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Sample records for activity varied depending

  1. Benzodiazepines consumption: does dependence vary with age?

    PubMed

    Gérardin, Marie; Victorri-Vigneau, Caroline; Guerlais, Marylène; Guillou-Landreat, Morgane; Grall-Bronnec, Marie; Jolliet, Pascale

    2014-09-01

    We have compared two groups of chronic benzodiazepines (or zolpidem/zopiclone) users: "Seniors," aged 65 years or more, and "Adults," aged less than 65 years. The study took place in the Pays de Loire region. The questionnaire assesses dependence based on items from the DSM-IV. The analysis was based on 176 Senior questionnaires and 212 Adult questionnaires. Whereas Senior patients take benzodiazepines routinely with little negative consequences, Adults suffer from underlying psychological trouble, mention a higher consumption than planned, which causes negative consequences. 35.2% of Seniors are dependent on benzodiazepines versus 49.8% of Adults. PMID:24810390

  2. Active spectral sensor evaluation under varying conditions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant stress has been estimated by spectral signature using both passive and active sensors. As optical sensors measure reflected light from a target, changes in illumination characteristics critically affect sensor response. Active sensors are of benefit in minimizing uncontrolled illumination effe...

  3. Mesenchymal stromal cell characteristics vary depending on their origin.

    PubMed

    Wegmeyer, Heike; Bröske, Ann-Marie; Leddin, Mathias; Kuentzer, Karin; Nisslbeck, Anna Katharina; Hupfeld, Julia; Wiechmann, Kornelius; Kuhlen, Jennifer; von Schwerin, Christoffer; Stein, Carsten; Knothe, Saskia; Funk, Jürgen; Huss, Ralf; Neubauer, Markus

    2013-10-01

    Mesenchymal stromal cells (MSCs) are rare progenitor cells that can be isolated from various tissues. They exhibit multilineage differentiation potential, support regenerative processes, and interact with various immune cells. Therefore, MSCs represent a promising tool for regenerative medicine. However, source-dependent and donor-dependent differences of MSC properties, including implications on their clinical application are still largely unknown. We evaluated MSCs derived from perinatal tissues umbilical cord (UC) and amniotic membrane (AM) in comparison to adult MSCs from bone marrow (BM), which were used as gold standard. We found genetic background-independent differences between MSCs from UC and AM. While AM- and UC-MSCs were closer to each other than to BM-MSCs, they also exhibited differences between each other. AM-MSCs from different donors but not UC-MSCs displayed high interdonor variability. In addition, we show that although all MSCs expressed similar surface markers, MSC populations from UC and AM showed differential profiles of gene expression and paracrine factor secretion to BM-derived MSCs. Notably, pathway analysis of gene expression data revealed intriguing differences between MSCs suggesting that MSCs from UC and AM possess in general a higher potential of immunomodulatory capacity, whereas BM-MSCs showed a higher potential of supporting regenerative processes as exemplified by neuronal differentiation and development. These differences between perinatal and BM-derived MSCs may be relevant for clinical applications. PMID:23676112

  4. The Activity of Antimicrobial Surfaces Varies by Testing Protocol Utilized

    PubMed Central

    Campos, Matias D.; Zucchi, Paola C.; Phung, Ann; Leonard, Steven N.; Hirsch, Elizabeth B.

    2016-01-01

    Background Contaminated hospital surfaces are an important source of nosocomial infections. A major obstacle in marketing antimicrobial surfaces is a lack of efficacy data based on standardized testing protocols. Aim We compared the efficacy of multiple testing protocols against several “antimicrobial” film surfaces. Methods Four clinical isolates were used: one Escherichia coli, one Klebsiella pneumoniae, and two Staphylococcus aureus strains. Two industry methods (modified ISO 22196 and ASTM E2149), a “dried droplet”, and a “transfer” method were tested against two commercially available antimicrobial films, one film in development, an untreated control, and a positive (silver) control film. At 2 (only ISO) and 24 hours following inoculation, bacteria were collected from film surfaces and enumerated. Results Compared to untreated films in all protocols, there were no significant differences in recovery on either commercial brand at 2 or 24 hours after inoculation. The silver surface demonstrated significant microbicidal activity (mean loss 4.9 Log10 CFU/ml) in all methods and time points with the exception of 2 hours in the ISO protocol and the transfer method. Using our novel droplet method, no differences between placebo and active surfaces were detected. The surface in development demonstrated variable activity depending on method, organism, and time point. The ISO demonstrated minimal activity at 2 hours but significant activity at 24 hours (mean 4.5 Log10 CFU/ml difference versus placebo). The ASTEM protocol exhibited significant differences in recovery of staphylococci (mean 5 Log10 CFU/ml) but not Gram-negative isolates (10 fold decrease). Minimal activity was observed with this film in the transfer method. Conclusions Varying results between protocols suggested that efficacy of antimicrobial surfaces cannot be easily and reproducibly compared. Clinical use should be considered and further development of representative methods is needed. PMID

  5. Neural Correlates of Math Gains Vary Depending on Parental Socioeconomic Status (SES)

    PubMed Central

    Demir-Lira, Özlem Ece; Prado, Jérôme; Booth, James R.

    2016-01-01

    We used functional magnetic resonance imaging (fMRI) to examine the neural predictors of math development, and asked whether these predictors vary as a function of parental socioeconomic status (SES) in children ranging in age from 8 to 13 years. We independently localized brain regions subserving verbal versus spatial processing in order to characterize relations between activation in these regions during an arithmetic task and long-term change in math skill (up to 3 years). Neural predictors of math gains encompassed brain regions subserving both verbal and spatial processing, but the relation between relative reliance on these regions and math skill growth varied depending on parental SES. Activity in an area of the left inferior frontal gyrus (IFG) identified by the verbal localizer was related to greater growth in math skill at the higher end of the SES continuum, but lesser improvements at the lower end. Activity in an area of the right superior parietal cortex identified by the spatial localizer was related to greater growth in math skill at the lower end of the SES continuum, but lesser improvements at the higher end. Results highlight early neural mechanisms as possible neuromarkers of long-term arithmetic learning and suggest that neural predictors of math gains vary with parental SES. PMID:27378987

  6. Neural Correlates of Math Gains Vary Depending on Parental Socioeconomic Status (SES).

    PubMed

    Demir-Lira, Özlem Ece; Prado, Jérôme; Booth, James R

    2016-01-01

    We used functional magnetic resonance imaging (fMRI) to examine the neural predictors of math development, and asked whether these predictors vary as a function of parental socioeconomic status (SES) in children ranging in age from 8 to 13 years. We independently localized brain regions subserving verbal versus spatial processing in order to characterize relations between activation in these regions during an arithmetic task and long-term change in math skill (up to 3 years). Neural predictors of math gains encompassed brain regions subserving both verbal and spatial processing, but the relation between relative reliance on these regions and math skill growth varied depending on parental SES. Activity in an area of the left inferior frontal gyrus (IFG) identified by the verbal localizer was related to greater growth in math skill at the higher end of the SES continuum, but lesser improvements at the lower end. Activity in an area of the right superior parietal cortex identified by the spatial localizer was related to greater growth in math skill at the lower end of the SES continuum, but lesser improvements at the higher end. Results highlight early neural mechanisms as possible neuromarkers of long-term arithmetic learning and suggest that neural predictors of math gains vary with parental SES. PMID:27378987

  7. ATP Dependence of the ICl, swell Channel Varies with Rate of Cell Swelling

    PubMed Central

    Bond, Tamara; Basavappa, Srisaila; Christensen, Michael; Strange, Kevin

    1999-01-01

    Swelling-induced activation of the outwardly rectifying anion current, ICl, swell, is modulated by intracellular ATP. The mechanisms by which ATP controls channel activation, however, are unknown. Whole cell patch clamp was employed to begin addressing this issue. Endogenous ATP production was inhibited by dialyzing N1E115 neuroblastoma cells for 4–5 min with solutions containing (μM): 40 oligomycin, 5 iodoacetate, and 20 rotenone. The effect of ATP on current activation was observed in the absence of intracellular Mg2+, in cells exposed to extracellular metabolic inhibitors for 25–35 min followed by intracellular dialysis with oligomycin, iodoacetate, and rotenone, after substitution of ATP with the nonhydrolyzable analogue AMP-PNP, and in the presence of AMP-PNP and alkaline phosphatase to dephosphorylate intracellular proteins. These results demonstrate that the ATP dependence of the channel requires ATP binding rather than hydrolysis and/or phosphorylation reactions. When cells were swollen at 15–55%/min in the absence of intracellular ATP, current activation was slow (0.3–0.8 pA/pF per min). ATP concentration increased the rate of current activation up to maximal values of 4–6 pA/pF per min, but had no effect on the sensitivity of the channel to cell swelling. Rate of current activation was a saturable, hyperbolic function of ATP concentration. The EC50 for ATP varied inversely with the rate of cell swelling. Activation of current was rapid (4–6 pA/pF per min) in the absence of ATP when cells were swollen at rates ≥65%/min. Intracellular ATP concentration had no effect on current activation induced by high rates of swelling. Current activation was transient when endogenous ATP was dialyzed out of the cytoplasm of cells swollen at 15%/min. Rundown of the current was reversed by increasing the rate of swelling to 65%/min. These results indicate that the channel and/or associated regulatory proteins are capable of sensing the rate of cell volume

  8. Constraints on global fire activity vary across a resource gradient.

    PubMed

    Krawchuk, Meg A; Moritz, Max A

    2011-01-01

    We provide an empirical, global test of the varying constraints hypothesis, which predicts systematic heterogeneity in the relative importance of biomass resources to burn and atmospheric conditions suitable to burning (weather/climate) across a spatial gradient of long-term resource availability. Analyses were based on relationships between monthly global wildfire activity, soil moisture, and mid-tropospheric circulation data from 2001 to 2007, synthesized across a gradient of long-term averages in resources (net primary productivity), annual temperature, and terrestrial biome. We demonstrate support for the varying constraints hypothesis, showing that, while key biophysical factors must coincide for wildfires to occur, the relative influence of resources to burn and moisture/weather conditions on fire activity shows predictable spatial patterns. In areas where resources are always available for burning during the fire season, such as subtropical/tropical biomes with mid-high annual long-term net primary productivity, fuel moisture conditions exert their strongest constraint on fire activity. In areas where resources are more limiting or variable, such as deserts, xeric shrublands, or grasslands/savannas, fuel moisture has a diminished constraint on wildfire, and metrics indicating availability of burnable fuels produced during the antecedent wet growing seasons reflect a more pronounced constraint on wildfire. This macro-scaled evidence for spatially varying constraints provides a synthesis with studies performed at local and regional scales, enhances our understanding of fire as a global process, and indicates how sensitivity to future changes in temperature and precipitation may differ across the world. PMID:21560682

  9. New delay dependent stability criteria for recurrent neural networks with interval time-varying delay.

    PubMed

    Yang, Qiongfen; Ren, Quanhong; Xie, Xuemei

    2014-07-01

    This paper is concerned with the delay dependent stability criteria for a class of static recurrent neural networks with interval time-varying delay. By choosing an appropriate Lyapunov-Krasovskii functional and employing a delay partitioning method, the less conservative condition is obtained. Furthermore, the LMIs-based condition depend on the lower and upper bounds of time delay. Finally, a numerical example is also designated to verify the reduced conservatism of developed criteria. PMID:24908560

  10. Innovation diffusion on time-varying activity driven networks

    NASA Astrophysics Data System (ADS)

    Rizzo, Alessandro; Porfiri, Maurizio

    2016-01-01

    Since its introduction in the 1960s, the theory of innovation diffusion has contributed to the advancement of several research fields, such as marketing management and consumer behavior. The 1969 seminal paper by Bass [F.M. Bass, Manag. Sci. 15, 215 (1969)] introduced a model of product growth for consumer durables, which has been extensively used to predict innovation diffusion across a range of applications. Here, we propose a novel approach to study innovation diffusion, where interactions among individuals are mediated by the dynamics of a time-varying network. Our approach is based on the Bass' model, and overcomes key limitations of previous studies, which assumed timescale separation between the individual dynamics and the evolution of the connectivity patterns. Thus, we do not hypothesize homogeneous mixing among individuals or the existence of a fixed interaction network. We formulate our approach in the framework of activity driven networks to enable the analysis of the concurrent evolution of the interaction and individual dynamics. Numerical simulations offer a systematic analysis of the model behavior and highlight the role of individual activity on market penetration when targeted advertisement campaigns are designed, or a competition between two different products takes place.

  11. Social communication intervention effects vary by dependent variable type in preschoolers with autism spectrum disorders

    PubMed Central

    Yoder, Paul J.; Bottema-Beutel, Kristen; Woynaroski, Tiffany; Chandrasekhar, Rameela; Sandbank, Michael

    2014-01-01

    Individuals with autism spectrum disorders (ASDs) have difficulty communicating in ways that are primarily for initiating and maintaining social relatedness (i.e., social communication). We hypothesized that the way researchers measured social communication would affect whether treatment effects were found. Using a best evidence review method, we found that treatments were shown to improve social communication outcomes approximately 54% of the time. The probability that a treatment affected social communication varied greatly depending on whether social communication was directly targeted (63%) or not (39%). Finally, the probability that a treatment affected social communication also varied greatly depending on whether social communication as measured in (a) contexts very similar to treatment sessions (82%) or (b) contexts that differed from treatment on at least setting, materials, and communication partner (33%). This paper also provides several methodological contributions. PMID:25346776

  12. Online Support Vector Regression with Varying Parameters for Time-Dependent Data

    SciTech Connect

    Omitaomu, Olufemi A; Jeong, Myong K; Badiru, Adedeji B

    2011-01-01

    Support vector regression (SVR) is a machine learning technique that continues to receive interest in several domains including manufacturing, engineering, and medicine. In order to extend its application to problems in which datasets arrive constantly and in which batch processing of the datasets is infeasible or expensive, an accurate online support vector regression (AOSVR) technique was proposed. The AOSVR technique efficiently updates a trained SVR function whenever a sample is added to or removed from the training set without retraining the entire training data. However, the AOSVR technique assumes that the new samples and the training samples are of the same characteristics; hence, the same value of SVR parameters is used for training and prediction. This assumption is not applicable to data samples that are inherently noisy and non-stationary such as sensor data. As a result, we propose Accurate On-line Support Vector Regression with Varying Parameters (AOSVR-VP) that uses varying SVR parameters rather than fixed SVR parameters, and hence accounts for the variability that may exist in the samples. To accomplish this objective, we also propose a generalized weight function to automatically update the weights of SVR parameters in on-line monitoring applications. The proposed function allows for lower and upper bounds for SVR parameters. We tested our proposed approach and compared results with the conventional AOSVR approach using two benchmark time series data and sensor data from nuclear power plant. The results show that using varying SVR parameters is more applicable to time dependent data.

  13. Natal departure timing from spatially varying environments is dependent of individual ontogenetic status

    NASA Astrophysics Data System (ADS)

    Cucherousset, Julien; Paillisson, Jean-Marc; Roussel, Jean-Marc

    2013-08-01

    Natal departure timing represents one of the first crucial decisions for juveniles born in spatially varying environments that ultimately disappear, but our knowledge on its determinants is limited. The present study aimed at understanding the determinants of juvenile natal departure by releasing individually tagged juvenile pike ( Esox lucius L.) with variable body size and trophic position in a temporary flooded grassland. Specifically, we investigated whether natal departure depends on individual competitive status (`competition hypothesis'), physiological tolerance to environmental conditions (`physiological hypothesis') or individual trophic position and the spatial heterogeneity of trophic resources (`trophic hypothesis'). The results indicated that departure timing was negatively correlated with body size at release, showing that the dominance status among competing individuals was not the main trigger of juvenile departure. A positive correlation between departure timing and individual body size at departure was observed, suggesting that inter-individual variability in physiological tolerance did not explain departure patterns. While individual growth performances were similar irrespective of the timing of natal departure, stable isotope analyses revealed that juveniles with higher trophic position departed significantly earlier than individuals with lower trophic position. Therefore, the trade-off driving the use of spatially varying environments was most likely dependent upon the benefits associated with energetic returns than the costs associated with inter-individual competition or physiological stress. This result highlighted how ontogeny, and particularly ontogenetic niche shift, can play a central role in juvenile's decision to depart from natal habitats in a predatory species.

  14. Stress and Drug Dependence Differentially Modulate Norepinephrine Signaling in Animals with Varied HPA Axis Function

    PubMed Central

    Fox, Megan E; Studebaker, R Isaac; Swofford, Nathaniel J; Wightman, R Mark

    2015-01-01

    Previous work has demonstrated the importance of genetic factors and stress-sensitive circuits in the development of affective disorders. Anxiety and numerous psychological disorders are comorbid with substance abuse, and noradrenergic signaling in the bed nucleus of the stria terminalis (BNST) is thought to be a source of this convergence. Here, we examined the effects of different stressors on behavior and norepinephrine dynamics in the BNST of rat strains known to differ in their HPA-axis function. We compared the effects of acute morphine dependence and social isolation in non-anxious Sprague Dawley (SD) rats, and a depression model, Wistar-Kyoto (WKY) rats. We found a shared phenotype in drug-dependent and singly housed SD rats, characterized by slowed norepinephrine clearance, decreased autoreceptor function, and elevated anxiety. WKY rats exhibited changes in anxiety and autoreceptor function only following morphine dependence. To ascertain the influence of LC inhibition on this plasticity, we administered the LC-terminal-selective toxin DSP-4 to SD and WKY rats. DSP-4-treated SD rats demonstrated a dependence-like phenotype, whereas WKY rats were unchanged. Overall, our findings suggest that individuals with varying stress susceptibilities have different noradrenergic signaling changes in response to stress. These changes may establish conditions that favor stress-induced reinstatement and increase the risk for addiction. PMID:25601230

  15. Early-Emerging Nicotine Dependence Has Lasting and Time-Varying Effects on Adolescent Smoking Behavior.

    PubMed

    Selya, Arielle S; Dierker, Lisa; Rose, Jennifer S; Hedeker, Donald; Mermelstein, Robin J

    2016-08-01

    Novice and light adolescent smokers can develop symptoms of nicotine dependence, which predicts smoking behavior several years into the future. However, little is known about how the association between these early - emerging symptoms and later smoker behaviors may change across time from early adolescence into young adulthood. Data were drawn from a 7-year longitudinal study of experimental (<100 cigarettes/lifetime; N = 594) and light (100+ cigarettes/lifetime, but ≤5 cigarettes/day; N = 152) adolescent smokers. Time-varying effect models were used to examine the relationship between baseline nicotine dependence (assessed at age 15 ± 2 years) and future smoking frequency through age 24, after controlling for concurrent smoking heaviness. Baseline smoking status, race, and sex were examined as potential moderators of this relationship. Nicotine dependence symptoms assessed at approximately age 15 significantly predicted smoking frequency through age 24, over and above concurrent smoking heaviness, though it showed declining trends at older ages. Predictive validity was weaker among experimenters at young ages (<16), but stronger at older ages (20-23), relative to light smokers. Additionally, nicotine dependence was a stronger predictor of smoking frequency for white smokers around baseline (ages 14.5-16), relative to nonwhite smokers. Nicotine dependence assessed in mid-adolescence predicts smoking frequency well into early adulthood, over and above concurrent smoking heaviness, especially among novice smokers and nonwhite smokers. Early-emerging nicotine dependence is a promising marker for screening and interventions aimed at preventing smoking progression. PMID:27312479

  16. Motoneuron and sensory neuron plasticity to varying neuromuscular activity levels

    NASA Technical Reports Server (NTRS)

    Ishihara, Akihiko; Roy, Roland R.; Ohira, Yoshinobu; Edgerton, V. Reggie

    2002-01-01

    The size and phenotypic properties of the neural and muscular elements of the neuromuscular unit are matched under normal conditions. When subjected to chronic decreases or increases in neuromuscular activity, however, the adaptations in these properties are much more limited in the neural compared with the muscular elements.

  17. A SPECTROPHOTOMETRIC ASSAY TO MEASURE RUBISCO ACTIVASE ACTIVATION ACTIVITY UNDER VARYING ATP:ADP RATIOS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ratio of ATP to ADP in the stroma is an important regulatory mechanism for controlling the activation state of Rubisco via Rubisco activase (activase). Understanding the response of activase to a varying ATP:ADP ratio should reveal insights into the regulation of photosynthesis. However, the cur...

  18. Delay-dependent passivity criteria for uncertain switched neural networks of neutral type with interval time-varying delay

    NASA Astrophysics Data System (ADS)

    Nagamani, G.; Balasubramaniam, P.

    2012-04-01

    This paper is concerned with the robust passivity analysis of uncertain switched neural networks of neutral type with interval time-varying delay. We first discuss the passivity conditions for the addressed model with norm bounded uncertainties and then extend this result to the case of interval uncertainties. For the neural networks under study, a generalized activation function is considered, where the traditional assumptions on the boundedness, monotonicity and differentiability of the activation functions are removed. Constructing a new Lyapunov-Krasovskii functional with triple integral terms and using a minimal number of free-weighting matrices, some passivity criteria are proposed in terms of linear matrix inequalities, which are dependent on the size of the time delay. Finally, some numerical examples are given to illustrate the effectiveness and merits of the developed techniques.

  19. Varying modulation of HIV-1 LTR activity by Baf complexes.

    PubMed

    Van Duyne, Rachel; Guendel, Irene; Narayanan, Aarthi; Gregg, Edward; Shafagati, Nazly; Tyagi, Mudit; Easley, Rebecca; Klase, Zachary; Nekhai, Sergei; Kehn-Hall, Kylene; Kashanchi, Fatah

    2011-08-19

    The human immunodeficiency virus type 1 (HIV-1) long terminal repeat is present on both ends of the integrated viral genome and contains regulatory elements needed for transcriptional initiation and elongation. Post-integration, a highly ordered chromatin structure consisting of at least five nucleosomes, is found at the 5' long terminal repeat, the location and modification state of which control the state of active viral replication as well as silencing of the latent HIV-1 provirus. In this context, the chromatin remodeling field rapidly emerges as having a critical role in the control of viral gene expression. In the current study, we focused on unique Baf subunits that are common to the most highly recognized of chromatin remodeling proteins, the SWI/SNF (switching-defective-sucrose non-fermenting) complexes. We find that at least two Baf proteins, Baf53 and Baf170, are highly regulated in HIV-1-infected cells. Previously, studies have shown that the depletion of Baf53 in uninfected cells leads to the expansion of chromosomal territories and the decompaction of the chromatin. Baf53, in the presence of HIV-1 infection, co-elutes off of a chromatographic column as a different-sized complex when compared to uninfected cells and appears to be predominantly phosphorylated. The innate function of Baf53-containing complexes appears to be transcriptionally suppressive, in that knocking down Baf53 increases viral gene expression from cells both transiently and chronically infected with HIV-1. Additionally, cdk9/cyclin T in the presence of Tat is able to phosphorylate Baf53 in vitro, implying that this posttranslationally modified form relieves the suppressive effect and allows for viral transcription to proceed. PMID:21699904

  20. Three African antelope species with varying water dependencies exhibit similar selective brain cooling.

    PubMed

    Strauss, W Maartin; Hetem, Robyn S; Mitchell, Duncan; Maloney, Shane K; Meyer, Leith C R; Fuller, Andrea

    2016-05-01

    The use of selective brain cooling, where warm arterial blood destined for the brain is cooled in the carotid rete via counter-current heat exchange when in close proximity to cooler venous blood, contributes to the conservation of body water. We simultaneously measured carotid blood and hypothalamic temperature in four gemsbok, five red hartebeest and six blue wildebeest to assess the extent to which these free-living animals, with varying water dependency, routinely rely on selective brain cooling. We investigated the hypothesis that innate differences in selective brain cooling exist in large, sympatric artiodactyls with varying water dependency. All three species used selective brain cooling, without any discernible differences in three selective brain cooling indices. GLMMs revealed no species differences in the threshold temperature for selective brain cooling (z = 0.79, P = 0.43), the magnitude (z = -0.51, P = 0.61), or the frequency of selective brain cooling use (z = -0.47, P = 0.64), after controlling for carotid blood temperature and black globe temperature. Comparison of anatomical attributes of the carotid retes of the three species revealed that the volume (F 2,9 = 5.54, P = 0.03) and height (F 2,9 = 5.43, P = 0.03) of the carotid rete, per kilogram body mass, were greater in the red hartebeest than in the blue wildebeest. Nevertheless, intraspecific variability in the magnitude, the frequency of use, and the threshold temperature for selective brain cooling exceeded any interspecific variability in the three indices of selective brain cooling. We conclude that the three species have similar underlying ability to make use of selective brain cooling in an environment with freely available water. It remains to be seen to what extent these three species would rely on selective brain cooling, as a water conservation mechanism, when challenged by aridity, a condition likely to become prevalent throughout much of southern Africa under

  1. AST: Activity-Security-Trust driven modeling of time varying networks

    PubMed Central

    Wang, Jian; Xu, Jiake; Liu, Yanheng; Deng, Weiwen

    2016-01-01

    Network modeling is a flexible mathematical structure that enables to identify statistical regularities and structural principles hidden in complex systems. The majority of recent driving forces in modeling complex networks are originated from activity, in which an activity potential of a time invariant function is introduced to identify agents’ interactions and to construct an activity-driven model. However, the new-emerging network evolutions are already deeply coupled with not only the explicit factors (e.g. activity) but also the implicit considerations (e.g. security and trust), so more intrinsic driving forces behind should be integrated into the modeling of time varying networks. The agents undoubtedly seek to build a time-dependent trade-off among activity, security, and trust in generating a new connection to another. Thus, we reasonably propose the Activity-Security-Trust (AST) driven model through synthetically considering the explicit and implicit driving forces (e.g. activity, security, and trust) underlying the decision process. AST-driven model facilitates to more accurately capture highly dynamical network behaviors and figure out the complex evolution process, allowing a profound understanding of the effects of security and trust in driving network evolution, and improving the biases induced by only involving activity representations in analyzing the dynamical processes. PMID:26888717

  2. AST: Activity-Security-Trust driven modeling of time varying networks

    NASA Astrophysics Data System (ADS)

    Wang, Jian; Xu, Jiake; Liu, Yanheng; Deng, Weiwen

    2016-02-01

    Network modeling is a flexible mathematical structure that enables to identify statistical regularities and structural principles hidden in complex systems. The majority of recent driving forces in modeling complex networks are originated from activity, in which an activity potential of a time invariant function is introduced to identify agents’ interactions and to construct an activity-driven model. However, the new-emerging network evolutions are already deeply coupled with not only the explicit factors (e.g. activity) but also the implicit considerations (e.g. security and trust), so more intrinsic driving forces behind should be integrated into the modeling of time varying networks. The agents undoubtedly seek to build a time-dependent trade-off among activity, security, and trust in generating a new connection to another. Thus, we reasonably propose the Activity-Security-Trust (AST) driven model through synthetically considering the explicit and implicit driving forces (e.g. activity, security, and trust) underlying the decision process. AST-driven model facilitates to more accurately capture highly dynamical network behaviors and figure out the complex evolution process, allowing a profound understanding of the effects of security and trust in driving network evolution, and improving the biases induced by only involving activity representations in analyzing the dynamical processes.

  3. AST: Activity-Security-Trust driven modeling of time varying networks.

    PubMed

    Wang, Jian; Xu, Jiake; Liu, Yanheng; Deng, Weiwen

    2016-01-01

    Network modeling is a flexible mathematical structure that enables to identify statistical regularities and structural principles hidden in complex systems. The majority of recent driving forces in modeling complex networks are originated from activity, in which an activity potential of a time invariant function is introduced to identify agents' interactions and to construct an activity-driven model. However, the new-emerging network evolutions are already deeply coupled with not only the explicit factors (e.g. activity) but also the implicit considerations (e.g. security and trust), so more intrinsic driving forces behind should be integrated into the modeling of time varying networks. The agents undoubtedly seek to build a time-dependent trade-off among activity, security, and trust in generating a new connection to another. Thus, we reasonably propose the Activity-Security-Trust (AST) driven model through synthetically considering the explicit and implicit driving forces (e.g. activity, security, and trust) underlying the decision process. AST-driven model facilitates to more accurately capture highly dynamical network behaviors and figure out the complex evolution process, allowing a profound understanding of the effects of security and trust in driving network evolution, and improving the biases induced by only involving activity representations in analyzing the dynamical processes. PMID:26888717

  4. A delay-dependent approach to robust control for neutral uncertain neural networks with mixed interval time-varying delays

    NASA Astrophysics Data System (ADS)

    Lu, Chien-Yu

    2011-04-01

    This paper considers the problem of delay-dependent global robust stabilization for discrete, distributed and neutral interval time-varying delayed neural networks described by nonlinear delay differential equations of the neutral type. The parameter uncertainties are norm bounded. The activation functions are assumed to be bounded and globally Lipschitz continuous. Using a Lyapunov functional approach and linear matrix inequality (LMI) techniques, the stability criteria for the uncertain neutral neural networks with interval time-varying delays are established in the form of LMIs, which can be readily verified using the standard numerical software. An important feature of the result reported is that all the stability conditions are dependent on the upper and lower bounds of the delays. Another feature of the results lies in that it involves fewer free weighting matrix strategy, and upper bounds of the inner product between two vectors are not introduced to reduce the conservatism of the criteria. Two illustrative examples are provided to demonstrate the effectiveness and the reduced conservatism of the proposed method.

  5. Autonomic activity assessed by heart rate spectral analysis varies with fat distribution in obese women.

    PubMed

    Gao, Y Y; Lovejoy, J C; Sparti, A; Bray, G A; Keys, L K; Partington, C

    1996-01-01

    Obesity in humans has been associated with altered autonomic nervous system activity. The objective of this study was to examine the relationship between autonomic function and body fat distribution in 16 obese, postmenopausal women using power spectrum analysis of heart rate variability. Using this technique, a low frequency peak (0.04-0.12 Hz) reflecting mixed sympathetic and parasympathetic activity, and a high frequency peak (0.22-0.28 Hz) reflecting parasympathetic activity, were identified from 5-minute consecutive heart rate data (both supine and standing). Autonomic activity in upper body (UBO) vs. lower body obesity (LBO)(by waist-to-hip ratio) and subcutaneous vs. visceral obesity (by CT scan) was evaluated. Power spectrum data were log transformed to normalize the data. The results showed that standing, low-frequency power (reflecting sympathetic activity) and supine, high-frequency power (reflecting parasympathetic activity) were significantly greater in UBO than in LBO, and in visceral compared to subcutaneous obesity. Women with combined UBO and visceral obesity had significantly higher cardiac sympathetic and parasympathetic activity than any other subgroup. We conclude that cardiac autonomic function as assessed by heart rate spectral analysis varies in women depending on their regional body fat distribution. PMID:8787938

  6. Emotion-induced retrograde amnesia varies as a function of noradrenergic-glucocorticoid activity

    PubMed Central

    Hurlemann, René; Matusch, Andreas; Hawellek, Barbara; Klingmuller, Dietrich; Kolsch, Heike; Maier, Wolfgang; Dolan, Raymond J.

    2009-01-01

    Rationale Privileged episodic encoding of an aversive event often comes at a cost of neutral events flanking the aversive event, resulting in decreased episodic memory for these neutral events. This peri-emotional amnesia is amygdala-dependent and varies as a function of norepinephrine activity. However, less is known about the amnesiogenic potential of cortisol. Objective We used a strategy of pharmacologically potentiating cortisol and norepinephrine activity to probe the putative neurochemical substrates of peri-emotional amnesia. Materials and methods Fifty-four healthy individuals participated in a randomized double-blind placebo-controlled study. Within the experimental context of an established peri-emotional amnesia paradigm, we tested the amnesiogenic potential of hydrocortisone (30 mg p.o.) in the presence or absence of the norepinephrine-reuptake inhibitor reboxetine (4 mg p.o.). Results Under dual challenge conditions, we observed a linear dose-response relationship in the magnitude and duration of emotion-induced retrograde amnesia. Conclusions Our results are consistent with a phenotypic expression of retrograde amnesia varying as a function of norepinephrine and cortisol coactivation during episodic encoding of aversive events. Our study demonstrates that the adverse cognitive and behavioral sequelae of aversive emotion can be experimentally modeled by a pharmacological manipulation of its putative neurochemical substrates. PMID:17588225

  7. Local regularity for time-dependent tug-of-war games with varying probabilities

    NASA Astrophysics Data System (ADS)

    Parviainen, Mikko; Ruosteenoja, Eero

    2016-07-01

    We study local regularity properties of value functions of time-dependent tug-of-war games. For games with constant probabilities we get local Lipschitz continuity. For more general games with probabilities depending on space and time we obtain Hölder and Harnack estimates. The games have a connection to the normalized p (x , t)-parabolic equation ut = Δu + (p (x , t) - 2) Δ∞Nu.

  8. Neurophysiology of Hungarian subject-verb dependencies with varying intervening complexity.

    PubMed

    Jolsvai, Hajnal; Sussman, Elyse; Csuhaj, Roland; Csépe, Valéria

    2011-12-01

    Non-adjacent dependencies are thought to be more costly to process than sentences wherein dependents immediately follow or precede what they depend on. In English locality effects have been revealed, while in languages with rich case marking (German and Hindi) sentence final structures show anti-locality-effects. The motivation of the current study is to test whether locality effects can be directly applied to a typologically different language than those investigated so far. Hungarian is a "topic prominent" language; it permits a variation of possible word sequencing for semantic reasons, including SVO word order. Hungarian also has a rich morphological system (e.g., rich case system) and postpositions to indicate grammatical functions. In the present ERP study, Hungarian subject-verb dependencies were compared by manipulating the mismatch of number agreement between the sentence's initial noun phrase and the sentence's final intransitive verb as well as the complexity of the intervening sentence material, interrupting the dependencies. Possible lexical class and frequency or cloze-probability effects for the first two words of the intervening sentence material were revealed when used separate baseline for each word, while at the third word of the intervening material as well as at the main verb ERPs were not modulated by complexity but at the verb ERPs were enhanced by grammaticality. Ungrammatical sentences enlarged the amplitude of both LAN and P600 components at the main verb. These results are in line with studies suggesting that the retrieval of the first element of a dependency is not influenced by distance from the second element, as the first element is directly accessible when needed for integration (e.g., McElree, 2000). PMID:21740931

  9. Value Representations by Rank Order in a Distributed Network of Varying Context Dependency

    ERIC Educational Resources Information Center

    Mullett, Timothy L.; Tunney, Richard J.

    2013-01-01

    We report the results of a human fMRI experiment investigating the influence of context upon value judgement. Trials were separated into high and low value blocks such that it is possible to investigate the effect of a change in surrounding trials upon the encoding of financial value. The ventral striatum was dependent upon "local context", with…

  10. Robust H∞ Control for Time-Varying Delay Systems with Frequency-Dependent Performance Weights

    NASA Astrophysics Data System (ADS)

    Nagahara, Masanori; Arai, Shingo; Uchimura, Yutaka

    This paper proposes a control design that enables us to shape the frequency-dependent performance using a modified Lyapunov-Krasovskii-based stabilizing condition. A stabilizing controller can be obtained by solving the condition formulated in Linear Matrix Inequality (LMI). The designed controller is evaluated using numerical simulations, and it is employed to realize the velocity control of a DC motor. Experimental results verified that the proposed controller achieved better performance with less conservativeness and that it is applicable to real plants.

  11. Performance of two-stage vegetable waste anaerobic digestion depending on varying recirculation rates.

    PubMed

    Zuo, Zhuang; Wu, Shubiao; Zhang, Wanqin; Dong, Renjie

    2014-06-01

    Vegetable waste, which characterized by high moisture content, was evaluated as a substrate for biogas production. The effects of recirculation rate (RR) on the performance of two-stage anaerobic digestion were investigated. The system was operated at an organic loading rate of 1.7 g VS/L/d with varying RRs (0, 0.6, 1, and 1.4). Results demonstrated that volumetric biogas production rates in acidogenic reactor increased from approximately 0.2 7 L/L/d to 0.97 L/L/d, when pH is increased from approximately 5.1 to 6.7. These indicate that recirculation of alkaline effluent from the methanogenic reactor helps create a favorable condition for biogas production in the acidogenic reactor. The decrease in chemical oxygen demand (COD) concentrations from approximately 21,000 mg/L to 6800 mg/L was also observed in the acidogenic reactor. This condition may be attributed to dilution under recirculation. The dynamics between hydrolysis and methanogenesis under recirculation indicated that mass transfer capacity between two-stage reactors improved. PMID:24759642

  12. The selectivity of task-dependent attention varies with surrounding context.

    PubMed

    Kim, Yee-Joon; Verghese, Preeti

    2012-08-29

    Attention is thought to operate by enhancing the target of interest and suppressing the surroundings. We hypothesized that the spatial profile of attention depends on the surround's relationship to the target. Using high-density electroencephalographic measurements, we examined the spatial profile of attention to a grating target surrounded by an annular grating that was either coextensive with the target (unsegmented) or appeared segmented from it due to a gap or phase offset. We directly probed the spread of attention from the central target into the surround by flickering the surround and monitoring frequency-tagged steady-state visual-evoked potentials. Observers were required to detect a contrast increment that occurred only on the target. Successful detection of the increment required selecting the target and suppressing the surround, particularly when the target did not readily segment from the surround. The profile of attention was investigated in five visual regions of interest (ROIs) (V1, V4, V3A, lateral occipital complex, and human middle temporal area), mapped in a separate anatomical magnetic resonance imaging scan. We found that in most ROIs, attention to the target generated smaller responses from the surrounding annulus when it was contiguous compared with when it was clearly segmented. This result shows that the profile of attention depends on task demands and on surrounding context; attention is tightly focused when the target region needs to be isolated but loosely focused when the target region is clearly segmented. PMID:22933800

  13. The metabolic response to postnatal leptin in rats varies with age and may be litter dependent.

    PubMed

    Granado, M; Diaz, F; Fuente-Martín, E; García-Cáceres, C; Argente, J; Chowen, J A

    2014-06-01

    Hyperleptinemia during postnatal life induces long-term effects on metabolism. However, these effects are controversial as both increased and decreased propensity towards obesity has been reported. To further analyze the effects of chronic neonatal hyperleptinemia on the subsequent metabolic profile, male Wistar rats proceeding from 18 different litters (8 pups/litter) received a daily subcutaneous injection of either saline (10 ml/kg, n=36) or leptin (3 μg/g, n=36) from postnatal day (PND) 2 to PND9. Rats were sacrificed at 10, 40, or 150 days of age. At 10 days of age, leptin treated rats had decreased body weight (p<0.001) and body fat (p<0.05). Leptin levels and glycemia were increased (p<0.01), whereas insulin, total lipids, triglycerides and glycerol levels were decreased (p<0.05). At PND40 rats receiving leptin had increased glycemia (p<0.01) and plasma HDL and LDL levels, but decreased total lipids (p<0.05). At PND150 neonatal leptin treatment induced different effects in rats raised in different litters. Rats from litter 1 had increased body weight (p<0.05), body fat (p<0.01), and plasma leptin (p<0.001), cholesterol (p<0.001), triglyceride (p<0.001), total lipid (p<0.001), LDL (p<0.05), and glycerol (p<0.001) levels. In rats from litter 2 these parameters did not differ from controls. Rats from litter 3 had decreased body weight (p<0.05), visceral fat (p<0.01) and plasma leptin (p<0.001), cholesterol (p<0.001), triglyceride (p<0.001), glycerol (p<0.001), and HDL (p<0.001) levels. In conclusion, the metabolic response to postnatal leptin varies with age, with the response in adulthood being variable and most likely influenced by other factors, including the genetic make-up. PMID:24446159

  14. Depth-dependent plasticity in opsin gene expression varies between damselfish (Pomacentridae) species.

    PubMed

    Stieb, Sara M; Carleton, Karen L; Cortesi, Fabio; Marshall, N Justin; Salzburger, Walter

    2016-08-01

    Phenotypic plasticity plays an important role in adapting the visual capability of many animal species to changing sensory requirements. Such variability may be driven by developmental change or may result from environmental changes in light habitat, thereby improving performance in different photic environments. In this study, we examined inter- and intraspecific plasticity of visual sensitivities in seven damselfish species, part of the species-rich and colourful fish fauna of the Great Barrier Reef in Australia. Our goal was to test whether the visual systems of damselfish were tuned to the prevailing light environment in different habitats and/or other aspects of their lifestyle. More specifically, we compared the opsin gene expression levels from individuals living in different photic habitats. We found that all species expressed rod opsin (RH1) used for dim-light vision, and primarily three cone opsins (SWS1, RH2B and RH2A) used for colour vision. While RH1 levels changed exclusively following a diurnal cycle, cone opsin expression varied with depth in four of the seven species. Estimates of visual pigment performance imply that changes in opsin expression adjust visual sensitivities to the dominant photic regime. However, we also discovered that some species show a more stable opsin expression profile. Further, we found indication that seasonal changes, possibly linked to changes in the photic environment, might also trigger opsin expression. These findings suggest that plasticity in opsin gene expression of damselfish is highly species-specific, possibly due to ecological differences in visual tasks or, alternatively, under phylogenetic constraints. PMID:27262029

  15. Anatomical and Physiological Responses of Citrus Trees to Varying Boron Availability Are Dependent on Rootstock

    PubMed Central

    Mesquita, Geisa L.; Zambrosi, Fernando C. B.; Tanaka, Francisco A. O.; Boaretto, Rodrigo M.; Quaggio, José A.; Ribeiro, Rafael V.; Mattos, Dirceu

    2016-01-01

    In Citrus, water, nutrient transport and thereby fruit production, are influenced among other factors, by the interaction between rootstock and boron (B) nutrition. This study aimed to investigate how B affects the anatomical structure of roots and leaves as well as leaf gas exchange in sweet orange trees grafted on two contrasting rootstocks in response to B supply. Plants grafted on Swingle citrumelo or Sunki mandarin were grown in a nutrient solution of varying B concentration (deficient, adequate, and excessive). Those grafted on Swingle were more tolerant to both B deficiency and toxicity than those on Sunki, as revealed by higher shoot and root growth. In addition, plants grafted on Sunki exhibited more severe anatomical and physiological damages under B deficiency, showing thickening of xylem cell walls and impairments in whole-plant leaf-specific hydraulic conductance and leaf CO2 assimilation. Our data revealed that trees grafted on Swingle sustain better growth under low B availablitlity in the root medium and still respond positively to increased B levels by combining higher B absorption and root growth as well as better organization of xylem vessels. Taken together, those traits improved water and B transport to the plant canopy. Under B toxicity, Swingle rootstock would also favor plant growth by reducing anatomical and ultrastructural damage to leaf tissue and improving water transport compared with plants grafted on Sunki. From a practical point of view, our results highlight that B management in citrus orchards shall take into account rootstock varieties, of which the Swingle rootstock was characterized by its performance on regulating anatomical and ultrastructural damages, improving water transport and limiting negative impacts of B stress conditions on plant growth. PMID:26973670

  16. Iterative solutions for one-dimensional diffusion with time varying surface composition and composition-dependent diffusion coefficient

    NASA Technical Reports Server (NTRS)

    Chow, M.; Houska, C. R.

    1980-01-01

    Solutions are given for one-dimensional diffusion problems with a time varying surface composition and also a composition dependent diffusion coefficient. The most general solution does not require special mathematical functions to fit the variation in surface composition or D(C). In another solution, a series expansion may be used to fit the time dependent surface concentration. These solutions make use of iterative calculations that converge rapidly and are highly stable. Computer times are much shorter than that required for finite difference calculations and can efficiently make use of interactive graphics terminals. Existing gas carburization data were used to provide an illustration of an iterative approach with a time varying carbon composition at the free surface.

  17. The estimation of adaptive capacity of plants - halophytes, depending on the varying degrees of soil salinity

    NASA Astrophysics Data System (ADS)

    Kononova, Natalia; Pechurkin, Nickolay

    2012-07-01

    The high osmotic pressure of soil solution and toxic salts restrict the possible growth of the most plant species. However, the plant halophytes are able to grow on soil with a very high degree of salinity. The object of this study is a halophytic vegetation located near the coastal zone of the Lake Kurinka (the South Siberia, Khakasia). The total lake mineralization varies from 72 to 108 g / l. Type of salinity - sulfate-soda (the content of SO42-- 0,086%; HCO3-- 1,74%). It was observed that each plant communitie are located on soils with the different soil salinity degree (0.2 - 7.16 g / l). That is why, they have a different species richness and structural organization. It is shown that the average values of above-ground dry phytomass of plant communities (over five years of research) changed to a limited extent by changing the size of a projective cover of the dominant species. It is noted that in Suaeda plant community (dominant Suaeda corniculata) productivity ranges from 100 to 210 g/m2. It was calculated the possible accumulation of plant community phytomass (taking into account changes in soil salinity) so if in this territory grows only one species, that in a real community was a dominant. Estimated phytomass of the monodominant (Sueda corniculata) in 2004 and 2008 (143 and 188 g/m2 for years, respectively) was comparable with the real growth of the community (174 and 201 g/m2 for years, respectively). For Puccinellia tenuissima, that is subdominant in this plant communities, characterized by a small increasing of phytomass and in the likely absence of competition, the total phytomass this plant communities are amounted to 54 and 111 g/m2, respectively, over the years. This values are almost two times lower than the actual value. It is obvious that the existing conditions of salinity are sufficiently extreme to Puccinellia tenuissima and its monospecific community would be able to compete with the real dominant - Suaeda corniculata.

