that is intrinsic to the ACC produces a component of the event-related brain potential (ERP) called the N200, and following unpredicted rewards, the N200 is suppressed by extrinsically applied positive dopamine reward signals, resulting in an ERP component called the feedback-ERN (fERN). Here we demonstrate that, despite extensive spatial and temporal overlap between the two ERP components, the functional processes indexed by the N200 (conflict) and the fERN (reward) are dissociable. These results point toward avenues for future investigation.

  12. Dissociated roles of the anterior cingulate cortex in reward and conflict processing as revealed by the feedback error-related negativity and N200.

    PubMed

    Baker, Travis E; Holroyd, Clay B

    2011-04-01

    The reinforcement learning theory of the error-related negativity (ERN) holds that the impact of reward signals carried by the midbrain dopamine system modulates activity of the anterior cingulate cortex (ACC), alternatively disinhibiting and inhibiting the ACC following unpredicted error and reward events, respectively. According to a recent formulation of the theory, activity that is intrinsic to the ACC produces a component of the event-related brain potential (ERP) called the N200, and following unpredicted rewards, the N200 is suppressed by extrinsically applied positive dopamine reward signals, resulting in an ERP component called the feedback-ERN (fERN). Here we demonstrate that, despite extensive spatial and temporal overlap between the two ERP components, the functional processes indexed by the N200 (conflict) and the fERN (reward) are dissociable. These results point toward avenues for future investigation. PMID:21295109

  13. Negative Feedback Control of Jasmonate Signaling by an Alternative Splice Variant of JAZ101[C][W][OA

    PubMed Central

    Moreno, Javier E.; Shyu, Christine; Campos, Marcelo L.; Patel, Lalita C.; Chung, Hoo Sun; Yao, Jian; He, Sheng Yang; Howe, Gregg A.

    2013-01-01

    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. PMID:23632853

  14. Synergism between insecticides permethrin and propoxur occurs through activation of presynaptic muscarinic negative feedback of acetylcholine release in the insect central nervous system.

    PubMed

    Corbel, Vincent; Stankiewicz, Maria; Bonnet, Julien; Grolleau, Françoise; Hougard, Jean Marc; Lapied, Bruno

    2006-07-01

    Although synergism between pesticides has been widely documented, the physiological mechanisms by which an insecticide synergizes another remains unclear. Toxicological and electrophysiological studies were carried out on two susceptible pest species (the mosquito Culex quinquefasciatus and the cockroach Periplaneta americana) to understand better the physiological process involved in pyrethroid and carbamate interactions. Larval bioassays were conducted with the susceptible reference strain SLAB of C. quinquefasciatus to assess the implication of multi-function oxidases and non-specific esterases in insecticide detoxification and synergism. Results showed that the general theory of synergism (competition between pesticides for a common detoxification enzyme) was unlikely to occur in the SLAB strain since the level of synergy recorded between permethrin and propoxur was unchanged in the presence of piperonyl butoxide and tribufos, two inhibitors of oxidases and esterases, respectively (synergism ratios were similar with and without synergists). We also showed that addition of a sub-lethal concentration of nicotine significantly increased the toxicity of permethrin and propoxur at the lower range of the dose-mortality regression lines, suggesting the manifestation of important physiological disruptions at synaptic level. The effects of both permethrin and propoxur were studied on the cercal-afferent giant-interneuron synapses in the terminal abdominal ganglion of the cockroach P. americana using the single-fibre oil-gap method. We demonstrated that permethrin and propoxur increased drastically the ACh concentration within the synaptic cleft, which thereby stimulated a negative feedback of ACh release. Atropine, a muscarinic receptor antagonist, reversed the effect of permethrin and propoxur mixtures. This demonstrates the implication of the presynaptic muscarinic receptors in the negative feedback regulation process and in synergism. Based on these findings, we

  15. ttm-1 encodes CDF transporters that excrete zinc from intestinal cells of C. elegans and act in a parallel negative feedback circuit that promotes homeostasis.

    PubMed

    Roh, Hyun Cheol; Collier, Sara; Deshmukh, Krupa; Guthrie, James; Robertson, J David; Kornfeld, Kerry

    2013-05-01

    Zinc is an essential metal involved in a wide range of biological processes, and aberrant zinc metabolism is implicated in human diseases. The gastrointestinal tract of animals is a critical site of zinc metabolism that is responsible for dietary zinc uptake and distribution to the body. However, the role of the gastrointestinal tract in zinc excretion remains unclear. Zinc transporters are key regulators of zinc metabolism that mediate the movement of zinc ions across membranes. Here, we identified a comprehensive list of 14 predicted Cation Diffusion Facilitator (CDF) family zinc transporters in Caenorhabditis elegans and demonstrated that zinc is excreted from intestinal cells by one of these CDF proteins, TTM-1B. The ttm-1 locus encodes two transcripts, ttm-1a and ttm-1b, that use different transcription start sites. ttm-1b expression was induced by high levels of zinc specifically in intestinal cells, whereas ttm-1a was not induced by zinc. TTM-1B was localized to the apical plasma membrane of intestinal cells, and analyses of loss-of-function mutant animals indicated that TTM-1B promotes zinc excretion into the intestinal lumen. Zinc excretion mediated by TTM-1B contributes to zinc detoxification. These observations indicate that ttm-1 is a component of a negative feedback circuit, since high levels of cytoplasmic zinc increase ttm-1b transcript levels and TTM-1B protein functions to reduce the level of cytoplasmic zinc. We showed that TTM-1 isoforms function in tandem with CDF-2, which is also induced by high levels of cytoplasmic zinc and reduces cytoplasmic zinc levels by sequestering zinc in lysosome-related organelles. These findings define a parallel negative feedback circuit that promotes zinc homeostasis and advance the understanding of the physiological roles of the gastrointestinal tract in zinc metabolism in animals.

  16. Fulfilling Desire: Evidence for negative feedback between men’s testosterone, sociosexual psychology, and sexual partner number

    PubMed Central

    Puts, David A.; Pope, Lauramarie E.; Hill, Alexander K.; Cárdenas, Rodrigo A.; Welling, Lisa L. M.; Wheatley, John R.; Breedlove, S. Marc

    2015-01-01

    Across human societies and many nonhuman animals, males have greater interest in uncommitted sex (more unrestricted sociosexuality) than do females. Testosterone shows positive associations with male-typical sociosexual behavior in nonhuman animals. Yet, it remains unclear whether the human sex difference in sociosexual psychology (attitudes and desires) is mediated by testosterone, whether any relationships between testosterone and sociosexuality differ between men and women, and what the nature of these possible relationships might be. In studies to resolve these questions, we examined relationships between salivary testosterone concentrations and sociosexual psychology and behavior in men and women. We measured testosterone in all men in our sample, but only in those women taking oral contraception (OC-using women) in order to reduce the influence of ovulatory cycle variation in ovarian hormone production. We found that OC-using women did not differ from normally-ovulating women in sociosexual psychology or behavior, but that circulating testosterone mediated the sex difference in human sociosexuality and predicted sociosexual psychology in men but not OC-using women. Moreover, when sociosexual psychology was controlled, men’s sociosexual behavior (number of sexual partners) was negatively related to testosterone, suggesting that testosterone drives sociosexual psychology in men and is inhibited when those desires are fulfilled. This more complex relationship between androgen and male sexuality may reconcile some conflicting prior reports. PMID:25644313

  17. A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling

    PubMed Central

    Vullhorst, Detlef; Mitchell, Robert M.; Keating, Carolyn; Roychowdhury, Swagata; Karavanova, Irina; Tao-Cheng, Jung-Hwa; Buonanno, Andres

    2015-01-01

    The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization. However, little is known about the endogenous ligands that engage ErbB4, the neural processes that activate them or their direct downstream targets. Here we demonstrate, in cultured neurons and in acute slices, that the NMDA receptor is both effector and target of neuregulin 2 (NRG2)/ErbB4 signalling in cortical interneurons. Interneurons co-express ErbB4 and NRG2, and pro-NRG2 accumulates on cell bodies atop subsurface cisternae. NMDA receptor activation rapidly triggers shedding of the signalling-competent NRG2 extracellular domain. In turn, NRG2 promotes ErbB4 association with GluN2B-containing NMDA receptors, followed by rapid internalization of surface receptors and potent downregulation of NMDA but not AMPA receptor currents. These effects occur selectively in ErbB4-positive interneurons and not in ErbB4-negative pyramidal neurons. Our findings reveal an intimate reciprocal relationship between ErbB4 and NMDA receptors with possible implications for the modulation of cortical microcircuits associated with cognitive deficits in psychiatric disorders. PMID:26027736

  18. Multistationarity, the basis of cell differentiation and memory. II. Logical analysis of regulatory networks in terms of feedback circuits.

    PubMed

    Thomas, R.; Kaufman, M.

    2001-03-01

    Circuits and their involvement in complex dynamics are described in differential terms in Part I of this work. Here, we first explain why it may be appropriate to use a logical description, either by itself or in symbiosis with the differential description. The major problem of a logical description is to find an adequate way to involve time. The procedure we adopted differs radically from the classical one by its fully asynchronous character. In Sec. II we describe our "naive" logical approach, and use it to illustrate the major laws of circuitry (namely, the involvement of positive circuits in multistationarity and of negative circuits in periodicity) and in a biological example. Already in the naive description, the major steps of the logical description are to: (i) describe a model as a set of logical equations, (ii) derive the state table from the equations, (iii) derive the graph of the sequences of states from the state table, and (iv) determine which of the possible pathways will be actually followed in terms of time delays. In the following sections we consider multivalued variables where required, the introduction of logical parameters and of logical values ascribed to the thresholds, and the concept of characteristic state of a circuit. This generalized logical description provides an image whose qualitative fit with the differential description is quite remarkable. A major interest of the generalized logical description is that it implies a limited and often quite small number of possible combinations of values of the logical parameters. The space of the logical parameters is thus cut into a limited number of boxes, each of which is characterized by a defined qualitative behavior of the system. Our analysis tells which constraints on the logical parameters must be fulfilled in order for any circuit (or combination of circuits) to be functional. Functionality of a circuit will result in multistationarity (in the case of a positive circuit) or in a cycle

  19. Initiation of active immunization against testosterone during early puberty alters negative feedback regulation of the hypothalamic-pituitary-testicular axis in rabbits.

    PubMed

    Han, X F; Cheng, W; Chen, Z Y; Du, X G; Cao, X H; Zeng, X Y

    2014-07-01

    To investigate the effects of antitestosterone immunization, initiated during early puberty, on hypothalamic-pituitary-testicular feedback in rabbits, 16 early pubertal male rabbits were randomly allocated into 2 groups (n = 8), control or immunized against testosterone-3(O-carboxymethyl)oxime-BSA in Freund adjuvant at 4 mo of age (with a booster immunization 4 wk later). Blood samples (for antibody titers and hormone concentrations) were collected at 2- or 4-wk intervals after immunization. Compared with controls, antitestosterone immunization triggered: a substantial and sustained antibody response (P < 0.01); increases in serum concentrations of luteinizing hormone (LH) and testosterone and testis weight and volume (P < 0.05); hyperplasia of testicular interstitial tissue with clustered and hypertrophic Leydig cells; and greater (P < 0.05) enzyme protein and messenger RNA (mRNA) expression levels for testicular cholesterol side-chain cleavage cytochrome P-450, 17α-hydroxylase cytochrome P-450, and 3β-dydroxysteroid dehydrogenase. Furthermore, immunoneutralization of testosterone upregulated mRNA expressions for genes in sex steroid negative feedback loops, including androgen receptor (AR), estrogen receptor alpha (ER-α), kisspeptin encoded gene (kiss-1) and kisspeptin receptor (G-coupled receptor 54) and gonadotropin-releasing hormone (GnRH) in the hypothalamic arcuate nucleus, GnRH receptor and LH-β in pituitary, and AR, inhibin-α and βA subunits in testes (P < 0.05). However, immunization did not affect mRNA expressions for follicle-stimulating hormone β, AR, and ER-α in pituitary, or ER-α in testes. We concluded that antitestosterone immunization in male rabbits, initiated during early puberty, increased GnRH mRNA expression, and in turn LH synthesis by reducing testicular feedback signaling. Reduction of direct steroidal effects on the testis may also have increased testosterone secretion. Consequently, there was an accelerated testicular

  20. Shrimp with knockdown of LvSOCS2, a negative feedback loop regulator of JAK/STAT pathway in Litopenaeus vannamei, exhibit enhanced resistance against WSSV.

    PubMed

    Wang, Sheng; Song, Xuan; Zhang, Zijian; Li, Haoyang; L, Kai; Yin, Bin; He, Jianguo; Li, Chaozheng

    2016-12-01

    JAK/STAT pathway is one of cytokine signaling pathways and mediates diversity immune responses to protect host from viral infection. In this study, LvSOCS2, a member of suppressor of cytokine signaling (SOCS) families, has been cloned and identified from Litopenaeus vannamei. The full length of LvSOCS2 is 1601 bp, including an 1194 bp open reading frame (ORF) coding for a putative protein of 397 amino acids with a calculated molecular weight of ∼42.3 kDa. LvSOCS2 expression was most abundant in gills and could respond to the challenge of LPS, Vibrio parahaemolyticus, Staphhylococcus aureus, Poly (I: C) and white spot syndrome virus (WSSV). There are several STAT binding motifs presented in the proximal promoter region of LvSOCS2 and its expression was induced by LvJAK or LvSTAT protein in a dose dependent manner, suggesting LvSOCS2 could be the transcriptional target gene of JAK/STAT pathway. Moreover, the transcription of DmVir-1, a read out of the activation of JAK/STAT pathway in Drosophila, was promoted by LvJAK but inhibited by LvSOCS2, indicating that LvSOCS2 could be a negative regulator in this pathway and thus can form a negative feedback loop. Our previous study indicated that shrimp JAK/STAT pathway played a positive role against WSSV. In this study, RNAi-mediated knockdown of LvSOCS2 shrimps showed lower susceptibility to WSSV infection and caused lessened virus loads, which further demonstrated that the JAK/STAT pathway could function as an anti-viral immunity in shrimp. PMID:27497874

  1. Shrimp with knockdown of LvSOCS2, a negative feedback loop regulator of JAK/STAT pathway in Litopenaeus vannamei, exhibit enhanced resistance against WSSV.

    PubMed

    Wang, Sheng; Song, Xuan; Zhang, Zijian; Li, Haoyang; L, Kai; Yin, Bin; He, Jianguo; Li, Chaozheng

    2016-12-01

    JAK/STAT pathway is one of cytokine signaling pathways and mediates diversity immune responses to protect host from viral infection. In this study, LvSOCS2, a member of suppressor of cytokine signaling (SOCS) families, has been cloned and identified from Litopenaeus vannamei. The full length of LvSOCS2 is 1601 bp, including an 1194 bp open reading frame (ORF) coding for a putative protein of 397 amino acids with a calculated molecular weight of ∼42.3 kDa. LvSOCS2 expression was most abundant in gills and could respond to the challenge of LPS, Vibrio parahaemolyticus, Staphhylococcus aureus, Poly (I: C) and white spot syndrome virus (WSSV). There are several STAT binding motifs presented in the proximal promoter region of LvSOCS2 and its expression was induced by LvJAK or LvSTAT protein in a dose dependent manner, suggesting LvSOCS2 could be the transcriptional target gene of JAK/STAT pathway. Moreover, the transcription of DmVir-1, a read out of the activation of JAK/STAT pathway in Drosophila, was promoted by LvJAK but inhibited by LvSOCS2, indicating that LvSOCS2 could be a negative regulator in this pathway and thus can form a negative feedback loop. Our previous study indicated that shrimp JAK/STAT pathway played a positive role against WSSV. In this study, RNAi-mediated knockdown of LvSOCS2 shrimps showed lower susceptibility to WSSV infection and caused lessened virus loads, which further demonstrated that the JAK/STAT pathway could function as an anti-viral immunity in shrimp.

  2. Brain-midgut cross-talk and autocrine metabolastat via the sNPF/CCAP negative feed-back loop in the American cockroach, Periplaneta americana.

    PubMed

    Mikani, Azam; Watari, Yasuhiko; Takeda, Makio

    2015-12-01

    Immunohistochemical reactivities against short neuropeptide F (sNPF-ir) and crustacean cardioactive peptide (CCAP-ir) were detected in both the brain-subesophageal ganglion (Br-SOG) and midgut epithelial cells of the male American cockroach, Periplaneta americana. Four weeks of starvation increased the number of sNPF-ir cells and decreased the CCAP-ir cells in the Br-SOG, whereas refeeding reversed these effects. The contents of sNPF in the Br-SOG, midgut and hemolymph titer decreased in response to an injection of CCAP into the hemocoel of normally fed male cockroaches, while CCAP titers/contents decreased in response to an injection of sNPF. The results of a double-labeling experiment demonstrated that sNPF-ir co-existed in CCAP-ir cells in the pars intercerebralis (PI), dorsolateral region of protocerebrum (DL), deutocerebrum (De) and SOG. sNPF-ir and CCAP-ir were also colocalized in the midgut. sNPF and CCAP are neuropeptides and midgut factors that interact with each other. Since the two peptides are known to be secreted by identical cells that affect each other, this constitutes autocrine negative feedback regulation for a quick response to food accessibility/inaccessibility. These peptides not only constitute the switch in the digestive mechanism but also couple digestive adaptation with behavior. A CCAP injection suppressed locomotor activity when cockroaches were starved, whereas sNPF activated it when they were fed.

  3. General, negative feedback mechanism for regulation of Trithorax-like gene expression in vivo: new roles for GAGA factor in flies.

    PubMed

    Bernués, Jordi; Piñeyro, David; Kosoy, Ana

    2007-01-01

    Expression of every gene is first regulated at the transcriptional level. While some genes show acute and discrete periods of expression others show a rather steady expression level throughout development. An example of the latter is Trithorax-like (Trl) a member of the Trithorax group that encodes GAGA factor in Drosophila. Among other functions, GAGA factor has been described to stimulate transcription of several genes, including some homeotic genes. Here we show that GAGA factor is continuously down-regulating the expression of its own promoter using a negative feedback mechanism in vivo. Like its expression, repression by GAGA factor is ubiquitous, prevents its accumulation, and takes place throughout development. Experimental alteration of GAGA factor dosage results in several unexpected phenotypes, not related to alteration of homeotic gene expression, but rather to functions that take place later during development and affect different morphogenetic processes. The results suggest that GAGA factor is essential during development, even after homeotic gene expression is established, and indicate the existence of an upper limit for GAGA factor dosage that should not be exceeded.

  4. TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING

    PubMed Central

    Yang, Bo; Yan, Shanshan; Zhou, Haiyan; He, Lan; Lin, Guomei; Lian, Zhexiong; Jiang, Zhengfan; Sun, Bing

    2015-01-01

    Uncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30α (TRIM30α) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30α augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING. PMID:26114947

  5. Identification of a negative feedback loop between cyclic di-GMP-induced levels of IFI16 and p202 cytosolic DNA sensors and STING.

    PubMed

    Panchanathan, Ravichandran; Liu, Hongzhu; Xin, Duan; Choubey, Divaker

    2014-10-01

    A host type I IFN response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP (c-di-GMP) by STING (stimulator of IFN genes). Because the STING, an adaptor protein, links the cytosolic detection of DNA by the cytosolic DNA sensors such as the IFN-inducible human IFI16 and murine p202 proteins to the TBK1/IRF3 axis, we investigated whether c-di-GMP-induced signaling could regulate expression of IFI16 and p202 proteins. Here, we report that activation of c-di-GMP-induced signaling in human and murine cells increased steady-state levels of IFI16 and p202 proteins. The increase was c-di-GMP concentration- and time-dependent. Unexpectedly, treatment of cells with type I IFN decreased levels of the adaptor protein STING. Therefore, we investigated whether the IFI16 or p202 protein could regulate the expression of STING and activation of the TBK1/IRF3 axis. We found that constitutive knockdown of IFI16 or p202 expression in cells increased steady-state levels of STING. Additionally, the knockdown of IFI16 resulted in activation of the TBK1/IRF3 axis. Accordingly, increased levels of the IFI16 or p202 protein in cells decreased STING levels. Together, our observations identify a novel negative feedback loop between c-di-GMP-induced levels of IFI16 and p202 cytosolic DNA sensors and the adaptor protein STING.

  6. Increasing Induction-Level Teachers' Positive-to-Negative Communication Ratio and Use of Behavior-Specific Praise through E-Mailed Performance Feedback and Its Effect on Students' Task Engagement

    ERIC Educational Resources Information Center

    Rathel, Jeanna M.; Drasgow, Erik; Brown, William H.; Marshall, Kathleen J.

    2014-01-01

    The purpose of this study was to examine the effects of e-mailed specific performance feedback that included progress monitoring graphs on induction-level teachers' ratios of positive-to-negative communication behaviors and their use of behavior-specific praise in classrooms for students with emotional and behavioral disorders, mild…

  7. The effect of negative autoregulation on eukaryotic gene expression

    NASA Astrophysics Data System (ADS)

    Nevozhay, Dmitry; Adams, Rhys; Murphy, Kevin; Josic, Kresimir; Balázsi, G. Ábor

    2009-03-01

    Negative autoregulation is a frequent motif in gene regulatory networks, which has been studied extensively in prokaryotes. Nevertheless, some effects of negative feedback on gene expression in eukaryotic transcriptional networks remain unknown. We studied how the strength of negative feedback regulation affects the characteristics of gene expression in yeast cells carrying synthetic transcriptional cascades. We observed a drastic reduction of gene expression noise and a change in the shape of the dose-response curve. We explained these experimentally observed effects by stochastic simulations and a simple set of algebraic equations.

  8. A Negative Regulatory Mechanism Involving 14-3-3ζ Limits Signaling Downstream of ROCK to Regulate Tissue Stiffness in Epidermal Homeostasis.

    PubMed

    Kular, Jasreen; Scheer, Kaitlin G; Pyne, Natasha T; Allam, Amr H; Pollard, Anthony N; Magenau, Astrid; Wright, Rebecca L; Kolesnikoff, Natasha; Moretti, Paul A; Wullkopf, Lena; Stomski, Frank C; Cowin, Allison J; Woodcock, Joanna M; Grimbaldeston, Michele A; Pitson, Stuart M; Timpson, Paul; Ramshaw, Hayley S; Lopez, Angel F; Samuel, Michael S

    2015-12-21

    ROCK signaling causes epidermal hyper-proliferation by increasing ECM production, elevating dermal stiffness, and enhancing Fak-mediated mechano-transduction signaling. Elevated dermal stiffness in turn causes ROCK activation, establishing mechano-reciprocity, a positive feedback loop that can promote tumors. We have identified a negative feedback mechanism that limits excessive ROCK signaling during wound healing and is lost in squamous cell carcinomas (SCCs). Signal flux through ROCK was selectively tuned down by increased levels of 14-3-3ζ, which interacted with Mypt1, a ROCK signaling antagonist. In 14-3-3ζ(-/-) mice, unrestrained ROCK signaling at wound margins elevated ECM production and reduced ECM remodeling, increasing dermal stiffness and causing rapid wound healing. Conversely, 14-3-3ζ deficiency enhanced cutaneous SCC size. Significantly, inhibiting 14-3-3ζ with a novel pharmacological agent accelerated wound healing 2-fold. Patient samples of chronic non-healing wounds overexpressed 14-3-3ζ, while cutaneous SCCs had reduced 14-3-3ζ. These results reveal a novel 14-3-3ζ-dependent mechanism that negatively regulates mechano-reciprocity, suggesting new therapeutic opportunities.

  9. A Negative Regulatory Mechanism Involving 14-3-3ζ Limits Signaling Downstream of ROCK to Regulate Tissue Stiffness in Epidermal Homeostasis.

    PubMed

    Kular, Jasreen; Scheer, Kaitlin G; Pyne, Natasha T; Allam, Amr H; Pollard, Anthony N; Magenau, Astrid; Wright, Rebecca L; Kolesnikoff, Natasha; Moretti, Paul A; Wullkopf, Lena; Stomski, Frank C; Cowin, Allison J; Woodcock, Joanna M; Grimbaldeston, Michele A; Pitson, Stuart M; Timpson, Paul; Ramshaw, Hayley S; Lopez, Angel F; Samuel, Michael S

    2015-12-21

    ROCK signaling causes epidermal hyper-proliferation by increasing ECM production, elevating dermal stiffness, and enhancing Fak-mediated mechano-transduction signaling. Elevated dermal stiffness in turn causes ROCK activation, establishing mechano-reciprocity, a positive feedback loop that can promote tumors. We have identified a negative feedback mechanism that limits excessive ROCK signaling during wound healing and is lost in squamous cell carcinomas (SCCs). Signal flux through ROCK was selectively tuned down by increased levels of 14-3-3ζ, which interacted with Mypt1, a ROCK signaling antagonist. In 14-3-3ζ(-/-) mice, unrestrained ROCK signaling at wound margins elevated ECM production and reduced ECM remodeling, increasing dermal stiffness and causing rapid wound healing. Conversely, 14-3-3ζ deficiency enhanced cutaneous SCC size. Significantly, inhibiting 14-3-3ζ with a novel pharmacological agent accelerated wound healing 2-fold. Patient samples of chronic non-healing wounds overexpressed 14-3-3ζ, while cutaneous SCCs had reduced 14-3-3ζ. These results reveal a novel 14-3-3ζ-dependent mechanism that negatively regulates mechano-reciprocity, suggesting new therapeutic opportunities. PMID:26702834

  10. Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man.