  18. Temperature Dependent Thermal Conductivity and Thermal Interface Resistance of Pentacene Thin Films with Varying Morphology.

    PubMed

    Epstein, Jillian; Ong, Wee-Liat; Bettinger, Christopher J; Malen, Jonathan A

    2016-07-27

    Temperature dependent thermal conductivities and thermal interface resistances of pentacene (Pn) thin films deposited on silicon substrates and self-assembled monolayer-modified [octadecyltrichlorosilane (OTS) and (3-aminopropyl)triethoxysilane (APTES)] silicon substrates were measured using frequency domain thermoreflectance. Atomic force microscopy images were used to derive an effective film thickness for thermal transport that accounts for surface roughness. Data taken over a temperature range of 77-300 K for various morphologies and film thicknesses show that the thermal conductivity increases with increasing Pn grain size. The sum of the substrate-Pn and Pn-gold thermal interface resistances was isolated from the intrinsic thermal resistance of the Pn films and found to be independent of surface chemistry. Corresponding Kapitza lengths of approximately 150 nm are larger than the physical thicknesses of typical Pn thin films and indicate that the interfaces play a dominant role in the total thermal resistance. This study has implications for increasing the performance and effective thermal management of small molecule electronic and energy conversion devices. PMID:27391107

  19. Passion and dependency in online shopping activities.

    PubMed

    Wang, Chih-Chien; Yang, Hui-Wen

    2007-04-01

    This study examines the influence of harmonious passion (HP) and obsessive passion (OP) to online shopping dependency. The results show that both HP and OP might lead to online shopping dependency and online shoppers with OP are more dependent on online shopping activities. In addition, this study also found out that HP and OP could be denoted as a sequence of different intensities of passion, where HP might be a necessity of OP. PMID:17474850

  20. Patients' perceptions of mortality risk for localized prostate cancer vary markedly depending on their treatment strategy.

    PubMed

    Kendel, Friederike; Helbig, Lukas; Neumann, Konrad; Herden, Jan; Stephan, Carsten; Schrader, Mark; Gaissmaier, Wolfgang

    2016-08-15

    Treatment choice for localized prostate cancer (PCa) is a controversial issue, and mortality risk is probably the most decisive factor in this regard. The study aimed to compare prostate-cancer-specific mortality risk estimates for different treatment options assigned by patients managed with active surveillance (AS), radical prostatectomy (RP) and patients who had discontinued AS (DAS). Patients initially managed with AS or RP (N = 370) were matched according to length of therapy. All patients completed mailed questionnaires assessing their mortality risk estimates (in %) and prostate-cancer-specific anxiety. Differences in risk estimates among the three treatment groups were analyzed using ANOVA, relationships of clinical and psychosocial variables with risk estimates using standard multiple regression. In all treatment groups, the prostate- cancer-specific mortality risk was overestimated. This applied whether it was the patient's own treatment or the alternative treatment option. RP patients assigned a mortality risk to AS that was almost three times higher than that assigned to RP (50.9 ± 25.0 vs. 17.8 ± 19.7, d = 1.48; p < 0.001). Anxiety was significantly associated with risk estimates for AS (p = 0.008) and RP (p = 0.001). Compared with clinical data that suggest that the prostate-cancer-specific mortality risk for AS is low and does not significantly differ from that for RP, patients strongly overestimated the mortality risk. This was most markedly so in RP patients, who drastically overestimated the benefits of RP compared to the risk of AS. This overestimation could increase overtreatment and should therefore be corrected by better patient education. PMID:27038059

  1. Classical-quantum arbitrarily varying wiretap channel: Ahlswede dichotomy, positivity, resources, super-activation

    NASA Astrophysics Data System (ADS)

    Boche, Holger; Cai, Minglai; Deppe, Christian; Nötzel, Janis

    2016-08-01

    We establish the Ahlswede dichotomy for arbitrarily varying classical-quantum wiretap channels, i.e., either the deterministic secrecy capacity of the channel is zero, or it equals its randomness-assisted secrecy capacity. We analyze the secrecy capacity of these channels when the sender and the receiver use various resources. It turns out that randomness, common randomness, and correlation as resources are very helpful for achieving a positive secrecy capacity. We prove the phenomenon "super-activation" for arbitrarily varying classical-quantum wiretap channels, i.e., two channels, both with zero deterministic secrecy capacity, if used together allow perfect secure transmission.

  2. Delay-dependent exponential passivity of uncertain cellular neural networks with discrete and distributed time-varying delays.

    PubMed

    Du, Yuanhua; Zhong, Shouming; Xu, Jia; Zhou, Nan

    2015-05-01

    This paper is concerned with the delay-dependent exponential passivity analysis issue for uncertain cellular neural networks with discrete and distributed time-varying delays. By decomposing the delay interval into multiple equidistant subintervals and multiple nonuniform subintervals, a suitable augmented Lyapunov-Krasovskii functionals are constructed on these intervals. A set of novel sufficient conditions are obtained to guarantee the exponential passivity analysis issue for the considered system. Finally, two numerical examples are provided to demonstrate the effectiveness of the proposed results. PMID:25702046

  3. Delay-dependent exponential stability for uncertain neutral stochastic neural networks with interval time-varying delay

    NASA Astrophysics Data System (ADS)

    Chen, Huabin; Zhao, Yang

    2015-10-01

    This paper is mainly concerned with the problem for the robustly exponential stability in mean square moment of uncertain neutral stochastic neural networks with interval time-varying delay. With an appropriate augmented Lyapunov-Krasovskii functional (LKF) formulated, the convex combination method is utilised to estimate the derivative of the LKF. Some new delay-dependent exponential stability criteria for such systems are obtained in terms of linear matrix inequalities, which involve fewer matrix variables and have less conservatism. Finally, two illustrative numerical examples are given to show the effectiveness of our obtained results.

  4. The Influence of Epoch Length on Physical Activity Patterns Varies by Child's Activity Level

    ERIC Educational Resources Information Center

    Nettlefold, Lindsay; Naylor, P. J.; Warburton, Darren E. R.; Bredin, Shannon S. D.; Race, Douglas; McKay, Heather A.

    2016-01-01

    Purpose: Patterns of physical activity (PA) and sedentary time, including volume of bouted activity, are important health indicators. However, the effect of accelerometer epoch length on measurement of these patterns and associations with health outcomes in children remain unknown. Method: We measured activity patterns in 308 children (52% girls,…

  5. Improved delay-dependent stability criteria for neutral-type systems with time-varying delays: a delayed decomposition approach

    NASA Astrophysics Data System (ADS)

    Liu, Pin-Lin

    2014-08-01

    This paper discusses the neutral system with time-varying delay. Firstly, by developing a delayed decomposition approach and introducing integral inequality approach, the information of the delayed plant states can be taken into full consideration, and new delay-dependent sufficient stability criteria are obtained in terms of linear matrix inequalities (LMIs). Then, based on the Lyapunov method, delay-dependent stability criteria are devised by taking the relationship between the terms in the Leibniz-Newton formula into account. The criteria are derived in terms of LMIs, which can be easily solved by using various convex optimization algorithms. Three illustrative numerical examples are given to show the less conservatism of our obtained results and the effectiveness of the proposed method.

  6. The uncertain role of diversity dependence in species diversification and the need to incorporate time-varying carrying capacities.

    PubMed

    Marshall, Charles R; Quental, Tiago B

    2016-04-01

    There is no agreement among palaeobiologists or biologists as to whether, or to what extent, there are limits on diversification and species numbers. Here, we posit that part of the disagreement stems from: (i) the lack of explicit criteria for defining the relevant species pools, which may be defined phylogenetically, ecologically or geographically; (ii) assumptions that must be made when extrapolating from population-level logistic growth to macro-evolutionary diversification; and (iii) too much emphasis being placed on fixed carrying capacities, rather than taking into account the opportunities for increased species richness on evolutionary timescales, for example, owing to increased biologically available energy, increased habitat complexity and the ability of many clades to better extract resources from the environment, or to broaden their resource base. Thus, we argue that a more effective way of assessing the evidence for and against the ideas of bound versus unbound diversification is through appropriate definition of the relevant species pools, and through explicit modelling of diversity-dependent diversification with time-varying carrying capacities. Here, we show that time-varying carrying capacities, either increases or decreases, can be accommodated through changing intrinsic diversification rates (diversity-independent effects), or changing the effects of crowding (diversity-dependent effects). PMID:26977059

  7. Effects of amphetamine on delay discounting in rats depend upon the manner in which delay is varied.

    PubMed

    Maguire, David R; Henson, Cedric; France, Charles P

    2014-12-01

    Whether stimulant drugs like amphetamine increase or decrease choice of larger delayed reinforcers over smaller immediately available reinforcers under delay discounting procedures can depend on several factors, including the order in which delay is presented. This study examined whether the order of delay presentation impacts drug effects on discounting in rats (n = 8) trained and tested under an ascending order, a descending order, as well as under a fixed delay condition. Responses on one lever delivered 1 food pellet immediately and responses on the other lever delivered 3 food pellets immediately or after a delay (4-32 s). In Experiment 1, the delay to the larger reinforcer varied within session and the order of delay presentation (ascending or descending) varied across conditions. In Experiment 2, the same delay value was presented in all blocks of the session (i.e., delay was fixed), and delay varied across conditions. Under the ascending order of delay, amphetamine (0.32-1.78 mg/kg) increased choice of the larger reinforcer in some rats and decreased choice in others. In the same rats responding under the descending and fixed delay conditions, amphetamine markedly decreased choice of the larger reinforcer even in the component associated with no delay. In some subjects, the effects of amphetamine differed depending on the manner in which delay was presented, indicating that drug-induced changes in performance were due, in part, to mechanisms other than altered sensitivity to reinforcer delay. These results also suggest that a history of responding under both orders of delay presentation can modulate drug effects. This article is part of the Special Issue entitled 'CNS Stimulants'. PMID:24780379

  8. Activity Therapy Services and Chemical Dependency Rehabilitation.

    ERIC Educational Resources Information Center

    James, Mark R.; Townsley, Robin K.

    1989-01-01

    Discusses how music, occupational, and recreation therapies can contribute to comprehensive treatment programs for chemical dependency. Sees prime contribution of activity therapy as lying in nature of experiential education, applying insight gained in counseling sessions and discussion groups to practical real-life situations. (Author/NB)

  9. Photocatalytic and antibacterial activity of cadmium sulphide/zinc oxide nanocomposite with varied morphology.

    PubMed

    Jana, T K; Maji, S K; Pal, A; Maiti, R P; Dolai, T K; Chatterjee, K

    2016-10-15

    Nanocomposites with multifunctional application prospects have already dragged accelerating interests of materials scientists. Here we present CdS/ZnO nanocomposites with different morphology engineering the precursor molar ratio in a facile wet chemical synthesis route. The materials were structurally and morphologically characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray analysis (EDX) and high-resolution transmission electron microscopy (HRTEM). The growth mechanism of the composite structure with varying molar ratio is delineated with oriented attachment self assemble techniques. Photocatalytic activity of CdS/ZnO nanocomposites with varying morphology were explored for the degradation of rhodamine B (RhB) dye in presence of visible light irradiation and the results reveal that the best catalytic performance arises in CdS/ZnO composite with 1: 1 ratio. The antibacterial efficiency of all nanocomposites were investigated on Escherichia coli, Staphylococcus aureus and Klebsiella pneumonia without light irradiation. Antibacterial activity of CdS/ZnO nanocomposites were studied using the bacteriological test-well diffusion agar method and results showed significant antibacterial activity in CdS/ZnO composite with 1:3 ratio. Overall, CdS/ZnO nanocomposites excel in different potential applications, such as visible light photocatalysis and antimicrobial activity with their tuneable structure. PMID:27399614

  10. Spatial Patterns of Persistent Neural Activity Vary with the Behavioral Context of Short-Term Memory

    PubMed Central

    Daie, Kayvon

    2015-01-01

    Summary A short-term memory can be evoked by different inputs and control separate targets in different behavioral contexts. To address the circuit mechanisms underlying context-dependent memory function, we determined through optical imaging how memory is encoded at the whole-network level in two behavioral settings. Persistent neural activity maintaining a memory of desired eye position was imaged throughout the oculomotor integrator after saccadic or optokinetic stimulation. While eye position was encoded by the amplitude of network activity, the spatial patterns of firing were context-dependent: cells located caudally generally were most persistent following saccadic input, whereas cells located rostrally were most persistent following optokinetic input. To explain these data, we computationally identified four independent modes of network activity and found these were differentially accessed by saccadic and optokinetic inputs. These results show how a circuit can simultaneously encode memory value and behavioral context, respectively, in its amplitude and spatial pattern of persistent firing. PMID:25661184

  11. Global robust dissipativity of interval recurrent neural networks with time-varying delay and discontinuous activations.

    PubMed

    Duan, Lian; Huang, Lihong; Guo, Zhenyuan

    2016-07-01

    In this paper, the problems of robust dissipativity and robust exponential dissipativity are discussed for a class of recurrent neural networks with time-varying delay and discontinuous activations. We extend an invariance principle for the study of the dissipativity problem of delay systems to the discontinuous case. Based on the developed theory, some novel criteria for checking the global robust dissipativity and global robust exponential dissipativity of the addressed neural network model are established by constructing appropriate Lyapunov functionals and employing the theory of Filippov systems and matrix inequality techniques. The effectiveness of the theoretical results is shown by two examples with numerical simulations. PMID:27475061

  12. Global robust dissipativity of interval recurrent neural networks with time-varying delay and discontinuous activations

    NASA Astrophysics Data System (ADS)

    Duan, Lian; Huang, Lihong; Guo, Zhenyuan

    2016-07-01

    In this paper, the problems of robust dissipativity and robust exponential dissipativity are discussed for a class of recurrent neural networks with time-varying delay and discontinuous activations. We extend an invariance principle for the study of the dissipativity problem of delay systems to the discontinuous case. Based on the developed theory, some novel criteria for checking the global robust dissipativity and global robust exponential dissipativity of the addressed neural network model are established by constructing appropriate Lyapunov functionals and employing the theory of Filippov systems and matrix inequality techniques. The effectiveness of the theoretical results is shown by two examples with numerical simulations.

  13. Thioredoxin f1 and NADPH-Dependent Thioredoxin Reductase C Have Overlapping Functions in Regulating Photosynthetic Metabolism and Plant Growth in Response to Varying Light Conditions1[OPEN

    PubMed Central

    Thormählen, Ina; Meitzel, Tobias; Groysman, Julia; Öchsner, Alexandra Bianca; von Roepenack-Lahaye, Edda; Naranjo, Belén; Cejudo, Francisco J.; Geigenberger, Peter

    2015-01-01

    Two different thiol redox systems exist in plant chloroplasts, the ferredoxin-thioredoxin (Trx) system, which depends on ferredoxin reduced by the photosynthetic electron transport chain and, thus, on light, and the NADPH-dependent Trx reductase C (NTRC) system, which relies on NADPH and thus may be linked to sugar metabolism in the dark. Previous studies suggested, therefore, that the two different systems may have different functions in plants. We now report that there is a previously unrecognized functional redundancy of Trx f1 and NTRC in regulating photosynthetic metabolism and growth. In Arabidopsis (Arabidopsis thaliana) mutants, combined, but not single, deficiencies of Trx f1 and NTRC led to severe growth inhibition and perturbed light acclimation, accompanied by strong impairments of Calvin-Benson cycle activity and starch accumulation. Light activation of key enzymes of these pathways, fructose-1,6-bisphosphatase and ADP-glucose pyrophosphorylase, was almost completely abolished. The subsequent increase in NADPH-NADP+ and ATP-ADP ratios led to increased nitrogen assimilation, NADP-malate dehydrogenase activation, and light vulnerability of photosystem I core proteins. In an additional approach, reporter studies show that Trx f1 and NTRC proteins are both colocalized in the same chloroplast substructure. Results provide genetic evidence that light- and NADPH-dependent thiol redox systems interact at the level of Trx f1 and NTRC to coordinately participate in the regulation of the Calvin-Benson cycle, starch metabolism, and growth in response to varying light conditions. PMID:26338951

  14. Thioredoxin f1 and NADPH-Dependent Thioredoxin Reductase C Have Overlapping Functions in Regulating Photosynthetic Metabolism and Plant Growth in Response to Varying Light Conditions.

    PubMed

    Thormählen, Ina; Meitzel, Tobias; Groysman, Julia; Öchsner, Alexandra Bianca; von Roepenack-Lahaye, Edda; Naranjo, Belén; Cejudo, Francisco J; Geigenberger, Peter

    2015-11-01

    Two different thiol redox systems exist in plant chloroplasts, the ferredoxin-thioredoxin (Trx) system, which depends on ferredoxin reduced by the photosynthetic electron transport chain and, thus, on light, and the NADPH-dependent Trx reductase C (NTRC) system, which relies on NADPH and thus may be linked to sugar metabolism in the dark. Previous studies suggested, therefore, that the two different systems may have different functions in plants. We now report that there is a previously unrecognized functional redundancy of Trx f1 and NTRC in regulating photosynthetic metabolism and growth. In Arabidopsis (Arabidopsis thaliana) mutants, combined, but not single, deficiencies of Trx f1 and NTRC led to severe growth inhibition and perturbed light acclimation, accompanied by strong impairments of Calvin-Benson cycle activity and starch accumulation. Light activation of key enzymes of these pathways, fructose-1,6-bisphosphatase and ADP-glucose pyrophosphorylase, was almost completely abolished. The subsequent increase in NADPH-NADP(+) and ATP-ADP ratios led to increased nitrogen assimilation, NADP-malate dehydrogenase activation, and light vulnerability of photosystem I core proteins. In an additional approach, reporter studies show that Trx f1 and NTRC proteins are both colocalized in the same chloroplast substructure. Results provide genetic evidence that light- and NADPH-dependent thiol redox systems interact at the level of Trx f1 and NTRC to coordinately participate in the regulation of the Calvin-Benson cycle, starch metabolism, and growth in response to varying light conditions. PMID:26338951

  15. Identification of human activities in a thermal system with noise varied in temporal frequency

    NASA Astrophysics Data System (ADS)

    Brooks, Jason; Jacobs, Eddie; Smith, Forrest

    2011-05-01

    The ability of observers to identify human activities in noise is expected to differ from performance with static targets in noise due to the unmasking that is provided by target motion. At a minimum, the probability of identification should increase when the temporal bandwidth of the noise is less than that of the system. Results from a human activities identification experiment are presented in this paper, along with results from a moving character experiment that is intended to provide better understanding of basic motion in noise with varied temporal bandwidth. These results along with further experiments and analysis will eventually be used to improve performance predictions derived from the Targeting Task Performance (TTP) metric.

  16. The effect of Cyclin-dependent kinase 5 on voltage-dependent calcium channels in PC12 cells varies according to channel type and cell differentiation state.

    PubMed

    Furusawa, Kotaro; Asada, Akiko; Saito, Taro; Hisanaga, Shin-ichi

    2014-08-01

    Cyclin-dependent kinase 5 (Cdk5) is a Ser/Thr kinase that plays an important role in the release of neurotransmitter from pre-synaptic terminals triggered by Ca(2+) influx into the pre-synaptic cytoplasm through voltage-dependent Ca(2+) channels (VDCCs). It is reported that Cdk5 regulates L-, P/Q-, or N-type VDCC, but there is conflicting data as to the effect of Cdk5 on VDCC activity. To clarify the mechanisms involved, we examined the role of Cdk5 in regulating the Ca(2+) -channel property of VDCCs, using PC12 cells expressing endogenous, functional L-, P/Q-, and N-type VDCCs. The Ca(2+) influx, induced by membrane depolarization with high K(+) , was monitored with a fluorescent Ca(2+) indicator protein in both undifferentiated and nerve growth factor (NGF)-differentiated PC12 cells. Overall, Ca(2+) influx was increased by expression of Cdk5-p35 in undifferentiated PC12 cells but suppressed in differentiated PC12 cells. Moreover, we found that different VDCCs are distinctly regulated by Cdk5-p35 depending on the differentiation states of PC12 cells. These results indicate that Cdk5-p35 regulates L-, P/Q-, or N-type VDCCs in a cellular context-dependent manner. Calcium (Ca(2+) ) influx through voltage-dependent Ca(2+) channels (VDCCs) triggers neurotransmitter release from pre-synaptic terminal of neurons. The channel activity of VDCCs is regulated by Cdk5-p35, a neuronal Ser/Thr kinase. However, there have been debates about the regulation of VDCCs by Cdk5. Using PC12 cells, we show that Cdk5-p35 regulates VDCCs in a type (L, P/Q, and N) and differentiation-dependent manner. NGF = nerve growth factor. PMID:24766160

  17. How does clear-sky terrestrial irradiance vary with solar activity?

    NASA Astrophysics Data System (ADS)

    Feulner, Georg

    2013-04-01

    I investigate recent claims for a strong variation of clear-sky terrestrial solar irradiance with solar activity (on the level of O(1%) over the 11-year cycle) derived from ground-based observations of the Sun. As it turns out, these erroneous results arise because important effects like the dimming by volcanic aerosols and long-term changes in atmospheric transmission independent of solar activity have to be corrected for. After taking these into account, clear-sky terrestrial solar irradiance can be shown to vary by O(0.1%) as expected from satellite-based measurements of the changes in Total Solar Irradiance over the solar cycle. On the one hand this example illustrates the usefulness of ground-based monitoring of solar irradiance data, but on the other hand it highlights the difficulties which can hamper an unbiased analysis of such datasets. References Feulner, G., 2011: The Smithsonian solar constant data revisited: no evidence for a strong effect of solar activity in ground-based insolation data, Atmos. Chem. Phys., 11, 3291-3301, doi:10.5194/acp-11-3291-2011 Feulner, G., 2013: On the relation between solar activity and clear-sky terrestrial irradiance, Solar Phys., 282, 615-627, doi:10.1007/s11207-012-0129-z

  18. Antioxidant activities and polyphenol content of Morus alba leaf extracts collected from varying regions

    PubMed Central

    KIM, DONG-SEON; KANG, YOUNG MIN; JIN, WEN YI; SUNG, YOON-YOUNG; CHOI, GOYA; KIM, HO KYOUNG

    2014-01-01

    Morus alba leaf (MAL), also known as Mori folium when used as a herbal medicine, has traditionally been used in Chinese medicine to treat diabetes, protect the liver and lower blood pressure. In the present study, MAL was collected from various regions in Korea and the antioxidant activity, total polyphenol contents and main flavonoid contents was investigated. MAL were collected from various areas in Korea and extracted with methanol. The total polyphenol contents were evaluated based on the Folin-Ciocalteu method using a spectrophotometer. The antioxidant activities were determined by a 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay method. The identification and quantification of three main polyphenol constituents was performed using high-performance liquid chromatography/diode array detection analysis. The total polyphenol contents of the MAL extracts varied between 23.2 and 55.4 mg gallic acid equivalent/g. The radical scavenging activity (SC50) of the MAL extracts ranged between 584 and 139 μg/ml. Three flavonol compounds (rutin, isoquercitrin and astragalin) were identified as main polyphenol constituents. These contents varied from 0.68–12.7, 0.69–9.86 and 0.05–3.55 mg/g, respectively. The average of the total was 9.52 mg/g, which was similar to that of commercial MAL extracts (10.58 mg/g). Among the three flavonol compounds, isoquercitrin showed the highest content (5.68 mg/g) followed by rutin (3.1 mg/g) and astragalin (2.4 mg/g). In the present study, the radical scavenging activity, polyphenol content and flavonol content of MAL were significantly different according to growing area. These three flavonol compounds were identified as main constituents of MAL in this study, and are known to have various biological activities, as well as strong antioxidant activities. Therefore, the sum of these three flavonol compounds was indicated as a good marker for the quality control of Mori folium. PMID:25054010

  19. An MHD simulation model of time-dependent global solar corona with temporally varying solar-surface magnetic field maps

    NASA Astrophysics Data System (ADS)

    Hayashi, K.

    2013-11-01

    We present a model of a time-dependent three-dimensional magnetohydrodynamics simulation of the sub-Alfvenic solar corona and super-Alfvenic solar wind with temporally varying solar-surface boundary magnetic field data. To (i) accommodate observational data with a somewhat arbitrarily evolving solar photospheric magnetic field as the boundary value and (ii) keep the divergence-free condition, we developed a boundary model, here named Confined Differential Potential Field model, that calculates the horizontal components of the magnetic field, from changes in the vertical component, as a potential field confined in a thin shell. The projected normal characteristic method robustly simulates the solar corona and solar wind, in response to the temporal variation of the boundary Br. We conduct test MHD simulations for two periods, from Carrington Rotation number 2009 to 2010 and from Carrington Rotation 2074 to 2075 at solar maximum and minimum of Cycle 23, respectively. We obtained several coronal features that a fixed boundary condition cannot yield, such as twisted magnetic field lines at the lower corona and the transition from an open-field coronal hole to a closed-field streamer. We also obtained slight improvements of the interplanetary magnetic field, including the latitudinal component, at Earth.

  20. Foraging success in a wild species of bird varies depending on which eye is used for anti-predator vigilance.

    PubMed

    Beauchamp, Guy

    2013-01-01

    Brain lateralisation in animals with laterally placed eyes often leads to preferential eye use for ecologically relevant tasks such as monitoring predators and companions. Few studies of preferential eye use have been conducted in the wild and it is not clear if such preferences in the wild are widespread, how individuals can benefit from them, and which ecological factors influence their evolution. In a wild species of bird the extent to which foraging success varied depending on which eye is used during concomitant anti-predator vigilance was examined. When foraging in open mudflats, semipalmated sandpipers (Calidris pusilla) are frequently exposed to predation attempts by falcons (Falco spp) that originate from the tree cover bordering mudflats. Sandpipers spread along the receding tideline and can face the riskier side of their habitat primarily with the left or the right eye as they forage. If foraging is mostly incompatible with vigilance, the rate at which prey items are collected should decrease when birds use their less-preferred eye to scan cover. If foraging and vigilance can be carried out simultaneously, time spent foraging should not be affected but the efficiency with which their burrowing amphipod prey are located may be reduced, thus leading to decreased capture rate. Birds facing the riskier side of the habitat with their right eye captured significantly more prey than those scanning the same side with their left eye. Specialised eye use in sandpipers may allow individuals to perform simultaneous tasks, such as foraging and vigilance, more efficiently. PMID:22397500

  1. Extracellular domain dependence of PTPα transforming activity

    PubMed Central

    Zheng, Xinmin; Holsinger, Leslie J.; Shalloway, David

    2016-01-01

    Two isoforms of the transmembrane protein tyrosine phosphatase PTPα, which differ by nine amino acids in their extracellular regions, are expressed in a tissue-specific manner. Over-expression of the shorter isoform transforms rodent cells, and it has previously been reasonable to assume that this was a direct consequence of its dephosphorylation and activation of Src. Transformation by the longer wild-type isoform has not previously been studied. We tested the activities of both isoforms in NIH3T3 cells and found that, while both dephosphorylated and activated Src similarly, only the shorter isoform induced focus formation or anchorage-independent growth. Differences in phosphorylation of PTPα at its known regulatory sites, Grb2 binding to PTPα, phosphorylation level of focal adhesion kinase by PTPα, or overall localization were excluded as possible explanations for the differences in transforming activities. The results suggest that transformation by PTPα involves at least one function other than, or in addition to, its activation of Src and that this depends on PTPα’s extracellular domain. Previous studies have suggested that PTPα might be a useful target in breast and colon cancer therapy, and the results presented here suggest that it may be advantageous to develop isoform-specific therapeutic reagents. PMID:20545765

  2. Individual differences in attentional bias associated with cocaine dependence are related to varying engagement of neural processing networks.

    PubMed

    Kilts, Clint D; Kennedy, Ashley; Elton, Amanda L; Tripathi, Shanti Prakash; Young, Jonathan; Cisler, Josh M; James, G Andrew

    2014-04-01

    Cocaine and other drug dependencies are associated with significant attentional bias for drug use stimuli that represents a candidate cognitive marker of drug dependence and treatment outcomes. We explored, using fMRI, the role of discrete neural processing networks in the representation of individual differences in the drug attentional bias effect associated with cocaine dependence (AB-coc) using a word counting Stroop task with personalized cocaine use stimuli (cocStroop). The cocStroop behavioral and neural responses were further compared with those associated with a negative emotional word Stroop task (eStroop) and a neutral word counting Stroop task (cStroop). Brain-behavior correlations were explored using both network-level correlation analysis following independent component analysis (ICA) and voxel-level, brain-wide univariate correlation analysis. Variation in the attentional bias effect for cocaine use stimuli among cocaine-dependent men and women was related to the recruitment of two separate neural processing networks related to stimulus attention and salience attribution (inferior frontal-parietal-ventral insula), and the processing of the negative affective properties of cocaine stimuli (frontal-temporal-cingulate). Recruitment of a sensory-motor-dorsal insula network was negatively correlated with AB-coc and suggested a regulatory role related to the sensorimotor processing of cocaine stimuli. The attentional bias effect for cocaine stimuli and for negative affective word stimuli were significantly correlated across individuals, and both were correlated with the activity of the frontal-temporal-cingulate network. Functional connectivity for a single prefrontal-striatal-occipital network correlated with variation in general cognitive control (cStroop) that was unrelated to behavioral or neural network correlates of cocStroop- or eStroop-related attentional bias. A brain-wide mass univariate analysis demonstrated the significant correlation of

  3. Individual Differences in Attentional Bias Associated with Cocaine Dependence Are Related to Varying Engagement of Neural Processing Networks

    PubMed Central

    Kilts, Clint D; Kennedy, Ashley; Elton, Amanda L; Tripathi, Shanti Prakash; Young, Jonathan; Cisler, Josh M; James, G Andrew

    2014-01-01

    Cocaine and other drug dependencies are associated with significant attentional bias for drug use stimuli that represents a candidate cognitive marker of drug dependence and treatment outcomes. We explored, using fMRI, the role of discrete neural processing networks in the representation of individual differences in the drug attentional bias effect associated with cocaine dependence (AB-coc) using a word counting Stroop task with personalized cocaine use stimuli (cocStroop). The cocStroop behavioral and neural responses were further compared with those associated with a negative emotional word Stroop task (eStroop) and a neutral word counting Stroop task (cStroop). Brain–behavior correlations were explored using both network-level correlation analysis following independent component analysis (ICA) and voxel-level, brain-wide univariate correlation analysis. Variation in the attentional bias effect for cocaine use stimuli among cocaine-dependent men and women was related to the recruitment of two separate neural processing networks related to stimulus attention and salience attribution (inferior frontal–parietal–ventral insula), and the processing of the negative affective properties of cocaine stimuli (frontal–temporal–cingulate). Recruitment of a sensory–motor–dorsal insula network was negatively correlated with AB-coc and suggested a regulatory role related to the sensorimotor processing of cocaine stimuli. The attentional bias effect for cocaine stimuli and for negative affective word stimuli were significantly correlated across individuals, and both were correlated with the activity of the frontal–temporal–cingulate network. Functional connectivity for a single prefrontal–striatal–occipital network correlated with variation in general cognitive control (cStroop) that was unrelated to behavioral or neural network correlates of cocStroop- or eStroop-related attentional bias. A brain-wide mass univariate analysis demonstrated the significant

  4. The Density of Knobs on Plasmodium falciparum-Infected Erythrocytes Depends on Developmental Age and Varies among Isolates

    PubMed Central

    Quadt, Katharina A.; Barfod, Lea; Andersen, Daniel; Bruun, Jonas; Gyan, Ben; Hassenkam, Tue; Ofori, Michael F.; Hviid, Lars

    2012-01-01

    Background The virulence of Plasmodium falciparum malaria is related to the parasite’s ability to evade host immunity through clonal antigenic variation and tissue-specific adhesion of infected erythrocytes (IEs). The P. falciparum erythrocyte membrane protein 1 (PfEMP1) family expressed on dome-shaped protrusions called knobs on the IE surface is central to both. Differences in receptor specificity and affinity of expressed PfEMP1 are important for IE adhesiveness, but it is not known whether differences in the number and size of the knobs on which the PfEMP1 proteins are expressed also play a role. Therefore, the aim of this study was to provide detailed information on isolate- and time-dependent differences in knob size and density. Methodology/Principal Findings We used atomic force microscopy to characterize knobs on the surface of P. falciparum-infected erythrocytes. Fourteen ex vivo isolates from Ghanaian children with malaria and 10 P. falciparum isolates selected in vitro for expression of a particular PfEMP1 protein (VAR2CSA) were examined. Knob density increased from ∼20 h to ∼35 h post-invasion, with significant variation among isolates. The knob density ex vivo, which was about five-fold higher than following long-term in vitro culture, started to decline within a few months of culture. Although knob diameter and height varied among isolates, we did not observe significant time-dependent variation in these dimensions. Conclusions/Significance The density of knobs on the P. falciparum-IE surface depends on time since invasion, but is also determined by the infecting isolate in a time-independent manner. This is the first study to quantitatively evaluate knob densities and dimensions on different P. falciparum isolates, to examine ex vivo isolates from humans, and to compare ex vivo and long-term in vitro-cultured isolates. Our findings contribute to the understanding of the interaction between P. falciparum parasites and the infected host. PMID

  5. Structure dependence of biological activities for primate cathelicidins.

    PubMed

    Tomasinsig, Linda; Morgera, Francesca; Antcheva, Nikolinka; Pacor, Sabrina; Skerlavaj, Barbara; Zanetti, Margherita; Tossi, Alessandro

    2009-09-01

    We have analysed the effects of variations in orang-utan (ppy), rhesus macaque (mmu) and leaf eater (pob) monkey orthologues of the human cathelicidin LL-37, on a range of relevant biological activities. These host defence peptides range in cationicity from +4 to +10, and while the more cationic pob and mmuRL-37 are in a monomeric and unstructured form in bulk solution (F-form), the human and ppyLL-37 are in an aggregated/helical form (A-form). The in vitro antibacterial activity depended strongly on both the structural form and the charge. F-form peptides were more potent against Gram-positive and -negative bacteria and less salt, medium or serum sensitive than A-form ones. CD studies suggested that A- and F-form peptides interact with LPS in different manners, but the ability to detoxify it did not correlate directly with either the charge or structure. Toxicity towards eukaryotic cells also showed a varied dependence on the peptides' physical characteristics. Haemolytic activity was similar for all the tested peptides while other cytotoxicity assays revealed the highly cationic, F-form pobRL-37 as the most toxic, followed by the A-form human LL-37. As shown with the human peptide, toxicity depended markedly on the nature and metabolic state of the target cell. Our results suggest that different evolutionary trajectories for each orthologue lead to distinct sets of physical characteristics, which significantly differentiates their biological activities. PMID:19472166

  6. Measurement of neutron spectra in varied environments by the foil-activation method with arbitrary trials

    SciTech Connect

    Kelly, J.G.; Vehar, D.W.

    1987-12-01

    Neutron spectra have been measured by the foil-activation method in 13 different environments in and around the Sandia Pulsed Reactor, the White Sands Missile Range Fast Burst Reactor, and the Sandia Annular Core Research Reactor. The spectra were obtained by using the SANDII code in a manner that was not dependent on the initial trial. This altered technique is better suited for the determination of spectra in environments that are difficult to predict by calculation, and it tends to reveal features that may be biased out by the use of standard trial-dependent methods. For some of the configurations, studies have also been made of how well the solution is determined in each energy region. The experimental methods and the techniques used in the analyses are thoroughly explained. 34 refs., 51 figs., 40 tabs.

  7. Changes in herbivore control in arable fields by detrital subsidies depend on predator species and vary in space

    PubMed Central

    von Berg, Karsten; Thies, Carsten; Tscharntke, Teja

    2010-01-01

    Prey from the decomposer subsystem may help sustain predator populations in arable fields. Adding organic residues to agricultural systems may therefore enhance pest control. We investigated whether resource addition (maize mulch) strengthens aboveground trophic cascades in winter wheat fields. Evaluating the flux of the maize-borne carbon into the food web after 9 months via stable isotope analysis allowed differentiating between prey in predator diets originating from the above- and belowground subsystems. Furthermore, we recorded aphid populations in predator-reduced and control plots of no-mulch and mulch addition treatments. All analyzed soil dwelling species incorporated maize-borne carbon. In contrast, only 2 out of 13 aboveground predator species incorporated maize carbon, suggesting that these 2 predators forage on prey from the above- and belowground systems. Supporting this conclusion, densities of these two predator species were increased in the mulch addition fields. Nitrogen isotope signatures suggested that these generalist predators in part fed on Collembola thereby benefiting indirectly from detrital resources. Increased density of these two predator species was associated by increased aphid control but the identity of predators responsible for aphid control varied in space. One of the three wheat fields studied even lacked aphid control despite of mulch-mediated increased density of generalist predators. The results suggest that detrital subsidies quickly enter belowground food webs but only a few aboveground predator species include prey out of the decomposer system into their diet. Variation in the identity of predator species benefiting from detrital resources between sites suggest that, depending on locality, different predator species are subsidised by prey out of the decomposer system and that these predators contribute to aphid control. Therefore, by engineering the decomposer subsystem via detrital subsidies, biological control by

  8. Growth and activity of black holes in galaxy mergers with varying mass ratios

    NASA Astrophysics Data System (ADS)

    Capelo, Pedro R.; Volonteri, Marta; Dotti, Massimo; Bellovary, Jillian M.; Mayer, Lucio; Governato, Fabio

    2015-03-01

    We study supermassive black holes (BHs) in merging galaxies, using a suite of hydrodynamical simulations with very high spatial (˜10 pc) and temporal (˜1 Myr) resolution, where we vary the initial mass ratio, the orbital configuration, and the gas fraction. (i) We address the question of when and why, during a merger, increased BH accretion occurs, quantifying gas inflows and BH accretion rates. (ii) We also quantify the relative effectiveness in inducing active galactic nuclei activity of merger-related versus secular-related causes, by studying different stages of the encounter: the stochastic (or early) stage, the (proper) merger stage, and the remnant (or late) stage. (iii) We assess which galaxy mergers preferentially enhance BH accretion, finding that the initial mass ratio is the most important factor. (iv) We study the evolution of the BH masses, finding that the BH mass contrast tends to decrease in minor mergers and to increase in major mergers. This effect hints at the existence of a preferential range of mass ratios for BHs in the final pairing stages. (v) In both merging and dynamically quiescent galaxies, the gas accreted by the BH is not necessarily the gas with low angular momentum, but the gas that loses angular momentum.

  9. Size Dependent Antioxidant Activity of Polypyrrole Nanofibers

    NASA Astrophysics Data System (ADS)

    Kumar, A.; Banerjee, Somik

    2011-07-01

    Polypyrrole (PPy) nanofibers have been synthesized employing surfactant assisted miceller polymerization by varying the surfactant concentration. The synthesized nanofibers have been characterized using TEM, XRD, FTIR and UV-Visible spectroscopy. TEM reveals that the diameter of the PPy nanowires decreases with the increase in surfactant concentration. X-ray spectra shows an amorphous peak centered around 2θ = 24.6° which is attributed to the π-π interaction of the partial PPy chains similar to that of aromatic groups. The domain length of the samples determined using the single-line approximation technique, decreases with decreasing diameter whereas the strain in the material increases, which have been attributed to the reduction of size with increase in the surfactant concentration as revealed by TEM. The vibrational bands observed from the FTIR spectra confirm the formation of surfactant free PPy nanowires. UV-Visible spectra shows a blue-shift in the π-π* absorption peak. Antioxidant activity of the samples has been determined using the DPPH free radical method. It has been observed that enhancement in free radical scavenging coincides with the decreasing diameter of the PPy nanofibers which has been associated with the increase in the surface reaction sites with the reduction of size.

  10. Morphology of 557.7 nm dayglow emission under varying solar activity conditions

    NASA Astrophysics Data System (ADS)

    Krishna, M. V. Sunil; Singh, Vir

    The atomic oxygen emission at 557.7 nm is the most widely observed airglow feature in the upper mesosphere and lower thermospheric regions. The approximation of solar irradiance fluxes is very crucial in the modeling of this emission. The recently introduced Solar2000 EUV flux model is a suitable candidate to provide the solar EUV flux for any level of solar activity on any given day. The Solar2000 EUV flux model has not been tested for its applicability in the airglow modeling studies. In the present study a comprehensive model has been developed to study the 557.7 nm dayglow emission using Solar2000 EUV flux model. This study presents the model results of diurnal and yearly variations of 557.7 nm dayglow emission under equinox conditions. The effect of varying solar activity on this emission is studied for a period of five years (2001-2005) at a fixed date of April 3. This date is chosen due to the fact of large variations in the solar activity during the period of five years. The volume emission rates obtained from the model in the upper mesospheric region are found higher than the observed results. This discrepancy is due to the extremely high values of solar EUV flux generated by the Solar2000 EUV flux model at 102.5 and 103.7 nm wavelengths. The model is found in good agreement with the measurements in the thermospheric region. The morphology is presented as a function of F10.7 solar index for five years (2001 -2005) equator and 45° N at a fixed longitude.

  11. Individual differences in oscillatory brain activity in response to varying attentional demands during a word recall and oculomotor dual task

    PubMed Central

    Kwon, Gusang; Lim, Sanghyun; Kim, Min-Young; Kwon, Hyukchan; Lee, Yong-Ho; Kim, Kiwoong; Lee, Eun-Ju; Suh, Minah

    2015-01-01

    Every day, we face situations that involve multi-tasking. How our brain utilizes cortical resources during multi-tasking is one of many interesting research topics. In this study, we tested whether a dual-task can be differentiated in the neural and behavioral responses of healthy subjects with varying degree of working memory capacity (WMC). We combined word recall and oculomotor tasks because they incorporate common neural networks including the fronto-parietal (FP) network. Three different types of oculomotor tasks (eye fixation, Fix-EM; predictive and random smooth pursuit eye movement, P-SPEM and R-SPEM) were combined with two memory load levels (low-load: five words, high-load: 10 words) for a word recall task. Each of those dual-task combinations was supposed to create varying cognitive loads on the FP network. We hypothesize that each dual-task requires different cognitive strategies for allocating the brain’s limited cortical resources and affects brain oscillation of the FP network. In addition, we hypothesized that groups with different WMC will show differential neural and behavioral responses. We measured oscillatory brain activity with simultaneous MEG and EEG recordings and behavioral performance by word recall. Prominent frontal midline (FM) theta (4–6 Hz) synchronization emerged in the EEG of the high-WMC group experiencing R-SPEM with high-load conditions during the early phase of the word maintenance period. Conversely, significant parietal upper alpha (10–12 Hz) desynchronization was observed in the EEG and MEG of the low-WMC group experiencing P-SPEM under high-load conditions during the same period. Different brain oscillatory patterns seem to depend on each individual’s WMC and varying attentional demands from different dual-task combinations. These findings suggest that specific brain oscillations may reflect different strategies for allocating cortical resources during combined word recall and oculomotor dual-tasks. PMID:26175681

  12. Cytoplasmic streaming in Drosophila oocytes varies with kinesin activity and correlates with the microtubule cytoskeleton architecture

    PubMed Central

    Ganguly, Sujoy; Williams, Lucy S.; Palacios, Isabel M.; Goldstein, Raymond E.