    PubMed

    Veldhuis, J D; Rogol, A D; Samojlik, E; Ertel, N H

    1984-07-01

    We have tested the participation of endogenous opiate pathways in the negative feedback actions of gonadal steroids on pulsatile properties of luteinizing (LH) hormone release in normal men. To this end, sex steroid hormones were infused intravenously at dosages that under steady state conditions selectively suppressed either the frequency or the amplitude of the pulsatile LH signal. The properties of pulsatile LH secretion were assessed quantitatively by computerized analysis of LH series derived from serial blood sampling over 12 h of observation. When the pure (nonaromatizable) androgen, 5-alpha-dihydrotestosterone, was infused continuously for 108 h at the blood production rate of testosterone, we were able to achieve selective inhibition of LH pulse frequency akin to that observed in experimental animals after low-dosage androgen replacement. Under these conditions, serum concentrations of testosterone and estradiol-17 beta did not change significantly, but serum 5 alpha-dihydrotestosterone concentrations increased approximately two- to threefold, with a corresponding increase in levels of its major metabolite, 5 alpha-androstan-3 alpha, 17 beta-diol. In separate experiments, the infusion of estradiol-17 beta at its blood production rate over a 4.5-d interval selectively suppressed LH pulse amplitude without influencing LH pulse frequency. Estrogen infusion increased serum estradiol-17 beta levels approximately twofold without significantly altering blood androgen concentrations. We then used these schedules of selective androgen or estrogen infusion to investigate the participation of endogenous opiates in the individual inhibitory feedback actions of pure androgen or estrogen on pulsatile LH release by administering a potent and specific opiate-receptor antagonist, naltrexone, during the infusions. Our observations indicate that, despite the continuous infusion of a dosage of 5 alpha-dihydrotestosterone that significantly suppresses LH pulse frequency, co

  11. Goblet-cell-specific transcription of mouse intestinal trefoil factor gene results from collaboration of complex series of positive and negative regulatory elements.

    PubMed Central

    Itoh, H; Inoue, N; Podolsky, D K

    1999-01-01

    Intestinal trefoil factor (ITF) is expressed selectively in intestinal goblet cells. Previous studies of the rat ITF gene identified one cis-regulatory element, designated the goblet-cell-response element (GCRE), present in the proximal region of the promoter. To identify additional cis-regulatory elements responsible for goblet-cell-specific expression, a DNA fragment containing 6353 bp of the 5'-flanking region of the mouse ITF gene was cloned and its promoter activity was examined extensively. In human and murine intestinal-derived cell lines (LS174T and CMT-93), the luciferase activities of a 6.3-kb construct were 5- and 2-fold greater than the smaller 1.8-kb construct, respectively. In contrast, the activity in non-intestinal cell lines (HepG2 and HeLa) was 2-4-fold lower than the smaller construct. In the region downstream from the 1.8-kb position, strong luciferase activities in LS174T and HepG2 cells were observed using a 201-bp construct. Interestingly, increased activity was almost completely suppressed in cells transfected with a 391-bp construct. Detailed analyses of this region revealed the existence of a 11-bp positive regulatory element (-181 to -170; ACCTCTTCCTG) and a 9-bp negative regulatory element (-208 to -200; ATTGACAGA) in addition to the GCRE. All three elements were well conserved among human, rat and mouse ITF gene promoters. In addition, a mutant 1.8-kb construct in which the negative regulatory region was deleted yielded the same approximate luciferase activity as a 6.3-kb construct, suggesting binding of a goblet-cell-specific silencer inhibitor (SI) between -6.3 and -1.8 kb. The SI present in goblet cells may block the silencers' binding to the pre-initiation complex and allow increased transcriptional activity driven by specific and non-specific enhancers. High-level expression of the mouse ITF gene specifically in intestinal goblet cells may be achieved through the combined effects of these regulatory elements. PMID:10393106

  12. Audio Feedback -- Better Feedback?

    ERIC Educational Resources Information Center

    Voelkel, Susanne; Mello, Luciane V.

    2014-01-01

    National Student Survey (NSS) results show that many students are dissatisfied with the amount and quality of feedback they get for their work. This study reports on two case studies in which we tried to address these issues by introducing audio feedback to one undergraduate (UG) and one postgraduate (PG) class, respectively. In case study one…

  13. IL-1 Receptor Regulates microRNA-135b Expression in a Negative Feedback Mechanism during Cigarette Smoke–Induced Inflammation

    PubMed Central

    Nikota, Jake; Wu, Dongmei; Williams, Andrew; Yauk, Carole L.; Stampfli, Martin

    2013-01-01

    Although microRNA-135b (miR-135b) is known to be associated with cancer, with recent work showing that it is massively induced in the pulmonary tissues of mice challenged with nanoparticles suggests a critical role for this microRNA in mediating inflammatory response. In this study, we investigated the expression and function of miR-135b in mice exposed to cigarette smoke or nontypeable Haemophilus influenzae (NTHi). Exposure to both cigarette smoke and NTHi elicited robust lung inflammation, but increased miR-135b expression was observed only in the lungs of cigarette smoke–exposed mice. Using IL-1R 1 knockout mice, we show that miR-135b expression is IL-1R1 dependent. A series of in vitro experiments confirmed the role of IL-1R1 in regulating miR-135b expression. In vitro activation of the IL-1R1 pathway in mouse embryonic fibroblast (NIH3T3) and lung epithelial (FE1) cells resulted in increased miR-135b, which was blocked by IL-1R1 antagonists or small interfering RNA–mediated silencing of IL-1R1 expression. Overexpression of mature miR-135b in NIH3T3 cells (pEGP-mmu-mir-135b) resulted in the suppression of endogenous levels of IL-1R1 expression. pEGP-mmu-miR-135b cells transiently transfected with luciferase reporter vector containing the 3′UTR of mouse IL-1R1 showed reduced luciferase activity. Finally, we demonstrate that miR-135b targets IL-1–stimulated activation of Caspase-1, the IL-1R1 downstream activator of IL-1β leading to suppressed synthesis of the active form of IL-1β protein. These results suggest that miR-135b expression during cigarette smoke–induced inflammation is regulated by IL-1R1 in a regulatory feedback mechanism to resolve inflammation. PMID:23440414

  14. Loss of the oncogenic phosphatase PRL-3 promotes a TNF-R1 feedback loop that mediates triple-negative breast cancer growth.

    PubMed

    Gari, H H; DeGala, G D; Lucia, M S; Lambert, J R

    2016-01-01

    Stimulating tumor cell senescence and apoptosis are proven methods for therapeutically combating cancer. However, senescence and apoptosis are conventionally viewed as parallel, not sequential, processes. We have discovered that the metastasis-promoting phosphatase, PRL-3, is transcriptionally regulated by the NF-ĸB pathway in triple-negative breast cancer (TNBC) cells, and that PRL-3 knockdown elicits an autocrine tumor necrosis factor receptor 1 (TNF-R1) feedback loop that results in TNBC cell senescence followed by apoptosis. Knockdown of PRL-3 leads to rapid G1 cell cycle arrest and induction of a strong TNFα cytokine response that promotes a period of cellular senescence through TNF-R1-mediated activation of NF-ĸB. Senescent PRL-3 knockdown cells subsequently underwent apoptosis as a result of increased TNF-R1 signaling through the TNFα-associated extrinsic death pathway, shunting signaling away from the NF-ĸB cascade. These data suggest that TNF-R1 signaling dynamically re-programs after PRL-3 knockdown, from sustaining cell senescence through NF-ĸB to promoting apoptosis through TNF-R1 internalization and caspase-8 activation. The molecular mechanisms that determine the survival-death balance of TNF-R1 signaling are poorly understood, despite the fact that TNF-R1 has been extensively studied. Our results describe PRL-3 knockdown as a novel survival-death balance modifier of the TNF-R1 pathway, and show that senescent TNBC tumor cells can be sensitized to undergo apoptosis in a sequential manner. PMID:27526109

  15. Alterations in glucocorticoid negative feedback following maternal Pb, prenatal stress and the combination: A potential biological unifying mechanism for their corresponding disease profiles

    SciTech Connect

    Rossi-George, A.; Virgolini, M.B.; Weston, D.; Cory-Slechta, D.A.

    2009-01-01

    Combined exposures to maternal lead (Pb) and prenatal stress (PS) can act synergistically to enhance behavioral and neurochemical toxicity in offspring. Maternal Pb itself causes permanent dysfunction of the body's major stress system, the hypothalamic pituitary adrenal (HPA) axis. The current study sought to determine the potential involvement of altered negative glucocorticoid feedback as a mechanistic basis of the effects in rats of maternal Pb (0, 50 or 150 ppm in drinking water beginning 2 mo prior to breeding), prenatal stress (PS; restraint on gestational days 16-17) and combined maternal Pb + PS in 8 mo old male and female offspring. Corticosterone changes were measured over 24 h following an i.p. injection stress containing vehicle or 100 or 300 {mu}g/kg (females) or 100 or 150 {mu}g/kg (males) dexamethasone (DEX). Both Pb and PS prolonged the time course of corticosterone reduction following vehicle injection stress. Pb effects were non-monotonic, with a greater impact at 50 vs. 150 ppm, particularly in males, where further enhancement occurred with PS. In accord with these findings, the efficacy of DEX in suppressing corticosterone was reduced by Pb and Pb + PS in both genders, with Pb efficacy enhanced by PS in females, over the first 6 h post-administration. A marked prolongation of DEX effects was found in males. Thus, Pb, PS and Pb + PS, sometimes additively, produced hypercortisolism in both genders, followed by hypocortisolism in males, consistent with HPA axis dysfunction. These findings may provide a plausible unifying biological mechanism for the reported links between Pb exposure and stress-associated diseases and disorders mediated via the HPA axis, including obesity, hypertension, diabetes, anxiety, schizophrenia and depression. They also suggest broadening of Pb screening programs to pregnant women in high stress environments.

  16. OsWOX3A is involved in negative feedback regulation of the gibberellic acid biosynthetic pathway in rice (Oryza sativa)

    PubMed Central

    Cho, Sung-Hwan; Kang, Kiyoon; Lee, Sang-Hwa; Lee, In-Jung; Paek, Nam-Chon

    2016-01-01

    The plant-specific WUSCHEL-related homeobox (WOX) nuclear proteins have important roles in the transcriptional regulation of many developmental processes. Among the rice (Oryza sativa) WOX proteins, a loss of OsWOX3A function in narrow leaf2 (nal2) nal3 double mutants (termed nal2/3) causes pleiotropic effects, such as narrow and curly leaves, opened spikelets, narrow grains, more tillers, and fewer lateral roots, but almost normal plant height. To examine OsWOX3A function in more detail, transgenic rice overexpressing OsWOX3A (OsWOX3A-OX) were generated; unexpectedly, all of them consistently exhibited severe dwarfism with very short and wide leaves, a phenotype that resembles that of gibberellic acid (GA)-deficient or GA-insensitive mutants. Exogenous GA3 treatment fully rescued the developmental defects of OsWOX3A-OX plants, suggesting that constitutive overexpression of OsWOX3A downregulates GA biosynthesis. Quantitative analysis of GA intermediates revealed significantly reduced levels of GA20 and bioactive GA1 in OsWOX3A-OX, possibly due to downregulation of the expression of KAO, which encodes ent-kaurenoic acid oxidase, a GA biosynthetic enzyme. Yeast one-hybrid and electrophoretic mobility shift assays revealed that OsWOX3A directly interacts with the KAO promoter. OsWOX3A expression is drastically and temporarily upregulated by GA3 and downregulated by paclobutrazol, a blocker of GA biosynthesis. These data indicate that OsWOX3A is a GA-responsive gene and functions in the negative feedback regulation of the GA biosynthetic pathway for GA homeostasis to maintain the threshold levels of endogenous GA intermediates throughout development. PMID:26767749

  17. Loss of the oncogenic phosphatase PRL-3 promotes a TNF-R1 feedback loop that mediates triple-negative breast cancer growth

    PubMed Central

    Gari, H H; DeGala, G D; Lucia, M S; Lambert, J R

    2016-01-01

    Stimulating tumor cell senescence and apoptosis are proven methods for therapeutically combating cancer. However, senescence and apoptosis are conventionally viewed as parallel, not sequential, processes. We have discovered that the metastasis-promoting phosphatase, PRL-3, is transcriptionally regulated by the NF-ĸB pathway in triple-negative breast cancer (TNBC) cells, and that PRL-3 knockdown elicits an autocrine tumor necrosis factor receptor 1 (TNF-R1) feedback loop that results in TNBC cell senescence followed by apoptosis. Knockdown of PRL-3 leads to rapid G1 cell cycle arrest and induction of a strong TNFα cytokine response that promotes a period of cellular senescence through TNF-R1-mediated activation of NF-ĸB. Senescent PRL-3 knockdown cells subsequently underwent apoptosis as a result of increased TNF-R1 signaling through the TNFα-associated extrinsic death pathway, shunting signaling away from the NF-ĸB cascade. These data suggest that TNF-R1 signaling dynamically re-programs after PRL-3 knockdown, from sustaining cell senescence through NF-ĸB to promoting apoptosis through TNF-R1 internalization and caspase-8 activation. The molecular mechanisms that determine the survival–death balance of TNF-R1 signaling are poorly understood, despite the fact that TNF-R1 has been extensively studied. Our results describe PRL-3 knockdown as a novel survival–death balance modifier of the TNF-R1 pathway, and show that senescent TNBC tumor cells can be sensitized to undergo apoptosis in a sequential manner. PMID:27526109

  18. Interrupted E2F1-miR-34c-SCF negative feedback loop by hyper-methylation promotes colorectal cancer cell proliferation

    PubMed Central

    Yang, Shu; Wu, Bo; Sun, Haimei; Ji, Fengqing; Sun, Tingyi; Zhao, Yan; Zhou, Deshan

    2015-01-01

    Tumour suppressor miR-34c deficiency resulted from hyper-methylation in its promoter is believed to be one of the main causes of colorectal cancer (CRC). Till date, miR-34c has been validated as a direct target of p53; but previous evidence suggested other transcription factor(s) must be involved in miR-34c transcription. In the present study, we in the first place identified a core promoter region (−1118 to −883 bp) of pre-miR-34c which was embedded within a hyper-methylated CpG island. Secondly, E2F1 promoted miR-34c transcription by physical interaction with the miR-34c promoter at site −897 to −889 bp. The transcriptional activating effect of E2F1 on miR-34c was in a p53 independent manner but profoundly promoted in the presence of p53 with exposure to 5-aza-2′-deoxycytidine (DAC). Thirdly, stem cell factor (SCF), a miR-34c target, was specifically reduced upon an introduction of E2F1 which lead to suppression of CRC cell proliferation. The E2F1-suppressed cell proliferation was partially abrogated by additional miR-34c inhibitor, indicating that the anti-proliferation effect of E2F1 was probably through activating miR-34c-SCF axis. Finally, SCF/KIT signalling increased E2F1 production by reducing its proteosomal degradation dependent on PI3K/Akt-GSK3β pathway. In conclusion, our results suggested the existence of E2F1-miR-34c-SCF negative feedback loop which was interrupted by the hyper-methylation of miR-34c promoter in CRC cells and increased cell proliferation. PMID:26704889

  19. Silencing of the transforming growth factor-beta (TGFbeta) receptor II by Kruppel-like factor 14 underscores the importance of a negative feedback mechanism in TGFbeta signaling.

    PubMed

    Truty, Mark J; Lomberk, Gwen; Fernandez-Zapico, Martin E; Urrutia, Raul

    2009-03-01

    The role of non-Smad proteins in the regulation of transforming growth factor-beta (TGFbeta) signaling is an emerging line of active investigation. Here, we characterize the role of KLF14, as a TGFbeta-inducible, non-Smad protein that silences the TGFbeta receptor II (TGFbetaRII) promoter. Together with endocytosis, transcriptional silencing is a critical mechanism for down-regulating TGFbeta receptors at the cell surface. However, the mechanisms underlying transcriptional repression of these receptors remain poorly understood. KLF14 has been chosen from a comprehensive screen of 24 members of the Sp/KLF family due to its TGFbeta inducibility, its ability to regulate the TGFbetaRII promoter, and the fact that this protein had yet to be functionally characterized. We find that KLF14 represses the TGFbetaRII, a function that is augmented by TGFbeta treatment. Mapping of the TGFbetaRII promoter, in combination with site-directed mutagenesis, electromobility shift, and chromatin immunoprecipitation assays, have identified distinct GC-rich sequences used by KLF14 to regulate this promoter. Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2. Furthermore, the TGFbeta pathway activation leads to recruitment of a KLF14-mSin3A-HDAC2 repressor complex to the TGFbetaRII promoter, as well as the remodeling of chromatin to increase histone marks that associate with transcriptional silencing. Thus, these results describe a novel negative-feedback mechanism by which TGFbetaRII activation at the cell surface induces the expression of KLF14 to ultimately silence the TGFbetaRII and further expand the network of non-Smad transcription factors that participate in the TGFbeta pathway. PMID:19088080

  20. Positive and Negative Regulatory Mechanisms for Fine-Tuning Cellularity and Functions of Medullary Thymic Epithelial Cells

    PubMed Central

    Akiyama, Taishin; Tateishi, Ryosuke; Akiyama, Nobuko; Yoshinaga, Riko; Kobayashi, Tetsuya J.

    2015-01-01

    Self-tolerant T cells and regulatory T cells develop in the thymus. A wide variety of cell–cell interactions in the thymus is required for the differentiation, proliferation, and repertoire selection of T cells. Various secreted and cell surface molecules expressed in thymic epithelial cells (TECs) mediate these processes. Moreover, cytokines expressed by cells of hematopoietic origin regulate the cellularity of TECs. Tumor necrosis factor (TNF) family RANK ligand, lymphotoxin, and CD40 ligand, expressed in T cells and innate lymphoid cells (ILCs), promote the differentiation and proliferation of medullary TECs (mTECs) that play critical roles in the induction of immune tolerance. A recent study suggests that interleukin-22 (IL-22) produced by ILCs promotes regeneration of TECs after irradiation. Intriguingly, tumor growth factor-β and osteoprotegerin limit cellularity of mTECs, thereby attenuating regulatory T cell generation. We will review recent insights into the molecular basis for cell–cell interactions regulating differentiation and proliferation of mTECs and also discuss about a perspective on use of mathematical models for understanding this complicated system. PMID:26441966

  1. Ubiquitin-associated Domain-containing Ubiquitin Regulatory X (UBX) Protein UBXN1 Is a Negative Regulator of Nuclear Factor κB (NF-κB) Signaling*

    PubMed Central

    Wang, Yu-Bo; Tan, Bo; Mu, Rui; Chang, Yan; Wu, Min; Tu, Hai-Qing; Zhang, Yu-Cheng; Guo, Sai-Sai; Qin, Xuan-He; Li, Tao; Li, Wei-Hua; Li, Ai-Ling; Zhang, Xue-Min; Li, Hui-Yan

    2015-01-01

    Excessive nuclear factor κB (NF-κB) activation should be precisely controlled as it contributes to multiple immune and inflammatory diseases. However, the negative regulatory mechanisms of NF-κB activation still need to be elucidated. Various types of polyubiquitin chains have proved to be involved in the process of NF-κB activation. Many negative regulators linked to ubiquitination, such as A20 and CYLD, inhibit IκB kinase activation in the NF-κB signaling pathway. To find new NF-κB signaling regulators linked to ubiquitination, we used a small scale siRNA library against 51 ubiquitin-associated domain-containing proteins and screened out UBXN1, which contained both ubiquitin-associated and ubiquitin regulatory X (UBX) domains as a negative regulator of TNFα-triggered NF-κB activation. Overexpression of UBXN1 inhibited TNFα-triggered NF-κB activation, although knockdown of UBXN1 had the opposite effect. UBX domain-containing proteins usually act as valosin-containing protein (VCP)/p97 cofactors. However, knockdown of VCP/p97 barely affected UBXN1-mediated NF-κB inhibition. At the same time, we found that UBXN1 interacted with cellular inhibitors of apoptosis proteins (cIAPs), E3 ubiquitin ligases of RIP1 in the TNFα receptor complex. UBXN1 competitively bound to cIAP1, blocked cIAP1 recruitment to TNFR1, and sequentially inhibited RIP1 polyubiquitination in response to TNFα. Therefore, our findings demonstrate that UBXN1 is an important negative regulator of the TNFα-triggered NF-κB signaling pathway by mediating cIAP recruitment independent of VCP/p97. PMID:25681446

  2. Expression of the Troponin C at 41C Gene in Adult Drosophila Tubular Muscles Depends upon Both Positive and Negative Regulatory Inputs.

    PubMed

    Chechenova, Maria B; Maes, Sara; Cripps, Richard M

    2015-01-01

    Most animals express multiple isoforms of structural muscle proteins to produce tissues with different physiological properties. In Drosophila, the adult muscles include tubular-type muscles and the fibrillar indirect flight muscles. Regulatory processes specifying tubular muscle fate remain incompletely understood, therefore we chose to analyze the transcriptional regulation of TpnC41C, a Troponin C gene expressed in the tubular jump muscles, but not in the fibrillar flight muscles. We identified a 300-bp promoter fragment of TpnC41C sufficient for the fiber-specific reporter expression. Through an analysis of this regulatory element, we identified two sites necessary for the activation of the enhancer. Mutations in each of these sites resulted in 70% reduction of enhancer activity. One site was characterized as a binding site for Myocyte Enhancer Factor-2. In addition, we identified a repressive element that prevents activation of the enhancer in other muscle fiber types. Mutation of this site increased jump muscle-specific expression of the reporter, but more importantly reporter expression expanded into the indirect flight muscles. Our findings demonstrate that expression of the TpnC41C gene in jump muscles requires integration of multiple positive and negative transcriptional inputs. Identification of the transcriptional regulators binding the cis-elements that we identified will reveal the regulatory pathways controlling muscle fiber differentiation.

  3. Identification of positive and negative regulatory regions controlling expression of the Xenopus laevis betaTrCP gene.

    PubMed

    Ballarino, Monica; Fruscalzo, Alberto; Marchioni, Marcella; Carnevali, Francesca

    2004-07-21

    betaTrCP mediates the ubiquitination and subsequent degradation of several key molecules thereby playing a relevant role in different cellular processes during development and in the adult. In Xenopus embryo, betaTrCP acts as a negative regulator of Wnt signaling by interacting with beta-catenin. In this paper, we report results of the study on expression and regulation of the Xenopus betaTrCP gene. We found that xbetaTrCP is expressed in Xenopus oocytes as three transcripts, which very likely correspond to the previously identified localized mRNAs, and four isoforms. The xbetaTrCP promoter functional and structural analysis showed the presence of elements target of positive transcriptional control. Among them, we have identified a beta-catenin/Tcf signaling responsive region and a 45-bp element containing a sequence motif conforming to the SRF binding site, closer to the transcription initiation sites. There are also elements of transcriptional negative control.

  4. The Power of Feedback

    ERIC Educational Resources Information Center

    Hattie, John; Timperley, Helen

    2007-01-01

    Feedback is one of the most powerful influences on learning and achievement, but this impact can be either positive or negative. Its power is frequently mentioned in articles about learning and teaching, but surprisingly few recent studies have systematically investigated its meaning. This article provides a conceptual analysis of feedback and…

  5. Implantation of unmarked regulatory and metabolic modules in Gram-negative bacteria with specialised mini-transposon delivery vectors.

    PubMed

    Nikel, Pablo I; de Lorenzo, Víctor

    2013-01-20

    Engineering of robust and safe microbial cell factories requires genetic tools somewhat different from those traditionally used for laboratory-adapted microorganisms. We took advantage of the properties of broad-host-range mini-Tn5 vectors and two regulated expression systems (LacI(Q)/P(trc) and XylS/Pm), together with FRT-flanked, excisable antibiotic resistance determinants, to generate a set of vectors for the delivery of gene(s) into the chromosome of Gram-negative bacteria. This arrangement of modular elements allows the cloning and subsequent markerless insertion of expression cargoes and leaves behind an antibiotic-sensitive host upon the action of the yeast Flp recombinase. We engineered a Pseudomonas putida KT2440 Pm::gfp strain that displayed strong fluorescence upon exposure to 3-methylbenzoate, a XylS effector, and allowed us to examine the performance of the Pm promoter at the single cell level. We also reconstructed a device for sugar transport and phosphorylation in Escherichia coli independent of the native phosphoenolpyruvate-dependent phosphotransferase system by the stable implantation of genes derived from the obligate anaerobe Zymomonas mobilis. In both cases, the information carried by the implanted genes was stably inherited in the absence of any selective pressure. Deliverable expression systems such as those described here will enhance the applicability of various Gram-negative bacteria in biocatalysis and environmental bioremediation.

  6. Localized structures in a nonlinear wave equation stabilized by negative global feedback: one-dimensional and quasi-two-dimensional kinks.

    PubMed

    Rotstein, Horacio G; Zhabotinsky, Anatol A; Epstein, Irving R

    2006-07-01

    We study the evolution of fronts in a nonlinear wave equation with global feedback. This equation generalizes the Klein-Gordon and sine-Gordon equations. Extending previous work, we describe the derivation of an equation governing the front motion, which is strongly nonlinear, and, for the two-dimensional case, generalizes the damped Born-Infeld equation. We study the motion of one- and two-dimensional fronts, finding a much richer dynamics than for the classical case (with no global feedback), leading in most cases to a localized solution; i.e., the stabilization of one phase inside the other. The nature of the localized solution depends on the strength of the global feedback as well as on other parameters of the model.