    2012-01-01

    Cells can localize molecules asymmetrically through the combined action of cytoplasmic streaming, which circulates their fluid contents, and specific anchoring mechanisms. Streaming also contributes to the distribution of nutrients and organelles such as chloroplasts in plants, the asymmetric position of the meiotic spindle in mammalian embryos, and the developmental potential of the zygote, yet little is known quantitatively about the relationship between streaming and the motor activity which drives it. Here we use Particle Image Velocimetry to quantify the statistical properties of Kinesin-dependent streaming during mid-oogenesis in Drosophila. We find that streaming can be used to detect subtle changes in Kinesin activity and that the flows reflect the architecture of the microtubule cytoskeleton. Furthermore, based on characterization of the rheology of the cytoplasm in vivo, we establish estimates of the number of Kinesins required to drive the observed streaming. Using this in vivo data as the basis of a model for transport, we suggest that the disordered character of transport at mid-oogenesis, as revealed by streaming, is an important component of the localization dynamics of the body plan determinant oskar mRNA. PMID:22949706

  13. Prolyl Hydroxylase PHD3 Activates Oxygen-dependent Protein Aggregation

    PubMed Central

    Rantanen, Krista; Pursiheimo, Juha; Högel, Heidi; Himanen, Virpi; Metzen, Eric

    2008-01-01

    The HIF prolyl hydroxylases (PHDs/EGLNs) are central regulators of the molecular responses to oxygen availability. One isoform, PHD3, is expressed in response to hypoxia and causes apoptosis in oxygenated conditions in neural cells. Here we show that PHD3 forms subcellular aggregates in an oxygen-dependent manner. The aggregation of PHD3 was seen under normoxia and was strongly reduced under hypoxia or by the inactivation of the PHD3 hydroxylase activity. The PHD3 aggregates were dependent on microtubular integrity and contained components of the 26S proteasome, chaperones, and ubiquitin, thus demonstrating features that are characteristic for aggresome-like structures. Forced expression of the active PHD3 induced the aggregation of proteasomal components and activated apoptosis under normoxia in HeLa cells. The apoptosis was seen in cells prone to PHD3 aggregation and the PHD3 aggregation preceded apoptosis. The data demonstrates the cellular oxygen sensor PHD3 as a regulator of protein aggregation in response to varying oxygen availability. PMID:18337469

  14. Active dynamics of colloidal particles in time-varying laser speckle patterns

    PubMed Central

    Bianchi, Silvio; Pruner, Riccardo; Vizsnyiczai, Gaszton; Maggi, Claudio; Di Leonardo, Roberto

    2016-01-01

    Colloidal particles immersed in a dynamic speckle pattern experience an optical force that fluctuates both in space and time. The resulting dynamics presents many interesting analogies with a broad class of non-equilibrium systems like: active colloids, self propelled microorganisms, transport in dynamical intracellular environments. Here we show that the use of a spatial light modulator allows to generate light fields that fluctuate with controllable space and time correlations and a prescribed average intensity profile. In particular we generate ring-shaped random patterns that can confine a colloidal particle over a quasi one-dimensional random energy landscape. We find a mean square displacement that is diffusive at both short and long times, while a superdiffusive or subdiffusive behavior is observed at intermediate times depending on the value of the speckles correlation time. We propose two alternative models for the mean square displacement in the two limiting cases of a short or long speckles correlation time. A simple interpolation formula is shown to account for the full phenomenology observed in the mean square displacement across the entire range from fast to slow fluctuating speckles. PMID:27279540

  15. Active dynamics of colloidal particles in time-varying laser speckle patterns

    NASA Astrophysics Data System (ADS)

    Bianchi, Silvio; Pruner, Riccardo; Vizsnyiczai, Gaszton; Maggi, Claudio; di Leonardo, Roberto

    2016-06-01

    Colloidal particles immersed in a dynamic speckle pattern experience an optical force that fluctuates both in space and time. The resulting dynamics presents many interesting analogies with a broad class of non-equilibrium systems like: active colloids, self propelled microorganisms, transport in dynamical intracellular environments. Here we show that the use of a spatial light modulator allows to generate light fields that fluctuate with controllable space and time correlations and a prescribed average intensity profile. In particular we generate ring-shaped random patterns that can confine a colloidal particle over a quasi one-dimensional random energy landscape. We find a mean square displacement that is diffusive at both short and long times, while a superdiffusive or subdiffusive behavior is observed at intermediate times depending on the value of the speckles correlation time. We propose two alternative models for the mean square displacement in the two limiting cases of a short or long speckles correlation time. A simple interpolation formula is shown to account for the full phenomenology observed in the mean square displacement across the entire range from fast to slow fluctuating speckles.

  16. Active dynamics of colloidal particles in time-varying laser speckle patterns.

    PubMed

    Bianchi, Silvio; Pruner, Riccardo; Vizsnyiczai, Gaszton; Maggi, Claudio; Di Leonardo, Roberto

    2016-01-01

    Colloidal particles immersed in a dynamic speckle pattern experience an optical force that fluctuates both in space and time. The resulting dynamics presents many interesting analogies with a broad class of non-equilibrium systems like: active colloids, self propelled microorganisms, transport in dynamical intracellular environments. Here we show that the use of a spatial light modulator allows to generate light fields that fluctuate with controllable space and time correlations and a prescribed average intensity profile. In particular we generate ring-shaped random patterns that can confine a colloidal particle over a quasi one-dimensional random energy landscape. We find a mean square displacement that is diffusive at both short and long times, while a superdiffusive or subdiffusive behavior is observed at intermediate times depending on the value of the speckles correlation time. We propose two alternative models for the mean square displacement in the two limiting cases of a short or long speckles correlation time. A simple interpolation formula is shown to account for the full phenomenology observed in the mean square displacement across the entire range from fast to slow fluctuating speckles. PMID:27279540

  17. Modeling Nonlinear Time-Dependent Treatment Effects: An Application of the Generalized Time-Varying Effect Model (TVEM)

    PubMed Central

    Shiyko, Mariya P.; Burkhalter, Jack; Li, Runze; Park, Bernard J.

    2014-01-01

    Objective The goal of this paper is to introduce to social and behavioral scientists the generalized time-varying effect model (TVEM), a semi-parametric approach for investigating time-varying effects of a treatment. The method is best suited for data collected intensively over time, e.g., experience sampling or ecological momentary assessment, and addresses questions pertaining to effects of treatment changing dynamically with time. Thus, of interest is the description of timing, magnitude, and (non-linear) pattern of the effect. Method Our presentation focuses on practical aspects of the model. A step-by step demonstration is presented in the context of an empirical study designed to evaluate effects of surgical treatment on quality of life among early stage lung cancer patients during post-hospitalization recovery (N = 59, 61% female, Mean age = 66.1). Frequency and level of distress associated with physical symptoms were assessed twice daily over a two-week period, providing a total of 1,544 momentary assessments. Results Traditional analyses (ANCOVA, repeated-measures ANCOVA, and multilevel modeling) yielded findings of no group differences. In contrast, generalized TVEM identified a pattern of the effect that varied in time and magnitude. Group differences manifested after day four. Conclusions Generalized TVEM is a flexible statistical approach that offers insight into the complexity of treatment effects and allows modeling of non-normal outcomes. The practical demonstration, shared syntax, and availability of a free set of macros aim to encourage researchers to apply TVEM to complex data and stimulate important scientific discoveries. PMID:24364799

  18. Dehydrogenase activity of forest soils depends on the assay used

    NASA Astrophysics Data System (ADS)

    Januszek, Kazimierz; Długa, Joanna; Socha, Jarosław

    2015-01-01

    Dehydrogenases are exclusively intracellular enzymes, which play an important role in the initial stages of oxidation of soil organic matter. One of the most frequently used methods to estimate dehydrogenase activity in soil is based on the use of triphenyltetrazolium chloride as an artificial electron acceptor. The purpose of this study was to compare the activity of dehydrogenases of forest soils with varied physicochemical properties using different triphenyltetrazolium chloride assays. The determination was carried out using the original procedure by Casida et al., a modification of the procedure which involves the use of Ca(OH)2 instead of CaCO3, the Thalmann method, and the assay by Casida et al. without addition of buffer or any salt. Soil dehydrogenase activity depended on the assay used. Dehydrogenase determined by the Casida et al. method without addition of buffer or any salt correlated with the pH values of soils. The autoclaved strongly acidic samples of control soils showed high concentrations of triphenylformazan, probably due to chemical reduction of triphenyltetrazolium chloride. There is, therefore, a need for a sterilization method other than autoclaving, ie a process that results in significant changes in soil properties, thus helping to increase the chemical reduction of triphenyltetrazolium chloride.

  19. Microbial community responses to 17 years of altered precipitation are seasonally dependent and coupled to co-varying effects of water content on vegetation and soil C

    USGS Publications Warehouse

    Sorensen, Patrick O.; Germino, Matthew J.; Feris, Kevin P.

    2013-01-01

    Precipitation amount and seasonal timing determine the duration and distribution of water available for plant and microbial activity in the cold desert sagebrush steppe. In this study, we sought to determine if a sustained shift in the amount and timing of precipitation would affect soil microbial diversity, community composition, and soil carbon (C) storage. Field plots were irrigated (+200 mm) during the dormant or growing-season for 17 years. Microbial community responses were assessed over the course of a year at two depths (15–20 cm, 95–100 cm) by terminal restriction fragment length polymorphism (T-RFLP), along with co-occurring changes in plant cover and edaphic properties. Bacterial richness, Shannon Weaver diversity, and composition in shallow soils (15–20 cm) as well as evenness in deep soils (95–100 cm) differed across irrigation treatments during July. Irrigation timing affected fungal community diversity and community composition during the dormant season and most strongly in deep soils (95–100 cm). Dormant-season irrigation increased the ratio of shrubs to forbs and reduced soil C in shallow soils by 16% relative to ambient conditions. It is unclear whether or not soil C will continue to decline with continued treatment application or if microbial adaptation could mitigate sustained soil C losses. Future changes in precipitation timing will affect soil microbes in a seasonally dependent manner and be coupled to co-varying effects of water content on vegetation and soil C.

  20. Does crustacean ethoxyresorufin O-deethylase activity vary during the molting cycle?

    PubMed

    Hotard, Kate; Zou, Enmin

    2013-10-01

    The authors examined fluctuation in microsomal ethoxyresorufin O-deethylase (EROD) activity in the hepatopancreas during the molting cycle of the fiddler crab, Uca pugilator. Results showed that microsomal EROD activity fluctuates significantly during the molting cycle, with the lowest enzymatic activity occurring in the late premolt stage. These results clearly show that molting physiology influences crustacean EROD activity, suggesting that when using crustacean EROD assays in evaluating pollution, only individuals from the same molt stage should be used. The authors propose that the high level of EROD activity in postmolt and intermolt stages is an additional mechanism crustaceans use to prevent any untimely rise in ecdysteroid levels. PMID:23843096

  1. A Comparison of Attitudes and Exercise Habits of Alumni from Colleges with Varying Degrees of Physical Education Activity Programs.

    ERIC Educational Resources Information Center

    Adams, Thomas M.; Brynteson, Paul

    1992-01-01

    Study compared the exercise attitudes and habits of alumni from four colleges with varying physical education activity (PEA) requirements. Survey results indicated the type of PEA programs offered influenced alumni attitudes toward fitness and exercise behaviors. Students from colleges with higher PEA requirements had more positive exercise…

  2. Temporal patterns of ascospore release in Leptosphaeria maculans vary depending on geographic region and time of observation.

    PubMed

    Savage, David; Barbetti, Martin J; MacLeod, William J; Salam, Moin U; Renton, Michael

    2013-04-01

    Diurnal patterns of spore release have been observed in a number of fungal pathogens that undergo wind-assisted dispersal. The mechanisms that drive these patterns, while not well understood, are thought to relate to the ability of dispersing spores to survive their journey and infect new hosts. In this paper, we characterise the diurnal pattern of ascospore release by a Western Australian population of Leptosphaeria maculans. Although L. maculans has been previously shown to exhibit diurnal patterns of ascospore release, these patterns appear to vary from region to region. In order to characterise the pattern of release in the Mediterranean climate of Western Australia, we analysed historical data describing the bi-hourly count of airborne ascospores at Mt Barker, Western Australia. Results of this analysis showed diurnal patterns that differ from those previously observed in other countries, with ascospore release in our study most likely to occur in the afternoon. Furthermore, we found that the time of peak release can shift from month to month within any one season, and from year to year. In explaining the hourly pattern of spore release over an entire season, time since rainfall, time since last release, temperature, hour and month were all shown to be significant variables. PMID:23271454

  3. Adaptive sliding control of non-autonomous active suspension systems with time-varying loadings

    NASA Astrophysics Data System (ADS)

    Chen, Po-Chang; Huang, An-Chyau

    2005-04-01

    An adaptive sliding controller is proposed in this paper for controlling a non-autonomous quarter-car suspension system with time-varying loadings. The bound of the car-body loading is assumed to be available. Then, the reference coordinate is placed at the static position under the nominal loading so that the system dynamic equation is derived. Due to spring nonlinearities, the system property becomes asymmetric after coordinate transformation. Besides, in practical cases, system parameters are not easy to be obtained precisely for controller design. Therefore, in this paper, system uncertainties are lumped into two unknown time-varying functions. Since the variation bound of one of the unknown functions is not available, conventional adaptive schemes and robust designs are not applicable. To deal with this problem, the function approximation technique is employed to represent the unknown function as a finite combination of basis functions. The Lyapunov direct method can thus be used to find adaptive laws for updating coefficients in the approximating series and to prove stability of the closed-loop system. Since the position and velocity measurements of the unsprung mass are lumped into the unknown function, there is no need to install sensors on the axle and wheel assembly in the actual implementation. Simulation results are presented to show the performance of the proposed strategy.

  4. "Choking Game" Yields Varying Responses from Educators: Some Fear Addressing the Dangerous Activity Could Prompt Copycats

    ERIC Educational Resources Information Center

    Samuels, Christina A.

    2006-01-01

    A spate of deaths among young people around the country in the past year has brought further media attention to an asphyxial activity known as "the choking game." But the subject is a sensitive one for schools. Some administrators have actively enlisted in efforts to inform students and parents about the risks of practices like the choking game,…

  5. Effect of varying accelerometry criteria on physical activity: the Look AHEAD Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The importance of physical activity in weight management is widely documented. Although accelerometers offer an objective measure of activity that provide a valuable tool for intervention research, considerations for processing these data need further development. Objective: This study tests the eff...

  6. Transcription activation at class II CRP-dependent promoters: the role of different activating regions.

    PubMed Central

    Rhodius, V A; West, D M; Webster, C L; Busby, S J; Savery, N J

    1997-01-01

    Transcription activation by the Escherichia coli cyclic AMP receptor protein (CRP) at Class II promoters is dependent on direct interactions between two surface-exposed activating regions (AR1 and AR2) and two contact sites in RNA polymerase. The effects on transcription activation of disrupting either AR1 or AR2 have been measured at different Class II promoters. AR2 but not AR1 is essential for activation at all the Class II promoters that were tested. The effects of single positive control substitutions in AR1 and AR2 vary from one promoter to another: the effects of the different substitutions are contingent on the -35 hexamer sequence. Abortive initiation assays have been used to quantify the effects of positive control substitutions in each activating region on the kinetics of transcription initiation at the Class II CRP- dependent promoter pmelRcon. At this promoter, the HL159 substitution in AR1 results in a defect in the initial binding of RNA polymerase whilst the KE101 substitution in AR2 reduces the rate of isomerization from the closed to the open complex. PMID:9016561

  7. Pupillometric Signs of Brain Activation Vary with Level of Cognitive Processing

    ERIC Educational Resources Information Center

    Beatty, Jackson; Wagoner, Brennis L.

    1978-01-01

    Reports increased central nervous system vigilance and activation was observed as indicated by pupillary dilation during the decision interval of a letter matching task as higher levels of processing were performed. (SL)

  8. Muscle activation and energy-requirements for varying postures in children and adolescents with cerebral palsy

    PubMed Central

    Peterson, Mark D.; Leferink, Svenja; Darrah, Johanna

    2015-01-01

    Objective To determine energy expenditure and muscle activity among children and adolescents with cerebral palsy (CP), across several conditions that approximate sedentary behavior, and standing. Study design Subjects with spastic CP (n=19; 4–20 years of age; Gross Motor Function Classification System [GMFCS] levels I to V) participated in this cohort study. Energy-expenditure and muscle activity were measured during lying supine, sitting with support, sitting without support, and standing. Energy-expenditure was measured using indirect calorimetry and expressed in metabolic equivalents (METs). Muscle activation was recorded using surface electromyography. The recorded values were calculated for every child and then averaged per posture. Results Mean energy expenditure was >1.5 METs during standing for all GMFCS levels. There was a non-significant trend for greater muscle activation for all postures with less support. Only for children classified at GMFCS level III standing resulted in significantly greater muscle activation (p<0.05) compared with rest. Conclusion Across all GMFCS levels, children and adolescents with CP had elevated energy expenditure during standing that exceeded the sedentary threshold of 1.5 METs. Our findings suggest that changing a child’s position to standing may contribute to the accumulation of light activity and reduction of long intervals of sedentary behavior. PMID:25151195

  9. Effect of Varying Accelerometry Criteria on Physical Activity: The Look AHEAD Study

    PubMed Central

    Miller, G. D.; Jakicic, J. M.; Rejeski, W. J.; Whit-Glover, M.; Lang, W.; Walkup, M. P.; Hodges, M.

    2012-01-01

    The importance of physical activity in weight management is widely documented. Although accelerometers offer an objective measure of activity that provide a valuable tool for intervention research, considerations for processing these data need further development. This study tests the effects of using different criteria for accelerometry data reduction. Data were obtained from 2,240 overweight and obese individuals with type 2 diabetes mellitus (T2DM) from the Look AHEAD study, with 2,177 baseline accelerometer files used for analysis. Number, duration, and intensity of moderate (≥3 METS) and vigorous (≥6 METS) activity bouts were compared using various data reduction criteria. Daily wear time was identified as 1,440 minutes per day minus non-wear time. Comparisons of physical activity patterns for non-wear time (using either 20, 30 or 60 minutes of continuous zeros), minimal daily wear time (8, 10, and 12 hours), number of days with available data (4, 5, and 6 days), weekdays versus weekends, and one- or two-minute time interruptions in an activity bout were performed. In this mostly obese population with T2DM (BMI = 36.4 kg/m2; mean age = 59.0 y), there were minimal differences in physical activity patterns using the different methods of data reduction. Altering criteria led to differences in the number of available data (sample size) meeting specific criteria. Although our results are likely directly applicable only to obese individuals with T2DM, an understudied population with regards to physical activity, the systematic analysis for data reduction employed can be more generalizable and provide guidance in this area in the absence of standard procedures. PMID:23505166

  10. The Prevalence of Left Ventricular Hypertrophy in Obese Children Varies Depending on the Method Utilized to Determine Left Ventricular Mass.

    PubMed

    Mahgerefteh, Joseph; Linder, Jarrett; Silver, Ellen J; Hazin, Penelope; Ceresnak, Scott; Hsu, Daphne; Lopez, Leo

    2016-08-01

    Obesity and left ventricular hypertrophy (LVH) have been identified as independent risk factors for cardiovascular events. The definition of LVH depends on the geometric algorithm used to calculate LV mass (LVM) by echocardiography and the method used to normalize LVM for body size. This study evaluates the effect of these methods on the prevalence of LVH in obese children. LVM for 109 obese and 109 age-matched non-obese children was calculated using M-mode or two-dimensional echocardiography (2DE). LVM was then normalized to height 2.7 as indexed LVM (LVMI), to body surface area (BSA), height, and lean body mass (LBM) as LVM Z-scores. LVH was defined as LVMI >95th ‰ using age-specific normal reference values or LVM Z-scores ≥2. The prevalence of LVH by LVMI and LVM Z-scores was compared. There was a correlation between LVM determined by M-mode and by 2DE (R (2) = 0.91), although M-mode LVM was greater than 2DE LVM. However, the difference between these values was greater in obese children than in non-obese children. Based on the method of normalization, the prevalence of LVH among obese children was 64 % using LVMI, 15 % using LVM Z-scores for height, 8 % using LVM Z-scores for BSA and 1 % using LVM Z-scores for LBM. Height-based normalization correlates with obesity and hypertension. The methods used to measure and normalize LVM have a profound influence on the diagnosis of LVH in obese children. Further study is needed to determine which method identifies children at risk for cardiovascular morbidity and mortality. PMID:27033247

  11. Comparative evaluation of antipyretic activity of ibuprofen and aspirin in children with pyrexia of varied aetiology.

    PubMed

    Kandoth, P W; Joshi, M K; Joshi, V R; Satoskar, R S

    1984-01-01

    The antipyretic activity of ibuprofen and aspirin was compared in sixteen children with pyrexia due to upper respiratory tract infection and in twelve with fever due to other causes. All 28 children received ibuprofen (7 mg/kg of body-weight) and aspirin (15 mg/kg of body-weight) in a single dose on 2 consecutive days in a crossover manner. Rectal temperature was recorded prior to and at regular intervals up to 8 hours after drug administration. Analysis of the results indicate that ibuprofen and aspirin effectively lower temperature and the two drugs are comparable in their antipyretic activity. In conclusion, significant antipyretic activity, good tolerance profile and availability in syrup form make ibuprofen a useful substitute for aspirin in children with fever. PMID:6500169

  12. The Engagement in Musical Activities of Young Children with Varied Hearing Abilities

    ERIC Educational Resources Information Center

    Chen-Hafteck, Lily; Schraer-Joiner, Lyn

    2011-01-01

    This multiple case study examined the musical experiences of five hard-of-hearing/deaf children (hearing loss ranging from 35-95 dB) and four typical-hearing children, ages 3-4. Their responses to various musical activities were observed and analysed using flow indicators. It was found that both groups of children: (1) were capable of engaging in…

  13. Effects of Varying Team Sizes on Physical Activity Levels of College Students

    ERIC Educational Resources Information Center

    Gaudreault, Karen Lux; Cluphf, David; Russell, Jared; Lecheminant, James

    2014-01-01

    The purpose of this exploratory study was to examine physical activity levels among various team sizes for basketball and soccer in a C/UIPAP setting. Twenty-eight university physical education majors participated in the study. Participants engaged in three-on-three and five-on-five basketball and five-on-five and 11-on-11 soccer games. All games…

  14. Activity Dependent Signal Transduction in Skeletal Muscle

    NASA Technical Reports Server (NTRS)

    Hamilton, Susan L.

    1999-01-01

    The overall goals of this project are: 1) to define the initial signal transduction events whereby the removal of gravitational load from antigravity muscles, such as the soleus, triggers muscle atrophy, and 2) to develop countermeasures to prevent this from happening. Our rationale for this approach is that, if countermeasures can be developed to regulate these early events, we could avoid having to deal with the multiple cascades of events that occur downstream from the initial event. One of our major findings is that hind limb suspension causes an early and sustained increase in intracellular Ca(2+) concentration ([Ca (2+)](sub i)). In most cells the consequences of changes in ([Ca (2+)](sub i))depend on the amplitude, frequency and duration of the Ca(2+) signal and on other factors in the intracellular environment. We propose that muscle remodeling in microgravity represents a change in the balance among several CA(2+) regulated signal transduction pathways, in particular those involving the transcription factors NFAT and NFkB and the pro-apoptotic protein BAD. Other Ca(2+) sensitive pathways involving PKC, ras, rac, and CaM kinase II may also contribute to muscle remodeling.

  15. Ribosome-dependent activation of stringent control.

    PubMed

    Brown, Alan; Fernández, Israel S; Gordiyenko, Yuliya; Ramakrishnan, V

    2016-06-01

    In order to survive, bacteria continually sense, and respond to, environmental fluctuations. Stringent control represents a key bacterial stress response to nutrient starvation that leads to rapid and comprehensive reprogramming of metabolic and transcriptional patterns. In general, transcription of genes for growth and proliferation is downregulated, while those important for survival and virulence are upregulated. Amino acid starvation is sensed by depletion of the aminoacylated tRNA pools, and this results in accumulation of ribosomes stalled with non-aminoacylated (uncharged) tRNA in the ribosomal A site. RelA is recruited to stalled ribosomes and activated to synthesize a hyperphosphorylated guanosine analogue, (p)ppGpp, which acts as a pleiotropic secondary messenger. However, structural information about how RelA recognizes stalled ribosomes and discriminates against aminoacylated tRNAs is missing. Here we present the cryo-electron microscopy structure of RelA bound to the bacterial ribosome stalled with uncharged tRNA. The structure reveals that RelA utilizes a distinct binding site compared to the translational factors, with a multi-domain architecture that wraps around a highly distorted A-site tRNA. The TGS (ThrRS, GTPase and SpoT) domain of RelA binds the CCA tail to orient the free 3' hydroxyl group of the terminal adenosine towards a β-strand, such that an aminoacylated tRNA at this position would be sterically precluded. The structure supports a model in which association of RelA with the ribosome suppresses auto-inhibition to activate synthesis of (p)ppGpp and initiate the stringent response. Since stringent control is responsible for the survival of pathogenic bacteria under stress conditions, and contributes to chronic infections and antibiotic tolerance, RelA represents a good target for the development of novel antibacterial therapeutics. PMID:27279228

  16. Alteration and modulation of protein activity by varying post-translational modification

    SciTech Connect

    Thompson, David N; Reed, David W; Thompson, Vicki S; Lacey, Jeffrey A; Apel, William A

    2015-03-03

    Embodiments of the invention include methods of altering the enzymatic activity or solubility of an extremophilic enzyme or post-translationally modifying a protein of interest via using isolated or partially purified glycosyltransferases and/or post-translational modification proteins, extracts of cells comprising glycosyltransferases and/or post-translational modification proteins, and/or in cells comprising one or more glycosyltransferases and/or post-translational modification proteins.

  17. Alteration and modulation of protein activity by varying post-translational modification

    DOEpatents

    Thompson, David N.; Reed, David W.; Thompson, Vicki S.; Lacey, Jeffrey A.; Apel, William A.

    2016-07-12

    Embodiments of the invention include methods of altering the enzymatic activity or solubility of an extremophilic enzyme or post-translationally modifying a protein of interest via using isolated or partially purified glycosyltransferases and/or post-translational modification proteins, extracts of cells comprising glycosyltransferases and/or post-translational modification proteins, and/or in cells comprising one or more glycosyltransferases and/or post-translational modification proteins.

  18. PCB concentrations and activity of sea lamprey Petromyzon marinus vary by sex

    USGS Publications Warehouse

    Madenjian, Charles P.; Johnson, Nicholas S.; Binder, Thomas R.; Rediske, Richard R.; O'Keefe, James P.

    2013-01-01

    We determined the polychlorinated biphenyl (PCB) concentrations of 40 male and 40 female adult sea lampreys Petromyzon marinus captured in the Cheboygan River, a tributary to Lake Huron, during May 2011. In addition, we performed a laboratory experiment using passive integrated transponder tags to determine whether male adult sea lampreys were more active than female adult sea lampreys. Sex had a significant effect on PCB concentration, and PCB concentration at a given level of sea lamprey condition was approximately 25 % greater in males than in females. Adjusting for the difference in condition between the sexes, males averaged a 17 % greater PCB concentration compared with females. Results from the laboratory experiment indicated that males were significantly more active than females. The observed sex difference in PCB concentrations was not due to female sea lampreys releasing eggs at spawning because the sea lamprey is semelparous, and we caught the sea lampreys before spawning. Rather, we attributed the sex difference in PCB concentrations to a greater rate of energy expenditure in males compared with females. We proposed that this greater rate of energy expenditure was likely due to greater activity. Our laboratory experiment results supported this hypothesis. A greater resting metabolic rate may also have contributed to a greater rate of energy expenditure. Our findings should eventually be applicable toward improving control of sea lamprey, a pest responsible for considerable damage to fisheries in lakes where it is not native.

  19. Pattern reactivation co-varies with activity in the core recollection network during source memory.

    PubMed

    Leiker, Emily K; Johnson, Jeffrey D

    2015-08-01

    Neuroimaging studies of episodic memory have consistently demonstrated that memory retrieval involves reactivating patterns of neural activity that were present during encoding, and these effects are thought to reflect the qualitative retrieval (recollection) of information that is specific to the content of an episode. By contrast, recollection is also accompanied by other neural correlates that generalize across episodic content and are consequently referred to as the "core recollection network". The neural mechanism by which these specific and core effects interact to give rise to episodic memory retrieval is largely unknown. The current study addressed this issue by testing for correlations (connectivity) between pattern reactivation and activity in the core recollection network. Subjects encoded a series of words with different tasks and then completed a two-step source memory test, whereby they identified the task (source) previously associated with the word and the confidence of that judgment. Multivariate pattern analysis (MVPA) was used in combination with fMRI to first identify encoding-related neural patterns and then test for their reactivation during retrieval. Consistent with prior findings, the magnitude of reactivation increased with source-memory confidence. Moreover, individual-trial measures of reactivation exhibited positive correlations with activity in multiple regions of the core recollection network. Importantly, evidence of functional connectivity between pattern reactivation and a region of left posterior parietal cortex supports the role of this region in tracking the retrieval of episodic information in service of making subjective memory decisions. PMID:26004057

  20. Impact of varying physical activity levels on airway sensitivity and bronchodilation in healthy humans.

    PubMed

    Smith, Joshua R; Kurti, Stephanie P; Johnson, Ariel M; Kolmer, Sarah A; Harms, Craig

    2015-12-01

    The purpose of this study was to determine if the amount of physical activity influences airway sensitivity and bronchodilation in healthy subjects across a range of physical activity levels. Thirty healthy subjects (age, 21.9 ± 2.6 years; 13 men/17 women) with normal pulmonary function reported to the laboratory on 2 separate occasions where they were randomized to breathe either hypertonic saline (HS) (nebulized hypertonic saline (25%) for 20 min) or HS followed by 5 deep inspirations (DIs), which has been reported to bronchodilate the airways. Pulmonary function tests (PFTs) were performed prior to both conditions and following the HS breathing or 5 DIs. Moderate to vigorous physical activity (MVPA) level was measured via accelerometer worn for 7 days. Following the HS breathing, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) significantly decreased from baseline by -11.8% ± 8.4% and -9.3% ± 6.7%, respectively. A 2-segment linear model determined significant relationships between MVPA and percent change in FEV1 (r = 0.50) and FVC (r = 0.55). MVPA above ∼497 and ∼500 min/week for FEV1 and FVC, respectively, resulted in minor additional improvements (p > 0.05) in PFTs following the HS breathing. Following the DIs, FEV1 and FVC decreased (p < 0.05) by -7.3% ± 8.6% and -5.7% ± 5.7%, respectively, from baseline, but were not related (p > 0.05) to MVPA. In conclusion, these data demonstrate that higher MVPA levels attenuated airway sensitivity but not bronchodilation in healthy subjects. PMID:26575101

  1. Multiple activation pathways of benzene leading to products with varying genotoxic characteristics

    SciTech Connect

    Glatt, H.; Ludewig, G.; Platt, K.L.; Klein, J.; Oesch, F. ); Padykula, R.; Berchtold, G.A. )

    1989-07-01

    Benzene and 13 potential metabolites were investigated for genotoxicity in Salmonella typhimurium and V79 Chinese hamster cells. In the presence of NADPH-fortified hepatic postmitochondrial fraction (S9 mix), benzene reverted his S. typhimurium strains. The effect was strongest in strain TA1535. Among the potential metabolites, only the trans-1,2-dihydrodiol, in the presence of S9 mix, and the diol epoxides, in the presence and absence of S9 mix, proved mutagenic in this strain. The anti-diol epoxide was more potent than the syndiastereomer. Both enantiomers of the anti-diastereomer showed similar activities. S9 mix did not appreciably affect the mutagenicity of the anti-diol epoxide. However, detoxification was observed when purified rat liver dihydrodiol dehydrogenase was used at concentrations comparable to that present in the liver. Elevated frequencies of micronucleated cells were observed after treatment with hydroquinone, 1,2,4-trihydroxybenzene, catechol, phenol, 1,2,3-trihydroxybenzene, and quinone. By far the most prominent effect in the whole study was the potent induction of gene mutations by quinone and hydroquinone. This unique and narrow spectrum of genotoxic activities differs from the broad spectrum observed with the antidiol epoxide, suggesting qualitative differences in their interaction with genetic material.

  2. Voltage Dependence of a Neuromodulator-Activated Ionic Current123

    PubMed Central

    2016-01-01

    Abstract The neuromodulatory inward current (IMI) generated by crab Cancer borealis stomatogastric ganglion neurons is an inward current whose voltage dependence has been shown to be crucial in the activation of oscillatory activity of the pyloric network of this system. It has been previously shown that IMI loses its voltage dependence in conditions of low extracellular calcium, but that this effect appears to be regulated by intracellular calmodulin. Voltage dependence is only rarely regulated by intracellular signaling mechanisms. Here we address the hypothesis that the voltage dependence of IMI is mediated by intracellular signaling pathways activated by extracellular calcium. We demonstrate that calmodulin inhibitors and a ryanodine antagonist can reduce IMI voltage dependence in normal Ca2+, but that, in conditions of low Ca2+, calmodulin activators do not restore IMI voltage dependence. Further, we show evidence that CaMKII alters IMI voltage dependence. These results suggest that calmodulin is necessary but not sufficient for IMI voltage dependence. We therefore hypothesize that the Ca2+/calmodulin requirement for IMI voltage dependence is due to an active sensing of extracellular calcium by a GPCR family calcium-sensing receptor (CaSR) and that the reduction in IMI voltage dependence by a calmodulin inhibitor is due to CaSR endocytosis. Supporting this, preincubation with an endocytosis inhibitor prevented W7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride)-induced loss of IMI voltage dependence, and a CaSR antagonist reduced IMI voltage dependence. Additionally, myosin light chain kinase, which is known to act downstream of the CaSR, seems to play a role in regulating IMI voltage dependence. Finally, a Gβγ-subunit inhibitor also affects IMI voltage dependence, in support of the hypothesis that this process is regulated by a G-protein-coupled CaSR. PMID:27257619

  3. The varied functions of aluminium-activated malate transporters-much more than aluminium resistance.

    PubMed

    Palmer, Antony J; Baker, Alison; Muench, Stephen P

    2016-06-15

    The ALMT (aluminium-activated malate transporter) family comprises a functionally diverse but structurally similar group of ion channels. They are found ubiquitously in plant species, expressed throughout different tissues, and located in either the plasma membrane or tonoplast. The first family member identified was TaALMT1, discovered in wheat root tips, which was found to be involved in aluminium resistance by means of malate exudation into the soil. However, since this discovery other family members have been shown to have many other functions such as roles in stomatal opening, general anionic homoeostasis, and in economically valuable traits such as fruit flavour. Recent evidence has also shown that ALMT proteins can act as key molecular actors in GABA (γ-aminobutyric acid) signalling, the first evidence that GABA can act as a signal transducer in plants. PMID:27284052

  4. Diagnostic investigation of steroid estrogen removal by activated sludge at varying solids retention time.

    PubMed

    Petrie, Bruce; McAdam, Ewan J; Hassard, Francis; Stephenson, Tom; Lester, John N; Cartmell, Elise

    2014-10-01

    The impact of solids retention time (SRT) on estrone (E1), 17β-estradiol (E2), estriol (E3) and 17α-ethinylestradiol (EE2) removal in an activated sludge plant (ASP) was examined using a pilot plant to closely control operation. Exsitu analytical methods were simultaneously used to enable discrimination of the dominant mechanisms governing estrogen removal following transitions in SRT from short (3d) to medium (10d) and long (27d) SRTs which broadly represent those encountered at full-scale. Total estrogen (∑EST, i.e., sum of E1, E2, E3 and EE2) removals which account for aqueous and particulate concentrations were 70±8, 95±1 and 93±2% at 3, 10 and 27d SRTs respectively. The improved removal observed following an SRT increase from 3 to 10d was attributable to the augmented biodegradation of the natural estrogens E1 and E2. Interestingly, estrogen biodegradation per bacterial cell increased with SRT. These were 499, 1361 and 1750ng 10(12) viable cells(-1)d(-1). This indicated an improved efficiency of the same group or the development of a more responsive group of bacteria. In this study no improvement in absolute ∑EST removal was observed in the ASP when SRT increased from 10 to 27d. However, batch studies identified an augmented biomass sorption capacity for the more hydrophobic estrogens E2 and EE2 at 27d, equivalent to an order of magnitude. The lack of influence on estrogen removal during pilot plant operation can be ascribed to their distribution within activated sludge being under equilibrium. Consequently, lower wastage of excess sludge inherent of long SRT operation counteracts any improvement in sorption. PMID:25065796

  5. Brain activity varies with modulation of dynamic pitch variance in sentence melody.

    PubMed

    Meyer, Martin; Steinhauer, Karsten; Alter, Kai; Friederici, Angela D; von Cramon, D Yves

    2004-05-01

    Fourteen native speakers of German heard normal sentences, sentences which were either lacking dynamic pitch variation (flattened speech), or comprised of intonation contour exclusively (degraded speech). Participants were to listen carefully to the sentences and to perform a rehearsal task. Passive listening to flattened speech compared to normal speech produced strong brain responses in right cortical areas, particularly in the posterior superior temporal gyrus (pSTG). Passive listening to degraded speech compared to either normal or flattened speech particularly involved fronto-opercular and subcortical (Putamen, Caudate Nucleus) regions bilaterally. Additionally the Rolandic operculum (premotor cortex) in the right hemisphere subserved processing of neat sentence intonation. As a function of explicit rehearsing sentence intonation we found several activation foci in the left inferior frontal gyrus (Broca's area), the left inferior precentral sulcus, and the left Rolandic fissure. The data allow several suggestions: First, both flattened and degraded speech evoked differential brain responses in the pSTG, particularly in the planum temporale (PT) bilaterally indicating that this region mediates integration of slowly and rapidly changing acoustic cues during comprehension of spoken language. Second, the bilateral circuit active whilst participants receive degraded speech reflects general effort allocation. Third, the differential finding for passive perception and explicit rehearsal of intonation contour suggests a right fronto-lateral network for processing and a left fronto-lateral network for producing prosodic information. Finally, it appears that brain areas which subserve speech (frontal operculum) and premotor functions (Rolandic operculum) coincidently support the processing of intonation contour in spoken sentence comprehension. PMID:15068910

  6. Fate of malathion and a phosphonic acid in activated sludge with varying solids retention times.

    PubMed

    Janeczko, Allen K; Walters, Edward B; Schuldt, Steven J; Magnuson, Matthew L; Willison, Stuart A; Brown, Lisa M; Ruiz, Oscar N; Felker, Daniel L; Racz, LeeAnn

    2014-06-15

    This study examined the ability of activated sludge (AS) to sorb and biodegrade ethylmethylphosphonic acid (EMPA) and malathion, a degradation product and surrogate, respectively, for an organophosphate chemical warfare agent. Sorption equilibrium isotherm experiments indicate that sorption of EMPA and malathion to AS is negligible. EMPA at a concentration of 1 mg L(-1) degraded by approximately 30% with apparent first-order kinetics, possibly via co-metabolism from nitrification. Heterotrophic bacteria and abiotic mechanisms, however, are largely responsible for malathion degradation also with apparent first-order kinetics. EMPA did not inhibit chemical oxygen demand (COD) oxidation or nitrification activity, although malathion did appear to induce a stress response resulting in inhibition of COD oxidation. The study also included a 30-day experiment in which malathion, at a concentration of 5 mg L(-1), was repeatedly fed to AS in bench-scale sequencing batch reactors (SBRs) operating at different solids retention times (SRTs). Peak malathion concentrations occurred at day 4.5, with the longer SRTs yielding greater peak malathion concentrations. The AS reduced the malathion concentrations to nearly zero by day 10 for all SRTs, even when the malathion concentration in the influent increased to 20.8 mg L(-1). The data suggest a biodegradation pathway for malathion involving an oxygenase. Phylogenetic analyses revealed that all samples had an abundance of Zoogloea, though there was greater bacterial diversity in the SBR with the SRT of 50 days. The SBR with an SRT of 9.5 days had an apparent reduction in the diversity of the bacterial community. PMID:24709533

  7. Gender Differences in Barriers to Physical Activity among College Students Reporting Varying Levels of Regular Physical Activity

    ERIC Educational Resources Information Center

    Munford, Shawn N.

    2011-01-01

    Researchers have studied the primary determinants of physical activity in an effort to enhance health promotion initiatives nationwide. These physical activity determinants have been observed to differ among various segments of the population, suggesting a further examination of physical activity barriers among differing populations. Little…

  8. Photosynthesis, Transpiration, Leaf Temperature, and Stomatal Activity of Cotton Plants under Varying Water Potentials

    PubMed Central

    Pallas, J. E.; Michel, B. E.; Harris, D. G.

    1967-01-01

    Cotton plants, Gossypium hirsutum L. were grown in a growth room under incident radiation levels of 65, 35, and 17 Langleys per hour to determine the effects of vapor pressure deficits (VPD's) of 2, 9, and 17 mm Hg at high soil water potential, and the effects of decreasing soil water potential and reirrigation on transpiration, leaf temperature, stomatal activity, photosynthesis, and respiration at a VPD of 9 mm Hg. Transpiration was positively correlated with radiation level, air VPD and soil water potential. Reirrigation following stress led to slow recovery, which may be related to root damage occurring during stress. Leaf water potential decreased with, but not as fast as, soil water potential. Leaf temperature was usually positively correlated with light intensity and negatively correlated with transpiration, air VPD, and soil water. At high soil water, leaf temperatures ranged from a fraction of 1 to a few degrees above ambient, except at medium and low light and a VPD of 19 mm Hg when they were slightly below ambient, probably because of increased transpirational cooling. During low soil water leaf temperatures as high as 3.4° above ambient were recorded. Reirrigation reduced leaf temperature before appreciably increasing transpiration. The upper leaf surface tended to be warmer than the lower at the beginning of the day and when soil water was adequate; otherwise there was little difference or the lower surface was warmer. This pattern seemed to reflect transpiration cooling and leaf position effects. Although stomata were more numerous in the lower than the upper epidermis, most of the time a greater percentage of the upper were open. With sufficient soil water present, stomata opened with light and closed with darkness. Fewer stomata opened under low than high light intensity and under even moderate, as compared with high soil water. It required several days following reirrigation for stomata to regain original activity levels. Apparent photosynthesis

  9. Functions of the extracellular histidine residues of receptor activity-modifying proteins vary within adrenomedullin receptors

    SciTech Connect

    Kuwasako, Kenji Kitamura, Kazuo; Nagata, Sayaka; Kato, Johji

    2008-12-05

    Receptor activity-modifying protein (RAMP)-2 and -3 chaperone calcitonin receptor-like receptor (CRLR) to the plasma membrane, where together they form heterodimeric adrenomedullin (AM) receptors. We investigated the contributions made by His residues situated in the RAMP extracellular domain to AM receptor trafficking and receptor signaling by co-expressing hCRLR and V5-tagged-hRAMP2 or -3 mutants in which a His residue was substituted with Ala in HEK-293 cells. Flow cytometric analysis revealed that hRAMP2-H71A mediated normal hCRLR surface delivery, but the resultant heterodimers showed significantly diminished [{sup 125}I]AM binding and AM-evoked cAMP production. Expression of hRAMP2-H124A and -H127A impaired surface delivery of hCRLR, which impaired or abolishing AM binding and receptor signaling. Although hRAMP3-H97A mediated full surface delivery of hCRLR, the resultant heterodimers showed impaired AM binding and signaling. Other His residues appeared uninvolved in hCRLR-related functions. Thus, the His residues of hRAMP2 and -3 differentially govern AM receptor function.

  10. Multiple activation pathways of benzene leading to products with varying genotoxic characteristics.

    PubMed Central

    Glatt, H; Padykula, R; Berchtold, G A; Ludewig, G; Platt, K L; Klein, J; Oesch, F

    1989-01-01

    Benzene and 13 potential metabolites were investigated for genotoxicity in Salmonella typhimurium and V79 Chinese hamster cells. In the presence of NADPH-fortified hepatic postmitochondrial fraction (S9 mix), benzene reverted his- S. typhimurium strains. The effect was strongest in strain TA1535. Among the potential metabolites, only the trans-1,2-dihydrodiol, in the presence of S9 mix, and the diol epoxides, in the presence and absence of S9 mix, proved mutagenic in this strain. The anti-diol epoxide was more potent than the syn-diastereomer. Both enantiomers of the anti-diastereomer showed similar activities. S9 mix did not appreciably affect the mutagenicity of the anti-diol epoxide. However, detoxification was observed when purified rat liver dihydrodiol dehydrogenase (EC 1.3.1.20) was used at concentrations comparable to that present in the liver. The (1S)-anti-diol epoxide was a much better substrate than the (1R)-enantiomer, as was true also for (1S)-versus (1R)-trans-1,2-dihydrodiol. The anti-diol epoxide reverted all six strains of S. typhimurium used and induced all four genotoxic effects studied in V79 cells (sister chromatid exchange greater than acquisition of 6-thioguanine resistance, acquisition of ouabain resistance, micronuclei). However, other potential benzene metabolites showed genotoxic effects in V79 cells, as well: sister chromatid exchange was induced by the syn-diol epoxide, 1,2,4-trihydroxybenzene, hydroquinone, catechol, and 1,2,3-trihydroxybenzene. Elevated frequencies of micronucleated cells were observed after treatment with hydroquinone, 1,2,4-trihydroxybenzene, catechol, phenol, 1,2,3-trihydroxybenzene, and quinone. Mutations to 6-thioguanine resistance were induced by quinone, hydroquinone, 1,2,4-trihydroxybenzene, catechol, and the trans-1,2-dihydrodiol.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2676505

  11. Physicochemical signatures of nanoparticle-dependent complement activation

    NASA Astrophysics Data System (ADS)

    Thomas, Dennis G.; Chikkagoudar, Satish; Heredia-Langner, Alejandro; Tardiff, Mark F.; Xu, Zhixiang; Hourcade, Dennis E.; Pham, Christine T. N.; Lanza, Gregory M.; Weinberger, Kilian Q.; Baker, Nathan A.

    2014-01-01

    Nanoparticles are potentially powerful therapeutic tools that have the capacity to target drug payloads and imaging agents. However, some nanoparticles can activate complement, a branch of the innate immune system, and cause adverse side-effects. Recently, we employed an in vitro hemolysis assay to measure the serum complement activity of perfluorocarbon nanoparticles that differed by size, surface charge, and surface chemistry, quantifying the nanoparticle-dependent complement activity using a metric called Residual Hemolytic Activity (RHA). In the present work, we have used a decision tree learning algorithm to derive the rules for estimating nanoparticle-dependent complement response based on the data generated from the hemolytic assay studies. Our results indicate that physicochemical properties of nanoparticles, namely, size, polydispersity index, zeta potential, and mole percentage of the active surface ligand of a nanoparticle, can serve as good descriptors for prediction of nanoparticle-dependent complement activation in the decision tree modeling framework.

  12. Varying behavior of different window sizes on the classification of static and dynamic physical activities from a single accelerometer.

    PubMed

    Fida, Benish; Bernabucci, Ivan; Bibbo, Daniele; Conforto, Silvia; Schmid, Maurizio

    2015-07-01

    Accuracy of systems able to recognize in real time daily living activities heavily depends on the processing step for signal segmentation. So far, windowing approaches are used to segment data and the window size is usually chosen based on previous studies. However, literature is vague on the investigation of its effect on the obtained activity recognition accuracy, if both short and long duration activities are considered. In this work, we present the impact of window size on the recognition of daily living activities, where transitions between different activities are also taken into account. The study was conducted on nine participants who wore a tri-axial accelerometer on their waist and performed some short (sitting, standing, and transitions between activities) and long (walking, stair descending and stair ascending) duration activities. Five different classifiers were tested, and among the different window sizes, it was found that 1.5 s window size represents the best trade-off in recognition among activities, with an obtained accuracy well above 90%. Differences in recognition accuracy for each activity highlight the utility of developing adaptive segmentation criteria, based on the duration of the activities. PMID:25983067

  13. Does the Effect of a Physical Activity Behavioral Intervention Vary by Characteristics of People with Multiple Sclerosis?

    PubMed Central

    Dlugonski, Deirdre; Pilutti, Lara A.; Klaren, Rachel E.

    2015-01-01

    Background: Behavioral interventions have significantly increased physical activity in people with multiple sclerosis (MS). Nevertheless, there has been interindividual variability in the pattern and magnitude of change. This study documented the efficacy and variability of a behavioral intervention for changing physical activity and examined the possibility that efficacy varied by the characteristics of individuals with MS. Methods: Eighty-two people with MS were randomly assigned to one of two conditions: behavioral intervention (n = 41) or waitlist control (n = 41). We collected information before the study on MS type, disability status, weight status based on body-mass index, and current medications. Furthermore, all participants completed the Godin Leisure Time Exercise Questionnaire and the abbreviated International Physical Activity Questionnaire and wore an accelerometer for 1 week to measure minutes of moderate-to-vigorous physical activity before and after the 6-month intervention period. Results: Analysis of covariance (ANCOVA) indicated that participants in the behavioral intervention had significantly higher levels of physical activity than control participants after the 6-month period (P < .001). There was substantial interindividual variability in the magnitude of change, and ANCOVA indicated that MS type (relapsing vs. progressive) (P < .01), disability status (mild vs. moderate) (P < .01), and weight status (normal weight vs. overweight/obese) (P < .05) moderated the efficacy of the behavioral intervention. Conclusions: The behavioral intervention was associated with improvements in physical activity, particularly for those with mild disability, relapsing-remitting MS, or normal weight status. PMID:25892976

  14. Effects of Varying Epoch Lengths, Wear Time Algorithms, and Activity Cut-Points on Estimates of Child Sedentary Behavior and Physical Activity from Accelerometer Data

    PubMed Central

    Banda, Jorge A.; Haydel, K. Farish; Davila, Tania; Desai, Manisha; Haskell, William L.; Matheson, Donna; Robinson, Thomas N.

    2016-01-01

    Objective To examine the effects of accelerometer epoch lengths, wear time (WT) algorithms, and activity cut-points on estimates of WT, sedentary behavior (SB), and physical activity (PA). Methods 268 7–11 year-olds with BMI ≥ 85th percentile for age and sex wore accelerometers on their right hips for 4–7 days. Data were processed and analyzed at epoch lengths of 1-, 5-, 10-, 15-, 30-, and 60-seconds. For each epoch length, WT minutes/day was determined using three common WT algorithms, and minutes/day and percent time spent in SB, light (LPA), moderate (MPA), and vigorous (VPA) PA were determined using five common activity cut-points. ANOVA tested differences in WT, SB, LPA, MPA, VPA, and MVPA when using the different epoch lengths, WT algorithms, and activity cut-points. Results WT minutes/day varied significantly by epoch length when using the NHANES WT algorithm (p < .0001), but did not vary significantly by epoch length when using the ≥ 20 minute consecutive zero or Choi WT algorithms. Minutes/day and percent time spent in SB, LPA, MPA, VPA, and MVPA varied significantly by epoch length for all sets of activity cut-points tested with all three WT algorithms (all p < .0001). Across all epoch lengths, minutes/day and percent time spent in SB, LPA, MPA, VPA, and MVPA also varied significantly across all sets of activity cut-points with all three WT algorithms (all p < .0001). Conclusions The common practice of converting WT algorithms and activity cut-point definitions to match different epoch lengths may introduce significant errors. Estimates of SB and PA from studies that process and analyze data using different epoch lengths, WT algorithms, and/or activity cut-points are not comparable, potentially leading to very different results, interpretations, and conclusions, misleading research and public policy. PMID:26938240

  15. AGE-DEPENDENT CHANGES IN ACTIVITY OF MALLARD PLASMA CHOLINESTERASES

    EPA Science Inventory

    Plasma acetylcholinesterase (AChE) and butrylcholinesterase (BChE) activity was measured repeatedly in 27 mallard (Anas platyrhynchos) ducklings between 7 and 85 days of age to determine age-dependent changes in enzyme activity. Plasma AChE, BChe, and total cholinesterase (ChE) a...

  16. Reversible, activity-dependent targeting of profilin to neuronal nuclei

    SciTech Connect

    Birbach, Andreas . E-mail: andreas.birbach@lbicr.lbg.ac.at; Verkuyl, J. Martin; Matus, Andrew . E-mail: aim@fmi.ch

    2006-07-15

    The actin cytoskeleton in pyramidal neurons plays a major role in activity-dependent processes underlying neuronal plasticity. The small actin-binding protein profilin shows NMDA receptor-dependent accumulation in dendritic spines, which is correlated with suppression of actin dynamics and long-term stabilization of synaptic morphology. Here we show that following NMDA receptor activation profilin also accumulates in the nucleus of hippocampal neurons via a process involving rearrangement of the actin cytoskeleton. This simultaneous targeting to dendritic spines and the cell nucleus suggests a novel mechanism of neuronal plasticity in which profilin both tags activated synapses and influences nuclear events.

  17. Observer-based robust finite time H∞ sliding mode control for Markovian switching systems with mode-dependent time-varying delay and incomplete transition rate.

    PubMed

    Gao, Lijun; Jiang, Xiaoxiao; Wang, Dandan

    2016-03-01

    This paper investigates the problem of robust finite time H∞ sliding mode control for a class of Markovian switching systems. The system is subjected to the mode-dependent time-varying delay, partly unknown transition rate and unmeasurable state. The main difficulty is that, a sliding mode surface cannot be designed based on the unknown transition rate and unmeasurable state directly. To overcome this obstacle, the set of modes is firstly divided into two subsets standing for known transition rate subset and unknown one, based on which a state observer is established. A component robust finite-time sliding mode controller is also designed to cope with the effect of partially unknown transition rate. It is illustrated that the reachability, finite-time stability, finite-time boundedness, finite-time H∞ state feedback stabilization of sliding mode dynamics can be ensured despite the unknown transition rate. Finally, the simulation results verify the effectiveness of robust finite time control problem. PMID:26777336

  18. Delay-dependent stability and stabilization criteria for T-S fuzzy singular systems with interval time-varying delay by improved delay partitioning approach.

    PubMed

    Sun, Chao; Wang, Fuli; He, Xiqin

    2016-01-01

    This paper deals with the stability analysis and fuzzy stabilizing controller design for a class of Takagi-Sugeno fuzzy singular systems with interval time-varying delay and linear fractional uncertainties. By decomposing the delay interval into two unequal subintervals and seeking a appropriate ρ, a new Lyapunov-Krasovskii functional is constructed to develop the improved delay-dependent stability criteria, which ensures the considered system to be regular, impulse-free and stable. Furthermore, the desired fuzzy controller gains are also presented by solving a set of strict linear matrix inequalities. Compared with some existing results, the obtained ones give the result with less conservatism. Finally, some examples are given to show the improvement and the effectiveness of the proposed method. PMID:27066363

  19. Novel TPP-riboswitch activators bypass metabolic enzyme dependency

    NASA Astrophysics Data System (ADS)

    Mayer, Günter; Lünse, Christina; Suckling, Colin; Scott, Fraser

    2014-07-01

    Riboswitches are conserved regions within mRNA molecules that bind specific metabolites and regulate gene expression. TPP-riboswitches, which respond to thiamine pyrophosphate (TPP), are involved in the regulation of thiamine metabolism in numerous bacteria. As these regulatory RNAs are often modulating essential biosynthesis pathways they have become increasingly interesting as promising antibacterial targets. Here, we describe thiamine analogs containing a central 1,2,3-triazole group to induce repression of thiM-riboswitch dependent gene expression in different E. coli strains. Additionally, we show that compound activation is dependent on proteins involved in the metabolic pathways of thiamine uptake and synthesis. The most promising molecule, triazolethiamine (TT), shows concentration dependent reporter gene repression that is dependent on the presence of thiamine kinase ThiK, whereas the effect of pyrithiamine (PT), a known TPP-riboswitch modulator, is ThiK independent. We further show that this dependence can be bypassed by triazolethiamine-derivatives that bear phosphate-mimicking moieties. As triazolethiamine reveals superior activity compared to pyrithiamine, it represents a very promising starting point for developing novel antibacterial compounds that target TPP-riboswitches. Riboswitch-targeting compounds engage diverse endogenous mechanisms to attain in vivo activity. These findings are of importance for the understanding of compounds that require metabolic activation to achieve effective riboswitch modulation and they enable the design of novel compound generations that are independent of endogenous activation mechanisms.

  20. Physicochemical signatures of nanoparticle-dependent complement activation

    SciTech Connect

    Thomas, Dennis G.; Chikkagoudar, Satish; Heredia-Langner, Alejandro; Tardiff, Mark F.; Xu, Zhixiang; Hourcade, Dennis; Pham, Christine; Lanza, Gregory M.; Weinberger, Kilian Q.; Baker, Nathan A.

    2014-03-21

    Nanoparticles are potentially powerful therapeutic tools that have the capacity to target drug payloads and imaging agents. However, some nanoparticles can activate complement, a branch of the innate immune system, and cause adverse side-effects. Recently, we developed an in vitro hemolytic assay protocol for measuring the nanoparticle-dependent complement activity of serum samples and applied this protocol to several nanoparticle formulations that differed in size, surface charge, and surface chemistry; quantifying the nanoparticle-dependent complement activity using a metric called Residual Hemolytic Activity (RHA). In the present work, we have used a decision tree learning algorithm to derive the rules for estimating nanoparticle-dependent complement response based on the data generated from the hemolytic assay studies. Our results indicate that physicochemical properties of nanoparticles, namely, size, polydispersity index, zeta potential, and mole percentage of the active surface ligand of a nanoparticle, can serve as good descriptors for prediction of nanoparticle-dependent complement activation in the decision tree modeling framework. The robustness and predictability of the model can be improved by training the model with additional data points that are uniformly distributed in the RHA/physicochemical descriptor space and by incorporating instability effects on nanoparticle physicochemical properties into the model.

  1. G13-dependent activation of MAPK by thyrotropin.

    PubMed

    Büch, Thomas R H; Biebermann, Heike; Kalwa, Hermann; Pinkenburg, Olaf; Hager, Denise; Barth, Holger; Aktories, Klaus; Breit, Andreas; Gudermann, Thomas

    2008-07-18

    Stimulation of the thyrotropin receptor (TSHR) activates G proteins of all four subfamilies (G(s), G(i/o), G(q/11), and G(12/13)). Whereas G(s)/cAMP-dependent cellular responses upon TSHR stimulation are well established, other signaling pathways are less characterized. We evaluated TSH-elicited cellular responses in human follicular thyroid carcinoma cells stably expressing the TSHR and in primary, nonneoplastic human thyrocytes. In these cellular models, stimulation with TSH caused activation of p44/42 MAPK and subsequent induction of c-Fos. MAPK stimulation occurred independently of G(s), G(i/o), and G(q/11) signaling. Dominant negative constructs of G(12) or G(13) as well as shRNA-mediated suppression of Galpha(12) or Galpha(13) revealed that MAPK activation was dependent on G(13) but not on G(12) signaling. Furthermore, G(13)-dependent transactivation of the epidermal growth factor receptor was necessary for MAPK activation in follicular carcinoma cells, whereas EGFR was not involved in MAPK activation in nonneoplastic primary thyrocytes. The use of bacterial inhibitors of monomeric GTPases revealed that MAPK activation proceeded independently of Rho proteins but was clostridial toxin B-sensitive, suggesting involvement of Cdc42 or Rac. Thus, our data shed new light on cAMP-independent TSHR signaling and identify the first G(13)-dependent TSHR signaling pathway in human thyrocytes. PMID:18445595

  2. Temperature dependence of the activity of Al in dilute Ni(Al) solid solutions

    SciTech Connect

    Jiang Yong; Smith, J. R.; Evans, A. G.

    2006-12-01

    Activities of dilute Al solid solutions in Ni are determined from a first-principles approach. Both thermal lattice vibration and electronic contributions to free energies are considered and compared. Vibrational contributions tend to dominate the temperature dependencies of the free energies, though electron thermal effects are significant. Calculations show opposing temperature trends for the formation enthalpies and entropies, leading to a partial cancellation of their role in the overall energetics. Nevertheless, their remaining temperature effects are strong. Over the temperature range, 400 Kactivity coefficient varies by 15 orders of magnitude, due to the relative strength of Al-Ni and Al-Al bonds. The Ni activity coefficient only varies less than 4% over the same range. Calculational results compare well with available experimental data. The thermodynamic principles elucidated from the calculations are used to provide a fundamental interpretation.

  3. Cumulative Activation of Voltage-Dependent KVS-1 Potassium Channels

    PubMed Central

    Rojas, Patricio; Garst-Orozco, Jonathan; Baban, Beravan; de Santiago-Castillo, Jose Antonio; Covarrubias, Manuel; Salkoff, Lawrence

    2008-01-01

    In this study, we reveal the existence of a novel use-dependent phenomenon in potassium channels, which we refer to as cumulative activation (CA). CA consists of an increase in current amplitude in response to repetitive depolarizing step pulses to the same potential. CA persists for up to 20 s and is similar to a phenomenon called “voltage-dependent facilitation” observed in some calcium channels. The KVS-1 K+ channel, which exhibits CA, is a rapidly activating and inactivating voltage-dependent potassium channel expressed in chemosensory and other neurons of Caenorhabditis elegans. It is unusual in being most closely related to the Shab (Kv2) family of potassium channels, which typically behave like delayed rectifier K+ channels in other species. The magnitude of CA depends on the frequency, voltage, and duration of the depolarizing step pulse. CA also radically changes the activation and inactivation kinetics of the channel, suggesting that the channel may undergo a physical modification in a use-dependent manner; thus, a model that closely simulates the behavior of the channel postulates the existence of two populations of channels, unmodified and modified. Use-dependent changes in the behavior of potassium channels, such as CA observed in KVS-1, could be involved in functional mechanisms of cellular plasticity such as synaptic depression that represent the cellular basis of learning and memory. PMID:18199775

  4. Surface-Energy Dependent Contact Activation of Blood Factor XII

    PubMed Central

    Golas, Avantika; Parhi, Purnendu; Dimachkie, Ziad O.; Siedlecki, Christopher A.; Vogler, Erwin A.

    2009-01-01

    Contact activation of blood factor XII (FXII, Hageman factor) in neat-buffer solution exhibits a parabolic profile when scaled as a function of silanized-glass-particle activator surface energy (measured as advancing water adhesion tension τao=γlvocosθ in dyne/cm, where γlvo is water interfacial tension in dyne/cm and θ is the advancing contact angle). Nearly equal activation is observed at the extremes of activator water-wetting properties −36<τao<72 dyne/cm (0° ≤ θ < 120°), falling sharply through a broad minimum within the 20<τao<40 dyne/cm (55° < θ < 75°) range over which activation yield (putatively FXIIa) rises just above detection limits. Activation is very rapid upon contact with all activators tested and did not significantly vary over 30 minutes of continuous FXII-procoagulant contact. Results suggest that materials falling within the 20<τao<40 dyne/cm surface-energy range should exhibit minimal activation of blood-plasma coagulation through the intrinsic pathway. Surface chemistries falling within this range are, however, a perplexingly difficult target for surface engineering because of the critical balance that must be struck between hydrophobicity and hydrophilicity. Results are interpreted within the context of blood plasma coagulation and the role of water and proteins at procoagulant surfaces. PMID:19892397

  5. Activity-Dependent Modulation of Neural Circuit Synaptic Connectivity

    PubMed Central

    Tessier, Charles R.; Broadie, Kendal

    2009-01-01

    In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; (1) early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and (2) subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circuits are “hard-wired” in a purely activity-independent manner. This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution. These recent studies reveal that activity-dependent mechanisms are indeed required to refine circuit maps in Drosophila during precise, restricted windows of late-phase development. Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS) and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function. This review focuses on our current understanding of activity-dependent synaptic connectivity in Drosophila, primarily through analyzing the role of the fragile X mental retardation protein (FMRP) in the Drosophila FXS disease model. The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail. PMID:19668708

  6. IKKα negatively regulates ASC-dependent inflammasome activation.

    PubMed

    Martin, Bradley N; Wang, Chenhui; Willette-Brown, Jami; Herjan, Tomasz; Gulen, Muhammet F; Zhou, Hao; Bulek, Katarzyna; Franchi, Luigi; Sato, Takashi; Alnemri, Emad S; Narla, Goutham; Zhong, Xiao-Ping; Thomas, James; Klinman, Dennis; Fitzgerald, Katherine A; Karin, Michael; Nuñez, Gabriel; Dubyak, George; Hu, Yinling; Li, Xiaoxia

    2014-01-01

    The inflammasomes are multiprotein complexes that activate caspase-1 in response to infections and stress, resulting in the secretion of pro-inflammatory cytokines. Here we report that IκB kinase α (IKKα) is a critical negative regulator of apoptosis-associated specklike protein containing a C-terminal caspase-activation-andrecruitment (CARD) domain (ASC)-dependent inflammasomes. IKKα controls the inflammasome at the level of the adaptor ASC, which interacts with IKKα in the nucleus of resting macrophages in an IKKα kinase-dependent manner. Loss of IKKα kinase activity results in inflammasome hyperactivation. Mechanistically, the downstream nuclear effector IKK-related kinase (IKKi) facilitates translocation of ASC from the nucleus to the perinuclear area during inflammasome activation. ASC remains under the control of IKKα in the perinuclear area following translocation of the ASC/IKKα complex. Signal 2 of NLRP3 activation leads to inhibition of IKKα kinase activity through the recruitment of PP2A, allowing ASC to participate in NLRP3 inflammasome assembly. Taken together, these findings reveal a IKKi-IKKα-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasomes. PMID:25266676

  7. Chloride dependence of hyperpolarization-activated chloride channel gates.

    PubMed

    Pusch, M; Jordt, S E; Stein, V; Jentsch, T J

    1999-03-01

    1. ClC proteins are a class of voltage-dependent Cl- channels with several members mutated in human diseases. The prototype ClC-0 Torpedo channel is a dimeric protein; each subunit forms a pore that can gate independently from the other one. A common slower gating mechanism acts on both pores simultaneously; slow gating activates ClC-0 at hyperpolarized voltages. The ClC-2 Cl- channel is also activated by hyperpolarization, as are some ClC-1 mutants (e.g. D136G) and wild-type (WT) ClC-1 at certain pH values. 2. We studied the dependence on internal Cl- ([Cl-]i) of the hyperpolarization-activated gates of several ClC channels (WT ClC-0, ClC-0 mutant P522G, ClC-1 mutant D136G and an N-terminal deletion mutant of ClC-2), by patch clamping channels expressed in Xenopus oocytes. 3. With all these channels, reducing [Cl-]i shifted activation to more negative voltages and reduced the maximal activation at most negative voltages. 4. We also investigated the external halide dependence of WT ClC-2 using two-electrode voltage-clamp recording. Reducing external Cl- ([Cl-]o) activated ClC-2 currents. Replacing [Cl-]o by the less permeant Br- reduced channel activity and accelerated deactivation. 5. Gating of the ClC-2 mutant K566Q in normal [Cl-]o resembled that of WT ClC-2 in low [Cl-]o, i.e. channels had a considerable open probability (Po) at resting membrane potential. Substituting external Cl- by Br- or I- led to a decrease in Po. 6. The [Cl-]i dependence of the hyperpolarization-activated gates of various ClC channels suggests a similar gating mechanism, and raises the possibility that the gating charge for the hyperpolarization-activated gate is provided by Cl-. 7. The external halide dependence of hyperpolarization-activated gating of ClC-2 suggests that it is mediated or modulated by anions as in other ClC channels. In contrast to the depolarization-activated fast gates of ClC-0 and ClC-1, the absence of Cl- favours channel opening. Lysine 556 may be important for the

  8. Unconscious Semantic Activation Depends on Feature-Specific Attention Allocation

    ERIC Educational Resources Information Center

    Spruyt, Adriaan; De Houwer, Jan; Everaert, Tom; Hermans, Dirk

    2012-01-01

    We examined whether semantic activation by subliminally presented stimuli is dependent upon the extent to which participants assign attention to specific semantic stimulus features and stimulus dimensions. Participants pronounced visible target words that were preceded by briefly presented, masked prime words. Both affective and non-affective…

  9. A Skew-t space-varying regression model for the spectral analysis of resting state brain activity.

    PubMed

    Ismail, Salimah; Sun, Wenqi; Nathoo, Farouk S; Babul, Arif; Moiseev, Alexader; Beg, Mirza Faisal; Virji-Babul, Naznin

    2013-08-01

    It is known that in many neurological disorders such as Down syndrome, main brain rhythms shift their frequencies slightly, and characterizing the spatial distribution of these shifts is of interest. This article reports on the development of a Skew-t mixed model for the spatial analysis of resting state brain activity in healthy controls and individuals with Down syndrome. Time series of oscillatory brain activity are recorded using magnetoencephalography, and spectral summaries are examined at multiple sensor locations across the scalp. We focus on the mean frequency of the power spectral density, and use space-varying regression to examine associations with age, gender and Down syndrome across several scalp regions. Spatial smoothing priors are incorporated based on a multivariate Markov random field, and the markedly non-Gaussian nature of the spectral response variable is accommodated by the use of a Skew-t distribution. A range of models representing different assumptions on the association structure and response distribution are examined, and we conduct model selection using the deviance information criterion. (1) Our analysis suggests region-specific differences between healthy controls and individuals with Down syndrome, particularly in the left and right temporal regions, and produces smoothed maps indicating the scalp topography of the estimated differences. PMID:22614763

  10. Modeling and classifying human activities from trajectories using a class of space-varying parametric motion fields.

    PubMed

    Nascimento, Jacinto C; Marques, Jorge S; Lemos, João M

    2013-05-01

    Many approaches to trajectory analysis, such as clustering or classification, use probabilistic generative models, thus not requiring trajectory alignment/registration. Switched linear dynamical models (e.g., HMMs) have been used in this context, due to their ability to describe different motion regimes. However, these models are not suitable for handling space-dependent dynamics that are more naturally captured by nonlinear models. As is well known, these are more difficult to identify. In this paper, we propose a new way of modeling trajectories, based on a mixture of parametric motion vector fields that depend on a small number of parameters. Switching among these fields follows a probabilistic mechanism, characterized by a field of stochastic matrices. This approach allows representing a wide variety of trajectories and modeling space-dependent behaviors without using global nonlinear dynamical models. Experimental evaluation is conducted in both synthetic and real scenarios. The latter concerning with human trajectory modeling for activity classification, a central task in video surveillance. PMID:23380856

  11. Cortical activation during delay discounting in abstinent methamphetamine dependent individuals

    PubMed Central

    Schwartz, Daniel L.; Huckans, Marilyn S.; McFarland, Bentson H.; Meiri, Gal; Stevens, Alexander A.; Mitchell, Suzanne H.

    2010-01-01

    Background Methamphetamine (MA)-dependent individuals prefer smaller immediate over larger delayed rewards in delay discounting (DD) tasks. Human and animal data implicate ventral (amygdala, ventral striatum, ventrolateral prefrontal cortex insula) and dorsal (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex and posterior parietal cortex) systems in DD decisions. The ventral system is hypothesized to respond to the salience and immediacy of rewards while the dorsal system is implicated in the process of comparison and choice. Methods We used functional Magnetic Resonance Imaging to probe the neural correlates of DD in 19 recently abstinent MA-dependent patients and 17 age- and gender-matched controls. Results Hard DD choices were associated with greatest activation in bilateral middle cingulate, posterior parietal cortex (PPC), and the right rostral insula. Control subjects showed more activation than MA patients bilaterally in the precuneus and in the right caudate nucleus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Magnitude of discounting was correlated with activity in the amygdala, DLPFC, posterior cingulate cortex and PPC. Conclusions Our findings were consistent with a model wherein dorsal cognitive systems modulate the neural response of ventral regions. Patients addicted to MA, who strongly prefer smaller immediate over larger delayed rewards, activate the dorsal cognitive control system in order to overcome their preference. Activation of the amygdala during choice of delayed rewards was associated with a greater degree of discounting, suggesting that heavily discounting MA-dependent individuals may be more responsive to the negative salience of delayed rewards than controls. PMID:18685833

  12. IKKα negatively regulates ASC-dependent inflammasome activation

    PubMed Central

    Martin, Bradley N.; Wang, Chenhui; Willette-Brown, Jami; Herjan, Tomasz; Gulen, Muhammet F.; Zhou, Hao; Bulek, Katarzyna; Franchi, Luigi; Sato, Takashi; Narla, Goutham; Zhong, Xiao-Ping; Thomas, James; Klinman, Dennis; Fitzgerald, Katherine A.; Karin, Michael; Nuñez, Gabriel; Dubyak, George; Hu, Yinling; Li, Xiaoxia

    2014-01-01

    The inflammasomes are multiprotein complexes that activate caspase-1 in response to infections and stress, resulting in the secretion of pro-inflammatory cytokines. Here we report that IKKα is a critical negative regulator of ASC-dependent inflammasomes. IKKα controls the inflammasome at the level of the adaptor ASC, which interacts with IKKα in the nucleus of resting macrophages in an IKKα kinase-dependent manner. Loss of IKKα kinase activity results in inflammasome hyperactivation. Mechanistically, the downstream nuclear effector IKKi facilitates translocation of ASC from the nucleus to the perinuclear area during inflammasome activation. ASC remains under the control of IKKα in the perinuclear area following translocation of the ASC/IKKα complex. Signal 2 of NLRP3 activation leads to inhibition of IKKα kinase activity through the recruitment of PP2A, allowing ASC to participate in NLRP3 inflammasome assembly. Taken together, these findings reveal a IKKi-IKKα-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasomes. PMID:25266676

  13. Activity-dependent plasticity of hippocampal place maps.

    PubMed

    Schoenenberger, Philipp; O'Neill, Joseph; Csicsvari, Jozsef

    2016-01-01

    Hippocampal neurons encode a cognitive map of space. These maps are thought to be updated during learning and in response to changes in the environment through activity-dependent synaptic plasticity. Here we examine how changes in activity influence spatial coding in rats using halorhodopsin-mediated, spatially selective optogenetic silencing. Halorhoposin stimulation leads to light-induced suppression in many place cells and interneurons; some place cells increase their firing through disinhibition, whereas some show no effect. We find that place fields of the unaffected subpopulation remain stable. On the other hand, place fields of suppressed place cells were unstable, showing remapping across sessions before and after optogenetic inhibition. Disinhibited place cells had stable maps but sustained an elevated firing rate. These findings suggest that place representation in the hippocampus is constantly governed by activity-dependent processes, and that disinhibition may provide a mechanism for rate remapping. PMID:27282121

  14. Activity-dependent plasticity of hippocampal place maps

    PubMed Central

    Schoenenberger, Philipp; O'Neill, Joseph; Csicsvari, Jozsef

    2016-01-01

    Hippocampal neurons encode a cognitive map of space. These maps are thought to be updated during learning and in response to changes in the environment through activity-dependent synaptic plasticity. Here we examine how changes in activity influence spatial coding in rats using halorhodopsin-mediated, spatially selective optogenetic silencing. Halorhoposin stimulation leads to light-induced suppression in many place cells and interneurons; some place cells increase their firing through disinhibition, whereas some show no effect. We find that place fields of the unaffected subpopulation remain stable. On the other hand, place fields of suppressed place cells were unstable, showing remapping across sessions before and after optogenetic inhibition. Disinhibited place cells had stable maps but sustained an elevated firing rate. These findings suggest that place representation in the hippocampus is constantly governed by activity-dependent processes, and that disinhibition may provide a mechanism for rate remapping. PMID:27282121

  15. Delay-dependent reliable H ∞ filtering for sector-bounded nonlinear continuous-time systems with time-varying state delays and sensor failures

    NASA Astrophysics Data System (ADS)

    Guo, Xiang-Gui; Yang, Guang-Hong

    2012-01-01

    In this article, the reliable H ∞ filtering problem against sensor failures is investigated for a class of continuous-time systems with simultaneous sector-bounded nonlinearities and varying time delays. The focus of this article is on designing a reliable filter such that the filtering error system is asymptotically stable and meets the prescribed H ∞ norm constraint in the normal case as well as in the sensor failure case simultaneously. Linear matrix inequality conditions, which depend not only on the upper and lower bounds of delay but also on the upper bound of delay derivative, are obtained for the existence of admissible filters and, based on these, the filter design is cast into a convex optimisation problem. What is worth mentioning is that the information about the upper bound of the delay derivative is taken into consideration even if this upper bound is not smaller than 1. A numerical example is presented to illustrate the effectiveness and advantage of the developed filter design method.

  16. Effects of acute smoking on brain activity vary with abstinence in smokers performing the N-Back Task: a preliminary study

    PubMed Central

    Xu, Jiansong; Mendrek, Adrianna; Cohen, Mark S.; Monterosso, John; Simon, Sara; Brody, Arthur L.; Jarvik, Murray; Rodriguez, Paul; Ernst, Monique; London, Edythe D.

    2007-01-01

    We previously reported that compared with a non-deprivation state, overnight abstinence from cigarette smoking was associated with higher brain activity in the left dorsolateral prefrontal cortex (L-DLPFC) during a low demanding working memory challenge, and little increase beyond this activity level during more taxing working memory conditions. In the present study, we aimed to assess how recent smoking (overnight abstinence Vs smoking ad libitum) influenced the effect of smoking a cigarette on brain activity related to a working memory challenge. Six smokers performed the N-Back working memory task during functional magnetic resonance imaging (fMRI) both before and after smoking a cigarette in each of two test sessions: one following overnight abstinence from smoking (>13 h) and the other following ad libitum smoking. Task-related activity in L-DLPFC showed a significant interaction between the effects of acute smoking, test session, and task load. After overnight abstinence, post-smoking brain activity in L-DLPFC was lower than before smoking at low task-load and higher at high task-load; corresponding activity on a day of ad libitum smoking was higher at low load and lower at high task-load after smoking during the session. These data suggest that the effect of acute smoking on working-memory processing depends on recent prior smoking and task-load. In particular, they provide preliminary evidence that functional efficiency of working memory is improved by smoking a cigarette during abstinence, while the effect of a cigarette in a non-deprived state varies with the nature and difficulty of the working memory challenge. This interaction merits further examination in larger studies specifically designed to consider this issue. PMID:17088048

  17. Cyclic AMP-dependent protein kinase activity in Trypanosoma cruzi.

    PubMed Central

    Ulloa, R M; Mesri, E; Esteva, M; Torres, H N; Téllez-Iñón, M T

    1988-01-01

    A cyclic AMP-dependent protein kinase activity from epimastigote forms of Trypanosoma cruzi was characterized. Cytosolic extracts were chromatographed on DEAE-cellulose columns, giving two peaks of kinase activity, which were eluted at 0.15 M- and 0.32 M-NaCl respectively. The second activity peak was stimulated by nanomolar concentrations of cyclic AMP. In addition, a cyclic AMP-binding protein co-eluted with the second kinase activity peak. Cyclic AMP-dependent protein kinase activity was further purified by gel filtration, affinity chromatography on histone-agarose and cyclic AMP-agarose, as well as by chromatography on CM-Sephadex. The enzyme ('holoenzyme') could be partially dissociated into two different components: 'catalytic' and 'regulatory'. The 'regulatory' component had specific binding for cyclic AMP, and it inhibited phosphotransferase activity of the homologous 'catalytic component' or of the 'catalytic subunit' from bovine heart. Cyclic AMP reversed these inhibitions. A 'holoenzyme preparation' was phosphorylated in the absence of exogenous phosphate acceptor and analysed by polyacrylamide-gel electrophoresis. A 56 kDa band was phosphorylated. The same preparation was analysed by Western blotting, by using polyclonal antibodies to the regulatory subunits of protein kinases type I or II. Both antibodies reacted with the 56 kDa band. Images Fig. 7. Fig. 8. PMID:2848508

  18. Solar activity dependence of nightside aurora in winter conditions

    NASA Astrophysics Data System (ADS)

    Zhou, Su; Luan, Xiaoli; Dou, Xiankang

    2016-02-01

    The dependence of the nightside (21:00-03:00 MLT; magnetic local time) auroral energy flux on solar activity was quantitatively studied for winter/dark and geomagnetically quiet conditions. Using data combined from Thermosphere, Ionosphere, Mesosphere Energetics and Dynamics/Global Ultraviolet Imager and Defense Meteorological Satellite Program/Special Sensor Ultraviolet Spectrographic Imager observations, we separated the effects of geomagnetic activity from those of solar flux on the nightside auroral precipitation. The results showed that the nightside auroral power was reduced by ~42% in solar maximum (F10.7 = 200 sfu; solar flux unit 1 sfu = 10-22 W m-2 Hz-1) with respect to that under solar minimum (F10.7 = 70 sfu) for the Kp = 1 condition, and this change rate became less (~21%) for the Kp = 3 condition. In addition, the solar cycle dependence of nightside auroral power was similar with that from both the premidnight (21:00-23:00 MLT) and postmidnight (01:00-03:00 MLT) sectors. These results indicated that as the ionospheric ionization increases with the enhanced auroral and geomagnetic activities, the solar activity dependences of nightside auroral power become weaker, at least under geomagnetically quiet conditions.

  19. An fMRI study of joint action-varying levels of cooperation correlates with activity in control networks.

    PubMed

    Chaminade, Thierry; Marchant, Jennifer L; Kilner, James; Frith, Christopher D

    2012-01-01

    As social agents, humans continually interact with the people around them. Here, motor cooperation was investigated using a paradigm in which pairs of participants, one being scanned with fMRI, jointly controlled a visually presented object with joystick movements. The object oscillated dynamically along two dimensions, color and width of gratings, corresponding to the two cardinal directions of joystick movements. While the overall control of each participant on the object was kept constant, the amount of cooperation along the two dimensions varied along four levels, from no (each participant controlled one dimension exclusively) to full (each participant controlled half of each dimension) cooperation. Increasing cooperation correlated with BOLD signal in the left parietal operculum and anterior cingulate cortex (ACC), while decreasing cooperation correlated with activity in the right inferior frontal and superior temporal gyri, the intraparietal sulci and inferior temporal gyri bilaterally, and the dorsomedial prefrontal cortex. As joint performance improved with the level of cooperation, we assessed the brain responses correlating with behavior, and found that activity in most of the areas associated with levels of cooperation also correlated with the joint performance. The only brain area found exclusively in the negative correlation with cooperation was in the dorso medial frontal cortex, involved in monitoring action outcome. Given the cluster location and condition-related signal change, we propose that this region monitored actions to extract the level of cooperation in order to optimize the joint response. Our results, therefore, indicate that, in the current experimental paradigm involving joint control of a visually presented object with joystick movements, the level of cooperation affected brain networks involved in action control, but not mentalizing. PMID:22715326

  20. An fMRI study of joint action–varying levels of cooperation correlates with activity in control networks

    PubMed Central

    Chaminade, Thierry; Marchant, Jennifer L.; Kilner, James; Frith, Christopher D.

    2012-01-01

    As social agents, humans continually interact with the people around them. Here, motor cooperation was investigated using a paradigm in which pairs of participants, one being scanned with fMRI, jointly controlled a visually presented object with joystick movements. The object oscillated dynamically along two dimensions, color and width of gratings, corresponding to the two cardinal directions of joystick movements. While the overall control of each participant on the object was kept constant, the amount of cooperation along the two dimensions varied along four levels, from no (each participant controlled one dimension exclusively) to full (each participant controlled half of each dimension) cooperation. Increasing cooperation correlated with BOLD signal in the left parietal operculum and anterior cingulate cortex (ACC), while decreasing cooperation correlated with activity in the right inferior frontal and superior temporal gyri, the intraparietal sulci and inferior temporal gyri bilaterally, and the dorsomedial prefrontal cortex. As joint performance improved with the level of cooperation, we assessed the brain responses correlating with behavior, and found that activity in most of the areas associated with levels of cooperation also correlated with the joint performance. The only brain area found exclusively in the negative correlation with cooperation was in the dorso medial frontal cortex, involved in monitoring action outcome. Given the cluster location and condition-related signal change, we propose that this region monitored actions to extract the level of cooperation in order to optimize the joint response. Our results, therefore, indicate that, in the current experimental paradigm involving joint control of a visually presented object with joystick movements, the level of cooperation affected brain networks involved in action control, but not mentalizing. PMID:22715326

  1. Stress versus temperature dependent activation energies in creep

    NASA Technical Reports Server (NTRS)

    Freed, A. D.; Raj, S. V.; Walker, K. P.

    1990-01-01

    The activation energy for creep at low stresses and elevated temperatures is lattice diffusion, where the rate controlling mechanism for deformation is dislocation climb. At higher stresses and intermediate temperatures, the rate controlling mechanism changes from that of dislocation climb to one of obstacle-controlled dislocation glide. Along with this change, there occurs a change in the activation energy. It is shown that a temperature-dependent Gibbs free energy does a good job of correlating steady-state creep data, while a stress-dependent Gibbs free energy does a less desirable job of correlating the same data. Applications are made to copper and a LiF-22 mol. percent CaF2 hypereutectic salt.

  2. Stress versus temperature dependence of activation energies for creep

    NASA Technical Reports Server (NTRS)

    Freed, A. D.; Raj, S. V.; Walker, K. P.

    1992-01-01

    The activation energy for creep at low stresses and elevated temperatures is associated with lattice diffusion, where the rate controlling mechanism for deformation is dislocation climb. At higher stresses and intermediate temperatures, the rate controlling mechanism changes from dislocation climb to obstacle-controlled dislocation glide. Along with this change in deformation mechanism occurs a change in the activation energy. When the rate controlling mechanism for deformation is obstacle-controlled dislocation glide, it is shown that a temperature-dependent Gibbs free energy does better than a stress-dependent Gibbs free energy in correlating steady-state creep data for both copper and LiF-22mol percent CaF2 hypereutectic salt.

  3. Online Activity Levels Are Related to Caffeine Dependency.

    PubMed

    Phillips, James G; Landhuis, C Erik; Shepherd, Daniel; Ogeil, Rowan P

    2016-05-01

    Online activity could serve in the future as behavioral markers of emotional states for computer systems (i.e., affective computing). Hence, this study considered relationships between self-reported stimulant use and online study patterns. Sixty-two undergraduate psychology students estimated their daily caffeine use, and this was related to study patterns as tracked by their use of a Learning Management System (Blackboard). Caffeine dependency was associated with less time spent online, lower rates of file access, and fewer online activities completed. Reduced breadth or depth of processing during work/study could be used as a behavioral marker of stimulant use. PMID:27096737

  4. The Zinc-Dependent Protease Activity of the Botulinum Neurotoxins

    PubMed Central

    Lebeda, Frank J.; Cer, Regina Z.; Mudunuri, Uma; Stephens, Robert; Singh, Bal Ram; Adler, Michael

    2010-01-01

    The botulinum neurotoxins (BoNT, serotypes A-G) are some of the most toxic proteins known and are the causative agents of botulism. Following exposure, the neurotoxin binds and enters peripheral cholinergic nerve endings and specifically and selectively cleaves one or more SNARE proteins to produce flaccid paralysis. This review centers on the kinetics of the Zn-dependent proteolytic activities of these neurotoxins, and briefly describes inhibitors, activators and factors underlying persistence of toxin action. Some of the structural, enzymatic and inhibitor data that are discussed here are available at the botulinum neurotoxin resource, BotDB (http://botdb.abcc.ncifcrf.gov). PMID:22069621

  5. Sex-dependent activity of the spinal excitatory amino acid transporter: Role of estrous cycle.

    PubMed

    Sajjad, Jahangir; Felice, Valeria D; Golubeva, Anna V; Cryan, John F; O'Mahony, Siobhain M

    2016-10-01

    Females are more likely to experience visceral pain than males, yet mechanisms underlying this sex bias are not fully elucidated. Moreover, pain sensitivity can change throughout the menstrual cycle. Alterations in the glutamatergic system have been implicated in several pain-disorders; however, whether these are sex-dependent is unclear. Thus, we aimed to investigate sex differences in the spinal cord glutamate uptake and how it varies across the estrous cycle. The activity of the glutamate transporters, excitatory amino acid transporters (EAATs) was assessed using an ex vivo aspartate radioactive uptake assay in the lumbosacral spinal cord in Sprague-Dawley male and female rats. The gene expression of EAATs, glutamate receptor subunits NR1 and NR2B and the estrogen receptors ERα & ERβ in the spinal cord were also analyzed. EAAT activity was lower in females, particularly during the estrus phase, and this was the only cycle stage that was responsive to the pharmacological effects of the EAATs activator riluzole. Interestingly, EAAT1 mRNA expression was lower in high-estrogen and high-ERα states compared to diestrus in females. We conclude that the Spinal EAAT activity in females is different to that in males, and varies across the estrous cycle. Furthermore, the expression levels of estrogen receptors also showed a cycle-dependent pattern that may affect EAATs function and expression. PMID:27471194

  6. Molecular Determinants of GS-9620-Dependent TLR7 Activation

    PubMed Central

    Rebbapragada, Indrani; Birkus, Gabriel; Perry, Jason; Xing, Weimei; Kwon, HyockJoo; Pflanz, Stefan

    2016-01-01

    GS-9620 is an orally administered agonist of Toll-like receptor (TLR)7 currently being evaluated in clinical studies for the treatment of chronic HBV and HIV patients. GS-9620 has shown antiviral efficacy in preclinical models of chronic hepadnavirus infection in woodchuck as well as chimpanzee. However, the molecular determinants of GS-9620-dependent activation of TLR7 are not well defined. The studies presented here elucidate GS-9620 subcellular distribution and characterize its molecular interactions with human TLR7 using structure-guided mutational analysis. Based on our results we present a molecular model of TLR7 bound to GS-9620. We also determine that several coding SNPs had no effect on GS-9620-dependent TLR7 activation. In addition, our studies provide evidence that TLR7 exists in a ligand-independent oligomeric state and that, TLR7 activation by GS-9620 is likely associated with compound-induced conformational changes. Finally, we demonstrate that activation of NF-κB and Akt pathways in primary plasmacytoid dendritic cells occur as immediate downstream cellular responses to GS-9620 stimulation. The data presented here further our understanding of the molecular parameters governing TLR7 activation by GS-9620, and more generally by nucleos/tide-related ligands. PMID:26784926

  7. Allosteric activation of apicomplexan calcium-dependent protein kinases.

    PubMed

    Ingram, Jessica R; Knockenhauer, Kevin E; Markus, Benedikt M; Mandelbaum, Joseph; Ramek, Alexander; Shan, Yibing; Shaw, David E; Schwartz, Thomas U; Ploegh, Hidde L; Lourido, Sebastian

    2015-09-01

    Calcium-dependent protein kinases (CDPKs) comprise the major group of Ca2+-regulated kinases in plants and protists. It has long been assumed that CDPKs are activated, like other Ca2+-regulated kinases, by derepression of the kinase domain (KD). However, we found that removal of the autoinhibitory domain from Toxoplasma gondii CDPK1 is not sufficient for kinase activation. From a library of heavy chain-only antibody fragments (VHHs), we isolated an antibody (1B7) that binds TgCDPK1 in a conformation-dependent manner and potently inhibits it. We uncovered the molecular basis for this inhibition by solving the crystal structure of the complex and simulating, through molecular dynamics, the effects of 1B7-kinase interactions. In contrast to other Ca2+-regulated kinases, the regulatory domain of TgCDPK1 plays a dual role, inhibiting or activating the kinase in response to changes in Ca2+ concentrations. We propose that the regulatory domain of TgCDPK1 acts as a molecular splint to stabilize the otherwise inactive KD. This dependence on allosteric stabilization reveals a novel susceptibility in this important class of parasite enzymes. PMID:26305940

  8. Allosteric activation of apicomplexan calcium-dependent protein kinases

    PubMed Central

    Ingram, Jessica R.; Knockenhauer, Kevin E.; Markus, Benedikt M.; Mandelbaum, Joseph; Ramek, Alexander; Shan, Yibing; Shaw, David E.; Schwartz, Thomas U.; Ploegh, Hidde L.; Lourido, Sebastian

    2015-01-01

    Calcium-dependent protein kinases (CDPKs) comprise the major group of Ca2+-regulated kinases in plants and protists. It has long been assumed that CDPKs are activated, like other Ca2+-regulated kinases, by derepression of the kinase domain (KD). However, we found that removal of the autoinhibitory domain from Toxoplasma gondii CDPK1 is not sufficient for kinase activation. From a library of heavy chain-only antibody fragments (VHHs), we isolated an antibody (1B7) that binds TgCDPK1 in a conformation-dependent manner and potently inhibits it. We uncovered the molecular basis for this inhibition by solving the crystal structure of the complex and simulating, through molecular dynamics, the effects of 1B7–kinase interactions. In contrast to other Ca2+-regulated kinases, the regulatory domain of TgCDPK1 plays a dual role, inhibiting or activating the kinase in response to changes in Ca2+ concentrations. We propose that the regulatory domain of TgCDPK1 acts as a molecular splint to stabilize the otherwise inactive KD. This dependence on allosteric stabilization reveals a novel susceptibility in this important class of parasite enzymes. PMID:26305940

  9. Activity-dependent genes in mouse olfactory sensory neurons.

    PubMed

    Fischl, Adrian M; Heron, Paula M; Stromberg, Arnold J; McClintock, Timothy S

    2014-06-01

    Activity-dependent survival of olfactory sensory neurons (OSNs) may allow animals to tune their olfactory systems to match their odor environment. Activity-dependent genes should play important roles in this process, motivating experiments to identify them. Both unilateral naris occlusion of mice for 6 days and genetic silencing of OSNs decreased S100A5, Lrrc3b, Kirrel2, Slc17a6, Rasgrp4, Pcp4l1, Plcxd3, and Kcnn2 while increasing Kirrel3. Naris occlusion also decreased Eml5, Ptprn, and Nphs1. OSN number was unchanged and stress-response mRNAs were unaffected after 6 days of naris occlusion. This leaves odor stimulation as the most likely cause of differential abundance of these mRNAs, but through a mechanism that is slow or indirect for most because 30-40 min of odor stimulation increased only 3 of 11 mRNAs decreased by naris occlusion: S100A5, Lrrc3b, and Kirrel2. Odorant receptor (OR) mRNAs were significantly more variable than the average mRNA, consistent with difficulty in reliably detecting changes in these mRNAs after 6 days of naris occlusion. One OR mRNA, Olfr855, was consistently decreased, however. These results suggest that the latency from the cessation of odor stimulation to effects on activity-dependent OSN survival must be a week or more in juvenile mice. PMID:24692514

  10. Activity-Dependent Genes in Mouse Olfactory Sensory Neurons

    PubMed Central

    2014-01-01

    Activity-dependent survival of olfactory sensory neurons (OSNs) may allow animals to tune their olfactory systems to match their odor environment. Activity-dependent genes should play important roles in this process, motivating experiments to identify them. Both unilateral naris occlusion of mice for 6 days and genetic silencing of OSNs decreased S100A5, Lrrc3b, Kirrel2, Slc17a6, Rasgrp4, Pcp4l1, Plcxd3, and Kcnn2 while increasing Kirrel3. Naris occlusion also decreased Eml5, Ptprn, and Nphs1. OSN number was unchanged and stress-response mRNAs were unaffected after 6 days of naris occlusion. This leaves odor stimulation as the most likely cause of differential abundance of these mRNAs, but through a mechanism that is slow or indirect for most because 30–40min of odor stimulation increased only 3 of 11 mRNAs decreased by naris occlusion: S100A5, Lrrc3b, and Kirrel2. Odorant receptor (OR) mRNAs were significantly more variable than the average mRNA, consistent with difficulty in reliably detecting changes in these mRNAs after 6 days of naris occlusion. One OR mRNA, Olfr855, was consistently decreased, however. These results suggest that the latency from the cessation of odor stimulation to effects on activity-dependent OSN survival must be a week or more in juvenile mice. PMID:24692514

  11. Bilateral Activity-Dependent Interactions in the Developing Corticospinal System

    PubMed Central

    Friel, Kathleen M.; Martin, John H.