  7. Regulation of the phosphate regulon in Escherichia coli K-12: regulation of the negative regulatory gene phoU and identification of the gene product.

    PubMed Central

    Nakata, A; Amemura, M; Shinagawa, H

    1984-01-01

    The phoU gene is one of the negative regulatory genes of the pho regulon of Escherichia coli. The DNA fragment carrying phoU has been cloned on pBR322 (Amemura et al., J. Bacteriol. 152:692-701, 1982). Further subcloning, Tn1000 insertion inactivation, and complementation tests localized the phoU gene within a 1.1-kilobase region on the cloned DNA fragment. The gene product of phoU was identified by the maxicell method as a protein with an approximate molecular weight of 27,000. A hybrid plasmid that contains a phoU'-lac'Z fused gene was constructed in vitro. This plasmid enabled us to study phoU gene expression by measuring the beta-galactosidase level in the cells. The plasmid was introduced into various regulatory mutants related to the pho regulon, and phoU gene expression in these strains was studied under limited and excess phosphate conditions. It was found that phoU is expressed at a higher level when the cells are cultured under the excess phosphate condition. The higher phoU expression was observed in a phoB mutant and a phoR-phoM double mutant. The implications of these findings for the regulation of pho genes are discussed. Images PMID:6090402

  8. Identification and functional characterization of the miRNA-gene regulatory network in chronic myeloid leukemia lineage negative cells.

    PubMed

    Agatheeswaran, S; Pattnayak, N C; Chakraborty, S

    2016-01-01

    Chronic myeloid leukemia (CML) is maintained by leukemic stem cells (LSCs) which are resistant to the existing TKI therapy. Hence a better understanding of the CML LSCs is necessary to eradicate these cells and achieve complete cure. Using the miRNA-gene interaction networks from the CML lin(-) cells we identified a set of up/down-regulated miRNAs and corresponding target genes. Association studies (Pearson correlation) from the miRNA and gene expression data showed that miR-1469 and miR-1972 have significantly higher number of target genes, 75 and 50 respectively. We observed that miR-1972 induces G2-M cell cycle arrest and miR-1469 moderately arrested G1 cell cycle when overexpressed in KCL22 cells. We have earlier shown that a combination of imatinib and JAK inhibitor I can significantly bring down the proliferation of CML lineage negative cells. Here we observed that imatinib and JAK inhibitor I combination restored the expression pattern of the down-regulated miRNAs in primary CML lin(-) cells. Thus effective manipulation of the deregulated miRNAs can restore the miRNA-mRNA networks that can efficiently inhibit CML stem and progenitor cells and alleviate the disease. PMID:27586591

  9. Identification and functional characterization of the miRNA-gene regulatory network in chronic myeloid leukemia lineage negative cells

    PubMed Central

    Agatheeswaran, S.; Pattnayak, N. C.; Chakraborty, S.

    2016-01-01

    Chronic myeloid leukemia (CML) is maintained by leukemic stem cells (LSCs) which are resistant to the existing TKI therapy. Hence a better understanding of the CML LSCs is necessary to eradicate these cells and achieve complete cure. Using the miRNA-gene interaction networks from the CML lin(−) cells we identified a set of up/down-regulated miRNAs and corresponding target genes. Association studies (Pearson correlation) from the miRNA and gene expression data showed that miR-1469 and miR-1972 have significantly higher number of target genes, 75 and 50 respectively. We observed that miR-1972 induces G2-M cell cycle arrest and miR-1469 moderately arrested G1 cell cycle when overexpressed in KCL22 cells. We have earlier shown that a combination of imatinib and JAK inhibitor I can significantly bring down the proliferation of CML lineage negative cells. Here we observed that imatinib and JAK inhibitor I combination restored the expression pattern of the down-regulated miRNAs in primary CML lin(−) cells. Thus effective manipulation of the deregulated miRNAs can restore the miRNA-mRNA networks that can efficiently inhibit CML stem and progenitor cells and alleviate the disease. PMID:27586591

  10. Lactobacilli Modulate Hypoxia-Inducible Factor (HIF)-1 Regulatory Pathway in Triple Negative Breast Cancer Cell Line

    PubMed Central

    Abedin-Do, Atieh; Mirfakhraie, Reza; Shirzad, Mahdieh; Ghafouri-Fard, Soudeh; Motevaseli, Elahe

    2016-01-01

    Objective Hypoxia-Inducible Factor (HIF)-1 plays an essential role in the body’s response to low oxygen concentrations and regulates expression of several genes implicated in homeostasis, vascularization, anaerobic metabolism as well as immunological responses. Increased levels of HIF-1α are associated with increased proliferation and more aggressive breast tumor development. Lactobacilli have been shown to exert anti-cancer effects on several malignancies including breast cancer. However, the exact mechanism of such effect is not clear yet. The aim of this study was to analyze the expression of selected genes from HIF pathway in a triple negative breast cancer cell line (expressing no estrogen and progesterone receptors as well as HER-2/Neu), MDA-MB-231, following treatment with two lactobacilli culture supernatants. Materials and Methods In this experimental study, we analyzed the expression of HIF-1α, SLC2A1, VHL, HSP90, XBP1 and SHARP1 genes from HIF pathway in MDA-MB-231 cells, before and after treatment with Lactobacillus crispatus and Lactobacillus rhamnosus culture supernatants (LCS and LRS, respectively) by means of quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Results Both LRS and LCS had cytotoxic effects on MDA-MB-231 cells, while the former type was more cytotoxic. LRS dramatically down-regulated expression levels of the HIF-1α, HSP90 and SLC2A1 in the MDA-MB-231 cells. LCS had similar effect on the expression of HSP90, to what was observed in the LRS treatment. The expression level of tumor suppressor genes VHL and SHARP1 were also decreased in LCS treated cells. Conclusion Although both LCS and LRS had cytotoxic effects on the MDA-MB-231 cells, it is proposed that LRS could be more appropriate for pathway directed treatment modalities, as it did not decrease expression of tumor suppressor genes involved in HIF pathway. Down-regulation of HIF pathway mediated oncogenes by LRS suggests that the cytotoxic effects of this

  11. Radiative and Dynamical Feedbacks Over the Equatorial Cold-Tongue: Results from Seven Atmospheric GCMs

    SciTech Connect

    Sun, D; Zhang, T; Covey, C; Klein, S; Collins, W; Kiehl, J; Meehl, J; Held, I; Suarez, M

    2005-01-04

    The equatorial Pacific is a region with strong negative feedbacks. Yet coupled GCMs have exhibited a propensity to develop a significant SST bias in that region, suggesting an unrealistic sensitivity in the coupled models to small energy flux errors that inevitably occur in the individual model components. Could this 'hypersensitivity' exhibited in a coupled model be due to an underestimate of the strength of the negative feedbacks in this region? With this suspicion, the feedbacks in the equatorial Pacific in seven atmospheric GCMs (AGCMs) have been quantified using the interannual variations in that region and compared with the corresponding calculations from the observations. The seven AGCMs are: the NCAR CAM1, the NCAR CAM2,the NCAR CAM3, the NASA/NSIPP Atmospheric Model, the Hadley Center Model, the GFDL AM2p10, and the GFDL AM2p12. All the corresponding coupled runs of these seven AGCMs have an excessive cold-tongue in the equatorial Pacific. The net atmospheric feedback over the equatorial Pacific in the two GFDL models is found to be comparable to the observed value. All other models are found to have a weaker negative net feedback from the atmosphere--a weaker regulating effect on the underlying SST than the real atmosphere. A weaker negative feedback from the cloud albedo and a weaker negative feedback from the atmospheric transport are the two leading contributors to the weaker regulating effect from the model atmosphere. All models overestimate somewhat the positive feedback from water vapor. These results confirm the suspicion that an underestimate of negative feedbacks from the atmosphere over the equatorial Pacific region is a prevalent problem. The results also suggest, however, that a weaker regulatory effect from the atmosphere is unlikely solely responsible for the 'hypersensitivity' in all models. The need to validate the feedbacks from the ocean transport is therefore highlighted.

  12. Selective expression of a dominant-negative type Iα PKA regulatory subunit in striatal medium spiny neurons impairs gene expression and leads to reduced feeding and locomotor activity.

    PubMed

    Yang, Linghai; Gilbert, Merle L; Zheng, Ruimao; McKnight, G Stanley

    2014-04-01

    Striatal medium spiny neurons (MSNs) mediate many of the physiological effects of dopamine, including the regulation of feeding and motor behaviors. Dopaminergic inputs from the midbrain modulate MSN excitability through pathways that involve cAMP and protein kinase A (PKA), but the physiological role of specific PKA isoforms in MSN neurons remains poorly understood. One of the major PKA regulatory (R) subunit isoforms expressed in MSNs is RIIβ, which localizes the PKA holoenzyme primarily to dendrites by interaction with AKAP5 and other scaffolding proteins. However, RI (RIα and RIβ) subunits are also expressed in MSNs and the RI holoenzyme has a weaker affinity for most scaffolding proteins and tends to localize in the cell body. We generated mice with selective expression of a dominant-negative RI subunit (RIαB) in striatal MSNs and show that this dominant-negative RIαB localizes to the cytoplasm and specifically inhibits type I PKA activity in the striatum. These mice are normal at birth; however, soon after weaning they exhibit growth retardation and the adult mice are hypophagic, lean, and resistant to high-fat diet-induced hyperphagia and obesity. The RIαB-expressing mice also exhibit decreased locomotor activity and decreased dopamine-regulated CREB phosphorylation and c-fos gene expression in the striatum. Our results demonstrate a critical role for cytoplasmic RI-PKA holoenzyme in gene regulation and the overall physiological function of MSNs. PMID:24695708

  13. Negative Correlation Between miR-326 and Ets-1 in Regulatory T Cells from new-Onset SLE Patients.

    PubMed

    Sun, Xiao-Ge; Tao, Jin-Hui; Xiang, Nan; Li, Xiao-Mei; Wang, Guo-Sheng; Fang, Xuan; Dai, Chao; Zhang, Min; Chen, Zhu; Li, Xiang-Pei

    2016-04-01

    To analyze the relationship between miR-326 and Ets-1 mRNA levels in Treg cells and clinical manifestations in patients with SLE and explore the role of miR-326 and Ets-1 in the pathogenesis and activity of SLE. Twenty-five new-onset SLE patients without treatment, twenty-eight inactive SLE patients (SLEDA ≤ 4) and twenty-two healthy controls were included in the present study. Clinical data of SLE patients were recorded. Treg cells were purified by MACS from 20 ml peripheral blood, in which the quantity of miR-326 and Ets-1 mRNA were assessed by real-time PCR. Data were analyzed using SPSS Version 17.0. The nonparametric Mann-Whitney U test was used to compare the groups, The Spearman test was used for correlation analyses. Two-tailed p values <0.05 were considered statistically significant. 1.The level of miR-326 was significantly higher in Treg cells from SLE patients [1.98(0.592,6.148)] than that in healthy controls [0.921(0.345, 1.879)] (p = 0.032). The difference between new-onset SLE patients [6.192(0.673, 15.298)] and healthy controls was significant (p = 0.019). Significant difference of the miR-326 expression was found between new-onset SLE patients with serous cavity effusion and new-onset SLE patients without it(P<0.05). Significant positive correlation was found between the expression of miR-326 mRNA in Treg cells with CRP and anti-C1q antibody from new-onset SLE patients. 2. The level of Ets-1 mRNA was decreased in SLE patients [0.382(0.232, 0.572)] compared to healthy controls(p = 0.013). The difference was also found in new-onset SLE patients [0.222(0.125, 0.296)] while compared to healthy controls. Also, the level in new-onset SLE patients was lower than that in inactive SLE patients [0.482(0.398, 0.512)] (p = 0.001). 3. Negative correlation was found between miR-326 and Ets-1 mRNA expression in Treg cells from new-onset SLE patients (r = -0.583 p = 0.01). 4. There was no correlation of miR-326 or Ets-1 m

  14. Supervisor Feedback.

    ERIC Educational Resources Information Center

    Hayman, Marilyn J.

    1981-01-01

    Investigated the effectiveness of supervisor feedback in contributing to learning counseling skills. Counselor trainees (N=64) were assigned to supervisor feedback, no supervisor feedback, or control groups for three training sessions. Results indicated counseling skills were learned best by students with no supervisor feedback but self and peer…

  15. Nerve growth factor-induced derepression of peripherin gene expression is associated with alterations in proteins binding to a negative regulatory element.

    PubMed Central

    Thompson, M A; Lee, E; Lawe, D; Gizang-Ginsberg, E; Ziff, E B

    1992-01-01

    The peripherin gene, which encodes a neuronal-specific intermediate filament protein, is transcriptionally induced with a late time course when nerve growth factor (NGF) stimulates PC12 cells to differentiate into neurons. We have studied its transcriptional regulation in order to better understand the neuronal-specific end steps of the signal transduction pathway of NGF. By 5' deletion mapping of the peripherin promoter, we have localized two positive regulatory elements necessary for full induction by NGF: a distal positive element and a proximal constitutive element within 111 bp of the transcriptional start site. In addition, there is a negative regulatory element (NRE; -179 to -111), the deletion of which results in elevated basal expression of the gene. Methylation interference footprinting of the NRE defined a unique sequence, GGCAGGGCGCC, as the binding site for proteins present in nuclear extracts from both undifferentiated and differentiated PC12 cells. However, DNA mobility shift assays using an oligonucleotide probe containing the footprinted sequence demonstrate a prominent retarded complex in extracts from undifferentiated PC12 cells which migrates with slower mobility than do the complexes produced by using differentiated PC12 cell extract. Transfection experiments using peripherin-chloramphenicol acetyltransferase constructs in which the footprinted sequence has been mutated confirm that the NRE has a functional, though not exclusive, role in repressing peripherin expression in undifferentiated and nonneuronal cells. We propose a two-step model of activation of peripherin by NGF in which dissociation of a repressor from the protein complex at the NRE, coupled with a positive signal from the distal positive element, results in depression of the gene. Images PMID:1588954

  16. Contributions of Two-Component Regulatory Systems, Alternative σ Factors, and Negative Regulators to Listeria monocytogenes Cold Adaptation and Cold Growth

    PubMed Central

    Chan, Yvonne C.; Hu, Yuewei; Chaturongakul, Soraya; Files, Kali D.; Bowen, Barbara M.; Boor, Kathryn J.; Wiedmann, Martin

    2011-01-01

    The ability of Listeria monocytogenes to grow at refrigeration temperatures is critical for transmission of this foodborne pathogen. We evaluated the contributions of different transcriptional regulators and two-component regulatory systems to L. monocytogenes cold adaptation and cold growth. L. monocytogenes parent strain 10403S and selected isogenic null mutants in genes encoding four alternative σ factors (sigB, sigH, sigC, and sigL), two regulators of σB (rsbT and rsbV), two negative regulators (ctsR and hrcA), and 15 two-component response regulators were grown in brain heart infusion broth at 4°C with (i) a high-concentration starting inoculum (108 CFU/ml), (ii) a low-concentration starting inoculum (102 CFU/ml), and (iii) a high-concentration starting inoculum of cold-adapted cells. With a starting inoculum of 108 CFU/ml, null mutants in genes encoding selected alternative σ factors (ΔsigH, ΔsigC, and ΔsigL), a negative regulator (ΔctsR), regulators of σB (ΔrsbT and ΔrsbV), and selected two-component response regulators (ΔlisR, Δlmo1172, and Δlmo1060) had significantly reduced growth (P < 0.05) compared with the parent strain after 12 days at 4°C. The growth defect for ΔsigL was limited and was not confirmed by optical density (OD600) measurement data. With a starting inoculum of 102 CFU/ml and after monitoring growth at 4°C over 84 days, only the ΔctsR strain had a consistent but limited growth defect; the other mutant strains had either no growth defects or limited growth defects apparent at only one or two of the nine sampling points evaluated during the 84-day growth period (ΔsigB, ΔsigC, and Δlmo1172). With a 108 CFU/ml starting inoculum of cold-adapted cells, none of the mutant strains that had a growth defect when inoculation was performed with cells pregrown at 37°C had reduced growth as compared with the parent strain after 12 days at 4°C, suggesting a specific defect in the ability of these mutant strains to adapt to 4

  17. Effects of invalid feedback on learning and feedback-related brain activity in decision-making.

    PubMed

    Ernst, Benjamin; Steinhauser, Marco

    2015-10-01

    For adaptive decision-making it is important to utilize only relevant, valid and to ignore irrelevant feedback. The present study investigated how feedback processing in decision-making is impaired when relevant feedback is combined with irrelevant and potentially invalid feedback. We analyzed two electrophysiological markers of feedback processing, the feedback-related negativity (FRN) and the P300, in a simple decision-making task, in which participants processed feedback stimuli consisting of relevant and irrelevant feedback provided by the color and meaning of a Stroop stimulus. We found that invalid, irrelevant feedback not only impaired learning, it also altered the amplitude of the P300 to relevant feedback, suggesting an interfering effect of irrelevant feedback on the processing of relevant feedback. In contrast, no such effect on the FRN was obtained. These results indicate that detrimental effects of invalid, irrelevant feedback result from failures of controlled feedback processing. PMID:26263382

  18. Regulation of glycoprotein D synthesis: does alpha 4, the major regulatory protein of herpes simplex virus 1, regulate late genes both positively and negatively?

    PubMed Central

    Arsenakis, M; Campadelli-Fiume, G; Roizman, B

    1988-01-01

    Earlier studies have described the alpha 4/c113 baby hamster kidney cell line which constitutively expresses the alpha 4 protein, the major regulatory protein of herpes simplex virus 1 (HSV-1). Introduction of the HSV-1 glycoprotein B (gB) gene, regulated as a gamma 1 gene, into these cells yielded a cell line which constitutively expressed both the alpha 4 and gamma 1 gB genes. The expression of the gB gene was dependent on the presence of functional alpha 4 protein. In this article we report that we introduced into the alpha 4/c113 and into the parental BHK cells, the HSV-1 BamHI J fragment, which encodes the domains of four genes, including those of glycoproteins D, G, and I (gD, gG, and gI), and most of the coding sequences of the glycoprotein E (gE) gene. In contrast to the earlier studies, we obtained significant constitutive expression of gD (also a gamma 1 gene) in a cell line (BJ) derived from parental BHK cells, but not in a cell line (alpha 4/BJ) which expresses functional alpha 4 protein. RNA homologous to the gD gene was present in significant amounts in the BJ cell line; smaller amounts of this RNA were detected in the alpha 4/BJ cell line. RNA homologous to gE, presumed to be polyadenylated from signals in the vector sequences, was present in the BJ cells but not in the alpha 4/BJ cells. The expression of the HSV-1 gD and gE genes was readily induced in the alpha 4/BJ cells by superinfection with HSV-2. The BJ cell line was, in contrast, resistant to expression of HSV-1 and HSV-2 genes. The BamHI J DNA fragment copy number was approximately 1 per BJ cell genome equivalent and 30 to 50 per alpha 4/BJ cell genome equivalent. We conclude that (i) the genes specifying gD and gB belong to different viral regulatory gene subsets, (ii) the gD gene is subject to both positive and negative regulation, (iii) both gD and gE mRNAs are subject to translational controls although they may be different, and (iv) the absence of expression of gD in the alpha 4/BJ

  19. Rab27a negatively regulates CFTR chloride channel function in colonic epithelia: Involvement of the effector proteins in the regulatory mechanism

    SciTech Connect

    Saxena, Sunil K. . E-mail: ssaxena@stevens.edu; Kaur, Simarna

    2006-07-21

    Cystic fibrosis, an autosomal recessive disorder, is caused by the disruption of biosynthesis or function of CFTR. CFTR regulatory mechanisms include channel transport to plasma membrane and protein-protein interactions. Rab proteins are small GTPases involved in vesicle transport, docking, and fusion. The colorectal epithelial HT-29 cells natively express CFTR and respond to cAMP with an increase in CFTR-mediated currents. DPC-inhibited currents could be completely eliminated with CFTR-specific SiRNA. Over-expression of Rab27a inhibited, while isoform specific SiRNA and Rab27a antibody stimulated CFTR-mediated currents in HT-29 cells. CFTR activity is inhibited both by Rab27a (Q78L) (constitutive active GTP-bound form of Rab27a) and Rab27a (T23N) (constitutive negative form that mimics the GDP-bound form). Rab27a mediated effects could be reversed by Rab27a-binding proteins, the synaptotagmin-like protein (SLP-5) and Munc13-4 accessory protein (a putative priming factor for exocytosis). The SLP reversal of Rab27a effect was restricted to C2A/C2B domains while the SHD motif imparted little more inhibition. The CFTR-mediated currents remain unaffected by Rab3 though SLP-5 appears to weakly bind it. The immunoprecipitation experiments suggest protein-protein interactions between Rab27a and CFTR. Rab27a appears to impair CFTR appearance at the cell surface by trapping CFTR in the intracellular compartments. Munc13-4 and SLP-5, on the other hand, limit Rab27a availability to CFTR, thus minimizing its effect on channel function. These observations decisively prove that Rab27a is involved in CFTR channel regulation through protein-protein interactions involving Munc13-4 and SLP-5 effector proteins, and thus could be a potential target for cystic fibrosis therapy.

  20. Daisyworld inhabited with daisies incorporating a seed size/number trade-off: the mechanism of negative feedback on selection from a standpoint of the competition theory.

    PubMed

    Seto, Mayumi; Akagi, Tasuku

    2005-05-21

    We reexamined a Daisyworld model from the traditional view of competition theory. Unlike the original model, white and black daisies in our model incorporate a seeding/germination trade-off against bare ground area without assuming the local temperature reward. As a result, the planetary temperature is automatically regulated by two species if the following conditions are met: (i) the species react equally to an environmental condition, but one can alter the environmental condition in the opposite direction to the other. (ii) that one of the two cannot have both a higher maximal growth rate (mu(max)) and lower half-saturation constant (K) than those of the other. In other words, a pair of phenotypes incorporates a trade-off between quality and number of seeds. We found that the homeostatic regulation can also be reconciled with the adaptive evolution of optimal temperature. The results of simulation imply that biotic environmental feedback can also be maintained when the emergence of polymorphisms (black and white daisies) is closely linked to such a trade-off.

  1. Daisyworld inhabited with daisies incorporating a seed size/number trade-off: the mechanism of negative feedback on selection from a standpoint of the competition theory.

    PubMed

    Seto, Mayumi; Akagi, Tasuku

    2005-05-21

    We reexamined a Daisyworld model from the traditional view of competition theory. Unlike the original model, white and black daisies in our model incorporate a seeding/germination trade-off against bare ground area without assuming the local temperature reward. As a result, the planetary temperature is automatically regulated by two species if the following conditions are met: (i) the species react equally to an environmental condition, but one can alter the environmental condition in the opposite direction to the other. (ii) that one of the two cannot have both a higher maximal growth rate (mu(max)) and lower half-saturation constant (K) than those of the other. In other words, a pair of phenotypes incorporates a trade-off between quality and number of seeds. We found that the homeostatic regulation can also be reconciled with the adaptive evolution of optimal temperature. The results of simulation imply that biotic environmental feedback can also be maintained when the emergence of polymorphisms (black and white daisies) is closely linked to such a trade-off. PMID:15757676

  2. Arabidopsis Triphosphate Tunnel Metalloenzyme2 Is a Negative Regulator of the Salicylic Acid-Mediated Feedback Amplification Loop for Defense Responses1[W][OPEN

    PubMed Central

    Ung, Huoi; Moeder, Wolfgang; Yoshioka, Keiko

    2014-01-01

    The triphosphate tunnel metalloenzyme (TTM) superfamily represents a group of enzymes that is characterized by their ability to hydrolyze a range of tripolyphosphate substrates. Arabidopsis (Arabidopsis thaliana) encodes three TTM genes, AtTTM1, AtTTM2, and AtTTM3. Although AtTTM3 has previously been reported to have tripolyphosphatase activity, recombinantly expressed AtTTM2 unexpectedly exhibited pyrophosphatase activity. AtTTM2 knockout mutant plants exhibit an enhanced hypersensitive response, elevated pathogen resistance against both virulent and avirulent pathogens, and elevated accumulation of salicylic acid (SA) upon infection. In addition, stronger systemic acquired resistance compared with wild-type plants was observed. These enhanced defense responses are dependent on SA, PHYTOALEXIN-DEFICIENT4, and NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1. Despite their enhanced pathogen resistance, ttm2 plants did not display constitutively active defense responses, suggesting that AtTTM2 is not a conventional negative regulator but a negative regulator of the amplification of defense responses. The transcriptional suppression of AtTTM2 by pathogen infection or treatment with SA or the systemic acquired resistance activator benzothiadiazole further supports this notion. Such transcriptional regulation is conserved among TTM2 orthologs in the crop plants soybean (Glycine max) and canola (Brassica napus), suggesting that TTM2 is involved in immunity in a wide variety of plant species. This indicates the possible usage of TTM2 knockout mutants for agricultural applications to generate pathogen-resistant crop plants. PMID:25185123

  3. STABILIZED FEEDBACK AMPLIFIER

    DOEpatents

    Fishbine, H.L.; Sewell, C. Jr.

    1957-08-01

    Negative feedback amplifiers, and particularly a negative feedback circuit which is economical on amode power consumption, are described. Basically, the disclosed circuit comprises two tetrode tubes where the output of the first tube is capacitamce coupled to the grid of the second tube, which in turn has its plate coupled to the cathode of the first tube to form a degenerative feedback circuit. Operating potential for screen of the second tube is supplied by connecting the cathode resistor of the first tube to the screen, while the screen is by-passed to the cathode of its tube for the amplified frequencies. Also, the amplifier incorporates a circuit to stabilize the transconductance of the tubes by making the grid potential of each tube interdependent on anode currents of both lubes by voltage divider circuitry.

  4. Model Predicts That MKP1 and TAB1 Regulate p38α Nuclear Pulse and Its Basal Activity through Positive and Negative Feedback Loops in Response to IL-1

    PubMed Central

    Singh, Raghvendra

    2016-01-01

    Interleukin-1 mediates inflammation and stress response through nuclear activity of p38α. Although IL-1 receptor is not degraded, p38α activation is transient. IL-1 also causes cell migration and EMT by modulating cell-cell junctions. Although molecules involved in p38 activation are known, mechanism of the transient nuclear response and its basal activity remains unknown. By mathematical modeling of IL1/p38 signaling network, we show that IL-1 induces robust p38α activation both in the nucleus and in the cytoplasm/membrane. While nuclear response consists of an acute phase, membrane response resembles a step change. Following stimulation, p38α activity returns to a basal level in absence of receptor degradation. While nuclear pulse is controlled by MKP1 through a negative feedback to pp38, its basal activity is controlled by both TAB1 and MKP1 through a positive feedback loop. Our model provides insight into the mechanism of p38α activation, reason for its transient nuclear response, and explanation of the basal activity of MKK3/6 and p38α, which has been experimentally observed by other groups. PMID:27314954

  5. Coupling between feedback loops in autoregulatory networks affects bistability range, open-loop gain and switching times

    NASA Astrophysics Data System (ADS)

    Tiwari, Abhinav; Igoshin, Oleg A.

    2012-10-01

    Biochemical regulatory networks governing diverse cellular processes such as stress-response, differentiation and cell cycle often contain coupled feedback loops. We aim at understanding how features of feedback architecture, such as the number of loops, the sign of the loops and the type of their coupling, affect network dynamical performance. Specifically, we investigate how bistability range, maximum open-loop gain and switching times of a network with transcriptional positive feedback are affected by additive or multiplicative coupling with another positive- or negative-feedback loop. We show that a network's bistability range is positively correlated with its maximum open-loop gain and that both quantities depend on the sign of the feedback loops and the type of feedback coupling. Moreover, we find that the addition of positive feedback could decrease the bistability range if we control the basal level in the signal-response curves of the two systems. Furthermore, the addition of negative feedback has the capacity to increase the bistability range if its dissociation constant is much lower than that of the positive feedback. We also find that the addition of a positive feedback to a bistable network increases the robustness of its bistability range, whereas the addition of a negative feedback decreases it. Finally, we show that the switching time for a transition from a high to a low steady state increases with the effective fold change in gene regulation. In summary, we show that the effect of coupled feedback loops on the bistability range and switching times depends on the underlying mechanistic details.

  6. Children's Reasoning about Evaluative Feedback

    ERIC Educational Resources Information Center

    Heyman, Gail D.; Fu, Genyue; Sweet, Monica A.; Lee, Kang

    2009-01-01

    Children's reasoning about the willingness of peers to convey accurate positive and negative performance feedback to others was investigated among a total of 179 6- to 11-year-olds from the USA and China. In Study 1, which was conducted in the USA only, participants responded that peers would be more likely to provide positive feedback than…

  7. Negative regulatory element associated with potentially functional promoter and enhancer elements in the long terminal repeats of endogenous murine leukemia virus-related proviral sequences.

    PubMed Central

    Ch'ang, L Y; Yang, W K; Myer, F E; Yang, D M

    1989-01-01

    Three series of recombinant DNA clones were constructed, with the bacterial chloramphenicol acetyltransferase (CAT) gene as a quantitative indicator, to examine the activities of promoter and enhancer sequence elements in the 5' long terminal repeat (LTR) of murine leukemia virus (MuLV)-related proviral sequences isolated from the mouse genome. Transient CAT expression was determined in mouse NIH 3T3, human HT1080, and mink CCL64 cultured cells transfected with the LTR-CAT constructs. The 700-base-pair (bp) LTRs of three polytropic MuLV-related proviral clones and the 750-bp LTRs of four modified polytropic proviral clones, in complete structures either with or without the adjacent downstream sequences, all showed very little or negligible activities for CAT expression, while ecotropic MuLV LTRs were highly active. The MuLV-related LTRs were divided into three portions and examined separately. The 3' portion of the MuLV-related LTRs that contains the CCAAC and TATAA boxes was found to be a functional promoter, being about one-half to one-third as active as the corresponding portion of ecotropic MuLV LTRs. A MboI-Bg/II fragment, representing the distinct 190- to 200-bp inserted segment in the middle, was found to be a potential enhancer, especially when examined in combination with the simian virus 40 promoter in CCL64 cells. A PstI-MboI fragment of the 5' portion, which contains the protein-binding motifs of the enhancer segment as well as the upstream LTR sequences, showed moderate enhancer activities in CCL6 cells but was virtually inactive in NIH 3T3 cells and HT1080 cells; addition of this fragment to the ecotropic LTR-CAT constructs depressed CAT expression. Further analyses using chimeric LTR constructs located the presence of a strong negative regulatory element within the region containing the 5' portion of the enhancer and the immediate upstream sequences in the MuLV-related LTRs. Images PMID:2542587

  8. Thymic commitment of regulatory T cells is a pathway of TCR-dependent selection that isolates repertoires undergoing positive or negative selection.

    PubMed

    Coutinho, A; Caramalho, I; Seixas, E; Demengeot, J

    2005-01-01

    The seminal work of Le Douarin and colleagues (Ohki et al. 1987; Ohki et al. 1988; Salaun et al. 1990; Coutinho et al. 1993) first demonstrated that peripheral tissue-specific tolerance is centrally established in the thymus, by epithelial stromal cells (TEC). Subsequent experiments have shown that TEC-tolerance is dominant and mediated by CD4 regulatory T cells (Treg) that are generated intrathymically by recognition of antigens expressed on TECs (Modigliani et al. 1995; Modigliani et al. 1996a). From these and other observations, in 1996 Modigliani and colleagues derived a general model for the establishment and maintenance of natural tolerance (MM96) (Modigliani et al. 1996b), with two central propositions: (1) T cell receptor (TCR)-dependent sorting of emergent repertoires generates TEC-specific Treg displaying the highest TCR self-affinities below deletion thresholds, thus isolating repertoires undergoing positive and negative selection; (2) Treg are intrathymically committed (and activated) for a unique differentiative pathway with regulatory effector functions. The model explained the embryonic/perinatal time window of natural tolerance acquisition, by developmental programs determining (1) TCR multireactivity, (2) the cellular composition in the thymic stroma (relative abundance of epithelial vs hemopoietic cells), and (3) the dynamics of peripheral lymphocyte pools, built by accumulation of recent thymic emigrants (RTE) that remain recruitable to regulatory functions. We discuss here the MM96 in the light of recent results demonstrating the promiscuous expression of tissue-specific antigens by medullary TECs (Derbinski et al. 2001; Anderson et al. 2002; Gotter et al. 2004) and indicating that Treg represent a unique differentiative pathway (Fontenot et al. 2003; Hori et al. 2003; Khattri et al. 2003), which is adopted by CD4 T cells with high avidity for TEC-antigens (Bensinger et al. 2001; Jordan et al. 2001; Apostolou et al. 2002). In the likelihood that

  9. Thymic commitment of regulatory T cells is a pathway of TCR-dependent selection that isolates repertoires undergoing positive or negative selection.

    PubMed

    Coutinho, A; Caramalho, I; Seixas, E; Demengeot, J

    2005-01-01

    The seminal work of Le Douarin and colleagues (Ohki et al. 1987; Ohki et al. 1988; Salaun et al. 1990; Coutinho et al. 1993) first demonstrated that peripheral tissue-specific tolerance is centrally established in the thymus, by epithelial stromal cells (TEC). Subsequent experiments have shown that TEC-tolerance is dominant and mediated by CD4 regulatory T cells (Treg) that are generated intrathymically by recognition of antigens expressed on TECs (Modigliani et al. 1995; Modigliani et al. 1996a). From these and other observations, in 1996 Modigliani and colleagues derived a general model for the establishment and maintenance of natural tolerance (MM96) (Modigliani et al. 1996b), with two central propositions: (1) T cell receptor (TCR)-dependent sorting of emergent repertoires generates TEC-specific Treg displaying the highest TCR self-affinities below deletion thresholds, thus isolating repertoires undergoing positive and negative selection; (2) Treg are intrathymically committed (and activated) for a unique differentiative pathway with regulatory effector functions. The model explained the embryonic/perinatal time window of natural tolerance acquisition, by developmental programs determining (1) TCR multireactivity, (2) the cellular composition in the thymic stroma (relative abundance of epithelial vs hemopoietic cells), and (3) the dynamics of peripheral lymphocyte pools, built by accumulation of recent thymic emigrants (RTE) that remain recruitable to regulatory functions. We discuss here the MM96 in the light of recent results demonstrating the promiscuous expression of tissue-specific antigens by medullary TECs (Derbinski et al. 2001; Anderson et al. 2002; Gotter et al. 2004) and indicating that Treg represent a unique differentiative pathway (Fontenot et al. 2003; Hori et al. 2003; Khattri et al. 2003), which is adopted by CD4 T cells with high avidity for TEC-antigens (Bensinger et al. 2001; Jordan et al. 2001; Apostolou et al. 2002). In the likelihood that

  10. Mean field analysis of a spatial stochastic model of a gene regulatory network.

    PubMed

    Sturrock, M; Murray, P J; Matzavinos, A; Chaplain, M A J

    2015-10-01

    A gene regulatory network may be defined as a collection of DNA segments which interact with each other indirectly through their RNA and protein products. Such a network is said to contain a negative feedback loop if its products inhibit gene transcription, and a positive feedback loop if a gene product promotes its own production. Negative feedback loops can create oscillations in mRNA and protein levels while positive feedback loops are primarily responsible for signal amplification. It is often the case in real biological systems that both negative and positive feedback loops operate in parameter regimes that result in low copy numbers of gene products. In this paper we investigate the spatio-temporal dynamics of a single feedback loop in a eukaryotic cell. We first develop a simplified spatial stochastic model of a canonical feedback system (either positive or negative). Using a Gillespie's algorithm, we compute sample trajectories and analyse their corresponding statistics. We then derive a system of equations that describe the spatio-temporal evolution of the stochastic means. Subsequently, we examine the spatially homogeneous case and compare the results of numerical simulations with the spatially explicit case. Finally, using a combination of steady-state analysis and data clustering techniques, we explore model behaviour across a subregion of the parameter space that is difficult to access experimentally and compare the parameter landscape of our spatio-temporal and spatially-homogeneous models.

  11. Feedback in Action--The Mechanism of the Iris.

    ERIC Educational Resources Information Center

    Pingnet, B.; And Others

    1988-01-01

    Describes two demonstration experiments. Outlines a demonstration of the general principle of positive and negative feedback and the influence of time delays in feedback circuits. Elucidates the principle of negative feedback with a model of the iris of the eye. Emphasizes the importance of feedback in biological systems. (CW)

  12. Feedback loop compensates for rectifier nonlinearity

    NASA Technical Reports Server (NTRS)

    1966-01-01

    Signal processing circuit with two negative feedback loops rectifies two sinusoidal signals which are 180 degrees out of phase and produces a single full-wave rectified output signal. Each feedback loop incorporates a feedback rectifier to compensate for the nonlinearity of the circuit.

  13. Neural correlates of feedback processing in toddlers.

    PubMed

    Meyer, Marlene; Bekkering, Harold; Janssen, Denise J C; de Bruijn, Ellen R A; Hunnius, Sabine

    2014-07-01

    External feedback provides essential information for successful learning. Feedback is especially important for learning in early childhood, as toddlers strongly rely on external signals to determine the consequences of their actions. In adults, many electrophysiological studies have elucidated feedback processes using a neural marker called the feedback-related negativity (FRN). The neural generator of the FRN is assumed to be the ACC, located in medial frontal cortex. As frontal brain regions are the latest to mature during brain development, it is unclear when in early childhood a functional feedback system develops. Is feedback differentiated on a neural level in toddlers and in how far is neural feedback processing related to children's behavioral adjustment? In an EEG experiment, we addressed these questions by measuring the brain activity and behavioral performance of 2.5-year-old toddlers while they played a feedback-guided game on a touchscreen. Electrophysiological results show differential brain activity for feedback with a more negative deflection for incorrect than correct outcomes, resembling the adult FRN. This provides the first neural evidence for feedback processing in toddlers. Notably, FRN amplitudes were predictive of adaptive behavior: the stronger the differential brain activity for feedback, the better the toddlers' adaptive performance during the game. Thus, already in early childhood toddlers' feedback-guided performance directly relates to the functionality of their neural feedback processing. Implications for early feedback-based learning as well as structural and functional brain development are discussed.

  14. Power semiconductor device with negative thermal feedback

    NASA Technical Reports Server (NTRS)

    Borky, J. M.; Thornton, R. D.

    1970-01-01

    Composite power semiconductor avoids second breakdown and provides stable operation. It consists of an array of parallel-connected integrated circuits fabricated in a single chip. The output power device and associated low-level amplifier are closely coupled thermally, so that they have a predetermined temperature relationship.

  15. Electrometer preamplifier has drift correction feedback

    NASA Technical Reports Server (NTRS)

    Labarthe, L. C.

    1965-01-01

    Negative feedback circuit corrects output drift in an electrometer. The negative feedback is used in the no signal state to maintain the output level at zero reference. Drift voltage storage in the signal on state is also used to provide a drift-free readout.

  16. Coress feedback

    PubMed Central

    2012-01-01

    This issue of CORESS feedback highlights yet again the importance of checking medications before administration and of adequate handover. Documentation of important medical data including drug allergies, as failed to happen in the case described below, is vital. We are grateful to the clinicians who have provided the material for these reports. The online reporting form is on our website (www.coress.org.uk), which also includes all previous feedback reports. Published contributions will be acknowledged by a ‘Certificate of Contribution’, which may be included in the contributor’s record of continuing professional development.

  17. A biomathematical model of time-delayed feedback in the human male hypothalamic-pituitary-Leydig cell axis.

    PubMed

    Keenan, D M; Veldhuis, J D

    1998-07-01

    We develop, implement, and test a feedback and feedforward biomathematical construct of the male hypothalamic [gonadotropin-releasing hormone (GnRH)]-pituitary [luteinizing hormone (LH)]-gonadal [testosterone (Te)] axis. This stochastic differential equation formulation consists of a nonstationary stochastic point process responsible for generating episodic release of GnRH, which is modulated negatively by short-loop (GnRH) and long-loop (Te) feedback. Pulsatile GnRH release in turn drives bursts of LH secretion via an agonistic dose-response curve that is partially damped by Te negative feedback. Circulating LH stimulates (feedforward) Te synthesis and release by a second dose response. Te acts via negative dose-responsive feedback on GnRH and LH output, thus fulfilling conditions of a closed-loop control system. Four computer simulations document expected feedback performance, as published earlier for the human male GnRH-LH-Te axis. Six other simulations test distinct within-model coupling mechanisms to link a circadian modulatory input to a pulsatile control node so as to explicate the known 24-h variations in Te and, to a lesser extent, LH. We conclude that relevant dynamic function, internodal dose-dependent regulatory connections, and within-system time-delayed coupling together provide a biomathematical basis for a nonlinear feedback-feedforward control model with combined pulsatile and circadian features that closely emulate the measurable output activities of the male hypothalamic-pituitary-Leydig cell axis.

  18. Galaxy-scale AGN feedback - theory

    NASA Astrophysics Data System (ADS)

    Wagner, A. Y.; Bicknell, G. V.; Umemura, M.; Sutherland, R. S.; Silk, J.

    2016-02-01

    Powerful relativistic jets in radio galaxies are capable of driving strong outflows but also inducing star-formation by pressure-triggering collapse of dense clouds. We review theoretical work on negative and positive active galactic nuclei feedback, discussing insights gained from recent hydrodynamical simulations of jet-driven feedback on galaxy scales that are applicable to compact radio sources. The simulations show that the efficiency of feedback and the relative importance of negative and positive feedback depend strongly on interstellar medium properties, especially the column depth and spatial distribution of clouds. Negative feedback is most effective if clouds are distributed spherically and individual clouds have small column depths, while positive feedback is most effective if clouds are predominantly in a disc-like configuration.

  19. Dissecting the Regulatory Microenvironment of a Large Animal Model of Non-Hodgkin Lymphoma: Evidence of a Negative Prognostic Impact of FOXP3+ T Cells in Canine B Cell Lymphoma

    PubMed Central

    Pinheiro, Dammy; Chang, Yu-Mei; Bryant, Hannah; Szladovits, Balazs; Dalessandri, Tim; Davison, Lucy J.; Yallop, Elizabeth; Mills, Emily; Leo, Chiara; Lara, Ana; Stell, Anneliese; Polton, Gerry; Garden, Oliver A.

    2014-01-01

    The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulatory cells that attenuate the anti-neoplastic immune response. While the negative prognostic impact of regulatory T cells (Tregs) in the context of most solid tissue tumors is well established, their role in lymphoid malignancies remains unclear. T cells expressing FOXP3 and Helios were documented in the fine needle aspirates of affected lymph nodes of dogs with spontaneous multicentric B cell lymphoma (BCL), proposed to be a model for human non-Hodgkin lymphoma. Multivariable analysis revealed that the frequency of lymph node FOXP3+ T cells was an independent negative prognostic factor, impacting both progression-free survival (hazard ratio 1.10; p = 0.01) and overall survival (hazard ratio 1.61; p = 0.01) when comparing dogs showing higher than the median FOXP3 expression with those showing the median value of FOXP3 expression or less. Taken together, these data suggest the existence of a population of Tregs operational in canine multicentric BCL that resembles thymic Tregs, which we speculate are co-opted by the tumor from the periphery. We suggest that canine multicentric BCL represents a robust large animal model of human diffuse large BCL, showing clinical, cytological and immunophenotypic similarities with the disease in man, allowing comparative studies of immunoregulatory mechanisms. PMID:25119018

  20. Dissecting the regulatory microenvironment of a large animal model of non-Hodgkin lymphoma: evidence of a negative prognostic impact of FOXP3+ T cells in canine B cell lymphoma.

    PubMed

    Pinheiro, Dammy; Chang, Yu-Mei; Bryant, Hannah; Szladovits, Balazs; Dalessandri, Tim; Davison, Lucy J; Yallop, Elizabeth; Mills, Emily; Leo, Chiara; Lara, Ana; Stell, Anneliese; Polton, Gerry; Garden, Oliver A

    2014-01-01

    The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulatory cells that attenuate the anti-neoplastic immune response. While the negative prognostic impact of regulatory T cells (Tregs) in the context of most solid tissue tumors is well established, their role in lymphoid malignancies remains unclear. T cells expressing FOXP3 and Helios were documented in the fine needle aspirates of affected lymph nodes of dogs with spontaneous multicentric B cell lymphoma (BCL), proposed to be a model for human non-Hodgkin lymphoma. Multivariable analysis revealed that the frequency of lymph node FOXP3(+) T cells was an independent negative prognostic factor, impacting both progression-free survival (hazard ratio 1.10; p = 0.01) and overall survival (hazard ratio 1.61; p = 0.01) when comparing dogs showing higher than the median FOXP3 expression with those showing the median value of FOXP3 expression or less. Taken together, these data suggest the existence of a population of Tregs operational in canine multicentric BCL that resembles thymic Tregs, which we speculate are co-opted by the tumor from the periphery. We suggest that canine multicentric BCL represents a robust large animal model of human diffuse large BCL, showing clinical, cytological and immunophenotypic similarities with the disease in man, allowing comparative studies of immunoregulatory mechanisms.

  1. Feedback loops and reciprocal regulation: recurring motifs in the systems biology of the cell cycle

    PubMed Central

    Ferrell, James E.

    2013-01-01

    The study of eukaryotic cell cycle regulation over the last several decades has led to a remarkably detailed understanding of the complex regulatory system that drives this fundamental process. This allows us to now look for recurring motifs in the regulatory system. Among these are negative feedback loops, which underpin checkpoints and generate cell cycle oscillations; positive feedback loops, which promote oscillations and make cell cycle transitions switch-like and unidirectional; and reciprocal regulation, which can increase the control a key regulator exerts. These simple motifs are found at multiple points in the cell cycle (e.g., S-phase and M-phase control) and are conserved in diverse organisms. These findings argue for an underlying unity in the principles of cell cycle control. PMID:23927869

  2. The 'regulatory' beta-subunit of protein kinase CK2 negatively influences p53-mediated allosteric effects on Chk2 activation.

    PubMed

    Bjørling-Poulsen, Marina; Siehler, Simone; Wiesmüller, Lisa; Meek, David; Niefind, Karsten; Issinger, Olaf-Georg

    2005-09-01

    The 'regulatory' beta-subunit of protein kinase CK2 has previously been shown to interact with protein kinases such as A-Raf, c-Mos, Lyn and Chk1 in addition to the catalytic subunit of CK2. Sequence alignments suggest that these interactions have a structural basis, and hence other protein kinases harboring corresponding sequences may be potential interaction partners for CK2beta. We show here that Chk2 specifically interacts with CK2beta in vitro and in cultured cells, and that activation of Chk2 leads to a reduction of this interaction. Additionally, we show that the presence of the CK2beta-subunit significantly reduces the Chk2-catalysed phosphorylation of p53 in vitro. These findings support the notion that CK2beta can act as a general modulator of remote docking sites in protein kinase--substrate interactions.

  3. Transcriptional feedback oscillators: maybe, maybe not...

    PubMed

    Lakin-Thomas, Patricia L

    2006-04-01

    The molecular mechanism of circadian rhythmicity is usually modeled by a transcription/translation feedback oscillator in which clock proteins negatively feed back on their own transcription to produce rhythmic levels of clock protein mRNAs, which in turn cause the production of rhythmic levels of clock proteins. This mechanism has been applied to all model organisms for which molecular data are available. This review summarizes the increasing number of anomalous observations that do not fit the standard molecular mechanism for the model organisms Acetabularia, Synechococcus, Drosophila, Neurospora, and mouse. The anomalies fall into 2 classes: observations of rhythmicity in the organism when transcription of clock genes is held constant, and rhythmicity in the organism when clock gene function is missing in knockout mutants. It is concluded that the weight of anomalies is now so large that the standard transcription/translation mechanism is no longer an adequate model for circadian oscillators. Rhythmic transcription may have other functions in the circadian system, such as participating in input and output pathways and providing robustness to the oscillations. It may be most useful to think in terms of a circadian system that uses a noncircadian oscillator consisting of metabolic feedback loops, which acquires its circadian properties from additional regulatory molecules such as the products of canonical clock genes.

  4. A novel double-negative feedback loop between miR-489 and the HER2-SHP2-MAPK signaling axis regulates breast cancer cell proliferation and tumor growth

    PubMed Central

    Lee, Ji Shin; Markoutsa, Eleni; Jie, Chunfa; Liu, Shou; Botbyl, Rachel; Reisman, David; Xu, Peisheng; Chen, Hexin

    2016-01-01

    Human epidermal growth factor receptor 2 (HER2 or ErBb2) is a receptor tyrosine kinase overexpressed in 20-30% of breast cancers and associated with poor prognosis and outcome. Dysregulation of several microRNAs (miRNAs) plays a key role in breast cancer progression and metastasis. In this study, we screened and identified miRNAs dysregualted in HER2-positive breast cancer cells. Our molecular study demonstrated that miR-489 was specifically downregulated by the HER2-downstream signaling, especially through the MAPK pathway. Restoration or overexpression of miR-489 in HER2-positive breast cancer cells significantly inhibited cell growth in vitro and decreased the tumorigenecity and tumor growth in xenograft mice. Mechanistically, we found that overexpression of miR-489 led to the decreased levels of HER2 and SHP2 and thus attenuated HER2-downstream signaling. Furthermore, we for the first time demonstrated that HER2 is a direct target of miR-489 and therefore HER2-SHP2-MAPK and miR-489 signaling pathways form a mutually inhibitory loop. Using quantitative real-time PCR analysis and Fluorescent in situ hybridization technique (FISH), we found that miR-489 was expressed at significantly lower level in tumor tissues compared to the adjacent normal tissues. Downregulation of miR-489 in breast cancers was associated with aggressive tumor phenotypes. Overall, our results define a double-negative feedback loop involving miR-489 and the HER2-SHP2-MAPK signaling axis that can regulate breast cancer cell proliferation and tumor progression and might have therapeutic relevance for HER2-positive breast cancer. PMID:26918448

  5. Antithetic Integral Feedback Ensures Robust Perfect Adaptation in Noisy Biomolecular Networks.

    PubMed

    Briat, Corentin; Gupta, Ankit; Khammash, Mustafa

    2016-01-27

    The ability to adapt to stimuli is a defining feature of many biological systems and critical to maintaining homeostasis. While it is well appreciated that negative feedback can be used to achieve homeostasis when networks behave deterministically, the effect of noise on their regulatory function is not understood. Here, we combine probability and control theory to develop a theory of biological regulation that explicitly takes into account the noisy nature of biochemical reactions. We introduce tools for the analysis and design of robust homeostatic circuits and propose a new regulation motif, which we call antithetic integral feedback. This motif exploits stochastic noise, allowing it to achieve precise regulation in scenarios where similar deterministic regulation fails. Specifically, antithetic integral feedback preserves the stability of the overall network, steers the population of any regulated species to a desired set point, and adapts perfectly. We suggest that this motif may be prevalent in endogenous biological circuits and useful when creating synthetic circuits. PMID:27136686

  6. Modular genetic regulatory networks increase organization during pattern formation.

    PubMed

    Mohamadlou, Hamid; Podgorski, Gregory J; Flann, Nicholas S

    2016-08-01

    Studies have shown that genetic regulatory networks (GRNs) consist of modules that are densely connected subnetworks that function quasi-autonomously. Modules may be recognized motifs that comprise of two or three genes with particular regulatory functions and connectivity or be purely structural and identified through connection density. It is unclear what evolutionary and developmental advantages modular structure and in particular motifs provide that have led to this enrichment. This study seeks to understand how modules within developmental GRNs influence the complexity of multicellular patterns that emerge from the dynamics of the regulatory networks. We apply an algorithmic complexity to measure the organization of the patterns. A computational study was performed by creating Boolean intracellular networks within a simulated epithelial field of embryonic cells, where each cell contains the same network and communicates with adjacent cells using contact-mediated signaling. Intracellular networks with random connectivity were compared to those with modular connectivity and with motifs. Results show that modularity effects network dynamics and pattern organization significantly. In particular: (1) modular connectivity alone increases complexity in network dynamics and patterns; (2) bistable switch motifs simplify both the pattern and network dynamics; (3) all other motifs with feedback loops increase multicellular pattern complexity while simplifying the network dynamics; (4) negative feedback loops affect the dynamics complexity more significantly than positive feedback loops.