    2009-01-01

    Activity-dependent competition between the corticospinal (CS) systems in each hemisphere drives postnatal development of motor skills and stable CS tract connections with contralateral spinal motor circuits. Unilateral restriction of motor cortex (M1) activity during an early postnatal critical period impairs contralateral visually guided movements later in development and in maturity. Silenced M1 develops aberrant connections with the contralateral spinal cord whereas the initially active M1, in the other hemisphere, develops bilateral connections. In this study, we determined whether the aberrant pattern of CS tract terminations and motor impairments produced by early postnatal M1 activity restriction could be abrogated by reducing activity-dependent synaptic competition from the initially active M1 later in development. We first inactivated M1 unilaterally between postnatal weeks 5–7. We next inactivated M1 on the other side from weeks 7–11 (alternate inactivation), to reduce the competitive advantage that this side may have over the initially inactivated side. Alternate inactivation redirected aberrant contralateral CS tract terminations from the initially silenced M1 to their normal spinal territories and reduced the density of aberrant ipsilateral terminations from the initially active side. Normal movement endpoint control during visually guided locomotion was fully restored. This reorganization of CS terminals reveals an unsuspected late plasticity after the critical period for establishing the pattern of CS terminations in the spinal cord. Our findings show that robust bilateral interactions between the developing CS systems on each side are important for achieving balance between contralateral and ipsilateral CS tract connections and visuomotor control. PMID:17928450

  12. Activation of muscarinic receptors by ACh release in hippocampal CA1 depolarizes VIP but has varying effects on parvalbumin-expressing basket cells

    PubMed Central

    Bell, L Andrew; Bell, Karen A; McQuiston, A Rory

    2015-01-01

    We investigated the effect of acetylcholine release on mouse hippocampal CA1 perisomatically projecting interneurons. Acetylcholine was optogenetically released in hippocampal slices by expressing the excitatory optogenetic protein oChIEF-tdTomato in medial septum/diagonal band of Broca cholinergic neurons using Cre recombinase-dependent adeno-associated virally mediated transfection. The effect of optogenetically released acetylcholine was assessed on interneurons expressing Cre recombinase in vasoactive intestinal peptide (VIP) or parvalbumin (PV) interneurons using whole cell patch clamp methods. Acetylcholine released onto VIP interneurons that innervate pyramidal neuron perisomatic regions (basket cells, BCs) were depolarized by muscarinic receptors. Although PV BCs were also excited by muscarinic receptor activation, they more frequently responded with hyperpolarizing or biphasic responses. Muscarinic receptor activation resulting from ACh release increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in downstream hippocampal CA1 pyramidal neurons with peak instantaneous frequencies occurring in both the gamma and theta bandwidths. Both PV and VIP BCs contributed to the increased sIPSC frequency in pyramidal neurons and optogenetic suppression of PV or VIP BCs inhibited sIPSCs occurring in the gamma range. Therefore, we propose acetylcholine release in CA1 has a complex effect on CA1 pyramidal neuron output through varying effects on perisomatically projecting interneurons. PMID:25556796

  13. Learning and memory in the forced swimming test: effects of antidepressants having varying degrees of anticholinergic activity.

    PubMed

    Enginar, Nurhan; Yamantürk-Çelik, Pınar; Nurten, Asiye; Güney, Dilvin Berrak

    2016-07-01

    The antidepressant-induced reduction in immobility time in the forced swimming test may depend on memory impairment due to the drug's anticholinergic efficacy. Therefore, the present study evaluated learning and memory of the immobility response in rats after the pretest and test administrations of antidepressants having potent, comparatively lower, and no anticholinergic activities. Immobility was measured in the test session performed 24 h after the pretest session. Scopolamine and MK-801, which are agents that have memory impairing effects, were used as reference drugs for a better evaluation of the memory processes in the test. The pretest administrations of imipramine (15 and 30 mg/kg), amitriptyline (7.5 and 15 mg/kg), trazodone (10 mg/kg), fluoxetine (10 and 20 mg/kg), and moclobemide (10 and 20 mg/kg) were ineffective, whereas the pretest administrations of scopolamine (0.5 mg/kg) and MK-801 (0.1 mg/kg) decreased immobility time suggesting impaired "learning to be immobile" in the animals. The test administrations of imipramine (30 mg/kg), amitriptyline (15 mg/kg), moclobemide (10 mg/kg), scopolamine (0.5 and 1 mg/kg), and MK-801 (0.1 mg/kg) decreased immobility time, which suggested that the drugs exerted antidepressant activity or the animals did not recall that attempting to escape was futile. The test administrations of trazodone (10 mg/kg) and fluoxetine (10 and 20 mg/kg) produced no effect on immobility time. Even though the false-negative and positive responses made it somewhat difficult to interpret the findings, this study demonstrated that when given before the pretest antidepressants with or without anticholinergic activity seemed to be devoid of impairing the learning process in the test. PMID:27037827

  14. Biotite dissolution in brine at varied temperatures and CO2 pressures: its activation energy and potential CO2 intercalation.

    PubMed

    Hu, Yandi; Jun, Young-Shin

    2012-10-16

    For sustainable geologic CO(2) sequestration (GCS), it is important to understand the effects of temperature and CO(2) pressure on mica's dissolution and surface morphological changes under saline hydrothermal conditions. Batch experiments were conducted with biotite (Fe-end member mica) under conditions relevant to GCS sites (35-95 °C and 75-120 atm CO(2)), and 1 M NaCl solution was used to mimic the brine. With increasing temperature, a transition from incongruent to congruent dissolution of biotite was observed. The dissolution activation energy based on Si release was calculated to be 52 ± 5 kJ mol(-1). By comparison with N(2) experiments, we showed that CO(2) injection greatly enhanced biotite's dissolution and its surface morphology evolutions, such as crack formation and detachment of newly formed fibrous illite. For biotite's dissolution and morphological evolutions, the pH effects of CO(2) were differentiated from the effects of bicarbonate complexation and CO(2) intercalation. Bicarbonate complexation effects on ion release from biotite were found to be minor under our experimental conditions. On the other hand, the CO(2) molecules in brine could get into the biotite interlayer and cause enhanced swelling of the biotite interlayer and hence the observed promotion of biotite surface cracking. The cracking created more reactive surface area in contact with brine and thus enhanced the later ion release from biotite. These results provide new information for understanding CO(2)-brine-mica interactions in saline aquifers with varied temperatures and CO(2) pressures, which can be useful for GCS site selection and operations. PMID:22989382

  15. In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant.

    PubMed

    van Haren, Simon D; Ganapathi, Lakshmi; Bergelson, Ilana; Dowling, David J; Banks, Michaela; Samuels, Ronald C; Reed, Steven G; Marshall, Jason D; Levy, Ofer

    2016-07-01

    Most infections occur in early life, prompting development of novel adjuvanted vaccines to protect newborns and infants. Several Toll-like receptor (TLR) agonists (TLRAs) are components of licensed vaccine formulations or are in development as candidate adjuvants. However, the type and magnitude of immune responses to TLRAs may vary with the TLR activated as well as age and geographic location. Most notably, in newborns, as compared to adults, the immune response to TLRAs is polarized with lower Th1 cytokine production and robust Th2 and anti-inflammatory cytokine production. The ontogeny of TLR-mediated cytokine responses in international cohorts has been reported, but no study has compared cytokine responses to TLRAs between U.S. neonates and infants at the age of 6months. Both are critical age groups for the currently pediatric vaccine schedule. In this study, we report quantitative differences in the production of a panel of 14 cytokines and chemokines after in vitro stimulation of newborn cord blood and infant and adult peripheral blood with agonists of TLR4, including monophosphoryl lipid A (MPLA) and glucopyranosyl lipid Adjuvant aqueous formulation (GLA-AF), as well as agonists of TLR7/8 (R848) and TLR9 (CpG). Both TLR4 agonists, MPLA and GLA-AF, induced greater concentrations of Th1 cytokines CXCL10, TNF and Interleukin (IL)-12p70 in infant and adult blood compared to newborn blood. All the tested TLRAs induced greater infant IFN-α2 production compared to newborn and adult blood. In contrast, CpG induced greater IFN-γ, IL-1β, IL-4, IL-12p40, IL-10 and CXCL8 in newborn than in infant and adult blood. Overall, to the extent that these in vitro studies mirror responses in vivo, our study demonstrates distinct age-specific effects of TLRAs that may inform their development as candidate adjuvants for early life vaccines. PMID:27081760

  16. A DNA enzyme with Mg(2+)-Dependent RNA Phosphoesterase Activity

    NASA Technical Reports Server (NTRS)

    Breaker, Ronald R.; Joyce, Gerald F.

    1995-01-01

    Previously we demonstrated that DNA can act as an enzyme in the Pb(2+)-dependent cleavage of an RNA phosphoester. This is a facile reaction, with an uncatalyzed rate for a typical RNA phosphoester of approx. 10(exp -4)/ min in the presence of 1 mM Pb(OAc)2 at pH 7.0 and 23 C. The Mg(2+) - dependent reaction is more difficult, with an uncatalyzed rate of approx. 10(exp -7)/ min under comparable conditions. Mg(2+) - dependent cleavage has special relevance to biology because it is compatible with intracellular conditions. Using in vitro selection, we sought to develop a family of phosphoester-cleaving DNA enzymes that operate in the presence of various divalent metals, focusing particularly on the Mg(2+) - dependent reaction. Results: We generated a population of greater than 10(exp 13) DNAs containing 40 random nucleotides and carried out repeated rounds of selective amplification, enriching for molecules that cleave a target RNA phosphoester in the presence of 1 mM Mg(2+), Mn(2+), Zn(2+) or Pb(2+). Examination of individual clones from the Mg(2+) lineage after the sixth round revealed a catalytic motif comprised of a three-stem junction.This motif was partially randomized and subjected to seven additional rounds of selective amplification, yielding catalysts with a rate of 0.01/ min. The optimized DNA catalyst was divided into separate substrate and enzyme domains and shown to have a similar level of activity under multiple turnover conditions. Conclusions: We have generated a Mg(2+) - dependent DNA enzyme that cleaves a target RNA phosphoester with a catalytic rate approx. 10(exp 5) - fold greater than that of the uncatalyzed reaction. This activity is compatible with intracellular conditions, raising the possibility that DNA enzymes might be made to operate in vivo.

  17. Activation Domain-dependent Degradation of Somatic Wee1 Kinase*

    PubMed Central

    Owens, Laura; Simanski, Scott; Squire, Christopher; Smith, Anthony; Cartzendafner, Jeff; Cavett, Valerie; Caldwell Busby, Jennifer; Sato, Trey; Ayad, Nagi G.

    2010-01-01

    Cell cycle progression is dependent upon coordinate regulation of kinase and proteolytic pathways. Inhibitors of cell cycle transitions are degraded to allow progression into the subsequent cell cycle phase. For example, the tyrosine kinase and Cdk1 inhibitor Wee1 is degraded during G2 and mitosis to allow mitotic progression. Previous studies suggested that the N terminus of Wee1 directs Wee1 destruction. Using a chemical mutagenesis strategy, we report that multiple regions of Wee1 control its destruction. Most notably, we find that the activation domain of the Wee1 kinase is also required for its degradation. Mutations in this domain inhibit Wee1 degradation in somatic cell extracts and in cells without affecting the overall Wee1 structure or kinase activity. More broadly, these findings suggest that kinase activation domains may be previously unappreciated sites of recognition by the ubiquitin proteasome pathway. PMID:20038582

  18. Calcium-dependent activation of Pyk2 by hypoxia.

    PubMed

    Beitner-Johnson, Dana; Ferguson, Tsuneo; Rust, Randy T; Kobayashi, Shuichi; Millhorn, David E

    2002-02-01

    The Pyk2 tyrosine kinase can be activated by both calcium-dependent and calcium-independent mechanisms. Exposure to moderate hypoxia (5% O(2)) induced a rapid and persistent tyrosine phosphorylation of Pyk2 in pheochromocytoma (PC12) cells. Hypoxia and KCl-depolarization increased the phosphotyrosine content of Pyk2 by twofold and fourfold, respectively. Both of these effects were abolished in the absence of extracellular calcium. There was a modest activation of MAPK in parallel with the onset of Pyk2 phosphorylation. However, there was no detectable activation of either JNK or c-src, two other known downstream targets of Pyk2. Thus, exposure to hypoxia may selectively target specific subsets of Pyk2 signalling pathways. PMID:11781137

  19. Altered Spontaneous Brain Activity in Betel Quid Dependence

    PubMed Central

    Liu, Tao; Li, Jian-jun; Zhao, Zhong-yan; Yang, Guo-shuai; Pan, Meng-jie; Li, Chang-qing; Pan, Su-yue; Chen, Feng

    2016-01-01

    Abstract It has been suggested by the first voxel-based morphometry investigation that betel quid dependence (BQD) individuals are presented with brain structural changes in previous reports, and there may be a neurobiological basis for BQD individuals related to an increased risk of executive dysfunction and disinhibition, subjected to the reward system, cognitive system, and emotion system. However, the effects of BQD on neural activity remain largely unknown. Individuals with impaired cognitive control of behavior often reveal altered spontaneous cerebral activity in resting-state functional magnetic resonance imaging and those changes are usually earlier than structural alteration. Here, we examined BQD individuals (n = 33) and age-, sex-, and education-matched healthy control participants (n = 32) in an resting-state functional magnetic resonance imaging study to observe brain function alterations associated with the severity of BQD. Amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values were both evaluated to stand for spontaneous cerebral activity. Gray matter volumes of these participants were also calculated for covariate. In comparison with healthy controls, BQD individuals demonstrated dramatically decreased ALFF and ReHo values in the prefrontal gurus along with left fusiform, and increased ALFF and ReHo values in the primary motor cortex area, temporal lobe as well as some regions of occipital lobe. The betel quid dependence scores (BQDS) were negatively related to decreased activity in the right anterior cingulate. The abnormal spontaneous cerebral activity revealed by ALFF and ReHo calculation excluding the structural differences in patients with BQD may help us probe into the neurological pathophysiology underlying BQD-related executive dysfunction and disinhibition. Diminished spontaneous brain activity in the right anterior cingulate cortex may, therefore, represent a biomarker of BQD individuals. PMID

  20. Activity-dependent plasticity of mouse hippocampal assemblies in vitro

    PubMed Central

    Keller, Martin K.; Draguhn, Andreas; Both, Martin; Reichinnek, Susanne

    2015-01-01

    Memory formation is associated with the generation of transiently stable neuronal assemblies. In hippocampal networks, such groups of functionally coupled neurons express highly ordered spatiotemporal activity patterns which are coordinated by local network oscillations. One of these patterns, sharp wave-ripple complexes (SPW-R), repetitively activates previously established groups of memory-encoding neurons, thereby supporting memory consolidation. This function implies that repetition of specific SPW-R induces plastic changes which render the underlying neuronal assemblies more stable. We modeled this repetitive activation in an in vitro model of SPW-R in mouse hippocampal slices. Weak electrical stimulation upstream of the CA3-CA1 networks reliably induced SPW-R of stereotypic waveform, thus representing re-activation of similar neuronal activity patterns. Frequent repetition of these patterns (100 times) reduced the variance of both, evoked and spontaneous SPW-R waveforms, indicating stabilization of pre-existing assemblies. These effects were most pronounced in the CA1 subfield and depended on the timing of stimulation relative to spontaneous SPW-R. Additionally, plasticity of SPW-R was blocked by application of a NMDA receptor antagonist, suggesting a role for associative synaptic plasticity in this process. Thus, repetitive activation of specific patterns of SPW-R causes stabilization of memory-related networks. PMID:26041998

  1. Multi-objective and Perishable Fuzzy Inventory Models Having Weibull Life-time With Time Dependent Demand, Demand Dependent Production and Time Varying Holding Cost: A Possibility/Necessity Approach

    NASA Astrophysics Data System (ADS)

    Pathak, Savita; Mondal, Seema Sarkar

    2010-10-01

    A multi-objective inventory model of deteriorating item has been developed with Weibull rate of decay, time dependent demand, demand dependent production, time varying holding cost allowing shortages in fuzzy environments for non- integrated and integrated businesses. Here objective is to maximize the profit from different deteriorating items with space constraint. The impreciseness of inventory parameters and goals for non-integrated business has been expressed by linear membership functions. The compromised solutions are obtained by different fuzzy optimization methods. To incorporate the relative importance of the objectives, the different cardinal weights crisp/fuzzy have been assigned. The models are illustrated with numerical examples and results of models with crisp/fuzzy weights are compared. The result for the model assuming them to be integrated business is obtained by using Generalized Reduced Gradient Method (GRG). The fuzzy integrated model with imprecise inventory cost is formulated to optimize the possibility necessity measure of fuzzy goal of the objective function by using credibility measure of fuzzy event by taking fuzzy expectation. The results of crisp/fuzzy integrated model are illustrated with numerical examples and results are compared.

  2. Death-receptor activation halts clathrin-dependent endocytosis

    PubMed Central

    Austin, Cary D.; Lawrence, David A.; Peden, Andrew A.; Varfolomeev, Eugene E.; Totpal, Klara; De Mazière, Ann M.; Klumperman, Judith; Arnott, David; Pham, Victoria; Scheller, Richard H.; Ashkenazi, Avi

    2006-01-01

    Endocytosis is crucial for various aspects of cell homeostasis. Here, we show that proapoptotic death receptors (DRs) trigger selective destruction of the clathrin-dependent endocytosis machinery. DR stimulation induced rapid, caspase-mediated cleavage of key clathrin-pathway components, halting cellular uptake of the classic cargo protein transferrin. DR-proximal initiator caspases cleaved the clathrin adaptor subunit AP2α between functionally distinct domains, whereas effector caspases processed clathrin’s heavy chain. DR5 underwent ligand-induced, clathrin-mediated endocytosis, suggesting that internalization of DR signaling complexes facilitates clathrin-pathway targeting by caspases. An endocytosis-blocking, temperature-sensitive dynamin-1 mutant attenuated DR internalization, enhanced caspase stimulation downstream of DRs, and increased apoptosis. Thus, DR-triggered caspase activity disrupts clathrin-dependent endocytosis, leading to amplification of programmed cell death. PMID:16801533

  3. The supramolecular structure of LPS-chitosan complexes of varied composition in relation to their biological activity.

    PubMed

    Davydova, V N; Volod'ko, A V; Sokolova, E V; Chusovitin, E A; Balagan, S A; Gorbach, V I; Galkin, N G; Yermak, I M; Solov'eva, T F

    2015-06-01

    The complexes of chitosan (Ch) with lipopolysaccharides (LPSs) from Escherichia coli O55:B5 (E-LPS) and Yersinia pseudotuberculosis 1B 598 (Y-LPS) of various weight compositions were investigated using quasi-elastic light scattering, ζ-potential distribution assay and atomic force microscopy. The alteration of ζ-potential of E-LPS-Ch complexes from negative to positive values depending on Ch content was detected. The Y-LPS-Ch complexes had similar positive ζ-potentials regardless of Ch content. The transformation of the supramolecular structure of E-LPS after binding with to Ch was revealed. Screening of E-LPS and Y-LPS particles by Ch in the complexes with high polycation was detected. The ability of LPS-Ch complex to induce biosynthesis of TNF-α and reactive oxygen species in stimulated human mononuclear cells was studied. A significant decrease in activity complexes compared to that of the initial LPS was observed only for E-LPS-Ch complexes. PMID:25843841

  4. Effectiveness of Prompts on Fourth-Grade Children’s Dietary Recall Accuracy Depends on Retention Interval and Varies by Gender1234

    PubMed Central

    Baxter, Suzanne D; Smith, Albert F; Hitchcock, David B; Guinn, Caroline H; Royer, Julie A; Collins, Kathleen L; Smith, Alyssa L; Puryear, Megan P; Vaadi, Kate K; Finney, Christopher J; Miller, Patricia H

    2015-01-01

    , although the effectiveness of different prompts depends on RI and varies by gender: at a short RI, the choice of prompts has little systematic effect on accuracy, whereas at a long RI, reverse prompts may elicit the most accurate recalls. PMID:26224752

  5. Shaping inhibition: activity dependent structural plasticity of GABAergic synapses

    PubMed Central

    Flores, Carmen E.; Méndez, Pablo

    2014-01-01

    Inhibitory transmission through the neurotransmitter γ-aminobutyric acid (GABA) shapes network activity in the mammalian cerebral cortex by filtering synaptic incoming information and dictating the activity of principal cells. The incredibly diverse population of cortical neurons that use GABA as neurotransmitter shows an equally diverse range of mechanisms that regulate changes in the strength of GABAergic synaptic transmission and allow them to dynamically follow and command the activity of neuronal ensembles. Similarly to glutamatergic synaptic transmission, activity-dependent functional changes in inhibitory neurotransmission are accompanied by alterations in GABAergic synapse structure that range from morphological reorganization of postsynaptic density to de novo formation and elimination of inhibitory contacts. Here we review several aspects of structural plasticity of inhibitory synapses, including its induction by different forms of neuronal activity, behavioral and sensory experience and the molecular mechanisms and signaling pathways involved. We discuss the functional consequences of GABAergic synapse structural plasticity for information processing and memory formation in view of the heterogenous nature of the structural plasticity phenomena affecting inhibitory synapses impinging on somatic and dendritic compartments of cortical and hippocampal neurons. PMID:25386117

  6. Transsynaptic signaling by activity-dependent cleavage of neuroligin-1.

    PubMed

    Peixoto, Rui T; Kunz, Portia A; Kwon, Hyungbae; Mabb, Angela M; Sabatini, Bernardo L; Philpot, Benjamin D; Ehlers, Michael D

    2012-10-18

    Adhesive contact between pre- and postsynaptic neurons initiates synapse formation during brain development and provides a natural means of transsynaptic signaling. Numerous adhesion molecules and their role during synapse development have been described in detail. However, once established, the mechanisms of adhesive disassembly and its function in regulating synaptic transmission have been unclear. Here, we report that synaptic activity induces acute proteolytic cleavage of neuroligin-1 (NLG1), a postsynaptic adhesion molecule at glutamatergic synapses. NLG1 cleavage is triggered by NMDA receptor activation, requires Ca2+ /calmodulin-dependent protein kinase, and is mediated by proteolytic activity of matrix metalloprotease 9 (MMP9). Cleavage of NLG1 occurs at single activated spines, is regulated by neural activity in vivo, and causes rapid destabilization of its presynaptic partner neurexin-1β (NRX1β). In turn, NLG1 cleavage depresses synaptic transmission by abruptly reducing presynaptic release probability. Thus, local proteolytic control of synaptic adhesion tunes synaptic transmission during brain development and plasticity. PMID:23083741

  7. relA-dependent RNA polymerase activity in Escherichia coli.

    PubMed Central

    Ryals, J; Bremer, H

    1982-01-01

    Parameters relating to RNA synthesis were measured after a temperature shift from 30 to 42 degrees C, in a relA+ and relA- isogenic pair of Escherichia coli strains containing a temperature-sensitive valyl tRNA synthetase. The following results were obtained: (i) the rRNA chain growth rate increased 2-fold in both strains; (ii) newly synthesized rRNA became unstable in both strains; (iii) the stable RNA gene activity (rRNA and tRNA, measured as stable RNA synthesis rate relative to the total instantaneous rate of RNA synthesis) decreased 1.7-fold in the relA+ strain and increased 1.9-fold in the relA mutant; and (iv) the RNA polymerase activity (measured by the percentage of total RNA polymerase enzyme active in transcription an any instant) decreased from 20 to 3.6% in the relA+ strain and remained unchanged (or increased at most to 22%) in the relA mutant. It is suggested that both rRNA gene activity and the RNA polymerase activity depend on the intracellular concentration of guanosine tetraphosphate, whereas the altered chain elongation rate and stability of rRNA are temperature or amino acid starvation effects, respectively, without involvement of relA function. PMID:6174501

  8. Shaping inhibition: activity dependent structural plasticity of GABAergic synapses.

    PubMed

    Flores, Carmen E; Méndez, Pablo

    2014-01-01

    Inhibitory transmission through the neurotransmitter γ-aminobutyric acid (GABA) shapes network activity in the mammalian cerebral cortex by filtering synaptic incoming information and dictating the activity of principal cells. The incredibly diverse population of cortical neurons that use GABA as neurotransmitter shows an equally diverse range of mechanisms that regulate changes in the strength of GABAergic synaptic transmission and allow them to dynamically follow and command the activity of neuronal ensembles. Similarly to glutamatergic synaptic transmission, activity-dependent functional changes in inhibitory neurotransmission are accompanied by alterations in GABAergic synapse structure that range from morphological reorganization of postsynaptic density to de novo formation and elimination of inhibitory contacts. Here we review several aspects of structural plasticity of inhibitory synapses, including its induction by different forms of neuronal activity, behavioral and sensory experience and the molecular mechanisms and signaling pathways involved. We discuss the functional consequences of GABAergic synapse structural plasticity for information processing and memory formation in view of the heterogenous nature of the structural plasticity phenomena affecting inhibitory synapses impinging on somatic and dendritic compartments of cortical and hippocampal neurons. PMID:25386117

  9. Sensitivity of breast cancer cells to erlotinib depends on cyclin-dependent kinase 2 activity

    PubMed Central

    Yamasaki, Fumiyuki; Zhang, Dongwei; Bartholomeusz, Chandra; Sudo, Tamotsu; Hortobagyi, Gabriel N.; Kurisu, Kaoru; Ueno, Naoto T.

    2008-01-01

    Inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinases,such as erlotinib and gefitinib, have not been very effective in the treatment of breast cancer although many breast cancer cells express EGFR. To address this apparent paradox, we examined possible predictors of the sensitivity of 10 breast cancer cell lines to erlotinib in light of cyclin-dependent kinase 2 (CDK2), considered the farthest downstream kinase that controls cell cycling in the EGFR signaling pathway. Expression of EGFR and HER2 were not associated with sensitivity to erlotinib. Expression of phosphorylated (p-)tyrosine, p-Akt, phosphorylated extracellular signal-regulated kinase (p-ERK) 1/ERK2 (p42/p44), and p27 after treatment of erlotinib was not associated with erlotinib sensitivity. However, suppression of CDK2 activity after erlotinib treatment correlated with erlotinib sensitivity (P < 0.0001). Restoration of CDK2 activity partially restored proliferation and induced erlotinib resistance in erlotinib-sensitive cell lines, indicating that sensitivity to erlotinib in these breast cancer cells depends, at least in part, on CDK2 activity. p27, an inhibitor of CDK2, was not translocated into the nucleus in erlotinib-resistant cell lines. Knocking down p27 protein partially blocked erlotinib-induced cell death and cell cycle arrest. These findings indicate that the ability of erlotinib to suppress CDK2 activity is critical for cellular sensitivity to erlotinib, regardless of EGFR expression level, and that the presence of p27 in the cytoplasm also participates in erlotinib resistance. PMID:17671085

  10. Alkylphenol Xenoestrogens with Varying Carbon Chain Lengths Differentially and Potently Activate Signaling and Functional Responses in GH3/B6/F10 Somatomammotropes

    PubMed Central

    Kochukov, Mikhail Y.; Jeng, Yow-Jiun; Watson, Cheryl S.

    2009-01-01

    Background Alkylphenols varying in their side-chain lengths [ethyl-, propyl-, octyl-, and nonylphenol (EP, PP, OP, and NP, respectively)] and bisphenol A (BPA) represent a large group of structurally related xenoestrogens that have endocrine-disruptive effects. Their rapid nongenomic effects that depend on structure for cell signaling and resulting functions are unknown. Objectives We compared nongenomic estrogenic activities of alkylphenols with BPA and 17β-estradiol (E2) in membrane estrogen receptor-α–enriched GH3/B6/F10 pituitary tumor cells. These actions included calcium (Ca) signaling, prolactin (PRL) release, extracellular-regulated kinase (ERK) phosphorylation, and cell proliferation. Methods We imaged Ca using fura-2, measured PRL release via radioimmunoassay, detected ERK phosphorylation by fixed cell immunoassay, and estimated cell number using the crystal violet assay. Results All compounds caused increases in Ca oscillation frequency and intracellular Ca volume at 100 fM to 1 nM concentrations, although long-chain alkylphenols were most effective. All estrogens caused rapid PRL release at concentrations as low as 1 fM to 10 pM; the potency of EP, PP, and NP exceeded that of E2. All compounds at 1 nM produced similar increases in ERK phosphorylation, causing rapid peaks at 2.5–5 min, followed by inactivation and additional 60-min peaks (except for BPA). Dose–response patterns of ERK activation at 5 min were similar for E2, BPA, and PP, whereas EP caused larger effects. Only E2 and NP increased cell number. Some rapid estrogenic responses showed correlations with the hydrophobicity of estrogenic molecules; the more hydrophobic OP and NP were superior at Ca and cell proliferation responses, whereas the less hydrophobic EP and PP were better at ERK activations. Conclusions Alkylphenols are potent estrogens in evoking these nongenomic responses contributing to complex functions; their hydrophobicity can largely predict these behaviors. PMID

  11. Effects of activation energy and activation volume on the temperature-dependent viscosity of water.

    PubMed

    Kwang-Hua, Chu Rainer

    2016-08-01

    Water transport in a leaf is vulnerable to viscosity-induced changes. Recent research has suggested that these changes may be partially due to variation at the molecular scale, e.g., regulations via aquaporins, that induce reductions in leaf hydraulic conductance. What are the quantitative as well as qualitative changes in temperature-dependent viscosity due to the role of aquaporins in tuning activation energy and activation volume? Using the transition-state approach as well as the boundary perturbation method, we investigate temperature-dependent viscosity tuned by activation energy and activation volume. To validate our approach, we compare our numerical results with previous temperature-dependent viscosity measurements. The rather good fit between our calculations and measurements confirms our present approach. We have obtained critical parameters for the temperature-dependent (shear) viscosity of water that might be relevant to the increasing and reducing of leaf hydraulic conductance. These parameters are sensitive to temperature, activation energy, and activation volume. Once the activation energy increases, the (shear) viscosity of water increases. Our results also show that as the activation volume increases (say, 10^{-23}m^{3}), the (shear) viscosity of water decreases significantly and the latter induces the enhancing of leaf hydraulic conductance. Within the room-temperature regime, a small increase in the activation energy will increase the water viscosity or reduce the leaf hydraulic conductance. Our approach and results can be applied to diverse plant or leaf attributes. PMID:27627349

  12. Position dependent rate dampening in any active hand controller

    NASA Technical Reports Server (NTRS)

    Gregory, William W. (Inventor); Kauffman, James W. (Inventor)

    1994-01-01

    A control system for an active hand controller, for example, uses a control stick connected to and controlled by a motor. Electronics are provided to control the motor to eliminate oscillations due to motor torque and high gain due to breakout at the control stick when the control stick is at about its null position. Both hardware as well as software implementations can provide position dependent dampening to the control sticks such that when the control stick is located about a null position, a higher rate of dampening is provided than when the control stick is located outside the null position, when a lower rate of dampening is provided. The system provides a stable active hand controller control stick without degraded force and feel characteristics of the system.

  13. Activity-dependent neural plasticity from bench to bedside.

    PubMed

    Ganguly, Karunesh; Poo, Mu-Ming

    2013-10-30

    Much progress has been made in understanding how behavioral experience and neural activity can modify the structure and function of neural circuits during development and in the adult brain. Studies of physiological and molecular mechanisms underlying activity-dependent plasticity in animal models have suggested potential therapeutic approaches for a wide range of brain disorders in humans. Physiological and electrical stimulations as well as plasticity-modifying molecular agents may facilitate functional recovery by selectively enhancing existing neural circuits or promoting the formation of new functional circuits. Here, we review the advances in basic studies of neural plasticity mechanisms in developing and adult nervous systems and current clinical treatments that harness neural plasticity, and we offer perspectives on future development of plasticity-based therapy. PMID:24183023

  14. Nanofiber diameter-dependent MAPK activity in osteoblasts.

    PubMed

    Jaiswal, Devina; Brown, Justin L

    2012-11-01

    The major challenge for bone tissue engineering lies in the fabrication of scaffolds that can mimic the extracellular matrix and promote osteogenesis. Electrospun fibers are being widely researched for this application due to high porosity, interconnectivity, and mechanical strength of the fibrous scaffolds. Electrospun poly methyl methacrylate (PMMA, 2.416 ± 0.100 μm) fibers were fabricated and etched using a 60% propylene glycol methyl ether acetate (PGMEA)/limonene (vol/vol) solution to obtain fiber diameters ranging from 2.5 to 0.5 μm in a time-dependent manner. The morphology of the fibrous scaffolds was evaluated using scanning electron microscopy and cellular compatibility with etchant-treated scaffold was assessed using immunoflurescence. Mitogen-activated protein kinases (MAPK) activation in response to different fiber diameter was evaluated with western blot as well as quantitative in-cell western. We report that electrospun micro-fibers can be etched to 0.552 ± 0.047 μm diameter without producing beads. Osteoblasts adhered to the fibers and a change in fiber diameter played a major role in modulating the activation of extracellular signal-regulated kinase (ERK) and p38 kinases with 0.882 ± 0.091 μm diameter fibers producing an inverse effect on ERK and p38 phosphorylation. These results indicate that nanofibers produced by wet etching can be effectively utilized to produce diameters that can differentially modulate MAPK activation patterns. PMID:22700490

  15. Characterization of Xylanolytic Enzymes in Clostridium cellulovorans: Expression of Xylanase Activity Dependent on Growth Substrates

    PubMed Central

    Kosugi, Akihiko; Murashima, Koichiro; Doi, Roy H.

    2001-01-01

    Xylanase activity of Clostridium cellulovorans, an anaerobic, mesophilic, cellulolytic bacterium, was characterized. Most of the activity was secreted into the growth medium when the bacterium was grown on xylan. Furthermore, when the extracellular material was separated into cellulosomal and noncellulosomal fractions, the activity was present in both fractions. Each of these fractions contained at least two major and three minor xylanase activities. In both fractions, the pattern of xylan hydrolysis products was almost identical based on thin-layer chromatography analysis. The major xylanase activities in both fractions were associated with proteins with molecular weights of about 57,000 and 47,000 according to zymogram analyses, and the minor xylanases had molecular weights ranging from 45,000 to 28,000. High α-arabinofuranosidase activity was detected exclusively in the noncellulosomal fraction. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed that cellulosomes derived from xylan-, cellobiose-, and cellulose-grown cultures had different subunit compositions. Also, when xylanase activity in the cellulosomes from the xylan-grown cultures was compared with that of cellobiose- and cellulose-grown cultures, the two major xylanases were dramatically increased in the presence of xylan. These results strongly indicated that C. cellulovorans is able to regulate the expression of xylanase activity and to vary the cellulosome composition depending on the growth substrate. PMID:11717260

  16. Does Nanoparticle Activity Depend upon Size and Crystal Phase?

    PubMed Central

    Jiang, Jingkun; Oberdörster, Günter; Elder, Alison; Gelein, Robert; Mercer, Pamela; Biswas, Pratim

    2010-01-01

    A method to investigate the dependence of the physicochemical properties of nanoparticles (e.g. size, surface area and crystal phase) on their oxidant generating capacity is proposed and demonstrated for TiO2 nanoparticles. Gas phase synthesis methods that allow for strict control of size and crystal phase were used to prepare TiO2 nanoparticles. The reactive oxygen species (ROS) generating capacity of these particles was then measured. The size dependent ROS activity was established using TiO2 nanoparticles of 9 different sizes (4 – 195 nm) but the same crystal phase. For a fixed total surface area, an S-shaped curve for ROS generation per unit surface area was observed as a function of particle size. The highest ROS activity per unit area was observed for 30 nm particles, and observed to be constant above 30 nm. There was a decrease in activity per unit area as size decreased from 30 nm to 10 nm; and again constant for particles smaller than 10 nm. The correlation between crystal phase and oxidant capacity was established using TiO2 nanoparticles of 11 different crystal phase combinations but similar size. The ability of different crystal phases of TiO2 nanoparticles to generate ROS was highest for amorphous, followed by anatase, and then anatase/rutile mixtures, and lowest for rutile samples. Based on evaluation of the entire dataset, important dose metrics for ROS generation are established. Their implications of these ROS studies on biological and toxicological studies using nanomaterials are discussed. PMID:20827377

  17. Brain region and activity-dependent properties of M for calibrated fMRI.

    PubMed

    Shu, Christina Y; Herman, Peter; Coman, Daniel; Sanganahalli, Basavaraju G; Wang, Helen; Juchem, Christoph; Rothman, Douglas L; de Graaf, Robin A; Hyder, Fahmeed

    2016-01-15

    Calibrated fMRI extracts changes in oxidative energy demanded by neural activity based on hemodynamic and metabolic dependencies of the blood oxygenation level-dependent (BOLD) response. This procedure requires the parameter M, which is determined from the dynamic range of the BOLD signal between deoxyhemoglobin (paramagnetic) and oxyhemoglobin (diamagnetic). Since it is unclear if the range of M-values in human calibrated fMRI is due to regional/state differences, we conducted a 9.4T study to measure M-values across brain regions in deep (α-chloralose) and light (medetomidine) anesthetized rats, as verified by electrophysiology. Because BOLD signal is captured differentially by gradient-echo (R2*) and spin-echo (R2) relaxation rates, we measured M-values by the product of the fMRI echo time and R2' (i.e., the reversible magnetic susceptibility component), which is given by the absolute difference between R2* and R2. While R2' mapping was shown to be dependent on the k-space sampling method used, at nominal spatial resolutions achieved at high magnetic field of 9.4T the M-values were quite homogenous across cortical gray matter. However cortical M-values varied in relation to neural activity between brain states. The findings from this study could improve precision of future calibrated fMRI studies by focusing on the global uniformity of M-values in gray matter across different resting activity levels. PMID:26529646

  18. Activation domains of transcription factors mediate replication dependent transcription from a minimal HIV-1 promoter.

    PubMed Central

    Williams, R D; Lee, B A; Jackson, S P; Proudfoot, N J

    1996-01-01

    Transcription from a minimal HIV-1 promoter containing the three Sp1 binding sites and TATA box can be activated without Tat by template DNA replication. Here we show that this activation can also be mediated by recombinant GAL4 fusion proteins containing the activation domains of Sp1, VP16 or CTF (or by full-length GAL4) targeted to the HIV-1 promoter by replacing the Sp1 sites with five GAL4 binding sites. Thus Sp1 is not unique in its ability to mediate replication activated transcription, although the degree of processivity elicited by the different activators varied significantly from strongly processive (GAL4-VP16) to relatively non-processive (GAL4-Sp1 or -CTF). Processive GAL4-VP16-activated transcription, but not efficient initiation, required multiple GAL4 binding sites. In the presence of Tat, transcription with GAL4-SP1 and GAL4-CTF was further activated (principally at the level of processivity) but GAL4-VP16-potentiated transcription was only slightly stimulated. The Tat-dependent switch from non-processive to fully processive transcription was particularly marked for GAL4-Sp1, an effect which may be relevant to the selection of Sp1 binding sites by the HIV-1 promoter. PMID:8604293

  19. Size-dependent catalytic activity of supported metal clusters

    NASA Astrophysics Data System (ADS)

    Xu, Z.; Xiao, F.-S.; Purnell, S. K.; Alexeev, O.; Kawi, S.; Deutsch, S. E.; Gates, B. C.

    1994-11-01

    BECAUSE catalysis by metals is a surface phenomenon, many technological catalysts contain small (typically nanometre-sized) supported metal particles with a large fraction of the atoms exposed1. Many reactions, such as hydrocarbon hydrogenations, are structure-insensitive, proceeding at approximately the same rate on metal particles of various sizes provided that they are larger than about 1 nm and show bulk-like metallic behaviour1. But it is not known whether the catalytic properties of metal particles become size-dependent as the particles become so small that they are no longer metallic in character. Here we investigate the catalytic behaviour of precisely defined clusters of just four and six iridium atoms on solid supports. We find that the Ir4 and Ir6 clusters differ in catalytic activity both from each other and from metallic Ir particles. This raises the possibility of tailoring the catalytic behaviour of metal clusters by controlling the cluster size.