  7. Emotion: The Self-regulatory Sense

    PubMed Central

    2014-01-01

    While emotion is a central component of human health and well-being, traditional approaches to understanding its biological function have been wanting. A dynamic systems model, however, broadly redefines and recasts emotion as a primary sensory system—perhaps the first sensory system to have emerged, serving the ancient autopoietic function of “self-regulation.” Drawing upon molecular biology and revelations from the field of epigenetics, the model suggests that human emotional perceptions provide an ongoing stream of “self-relevant” sensory information concerning optimally adaptive states between the organism and its immediate environment, along with coupled behavioral corrections that honor a universal self-regulatory logic, one still encoded within cellular signaling and immune functions. Exemplified by the fundamental molecular circuitry of sensorimotor control in the E coli bacterium, the model suggests that the hedonic (affective) categories emerge directly from positive and negative feedback processes, their good/bad binary appraisals relating to dual self-regulatory behavioral regimes—evolutionary purposes, through which organisms actively participate in natural selection, and through which humans can interpret optimal or deficit states of balanced being and becoming. The self-regulatory sensory paradigm transcends anthropomorphism, unites divergent theoretical perspectives and isolated bodies of literature, while challenging time-honored assumptions. While suppressive regulatory strategies abound, it suggests that emotions are better understood as regulating us, providing a service crucial to all semantic language, learning systems, evaluative decision-making, and fundamental to optimal physical, mental, and social health. PMID:24808986

  8. Fas-Associated Factor 1 Negatively Regulates the Antiviral Immune Response by Inhibiting Translocation of Interferon Regulatory Factor 3 to the Nucleus

    PubMed Central

    Song, Soonhwa; Lee, Jae-Jin; Kim, Hee-Jung; Lee, Jeong Yoon; Chang, Jun

    2016-01-01

    This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitin-related domains. Microarray analyses revealed that interferon-stimulated genes related to the antiviral response are significantly increased in FAF1-knockdown HeLa cells. Silencing FAF1 enhanced the poly(I·C)- and respiratory syncytial virus (RSV)-induced production of type I interferons (IFNs), the target genes of interferon regulator factor 3 (IRF3). IRF3 is a key transcription factor in IFN-β signaling responsible for the host innate immune response. This study also found that FAF1 and IRF3 physically associate with IPO5/importin-β3 and that overexpression of FAF1 reduces the interaction between IRF3 and IPO5/importin-β3. These findings suggest that FAF1 negatively regulates IRF3-mediated IFN-β production and the antiviral innate immune response by regulating nuclear translocation of IRF3. We conclude that FAF1 plays a novel role in negatively regulating virus-induced IFN-β production and the antiviral response by inhibiting the translocation of active, phosphorylated IRF3 from the cytosol to the nucleus. PMID:26811330

  9. Regulatory architecture determines optimal regulation of gene expression in metabolic pathways.

    PubMed

    Chubukov, Victor; Zuleta, Ignacio A; Li, Hao

    2012-03-27

    In response to environmental changes, the connections ("arrows") in gene regulatory networks determine which genes modulate their expression, but the quantitative parameters of the network ("the numbers on the arrows") are equally important in determining the resulting phenotype. What are the objectives and constraints by which evolution determines these parameters? We explore these issues by analyzing gene expression changes in a number of yeast metabolic pathways in response to nutrient depletion. We find that a striking pattern emerges that couples the regulatory architecture of the pathway to the gene expression response. In particular, we find that pathways controlled by the intermediate metabolite activation (IMA) architecture, in which an intermediate metabolite activates transcription of pathway genes, exhibit the following response: the enzyme immediately downstream of the regulatory metabolite is under the strongest transcriptional control, whereas the induction of the enzymes upstream of the regulatory intermediate is relatively weak. This pattern of responses is absent in pathways not controlled by an IMA architecture. The observation can be explained by the constraint imposed by the fundamental feedback structure of the network, which places downstream enzymes under a negative feedback loop and upstream ones under a positive feedback loop. This general design principle for transcriptional control of a metabolic pathway can be derived from a simple cost/benefit model of gene expression, in which the observed pattern is an optimal solution. Our results suggest that the parameters regulating metabolic enzyme expression are optimized by evolution, under the strong constraint of the underlying regulatory architecture.

  10. Overlapping protein-binding sites within a negative regulatory element modulate the brain-preferential expression of the human HPRT gene

    SciTech Connect

    Rincon-Limas, D.E.; Amaya-Manzanares, E.; Nino-Rosales, M.L.

    1994-09-01

    The hypoxanthine phosphoribosyltransferase (HPRT) gene, whose deficiency in humans causes the Lesch-Nyhan syndrome, is constitutively expressed at low levels in all tissues but at higher levels in the brain, the significance and mechanism of which is unknown. Towards dissecting this molecular mechanism, we have previously identified a 182 bp element (hHPRT-NE) within the 5{prime}-flanking region of the human HPRT gene which is involved not only in conferring neuronal specificity but also in repressing gene expression in non-neuronal tissues. Here we report that this element interacts with different nuclear proteins, some of which are present specifically in neuronal cells (complex I) and others of which are present in cells showing constitutive expression of the gene (complex II). In addition, we found that complex I factors are expressed in human NT2/D1 cells following induction of neuronal differentiation by retinoic acid. This finding correlates with an increase of HPRT gene transcription following neuronal differentiation, as demonstrated by RT-PCR and RNAase protection assays. We also mapped the binding sites for both complexes to a 60 bp region which, when tested by transient transfections in cultured fibroblasts, functioned as a repressor element. Methylation interference footprinting revealed a minimal unique DNA motif as the binding site for nuclear proteins from both neuronal and non-neuronal sources. Moreover, UV-crosslinking experiments showed that both complexes are formed by the association of several distinct proteins. Strikingly, site-directed mutagenesis of the footprinted region indicated that different nucleotides are essential for the association of these two complexes. These data suggest that differential formation of DNA-protein complexes at this regulatory domain could be a major determinant in the brain-preferential expression of the human HPRT gene.

  11. Dominating expression of negative regulatory factors downmodulates major histocompatibility complex Class-II expression on dendritic cells in chronic hepatitis C infection

    PubMed Central

    Tomer, Shallu; Chawla, Yogesh K; Duseja, Ajay; Arora, Sunil K

    2016-01-01

    AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells (DCs) in chronic hepatitis C (CHC) patients infected with genotype 3 virus. METHODS: This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c (BDCA1)+ DC isolation Kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus (HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time PCR. RESULTS: Non-responders [sustained virological response (SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1 (6-fold) and negative regulators of JAK-STAT pathway such as SOCS (6-fold) as compared to responders (SVR+ve) to antiviral therapy. The down-regulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex (MHC) Class-II family as HLA-DP, HLA-DQ (2-fold) and superoxide dismutase (2-fold). Cells grown in the presence of HCV viral proteins had genes down-regulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors (4-fold) were up-regulated as compared to cells grown in absence of viral proteins. CONCLUSION: Underexpressed MHC class-II genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs. PMID:27298560

  12. Chemical feedbacks in climate sensitivity studies

    NASA Astrophysics Data System (ADS)

    Dietmüller, Simone; Ponater, Michael; Sausen, Robert

    2013-04-01

    Interactively coupled climate chemistry models extend the number of feedback mechanisms in climate change simulations by allowing a variation of several radiatively actice chemical tracers that are prescribed in conventional climate models. Different perturbation experiments including chemical feedbacks were performed using the chemistry-climate model system EMAC coupled to the mixed layer ocean model MLO. The influence of the chemical feedbacks O3, CH4 and N2O on climate response and climate sensitivity is quantified for a series of CO2-perturbation simulations: Equilibrium climate sensitivity is dampened, if chemical feedbacks are included. In case of a CO2 doubling simulation chemical feedbacks decrease climate sensitivity by -3.6% and in case of a 4*CO2 simulation by -8.1%. Analysis of the chemical feedbacks reveals, that the negative feedback of ozone, mainly the feedback of stratospheric ozone, is responsible for this dampening. The radiative feedbacks of CH4 and N2O are negligible, mainly because the model system does not allow interactive emission feedbacks at the Earth's surface for these gases. The feedback of physical parameters is significantly modified by the presence of chemical feedbacks. In case of the CO2-perturbation experiments the negative stratospheric ozone feedback is accompanied by a negative stratospheric H2O feedback change of the same order of magnitude. So the dampening effect of the direct O3 radiative feedback is enhanced. A non-linearity in the damping is found with increasing CO2 concentrations. Reasons are the nonlinear feedbacks of ozone, temperature, and stratospheric water vapor. Additional 6*CO2 simulations with and without chemical feedbacks included show, that the presence of chemic feedbacks helps to prevent a runaway greenhouse effect, as the O3 distribution can react to the upward shift of the tropopause. Also experiments driven by anthropogenic NOx- and CO-emissions were performed, where chemically active trace gases act

  13. A 53-base-pair inverted repeat negatively regulates expression of the adjacent and divergently oriented cytochrome P450(BM-1) gene and its regulatory gene, bm1P1, in Bacillus megaterium.

    PubMed Central

    Shaw, G C; Sung, C C; Liu, C H; Kao, H S

    1997-01-01

    To study the role of the cis-acting element(s) in controlling the expression of the cytochrome P450(BM-1) gene and its upstream regulatory gene, bm1P1, in Bacillus megaterium, various deletion derivatives were constructed. A 53-bp inverted repeat located midway between the P450(BM-1) gene and bm1P1 gene was found in vivo to negatively regulate the expression of both genes, the regulation of which may occur at the transcriptional level. The promoter of the P450(BM-1), gene was also identified and found to be similar to those recognized by the sigmaA RNA polymerase of Bacillus subtilis. Possible mechanisms by which the 53-bp inverted repeat regulates the gene expression are discussed. PMID:8982010

  14. Topological origin of global attractors in gene regulatory networks

    NASA Astrophysics Data System (ADS)

    Zhang, YunJun; Ouyang, Qi; Geng, Zhi

    2015-02-01

    Fixed-point attractors with global stability manifest themselves in a number of gene regulatory networks. This property indicates the stability of regulatory networks against small state perturbations and is closely related to other complex dynamics. In this paper, we aim to reveal the core modules in regulatory networks that determine their global attractors and the relationship between these core modules and other motifs. This work has been done via three steps. Firstly, inspired by the signal transmission in the regulation process, we extract the model of chain-like network from regulation networks. We propose a module of "ideal transmission chain (ITC)", which is proved sufficient and necessary (under certain condition) to form a global fixed-point in the context of chain-like network. Secondly, by examining two well-studied regulatory networks (i.e., the cell-cycle regulatory networks of Budding yeast and Fission yeast), we identify the ideal modules in true regulation networks and demonstrate that the modules have a superior contribution to network stability (quantified by the relative size of the biggest attraction basin). Thirdly, in these two regulation networks, we find that the double negative feedback loops, which are the key motifs of forming bistability in regulation, are connected to these core modules with high network stability. These results have shed new light on the connection between the topological feature and the dynamic property of regulatory networks.

  15. Osteocyte Network; a Negative Regulatory System for Bone Mass Augmented by the Induction of Rankl in Osteoblasts and Sost in Osteocytes at Unloading

    PubMed Central

    Moriishi, Takeshi; Fukuyama, Ryo; Ito, Masako; Miyazaki, Toshihiro; Maeno, Takafumi; Kawai, Yosuke; Komori, Hisato; Komori, Toshihisa

    2012-01-01

    Reduced mechanical stress is a major cause of osteoporosis in the elderly, and the osteocyte network, which comprises a communication system through processes and canaliculi throughout bone, is thought to be a mechanosensor and mechanotransduction system; however, the functions of osteocytes are still controversial and remain to be clarified. Unexpectedly, we found that overexpression of BCL2 in osteoblasts eventually caused osteocyte apoptosis. Osteoblast and osteoclast differentiation were unaffected by BCL2 transgene in vitro. However, the cortical bone mass increased due to enhanced osteoblast function and suppressed osteoclastogenesis at 4 months of age, when the frequency of TUNEL-positive lacunae reached 75%. In the unloaded condition, the trabecular bone mass decreased in both wild-type and BCL2 transgenic mice at 6 weeks of age, while it decreased due to impaired osteoblast function and enhanced osteoclastogenesis in wild-type mice but not in BCL2 transgenic mice at 4 months of age. Rankl and Opg were highly expressed in osteocytes, but Rankl expression in osteoblasts but not in osteocytes was increased at unloading in wild-type mice but not in BCL2 transgenic mice at 4 months of age. Sost was locally induced at unloading in wild-type mice but not in BCL2 transgenic mice, and the dissemination of Sost was severely interrupted in BCL2 transgenic mice, showing the severely impaired osteocyte network. These findings indicate that the osteocyte network is required for the upregulation of Rankl in osteoblasts and Sost in osteocytes in the unloaded condition. These findings suggest that the osteocyte network negatively regulate bone mass by inhibiting osteoblast function and activating osteoclastogenesis, and these functions are augmented in the unloaded condition at least partly through the upregulation of Rankl expression in osteoblasts and that of Sost in osteocytes, although it cannot be excluded that low BCL2 transgene expression in osteoblasts contributed

  16. Nuclear factor kappaB/p49 is a negative regulatory factor in nerve growth factor-induced choline acetyltransferase promoter activity in PC12 cells.

    PubMed

    Toliver-Kinsky, T; Wood, T; Perez-Polo, J R

    2000-12-01

    Anovel nuclear factor kappaB (NF-kappaB) binding site has been identified within the promoter region of the mouse gene encoding choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine and has been implicated in the cognitive deficits associated with aging and Alzheimer's disease. This binding site, which is located within the nerve growth factor (NGF)-responsive enhancer element, was recognized by the NF-kappaB protein p49 but not p65 or p50. p49 from both basal forebrain and PC12 nuclear extracts interacted with this specific sequence in electrophoretic mobility shift assays. Mutation of the NF-kappaB site caused an increase in NGF-induced promoter activation, whereas overexpression of p49 in NGF-differentiated PC12 cells caused a decrease in endogenous ChAT enzyme activity and a decrease in promoter activity that was specifically mediated through this NF-kappaB binding site. Treatment of PC12 cells with NGF resulted in a drastic reduction in nuclear p49 binding to the ChAT NF-kappaB site after 24 h, but nuclear p49 levels were not altered, suggesting that late NGF-mediated events prevent binding of p49 to the ChAT promoter by an unknown mechanism other than nuclear translocation. Decreased ChAT expression and increased NF-kappaB activity in the brain are associated with aging and Alzheimer's disease. These data indicate that p49 is a negative regulator of ChAT expression and suggest a possible mechanism for aging-associated declines in cholinergic function.

  17. Adaptive feedback cancellation in hearing aids with clipping in the feedback path.

    PubMed

    Freed, Daniel J

    2008-03-01

    Adaptive linear filtering algorithms are commonly used to cancel feedback in hearing aids. The use of these algorithms is based on the assumption that the feedback path is linear, so nonlinearities in the feedback path may affect performance. This study investigated the effect on feedback canceller performance of clipping of the feedback signal arriving at the microphone, as well as the benefit of applying identical clipping to the cancellation signal so that the cancellation path modeled the nonlinearity of the feedback path. Feedback signal clipping limited the amount of added stable gain that the feedback canceller could provide, and caused misadjustment in response to high-level inputs, by biasing adaptive filter coefficients toward lower magnitudes. Cancellation signal clipping mitigated these negative effects, permitting higher amounts of added stable gain and less misadjustment in response to high-level inputs, but the benefit was reduced in the presence of the highest-level inputs. PMID:18345849

  18. Understanding the Influence of Emotions and Reflection upon Multi-Source Feedback Acceptance and Use

    ERIC Educational Resources Information Center

    Sargeant, Joan; Mann, Karen; Sinclair, Douglas; Van der Vleuten, Cees; Metsemakers, Job

    2008-01-01

    Introduction: Receiving negative performance feedback can elicit negative emotional reactions which can interfere with feedback acceptance and use. This study investigated emotional responses of family physicians' participating in a multi-source feedback (MSF) program, sources of these emotions, and their influence upon feedback acceptance and…

  19. A Framework for Teacher Verbal Feedback: Lessons from Chinese Mathematics Classrooms

    ERIC Educational Resources Information Center

    Li, Na; Cao, Yiming; Mok, Ida Ah Chee

    2016-01-01

    Teacher verbal feedback plays an important role in classroom teaching. Different types of feedback can have different effect on students' learning. Praise and blame feedback could provide positive and negative results for learners. The gap was left in considering teachers' attitudes in providing verbal feedback to students. Due to feedback which…

  20. Role of prolactin in the regulation of sensitivity of the hypothalamic-pituitary system to steroid feedback.

    PubMed

    Bartke, A; Matt, K S; Steger, R W; Clayton, R N; Chandrashekar, V; Smith, M S

    1987-01-01

    During sexual maturation, pituitary gonadotropins stimulate the gonads to produce increasing amounts of biologically active steroids and yet gonadotropin release does not become suppressed until concentrations of sex hormones, LH and FSH, in peripheral circulation stabilizes at a higher adult level. There is a substantial amount of evidence that in many mammals, this transition from prepubertal to adult level of activity of the pituitary-gonadal axis is associated with a reduction in the sensitivity of the hypothalamic-adenohypophyseal system to negative feedback of gonadal steroids. In the female, these changes are accompanied by the appearance of positive estrogen feedback on gonadotropin release. In seasonal breeders, annual transitions between the periods of gonadal activity and quiescence are associated with corresponding shifts in the sensitivity to steroid feedback. Peripheral levels of pituitary prolactin (PRL) typically increase during sexual maturation and exhibit large seasonal fluctuations in response to changes in photoperiod and ambient temperature. We propose that PRL is one of the factors which regulate the sensitivity of gonadotropin release to gonadal steroid feedback. In hyperprolactinemic women, responsiveness to negative estrogen feedback increases, while LH response to positive estrogen feedback is reduced or absent. In hyperprolactinemic men, both LH and testosterone levels are reduced, implying increased sensitivity of LH release to negative testosterone feedback. In the male rat, both physiological amounts of PRL and experimentally-induced hyperprolactinemia increase the ability of exogenous testosterone to suppress LH and FSH release. Different regulatory mechanisms appear to operate in the seasonally breeding male golden hamster, in which short photoperiod causes concomitant suppression of PRL, LH, FSH and testosterone release. In this species, pharmacologic suppression of PRL release leads to increased responsiveness of plasma

  1. Insights from a refined decomposition of cloud feedbacks

    NASA Astrophysics Data System (ADS)

    Zelinka, Mark D.; Zhou, Chen; Klein, Stephen A.

    2016-09-01

    Decomposing cloud feedback into components due to changes in several gross cloud properties provides valuable insights into its physical causes. Here we present a refined decomposition that separately considers changes in free tropospheric and low cloud properties, better connecting feedbacks to individual governing processes and avoiding ambiguities present in a commonly used decomposition. It reveals that three net cloud feedback components are robustly nonzero: positive feedbacks from increasing free tropospheric cloud altitude and decreasing low cloud cover and a negative feedback from increasing low cloud optical depth. Low cloud amount feedback is the dominant contributor to spread in net cloud feedback but its anticorrelation with other components damps overall spread. The ensemble mean free tropospheric cloud altitude feedback is roughly 60% as large as the standard cloud altitude feedback because it avoids aliasing in low cloud reductions. Implications for the "null hypothesis" climate sensitivity from well-understood and robustly simulated feedbacks are discussed.

  2. Different aspects of performance feedback engage different brain areas: disentangling valence and expectancy in feedback processing.

    PubMed

    Ferdinand, Nicola K; Opitz, Bertram

    2014-08-07

    Evaluating the positive and negative outcomes of our behaviour is important for action selection and learning. Such reinforcement learning has been shown to engage a specific neural circuitry including the mesencephalic dopamine system and its target areas, the striatum and medial frontal cortex, especially the anterior cingulate cortex (ACC). An intensively pursued debate regards the prevailing influence of feedback expectancy and feedback valence on the engagement of these two brain regions in reinforcement learning and their respective roles are far from being understood. To this end, we used a time estimation task with three different types of feedback that allows disentangling the effect of feedback valence and expectancy using functional magnetic resonance imaging (fMRI). Our results show greater ACC activation after unexpected positive and unexpected negative feedback than after expected feedback and by this sensitivity to unexpected events in general irrespective of their valence.

  3. Reducing the uncertainty in subtropical cloud feedback

    NASA Astrophysics Data System (ADS)

    Myers, Timothy A.; Norris, Joel R.

    2016-03-01

    Large uncertainty remains on how subtropical clouds will respond to anthropogenic climate change and therefore whether they will act as a positive feedback that amplifies global warming or negative feedback that dampens global warming by altering Earth's energy budget. Here we reduce this uncertainty using an observationally constrained formulation of the response of subtropical clouds to greenhouse forcing. The observed interannual sensitivity of cloud solar reflection to varying meteorological conditions suggests that increasing sea surface temperature and atmospheric stability in the future climate will have largely canceling effects on subtropical cloudiness, overall leading to a weak positive shortwave cloud feedback (0.4 ± 0.9 W m-2 K-1). The uncertainty of this observationally based approximation of the cloud feedback is narrower than the intermodel spread of the feedback produced by climate models. Subtropical cloud changes will therefore complement positive cloud feedbacks identified by previous work, suggesting that future global cloud changes will amplify global warming.

  4. Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), a negative regulator of luteinizing/chorionic gonadotropin hormone-induced steroidogenesis in Leydig cells: central role of steroidogenic acute regulatory protein (StAR).

    PubMed

    Fukushima, Masato; Villar, Joaquin; Tsai-Morris, Chon-Hwa; Dufau, Maria L

    2011-08-26

    Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) is a testis-specific gonadotropin-regulated RNA helicase that is present in Leydig cells (LCs) and germ cells and is essential for spermatid development and completion of spermatogenesis. Normal basal levels of testosterone in serum and LCs were observed in GRTH null (GRTH(-/-)) mice. However, testosterone production was enhanced in LCs of GRTH(-/-) mice compared with WT mice by both in vivo and in vitro human chorionic gonadotropin stimulation. LCs of GRTH(-/-) mice had swollen mitochondria with a significantly increased cholesterol content in the inner mitochondrial membrane. Basal protein levels of SREBP2, HMG-CoA reductase, and steroidogenic acute regulatory protein (StAR; a protein that transports cholesterol to the inner mitochondrial membrane) were markedly increased in LCs of GRTH(-/-) mice compared with WT mice. Gonadotropin stimulation caused an increase in StAR mRNA levels and protein expression in GRTH(-/-) mice versus WT mice, with no further increase in SREBP2 and down-regulation of HMG-CoA reductase protein. The half-life of StAR mRNA was significantly increased in GRTH(-/-) mice. Moreover, association of StAR mRNA with GRTH protein was observed in WT mice. Human chorionic gonadotropin increased GRTH gene expression and its associated StAR protein at cytoplasmic sites. Taken together, these findings indicate that, through its negative role in StAR message stability, GRTH regulates cholesterol availability at the mitochondrial level. The finding of an inhibitory action of GRTH associated with gonadotropin-mediated steroidogenesis has provided insights into a novel negative autocrine molecular control mechanism of this helicase in the regulation of steroid production in the male.