  20. A Solar Cycle Dependence of Nonlinearity in Magnetospheric Activity

    SciTech Connect

    Johnson, Jay R; Wing, Simon

    2005-03-08

    The nonlinear dependencies inherent to the historical K(sub)p data stream (1932-2003) are examined using mutual information and cumulant based cost as discriminating statistics. The discriminating statistics are compared with surrogate data streams that are constructed using the corrected amplitude adjustment Fourier transform (CAAFT) method and capture the linear properties of the original K(sub)p data. Differences are regularly seen in the discriminating statistics a few years prior to solar minima, while no differences are apparent at the time of solar maximum. These results suggest that the dynamics of the magnetosphere tend to be more linear at solar maximum than at solar minimum. The strong nonlinear dependencies tend to peak on a timescale around 40-50 hours and are statistically significant up to one week. Because the solar wind driver variables, VB(sub)s and dynamical pressure exhibit a much shorter decorrelation time for nonlinearities, the results seem to indicate that the nonlinearity is related to internal magnetospheric dynamics. Moreover, the timescales for the nonlinearity seem to be on the same order as that for storm/ring current relaxation. We suggest that the strong solar wind driving that occurs around solar maximum dominates the magnetospheric dynamics suppressing the internal magnetospheric nonlinearity. On the other hand, in the descending phase of the solar cycle just prior to solar minimum, when magnetospheric activity is weaker, the dynamics exhibit a significant nonlinear internal magnetospheric response that may be related to increased solar wind speed.

  1. Interface dynamics explain assembly dependency of influenza neuraminidase catalytic activity

    PubMed Central

    von Grafenstein, Susanne; Wallnoefer, Hannes G.; Kirchmair, Johannes; Fuchs, Julian E.; Huber, Roland G.; Schmidtke, Michaela; Sauerbrei, Andreas; Rollinger, Judith M.; Liedl, Klaus R.

    2015-01-01

    Influenza virus neuraminidase (iNA) is a homotetrameric surface protein of the influenza virus and an established target for antiviral drugs. In contrast to neuraminidases (NAs) of other biological systems (non-iNAs), enzymatic activity of iNA is only observed in a quaternary assembly and iNA needs the tetramerization to mediate enzymatic activity. Obviously, differences on a molecular level between iNA and non-iNAs are responsible for this intriguing observation. Comparison between protein structures and multiple sequence alignment allow the identification of differences in amino acid composition in crucial regions of the enzyme, such as next to the conserved D151 and the 150-loop. These differences in amino acid sequence and protein tetramerization are likely to alter the dynamics of the system. Therefore, we performed molecular dynamics simulations to investigate differences in the molecular flexibility of monomers, dimers, and tetramers of iNAs of subtype N1 (avian 2004, pandemic 1918 and pandemic 2009 iNA) and as comparison the non-iNA monomer from Clostridium perfringens. We show that conformational transitions of iNA are crucially influenced by its assembly state. The protein–protein interface induces a complex hydrogen-bonding network between the 110-helix and the 150-loop, which consequently stabilizes the structural arrangement of the binding site. Therefore, we claim that these altered dynamics are responsible for the dependence of iNA’s catalytic activity on the tetrameric assembly. Only the tetramerization-induced balance between stabilization and altered local flexibility in the binding site provides the appropriate arrangement of key residues for iNA’s catalytic activity. PMID:24279589

  2. Chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis.

    PubMed

    Vignjević, Sanja; Budeč, Mirela; Marković, Dragana; Dikić, Dragoslava; Mitrović, Olivera; Mojsilović, Slavko; Durić, Sanja Vranješ; Koko, Vesna; Cokić, Bojana Beleslin; Cokić, Vladan; Jovčić, Gordana

    2014-01-01

    Psychological stress affects different physiological processes including haematopoiesis. However, erythropoietic effects of chronic psychological stress remain largely unknown. The adult spleen contains a distinct microenvironment favourable for rapid expansion of erythroid progenitors in response to stressful stimuli, and emerging evidence suggests that inappropriate activation of stress erythropoiesis may predispose to leukaemic transformation. We used a mouse model to study the influence of chronic psychological stress on erythropoiesis in the spleen and to investigate potential mediators of observed effects. Adult mice were subjected to 2 hrs daily restraint stress for 7 or 14 consecutive days. Our results showed that chronic exposure to restraint stress decreased the concentration of haemoglobin in the blood, elevated circulating levels of erythropoietin and corticosterone, and resulted in markedly increased number of erythroid progenitors and precursors in the spleen. Western blot analysis revealed significantly decreased expression of both erythropoietin receptor and glucocorticoid receptor in the spleen of restrained mice. Furthermore, chronic stress enhanced the expression of stem cell factor receptor in the red pulp. Moreover, chronically stressed animals exhibited significantly increased expression of bone morphogenetic protein 4 (BMP4) in the red pulp as well as substantially enhanced mRNA expression levels of its receptors in the spleen. These findings demonstrate for the first time that chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis and leads to the prolonged activation of stress erythropoiesis pathways. Prolonged activation of these pathways along with an excessive production of immature erythroid cells may predispose chronically stressed subjects to a higher risk of leukaemic transformation. PMID:24283209

  3. Altered Cingulate and Insular Cortex Activation During Risk-Taking in Methamphetamine Dependence: Losses Lose Impact

    PubMed Central

    Gowin, Joshua L.; Stewart, Jennifer L.; May, April C.; Ball, Tali M.; Wittmann, Marc; Tapert, Susan F.; Paulus, Martin P.

    2013-01-01

    Aims To determine if methamphetamine-dependent (MD) individuals exhibit behavioral or neural processing differences in risk-taking relative to healthy comparison participants (CTL). Design This was a cross-sectional study comparing two groups’ behavior on a risk-taking task and neural processing as assessed using functional magnetic resonance imaging (fMRI). Settings The study was conducted in an inpatient treatment center and a research fMRI facility in the United States. Participants Sixty-eight recently abstinent MD individuals recruited from a treatment program and forty CTL recruited from the community completed the study. Measurements The study assessed risk-taking behavior (overall and post-loss) using the Risky Gains Task (RGT), sensation-seeking, impulsivity and blood-oxygenation level dependent activation in the brain during the decision phase of the RGT. Findings Relative to CTL, MD displayed decreased activation in the bilateral rostral anterior cingulate cortex (ACC) and greater activation in the left insula across risky and safe decisions (p<.05). Right mid insula activation among CTL did not vary between risky and safe decisions, but among MD it was higher during risky relative to safe decisions (p<.05). Among MD, lower activation in the right rostral ACC (r=−.39, p<.01) and higher activation in the right mid insula (r=.35, p<.01) during risky decisions were linked to a higher likelihood of choosing a risky option following a loss. Conclusions Methamphetamine-dependent individuals show disrupted risk-related processing in both anterior cingulate and insula, brain areas that have been implicated in cognitive control and interoceptive processing. Attenuated neural processing of risky options may lead to risk-taking despite experiencing negative consequences. PMID:24033715

  4. Motor-Skill Learning Is Dependent on Astrocytic Activity

    PubMed Central

    Padmashri, Ragunathan; Suresh, Anand; Boska, Michael D.; Dunaevsky, Anna

    2015-01-01

    Motor-skill learning induces changes in synaptic structure and function in the primary motor cortex through the involvement of a long-term potentiation- (LTP-) like mechanism. Although there is evidence that calcium-dependent release of gliotransmitters by astrocytes plays an important role in synaptic transmission and plasticity, the role of astrocytes in motor-skill learning is not known. To test the hypothesis that astrocytic activity is necessary for motor-skill learning, we perturbed astrocytic function using pharmacological and genetic approaches. We find that perturbation of astrocytes either by selectively attenuating IP3R2 mediated astrocyte Ca2+ signaling or using an astrocyte specific metabolic inhibitor fluorocitrate (FC) results in impaired motor-skill learning of a forelimb reaching-task in mice. Moreover, the learning impairment caused by blocking astrocytic activity using FC was rescued by administration of the gliotransmitter D-serine. The learning impairments are likely caused by impaired LTP as FC blocked LTP in slices and prevented motor-skill training-induced increases in synaptic AMPA-type glutamate receptor in vivo. These results support the conclusion that normal astrocytic Ca2+ signaling during a reaching task is necessary for motor-skill learning. PMID:26346977

  5. Fluency-dependent cortical activation associated with speech production and comprehension in second language learners.

    PubMed

    Shimada, K; Hirotani, M; Yokokawa, H; Yoshida, H; Makita, K; Yamazaki-Murase, M; Tanabe, H C; Sadato, N

    2015-08-01

    This functional magnetic resonance imaging (fMRI) study investigated the brain regions underlying language task performance in adult second language (L2) learners. Specifically, we identified brain regions where the level of activation was associated with L2 fluency levels. Thirty Japanese-speaking adults participated in the study. All participants were L2 learners of English and had achieved varying levels of fluency, as determined by a standardized L2 English proficiency test, the Versant English Test (Pearson Education Inc., 2011). When participants performed the oral sentence building task from the production tasks administered, the dorsal part of the left inferior frontal gyrus (dIFG) showed activation patterns that differed depending on the L2 fluency levels: The more fluent the participants were, the more dIFG activation decreased. This decreased activation of the dIFG might reflect the increased automaticity of a syntactic building process. In contrast, when participants performed an oral story comprehension task, the left posterior superior temporal gyrus (pSTG) showed increased activation with higher fluency levels. This suggests that the learners with higher L2 fluency were actively engaged in post-syntactic integration processing supported by the left pSTG. These data imply that L2 fluency predicts neural resource allocation during language comprehension tasks as well as in production tasks. This study sheds light on the neural underpinnings of L2 learning by identifying the brain regions recruited during different language tasks across different modalities (production vs. comprehension). PMID:26026679

  6. A Calcium-dependent switch in a CREST-BRG1 complex regulates activity-dependent gene expression

    PubMed Central

    Qiu, Zilong; Ghosh, Anirvan

    2009-01-01

    Activity-dependent gene expression plays an important role in mediating the effects of sensory experience on nervous system development and function. While several activity-dependent transcription factors have been identified, the mechanism by which calcium signaling converts a promoter from a silenced to an active state is not well understood. Here we show that a CREST-BRG1 complex plays a critical role in regulating promoter activation by orchestrating a calcium-dependent release of a repressor complex, and a recruitment of an activator complex. In resting neurons, transcription of the c-fos promoter is inhibited by BRG1-dependent recruitment of a phospho-Rb-HDAC repressor complex. Upon calcium influx, Rb becomes dephosphorylated at Serine 795 by Calcineurin, which leads to release of the repressor complex. At the same time there is increased recruitment of CBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 also binds to the NR2B promoter and activity-dependent induction of NR2B expression involves a release of HDAC1 and recruitment of CBP, suggesting that this mechanism may be generally involved in regulating calcium-dependent transcription of neuronal genes. PMID:19081374

  7. Basal activity of a PARP1-NuA4 complex varies dramatically across cancer cell lines

    PubMed Central

    Krukenberg, Kristin A.; Jiang, Ruomu; Steen, Judith A.; Mitchison, Timothy J.

    2014-01-01

    Summary Poly(ADP-ribose) polymerases (PARPs) catalyze poly(ADP-ribose) addition onto proteins, an important post-translational modification involved in transcription, DNA damage repair, and stem cell identity. Previous studies established the activation of PARP1 in response to DNA damage, but little is known about PARP1 regulation outside of DNA repair. We developed a new assay for measuring PARP activity in cell lysates, and found that the basal activity of PARP1 was highly variable across breast cancer cell lines, independent of DNA damage. Sucrose gradient fractionation demonstrated that PARP1 existed in at least three biochemically distinct states in both high and low activity lines. A newly discovered complex containing the NuA4 chromatin remodeling complex and PARP1 was responsible for high basal PARP1 activity, and NuA4 subunits were required for this activity. These findings present a new pathway for PARP1 activation and a direct link between PARP1 and chromatin remodeling outside of the DNA damage response. PMID:25199834

  8. Cre-dependent DNA recombination activates a STING-dependent innate immune response

    PubMed Central

    Pépin, Geneviève; Ferrand, Jonathan; Höning, Klara; Jayasekara, W. Samantha N.; Cain, Jason E.; Behlke, Mark A.; Gough, Daniel J.; G. Williams, Bryan R.; Hornung, Veit; Gantier, Michael P.

    2016-01-01

    Gene-recombinase technologies, such as Cre/loxP-mediated DNA recombination, are important tools in the study of gene function, but have potential side effects due to damaging activity on DNA. Here we show that DNA recombination by Cre instigates a robust antiviral response in mammalian cells, independent of legitimate loxP recombination. This is due to the recruitment of the cytosolic DNA sensor STING, concurrent with Cre-dependent DNA damage and the accumulation of cytoplasmic DNA. Importantly, we establish a direct interplay between this antiviral response and cell–cell interactions, indicating that low cell densities in vitro could be useful to help mitigate these effects of Cre. Taking into account the wide range of interferon stimulated genes that may be induced by the STING pathway, these results have broad implications in fields such as immunology, cancer biology, metabolism and stem cell research. Further, this study sets a precedent in the field of gene-engineering, possibly applicable to other enzymatic-based genome editing technologies. PMID:27166376

  9. Cre-dependent DNA recombination activates a STING-dependent innate immune response.

    PubMed

    Pépin, Geneviève; Ferrand, Jonathan; Höning, Klara; Jayasekara, W Samantha N; Cain, Jason E; Behlke, Mark A; Gough, Daniel J; G Williams, Bryan R; Hornung, Veit; Gantier, Michael P

    2016-06-20

    Gene-recombinase technologies, such as Cre/loxP-mediated DNA recombination, are important tools in the study of gene function, but have potential side effects due to damaging activity on DNA. Here we show that DNA recombination by Cre instigates a robust antiviral response in mammalian cells, independent of legitimate loxP recombination. This is due to the recruitment of the cytosolic DNA sensor STING, concurrent with Cre-dependent DNA damage and the accumulation of cytoplasmic DNA. Importantly, we establish a direct interplay between this antiviral response and cell-cell interactions, indicating that low cell densities in vitro could be useful to help mitigate these effects of Cre. Taking into account the wide range of interferon stimulated genes that may be induced by the STING pathway, these results have broad implications in fields such as immunology, cancer biology, metabolism and stem cell research. Further, this study sets a precedent in the field of gene-engineering, possibly applicable to other enzymatic-based genome editing technologies. PMID:27166376

  10. Microbial dynamics and enzyme activities in tropical Andosols depending on land use and nutrient inputs

    NASA Astrophysics Data System (ADS)

    Mganga, Kevin; Razavi, Bahar; Kuzyakov, Yakov

    2015-04-01

    Microbial decomposition of soil organic matter is mediated by enzymes and is a key source of terrestrial CO2 emissions. Microbial and enzyme activities are necessary to understand soil biochemical functioning and identify changes in soil quality. However, little is known about land use and nutrients availability effects on enzyme activities and microbial processes, especially in tropical soils of Africa. This study was conducted to examine how microbial and enzyme activities differ between different land uses and nutrient availability. As Andosols of Mt. Kilimanjaro are limited by nutrient concentrations, we hypothesize that N and P additions will stimulate enzyme activity. N and P were added to soil samples (0-20 cm) representing common land use types in East Africa: (1) savannah, (2) maize fields, (3) lower montane forest, (4) coffee plantation, (5) grasslands and (6) traditional Chagga homegardens. Total CO2 efflux from soil, microbial biomass and activities of β-glucosidase, cellobiohydrolase, chitinase and phosphatase involved in C, N and P cycling, respectively was monitored for 60 days. Total CO2 production, microbial biomass and enzyme activities varied in the order forest soils > grassland soils > arable soils. Increased β-glucosidase and cellobiohydrolase activities after N addition of grassland soils suggest that microorganisms increased N uptake and utilization to produce C-acquiring enzymes. Low N concentration in all soils inhibited chitinase activity. Depending on land use, N and P addition had an inhibitory or neutral effect on phosphatase activity. We attribute this to the high P retention of Andosols and low impact of N and P on the labile P fractions. Enhanced CO2 production after P addition suggests that increased P availability could stimulate soil organic matter biodegradation in Andosols. In conclusion, land use and nutrients influenced soil enzyme activities and microbial dynamics and demonstrated the decline in soil quality after landuse

  11. Time-varying covariance of neural activities recorded in striatum and frontal cortex as monkeys perform sequential-saccade tasks.

    PubMed

    Fujii, N; Graybiel, A M

    2005-06-21

    Cortico-basal ganglia circuits are key parts of the brain's habit system, but little is yet known about how these forebrain pathways function as ingrained habits are performed. We simultaneously recorded spike and local field potential (LFP) activity from regions of the frontal cortex and basal ganglia implicated in visuo-oculomotor control as highly trained macaque monkeys performed sequences of visually guided saccades. The tasks were repetitive, required no new learning, and could be performed nearly automatically. Our findings demonstrate striking differences between the relative timing of striatal and cortical activity during performance of the tasks. At the onset of the visual cues, LFPs in the prefrontal cortex and the oculomotor zone of the striatum showed near-synchronous activation. During the period of sequential-saccade performance, however, peak LFP activity occurred 100-300 msec later in the striatum than in the prefrontal cortex. Peak prefrontal activity tended to be peri-saccadic, whereas peak striatal activity tended to be post-saccadic. This temporal offset was also apparent in pairs of simultaneously recorded prefrontal and striatal neurons. In triple-site recordings, the LFP activity recorded in the supplementary eye field shared temporal characteristics of both the prefrontal and the striatal patterns. The near simultaneity of prefrontal and striatal peak responses at cue onsets, but temporal lag of striatal activity in the movement periods, suggests that the striatum may integrate corollary discharge or confirmatory response signals during sequential task performance. These timing relationships may be signatures of the normal functioning of striatal and frontal cortex during repetitive performance of learned behaviors. PMID:15956185

  12. Time-varying covariance of neural activities recorded in striatum and frontal cortex as monkeys perform sequential-saccade tasks

    PubMed Central

    Fujii, N.; Graybiel, A. M.

    2005-01-01

    Cortico-basal ganglia circuits are key parts of the brain's habit system, but little is yet known about how these forebrain pathways function as ingrained habits are performed. We simultaneously recorded spike and local field potential (LFP) activity from regions of the frontal cortex and basal ganglia implicated in visuo-oculomotor control as highly trained macaque monkeys performed sequences of visually guided saccades. The tasks were repetitive, required no new learning, and could be performed nearly automatically. Our findings demonstrate striking differences between the relative timing of striatal and cortical activity during performance of the tasks. At the onset of the visual cues, LFPs in the prefrontal cortex and the oculomotor zone of the striatum showed near-synchronous activation. During the period of sequential-saccade performance, however, peak LFP activity occurred 100–300 msec later in the striatum than in the prefrontal cortex. Peak prefrontal activity tended to be peri-saccadic, whereas peak striatal activity tended to be post-saccadic. This temporal offset was also apparent in pairs of simultaneously recorded prefrontal and striatal neurons. In triple-site recordings, the LFP activity recorded in the supplementary eye field shared temporal characteristics of both the prefrontal and the striatal patterns. The near simultaneity of prefrontal and striatal peak responses at cue onsets, but temporal lag of striatal activity in the movement periods, suggests that the striatum may integrate corollary discharge or confirmatory response signals during sequential task performance. These timing relationships may be signatures of the normal functioning of striatal and frontal cortex during repetitive performance of learned behaviors. PMID:15956185

  13. Particle-size dependence of the activation energy for decomposition of lithium amide

    NASA Astrophysics Data System (ADS)

    van de Walle, Chris; Hoang, Khang; Janotti, Anderson

    2012-02-01

    Lithium amide (LiNH2) is a promising material for reversible hydrogen storage, yet atomistic mechanisms behind the dehydrogenation process are unknown. The activation energy for LiNH2 decomposition has been observed to strongly vary with ball milling, suggesting a dependence of the thermodynamics and kinetics of the decomposition on the particle size. We have examined these mechanisms based on first-principles calculations for native point defects and defect complexes in LiNH2. We propose that the decomposition of LiNH2 into lithium imide (Li2NH) and ammonia (NH3) occurs through two competing mechanisms, one involving the formation of native defects in the interior of the material and the other at the surface. As a result, the prevailing mechanism and hence the activation energy depend on the surface-to-volume ratio, or the specific surface area, which changes with the particle size. We explain the observed variations of activation energy, and address the role played by LiH in the dehydrogenation of (LiNH2+LiH) mixtures. The relationship between the structure of hydrogen-related defects and the end products in the decomposition reaction can be extended to other complex hydrides.

  14. Activity-dependent changes in excitability of perirhinal cortex networks in vitro

    PubMed Central

    Biagini, Giuseppe; D’Antuono, Margherita; Inaba, Yuji; Kano, Toshiyuki; Ragsdale, David

    2016-01-01

    Rat brain slices comprising the perirhinal cortex (PC) and a portion of the lateral nucleus of the amygdala (LA), in standard medium, can generate synchronous oscillatory activity that is associated with action potential discharge and reflects the activation of glutamatergic and GABAergic receptors. We report here that similar synchronous oscillatory events are recorded in the PC in response to single-shock, electrical stimuli delivered in LA. In addition, we found that the latency of these responses progressively increased when the stimulus interval was varied from 10 to 1 s; for example, the response latency during stimuli delivered at 1 Hz was more than twofold longer than that seen during stimulation at 0.1 Hz. This prolongation in latency occurred after approximately 5 stimuli, attained a steady value after 24–35 stimuli, and recovered to control values 30 s after stimulation arrest. These frequency-dependent changes in latency continued to occur during NMDA receptor antagonism but weakened following application of GABAA and/or GABAB receptor blockers. Our findings identify a new type of short-term plasticity that is mediated by GABA receptor function and may play a role in decreasing neuronal network synchronization during repeated activation. We propose that this frequency-dependent adaptive mechanism influences the excitability of limbic networks, thus potentially controlling epileptiform synchronization. PMID:24903241

  15. Hepatitis C Virus Translation Preferentially Depends on Active RNA Replication

    PubMed Central

    Liu, Helene Minyi; Aizaki, Hideki; Machida, Keigo; Ou, J.-H. James; Lai, Michael M. C.

    2012-01-01

    Hepatitis C virus (HCV) RNA initiates its replication on a detergent-resistant membrane structure derived from the endoplasmic reticulum (ER) in the HCV replicon cells. By performing a pulse-chase study of BrU-labeled HCV RNA, we found that the newly-synthesized HCV RNA traveled along the anterograde-membrane traffic and moved away from the ER. Presumably, the RNA moved to the site of translation or virion assembly in the later steps of viral life cycle. In this study, we further addressed how HCV RNA translation was regulated by HCV RNA trafficking. When the movement of HCV RNA from the site of RNA synthesis to the Golgi complex was blocked by nocodazole, an inhibitor of ER-Golgi transport, HCV protein translation was surprisingly enhanced, suggesting that the translation of viral proteins occurred near the site of RNA synthesis. We also found that the translation of HCV proteins was dependent on active RNA synthesis: inhibition of viral RNA synthesis by an NS5B inhibitor resulted in decreased HCV viral protein synthesis even when the total amount of intracellular HCV RNA remained unchanged. Furthermore, the translation activity of the replication-defective HCV replicons or viral RNA with an NS5B mutation was greatly reduced as compared to that of the corresponding wildtype RNA. By performing live cell labeling of newly synthesized HCV RNA and proteins, we further showed that the newly synthesized HCV proteins colocalized with the newly synthesized viral RNA, suggesting that HCV RNA replication and protein translation take place at or near the same site. Our findings together indicate that the translation of HCV RNA is coupled to RNA replication and that the both processes may occur at the same subcellular membrane compartments, which we term the replicasome. PMID:22937067

  16. Relative activity of cerebral subcortical gray matter in varying states of attention and awareness in normal subjects and patient studies

    SciTech Connect

    Cooper, M.; Chen, C.T.; Levy, J.; Wagner, N.; Spire, J.P.; Jacobsen, J.; Meltzer, H.; Metz, J.; Beck, R.N.

    1985-05-01

    An important aspect of the study of brain function involves measurement of the relationships; between activities in the subcortical gray matter of the caudate and of the thalamus; and between these structures and functional cortical areas. The authors have studied these relationships in 22 subjects under different conditions of activation, sleep and sensory deprivation using a PET VI system and F-18-2DG to determine regional cerebral metabolism. Subject activating conditions were maintained throughout the period of equilibration of F-18-2DG and E.E.G.'s were monitored. Multiple tomographic slices of 1-2 million counts were obtained simultaneously with slice separation of 14mm and each plane parallel to the cantho-meatal line. In activated and non-activated awake conditions for normal subjects, left and right thalmus-to-caudate ratios were similar and greater than unity. This relationship was maintained in non-REM sleep, but was reversed and divergent in REM sleep and sensory deprivation; this was also evident in 3/4 narcoleptics awake and asleep in non-REM and REM and 2/3 schizophrenics and affective disorder, subjects. This approach appears to have potential for characterizating normal and disordered regional cerebral function.

  17. Fire activity and severity in the western US vary along proxy gradients representing fuel amount and fuel moisture.

    PubMed

    Parks, Sean A; Parisien, Marc-André; Miller, Carol; Dobrowski, Solomon Z

    2014-01-01

    Numerous theoretical and empirical studies have shown that wildfire activity (e.g., area burned) at regional to global scales may be limited at the extremes of environmental gradients such as productivity or moisture. Fire activity, however, represents only one component of the fire regime, and no studies to date have characterized fire severity along such gradients. Given the importance of fire severity in dictating ecological response to fire, this is a considerable knowledge gap. For the western US, we quantify relationships between climate and the fire regime by empirically describing both fire activity and severity along two climatic water balance gradients, actual evapotranspiration (AET) and water deficit (WD), that can be considered proxies for fuel amount and fuel moisture, respectively. We also concurrently summarize fire activity and severity among ecoregions, providing an empirically based description of the geographic distribution of fire regimes. Our results show that fire activity in the western US increases with fuel amount (represented by AET) but has a unimodal (i.e., humped) relationship with fuel moisture (represented by WD); fire severity increases with fuel amount and fuel moisture. The explicit links between fire regime components and physical environmental gradients suggest that multivariable statistical models can be generated to produce an empirically based fire regime map for the western US. Such models will potentially enable researchers to anticipate climate-mediated changes in fire recurrence and its impacts based on gridded spatial data representing future climate scenarios. PMID:24941290

  18. Fire Activity and Severity in the Western US Vary along Proxy Gradients Representing Fuel Amount and Fuel Moisture

    PubMed Central

    Parks, Sean A.; Parisien, Marc-André; Miller, Carol; Dobrowski, Solomon Z.

    2014-01-01

    Numerous theoretical and empirical studies have shown that wildfire activity (e.g., area burned) at regional to global scales may be limited at the extremes of environmental gradients such as productivity or moisture. Fire activity, however, represents only one component of the fire regime, and no studies to date have characterized fire severity along such gradients. Given the importance of fire severity in dictating ecological response to fire, this is a considerable knowledge gap. For the western US, we quantify relationships between climate and the fire regime by empirically describing both fire activity and severity along two climatic water balance gradients, actual evapotranspiration (AET) and water deficit (WD), that can be considered proxies for fuel amount and fuel moisture, respectively. We also concurrently summarize fire activity and severity among ecoregions, providing an empirically based description of the geographic distribution of fire regimes. Our results show that fire activity in the western US increases with fuel amount (represented by AET) but has a unimodal (i.e., humped) relationship with fuel moisture (represented by WD); fire severity increases with fuel amount and fuel moisture. The explicit links between fire regime components and physical environmental gradients suggest that multivariable statistical models can be generated to produce an empirically based fire regime map for the western US. Such models will potentially enable researchers to anticipate climate-mediated changes in fire recurrence and its impacts based on gridded spatial data representing future climate scenarios. PMID:24941290

  19. DCC constrains tumour progression via its dependence receptor activity.

    PubMed

    Castets, Marie; Broutier, Laura; Molin, Yann; Brevet, Marie; Chazot, Guillaume; Gadot, Nicolas; Paquet, Armelle; Mazelin, Laetitia; Jarrosson-Wuilleme, Loraine; Scoazec, Jean-Yves; Bernet, Agnès; Mehlen, Patrick

    2012-02-23

    The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers and, by functioning as a dependence receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis. PMID:22158121

  20. Homeostatic Activity-Dependent Tuning of Recurrent Networks for Robust Propagation of Activity

    PubMed Central

    Evers, Jan Felix; Eglen, Stephen J.

    2016-01-01

    Developing neuronal networks display spontaneous bursts of action potentials that are necessary for circuit organization and tuning. While spontaneous activity has been shown to instruct map formation in sensory circuits, it is unknown whether it plays a role in the organization of motor networks that produce rhythmic output. Using computational modeling, we investigate how recurrent networks of excitatory and inhibitory neuronal populations assemble to produce robust patterns of unidirectional and precisely timed propagating activity during organism locomotion. One example is provided by the motor network in Drosophila larvae, which generates propagating peristaltic waves of muscle contractions during crawling. We examine two activity-dependent models, which tune weak network connectivity based on spontaneous activity patterns: a Hebbian model, where coincident activity in neighboring populations strengthens connections between them; and a homeostatic model, where connections are homeostatically regulated to maintain a constant level of excitatory activity based on spontaneous input. The homeostatic model successfully tunes network connectivity to generate robust activity patterns with appropriate timing relationships between neighboring populations. These timing relationships can be modulated by the properties of spontaneous activity, suggesting its instructive role for generating functional variability in network output. In contrast, the Hebbian model fails to produce the tight timing relationships between neighboring populations required for unidirectional activity propagation, even when additional assumptions are imposed to constrain synaptic growth. These results argue that homeostatic mechanisms are more likely than Hebbian mechanisms to tune weak connectivity based on spontaneous input in a recurrent network for rhythm generation and robust activity propagation. SIGNIFICANCE STATEMENT How are neural circuits organized and tuned to maintain stable function

  1. Leisure-Time Physical Activity, Sedentary Behavior, and Physical Fitness among Adolescents: Varying Definitions Yield Differing Results in Fitness Research

    ERIC Educational Resources Information Center

    Kerner, Matthew S.

    2005-01-01

    The aims of the study were (1) to assess the relationships among leisure-time physical activity, sedentary behaviors, and measures of health-related and performance-related physical fitness, and (2) to determine the primary predictors of performance-related physical fitness from the variables investigated. This study updates the literature with…

  2. Associations of Participation in Service Activities with Academic, Behavioral, and Civic Outcomes of Adolescents at Varying Risk Levels

    ERIC Educational Resources Information Center

    Schmidt, Jennifer A.; Shumow, Lee; Kackar, Hayal Z.

    2012-01-01

    Youth who participate in service activities differ from those who do not on a number of key demographic characteristics like socio-economic status and other indicators of risk; and most studies demonstrating positive outcomes among service participants employ small non-representative samples. Thus, there is little evidence as to whether the…

  3. Sulphate-activated phosphorylase b: the pH-dependence of catalytic activity.

    PubMed Central

    Zographos, S E; Oikonomakos, N G; Dixon, H B; Griffin, W G; Johnson, L N; Leonidas, D D

    1995-01-01

    The pH-dependence of sulphate-activated phosphorylase b has been studied in the direction of glycogen synthesis. The bell-shaped curve of the pH-dependence of the catalytic constant for the AMP-activated enzyme showed pK values of 6.1 and 7.3, but the curve for the enzyme activated by 0.9 M ammonium sulphate showed a drop of activity on the acid side at much higher pH values. Its bell was centred at pH 7.8 but it was too narrow to be characterized by only two pK values. The narrowness of the curve could be explained by positive co-operativity, but not its unusually steep acid side. We suggest that the fall on the acid side is due to more than one hydronation (addition of H+). The points can be fitted by a curve with two de-activating hydronations and a de-activating dehydronation having identical titration pK values of 7.5, and hence molecular values of 7.0, 7.5 and 8.0. If both 0.9 M ammonium sulphate and 5 mM AMP are added, the bell is as broad as with AMP alone, but is somewhat raised in pH optimum. The results are discussed in the light of new structural data from crystallographic studies on binary complexes of the enzyme. PMID:7654195

  4. Sulphate-activated phosphorylase b: the pH-dependence of catalytic activity.

    PubMed

    Zographos, S E; Oikonomakos, N G; Dixon, H B; Griffin, W G; Johnson, L N; Leonidas, D D

    1995-09-01

    The pH-dependence of sulphate-activated phosphorylase b has been studied in the direction of glycogen synthesis. The bell-shaped curve of the pH-dependence of the catalytic constant for the AMP-activated enzyme showed pK values of 6.1 and 7.3, but the curve for the enzyme activated by 0.9 M ammonium sulphate showed a drop of activity on the acid side at much higher pH values. Its bell was centred at pH 7.8 but it was too narrow to be characterized by only two pK values. The narrowness of the curve could be explained by positive co-operativity, but not its unusually steep acid side. We suggest that the fall on the acid side is due to more than one hydronation (addition of H+). The points can be fitted by a curve with two de-activating hydronations and a de-activating dehydronation having identical titration pK values of 7.5, and hence molecular values of 7.0, 7.5 and 8.0. If both 0.9 M ammonium sulphate and 5 mM AMP are added, the bell is as broad as with AMP alone, but is somewhat raised in pH optimum. The results are discussed in the light of new structural data from crystallographic studies on binary complexes of the enzyme. PMID:7654195

  5. Ligand-dependent Enhancer Activation Regulated by Topoisomerase-I Activity

    PubMed Central

    Puc, Janusz; Kozbial, Piotr; Li, Wenbo; Tan, Yuliang; Liu, Zhijie; Suter, Tom; Ohgi, Kenneth A.; Zhang, Jie; Aggarwal, Aneel K.; Rosenfeld, Michael G.

    2014-01-01

    SUMMARY The discovery that enhancers are regulated transcription units, encoding eRNAs, has raised new questions about the mechanisms of their activation. Here, we report an unexpected molecular mechanism that underlies ligand-dependent enhancer activation, based on DNA nicking to relieve torsional stress from eRNA synthesis. Using dihydrotestosterone (DHT)-induced binding of androgen receptor (AR) to prostate cancer cell enhancers as a model, we show rapid recruitment, within minutes, of DNA topoisomerase I (TOP1) to a large cohort of AR-regulated enhancers. Furthermore, we show that the DNA nicking activity of TOP1 is a prerequisite for robust eRNA synthesis and enhancer activation, and is kinetically accompanied by the recruitment of ATR and the MRN complex, followed by additional components of DNA damage repair machinery to the AR-regulated enhancers. Together, our studies reveal a linkage between eRNA synthesis and ligand-dependent TOP1-mediated nicking a strategy exerting quantitative effects on eRNA expression in regulating AR-bound enhancer-dependent transcriptional programs. PMID:25619691

  6. Analysis of the locomotor activity of a nocturnal desert lizard (Reptilia: Gekkonidae: Teratoscincus scincus) under varying moonlight.

    PubMed

    Seligmann, Hervé; Anderson, Steven C; Autumn, Kellar; Bouskila, Amos; Saf, Rachel; Tuniyev, Boris S; Werner, Yehudah L

    2007-01-01

    1. This project seeks to identify determinants of the variation observed in the foraging behavior of predatory animals, especially in moonlight, using a lizard as a model. 2. Moonlight generally enhances the foraging efficiency of nocturnal visual predators and often depresses the locomotor activity of prey animals. Previous evidence has indicated for three different nocturnal species of smallish gecko lizards that they respond to moonlight by increasing their activity. 3. In this study some aspects of the foraging activity of the somewhat larger nocturnal psammophilous Teratoscincus scincus, observed near Repetek and Ashgabat, Turkmenistan, were significantly depressed by moonlight, while several confounding factors (sex, maturity, size, sand temperature, hour, prior handling and observer effect) were taken into account. 4. This behavioral difference may relate to the eye size of the various species. 5. Additionally, a novel method of analyzing foraging behavior shows that in this species the duration of moves increases the duration of subsequent stationary pauses. Measurement of locomotor speed, yielding an average speed of 220% of the maximum aerobic speed, indicates a need for these pauses. Secondarily, pause duration decreases the duration of subsequent moves, precluding escalation of move duration. 6. The results of this and related projects advocate the taking into account of physiological and environmental factors that may affect an animal's foraging behavior. PMID:17408939

  7. Continuous, Long-term, Cyclic, Varied Eruptive Activity Observed at NW Rota-1 Submarine Volcano, Mariana Arc

    NASA Astrophysics Data System (ADS)

    Chadwick, B.; Dziak, R. P.; Baker, E. T.; Cashman, K. V.; Embley, R. W.; Ferrini, V.; de Ronde, C. E.; Butterfield, D. A.; Deardorff, N.; Haxel, J. H.; Matsumoto, H.; Fowler, M. J.; Walker, S. L.; Bobbitt, A. M.; Merle, S. G.

    2009-12-01

    NW Rota-1 is a conical, basaltic-andesite submarine volcano in the Mariana arc with a summit depth of 520 m. Eruptive activity was first witnessed here during remotely operated vehicle (ROV) dives in 2004, and was also observed during all four subsequent ROV expeditions in 2005, 2006, and 2009. Cyclic explosive bursts were documented by a portable hydrophone during the 2006 ROV dives. More recently, a year of instrumental monitoring data from a moored hydrophone and plume sensor show that the volcano was continuously active from February 2008 to February 2009, and that the cyclic character of the eruptions occurred with variable intensity and periodicity. The 2008-2009 hydrophone record includes explosive bursts every 1-2 minutes, with high acoustic amplitudes in the first half of the year and lower more variable amplitudes in the second half. In contrast, the moored turbidity sensor recorded major eruptive plumes on a time scale of every few days to weeks, and at approximately the same frequency throughout the year. This apparent disparity may be explained by the most recent ROV and portable hydrophone observations at NW Rota-1 in April 2009, which confirmed continuous and diverse eruptive activity with cyclicity over several time scales, from minutes to days. Visual observations at the eruptive vent provided new insight into the process of very slow lava extrusion on the seafloor. During slow extrusion (at rates of 1-2 m3/hr), lava spines rose in the eruptive vent, then gradually disintegrated into angular blocks as they cooled and were shoved aside by the next lava to emerge. Freshly erupted lava blocks periodically tumbled down the sides of a growing cone (40-m high and 300-m wide) that had been constructed by this process since the last visit in 2006. Thus auto-brecciation during slow lava extrusion underwater produces primary deposits that could easily be mistaken as secondary, and can construct substantial landforms on submarine arc volcanoes. Even during

  8. Obscuration-dependent Evolution of Active Galactic Nuclei

    NASA Astrophysics Data System (ADS)

    Buchner, Johannes; Georgakakis, Antonis; Nandra, Kirpal; Brightman, Murray; Menzel, Marie-Luise; Liu, Zhu; Hsu, Li-Ting; Salvato, Mara; Rangel, Cyprian; Aird, James; Merloni, Andrea; Ross, Nicholas

    2015-04-01

    We aim to constrain the evolution of active galactic nuclei (AGNs) as a function of obscuration using an X-ray-selected sample of ~2000 AGNs from a multi-tiered survey including the CDFS, AEGIS-XD, COSMOS, and XMM-XXL fields. The spectra of individual X-ray sources are analyzed using a Bayesian methodology with a physically realistic model to infer the posterior distribution of the hydrogen column density and intrinsic X-ray luminosity. We develop a novel non-parametric method that allows us to robustly infer the distribution of the AGN population in X-ray luminosity, redshift, and obscuring column density, relying only on minimal smoothness assumptions. Our analysis properly incorporates uncertainties from low count spectra, photometric redshift measurements, association incompleteness, and the limited sample size. We find that obscured AGNs with N H > 1022 cm-2 account for {77}+4-5% of the number density and luminosity density of the accretion supermassive black hole population with L X > 1043 erg s-1, averaged over cosmic time. Compton-thick AGNs account for approximately half the number and luminosity density of the obscured population, and {38}+8-7% of the total. We also find evidence that the evolution is obscuration dependent, with the strongest evolution around N H ≈ 1023 cm-2. We highlight this by measuring the obscured fraction in Compton-thin AGNs, which increases toward z ~ 3, where it is 25% higher than the local value. In contrast, the fraction of Compton-thick AGNs is consistent with being constant at ≈35%, independent of redshift and accretion luminosity. We discuss our findings in the context of existing models and conclude that the observed evolution is, to first order, a side effect of anti-hierarchical growth.

  9. Toll-like receptor 2 activation depends on lipopeptide shedding by bacterial surfactants

    PubMed Central

    Hanzelmann, Dennis; Joo, Hwang-Soo; Franz-Wachtel, Mirita; Hertlein, Tobias; Stevanovic, Stefan; Macek, Boris; Wolz, Christiane; Götz, Friedrich; Otto, Michael; Kretschmer, Dorothee; Peschel, Andreas

    2016-01-01

    Sepsis caused by Gram-positive bacterial pathogens is a major fatal disease but its molecular basis remains elusive. Toll-like receptor 2 (TLR2) has been implicated in the orchestration of inflammation and sepsis but its role appears to vary for different pathogen species and clones. Accordingly, Staphylococcus aureus clinical isolates differ substantially in their capacity to activate TLR2. Here we show that strong TLR2 stimulation depends on high-level production of phenol-soluble modulin (PSM) peptides in response to the global virulence activator Agr. PSMs are required for mobilizing lipoproteins, the TLR2 agonists, from the staphylococcal cytoplasmic membrane. Notably, the course of sepsis caused by PSM-deficient S. aureus is similar in wild-type and TLR2-deficient mice, but TLR2 is required for protection of mice against PSM-producing S. aureus. Thus, a crucial role of TLR2 depends on agonist release by bacterial surfactants. Modulation of this process may lead to new therapeutic strategies against Gram-positive infections. PMID:27470911

  10. Toll-like receptor 2 activation depends on lipopeptide shedding by bacterial surfactants.

    PubMed

    Hanzelmann, Dennis; Joo, Hwang-Soo; Franz-Wachtel, Mirita; Hertlein, Tobias; Stevanovic, Stefan; Macek, Boris; Wolz, Christiane; Götz, Friedrich; Otto, Michael; Kretschmer, Dorothee; Peschel, Andreas

    2016-01-01

    Sepsis caused by Gram-positive bacterial pathogens is a major fatal disease but its molecular basis remains elusive. Toll-like receptor 2 (TLR2) has been implicated in the orchestration of inflammation and sepsis but its role appears to vary for different pathogen species and clones. Accordingly, Staphylococcus aureus clinical isolates differ substantially in their capacity to activate TLR2. Here we show that strong TLR2 stimulation depends on high-level production of phenol-soluble modulin (PSM) peptides in response to the global virulence activator Agr. PSMs are required for mobilizing lipoproteins, the TLR2 agonists, from the staphylococcal cytoplasmic membrane. Notably, the course of sepsis caused by PSM-deficient S. aureus is similar in wild-type and TLR2-deficient mice, but TLR2 is required for protection of mice against PSM-producing S. aureus. Thus, a crucial role of TLR2 depends on agonist release by bacterial surfactants. Modulation of this process may lead to new therapeutic strategies against Gram-positive infections. PMID:27470911

  11. A comparison of attitudes and exercise habits of alumni from colleges with varying degrees of physical education activity programs.

    PubMed

    Adams, T M; Brynteson, P

    1992-06-01

    A survey of alumni attitudes about their college physical education activity (PEA) program and current exercise habits was sent to a representative sample (N = 3169) of alumni who had graduated between 1970 and 1984 from four private colleges. The percent returned was 48, 31, 43, and 41 from Colleges A-D, respectively. Three of the four colleges had required PEA programs. College A had an eight-credit-hour requirement, College B required four credit-hours, College C required two credits, and College D did not have a PEA requirement. Results indicated a significant difference among the four colleges in the alumni's perceived value of their college PEA program in terms of its contribution to their knowledge about fitness, attitude towards fitness, and current exercise habits. Additionally, alumni differed in their perception of the health value of exercise and in their frequency of weekly exercise. When alumni exercise behaviors were quantified by aerobic points and classified according to type of activity, no statistically significant differences were found. The conclusion of the study was that the attitudes and exercise behaviors of alumni are related to the type of college PEA requirement; however, aerobic points earned are not affected. Students graduating from colleges with higher PEA requirements demonstrate more positive exercise attitudes and behaviors. PMID:1585061

  12. Erythrocyte-dependent regulation of human skeletal muscle blood flow: role of varied oxyhemoglobin and exercise on nitrite, S-nitrosohemoglobin, and ATP.

    PubMed

    Dufour, Stéphane P; Patel, Rakesh P; Brandon, Angela; Teng, Xinjun; Pearson, James; Barker, Horace; Ali, Leena; Yuen, Ada H Y; Smolenski, Ryszard T; González-Alonso, José

    2010-12-01

    The erythrocyte is proposed to play a key role in the control of local tissue perfusion via three O(2)-dependent signaling mechanisms: 1) reduction of circulating nitrite to vasoactive NO, 2) S-nitrosohemoglobin (SNO-Hb)-dependent vasodilatation, and 3) release of the vasodilator and sympatholytic ATP; however, their relative roles in vivo remain unclear. Here we evaluated each mechanism to gain insight into their roles in the regulation of human skeletal muscle blood flow during hypoxia and hyperoxia at rest and during exercise. Arterial and femoral venous hemoglobin O(2) saturation (O(2)Hb), plasma and erythrocyte NO and ATP metabolites, and leg and systemic hemodynamics were measured in 10 healthy males exposed to graded hypoxia, normoxia, and graded hyperoxia both at rest and during submaximal one-legged knee-extensor exercise. At rest, leg blood flow and NO and ATP metabolites in plasma and erythrocytes remained unchanged despite large alterations in O(2)Hb. During exercise, however, leg and systemic perfusion and vascular conductance increased in direct proportion to decreases in arterial and venous O(2)Hb (r(2) = 0.86-0.98; P = 0.01), decreases in venous plasma nitrite (r(2) = 0.93; P < 0.01), increases in venous erythrocyte nitroso species (r(2) = 0.74; P < 0.05), and to a lesser extent increases in erythrocyte SNO (r(2) = 0.59; P = 0.07). No relationship was observed with plasma ATP (r(2) = 0.01; P = 0.99) or its degradation compounds. These in vivo data indicate that, during low-intensity exercise and hypoxic stress, but not hypoxic stress alone, plasma nitrite consumption and formation of erythrocyte nitroso species are associated with limb vasodilatation and increased blood flow in the human skeletal muscle vasculature. PMID:20852046

  13. Time-Independent and Time-Dependent Rheological Characterization of Dispersions with Varying Contents of Chickpea Flour and Gum Arabic Employing the Multiple Loop Experiments.