  5. Neural correlates of experienced moral emotion: an fMRI investigation of emotion in response to prejudice feedback.

    PubMed

    Fourie, Melike M; Thomas, Kevin G F; Amodio, David M; Warton, Christopher M R; Meintjes, Ernesta M

    2014-01-01

    Guilt, shame, and embarrassment are quintessential moral emotions with important regulatory functions for the individual and society. Moral emotions are, however, difficult to study with neuroimaging methods because their elicitation is more intricate than that of basic emotions. Here, using functional MRI (fMRI), we employed a novel social prejudice paradigm to examine specific brain regions associated with real-time moral emotion, focusing on guilt and related moral-negative emotions. The paradigm induced intense moral-negative emotion (primarily guilt) in 22 low-prejudice individuals through preprogrammed feedback indicating implicit prejudice against Black and disabled people. fMRI data indicated that this experience of moral-negative emotion was associated with increased activity in anterior paralimbic structures, including the anterior cingulate cortex (ACC) and anterior insula, in addition to areas associated with mentalizing, including the dorsomedial prefrontal cortex, posterior cingulate cortex, and precuneus. Of significance was prominent conflict-related activity in the supragenual ACC, which is consistent with theories proposing an association between acute guilt and behavioral inhibition. Finally, a significant negative association between self-reported guilt and neural activity in the pregenual ACC suggested a role of self-regulatory processes in response to moral-negative affect. These findings are consistent with the multifaceted self-regulatory functions of moral-negative emotions in social behavior.

  6. Student Engagement with Feedback

    ERIC Educational Resources Information Center

    Scott, Jon; Shields, Cathy; Gardner, James; Hancock, Alysoun; Nutt, Alex

    2011-01-01

    This report considers Biological Sciences students' perceptions of feedback, compared with those of the University as a whole, this includes what forms of feedback were considered most useful and how feedback used. Compared with data from previous studies, Biological Sciences students gave much greater recognition to oral feedback, placing it on a…

  7. Identification of feedback loops embedded in cellular circuits by investigating non-causal impulse response components.

    PubMed

    Dong, Chao-Yi; Yoon, Tae-Woong; Bates, Declan G; Cho, Kwang-Hyun

    2010-02-01

    Feedback circuits are crucial dynamic motifs which occur in many biomolecular regulatory networks. They play a pivotal role in the regulation and control of many important cellular processes such as gene transcription, signal transduction, and metabolism. In this study, we develop a novel computationally efficient method to identify feedback loops embedded in intracellular networks, which uses only time-series experimental data and requires no knowledge of the network structure. In the proposed approach, a non-parametric system identification technique, as well as a spectral factor analysis, is applied to derive a graphical criterion based on non-causal components of the system's impulse response. The appearance of non-causal components in the impulse response sequences arising from stochastic output perturbations is shown to imply the presence of underlying feedback connections within a linear network. In order to extend the approach to nonlinear networks, we linearize the intracellular networks about an equilibrium point, and then choose the magnitude of the output perturbations sufficiently small so that the resulting time-series responses remain close to the chosen equilibrium point. In this way, the impulse response sequences of the linearized system can be used to determine the presence or absence of feedback loops in the corresponding nonlinear network. The proposed method utilizes the time profile data from intracellular perturbation experiments and only requires the perturbability of output nodes. Most importantly, the method does not require any a priori knowledge of the system structure. For these reasons, the proposed approach is very well suited to identifying feedback loops in large-scale biomolecular networks. The effectiveness of the proposed method is illustrated via two examples: a synthetic network model with a negative feedback loop and a nonlinear caspase function model of apoptosis with a positive feedback loop. PMID:19333603

  8. Signatures of AGN feedback

    NASA Astrophysics Data System (ADS)

    Wylezalek, D.; Zakamska, N.

    2016-06-01

    Feedback from active galactic nuclei (AGN) is widely considered to be the main driver in regulating the growth of massive galaxies. It operates by either heating or driving the gas that would otherwise be available for star formation out of the galaxy, preventing further increase in stellar mass. Observational proof for this scenario has, however, been hard to come by. We have assembled a large sample of 133 radio-quiet type-2 and red AGN at 0.1negative correlation between W_{90} and sSFR in the AGN hosts with the highest star formation rates, i.e., with the highest gas content. This relationship implies that AGN with strong outflow signatures are hosted in galaxies that are more `quenched' considering their stellar mass than galaxies with weaker outflow signatures. This correlation is only seen in AGN host galaxies with SFR >100 M_{⊙} yr^{-1} where presumably the coupling of the AGN-driven wind to the gas is strongest. This observation is consistent with the AGN having a net suppression, or `negative' impact, through feedback on the galaxies' star formation history.

  9. Feedback type variable venturi carburetor

    SciTech Connect

    Morino, T.; Takada, S.; Takeuchi, Y.

    1982-02-09

    A feedback type variable venturi carburetor in which the negative pressure regulated by the variable venturi at a constant level is supplied to a solenoid valve which is opened and closed at a frequency of 5-30 hz and whose open-close time ratio is controlled in accordance with the signal from exhaust gas sensor to control the vacuum pressure applied to a diaphragm chamber of an air-bleed flow control means thereby controlling the air-fuel ratio of the mixture at an optimum level. This invention obviates the use of a regulator for regulating the negative pressure from the intake manifold and precludes the drawbacks experienced with conventional carburetors, such as the slow response in the feedback control caused when the main fuel system and the idling system of the conventional carburetor are switched over, and the unstable supply of fuel when the fuel begins to be delivered from the main fuel system.

  10. Event-triggered feedback in noise-driven phase oscillators

    NASA Astrophysics Data System (ADS)

    Kromer, Justus A.; Lindner, Benjamin; Schimansky-Geier, Lutz

    2014-03-01

    Using a stochastic nonlinear phase oscillator model, we study the effect of event-triggered feedback on the statistics of interevent intervals. Events are associated with the entering of a new cycle. The feedback is modeled by an instantaneous increase (positive feedback) or decrease (negative feedback) of the oscillator frequency whenever an event occurs followed by an exponential decay on a slow time scale. In addition to the known excitable and oscillatory regimes, which are separated by a saddle node on invariant circle bifurcation, positive feedback can lead to bistable dynamics and a change of the system's excitability. The feedback has also a strong effect on noise-induced phenomena like coherence resonance or anticoherence resonance. Both positive and negative feedback can lead to more regular output for particular noise strengths. Finally, we investigate serial correlations in the sequence of interevent intervals that occur due to the additional slow dynamics. We derive approximations for the serial correlation coefficient and show that positive feedback results in extended positive interval correlations, whereas negative feedback yields short-ranging negative correlations. Investigating the interplay of feedback and the nonlinear phase dynamics close to the bifurcation, we find that correlations are most pronounced for optimal feedback strengths.

  11. Regulatory mechanisms of EGFR signalling during Drosophila eye development.

    PubMed

    Malartre, Marianne

    2016-05-01

    EGFR signalling is a well-conserved signalling pathway playing major roles during development and cancers. This review explores what studying the EGFR pathway during Drosophila eye development has taught us in terms of the diversity of its regulatory mechanisms. This model system has allowed the identification of numerous positive and negative regulators acting at specific time and place, thus participating to the tight control of signalling. EGFR signalling regulation is achieved by a variety of mechanisms, including the control of ligand processing, the availability of the receptor itself and the transduction of the cascade in the cytoplasm. Ultimately, the transcriptional responses contribute to the establishment of positive and negative feedback loops. The combination of these multiple mechanisms employed to regulate the EGFR pathway leads to specific cellular outcomes involved in functions as diverse as the acquisition of cell fate, proliferation, survival, adherens junction remodelling and morphogenesis. PMID:26935860

  12. Regulatory mechanisms of EGFR signalling during Drosophila eye development.

    PubMed

    Malartre, Marianne

    2016-05-01

    EGFR signalling is a well-conserved signalling pathway playing major roles during development and cancers. This review explores what studying the EGFR pathway during Drosophila eye development has taught us in terms of the diversity of its regulatory mechanisms. This model system has allowed the identification of numerous positive and negative regulators acting at specific time and place, thus participating to the tight control of signalling. EGFR signalling regulation is achieved by a variety of mechanisms, including the control of ligand processing, the availability of the receptor itself and the transduction of the cascade in the cytoplasm. Ultimately, the transcriptional responses contribute to the establishment of positive and negative feedback loops. The combination of these multiple mechanisms employed to regulate the EGFR pathway leads to specific cellular outcomes involved in functions as diverse as the acquisition of cell fate, proliferation, survival, adherens junction remodelling and morphogenesis.

  13. Sex Differences in the Meaning of Negative Evaluation in Achievement Situations: Determinants and Consequences.

    ERIC Educational Resources Information Center

    Dweck, Carol S.

    Sex differences in children's reactions to failure feedback in school situations were investigated by assessing the ways in which teachers use negative evaluation in the classroom. Three aspects of teachers' evaluative feedback were studied: (1) ratio of negative to positive feedback; (2) contingency vs. noncontingency of feedback; and (3) (the…

  14. Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli.

    PubMed

    Seo, Sang Woo; Kim, Donghyuk; Latif, Haythem; O'Brien, Edward J; Szubin, Richard; Palsson, Bernhard O

    2014-09-15

    The ferric uptake regulator (Fur) plays a critical role in the transcriptional regulation of iron metabolism. However, the full regulatory potential of Fur remains undefined. Here we comprehensively reconstruct the Fur transcriptional regulatory network in Escherichia coli K-12 MG1655 in response to iron availability using genome-wide measurements. Integrative data analysis reveals that a total of 81 genes in 42 transcription units are directly regulated by three different modes of Fur regulation, including apo- and holo-Fur activation and holo-Fur repression. We show that Fur connects iron transport and utilization enzymes with negative-feedback loop pairs for iron homeostasis. In addition, direct involvement of Fur in the regulation of DNA synthesis, energy metabolism and biofilm development is found. These results show how Fur exhibits a comprehensive regulatory role affecting many fundamental cellular processes linked to iron metabolism in order to coordinate the overall response of E. coli to iron availability.

  15. Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli.

    PubMed

    Seo, Sang Woo; Kim, Donghyuk; Latif, Haythem; O'Brien, Edward J; Szubin, Richard; Palsson, Bernhard O

    2014-01-01

    The ferric uptake regulator (Fur) plays a critical role in the transcriptional regulation of iron metabolism. However, the full regulatory potential of Fur remains undefined. Here we comprehensively reconstruct the Fur transcriptional regulatory network in Escherichia coli K-12 MG1655 in response to iron availability using genome-wide measurements. Integrative data analysis reveals that a total of 81 genes in 42 transcription units are directly regulated by three different modes of Fur regulation, including apo- and holo-Fur activation and holo-Fur repression. We show that Fur connects iron transport and utilization enzymes with negative-feedback loop pairs for iron homeostasis. In addition, direct involvement of Fur in the regulation of DNA synthesis, energy metabolism and biofilm development is found. These results show how Fur exhibits a comprehensive regulatory role affecting many fundamental cellular processes linked to iron metabolism in order to coordinate the overall response of E. coli to iron availability. PMID:25222563

  16. Distinguishing Feedback Mechanisms in Clock Models

    NASA Astrophysics Data System (ADS)

    Golden, Alexander; Lubensky, David

    Biological oscillators are very diverse but can be classified based on dynamical motifs such as type of feedback. The S. Elongatus circadian oscillator is a novel circadian oscillator that can operate at constant protein number by modifying covalent states. It can be reproduced in vitro with only 3 different purified proteins: KaiA, KaiB, and KaiC. We use computational and analytic techniques to compare models of the S. Elongatus post-translational oscillator that rely on positive feedback with models that rely on negative feedback. We show that introducing a protein that binds competitively with KaiA to the KaiB-KaiC complex can distinguish between positive and negative feedback as the primary driver of the rhythm, which has so far been difficult to address experimentally. NSF Grant DMR-1056456.

  17. Feedback on Feedback--Does It Work?

    ERIC Educational Resources Information Center

    Speicher, Oranna; Stollhans, Sascha

    2015-01-01

    It is well documented that providing assessment feedback through the medium of screencasts is favourably received by students and encourages deeper engagement with the feedback given by the language teacher (inter alia Abdous & Yoshimura, 2010; Brick & Holmes, 2008; Cann, 2007; Stannard, 2007). In this short paper we will report the…

  18. Feedback Seeking in Early Adolescence: Self-Enhancement or Self-Verification?

    ERIC Educational Resources Information Center

    Rosen, Lisa H.; Principe, Connor P.; Langlois, Judith H.

    2013-01-01

    The authors examined whether early adolescents ("N" = 90) solicit self-enhancing feedback (i.e., positive feedback) or self-verifying feedback (i.e., feedback congruent with self-views, even when these views are negative). Sixth, seventh, and eighth graders first completed a self-perception measure and then selected whether to receive…

  19. Types and Frequencies of Feedback Interventions in Classroom Interaction in Secondary Education

    ERIC Educational Resources Information Center

    Voerman, Lia; Meijer, Paulien C.; Korthagen, Fred A. J.; Simons, Robert Jan

    2012-01-01

    Contributing to the growing amount of literature on learning-enhancing feedback, this article attempts to distinguish between progress feedback and discrepancy feedback. Building on relevant literature drawn from psychology, we propose the use of a ratio of 3:1, positive:negative feedback. We analyzed contiguous 10 min blocks of classroom…

  20. Molecular Framework of a Regulatory Circuit Initiating Two-Dimensional Spatial Patterning of Stomatal Lineage

    PubMed Central

    Rychel, Amanda L.; Garrick, Jacqueline M.; Kawaguchi, Masayoshi; Peterson, Kylee M.; Torii, Keiko U.

    2015-01-01

    Stomata, valves on the plant epidermis, are critical for plant growth and survival, and the presence of stomata impacts the global water and carbon cycle. Although transcription factors and cell-cell signaling components regulating stomatal development have been identified, it remains unclear as to how their regulatory interactions are translated into two-dimensional patterns of stomatal initial cells. Using molecular genetics, imaging, and mathematical simulation, we report a regulatory circuit that initiates the stomatal cell-lineage. The circuit includes a positive feedback loop constituting self-activation of SCREAMs that requires SPEECHLESS. This transcription factor module directly binds to the promoters and activates a secreted signal, EPIDERMAL PATTERNING FACTOR2, and the receptor modifier TOO MANY MOUTHS, while the receptor ERECTA lies outside of this module. This in turn inhibits SPCH, and hence SCRMs, thus constituting a negative feedback loop. Our mathematical model accurately predicts all known stomatal phenotypes with the inclusion of two additional components to the circuit: an EPF2-independent negative-feedback loop and a signal that lies outside of the SPCH•SCRM module. Our work reveals the intricate molecular framework governing self-organizing two-dimensional patterning in the plant epidermis. PMID:26203655

  1. Molecular Framework of a Regulatory Circuit Initiating Two-Dimensional Spatial Patterning of Stomatal Lineage.

    PubMed

    Horst, Robin J; Fujita, Hironori; Lee, Jin Suk; Rychel, Amanda L; Garrick, Jacqueline M; Kawaguchi, Masayoshi; Peterson, Kylee M; Torii, Keiko U

    2015-07-01

    Stomata, valves on the plant epidermis, are critical for plant growth and survival, and the presence of stomata impacts the global water and carbon cycle. Although transcription factors and cell-cell signaling components regulating stomatal development have been identified, it remains unclear as to how their regulatory interactions are translated into two-dimensional patterns of stomatal initial cells. Using molecular genetics, imaging, and mathematical simulation, we report a regulatory circuit that initiates the stomatal cell-lineage. The circuit includes a positive feedback loop constituting self-activation of SCREAMs that requires SPEECHLESS. This transcription factor module directly binds to the promoters and activates a secreted signal, EPIDERMAL PATTERNING FACTOR2, and the receptor modifier TOO MANY MOUTHS, while the receptor ERECTA lies outside of this module. This in turn inhibits SPCH, and hence SCRMs, thus constituting a negative feedback loop. Our mathematical model accurately predicts all known stomatal phenotypes with the inclusion of two additional components to the circuit: an EPF2-independent negative-feedback loop and a signal that lies outside of the SPCH•SCRM module. Our work reveals the intricate molecular framework governing self-organizing two-dimensional patterning in the plant epidermis. PMID:26203655

  2. A model for improving microbial biofuel production using a synthetic feedback loop

    SciTech Connect

    Dunlop, Mary; Keasling, Jay; Mukhopadhyay, Aindrila

    2011-07-14

    Cells use feedback to implement a diverse range of regulatory functions. Building synthetic feedback control systems may yield insight into the roles that feedback can play in regulation since it can be introduced independently of native regulation, and alternative control architectures can be compared. We propose a model for microbial biofuel production where a synthetic control system is used to increase cell viability and biofuel yields. Although microbes can be engineered to produce biofuels, the fuels are often toxic to cell growth, creating a negative feedback loop that limits biofuel production. These toxic effects may be mitigated by expressing efflux pumps that export biofuel from the cell. We developed a model for cell growth and biofuel production and used it to compare several genetic control strategies for their ability to improve biofuel yields. We show that controlling efflux pump expression directly with a biofuel-responsive promoter is a straight forward way of improving biofuel production. In addition, a feed forward loop controller is shown to be versatile at dealing with uncertainty in biofuel production rates.

  3. Chromaticity Feedback at RHIC

    SciTech Connect

    Marusic, A.; Minty, M.; Tepikian, S.

    2010-05-23

    Chromaticity feedback during the ramp to high beam energies has been demonstrated in the Relativistic Heavy Ion Collider (RHIC). In this report we review the feedback design and measurement technique. Commissioning experiences including interaction with existing tune and coupling feedback are presented together with supporting experimental data.

  4. The Mythology of Feedback

    ERIC Educational Resources Information Center

    Adcroft, Andy

    2011-01-01

    Much of the general education and discipline-specific literature on feedback suggests that it is a central and important element of student learning. This paper examines feedback from a social process perspective and suggests that feedback is best understood through an analysis of the interactions between academics and students. The paper argues…

  5. Preventing Feedback Fizzle

    ERIC Educational Resources Information Center

    Brookhart, Susan M.

    2012-01-01

    Feedback is certainly about saying or writing helpful, learning-focused comments. But that is only part of it. What happens beforehand? What happens afterward? Feedback that is helpful and learning-focused fits into a context. Before a teacher gives feedback, students need to know the learning target so they have a purpose for using the feedback…

  6. Developing Sustainable Feedback Practices

    ERIC Educational Resources Information Center

    Carless, David; Salter, Diane; Yang, Min; Lam, Joy

    2011-01-01

    Feedback is central to the development of student learning, but within the constraints of modularized learning in higher education it is increasingly difficult to handle effectively. This article makes a case for sustainable feedback as a contribution to the reconceptualization of feedback processes. The data derive from the Student Assessment and…

  7. Feedback effect on flute dynamics in a mirror machine

    NASA Astrophysics Data System (ADS)

    Be'Ery, Ilan; Seemann, Omri

    2015-11-01

    Active feedback techniques may stabilize the flute instability in mirror traps and make them viable candidates for fusion machines. A fast feedback with optical sensors and electrical actuators was implemented in a table-top mirror machine and used to study several aspects of feedback stabilization. For a cold, dense plasma the feedback reduces dramatically the flute amplitude of the first two mode. For higher temperature plasma, a significant increase of plasma density due to feedback stabilization is also demonstrated. The effect of changing feedback gain and phase has some interesting feature such as asymmetry with respect to positive and negative phase shifts and non-monotonic dependence of flute amplitude on feedback gain. These effects are explained using simplified analytic model of the flute and feedback.

  8. Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses

    PubMed Central

    Kriete, Andres; Bosl, William J.; Booker, Glenn

    2010-01-01

    Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-κB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype. PMID:20585546

  9. Neural correlates of anticipation and processing of performance feedback in social anxiety.

    PubMed

    Heitmann, Carina Y; Peterburs, Jutta; Mothes-Lasch, Martin; Hallfarth, Marlit C; Böhme, Stephanie; Miltner, Wolfgang H R; Straube, Thomas

    2014-12-01

    Fear of negative evaluation, such as negative social performance feedback, is the core symptom of social anxiety. The present study investigated the neural correlates of anticipation and perception of social performance feedback in social anxiety. High (HSA) and low (LSA) socially anxious individuals were asked to give a speech on a personally relevant topic and received standardized but appropriate expert performance feedback in a succeeding experimental session in which neural activity was measured during anticipation and presentation of negative and positive performance feedback concerning the speech performance, or a neutral feedback-unrelated control condition. HSA compared to LSA subjects reported greater anxiety during anticipation of negative feedback. Functional magnetic resonance imaging results showed deactivation of medial prefrontal brain areas during anticipation of negative feedback relative to the control and the positive condition, and medial prefrontal and insular hyperactivation during presentation of negative as well as positive feedback in HSA compared to LSA subjects. The results indicate distinct processes underlying feedback processing during anticipation and presentation of feedback in HSA as compared to LSA individuals. In line with the role of the medial prefrontal cortex in self-referential information processing and the insula in interoception, social anxiety seems to be associated with lower self-monitoring during feedback anticipation, and an increased self-focus and interoception during feedback presentation, regardless of feedback valence.

  10. Convection and the Soil-Moisture Precipitation Feedback

    NASA Astrophysics Data System (ADS)

    Schar, C.; Froidevaux, P.; Keller, M.; Schlemmer, L.; Langhans, W.; Schmidli, J.

    2014-12-01

    The soil moisture - precipitation (SMP) feedback is of key importance for climate and climate change. A positive SMP feedback tends to amplify the hydrological response to external forcings (and thereby fosters precipitation and drought extremes), while a negative SMP feedback tends to moderate the influence of external forcings (and thereby stabilizes the hydrological cycle). The sign of the SMP feedback is poorly constrained by the current literature. Theoretical, modeling and observational studies partly disagree, and have suggested both negative and positive feedback loops. Can wet soil anomalies indeed result in either an increase or a decrease of precipitation (positive or negative SMP feedback, respectively)? Here we investigate the local SMP feedback using real-case and idealized convection-resolving simulations. An idealized simulation strategy is developed, which is able to replicate both signs of the feedback loop, depending on the environmental parameters. The mechanism relies on horizontal soil moisture variations, which may develop and intensify spontaneously. The positive expression of the feedback is associated with the initiation of convection over dry soil patches, but the convective cells then propagate over wet patches, where they strengthen and preferentially precipitate. The negative feedback may occur when the wind profile is too weak to support the propagation of convective features from dry to wet areas. Precipitation is then generally weaker and falls preferentially over dry patches. The results highlight the role of the mid-tropospheric flow in determining the sign of the feedback. A key element of the positive feedback is the exploitation of both low convective inhibition (CIN) over dry patches (for the initiation of convection), and high CAPE over wet patches (for the generation of precipitation). The results of this study will also be discussed in relation to climate change scenarios that exhibit large biases in surface temperature and

  11. A Positive Feedback Synapse from Retinal Horizontal Cells to Cone Photoreceptors

    PubMed Central

    Jackman, Skyler L.; Babai, Norbert; Chambers, James J.; Thoreson, Wallace B.; Kramer, Richard H.

    2011-01-01

    Cone photoreceptors and horizontal cells (HCs) have a reciprocal synapse that underlies lateral inhibition and establishes the antagonistic center-surround organization of the visual system. Cones transmit to HCs through an excitatory synapse and HCs feed back to cones through an inhibitory synapse. Here we report that HCs also transmit to cone terminals a positive feedback signal that elevates intracellular Ca2+ and accelerates neurotransmitter release. Positive and negative feedback are both initiated by AMPA receptors on HCs, but positive feedback appears to be mediated by a change in HC Ca2+, whereas negative feedback is mediated by a change in HC membrane potential. Local uncaging of AMPA receptor agonists suggests that positive feedback is spatially constrained to active HC-cone synapses, whereas the negative feedback signal spreads through HCs to affect release from surrounding cones. By locally offsetting the effects of negative feedback, positive feedback may amplify photoreceptor synaptic release without sacrificing HC-mediated contrast enhancement. PMID:21559323

  12. Feedback effect on flute dynamics in a mirror machine

    NASA Astrophysics Data System (ADS)

    Be'ery, I.; Seemann, O.

    2015-08-01

    The effect of active feedback on flute instability is experimentally studied in a table-top mirror machine. Changing the plasma conditions from mirror-loss dominated to flute-loss dominated, it is demonstrated that while the feedback has no effect on plasma density in the first case, it increases the plasma density by up to 50% in the second case. Measurements of the dependence of instability amplitude on feedback gain show that large gain stimulates high frequency perturbations. The period of these perturbations corresponds to the inherent delay of immersed electrode feedback. Variation of the spatial phase between the input and output of the phase reveals a large asymmetry between positive and negative phase shifts. A simplified model is introduced to explain how a negative phase shift causes positive feedback between the external feedback and the centrifugally driven rotation.

  13. Analysis of snow feedbacks in 14 general circulation models

    NASA Technical Reports Server (NTRS)

    Randall, D. A.; Cess, R. D.; Blanchet, J. P.; Chalita, S.; Colman, R.; Dazlich, D. A.; Del Genio, A. D.; Keup, E.; Lacis, A.; Le Treut, H.

    1994-01-01

    Snow feedbacks produced by 14 atmospheric general circulation models have been analyzed through idealized numerical experiments. Included in the analysis is an investigation of the surface energy budgets of the models. Negative or weak positive snow feedbacks occurred in some of the models, while others produced strong positive snow feedbacks. These feedbacks are due not only to melting snow, but also to increases in boundary temperature, changes in air temperature, changes in water vapor, and changes in cloudiness. As a result, the net response of each model is quite complex. We analyze in detail the responses of one model with a strong positive snow feedback and another with a weak negative snow feedback. Some of the models include a temperature dependence of the snow albedo, and this has significantly affected the results.

  14. The Greenhouse Effect and Climate Feedbacks

    NASA Astrophysics Data System (ADS)

    Covey, C.; Haberle, R. M.; McKay, C. P.; Titov, D. V.