    PubMed

    J, Shanthilal; Bhattacharya, Suvendu

    2016-08-01

    The chickpea (Cicer arietinum) flour dispersions as the model system with different contents of flour (37% to 43%) and gum arabic (0% to 5%) were subjected to multiple loop experiments for simultaneous determination of the time-independent and time-dependent rheological characteristics. The Herschel-Bulkley model was suitable (0.993 ≤ r ≤ 0.999) to relate the time-independent characteristics linking shear stress and shear rate data for the individual upward and downward curves. The yield stress, consistency index, and apparent viscosity increased with the increasing flour and/or gum contents while flow behavior index (n) decreased. The yield stress generally decreased with the number of loops but n increased. In the individual loop tests, the n values for the decreasing shear stress/shear rate curves were always higher than corresponding increasing curves meaning a shift toward Newtonian characteristics. The time-independent properties (yield stress, apparent viscosity, consistency index, and n), the time-dependent characteristics like the area of the loop, and liquid characteristics like pourability and the nonoral sensory attributes (viscosity, spreadability, and tackiness) were individually predicted by artificial neural networks wherein the root mean square errors were between 3.6% and 17.2%. The sensory assessment indicated that the desirable parameters for a free-flowing and easily pourable spherical chickpea batter droplets occurred when the average pourability and spreadability values were 6.9 and 5.9, respectively. The normalized indices for these 2 parameters indicated that the batter having 40% flour and 2% gum contents was most suitable exhibiting a deviation of only 10% from the ideal sensory scores; these values were 40% and 0% to 3%, and 43% and 0%, respectively exhibiting up to 20% deviation. PMID:27331658

  14. Erythrocyte-dependent regulation of human skeletal muscle blood flow: role of varied oxyhemoglobin and exercise on nitrite, S-nitrosohemoglobin, and ATP

    PubMed Central

    Patel, Rakesh P.; Brandon, Angela; Teng, Xinjun; Pearson, James; Barker, Horace; Ali, Leena; Yuen, Ada H. Y.; Smolenski, Ryszard T.; González-Alonso, José

    2010-01-01

    The erythrocyte is proposed to play a key role in the control of local tissue perfusion via three O2-dependent signaling mechanisms: 1) reduction of circulating nitrite to vasoactive NO, 2) S-nitrosohemoglobin (SNO-Hb)-dependent vasodilatation, and 3) release of the vasodilator and sympatholytic ATP; however, their relative roles in vivo remain unclear. Here we evaluated each mechanism to gain insight into their roles in the regulation of human skeletal muscle blood flow during hypoxia and hyperoxia at rest and during exercise. Arterial and femoral venous hemoglobin O2 saturation (O2Hb), plasma and erythrocyte NO and ATP metabolites, and leg and systemic hemodynamics were measured in 10 healthy males exposed to graded hypoxia, normoxia, and graded hyperoxia both at rest and during submaximal one-legged knee-extensor exercise. At rest, leg blood flow and NO and ATP metabolites in plasma and erythrocytes remained unchanged despite large alterations in O2Hb. During exercise, however, leg and systemic perfusion and vascular conductance increased in direct proportion to decreases in arterial and venous O2Hb (r2 = 0.86–0.98; P = 0.01), decreases in venous plasma nitrite (r2 = 0.93; P < 0.01), increases in venous erythrocyte nitroso species (r2 = 0.74; P < 0.05), and to a lesser extent increases in erythrocyte SNO (r2 = 0.59; P = 0.07). No relationship was observed with plasma ATP (r2 = 0.01; P = 0.99) or its degradation compounds. These in vivo data indicate that, during low-intensity exercise and hypoxic stress, but not hypoxic stress alone, plasma nitrite consumption and formation of erythrocyte nitroso species are associated with limb vasodilatation and increased blood flow in the human skeletal muscle vasculature. PMID:20852046

  15. Regional and total body active heating and cooling of a resting diver in water of varied temperatures

    NASA Astrophysics Data System (ADS)

    Bardy, Erik; Mollendorf, Joseph; Pendergast, David

    2008-02-01

    Passive insulations alone are not sufficient for maintaining underwater divers in thermal balance or comfort. The purpose of this study was to experimentally determine the active heating and cooling requirements to keep a diver at rest in thermal balance and comfort in water temperatures between 10 and 40 °C. A diver wearing a prototype tubesuit and a wetsuit (3 or 6.5 mm foam neoprene) was fully submersed (0.6 m) in water at a specified temperature (10, 20, 30 and 40 °C). During immersion, the tubesuit was perfused with 30 °C water at a flow rate of 0.5 L min-1 to six individual body regions. An attempt was made to keep skin temperatures below 42 °C in hot water (>30 °C) and elevated but below 32 °C in cold water (<20 °C). A skin temperature of 32 °C is the threshold for maximal body thermal resistance due to vasoconstriction. Skin temperatures and core temperature were monitored during immersion to ensure they remained within set thermal limits. In addition skin heat flux, oxygen consumption and the thermal exchange of the tubesuit were measured. In both wetsuit thicknesses there was a linear correlation between the thermal exchange of the tubesuit and ambient water temperature. In the 6.5 mm wetsuit -214 W to 242 W of heating (-) and cooling (+) was necessary in 10 °C to 40 °C water, respectively. In the 3 mm wetsuit -462 to 342 W was necessary in 10 °C to 40 °C water, respectively. It was therefore concluded that a diver at rest can be kept in thermal balance in 10-40 °C water with active heating and cooling.

  16. Hyperosmotic stress activates Rho: differential involvement in Rho kinase-dependent MLC phosphorylation and NKCC activation.

    PubMed

    Di Ciano-Oliveira, Caterina; Sirokmány, Gábor; Szászi, Katalin; Arthur, William T; Masszi, András; Peterson, Mark; Rotstein, Ori D; Kapus, András

    2003-09-01

    Hyperosmotic stress initiates adaptive responses, including phosphorylation of myosin light chain (MLC) and concomitant activation of Na+-K+-Cl- cotransporter (NKCC). Because the small GTPase Rho is a key regulator of MLC phosphorylation, we investigated 1) whether Rho is activated by hyperosmotic stress, and if so, what the triggering factors are, and 2) whether the Rho/Rho kinase (ROK) pathway is involved in MLC phosphorylation and NKCC activation. Rho activity was measured in tubular epithelial cells by affinity pulldown assay. Hyperosmolarity induced rapid (<1 min) and sustained (>20 min) Rho activation that was proportional to the osmotic concentration and reversed within minutes upon restoration of isotonicity. Both decreased cell volume at constant ionic strength and elevated total ionic strength at constant cell volume were capable of activating Rho. Changes in [Na+] and [K+] at normal total salinity failed to activate Rho, and Cl- depletion did not affect the hyperosmotic response. Thus alterations in cellular volume and ionic strength but not individual ion concentrations seem to be the critical triggering factors. Hyperosmolarity induced mono- and diphosphorylation of MLC, which was abrogated by the Rho-family blocker Clostridium toxin B. ROK inhibitor Y-27632 suppressed MLC phosphorylation under isotonic conditions and prevented its rise over isotonic levels in hypertonically stimulated cells. ML-7 had a smaller inhibitory effect. In contrast, it abolished the hypertonic activation of NKCC, whereas Y-27632 failed to inhibit this response. Thus hyperosmolarity activates Rho, and Rho/ROK pathway contributes to basal and hyperosmotic MLC phosphorylation. However, the hypertonic activation of NKCC is ROK independent, implying that the ROK-dependent component of MLC phosphorylation can be uncoupled from NKCC activation. PMID:12748065

  17. The content of macro- and microelements and the phosphatase activity of soils under a varied plant cultivation technology

    NASA Astrophysics Data System (ADS)

    Bartkowiak, A.; Lemanowicz, J.; Kobierski, M.

    2015-12-01

    The paper presents the results of the analyses of selected physicochemical properties and the activity of alkaline and acid phosphatase in the soils which differed in terms of plant cultivation technology. Profile sI represented arable land in the crop rotation with cereals dominating (medium intensive technology), without irrigation, while profile sII—represented arable land with vegetable crops cultivation (intensive technology), intensively fertilized and irrigated. The content of available phosphorus in the two soil profiles investigated ranged from 6.6 to 69.1 mg/kg. The highest contents of phosphorus available to plants were reported in the plough horizon of both soils, while the abundance of potassium and magnesium was highest in the illuvial horizon of both soils. The soil profiles investigated showed a significant variation in terms of the cultivation technologies applied. The contents of plant-available Cu and Zn in soil were low and they resulted in the inhibition of neither alkaline nor acid phosphatase. The intensive vegetable crops cultivation technology decreased the content of organic matter and increased the content of the nutrients in soil. Using the Ward method, it was found that relatively similar physicochemical and chemical properties were reported for the genetic horizons of both soil profiles, especially Ap horizon of the soil representing arable land with intensive cultivation of vegetable crops.

  18. Penicillium verruculosum SG: a source of polyketide and bioactive compounds with varying cytotoxic activities against normal and cancer lines.

    PubMed

    Shah, Salma Gul; Shier, W Thomas; Jamaluddin; Tahir, Nawaz; Hameed, Abdul; Ahmad, Safia; Ali, Naeem

    2014-04-01

    A newly isolated fungus Penicillium verruculosum SG was evaluated for the production and characterization of bioactive colored secondary metabolites using solid-state fermentation along with their cytotoxic activities against normal and cancer cell lines. Logical fragmentation pattern following column chromatography, thin layer chromatography and liquid chromatography and mass spectrometry of crude culture filtrate of fungus revealed the presence of different polyketide pigments and other bioactive compounds. Cytotoxicity of the selected colored fractions of fungal filtrate containing different compounds revealed IC50 (μg/ml) values ranging from 5 to 100. It was significantly higher in case of orevactaene (5 + 0.44) and monascorubrine followed by pyripyropene (8 + 0.63) against cancer cell line KA3IT. Overall, these compounds considerably showed less toxicity toward normal cell lines NIH3T3, HSCT6, HEK293 and MDCK. XRD of a yellow crystalline compound (224.21 m/z) confirmed its 3-dimensional structure as phenazine 1 carboxylic acid (C13H8N2O2) (broad spectrum antibiotic), and it is first time reported in fungi. PMID:24563022

  19. Active fault detection and isolation of discrete-time linear time-varying systems: a set-membership approach

    NASA Astrophysics Data System (ADS)

    Mojtaba Tabatabaeipour, Seyed

    2015-08-01

    Active fault detection and isolation (AFDI) is used for detection and isolation of faults that are hidden in the normal operation because of a low excitation signal or due to the regulatory actions of the controller. In this paper, a new AFDI method based on set-membership approaches is proposed. In set-membership approaches, instead of a point-wise estimation of the states, a set-valued estimation of them is computed. If this set becomes empty the given model of the system is not consistent with the measurements. Therefore, the model is falsified. When more than one model of the system remains un-falsified, the AFDI method is used to generate an auxiliary signal that is injected into the system for detection and isolation of faults that remain otherwise hidden or non-isolated using passive FDI (PFDI) methods. Having the set-valued estimation of the states for each model, the proposed AFDI method finds an optimal input signal that guarantees FDI in a finite time horizon. The input signal is updated at each iteration in a decreasing receding horizon manner based on the set-valued estimation of the current states and un-falsified models at the current sample time. The problem is solved by a number of linear and quadratic programming problems, which result in a computationally efficient algorithm. The method is tested on a numerical example as well as on the pitch actuator of a benchmark wind turbine.

  20. Does the relative impact of climate and land use changes on groundwater recharge vary depending on the degree of subsurface heterogeneity?

    NASA Astrophysics Data System (ADS)

    Sarrazin, F.; Hartmann, A. J.; Pianosi, F.; Wagener, T.

    2015-12-01

    Karst aquifers are an important source of drinking water in many regions of the world, but their resources are likely to be affected by changes in climate and land use. In fact, climate characteristics control the supply of water to karst systems and the evaporative demand, while land use characteristics control the actual evapotranspiration losses. Understanding karst hydrology and estimating karst groundwater resources at a large-scale is critical for preventing threats to water supply in a changing world. Hartmann et al. (2015, Geosci. Model Dev.) introduced a parsimonious karst recharge model, called VarKarst-R, which allows for large-scale simulations of groundwater recharge while explicitly taking into account karst heterogeneities, i.e. preferential flow paths. The first objective of the present study is to introduce vegetation processes into the VarKarst-R model to better estimate evapotranspiration losses depending on the land use characteristics. Secondly, the VarKarst-R model so modified will be used to assess the relative influence of changes in climate and land use on aquifer recharge. We establish a sensitivity analysis framework to analyse the interactions between climate descriptors (e.g. mean precipitation, precipitation seasonality), vegetation parameters (e.g. canopy storage capacity, rooting depth) and soil parameters (e.g. soil storage).

  1. Negative density-dependent mortality varies over time in a wet tropical forest, advantaging rare species, common species, or no species.

    PubMed

    Bachelot, Bénédicte; Kobe, Richard K; Vriesendorp, Corine

    2015-11-01

    Although one of the most widely studied hypotheses for high tree diversity in the tropics, the Janzen-Connell hypothesis (JC), and the community compensatory trend upon which it is based, have conflicting support from prior studies. Some of this variation could arise from temporal variation in seedling survival of common and rare species. Using 10 years of data from La Selva Biological Station in Costa Rica, we analyzed annual seedling survival and found that negative density-dependence (negative DD) was significantly stronger for rare species than for common species in 2 years and was significantly stronger for common species than for rare species in 4 years. This temporal variation in survival was correlated with climatic variables: in warmer and wetter years, common species had higher negative DD than rare species. The relationship between climate and variation in JC effects on seedling survival of common and rare species could have important consequences for the maintenance of tree species diversity in Central America, which is predicted to experience warmer and wetter years as global change proceeds. PMID:26227367

  2. Activated platelets rescue apoptotic cells via paracrine activation of EGFR and DNA-dependent protein kinase

    PubMed Central

    Au, A E-L; Sashindranath, M; Borg, R J; Kleifeld, O; Andrews, R K; Gardiner, E E; Medcalf, R L; Samson, A L

    2014-01-01

    Platelet activation is a frontline response to injury, not only essential for clot formation but also important for tissue repair. Indeed, the reparative influence of platelets has long been exploited therapeutically where application of platelet concentrates expedites wound recovery. Despite this, the mechanisms of platelet-triggered cytoprotection are poorly understood. Here, we show that activated platelets accumulate in the brain to exceptionally high levels following injury and release factors that potently protect neurons from apoptosis. Kinomic microarray and subsequent kinase inhibitor studies showed that platelet-based neuroprotection relies upon paracrine activation of the epidermal growth factor receptor (EGFR) and downstream DNA-dependent protein kinase (DNA-PK). This same anti-apoptotic cascade stimulated by activated platelets also provided chemo-resistance to several cancer cell types. Surprisingly, deep proteomic profiling of the platelet releasate failed to identify any known EGFR ligand, indicating that activated platelets release an atypical activator of the EGFR. This study is the first to formally associate platelet activation to EGFR/DNA-PK – an endogenous cytoprotective cascade. PMID:25210793

  3. Activation of antioxidant response element (ARE)-dependent genes by roasted coffee extracts.

    PubMed

    Yazheng, Liu; Kitts, David D

    2012-09-01

    Coffee beans contain numerous bioactive components that exhibit antioxidant capacity when assessed using both chemical, cell free, and biological, cell-based model systems. However, the mechanisms underlying the antioxidant effects of coffee in biological systems are not totally understood and in some cases vary considerably from results obtained with simpler in vitro chemical assays. In the present study, the physicochemical characteristics and antioxidant activity of roasted and non-roasted coffee extracts were investigated in both cell free (ORAC(FL)) and cell-based systems. A profile of antioxidant gene expression in cultured human colon adenocarcinoma Caco-2 cells treated with both roasted and non-roasted coffee extracts, respectively, was investigated using Real-Time polymerase chain reaction (PCR) array technology. Results demonstrated that the mechanisms of the antioxidant activity associated with coffee constituents assessed by the ORAC(FL) assay were different to those observed using an intracellular oxidation assay with Caco-2 cells. Moreover, roasted coffee (both light and dark roasted) extracts produced both increased- and decreased-expressions of numerous genes that are involved in the management of oxidative stress via the antioxidant defence system. The selective and specific positive induction of antioxidant response element (ARE)-dependent genes, including gastrointestinal glutathione peroxidase (GPX2), sulfiredoxin (SRXN1), thioredoxin reductase 1 (TXNRD1), peroxiredoxin 1 (PRDX1), peroxiredoxin 4 (PDRX4) and peroxiredoxin 6 (PDRX6) were identified with the activation of the endogenous antioxidant defence system in Caco-2 cells. PMID:22699814

  4. Cell Penetrating Peptide-Mediated Caveolae-Dependent Activation of Lung Endothelial Nitric Oxide Synthase.

    PubMed

    Hutchinson, Tarun E; Hu, Hanbo; Patel, Jawaharlal M

    2016-01-01

    Cell penetrating peptides can be used as therapeutic agents via modulation of selective cell functions. Nitric oxide (NO) generated by vascular endothelial NO synthase (eNOS) plays a critical role in the NO/ cyclic guanosine 5'-monophosphate (cGMP)-mediated pulmonary vascular function. Here we examined whether internalization of a fifteen amino acid (KRFNSISCSSWRRKR) synthetic peptide (P3) enhances the catalytic activity of eNOS via caveolae/eNOS dissociation leading to NO release and increased cGMP production in pulmonary artery endothelial cells (EC). ECs were treated with varying concentrations of P3 and used to monitor internalization, isolation of caveolae-enriched fraction, the catalytic activity of eNOS, NO/cGMP production, and intracellular Ca(2+) release. Confocal images show timedependent internalization of P3 in EC. Treatment of EC with P3, but not scrambled P3, increased the catalytic activity of eNOS in a dose-dependent manner without change in eNOS expression or phosphorylation. Treatment of EC with P3 stimulated intracellular Ca(2+) release, increased the catalytic activity of phospatidylinsositide 3 kinase (PI3K) and resulted in eNOS/caveolae-1 (Cav-1) dissociation leading to translocation of eNOS to intracellular compartment in EC. P3- mediated activation of eNOS was abolished by intracellular Ca(2+) chelator 1,2-bis(2-aminophenooxy)ethane-N,N,N',N'- tertraacetic acid-AM (BAPTA-AM), PI3K inhibition, or by siRNA-mediated Cav-1 suppression. These results demonstrate that exogenous peptide consisting of cationic amino acids can internalize and enhance the catalytic activity of eNOS via modulation of caveolar signaling and intracellular Ca(2+) release in EC. PMID:26655728

  5. Dietary modulation of rat colonic cAMP-dependent protein kinase activity.

    PubMed

    Aukema, H M; Davidson, L A; Chang, W C; Lupton, J R; Derr, J N; Chapkin, R S

    1994-10-20

    Malignant transformation of cells is associated with enhanced proliferation and alterations in cAMP-dependent protein kinase (PKA) activity. To investigate the role of PKA in normal colonic cell proliferation, PKA was characterized in rat colonic mucosa. In addition, rats were fed diets containing different fats (corn oil, fish oil) and fibers (pectin, cellulose, fiber free) to elicit varying levels of colonic cell proliferation in order to study this signaling system under normal physiologic conditions. Overall, PKA activities were higher in cytosolic compared to membrane fractions. PKA type II (PKA II) isozyme contributed 89 +/- 1% and 96 +/- 1% of total PKA activity in cytosolic and membrane fractions, respectively. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed the presence of mRNA for both the alpha and beta isoforms of the regulatory subunits of PKA II. PKA activities were 21-33% higher in distal membrane and total distal fractions in rats fed a cellulose/corn oil diet compared to animals consuming the other fiber/fat diets. These effects were seen only in the distal colon, where the number of cells per crypt column was elevated only in animals fed the cellulose/corn oil diet relative to other diets. Diet-induced mitogenic responses did not involve significant changes in the relative activity of PKA I and II isozymes. These data demonstrate that dietary effects on PKA activity in the distal colon may be related to changes in cell differentiation as indicated by the number of cells per crypt column. PMID:7948042

  6. A position-dependent transcription-activating domain in TFIIIA.

    PubMed

    Mao, X; Darby, M K

    1993-12-01

    Transcription of the Xenopus 5S RNA gene by RNA polymerase III requires the gene-specific factor TFIIIA. To identify domains within TFIIIA that are essential for transcriptional activation, we have expressed C-terminal deletion, substitution, and insertion mutants of TFIIIA in bacteria as fusions with maltose-binding protein (MBP). The MBP-TFIIIA fusion protein specifically binds to the 5S RNA gene internal control region and complements transcription in a TFIIIA-depleted oocyte nuclear extract. Random, cassette-mediated mutagenesis of the carboxyl region of TFIIIA, which is not required for promoter binding, has defined a 14-amino-acid region that is critical for transcriptional activation. In contrast to activators of RNA polymerase II, the activity of the TFIIIA activation domain is strikingly sensitive to its position relative to the DNA-binding domain. When the eight amino acids that separate the transcription-activating domain from the last zinc finger are deleted, transcriptional activity is lost. Surprisingly, diverse amino acids can replace these eight amino acids with restoration of full transcriptional activity, suggesting that the length and not the sequence of this region is important. Insertion of amino acids between the zinc finger region and the transcription-activating domain causes a reduction in transcription proportional to the number of amino acids introduced. We propose that to function, the transcription-activating domain of TFIIIA must be correctly positioned at a minimum distance from the DNA-binding domain. PMID:8246967

  7. Neuroserpin Differentiates Between Forms of Tissue Type Plasminogen Activator via pH Dependent Deacylation.

    PubMed

    Carlson, Karen-Sue B; Nguyen, Lan; Schwartz, Kat; Lawrence, Daniel A; Schwartz, Bradford S

    2016-01-01

    Tissue-type plasminogen activator (t-PA), initially characterized for its critical role in fibrinolysis, also has key functions in both physiologic and pathologic processes in the CNS. Neuroserpin (NSP) is a t-PA specific serine protease inhibitor (serpin) found almost exclusively in the CNS that regulates t-PA's proteolytic activity and protects against t-PA mediated seizure propagation and blood-brain barrier disruption. This report demonstrates that NSP inhibition of t-PA varies profoundly as a function of pH within the biologically relevant pH range for the CNS, and reflects the stability, rather than the formation of NSP: t-PA acyl-enzyme complexes. Moreover, NSP differentiates between the zymogen-like single chain form (single chain t-PA, sct-PA) and the mature protease form (two chain t-PA, tct-PA) of t-PA, demonstrating different pH profiles for protease inhibition, different pH ranges over which catalytic deacylation occurs, and different pH dependent profiles of deacylation rates for each form of t-PA. NSP's pH dependent inhibition of t-PA is not accounted for by differential acylation, and is specific for the NSP-t-PA serpin-protease pair. These results demonstrate a novel mechanism for the differential regulation of the two forms of t-PA in the CNS, and suggest a potential specific regulatory role for CNS pH in controlling t-PA proteolytic activity. PMID:27378851

  8. Neuroserpin Differentiates Between Forms of Tissue Type Plasminogen Activator via pH Dependent Deacylation

    PubMed Central

    Carlson, Karen-Sue B.; Nguyen, Lan; Schwartz, Kat; Lawrence, Daniel A.; Schwartz, Bradford S.

    2016-01-01

    Tissue-type plasminogen activator (t-PA), initially characterized for its critical role in fibrinolysis, also has key functions in both physiologic and pathologic processes in the CNS. Neuroserpin (NSP) is a t-PA specific serine protease inhibitor (serpin) found almost exclusively in the CNS that regulates t-PA’s proteolytic activity and protects against t-PA mediated seizure propagation and blood–brain barrier disruption. This report demonstrates that NSP inhibition of t-PA varies profoundly as a function of pH within the biologically relevant pH range for the CNS, and reflects the stability, rather than the formation of NSP: t-PA acyl-enzyme complexes. Moreover, NSP differentiates between the zymogen-like single chain form (single chain t-PA, sct-PA) and the mature protease form (two chain t-PA, tct-PA) of t-PA, demonstrating different pH profiles for protease inhibition, different pH ranges over which catalytic deacylation occurs, and different pH dependent profiles of deacylation rates for each form of t-PA. NSP’s pH dependent inhibition of t-PA is not accounted for by differential acylation, and is specific for the NSP-t-PA serpin-protease pair. These results demonstrate a novel mechanism for the differential regulation of the two forms of t-PA in the CNS, and suggest a potential specific regulatory role for CNS pH in controlling t-PA proteolytic activity. PMID:27378851

  9. Comparison of proteolytic activity of Candida sp. strains depending on their origin.

    PubMed

    Modrzewska, B; Kurnatowski, P; Khalid, K

    2016-06-01

    The aim of the research was to evaluate the proteolytic activity of various Candida strains isolated from the oral cavity of persons without clinical symptoms of fungal infection, outpatients with oral cavity disorders and patients hospitalized due to head and neck tumors. A secondary aim was to confirm the presence of secreted aspartyl protease (SAP) genes in the isolated strains and then to compare it depending on the fungal species. Material consisted of 134 fungal strains that were analysed by a modified Staib method and polymerase chain reaction (PCR) with the use of specific primer pairs. The greatest proteolytic activity of fungi was observed at pH 3.5. The proteolysis were the strongest for strains isolated from dental patients and the weakest from persons without changes in the oral cavity. In total, 61.9% of the strains exhibited the presence of at least one of the SAP1-3 genes in all examined groups, SAP1 being the most common; SAP4-6 genes were not observed. All genes were more frequent in the strains isolated from the dental patients than from other groups. SAP1-3 genes were present in Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, C. humicola and C. lipolytica, but were not noted in other isolated species. The lowest activity of proteolytic enzymes and the least number of aspartyl protease genes are observed among strains isolated from patients without clinical symptoms of mycosis. SAP1-3 genes are most frequently detected in the strains isolated from the oral cavity; their presence varies depending on the species of the fungi. PMID:26922385

  10. Sequential Reinstatement of Neocortical Activity during Slow Oscillations Depends on Cells’ Global Activity

    PubMed Central

    Peyrache, Adrien; Benchenane, Karim; Khamassi, Mehdi; Wiener, Sidney I.; Battaglia, Francesco P.

    2009-01-01

    During Slow Wave Sleep (SWS), cortical activity is dominated by endogenous processes modulated by slow oscillations (0.1–1 Hz): cell ensembles fluctuate between states of sustained activity (UP states) and silent epochs (DOWN states). We investigate here the temporal structure of ensemble activity during UP states by means of multiple single unit recordings in the prefrontal cortex of naturally sleeping rats. As previously shown, the firing rate of each PFC cell peaks at a distinct time lag after the DOWN/UP transition in a consistent order. We show here that, conversely, the latency of the first spike after the UP state onset depends primarily on the session-averaged firing rates of cells (which can be considered as an indirect measure of their intrinsic excitability). This latency can be explained by a simple homogeneous process (Poisson model) of cell firing, with sleep averaged firing rates employed as parameters. Thus, at DOWN/UP transitions, neurons are affected both by a slow process, possibly originating in the cortical network, modulating the time course of firing for each cell, and by a fast, relatively stereotyped reinstatement of activity, related mostly to global activity levels. PMID:20130754

  11. Secretion of macrophage urokinase plasminogen activator is dependent on proteoglycans.

    PubMed

    Pejler, Gunnar; Winberg, Jan-Olof; Vuong, Tram T; Henningsson, Frida; Uhlin-Hansen, Lars; Kimata, Koji; Kolset, Svein O

    2003-10-01

    The importance of proteoglycans for secretion of proteolytic enzymes was studied in the murine macrophage cell line J774. Untreated or 4beta-phorbol 12-myristate 13-acetate (PMA)-stimulated macrophages were treated with hexyl-beta-d-thioxyloside to interfere with the attachment of glycosaminoglycan chains to their respective protein cores. Activation of the J774 macrophages with PMA resulted in increased secretion of trypsin-like serine proteinase activity. This activity was completely inhibited by plasminogen activator inhibitor 1 and by amiloride, identifying the activity as urokinase plasminogen activator (uPA). Treatment of both the unstimulated or PMA-stimulated macrophages with xyloside resulted in decreased uPA activity and Western blotting analysis revealed an almost complete absence of secreted uPA protein after xyloside treatment of either control- or PMA-treated cells. Zymography analyses with gels containing both gelatin and plasminogen confirmed these findings. The xyloside treatment did not reduce the mRNA levels for uPA, indicating that the effect was at the post-translational level. Treatment of the macrophages with xylosides did also reduce the levels of secreted matrix metalloproteinase 9. Taken together, these findings indicate a role for proteoglycans in the secretion of uPA and MMP-9. PMID:14511379

  12. Muscle activity pattern dependent pain development and alleviation.

    PubMed

    Sjøgaard, Gisela; Søgaard, Karen

    2014-12-01

    Muscle activity is for decades considered to provide health benefits irrespectively of the muscle activity pattern performed and whether it is during e.g. sports, transportation, or occupational work tasks. Accordingly, the international recommendations for public health-promoting physical activity do not distinguish between occupational and leisure time physical activity. However, in this body of literature, attention has not been paid to the extensive documentation on occupational physical activity imposing a risk of impairment of health - in particular musculoskeletal health in terms of muscle pain. Focusing on muscle activity patterns and musculoskeletal health it is pertinent to elucidate the more specific aspects regarding exposure profiles and body regional pain. Static sustained muscle contraction for prolonged periods often occurs in the neck/shoulder area during occupational tasks and may underlie muscle pain development in spite of rather low relative muscle load. Causal mechanisms include a stereotype recruitment of low threshold motor units (activating type 1 muscle fibers) characterized by a lack of temporal as well as spatial variation in recruitment. In contrast during physical activities at leisure and sport the motor recruitment patterns are more dynamic including regularly relatively high muscle forces - also activating type 2 muscles fibers - as well as periods of full relaxation even of the type 1 muscle fibers. Such activity is unrelated to muscle pain development if adequate recovery is granted. However, delayed muscle soreness may develop following intensive eccentric muscle activity (e.g. down-hill skiing) with peak pain levels in thigh muscles 1-2 days after the exercise bout and a total recovery within 1 week. This acute pain profile is in contrast to the chronic muscle pain profile related to repetitive monotonous work tasks. The painful muscles show adverse functional, morphological, hormonal, as well as metabolic characteristics. Of

  13. 78 FR 46422 - Proposed Information Collection (Status of Dependents Questionnaire) Activity: Comment Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-31

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS AFFAIRS Proposed Information Collection (Status of Dependents Questionnaire) Activity: Comment Request... of Dependents Questionnaire, VA Form 21-0538. OMB Control Number: 2900-0500. Type of...

  14. 75 FR 62636 - Proposed Information Collection (Status of Dependents Questionnaire) Activity: Comment Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-12

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS AFFAIRS Proposed Information Collection (Status of Dependents Questionnaire) Activity: Comment Request... techniques or the use of other forms of information technology. Title: Status of Dependents Questionnaire,...

  15. Benefits of physical activity on COPD hospitalisation depend on intensity.

    PubMed

    Donaire-Gonzalez, David; Gimeno-Santos, Elena; Balcells, Eva; de Batlle, Jordi; Ramon, Maria A; Rodriguez, Esther; Farrero, Eva; Benet, Marta; Guerra, Stefano; Sauleda, Jaume; Ferrer, Antoni; Ferrer, Jaume; Barberà, Joan A; Rodriguez-Roisin, Robert; Gea, Joaquim; Agustí, Alvar; Antó, Josep M; Garcia-Aymerich, Judith

    2015-11-01

    The present study aims to disentangle the independent effects of the quantity and the intensity of physical activity on the risk reduction of chronic obstructive pulmonary disease (COPD) hospitalisations.177 patients from the Phenotype Characterization and Course of COPD (PAC-COPD) cohort (mean±sd age 71±8 years, forced expiratory volume in 1 s 52±16% predicted) wore the SenseWear Pro 2 Armband accelerometer (BodyMedia, Pittsburgh, PA, USA) for eight consecutive days, providing data on quantity (steps per day, physically active days and daily active time) and intensity (average metabolic equivalent tasks) of physical activity. Information on COPD hospitalisations during follow-up (2.5±0.8 years) was obtained from validated centralised datasets. During follow-up 67 (38%) patients were hospitalised. There was an interaction between quantity and intensity of physical activity in their effects on COPD hospitalisation risk. After adjusting for potential confounders in the Cox regression model, the risk of COPD hospitalisation was reduced by 20% (hazard ratio (HR) 0.79, 95% CI 0.67-0.93; p=0.005) for every additional 1000 daily steps at low average intensity. A greater quantity of daily steps at high average intensity did not influence the risk of COPD hospitalisations (HR 1.01, p=0.919). Similar results were found for the other measures of quantity of physical activity. Greater quantity of low-intensity physical activity reduces the risk of COPD hospitalisation, but high-intensity physical activity does not produce any risk reduction. PMID:26206873

  16. Wdr1-Dependent Actin Reorganization in Platelet Activation.

    PubMed

    Dasgupta, Swapan K; Le, Anhquyen; Da, Qi; Cruz, Miguel; Rumbaut, Rolando E; Thiagarajan, Perumal

    2016-01-01

    In resting platelets, the integrin αIIbβ3 is present in a low-affinity "bent" state. During platelet aggregation, intracytoplasmic signals induce conformational changes (inside-out signaling) that result in a "swung-out" conformation competent to bind ligands such as fibrinogen. The cytoskeleton plays an essential role in αIIbβ3 activation. We investigated the role of the actin interacting protein Wdr1 in αIIbβ3 activation. Wdr1-hypomorphic mice had a prolonged bleeding time (> 10 minutes) compared to that of wild-type mice (2.1 ± 0.7 minutes). Their platelets had impaired aggregation to collagen and thrombin. In a FeCl3 induced carotid artery thrombosis model, vessel occlusion in Wdr1-hypomorphic mice was prolonged significantly compared to wild-type mice (9.0 ± 10.5 minutes versus 5.8 ± 12.6 minutes (p = 0.041). Activation-induced binding of JON/A (a conformation-specific antibody to activated αIIbβ3) was significantly less in Wdr1-hypomorphic platelets at various concentrations of collagen, indicating impaired inside-out activation of αIIbβ3, despite a normal calcium response. Actin turnover, assessed by measuring F-actin and G-actin ratios during collagen- and thrombin-induced platelet aggregation, was highly impaired in Wdr1-hypomorphic platelets. Furthermore, talin failed to redistribute and translocate to the cytoskeleton following activation in Wdr1-hypomorphic platelets. These studies show that Wdr1 is essential for talin-induced activation of αIIbβ3 during platelet activation. PMID:27627652

  17. Activity-dependent acceleration of endocytosis at a central synapse.

    PubMed

    Wu, Wei; Xu, Jianhua; Wu, Xin-Sheng; Wu, Ling-Gang

    2005-12-14

    Accumulated evidence indicates the existence of rapid and slow endocytosis at many synapses. It has been proposed that rapid endocytosis is activated by intense stimulation when vesicle recycling needs to be speeded up to supply vesicles at hippocampal synapses. However, the evidence, as obtained with imaging techniques, which are somewhat indirect in indicating rapid endocytosis, is controversial. Furthermore, a slower time course of endocytosis is often found after more intense nerve activity, casting doubt on the role of rapid endocytosis at synapses. Here, we addressed this issue at a mammalian central synapse, the calyx of Held, using a capacitance measurement technique that provides a higher time resolution than imaging techniques. We found that rapid endocytosis with a time constant of approximately 1-2 s was activated during intense nerve activity. Reducing the presynaptic calcium current or buffering the intracellular calcium with EGTA significantly inhibited rapid endocytosis, suggesting that calcium triggers rapid endocytosis. During intense stimulation, rapid endocytosis retrieved up to approximately eight vesicles per second per active zone, approximately eightfold larger than reported in the hippocampus, and thus played a dominant role during and within 3 s after intense stimulation. Slow endocytosis became dominant 3 s after intense stimulation likely because of the fall of the intracellular calcium level that deactivated rapid endocytosis. These results underscore the importance of calcium-triggered rapid endocytosis, which offers the nerve terminal the plasticity to speed up vesicle cycling during intense nerve activity. PMID:16354926

  18. Piccolo Directs Activity Dependent F-Actin Assembly from Presynaptic Active Zones via Daam1

    PubMed Central

    Wagh, Dhananjay; Terry-Lorenzo, Ryan; Waites, Clarissa L.; Leal-Ortiz, Sergio A.; Maas, Christoph; Reimer, Richard J.; Garner, Craig C.

    2015-01-01

    The dynamic assembly of filamentous (F) actin plays essential roles in the assembly of presynaptic boutons, the fusion, mobilization and recycling of synaptic vesicles (SVs), and presynaptic forms of plasticity. However, the molecular mechanisms that regulate the temporal and spatial assembly of presynaptic F-actin remain largely unknown. Similar to other F-actin rich membrane specializations, presynaptic boutons contain a set of molecules that respond to cellular cues and trans-synaptic signals to facilitate activity-dependent assembly of F-actin. The presynaptic active zone (AZ) protein Piccolo has recently been identified as a key regulator of neurotransmitter release during SV cycling. It does so by coordinating the activity-dependent assembly of F-Actin and the dynamics of key plasticity molecules including Synapsin1, Profilin and CaMKII. The multidomain structure of Piccolo, its exquisite association with the AZ, and its ability to interact with a number of actin-associated proteins suggest that Piccolo may function as a platform to coordinate the spatial assembly of F-actin. Here we have identified Daam1, a Formin that functions with Profilin to drive F-actin assembly, as a novel Piccolo binding partner. We also found that within cells Daam1 activation promotes Piccolo binding, an interaction that can spatially direct the polymerization of F-Actin. Moreover, similar to Piccolo and Profilin, Daam1 loss of function impairs presynaptic-F-actin assembly in neurons. These data suggest a model in which Piccolo directs the assembly of presynaptic F-Actin from the AZ by scaffolding key actin regulatory proteins including Daam1. PMID:25897839

  19. Glutathione-dependent extracellular ferric reductase activities in dimorphic zoopathogenic fungi

    PubMed Central

    Zarnowski, Robert; Woods, Jon P.

    2009-01-01

    In this study, extracellular glutathione-dependent ferric reductase (GSH-FeR) activities in different dimorphic zoopathogenic fungal species were characterized. Supernatants from Blastomyces dermatitidis, Histoplasma capsulatum, Paracoccidioides brasiliensis and Sporothrix schenckii strains grown in their yeast form were able to reduce iron enzymically with glutathione as a cofactor. Some variations in the level of reduction were noted amongst the strains. This activity was stable in acidic, neutral and slightly alkaline environments and was inhibited when trivalent aluminium and gallium ions were present. Using zymography, single bands of GSH-FeRs with apparent molecular masses varying from 430 to 460 kDa were identified in all strains. The same molecular mass range was determined by size exclusion chromatography. These data demonstrate that dimorphic zoopathogenic fungi produce and secrete a family of similar GSH-FeRs that may be involved in the acquisition and utilization of iron. Siderophore production by these and other fungi has sometimes been considered to provide a full explanation of iron acquisition in these organisms. Our work reveals an additional common mechanism that may be biologically and pathogenically important. Furthermore, while some characteristics of these enzymes such as extracellular location, cofactor utilization and large size are not individually unique, when considered together and shared across a range of fungi, they represent an important novel physiological feature. PMID:16000713

  20. Activity-Dependent Neurorehabilitation Beyond Physical Trainings: "Mental Exercise" Through Mirror Neuron Activation.

    PubMed

    Yuan, Ti-Fei; Chen, Wei; Shan, Chunlei; Rocha, Nuno; Arias-Carrión, Oscar; Paes, Flávia; de Sá, Alberto Souza; Machado, Sergio

    2015-01-01

    The activity dependent brain repair mechanism has been widely adopted in many types of neurorehabilitation. The activity leads to target specific and non-specific beneficial effects in different brain regions, such as the releasing of neurotrophic factors, modulation of the cytokines and generation of new neurons in adult hood. However physical exercise program clinically are limited to some of the patients with preserved motor functions; while many patients suffered from paralysis cannot make such efforts. Here the authors proposed the employment of mirror neurons system in promoting brain rehabilitation by "observation based stimulation". Mirror neuron system has been considered as an important basis for action understanding and learning by mimicking others. During the action observation, mirror neuron system mediated the direct activation of the same group of motor neurons that are responsible for the observed action. The effect is clear, direct, specific and evolutionarily conserved. Moreover, recent evidences hinted for the beneficial effects on stroke patients after mirror neuron system activation therapy. Finally some music-relevant therapies were proposed to be related with mirror neuron system. PMID:26556068

  1. Multistability analysis of a general class of recurrent neural networks with non-monotonic activation functions and time-varying delays.