    This chapter reviews the theory of the greenhouse effect and climate feedback. It also compares the theory with observations, using examples taken from all four known terrestrial worlds with substantial atmospheres: Venus, Earth, Mars, and Titan. The greenhouse effect traps infrared radiation in the atmosphere, thereby increasing surface temperature. It is one of many factors that affect a world's climate. (Others include solar luminosity and the atmospheric scattering and absorption of solar radiation.) A change in these factors — defined as climate forcing — may change the climate in a way that brings other processes — defined as feedbacks — into play. For example, when Earth's atmospheric carbon dioxide increases, warming the surface, the water vapor content of the atmosphere increases. This is a positive feedback on global warming because water vapor is itself a potent greenhouse gas. Many positive and negative feedback processes are significant in determining Earth's climate, and probably the climates of our terrestrial neighbors.

  15. Stress-induced alterations in the programmed natural cycles of post-natal lymphoid organ development in C57BL/6 mice: Evidence for a regulatory feedback relationship between bone marrow and thymus.

    PubMed

    Domínguez-Gerpe, Lourdes

    2007-01-01

    This study investigated some effects of weaning and immobilization stress in C57BL/6 mice aged 22-68 days, i.e., over a period including activation of the hypothalamus-pituitary-adrenal (HPA) axis and puberty. Specifically, the study evaluated the evolution, over the referred age interval, of a set of variables (body, thymus, spleen and axillary lymph nodes weights, the proportion of lymphoid cells in the bone marrow, the relative chemoattraction capacity of thymic supernatants for lymphoid cells and the migratory capacity of bone marrow lymphoid cells) in either weaned mice or weaned mice subjected to immobilization stress, compared to "non-stressed" unweaned mice. Cyclic patterns, observed for most variables in unweaned mice, were especially pronounced in two cases: the relative migratory capacity of bone marrow lymphoid cells collected at different ages towards neonatal thymic supernatant, and the relative chemoattraction capacity of thymic supernatants of different ages as tested against a sample of bone marrow lymphoid cells from mice aged 35 days. Weaning stress tended to intensify the involution stages of the cycles in thymus, spleen and lymph node weight, but increased the relative proportion of lymphoid cells in the bone marrow cell population. Both types of exogenous stress tended to affect cycle phase, i.e., cycle peaks and troughs were shifted in time. Correlations were observed between patterns seen in the thymus and bone marrow, suggesting the existence of an autoregulatory feedback loop governing pre-T cell migration and bone marrow/thymus homeostasis. These results also suggest that exogenous stress acts as a non-programmed regulator, modulating the naturally programmed cyclic patterns.

  16. Neural cryptography with feedback.

    PubMed

    Ruttor, Andreas; Kinzel, Wolfgang; Shacham, Lanir; Kanter, Ido

    2004-04-01

    Neural cryptography is based on a competition between attractive and repulsive stochastic forces. A feedback mechanism is added to neural cryptography which increases the repulsive forces. Using numerical simulations and an analytic approach, the probability of a successful attack is calculated for different model parameters. Scaling laws are derived which show that feedback improves the security of the system. In addition, a network with feedback generates a pseudorandom bit sequence which can be used to encrypt and decrypt a secret message.

  17. The challenge of giving written thesis feedback to nursing students.

    PubMed

    Tuvesson, Hanna; Borglin, Gunilla

    2014-11-01

    Providing effective written feedback on nursing student's assignments can be a challenging task for any assessor. Additionally, as the student groups tend to become larger, written feedback is likely to gain an overall more prominent position than verbal feedback. Lack of formal training or regular discussion in the teaching faculty about the skill set needed to provide written feedback could negatively affect the students' learning abilities. In this brief paper, we discuss written feedback practices, whilst using the Bachelor of Science in Nursing thesis as an example. Our aim is to highlight the importance of an informed understanding of the impact written feedback can have on students. Creating awareness about this can facilitate the development of more strategic and successful written feedback strategies. We end by offering examples of some relatively simple strategies for improving this practice.

  18. The challenge of giving written thesis feedback to nursing students.

    PubMed

    Tuvesson, Hanna; Borglin, Gunilla

    2014-11-01

    Providing effective written feedback on nursing student's assignments can be a challenging task for any assessor. Additionally, as the student groups tend to become larger, written feedback is likely to gain an overall more prominent position than verbal feedback. Lack of formal training or regular discussion in the teaching faculty about the skill set needed to provide written feedback could negatively affect the students' learning abilities. In this brief paper, we discuss written feedback practices, whilst using the Bachelor of Science in Nursing thesis as an example. Our aim is to highlight the importance of an informed understanding of the impact written feedback can have on students. Creating awareness about this can facilitate the development of more strategic and successful written feedback strategies. We end by offering examples of some relatively simple strategies for improving this practice. PMID:25042741

  19. Feedback stabilization initiative

    SciTech Connect

    1997-06-01

    Much progress has been made in attaining high confinement regimes in magnetic confinement devices. These operating modes tend to be transient, however, due to the onset of MHD instabilities, and their stabilization is critical for improved performance at steady state. This report describes the Feedback Stabilization Initiative (FSI), a broad-based, multi-institutional effort to develop and implement methods for raising the achievable plasma betas through active MHD feedback stabilization. A key element in this proposed effort is the Feedback Stabilization Experiment (FSX), a medium-sized, national facility that would be specifically dedicated to demonstrating beta improvement in reactor relevant plasmas by using a variety of MHD feedback stabilization schemes.

  20. When to throw the switch: The adaptiveness of modifying emotion regulation strategies based on affective and physiological feedback.

    PubMed

    Birk, Jeffrey L; Bonanno, George A

    2016-08-01

    Particular emotion regulation (ER) strategies are beneficial in certain contexts, but little is known about the adaptiveness of switching strategies after implementing an initial strategy. Research and theory on regulatory flexibility suggest that people switch strategies dynamically and that internal states provide feedback indicating when switches are appropriate. Frequent switching may predict positive outcomes among people who respond to this feedback. We investigated whether internal feedback (particularly corrugator activity, heart rate, or subjective negative intensity) guides people to switch to an optimal (i.e., distraction) but not nonoptimal (i.e., reappraisal) strategy for regulating strong emotion. We also tested whether switching frequency and responsiveness to internal feedback (RIF) together predict well-being. While attempting to regulate emotion elicited by unpleasant pictures, participants could switch to an optimal (Study 1; reappraisal-to-distraction order; N = 90) or nonoptimal (Study 2; distraction-to-reappraisal order; N = 95) strategy for high-arousal emotion. A RIF score for each emotion measure indexed the relative strength of emotion during the initial phase for trials on which participants later switched strategies. As hypothesized, negative intensity, corrugator activity, and the magnitude of heart rate deceleration during this early phase were higher on switch than maintain trials in Study 1 only. Critically, in Study 1 only, greater switching frequency predicted higher and lower life satisfaction for participants with high and low corrugator RIF, respectively, even after controlling for reappraisal success. Individual differences in RIF may contribute to subjective well-being provided that the direction of strategy switching aligns well with regulatory preferences for high emotion. (PsycINFO Database Record PMID:26900993

  1. The MYB23 gene provides a positive feedback loop for cell fate specification in the Arabidopsis root epidermis.

    PubMed

    Kang, Yeon Hee; Kirik, Victor; Hulskamp, Martin; Nam, Kyoung Hee; Hagely, Katherine; Lee, Myeong Min; Schiefelbein, John

    2009-04-01

    The specification of cell fates during development requires precise regulatory mechanisms to ensure robust cell type patterns. Theoretical models of pattern formation suggest that a combination of negative and positive feedback mechanisms are necessary for efficient specification of distinct fates in a field of differentiating cells. Here, we examine the role of the R2R3-MYB transcription factor gene, AtMYB23 (MYB23), in the establishment of the root epidermal cell type pattern in Arabidopsis thaliana. MYB23 is closely related to, and is positively regulated by, the WEREWOLF (WER) MYB gene during root epidermis development. Furthermore, MYB23 is able to substitute for the function of WER and to induce its own expression when controlled by WER regulatory sequences. We also show that the MYB23 protein binds to its own promoter, suggesting a MYB23 positive feedback loop. The localization of MYB23 transcripts and MYB23-green fluorescent protein (GFP) fusion protein, as well as the effect of a chimeric MYB23-SRDX repressor construct, links MYB23 function to the developing non-hair cell type. Using mutational analyses, we find that MYB23 is necessary for precise establishment of the root epidermal pattern, particularly under conditions that compromise the cell specification process. These results suggest that MYB23 participates in a positive feedback loop to reinforce cell fate decisions and ensure robust establishment of the cell type pattern in the Arabidopsis root epidermis.

  2. Cpeb4-mediated translational regulatory circuitry controls terminal erythroid differentiation

    PubMed Central

    Hu, Wenqian; Yuan, Bingbing; Lodish, Harvey F.

    2014-01-01

    SUMMARY While we have considerable understanding of the transcriptional networks controlling mammalian cell differentiation, our knowledge of post-transcriptional regulatory events is very limited. Using differentiation of primary erythroid cells as a model, we show that the sequence-specific mRNA-binding protein Cpeb4 is strongly induced by the erythroid important transcription factors Gata1 and Tal1 and is essential for terminal erythropoiesis. By interacting with the translation initiation factor eIF3 Cpeb4 represses the translation of a large set of mRNAs, including its own mRNA. Thus transcriptional induction and translational repression combine to form a negative feedback loop to control Cpeb4 protein levels within a specific range that is required for terminal erythropoiesis. Our study provides an example of how translational control is integrated with transcriptional regulation to precisely control gene expression during mammalian cell differentiation. PMID:25220394

  3. Cpeb4-mediated translational regulatory circuitry controls terminal erythroid differentiation.

    PubMed

    Hu, Wenqian; Yuan, Bingbing; Lodish, Harvey F

    2014-09-29

    While we have considerable understanding of the transcriptional networks controlling mammalian cell differentiation, our knowledge of posttranscriptional regulatory events is very limited. Using differentiation of primary erythroid cells as a model, we show that the sequence-specific mRNA-binding protein Cpeb4 is strongly induced by the erythroid-important transcription factors Gata1 and Tal1 and is essential for terminal erythropoiesis. By interacting with the translation initiation factor eIF3, Cpeb4 represses the translation of a large set of mRNAs, including its own mRNA. Thus, transcriptional induction and translational repression combine to form a negative feedback loop to control Cpeb4 protein levels within a specific range that is required for terminal erythropoiesis. Our study provides an example of how translational control is integrated with transcriptional regulation to precisely control gene expression during mammalian cell differentiation.

  4. Learning from delayed feedback: neural responses in temporal credit assignment

    PubMed Central

    Walsh, Matthew M.; Anderson, John R.

    2011-01-01

    When feedback follows a sequence of decisions, relationships between actions and outcomes can be difficult to learn. We used event-related potentials (ERPs) to understand how people overcome this temporal credit assignment problem. Participants performed a sequential decision task that required two decisions on each trial. The first decision led to an intermediate state that was predictive of the trial outcome, and the second decision was followed by positive or negative trial feedback. The feedback-related negativity (fERN), a component thought to reflect reward prediction error, followed negative feedback and negative intermediate states. This suggests that participants evaluated intermediate states in terms of expected future reward, and that these evaluations supported learning of earlier actions within sequences. We examine the predictions of several temporal-difference models to determine whether the behavioral and ERP results reflected a reinforcement-learning process. PMID:21416212

  5. Four perspectives on climate feedbacks

    NASA Astrophysics Data System (ADS)

    Feldl, N.; Roe, G. H.

    2013-08-01

    The spatial pattern of climate feedbacks depends on how the feedbacks are defined. We employ an idealized aquaplanet simulation with radiative kernels diagnosed for the precise model setup and characterize the meridional structure of feedbacks under four different definitions: local feedbacks, global feedbacks, nondimensional feedback factors, and relative humidity feedbacks. First, the spatial pattern of the reference response (i.e., the Planck feedback) is found to vary with definition, largely as a consequence of polar-amplified warming, which affects other high-latitude feedbacks as well. Second, locally defined feedbacks allow for decomposition of the surface temperature response as a function of feedbacks, forcing, and heat transport. Third, different insights into the dynamical and thermodynamical underpinnings of the subtropical moisture response are gained by comparing different versions of humidity feedbacks. Thus, alternative approaches to the conventional, global definition of feedbacks offer several advantages for understanding patterns of warming and, ultimately, regional climate predictability.

  6. Ozone Radiative Feedback in Global Warming Simulations with CO2 and non-CO2 Forcings

    NASA Astrophysics Data System (ADS)

    Ponater, M.; Rieger, V.; Dietmüller, S.

    2015-12-01

    It has been found that ozone radiative feedback acts to reduce the climate sensitivity in global warming simulations including interactive atmospheric chemistry, if the radiative forcing origins from CO2 increase. The effect can be traced to a negative feedback from stratospheric ozone changes and it is amplified by a reduced positive feedback from stratospheric water vapor.These findings cannot be simply transferred to simulations in which the warming is driven by a non-CO2 radiative forcing. Using a perturbation of surface NOx and CO emissions as an example, we demonstrate that a tropospheric ozone feedback may have significant impacts on physical feedbacks. These interactions can act to an extent that the effect of a negative ozone feedback can be reversed by changes in other feedbacks, thus increasing the climate sensitivity instead of reducing it. We also address some conceptual issues showing up as chemical feedbacks are added to set of physical feedbacks in simulation with interactive chemistry.

  7. Designing Genetic Feedback Controllers.

    PubMed

    Harris, Andreas W K; Dolan, James A; Kelly, Ciarán L; Anderson, James; Papachristodoulou, Antonis

    2015-08-01

    By incorporating feedback around systems we wish to manipulate, it is possible to improve their performance and robustness properties to meet pre-specified design objectives. For decades control engineers have been successfully implementing feedback controllers for complex mechanical and electrical systems such as aircraft and sports cars. Natural biological systems use feedback extensively for regulation and adaptation but apart from the most basic designs, there is no systematic framework for designing feedback controllers in Synthetic Biology. In this paper we describe how classical approaches from linear control theory can be used to close the loop. This includes the design of genetic circuits using feedback control and the presentation of a biological phase lag controller. PMID:26390502

  8. An analysis of the short-term cloud feedback using MODIS data

    NASA Astrophysics Data System (ADS)

    Dessler, A. E.; Zhou, C.; Zelinka, M. D.; Yang, P.

    2012-12-01

    We have calculated the cloud feedback in response to short-term climate variations using cloud measurements made by the Moderate Resolution Imaging Spectroradiometer (MODIS) on NASA's Terra satellite over the period 2000-2010. Low clouds provide a strong negative cloud feedback, mainly due to their impact in the shortwave (SW). Mid-level clouds provide a positive net cloud feedback that is a combination of a positive SW feedback partially canceled by a negative longwave (LW) one. High clouds have only a small impact on the net cloud feedback due to a close cancellation between large LW and SW cloud feedbacks. Segregating the clouds by optical depth (τ), we find that the net cloud feedback is set by a positive cloud feedback due to changes in the thickest clouds (mainly in the SW) and a cancelling negative feedback from changes in mid-τ clouds (also mainly in the SW). Putting this all together, the net cloud feedback is due to a negative feedback from changes in cloud fraction (primarily increases in clouds near the surface, partially cancelled by decreases in higher clouds) that is offset by a positive feedback from an overall decrease in cloud τ. Finally, we show that the apparent small dependence of cloud-induced radiation anomalies on global mean surface temperature and the subsequent uncertainty in global mean short-term cloud feedback is caused by statistically significant but offsetting relationships between individual cloud types and global mean surface temperature.

  9. Rapid feedback processing in human nucleus accumbens and motor thalamus.

    PubMed

    Schüller, Thomas; Gruendler, Theo O J; Jocham, Gerhard; Klein, Tilmann A; Timmermann, Lars; Visser-Vandewalle, Veerle; Kuhn, Jens; Ullsperger, Markus

    2015-04-01

    The nucleus accumbens (NAcc) and thalamus are integral parts in models of feedback processing. Deep brain stimulation (DBS) has been successfully employed to alleviate symptoms of psychiatric conditions including obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Common target structures are the NAcc and the ventral anterior and ventro-lateral nuclei (VA/VL) of the thalamus, for OCD and TS, respectively. The feedback related negativity (FRN) is an event-related potential associated with feedback processing reflecting posterior medial frontal cortex (pMFC) activity. Here we report on three cases where we recorded scalp EEG and local field potentials (LFP) from externalized electrodes located in the NAcc or thalamus (VA/VL) while patients engaged in a modified time estimation task, known to engage feedback processing and elicit the FRN. Additionally, scalp EEG were recorded from 29 healthy participants (HP) engaged in the same task. The signal in all structures (pMFC, NAcc, and thalamus) was differently modulated by positive and negative feedback. LFP activity in the NAcc showed a biphasic time course after positive feedback during the FRN time interval. Negative feedback elicited a much weaker and later response. In the thalamus a monophasic modulation was recorded during the FRN time interval. Again, this modulation was more pronounced after positive performance feedback compared to negative feedback. In channels outside the target area no modulation was observed. The surface-FRN was reliably elicited on a group level in HP and showed no significant difference following negative feedback between patients and HP. German Clinical Trial Register: Neurocognitive specification of dysfunctions within basal ganglia-cortex loops and their therapeutic modulation by deep brain stimulation in patients with obsessive compulsive disorder and Tourette syndrome, http://www.drks.de/DRKS00005316. PMID:25726897

  10. Strategies in probabilistic feedback learning in Parkinson patients OFF medication.

    PubMed

    Bellebaum, C; Kobza, S; Ferrea, S; Schnitzler, A; Pollok, B; Südmeyer, M

    2016-04-21

    Studies on classification learning suggested that altered dopamine function in Parkinson's Disease (PD) specifically affects learning from feedback. In patients OFF medication, enhanced learning from negative feedback has been described. This learning bias was not seen in observational learning from feedback, indicating different neural mechanisms for this type of learning. The present study aimed to compare the acquisition of stimulus-response-outcome associations in PD patients OFF medication and healthy control subjects in active and observational learning. 16 PD patients OFF medication and 16 controls were examined with three parallel learning tasks each, two feedback-based (active and observational) and one non-feedback-based paired associates task. No acquisition deficit was seen in the patients for any of the tasks. More detailed analyses on the learning strategies did, however, reveal that the patients showed more lose-shift responses during active feedback learning than controls, and that lose-shift and win-stay responses more strongly determined performance accuracy in patients than controls. For observational feedback learning, the performance of both groups correlated similarly with the performance in non-feedback-based paired associates learning and with the accuracy of observed performance. Also, patients and controls showed comparable evidence of feedback processing in observational learning. In active feedback learning, PD patients use alternative learning strategies than healthy controls. Analyses on observational learning did not yield differences between patients and controls, adding to recent evidence of a differential role of the human striatum in active and observational learning from feedback.

  11. ACTIVE GALACTIC NUCLEUS FEEDBACK WORKS BOTH WAYS

    SciTech Connect

    Zinn, P.-C.; Middelberg, E.; Dettmar, R.-J.; Norris, R. P.

    2013-09-01

    Simulations of galaxy growth need to invoke strong negative feedback from active galactic nuclei (AGNs) to suppress the formation of stars and thus prevent the over-production of very massive systems. While some observations provide evidence for such negative feedback, other studies find either no feedback or even positive feedback, with increased star formation associated with higher AGN luminosities. Here we report an analysis of several hundred AGNs and their host galaxies in the Chandra Deep Field South using X-ray and radio data for sample selection. Combined with archival far-infrared data as a reliable tracer of star formation activity in the AGN host galaxies, we find that AGNs with pronounced radio jets exhibit a much higher star formation rate (SFR) than the purely X-ray-selected ones, even at the same X-ray luminosities. This difference implies that positive AGN feedback plays an important role, too, and therefore has to be accounted for in all future simulation work. We interpret this to indicate that the enhanced SFR of radio-selected AGNs arises because of jet-induced star formation, as is suggested by the different jet powers among our AGN samples, while the suppressed SFR of X-ray selected AGN is caused by heating and photo-dissociation of molecular gas by the hot AGN accretion disk.

  12. Does Constructive Performance Feedback Improve Citizenship Intentions and Job Satisfaction? The Roles of Perceived Opportunities for Advancement, Respect, and Mood

    ERIC Educational Resources Information Center

    Sommer, Kristin L.; Kulkarni, Mukta

    2012-01-01

    Organizational experts have long touted the importance of delivering negative performance feedback in a manner that enhances employee receptivity to feedback, yet the broader impacts of constructive feedback have received relatively little attention. The present investigation explored the impact of constructive, critical feedback on organizational…

  13. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors.

    PubMed

    Thiault, Nicolas; Darrigues, Julie; Adoue, Véronique; Gros, Marine; Binet, Bénédicte; Perals, Corine; Leobon, Bertrand; Fazilleau, Nicolas; Joffre, Olivier P; Robey, Ellen A; van Meerwijk, Joost P M; Romagnoli, Paola

    2015-06-01

    Most T lymphocytes, including regulatory T cells (Treg cells), differentiate in the thymus. The age-dependent involution of this organ leads to decreasing production of T cells. Here we found that the output of new Treg cells from the thymus decreased substantially more than that of conventional T cells. Peripheral mouse and human Treg cells recirculated back to the thymus, where they constituted a large proportion of the pool of Treg cells and displayed an activated and differentiated phenotype. In the thymus, the recirculating cells exerted their regulatory function by inhibiting interleukin 2 (IL-2)-dependent de novo differentiation of Treg cells. Thus, Treg cell development is controlled by a negative feedback loop in which mature progeny cells return to the thymus and restrain development of precursors of Treg cells.

  14. Revised Morning Loops of the Arabidopsis Circadian Clock Based on Analyses of Direct Regulatory Interactions.

    PubMed

    Adams, Sally; Manfield, Ian; Stockley, Peter; Carré, Isabelle A

    2015-01-01

    The network structure of the plant circadian clock is complex and direct regulatory interactions between individual components have proven particularly difficult to predict from genetic analyses. Here, we systematically investigate in vivo binding interactions between the morning-specific transcription factor, LATE ELONGATED HYPOCOTYL (LHY) and the promoters of other components of the network. We then demonstrate the functionality of these interactions by testing the responsiveness of the target gene to an ethanol-induced change in expression level of the LHY protein. We uncover novel, negative autoregulatory feedback loops from LHY and the closely related CIRCADIAN CLOCK ASSOCIATED-1 (CCA1) onto their own and each other's expression. Furthermore we show that LHY acts as a repressor of all other clock components, including PSEUDO-RESPONSE REGULATORs (PRRs) 9 and 7, which were previously thought to be positive regulatory targets. These experimental results lead to a substantial revision of the morning loops of the clock. PMID:26625126

  15. Strategies for effective feedback.

    PubMed

    Kritek, Patricia A

    2015-04-01

    Provision of regular feedback to trainees on clinical performance by supervising providers is increasingly recognized as an essential component of undergraduate and graduate health sciences education; however, many individuals have not been formally trained in this pedagogical skill. At the bedside or in the clinic, effective performance feedback can be accomplished by following four key steps. Begin by setting expectations that incorporate the trainee's personal goals and external objectives. Delineate how and when you will provide feedback to the learner. Next, directly observe the trainee's performance. This can be challenging while engaged on a busy clinical service, but a focus on discrete activities or interactions (e.g., family meeting, intravascular volume assessment using bedside ultrasound, or obtaining informed consent) is helpful. The third step is to plan and prioritize the feedback session. Feedback is most effective when given in a timely fashion and delivered in a safe environment. Limit the issues addressed because learners often disengage if confronted with too many deficiencies. Finally, when delivering feedback, begin by listening to the trainee's self-evaluation and then take a balanced approach. Describe in detail what the trainee does well and discuss opportunities for improvement with emphasis on specific, modifiable behaviors. The feedback loop is completed with a plan for follow-up reassessment. Through the use of these relatively simple practices, both the trainee and teacher can have a more productive learning experience.

  16. Feedback in distance education.

    PubMed

    Hudspeth, D

    1988-01-01

    Some tips, strategies, and techniques are presented for incorporating learner feedback into distance education courses. The most common form of learner feedback is immediate Knowledge of Response (KR). This general term can be delineated further as either Knowledge of Correct Response (KCR) or Knowledge of Incorrect Response (KIR). KCR is most useful for learning tasks that require a high level of automatic response such as vocabulary development and naming chemical structures. It also can be used for higher levels of learning. KIR occurs when the learner makes a response and knows only whether the response was correct or incorrect. If the learner was incorrect, the correct answer is not provided. Distant learners, as well as learners in a typical classroom, benefit from positive feedback, e.g., a few words written on the side of an assignment or a short note of encouragement. Personalized feedback tells students if they are performing satisfactorily and, if provided early in a course, can help reduce student attrition. If immediate feedback after an examination cannot be provided, every effort should be made to score and return the test as soon as possible before the student is expected to begin study on subsequent lessons. If this is not possible, a test review sheet could be mailed back upon receipt of the examination. Microcomputers are devices that can provide rapid and useful feedback, yet many methods that do not rely on computers can provide feedback. These include practice tests, small group exercises, and checklist response sheets. In addition to formally providing feedback after an assignment or examination, it is possible to use the principles of feedback by embedding questions and answers in text, audio, or video materials.

  17. A calculation of feedbacks based on climate variations over the last decade

    NASA Astrophysics Data System (ADS)

    Dessler, A. E.

    2011-12-01

    I have calculated the strength of the temperature, water vapor, cloud, and albedo feedbacks in response to climate variations over the last decade. In general, the global average feedbacks agree well with those in comparable climate model runs. For the temperature and water vapor feedbacks, the average of the ensemble of climate models faithfully reproduces the spatial pattern of the feedbacks. The model ensemble average does a reasonable job simulating the spatial pattern of longwave and shortwave cloud feedbacks, but there are important differences in the net cloud feedback. The models predict a positive feedback in the tropics and a near-zero feedback in the northern hemisphere extratropics, while the observations show a negative feedback in the tropics and a strong positive feedback in the northern hemisphere extratropics. These disagreements tend to cancel in the global average, leading to better agreement there.

  18. Feedback from horizontal cells to rod photoreceptors in vertebrate retina

    PubMed Central

    Thoreson, Wallace B.; Babai, Norbert; Bartoletti, Theodore M.

    2013-01-01

    Retinal horizontal cells (HCs) provide negative feedback to cones but, largely because annular illumination fails to evoke a depolarizing response in rods, it is widely believed that there is no feedback from HCs to rods. However, feedback from HCs to cones involves small changes in the calcium current (ICa) that does not always generate detectable depolarizing responses. We therefore recorded ICa directly from rods to test whether they were modulated by feedback from HCs. To circumvent problems presented by overlapping receptive fields of HCs and rods, we manipulated the membrane potential of voltage clamped HCs while simultaneously recording from rods in a salamander retinal slice preparation. Like HC feedback in cones, hyperpolarizing HCs from −14 to −54, −84, and −104 mV increased the amplitude of ICa recorded from synaptically connected rods and caused hyperpolarizing shifts in ICa voltage dependence. These effects were blocked by supplementing the bicarbonate-buffered saline solution with HEPES. In rods lacking light-responsive outer segments, hyperpolarizing neighboring HCs with light caused a negative activation shift and increased the amplitude of ICa. These changes in ICa were blocked by HEPES and by inhibiting HC light responses with a glutamate antagonist indicating they were due to HC feedback. These results show that rods, like cones, receive negative feedback from HCs that regulates the amplitude and voltage dependence of ICa. HC to rod feedback counters light-evoked decreases in synaptic output and thus shapes the transmission of rod responses to downstream visual neurons. PMID:18509030

  19. Global Feedback Simulator

    SciTech Connect

    Carlos Serrano, Lawrence Doolittle

    2015-10-29

    GFS is a simulation engine that is used for the characterization of Accelerator performance parameters based on the machine layout, configuration and noise sources. It combines extensively tested Feedback models with a longitudinal phase space tracking simulator along with the interaction between the two via beam-based feedback using a computationally efficient simulation engine. The models include beam instrumentation, considerations on loop delays for in both the R and beam-based feedback loops, as well as the ability to inject noise (both correlated and uncorrelated) at different points of the machine including a full characterization of the electron gun performance parameters.

  20. Global Feedback Simulator

    2015-10-29

    GFS is a simulation engine that is used for the characterization of Accelerator performance parameters based on the machine layout, configuration and noise sources. It combines extensively tested Feedback models with a longitudinal phase space tracking simulator along with the interaction between the two via beam-based feedback using a computationally efficient simulation engine. The models include beam instrumentation, considerations on loop delays for in both the R and beam-based feedback loops, as well as themore » ability to inject noise (both correlated and uncorrelated) at different points of the machine including a full characterization of the electron gun performance parameters.« less

  1. Social closeness and feedback modulate susceptibility to the framing effect

    PubMed Central

    Sip, Kamila E.; Smith, David V.; Porcelli, Anthony J.; Kar, Kohitij; Delgado, Mauricio R.

    2014-01-01

    Although, we often seek social feedback from others to help us make decisions, little is known about how social feedback affects decisions under risk, particularly from a close peer. We conducted two experiments using an established framing task to probe how decision making is modulated by social feedback valence (positive, negative) and the level of closeness with feedback provider (friend, confederate). Participants faced mathematically equivalent decisions framed as either an opportunity to keep (gain frame) or lose (loss frame) part of an initial endowment. Periodically, participants were provided with positive (e.g., “Nice!”) or negative (e.g., “Lame!”) feedback about their choices. Such feedback was provided by either a confederate (Experiment 1), or a gender-matched close friend (Experiment 2). As expected, the framing effect was observed in both experiments. Critically, an individual’s susceptibility to the framing effect was modulated by the valence of the social feedback, but only when the feedback provider was a close friend. This effect was reflected in the activation patterns of ventromedial prefrontal cortex and posterior cingulate cortex, regions involved in complex decision making. Taken together, these results highlight social closeness as an important factor in understanding the impact of social feedback on neural mechanisms of decision making. PMID:25074501

  2. Cloud-radiation interactions - Effects of cirrus optical thickness feedbacks

    NASA Technical Reports Server (NTRS)

    Somerville, Richard C. J.; Iacobellis, Sam

    1987-01-01

    The paper is concerned with a cloud-radiation feedback mechanism which may be an important component of the climate changes expected from increased atmospheric concentrations of carbon dioxide and other trace greenhouse gases. A major result of the study is that cirrus cloud optical thickness feedbacks may indeed tend to increase the surface warming due to trace gas increases. However, the positive feedback from cirrus appears to be generally weaker than the negative effects due to lower clouds. The results just confirm those of earlier research indicating that the net effect of cloud optical thickness feedbacks may be a negative feedback which may substantially (by a factor of about 2) reduce the surface warming due to the doubling of CO2, even in the presence of cirrus clouds.

  3. Negative necrotaxis.

    PubMed

    Ragot, R

    1993-01-01

    We studied necrotaxis in several strains of protists and compared the reaction of living cells in the vicinity of cells killed by a ruby laser. Negative necrotaxis was observed for the unicellular green alga Euglena gracilis, whereas Chlamydomonas was shown to exhibit positive necrotaxis. The cellular colony Pandorina morum exhibited no reaction to the killing of nearby colonies. Both the colorless cryptomonad Chilomonas paramecium and the ciliate Tetrahymena pyriformis exhibited negative necrotaxis following the lysis of vitally stained specimens of their own species. They also exhibited negative necrotaxis following the lysis of Euglena cells. It was also demonstrated that the cellular content of Euglena cells lysed by heat or by a mechanical procedure acts as a repellent to intact Euglena cells. These results suggest that the negative necrotaxis provoked in Euglena by the laser irradiation is probably due to the chemotactic effect produced by the release of cell content in the extracellular medium. This cell content could, according to its chemical composition, act either as a repellent, an attractant, or be inactive. The sensitivity of cells (specific or nonspecific ion channels or chemoreceptors) are also of prime importance in the process.

  4. Thermocline Feedback Influence on Indian Ocean Dipole Skewness

    NASA Astrophysics Data System (ADS)

    Ng, B.; Cai, W.; Walsh, K. J.

    2014-12-01

    A positive Indian Ocean Dipole (IOD) tends to have stronger cold sea surface temperature anomalies (SSTAs) over the eastern Indian Ocean with greater impacts than warm SSTAs that occur during its negative phase. These impacts from positive IODs range from drought over Australia and Indonesia, to flooding over East Africa and India. Two feedbacks have been suggested as the cause of positive IOD skewness, a positive Bjerknes feedback and a negative SST-cloud-radiation (SCR) feedback, but their relative importance is debated. Using models from phase 5 of the Coupled Model Intercomparison Project (CMIP5) and inter-model statistics, we show that the most important process for IOD skewness is an asymmetry in the thermocline feedback, whereby SSTAs respond to thermocline depth anomalies more strongly during the positive phase than negative phase. This asymmetric thermocline feedback drives IOD skewness despite positive IODs receiving greater damping from the SCR feedback. In response to global warming, although the thermocline feedback strengthens, its asymmetry between positive and negative IODs weakens. This behaviour change explains the reduction in IOD skewness that many models display under global warming.

  5. Cloud feedback - A stabilizing effect for the early earth

    NASA Technical Reports Server (NTRS)

    Rossow, W. B.; Weinreich, S. K.; Henderson-Sellers, A.

    1982-01-01

    The effect of variations in cloud cover, optical properties, and fractional distribution with altitude on the mean surface temperature of a model of the early earth has been investigated. In all cases examined, cloud-climate feedbacks result in temperatures greater than those in models with no cloud feedbacks. If the model of hydrospheric feedback effects is correct, then cloud feedbacks are as important to the climate as changes in solar luminosity and atmospheric composition during the earth's atmospheric evolution. In particular, the early earth need not become completely ice-covered if strong negative cloud feedbacks occur. However, until a proper understanding of cloud feedbacks is available, conclusions regarding conditions in the early atmosphere must remain in doubt.

  6. Praise in Public, Criticize in Private? An Assessment of Performance Feedback Transparency in a Classroom Setting

    ERIC Educational Resources Information Center

    Seevers, Matthew T.; Rowe, William J.; Skinner, Steven J.

    2014-01-01

    Conventional wisdom in sales management encourages public delivery of positive feedback, and private delivery of negative feedback. In stark contrast, U.S. educators typically provide all performance feedback in relative (if not strict) privacy to comply with the Family Educational Rights and Privacy Act (FERPA). To investigate this discrepancy,…

  7. The Effect of Positive Feedback in a Constraint-Based Intelligent Tutoring System

    ERIC Educational Resources Information Center

    Mitrovic, Antonija; Ohlsson, Stellan; Barrow, Devon K.

    2013-01-01

    Tutoring technologies for supporting learning from errors via negative feedback are highly developed and have proven their worth in empirical evaluations. However, observations of empirical tutoring dialogs highlight the importance of positive feedback in the practice of expert tutoring. We hypothesize that positive feedback works by reducing…

  8. Using a Dialogical Approach to Examine Peer Feedback during Chemistry Investigative Task Discussion

    ERIC Educational Resources Information Center

    Gan Joo Seng, Mark; Hill, Mary

    2014-01-01

    Peer feedback is an inherent feature of classroom collaborative learning. Students invariably turn to their peers for feedback when carrying out an investigative task, and this feedback is usually implicit, unstructured and may positively or negatively influence students' learning when they work on a task. This study explored the…

  9. The Influence of Teacher Feedback on Children's Perceptions of Student-Teacher Relationships

    ERIC Educational Resources Information Center

    Skipper, Yvonne; Douglas, Karen

    2015-01-01

    Background: Teachers can deliver feedback using person ("you are clever") or process terms ("you worked hard"). Person feedback can lead to negative academic outcomes, but there is little experimental research examining the impact of feedback on children's perceptions of the student-teacher relationship. Aim: We examined the…

  10. PECAM-1 ligation negatively regulates TLR4 signaling in macrophages.

    PubMed

    Rui, Yuxiang; Liu, Xingguang; Li, Nan; Jiang, Yingming; Chen, Guoyou; Cao, Xuetao; Wang, Jianli

    2007-12-01

    Uncontrolled TLR4 signaling may induce excessive production of proinflammatory cytokines and lead to harmful inflammation; therefore, negative regulation of TLR4 signaling attracts much attention now. PECAM-1, a member of Ig-ITIM family, can mediate inhibitory signals in T cells and B cells. However, the role and the mechanisms of PECAM-1 in the regulation of TLR4-mediated LPS response in macrophages remain unclear. In this study, we demonstrate that PECAM-1 ligation with CD38-Fc fusion protein negatively regulates LPS-induced proinflammatory cytokine TNF-alpha, IL-6, and IFN-beta production by inhibiting JNK, NF-kappaB, and IFN regulatory factor 3 activation in macrophages. In addition, PECAM-1 ligation-recruited Src homology region 2 domain-containing phosphatase 1 (SHP-1) and Src homology region 2 domain-containing phosphatase 2 (SHP-2) may be involved in the inhibitory effect of PECAM-1 on TLR4 signaling. Consistently, silencing of PECAM-1 enhances the macrophage response to LPS stimulation. Taken together with the data that PECAM-1 is constitutively expressed in macrophages and its expression is up-regulated by LPS stimulation, PECAM-1 might function as a feedback negative regulator of LPS inflammatory response in macrophages. This study may provide a potential target for intervention of inflammatory diseases. PMID:18025177

  11. Making Time for Feedback

    ERIC Educational Resources Information Center

    Fisher, Douglas; Frey, Nancy

    2012-01-01

    Ask any teacher what he or she needs more of, and it is a good bet that time will top the list. Anything that promises to recoup a little bit of their workday time is sure to be a best seller. One overlooked time-saver is in how they use feedback. Teachers know that feedback is important for teaching and learning. Unfortunately, most secondary…

  12. Regulatory gene networks and the properties of the developmental process

    NASA Technical Reports Server (NTRS)

    Davidson, Eric H.; McClay, David R.; Hood, Leroy

    2003-01-01

    Genomic instructions for development are encoded in arrays of regulatory DNA. These specify large networks of interactions among genes producing transcription factors and signaling components. The architecture of such networks both explains and predicts developmental phenomenology. Although network analysis is yet in its early stages, some fundamental commonalities are already emerging. Two such are the use of multigenic feedback loops to ensure the progressivity of developmental regulatory states and the prevalence of repressive regulatory interactions in spatial control processes. Gene regulatory networks make it possible to explain the process of development in causal terms and eventually will enable the redesign of developmental regulatory circuitry to achieve different outcomes.

  13. Feedback and rewards, part II: formal and informal feedback reviews.

    PubMed

    Harolds, Jay

    2013-02-01

    There are 2 major classes of feedback. One class of feedback consists of the informal, numerous conversations between various people in the organization regarding the performance, behavior, and goals of an individual. Another class of feedback consists of formal reviews held once or twice a year between a supervisor and an individual. This article discusses both types of feedback.

  14. Feedback, Lineages and Self-Organizing Morphogenesis

    PubMed Central

    Calof, Anne L.; Lowengrub, John S.; Lander, Arthur D.

    2016-01-01

    Feedback regulation of cell lineage progression plays an important role in tissue size homeostasis, but whether such feedback also plays an important role in tissue morphogenesis has yet to be explored. Here we use mathematical modeling to show that a particular feedback architecture in which both positive and negative diffusible signals act on stem and/or progenitor cells leads to the appearance of bistable or bi-modal growth behaviors, ultrasensitivity to external growth cues, local growth-driven budding, self-sustaining elongation, and the triggering of self-organization in the form of lamellar fingers. Such behaviors arise not through regulation of cell cycle speeds, but through the control of stem or progenitor self-renewal. Even though the spatial patterns that arise in this setting are the result of interactions between diffusible factors with antagonistic effects, morphogenesis is not the consequence of Turing-type instabilities. PMID:26989903

  15. Feedback, Lineages and Self-Organizing Morphogenesis.

    PubMed

    Kunche, Sameeran; Yan, Huaming; Calof, Anne L; Lowengrub, John S; Lander, Arthur D

    2016-03-01

    Feedback regulation of cell lineage progression plays an important role in tissue size homeostasis, but whether such feedback also plays an important role in tissue morphogenesis has yet to be explored. Here we use mathematical modeling to show that a particular feedback architecture in which both positive and negative diffusible signals act on stem and/or progenitor cells leads to the appearance of bistable or bi-modal growth behaviors, ultrasensitivity to external growth cues, local growth-driven budding, self-sustaining elongation, and the triggering of self-organization in the form of lamellar fingers. Such behaviors arise not through regulation of cell cycle speeds, but through the control of stem or progenitor self-renewal. Even though the spatial patterns that arise in this setting are the result of interactions between diffusible factors with antagonistic effects, morphogenesis is not the consequence of Turing-type instabilities. PMID:26989903

  16. Climate stability and cloud optical thickness feedbacks

    NASA Technical Reports Server (NTRS)

    Somerville, Richard C. J.; Iacobellis, Sam

    1989-01-01

    An improved radiative-convective model (RCM) has been developed and used to examine the role of cirrus clouds in the optical thickness feedback mechanism. Low and middle clouds are approximately black bodies for infrared radiative transfer, and so any increase in their optical thickness primarily increases the cloud albedo. Thus, if a climate warming is accompanied by an increase in average atmospheric absolute humidity and hence in average cloud liquid water content, low and middle cloud optical thickness and albedo may increase. The result is a negative feedback on the climate change, tending to reduce the surface temperature increase. Recent research suggests that the optical thickness feedback can depend sensitively on aspects of cirrus which are not well observed or adequately incorporated in typical present-day climate models.

  17. Negative Feedback Regulation of HIV-1 by Gene Editing Strategy.

    PubMed

    Kaminski, Rafal; Chen, Yilan; Salkind, Julian; Bella, Ramona; Young, Won-Bin; Ferrante, Pasquale; Karn, Jonathan; Malcolm, Thomas; Hu, Wenhui; Khalili, Kamel

    2016-01-01

    The CRISPR/Cas9 gene editing method is comprised of the guide RNA (gRNA) to target a specific DNA sequence for cleavage and the Cas9 endonuclease for introducing breaks in the double-stranded DNA identified by the gRNA. Co-expression of both a multiplex of HIV-1-specific gRNAs and Cas9 in cells results in the modification and/or excision of the segment of viral DNA, leading to replication-defective virus. In this study, we have personalized the activity of CRISPR/Cas9 by placing the gene encoding Cas9 under the control of a minimal promoter of HIV-1 that is activated by the HIV-1 Tat protein. We demonstrate that functional activation of CRISPR/Cas9 by Tat during the course of viral infection excises the designated segment of the integrated viral DNA and consequently suppresses viral expression. This strategy was also used in a latently infected CD4+ T-cell model after treatment with a variety of HIV-1 stimulating agents including PMA and TSA. Controlled expression of Cas9 by Tat offers a new strategy for safe implementation of the Cas9 technology for ablation of HIV-1 at a very early stage of HIV-1 replication during the course of the acute phase of infection and the reactivation of silent proviral DNA in latently infected cells. PMID:27528385

  18. Negative Feedback Regulation of HIV-1 by Gene Editing Strategy

    PubMed Central

    Kaminski, Rafal; Chen, Yilan; Salkind, Julian; Bella, Ramona; Young, Won-bin; Ferrante, Pasquale; Karn, Jonathan; Malcolm, Thomas; Hu, Wenhui; Khalili, Kamel

    2016-01-01

    The CRISPR/Cas9 gene editing method is comprised of the guide RNA (gRNA) to target a specific DNA sequence for cleavage and the Cas9 endonuclease for introducing breaks in the double-stranded DNA identified by the gRNA. Co-expression of both a multiplex of HIV-1-specific gRNAs and Cas9 in cells results in the modification and/or excision of the segment of viral DNA, leading to replication-defective virus. In this study, we have personalized the activity of CRISPR/Cas9 by placing the gene encoding Cas9 under the control of a minimal promoter of HIV-1 that is activated by the HIV-1 Tat protein. We demonstrate that functional activation of CRISPR/Cas9 by Tat during the course of viral infection excises the designated segment of the integrated viral DNA and consequently suppresses viral expression. This strategy was also used in a latently infected CD4+ T-cell model after treatment with a variety of HIV-1 stimulating agents including PMA and TSA. Controlled expression of Cas9 by Tat offers a new strategy for safe implementation of the Cas9 technology for ablation of HIV-1 at a very early stage of HIV-1 replication during the course of the acute phase of infection and the reactivation of silent proviral DNA in latently infected cells. PMID:27528385

  19. Effects of Stratospheric Ozone Depletion, Solar UV Radiation, and Climate Change on Biogeochemical Cycling: Interactions and Feedbacks

    EPA Science Inventory

    Climate change modulates the effects of solar UV radiation on biogeochemical cycles in terrestrial and aquatic ecosystems, particularly for carbon cycling, resulting in UV-mediated positive or negative feedbacks on climate. Possible positive feedbacks discussed in this assessment...

  20. Feedback and rewards, Part I: Introduction to effective feedback.

    PubMed

    Harolds, Jay A

    2013-01-01

    This series of articles discusses conversations regarding feedback. Feedback can include input from numerous sources, including one's supervisor, peers, subordinates, suppliers, customers, patients, and/or society members. Effective feedback is very important to the operation of any organization and to the growth of the individual. However, feedback done poorly does not appear to be rare and can be highly destructive to all. A variety of tips on how to do feedback well are included in this article.

  1. Multivariate analysis of noise in genetic regulatory networks.

    PubMed

    Tomioka, Ryota; Kimura, Hidenori; J Kobayashi, Tetsuya; Aihara, Kazuyuki

    2004-08-21

    Stochasticity is an intrinsic property of genetic regulatory networks due to the low copy numbers of the major molecular species, such as, DNA, mRNA, and regulatory proteins. Therefore, investigation of the mechanisms that reduce the stochastic noise is essential in understanding the reproducible behaviors of real organisms and is also a key to design synthetic genetic regulatory networks that can reliably work. We use an analytical and systematic method, the linear noise approximation of the chemical master equation along with the decoupling of a stoichiometric matrix. In the analysis of fluctuations of multiple molecular species, the covariance is an important measure of noise. However, usually the representation of a covariance matrix in the natural coordinate system, i.e. the copy numbers of the molecular species, is intractably complicated because reactions change copy numbers of more than one molecular species simultaneously. Decoupling of a stoichiometric matrix, which is a transformation of variables, significantly simplifies the representation of a covariance matrix and elucidates the mechanisms behind the observed fluctuations in the copy numbers. We apply our method to three types of fundamental genetic regulatory networks, that is, a single-gene autoregulatory network, a two-gene autoregulatory network, and a mutually repressive network. We have found that there are multiple noise components differently originating. Each noise component produces fluctuation in the characteristic direction. The resulting fluctuations in the copy numbers of the molecular species are the sum of these fluctuations. In the examples, the limitation of the negative feedback in noise reduction and the trade-off of fluctuations in multiple molecular species are clearly explained. The analytical representations show the full parameter dependence. Additionally, the validity of our method is tested by stochastic simulations. PMID:15246787

  2. Seven Keys to Effective Feedback

    ERIC Educational Resources Information Center

    Wiggins, Grant

    2012-01-01

    The term "feedback" is often used to describe all kinds of comments made after the fact, including advice, praise, and evaluation. But none of these are feedback, strictly speaking. Basically, feedback is information about how one is doing in his or her efforts to reach a goal. Whether feedback is just there to be grasped or is provided by another…

  3. Feedback: How Does It Function?

    ERIC Educational Resources Information Center

    Bardwell, Rebecca

    1981-01-01

    A study of feedback delay, expectation, and development was conducted in grades four, six, and eight, to assess whether feedback on a school related learning task serves an informational or reinforcing function. Results indicate that feedback serves an informational function and delayed feedback facilitates retention, contrary to reinforcement…

  4. A Case Study of Representing Signal Transduction in Liver Cells as a Feedback Control Problem

    ERIC Educational Resources Information Center

    Singh, Abhay; Jayaraman, Arul; Hahn, Juergen

    2007-01-01

    Cell signaling pathways often contain feedback loops where proteins are produced that regulate signaling. While feedback regulatory mechanisms are commonly found in signaling pathways, there is no example available in the literature that is simple enough to be presented in an undergraduate control class. This paper presents a simulation study of…

  5. Simple models of assortment through environmental feedback.

    PubMed

    Pepper, John W

    2007-01-01

    Social evolution depends critically on assortment, or segregation versus even mixing, between cooperators and noncooperators. Altruistic traits, which reduce the absolute fitness of their bearers, cannot evolve without positive assortment (excess segregation). The question of how positive assortment can arise has been controversial, but most evolutionary biologists believe that common descent is the only effective general mechanism. Here I investigate another recently proposed mechanism for generating nonrandom assortment, termed environmental feedback. This requires only that two forms of a trait affect the quality of the local environment differently in such a way that all individuals are more likely to leave low-quality locales. Experiments with simple computational models confirm that environmental feedback generates significant levels of genetic similarity among non-kin within locales. The mechanism is fairly general, and can under some conditions produce levels of genetic similarity comparable to those resulting from close genealogical relationship. Environmental feedback can also generate the negative assortment necessary for the evolution of spiteful traits. Environmental feedback is expected to create positive frequency-dependent selection, which thus favor any social trait that becomes common in the population. Results from this stylized model suggest that environmental feedback could be important in the evolution of both cooperation and spite, within as well as between species.

  6. Stochastic analysis of bistability in coherent mixed feedback loops combining transcriptional and posttranscriptional regulations

    NASA Astrophysics Data System (ADS)

    Nitzan, Mor; Shimoni, Yishai; Rosolio, Oded; Margalit, Hanah; Biham, Ofer

    2015-05-01

    Mixed feedback loops combining transcriptional and posttranscriptional regulations are common in cellular regulatory networks. They consist of two genes, encoding a transcription factor and a small noncoding RNA (sRNA), which mutually regulate each other's expression. We present a theoretical and numerical study of coherent mixed feedback loops of this type, in which both regulations are negative. Under suitable conditions, these feedback loops are expected to exhibit bistability, namely, two stable states, one dominated by the transcriptional repressor and the other dominated by the sRNA. We use deterministic methods based on rate equation models, in order to identify the range of parameters in which bistability takes place. However, the deterministic models do not account for the finite lifetimes of the bistable states and the spontaneous, fluctuation-driven transitions between them. Therefore, we use stochastic methods to calculate the average lifetimes of the two states. It is found that these lifetimes strongly depend on rate coefficients such as the transcription rates of the transcriptional repressor and the sRNA. In particular, we show that the fraction of time the system spends in the sRNA-dominated state follows a monotonically decreasing sigmoid function of the transcriptional repressor transcription rate. The biological relevance of these results is discussed in the context of such mixed feedback loops in Escherichia coli. It is shown that the fluctuation-driven transitions and the dependence of some rate coefficients on the biological conditions enable