    PubMed

    Liu, Peng; Zeng, Zhigang; Wang, Jun

    2016-07-01

    This paper addresses the multistability for a general class of recurrent neural networks with time-varying delays. Without assuming the linearity or monotonicity of the activation functions, several new sufficient conditions are obtained to ensure the existence of (2K+1)(n) equilibrium points and the exponential stability of (K+1)(n) equilibrium points among them for n-neuron neural networks, where K is a positive integer and determined by the type of activation functions and the parameters of neural network jointly. The obtained results generalize and improve the earlier publications. Furthermore, the attraction basins of these exponentially stable equilibrium points are estimated. It is revealed that the attraction basins of these exponentially stable equilibrium points can be larger than their originally partitioned subsets. Finally, three illustrative numerical examples show the effectiveness of theoretical results. PMID:27136665

  2. Dynamic multiphosphorylation passwords for activity-dependent gene expression.

    PubMed

    Deisseroth, Karl; Tsien, Richard W

    2002-04-11

    Synapse-to-nucleus signaling leading to CREB-mediated transcription is important for neuronal plasticity. Nuclear CREB phosphorylation at Ser133 allows convergence of multiple kinase pathways driven by neuronal activity and links them to transcriptional activation. But, can various pathways share a common effector mechanism (phosphorylating Ser133) while generating distinct patterns of gene expression? We review three Neuron articles that highlight novel ways Ca(2+) signals can trigger multiple phosphorylation events working in combination to control CREB and its interaction with coactivator molecules. PMID:11970860

  3. Biological activity, pH dependent redox behavior and UV-Vis spectroscopic studies of naphthalene derivatives.

    PubMed

    Rauf, Abdur; Subhan, Hanif; Abbasi, Rashda; Adhikari, Bimalendu; Shah, Aamir Hassan; Rana, Usman Ali; Abbas, Qamar; Qureshi, Irfan Zia; Hussain, Hidayat; Mazhar, Kehkashan; Badshah, Amin; Kraatz, Heinz-Bernhard; Shah, Afzal

    2014-11-01

    Two naphthalene derivatives, naphthalene-2,3-dicarboxylic acid (NDA) and 1,8-dimethoxynaphthalene (DMN) were screened for antioxidant and anti-diabetic activities. Biological antioxidant studies revealed NDA as more effective antioxidant as compared to DMN. Both compounds significantly increased the cholesterol level but showed varied biological activities as regards glucose and triglyceride concentrations. The cytotoxicity results evidenced DMN to significantly inhibit the cell proliferation in a dose dependent manner with IC₅₀ of 0.13 mM. Like the biological antioxidant studies, the electrochemical results also witnessed NDA as stronger antioxidant than DMN. The pH dependent spectrophotometric and electrochemical behavior was investigated in order to provide useful mechanistic insights about the biological role of the selected compounds. PMID:25150500

  4. Incorporating Nondrug Social & Recreational Activities in Outpatient Chemical Dependency Treatment

    ERIC Educational Resources Information Center

    Siporin, Sheldon; Baron, Lisa

    2012-01-01

    "Contingency Management programs (CMP) and non-drug social and recreational activities (NDSRA) are interventions premised on behavior theory that rely on external sources of reinforcement alternative to drug-based forms to decrease drug use. CMP usually employs vouchers as reinforcement for negative toxicologies. Despite research support, CMP…

  5. Locality and Word Order in Active Dependency Formation in Bangla

    PubMed Central

    Chacón, Dustin A.; Imtiaz, Mashrur; Dasgupta, Shirsho; Murshed, Sikder M.; Dan, Mina; Phillips, Colin

    2016-01-01

    Research on filler-gap dependencies has revealed that there are constraints on possible gap sites, and that real-time sentence processing is sensitive to these constraints. This work has shown that comprehenders have preferences for potential gap sites, and immediately detect when these preferences are not met. However, neither the mechanisms that select preferred gap sites nor the mechanisms used to detect whether these preferences are met are well-understood. In this paper, we report on three experiments in Bangla, a language in which gaps may occur in either a pre-verbal embedded clause or a post-verbal embedded clause. This word order variation allows us to manipulate whether the first gap linearly available is contained in the same clause as the filler, which allows us to dissociate structural locality from linear locality. In Experiment 1, an untimed ambiguity resolution task, we found a global bias to resolve a filler-gap dependency with the first gap linearly available, regardless of structural hierarchy. In Experiments 2 and 3, which use the filled-gap paradigm, we found sensitivity to disruption only when the blocked gap site is both structurally and linearly local, i.e., the filler and the gap site are contained in the same clause. This suggests that comprehenders may not show sensitivity to the disruption of all preferred gap resolutions. PMID:27610090

  6. Locality and Word Order in Active Dependency Formation in Bangla.

    PubMed

    Chacón, Dustin A; Imtiaz, Mashrur; Dasgupta, Shirsho; Murshed, Sikder M; Dan, Mina; Phillips, Colin

    2016-01-01

    Research on filler-gap dependencies has revealed that there are constraints on possible gap sites, and that real-time sentence processing is sensitive to these constraints. This work has shown that comprehenders have preferences for potential gap sites, and immediately detect when these preferences are not met. However, neither the mechanisms that select preferred gap sites nor the mechanisms used to detect whether these preferences are met are well-understood. In this paper, we report on three experiments in Bangla, a language in which gaps may occur in either a pre-verbal embedded clause or a post-verbal embedded clause. This word order variation allows us to manipulate whether the first gap linearly available is contained in the same clause as the filler, which allows us to dissociate structural locality from linear locality. In Experiment 1, an untimed ambiguity resolution task, we found a global bias to resolve a filler-gap dependency with the first gap linearly available, regardless of structural hierarchy. In Experiments 2 and 3, which use the filled-gap paradigm, we found sensitivity to disruption only when the blocked gap site is both structurally and linearly local, i.e., the filler and the gap site are contained in the same clause. This suggests that comprehenders may not show sensitivity to the disruption of all preferred gap resolutions. PMID:27610090

  7. Curcumin Attenuates Opioid Tolerance and Dependence by Inhibiting Ca2+/Calmodulin-Dependent Protein Kinase II α Activity

    PubMed Central

    Hu, Xiaoyu; Huang, Fang; Szymusiak, Magdalena

    2015-01-01

    Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα), a protein kinase that has been previously proposed to be critical for opioid tolerance and dependence. In this study, we used state-of-the-art polymeric formulation technology to produce poly(lactic-co-glycolic acid) (PLGA)-curcumin nanoparticles (nanocurcumin) to overcome the drug’s poor solubility and bioavailability, which has made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11- to 33-fold. Pretreatment with PLGA-curcumin (by mouth) prevented the development of opioid tolerance and dependence in a dose-dependent manner, with ED50 values of 3.9 and 3.2 mg/kg, respectively. PLGA-curcumin dose-dependently attenuated already-established opioid tolerance (ED50 = 12.6 mg/kg p.o.) and dependence (ED50 = 3.1 mg/kg p.o.). Curcumin or PLGA-curcumin did not produce antinociception by itself or affect morphine (1–10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIα activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIα activity. PMID:25515789

  8. CRTC2 activation in the suprachiasmatic nucleus, but not paraventricular nucleus, varies in a diurnal fashion and increases with nighttime light exposure

    PubMed Central

    Highland, Julie A.; Weiser, Michael J.; Hinds, Laura R.

    2014-01-01

    Entrainment of the intrinsic suprachiasmatic nucleus (SCN) molecular clock to the light-dark cycle depends on photic-driven intracellular signal transduction responses of SCN neurons that converge on cAMP response element-binding protein (CREB)-mediated regulation of gene transcription. Characterization of the CREB coactivator proteins CREB-regulated transcriptional coactivators (CRTCs) has revealed a greater degree of differential activity-dependent modulation of CREB transactivational function than previously appreciated. In confirmation of recent reports, we found an enrichment of crtc2 mRNA and prominent CRTC2 protein expression within the SCN of adult male rats. With use of a hypothalamic organotypic culture preparation for initial CRTC2-reactive antibody characterization, we found that CRTC2 immunoreactivity in hypothalamic neurons shifted from a predominantly cytoplasmic profile under basal culture conditions to a primarily nuclear localization (CRTC2 activation) 30 min after adenylate cyclase stimulation. In adult rat SCN, we found a diurnal variation in CRTC2 activation (peak at zeitgeber time of 4 h and trough at zeitgeber time of 16–20 h) but no variation in the total number of CRTC2-immunoreactive cells. There was no diurnal variation of CRTC2 activation in the hypothalamic paraventricular nucleus, another site of enriched CRTC2 expression. Exposure of rats to light (50 lux) for 30 min during the second half of their dark (nighttime) phase produced CRTC2 activation. We observed in the SCN a parallel change in the expression of a CREB-regulated gene (FOS). In contrast, nighttime light exposure had no effect on CRTC2 activation or FOS expression in the paraventricular nucleus, nor did it affect corticosterone hormone levels. These results suggest that CRTC2 participates in CREB-dependent photic entrainment of SCN function. PMID:25080490

  9. Tuning the Catalytic Activity of Ru@Pt Core-Shell Nanoparticles for the Oxygen Reduction Reaction by Varying the Shell Thickness

    SciTech Connect

    Yang, Lijun; Vukmirovic, Miomir B.; Su, Dong; Sasaki, Kotaro; Herron, Jeffrey A.; Mavrikakis, Manos; Liao, Shijun; Adzic, Radoslav R.

    2013-01-31

    The kinetics of the oxygen reduction reaction (ORR) was investigated in acid solutions on Pt monolayers that were deposited on carbon-supported Ru nanoparticles using the rotating disk electrode technique. The Pt mass and specific ORR activities greatly depend on the number of Pt monolayers, and the optimum activity occurs with two Pt monolayers. Density functional theory calculations showed that Pt overlayers destabilize O* and OH* with respect to pure Pt, leading to more favorable hydrogenation kinetics. However, with only a single Pt overlayer, the destabilization is too much, and O–O bond breaking becomes rate limiting. Two to three Pt monolayers supported on the Ru core of our nanoparticles lead to increased activity. This work demonstrates that one can modulate the ORR activity of Pt monolayers supported on other metals by eliminating a part of the ligand effect by increasing the thickness of the Pt shell on top of the supporting metal surface.

  10. Antibody-dependent haemolytic activity of human leukaemic cells.

    PubMed Central

    Holm, G; Björkholm, M; Böttiger, B; Mellstedt, H; Pettersson, D; Simonsson-Lindemalm, C

    1980-01-01

    Antibody-dependent cellular cytotoxicity (ADCC) of human leukaemic blood cells against human RBC treated with IgG isoantibody was studied by the 51Cr-release method. ADCC in this particular system is a property of normal phagocytic cells of the monocytic and myeloid series while lymphocytes are inactive. Well differentiated leukaemic monocytes from patients with acute monocytic leukaemia were highly cytotoxic and engulfed opsonized RBC. Promyelocytic leukaemic cells from two patients with acute promyelocytic leukaemia were cytotoxic and phagocytic. Seven patients with low differentiated acute myeloblastic leukaemia had no cytotoxic or phagocytic blood cells. Leukaemic B cells from patients with chronic lymphocytic leukaemia or prolymphocytic leukaemia lacked cytotoxic and phagocytic properties. It is concluded that ADCC against isoantibody-treated human RBC may be a tool to distinguish between well and poorly differentiated leukaemic cells of the monocytic or myeloid series. PMID:7460388

  11. Energy dependence on the electric activities of a neuron

    NASA Astrophysics Data System (ADS)

    Song, Xin-Lin; Jin, Wu-Yin; Ma, Jun

    2015-12-01

    A nonlinear circuit can be designed by using inductor, resistor, capacitor and other electric devices, and the electromagnetic field energy can be released from the circuit in the oscillating state. The generation of spikes or bursting states in neurons could be energetically a costly process. Based on the Helmholtz’s theorem, a Hamilton energy function is defined to detect the energy shift induced by transition of electric modes in a Hindmarsh-Rose neuron. It is found that the energy storage is dependent on the external forcing, and energy release is associated with the electric mode. As a result, the bursting state and chaotic state could be helpful to release the energy in the neuron quickly. Project supported by the National Natural Science Foundation of China (Grant Nos. 11372122 and 11365014).

  12. Activity-dependent regulation of astrocyte GAT levels during synaptogenesis

    PubMed Central

    Muthukumar, Allie K.; Stork, Tobias; Freeman, Marc R.

    2014-01-01

    Astrocytic uptake of GABA through GABA transporters (GATs) is an important mechanism regulating excitatory/inhibitory balance in the nervous system, however mechanisms by which astrocytes regulate GAT levels are undefined. Here we show at mid-pupal stages the Drosophila CNS neuropil is devoid of astrocyte membranes and synapses. Astrocyte membranes subsequently infiltrate the neuropil coordinate with synaptogenesis and a strocyte ablation reduces synapse numbers by half, indicating that Drosophila astrocytes are pro-synaptogenic. Shortly after synapses form in earnest, the GABA transporter, GAT, is up-regulated in astrocytes. Ablation or silencing of GABAergic neurons or disruption of metabotropic GABA receptor (GABABR1/2) signaling in astrocytes leads to decreased astrocytic GAT levels. Interestingly, developmental depletion of astrocytic GABABR1/2 signaling suppresses mechanosensory-induced seizure activity in mutants with hyperexcitable neurons. These data reveal astrocytes actively modulate GAT expression via metabotropic GABA receptor signaling, and highlight the importance of precise regulation of astrocytic GAT in modulation of seizure activity. PMID:25151265

  13. Vitamin K dependent protein activity and incident ischemic cardiovascular disease: The multi ethnic study of atherosclerosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    OBJECTIVE: Vitamin K-dependent proteins (VKDPs), which require post-translational modification to achieve biological activity, seem to contribute to thrombus formation, vascular calcification, and vessel stiffness. Whether VKDP activity is prospectively associated with incident cardiovascular diseas...

  14. Stimulus-induced and state-dependent sustained gamma activity is tightly coupled to the hemodynamic response in humans.

    PubMed

    Koch, Stefan P; Werner, Peter; Steinbrink, Jens; Fries, Pascal; Obrig, Hellmuth

    2009-11-01

    A prompt behavioral response to a stimulus depends both on the salience of the stimulus as well as the subject's preparedness. Thus, both stimulus properties and cognitive factors, such as attention, may determine the strength of neuronal synchronization in the gamma range. For a comprehensive investigation of stimulus-response processing through noninvasive imaging, it is, however, a crucial issue whether both kinds of gamma modulation elicit a hemodynamic response. Here, we show that, in the human visual cortex, stimulus strength and internal state modulate sustained gamma activity and hemodynamic response in close correspondence. When participants reported velocity changes of gratings varying in contrast, gamma activity (35-70 Hz) increased systematically with contrast. For stimuli of constant contrast, the amplitude of gamma activity before the behaviorally relevant velocity change was inversely correlated to the behavioral response latency. This indicates that gamma activity also reflects an overall attentive state. For both sources of variance, gamma activity was tightly coupled to the hemodynamic response measured through optical topography. Because of the close relationship between high-frequency neuronal activity and the hemodynamic signal, we conclude that both stimulus-induced and state-dependent gamma activity trigger a metabolic demand and are amenable to vascular-based imaging. PMID:19890006

  15. Binding of nickel and copper to fish gills predicts toxicity when water hardness varies, but free-ion activity does not

    SciTech Connect

    Meyer, J.S.; Bobbitt, J.P.; Debrey, L.D.; Boese, C.J.; Bergman, H.L.; Santore, R.C.; Paquin, P.R.; Ditoro, D.M.; Allen, H.E.

    1999-03-15

    Based on a biotic-ligand model (BLM), the authors hypothesized that the concentration of a transition metal bound to fish gills ([M{sub gill}]) will be a constant predictor of mortality, whereas a free-ion activity model is generally interpreted to imply that the chemical activity of the aquo (free) ion of the metal will be a constant predictor of mortality. In laboratory tests, measured [Ni{sub gill}] and calculated [Cu{sub gill}] were constant predictors of acute toxicity of Ni and Cu to fathead minnows (Pimephales promelas) when water hardness varied up to 10-fold, whereas total aqueous concentrations and free-ion activities of Ni and Cu were not. Thus, the BLM, which simultaneously accounts for (a) metal speciation in the exposure water and (b) competitive binding of transition-metal ions and other cations to biotic ligands predicts acute toxicity better than does free-ion activity of Ni or Cu. Adopting a biotic-ligand modeling approach could help establish a more defensible, mechanistic basis for regulating aqueous discharges of metals.

  16. Trypsin stimulates proteinase-activated receptor-2-dependent and -independent activation of mitogen-activated protein kinases.

    PubMed Central

    Belham, C M; Tate, R J; Scott, P H; Pemberton, A D; Miller, H R; Wadsworth, R M; Gould, G W; Plevin, R

    1996-01-01

    We have examined protease-mediated activation of the mitogen-activated protein (MAP) kinase cascade in rat aortic smooth-muscle cells and bovine pulmonary arterial fibroblasts. Exposure of smooth-muscle cells to trypsin evoked rapid and transient activation of c-Raf-1, MAP kinase kinase 1 and 2 and MAP kinase that was sensitive to inhibition by soybean trypsin inhibitor. The actions of trypsin were closely mimicked by the proteinase-activated receptor 2 (PAR-2)-activating peptide sequence SLIGRL but not LSIGRL. Peak MAP kinase activation in response to both trypsin and SLIGRL was also dependent on concentration, with EC50 values of 12.1 +/- 3.4 nM and 62.5 +/- 4.5 microM respectively. Under conditions where MAP kinase activation by SLIGRL was completely desensitized by prior exposure of smooth-muscle cells to the peptide, trypsin-stimulated MAP kinase activity was markedly attenuated (78.9 +/- 15.1% desensitization), whereas the response to thrombin was only marginally affected (16.6 +/- 12.1% desensitization). Trypsin and SLIGRL also weakly stimulated the activation of the MAP kinase homologue p38 in smooth-muscle cells without any detectable activation of c-Jun N-terminal kinase. Strong activation of the MAP kinase cascade and modest activation of p38 by trypsin were also observed in fibroblasts, although in this cell type these effects were not mimicked by SLIGRL nor by the thrombin receptor-activating peptide SFLLRNPNDKYEPF. Reverse transcriptase-PCR analysis confirmed the presence of PAR-2 mRNA in smooth-muscle cells but not fibroblasts. Our results suggest that in vascular smooth-muscle cells, trypsin stimulates the activation of the MAP kinase cascade relatively selectively, in a manner consistent with an interaction with the recently described PAR-2. Activation of MAP kinase by trypsin in vascular fibroblasts, however, seems to be independent of PAR-2 and occurs by an undefined mechanism possibly involving novel receptor species. PMID:9003384

  17. Activity-Dependent Plasticity of Astroglial Potassium and Glutamate Clearance

    PubMed Central

    Cheung, Giselle; Sibille, Jérémie; Zapata, Jonathan; Rouach, Nathalie

    2015-01-01

    Recent evidence has shown that astrocytes play essential roles in synaptic transmission and plasticity. Nevertheless, how neuronal activity alters astroglial functional properties and whether such properties also display specific forms of plasticity still remain elusive. Here, we review research findings supporting this aspect of astrocytes, focusing on their roles in the clearance of extracellular potassium and glutamate, two neuroactive substances promptly released during excitatory synaptic transmission. Their subsequent removal, which is primarily carried out by glial potassium channels and glutamate transporters, is essential for proper functioning of the brain. Similar to neurons, different forms of short- and long-term plasticity in astroglial uptake have been reported. In addition, we also present novel findings showing robust potentiation of astrocytic inward currents in response to repetitive stimulations at mild frequencies, as low as 0.75 Hz, in acute hippocampal slices. Interestingly, neurotransmission was hardly affected at this frequency range, suggesting that astrocytes may be more sensitive to low frequency stimulation and may exhibit stronger plasticity than neurons to prevent hyperexcitability. Taken together, these important findings strongly indicate that astrocytes display both short- and long-term plasticity in their clearance of excess neuroactive substances from the extracellular space, thereby regulating neuronal activity and brain homeostasis. PMID:26346563

  18. Nonbonded interactions in membrane active cyclic biopolymers. IV - Cation dependence

    NASA Technical Reports Server (NTRS)

    Radhakrishnan, R.; Srinivasan, S.; Prasad, C. V.; Brinda, S. R.; Macelroy, R. D.; Sundaram, K.

    1980-01-01

    Interactions of valinomycin and form of its analogs in several conformations with the central ions Li(+), Na(+), K(+), Rb(+) and Cs(+) are investigated as part of a study of the specific preference of valinomycin for potassium and the mechanisms of carrier-mediated ion transport across membranes. Ion binding energies and conformational potential energies are calculated taking into account polarization energy formulas and repulsive energy between the central ion and the ligand atoms for conformations representing various stages in ion capture and release for each of the two ring chiralities of valinomycin and its analogs. Results allow the prediction of the chirality and conformation most likely to be observed for a given analog, and may be used to synthesize analogs with a desired rigidity or flexibility. The binding energies with the alkali metal cations are found to decrease with increasing ion size, and to be smaller than the corresponding ion hydration energies. It is pointed out that the observed potassium preference may be explainable in terms of differences between binding and hydration energies. Binding energies are also noted to depend on ligand conformation.

  19. [Activity of Ca(2+)-dependent neutral proteinases in rat organs under cobalt and mercury chloride injection].

    PubMed

    Kaliman, P A; Samokhin, A A; Samokhina, L M

    2003-01-01

    The activity of Ca(2+)-dependent neutral proteinases in rats under cobalt and mercury chloride injection was investigated. The calpains activity increase in the lungs, heart, liver and kidneys was revealed after 2 h cobalt chloride action. The mercury chloride gives a reliable increase of calcium-dependent neutral proteinases only in the kidneys. PMID:14574747

  20. Redox-Dependent Solubility of Technetium in Low Activity Waste Glass

    SciTech Connect

    Soderquist, Chuck Z.; Schweiger, Michael J.; Kim, Dong-Sang; Lukens, Wayne W.; Mccloy, John S.

    2014-03-01

    The solubility of technetium was measured in a Hanford low activity waste glass simulant. The simulant glass was melted, quenched and pulverized to make a stock of powdered glass. A series of glass samples were prepared using the powdered glass and varying amounts of solid potassium pertechnetate. Samples were melted at 1000°C in sealed fused quartz ampoules. After cooling, the bulk glass and the salt phase above the glass (when present) were sampled for physical and chemical characterization. Technetium was found in the bulk glass up to 2000 ppm (using the glass as prepared) and 3000 ppm (using slightly reducing conditions). The chemical form of technetium obtained by x-ray absorption near edge spectroscopy can be mainly assigned to isolated Tc(IV), with a minority of Tc(VII) in some glasses and TcO2 in two glasses. The concentration and speciation of technetium depends on glass redox and amount of technetium added. Solid crystals of pertechnetate salts were found in the salt cake layer that formed at the top of some glasses during the melt.

  1. Dependence of the amplitude of Pc5-band magnetic field variations on the solar wind and solar activity

    NASA Astrophysics Data System (ADS)

    Takahashi, Kazue; Yumoto, Kiyohumi; Claudepierre, Seth G.; Sanchez, Ennio R.; Troshichev, Oleg A.; Janzhura, Alexander S.

    2012-04-01

    We have studied the dependence of the amplitude of magnetic field variations in the Pc5 band (1.6-6.7 mHz) on the solar wind and solar activity. Solar wind parameters considered are the bulk velocity Vsw and the variation of the solar wind dynamic pressure δPsw. The solar activity dependence is examined by contrasting observations made in 2001 (solar activity maximum) and 2006 (solar activity declining phase). We calculated hourly Pc5 amplitude using data from geostationary satellites at L = 6.8 and ground stations covering 1 < L < 9. The amplitude is positively correlated with both Vsw and δPsw, but the degree of correlation varies with L and magnetic local time. As measured by the correlation coefficient, the amplitude dependence on both Vsw and δPsw is stronger on the dayside than on the nightside, and the dependence on Vsw (δPsw) tends to be stronger at higher (lower) L, with the relative importance of the two solar wind parameters switching at L ˜ 5. We attribute the Vsw control to the Kelvin-Helmholtz instability on the magnetopause, occurring both at high and low latitudes, and the δPsw control to buffeting of the magnetosphere by variation of solar wind dynamic pressure. The GOES amplitude is higher at the solar maximum at all local times and the same feature is seen on the ground in the dawn sector at L > 6. A radial shift of the fast mode wave turning point, associated with the solar cycle variation of magnetosphere mass density, is a possible cause of this solar activity dependence.

  2. Acute and subacute effects of miconazole nitrate on hepatic styrene oxide hydrolase and cytochrome P-450-dependent monooxygenase activities in male and female AKR/J mice.

    PubMed

    James, M O

    1988-08-01

    The imidazole-containing anti-fungal drug, miconazole nitrate, was shown to enhance hepatic microsomal styrene oxide hydrolase and inhibit several cytochrome P-450-dependent monooxygenase activities in the AKR/J mouse. Miconazole was a more potent inhibitor of cytochrome P-450-dependent monooxygenase activities in microsomes from male than female mice, and inhibitory potency also varied with substrate. When administered in vivo miconazole nitrate stimulated epoxide hydrolase activity, but had a substrate-dependent biphasic effect on cytochrome P-450-dependent monooxygenase activities. Monooxygenase activities with benzo[a]pyrene and benzphetamine were inhibited to varying degrees in liver homogenate and hepatic microsomes from mice sacrificed 45 min after miconazole administration. After repeated administration of miconazole, liver weight, microsomal protein yield and cytochrome P-450 were increased, as were specific monooxygenase activities with ethoxycoumarin and ethoxyresorufin, but benzphetamine N-demethylase activity was decreased. These results suggested that a metabolite of miconazole was responsible for the inhibition of benzphetamine N-demethylase. It was of special interest that ethoxyresorufin O-deethylase activity was induced in the AKR/J mouse by miconazole, since the AKR/J mouse is not responsive to induction by aromatic hydrocarbons. PMID:3394155

  3. Activity-dependent FUS dysregulation disrupts synaptic homeostasis

    PubMed Central

    Sephton, Chantelle F.; Tang, Amy A.; Kulkarni, Ashwinikumar; West, James; Brooks, Mieu; Stubblefield, Jeremy J.; Liu, Yun; Zhang, Michael Q.; Green, Carla B.; Huber, Kimberly M.; Huang, Eric J.; Herz, Joachim; Yu, Gang

    2014-01-01

    The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUSWT) and a pathological mutation (FUSR521G). FUSWT and FUSR521G mice that develop severe motor deficits also show neuroinflammation, denervated neuromuscular junctions, and premature death, phenocopying the human diseases. A portion of FUSR521G mice escape early lethality; these escapers have modest motor impairments and altered sociability, which correspond with a reduction of dendritic arbors and mature spines. Remarkably, only FUSR521G mice show dendritic defects; FUSWT mice do not. Activation of metabotropic glutamate receptors 1/5 in neocortical slices and isolated synaptoneurosomes increases endogenous mouse FUS and FUSWT protein levels but decreases the FUSR521G protein, providing a potential biochemical basis for the dendritic spine differences between FUSWT and FUSR521G mice. PMID:25324524

  4. Calculated viscosity-distance dependence for some actively flowing lavas

    NASA Technical Reports Server (NTRS)

    Pieri, David

    1987-01-01

    The importance of viscosity as a gauge of the various energy and momentum dissipation regimes of lava flows has been realized for a long time. Nevertheless, despite its central role in lava dynamics and kinematics, it remains among the most difficult of flow physical properties to measure in situ during an eruption. Attempts at reconstructing the actual emplacement viscosities of lava flows from their solidified topographic form are difficult. Where data are available on the position of an advancing flow front as a function of time, it is possible to calculate the effective viscosity of the front as a function of distance from the vent, under the assumptions of a steady state regime. As an application and test of an equation given, relevant parameters from five recent flows on Mauna Loa and Kilauea were utilized to infer the dynamic structure of their aggregate flow front viscosity as they advanced, up to cessation. The observed form of the viscosity-distance relation for the five active Hawaiian flows examined appears to be exponential, with a rapid increase just before the flows stopped as one would expect.

  5. Adsorption capacities of activated carbons for geosmin and 2-methylisoborneol vary with activated carbon particle size: Effects of adsorbent and adsorbate characteristics.

    PubMed

    Matsui, Yoshihiko; Nakao, Soichi; Sakamoto, Asuka; Taniguchi, Takuma; Pan, Long; Matsushita, Taku; Shirasaki, Nobutaka

    2015-11-15

    The adsorption capacities of nine activated carbons for geosmin and 2-methylisoborneol (MIB) were evaluated. For some carbons, adsorption capacity substantially increased when carbon particle diameter was decreased from a few tens of micrometers to a few micrometers, whereas for other carbons, the increase of adsorption capacity was small for MIB and moderate for geosmin. An increase of adsorption capacity was observed for other hydrophobic adsorbates besides geosmin and MIB, but not for hydrophilic adsorbates. The parameter values of a shell adsorption model describing the increase of adsorption capacity were negatively correlated with the oxygen content of the carbon among other characteristics. Low oxygen content indicated low hydrophilicity. The increase of adsorption capacity was related to the hydrophobic properties of both adsorbates and activated carbons. For adsorptive removal of hydrophobic micropollutants such as geosmin, it is therefore recommended that less-hydrophilic activated carbons, such as coconut-shell-based carbons, be microground to a particle diameter of a few micrometers to enhance their equilibrium adsorption capacity. In contrast, adsorption by hydrophilic carbons or adsorption of hydrophilic adsorbates occur in the inner pores, and therefore adsorption capacity is unchanged by particle size reduction. PMID:26302219

  6. Redox-dependent complex formation by an ATP-dependent activator of the corrinoid/iron-sulfur protein

    PubMed Central

    Hennig, Sandra E.; Jeoung, Jae-Hun; Goetzl, Sebastian; Dobbek, Holger

    2012-01-01

    Movement, cell division, protein biosynthesis, electron transfer against an electrochemical gradient, and many more processes depend on energy conversions coupled to the hydrolysis of ATP. The reduction of metal sites with low reduction potentials (E0′ < -500 mV) is possible by connecting an energetical uphill electron transfer with the hydrolysis of ATP. The corrinoid-iron/sulfur protein (CoFeSP) operates within the reductive acetyl-CoA pathway by transferring a methyl group from methyltetrahydrofolate bound to a methyltransferase to the [Ni-Ni-Fe4S4] cluster of acetyl-CoA synthase. Methylation of CoFeSP only occurs in the low-potential Co(I) state, which can be sporadically oxidized to the inactive Co(II) state, making its reductive reactivation necessary. Here we show that an open-reading frame proximal to the structural genes of CoFeSP encodes an ATP-dependent reductive activator of CoFeSP. Our biochemical and structural analysis uncovers a unique type of reductive activator distinct from the electron-transferring ATPases found to reduce the MoFe-nitrogenase and 2-hydroxyacyl-CoA dehydratases. The CoFeSP activator contains an ASKHA domain (acetate and sugar kinases, Hsp70, and actin) harboring the ATP-binding site, which is also present in the activator of 2-hydroxyacyl-CoA dehydratases and a ferredoxin-like [2Fe-2S] cluster domain acting as electron donor. Complex formation between CoFeSP and its activator depends on the oxidation state of CoFeSP, which provides evidence for a unique strategy to achieve unidirectional electron transfer between two redox proteins. PMID:22431597

  7. On dependence of seismic activity on 11 year variations in solar activity and/or cosmic rays

    NASA Astrophysics Data System (ADS)

    Zhantayev, Zhumabek; Khachikyan, Galina; Breusov, Nikolay

    2014-05-01

    It is found in the last decades that seismic activity of the Earth has a tendency to increase with decreasing solar activity (increasing cosmic rays). A good example of this effect may be the growing number of catastrophic earthquakes in the recent rather long solar minimum. Such results support idea on existence a solar-lithosphere relationship which, no doubts, is a part of total pattern of solar-terrestrial relationships. The physical mechanism of solar-terrestrial relationships is not developed yet. It is believed at present that one of the main contenders for such mechanism may be the global electric circuit (GEC) - vertical current loops, piercing and electrodynamically coupling all geospheres. It is also believed, that the upper boundary of the GEC is located at the magnetopause, where magnetic field of the solar wind reconnects with the geomagnetic field, that results in penetrating solar wind energy into the earth's environment. The effectiveness of the GEC operation depends on intensity of cosmic rays (CR), which ionize the air in the middle atmosphere and provide its conductivity. In connection with the foregoing, it can be expected: i) quantitatively, an increasing seismic activity from solar maximum to solar minimum may be in the same range as increasing CR flux; and ii) in those regions of the globe, where the crust is shipped by the magnetic field lines with number L= ~ 2.0, which are populated by anomalous cosmic rays (ACR), the relationship of seismic activity with variations in solar activity will be manifested most clearly, since there is a pronounced dependence of ACR on solar activity variations. Checking an assumption (i) with data of the global seismological catalog of the NEIC, USGS for 1973-2010, it was found that yearly number of earthquake with magnitude M≥4.5 varies into the 11 year solar cycle in a quantitative range of about 7-8% increasing to solar minimum, that qualitatively and quantitatively as well is in agreement with the

  8. Mass dependence of the activation enthalpy and entropy of unentangled linear alkane chains

    SciTech Connect

    Jeong, Cheol; Douglas, Jack F.

    2015-10-14

    The mass scaling of the self-diffusion coefficient D of polymers in the liquid state, D ∼ M{sup β}, is one of the most basic characteristics of these complex fluids. Although traditional theories such as the Rouse and reptation models of unentangled and entangled polymer melts, respectively, predict that β is constant, this exponent for alkanes has been estimated experimentally to vary from −1.8 to −2.7 upon cooling. Significantly, β changes with temperature T under conditions where the chains are not entangled and at temperatures far above the glass transition temperature T{sub g} where dynamic heterogeneity does not complicate the description of the liquid dynamics. Based on atomistic molecular dynamics simulations on unentangled linear alkanes in the melt, we find that the variation of β with T can be directly attributed to the dependence of the enthalpy ΔH{sub a} and entropy ΔS{sub a} of activation on the number of alkane backbone carbon atoms, n. In addition, we find a sharp change in the melt dynamics near a “critical” chain length, n ≈ 17. A close examination of this phenomenon indicates that a “buckling transition” from rod-like to coiled chain configurations occurs at this characteristic chain length and distinct entropy-enthalpy compensation relations, ΔS{sub a} ∝ ΔH{sub a}, hold on either side of this polymer conformational transition. We conclude that the activation free energy parameters exert a significant influence on the dynamics of polymer melts that is not anticipated by either the Rouse and reptation models. In addition to changes of ΔH{sub a} and ΔS{sub a} with M, we expect changes in these free energy parameters to be crucial for understanding the dynamics of polymer blends, nanocomposites, and confined polymers because of changes of the fluid free energy by interfacial interactions and geometrical confinement.

  9. Mass dependence of the activation enthalpy and entropy of unentangled linear alkane chains

    NASA Astrophysics Data System (ADS)

    Jeong, Cheol; Douglas, Jack F.

    2015-10-01

    The mass scaling of the self-diffusion coefficient D of polymers in the liquid state, D ˜ Mβ, is one of the most basic characteristics of these complex fluids. Although traditional theories such as the Rouse and reptation models of unentangled and entangled polymer melts, respectively, predict that β is constant, this exponent for alkanes has been estimated experimentally to vary from -1.8 to -2.7 upon cooling. Significantly, β changes with temperature T under conditions where the chains are not entangled and at temperatures far above the glass transition temperature Tg where dynamic heterogeneity does not complicate the description of the liquid dynamics. Based on atomistic molecular dynamics simulations on unentangled linear alkanes in the melt, we find that the variation of β with T can be directly attributed to the dependence of the enthalpy ΔHa and entropy ΔSa of activation on the number of alkane backbone carbon atoms, n. In addition, we find a sharp change in the melt dynamics near a "critical" chain length, n ≈ 17. A close examination of this phenomenon indicates that a "buckling transition" from rod-like to coiled chain configurations occurs at this characteristic chain length and distinct entropy-enthalpy compensation relations, ΔSa ∝ ΔHa, hold on either side of this polymer conformational transition. We conclude that the activation free energy parameters exert a significant influence on the dynamics of polymer melts that is not anticipated by either the Rouse and reptation models. In addition to changes of ΔHa and ΔSa with M, we expect changes in these free energy parameters to be crucial for understanding the dynamics of polymer blends, nanocomposites, and confined polymers because of changes of the fluid free energy by interfacial interactions and geometrical confinement.

  10. Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation

    PubMed Central

    2012-01-01

    Background Inheritance of the human ϵ4 allele of the apolipoprotein (apo) E gene (APOE) significantly increases the risk of developing Alzheimer’s disease (AD), in addition to adversely influencing clinical outcomes of other neurologic diseases. While apoE isoforms differentially interact with amyloid β (Aβ), a pleiotropic neurotoxin key to AD etiology, more recent work has focused on immune regulation in AD pathogenesis and on the mechanisms of innate immunomodulatory effects associated with inheritance of different APOE alleles. APOE genotype modulates expression of proximal genes including APOC1, which encodes a small apolipoprotein that is associated with Aβ plaques. Here we tested the hypothesis that APOE-genotype dependent innate immunomodulation may be mediated in part by apoC-I. Methods ApoC-I concentration in cerebrospinal fluid from control subjects of differing APOE genotypes was quantified by ELISA. Real-time PCR and ELISA were used to analyze apoC-I mRNA and protein expression, respectively, in liver, serum, cerebral cortex, and cultured primary astrocytes derived from mice with targeted replacement of murine APOE for human APOE ϵ3 or ϵ4. ApoC-I direct modulation of innate immune activity was investigated in cultured murine primary microglia and astrocytes, as well as human differentiated macrophages, using specific toll-like receptor agonists LPS and PIC as well as Aβ. Results ApoC-I levels varied with APOE genotype in humans and in APOE targeted replacement mice, with ϵ4 carriers showing significantly less apoC-I in both species. ApoC-I potently reduced pro-inflammatory cytokine secretion from primary murine microglia and astrocytes, and human macrophages, stimulated with LPS, PIC, or Aβ. Conclusions ApoC-I is immunosuppressive. Our results illuminate a novel potential mechanism for APOE genotype risk for AD; one in which patients with an ϵ4 allele have decreased expression of apoC-I resulting in increased innate immune activity. PMID

  11. Activity-Dependent Dendritic Spine Shrinkage and Growth Involve Downregulation of Cofilin via Distinct Mechanisms

    PubMed Central

    Calabrese, Barbara; Saffin, Jean-Michel; Halpain, Shelley

    2014-01-01

    A current model posits that cofilin-dependent actin severing negatively impacts dendritic spine volume. Studies suggested that increased cofilin activity underlies activity-dependent spine shrinkage, and that reduced cofilin activity induces activity-dependent spine growth. We suggest instead that both types of structural plasticity correlate with decreased cofilin activity. However, the mechanism of inhibition determines the outcome for spine morphology. RNAi in rat hippocampal cultures demonstrates that cofilin is essential for normal spine maintenance. Cofilin-F-actin binding and filament barbed-end production decrease during the early phase of activity-dependent spine shrinkage; cofilin concentration also decreases. Inhibition of the cathepsin B/L family of proteases prevents both cofilin loss and spine shrinkage. Conversely, during activity-dependent spine growth, LIM kinase stimulates cofilin phosphorylation, which activates phospholipase D-1 to promote actin polymerization. These results implicate novel molecular mechanisms and prompt a revision of the current model for how cofilin functions in activity-dependent structural plasticity. PMID:24740405

  12. Puerarin activates endothelial nitric oxide synthase through estrogen receptor-dependent PI3-kinase and calcium-dependent AMP-activated protein kinase

    SciTech Connect

    Hwang, Yong Pil; Kim, Hyung Gyun; Hien, Tran Thi; Jeong, Myung Ho; Jeong, Tae Cheon; Jeong, Hye Gwang

    2011-11-15

    The cardioprotective properties of puerarin, a natural product, have been attributed to the endothelial nitric oxide synthase (eNOS)-mediated production of nitric oxide (NO) in EA.hy926 endothelial cells. However, the mechanism by which puerarin activates eNOS remains unclear. In this study, we sought to identify the intracellular pathways underlying eNOS activation by puerarin. Puerarin induced the activating phosphorylation of eNOS on Ser1177 and the production of NO in EA.hy926 cells. Puerarin-induced eNOS phosphorylation required estrogen receptor (ER)-mediated phosphatidylinositol 3-kinase (PI3K)/Akt signaling and was reversed by AMP-activated protein kinase (AMPK) and calcium/calmodulin-dependent kinase II (CaMKII) inhibition. Importantly, puerarin inhibited the adhesion of tumor necrosis factor (TNF)-{alpha}-stimulated monocytes to endothelial cells and suppressed the TNF-{alpha} induced expression of intercellular cell adhesion molecule-1. Puerarin also inhibited the TNF-{alpha}-induced nuclear factor-{kappa}B activation, which was attenuated by pretreatment with N{sup G}-nitro-L-arginine methyl ester, a NOS inhibitor. These results indicate that puerarin stimulates eNOS phosphorylation and NO production via activation of an estrogen receptor-mediated PI3K/Akt- and CaMKII/AMPK-dependent pathway. Puerarin may be useful for the treatment or prevention of endothelial dysfunction associated with diabetes and cardiovascular disease. -- Highlights: Black-Right-Pointing-Pointer Puerarin induced the phosphorylation of eNOS and the production of NO. Black-Right-Pointing-Pointer Puerarin activated eNOS through ER-dependent PI3-kinase and Ca{sup 2+}-dependent AMPK. Black-Right-Pointing-Pointer Puerarin-induced NO was involved in the inhibition of NF-kB activation. Black-Right-Pointing-Pointer Puerarin may help for prevention of vascular dysfunction and diabetes.

  13. Statistical modeling of time-dependent fMRI activation effects.

    PubMed

    Kalus, Stefanie; Bothmann, Ludwig; Yassouridis, Christina; Czisch, Michael; Sämann, Philipp G; Fahrmeir, Ludwig

    2015-02-01

    Functional magnetic resonance imaging (fMRI) activation detection within stimulus-based experimental paradigms is conventionally based on the assumption that activation effects remain constant over time. This assumption neglects the fact that the strength of activation may vary, for example, due to habituation processes or changing attention. Neither the functional form of time variation can be retrieved nor short-lasting effects can be detected by conventional methods. In this work, a new dynamic approach is proposed that allows to estimate time-varying effect profiles and hemodynamic response functions in event-related fMRI paradigms. To this end, we incorporate the time-varying coefficient methodology into the fMRI general regression framework. Inference is based on a voxelwise penalized least squares procedure. We assess the strength of activation and corresponding time variation on the basis of pointwise confidence intervals on a voxel level. Additionally, spatial clusters of effect curves are presented. Results of the analysis of an active oddball experiment show that activation effects deviating from a constant trend coexist with time-varying effects that exhibit different types of shapes, such as linear, (inversely) U-shaped or fluctuating forms. In a comparison to conventional approaches, like classical SPM, we observe that time-constant methods are rather insensitive to detect temporary effects, because these do not emerge when aggregated across the entire experiment. Hence, it is recommended to base activation detection analyses not merely on time-constant procedures but to include flexible time-varying effects that harbour valuable information on individual response patterns. PMID:25339617

  14. A Novel Time-Varying Spectral Filtering Algorithm for Reconstruction of Motion Artifact Corrupted Heart Rate Signals During Intense Physical Activities Using a Wearable Photoplethysmogram Sensor.

    PubMed

    Salehizadeh, Seyed M A; Dao, Duy; Bolkhovsky, Jeffrey; Cho, Chae; Mendelson, Yitzhak; Chon, Ki H

    2015-01-01

    Accurate estimation of heart rates from photoplethysmogram (PPG) signals during intense physical activity is a very challenging problem. This is because strenuous and high intensity exercise can result in severe motion artifacts in PPG signals, making accurate heart rate (HR) estimation difficult. In this study we investigated a novel technique to accurately reconstruct motion-corrupted PPG signals and HR based on time-varying spectral analysis. The algorithm is called Spectral filter algorithm for Motion Artifacts and heart rate reconstruction (SpaMA). The idea is to calculate the power spectral density of both PPG and accelerometer signals for each time shift of a windowed data segment. By comparing time-varying spectra of PPG and accelerometer data, those frequency peaks resulting from motion artifacts can be distinguished from the PPG spectrum. The SpaMA approach was applied to three different datasets and four types of activities: (1) training datasets from the 2015 IEEE Signal Process. Cup Database recorded from 12 subjects while performing treadmill exercise from 1 km/h to 15 km/h; (2) test datasets from the 2015 IEEE Signal Process. Cup Database recorded from 11 subjects while performing forearm and upper arm exercise. (3) Chon Lab dataset including 10 min recordings from 10 subjects during treadmill exercise. The ECG signals from all three datasets provided the reference HRs which were used to determine the accuracy of our SpaMA algorithm. The performance of the SpaMA approach was calculated by computing the mean absolute error between the estimated HR from the PPG and the reference HR from the ECG. The average estimation errors using our method on the first, second and third datasets are 0.89, 1.93 and 1.38 beats/min respectively, while the overall error on all 33 subjects is 1.86 beats/min and the performance on only treadmill experiment datasets (22 subjects) is 1.11 beats/min. Moreover, it was found that dynamics of heart rate variability can be

  15. A Novel Time-Varying Spectral Filtering Algorithm for Reconstruction of Motion Artifact Corrupted Heart Rate Signals During Intense Physical Activities Using a Wearable Photoplethysmogram Sensor

    PubMed Central

    Salehizadeh, Seyed M. A.; Dao, Duy; Bolkhovsky, Jeffrey; Cho, Chae; Mendelson, Yitzhak; Chon, Ki H.

    2015-01-01

    Accurate estimation of heart rates from photoplethysmogram (PPG) signals during intense physical activity is a very challenging problem. This is because strenuous and high intensity exercise can result in severe motion artifacts in PPG signals, making accurate heart rate (HR) estimation difficult. In this study we investigated a novel technique to accurately reconstruct motion-corrupted PPG signals and HR based on time-varying spectral analysis. The algorithm is called Spectral filter algorithm for Motion Artifacts and heart rate reconstruction (SpaMA). The idea is to calculate the power spectral density of both PPG and accelerometer signals for each time shift of a windowed data segment. By comparing time-varying spectra of PPG and accelerometer data, those frequency peaks resulting from motion artifacts can be distinguished from the PPG spectrum. The SpaMA approach was applied to three different datasets and four types of activities: (1) training datasets from the 2015 IEEE Signal Process. Cup Database recorded from 12 subjects while performing treadmill exercise from 1 km/h to 15 km/h; (2) test datasets from the 2015 IEEE Signal Process. Cup Database recorded from 11 subjects while performing forearm and upper arm exercise. (3) Chon Lab dataset including 10 min recordings from 10 subjects during treadmill exercise. The ECG signals from all three datasets provided the reference HRs which were used to determine the accuracy of our SpaMA algorithm. The performance of the SpaMA approach was calculated by computing the mean absolute error between the estimated HR from the PPG and the reference HR from the ECG. The average estimation errors using our method on the first, second and third datasets are 0.89, 1.93 and 1.38 beats/min respectively, while the overall error on all 33 subjects is 1.86 beats/min and the performance on only treadmill experiment datasets (22 subjects) is 1.11 beats/min. Moreover, it was found that dynamics of heart rate variability can be

  16. Novel activity-dependent approaches to therapeutic hypnosis and psychotherapy: the general waking trance.

    PubMed

    Rossi, Ernest; Erickson-Klein, Roxanna; Rossi, Kathryn

    2008-10-01

    This paper presents a highly edited version of a videotape made in 1980 by Marion Moore, M.D., showing Milton H. Erickson and Moore demonstrating novel, activity-dependent approaches to hand-levitation and therapeutic hypnosis on their subject, Ernest Rossi. Erickson's naturalistic and utilization approach is described in his very direct and surprising induction in a trance challenged patient. These novel, and surprising inductions are examples of how Erickson was prescient in developing activity-dependent approaches to therapeutic hypnosis and psychotherapy several generations before modern neuroscience documented the activity-dependent molecular-genomic mechanisms of memory, learning, and behavior change. Erickson describes a case where he utilized what he called, "The General Waking Trance" when he "dared" not use an obvious hypnotic induction. It is proposed that the states of intense mental absorption and response attentiveness that are facilitated by the general waking trance are functionally related to the three conditions neuroscientists have identified as novelty, enrichment, and exercise (both mental and physical), which can turn on activity-dependent gene expression and activity-dependent brain plasticity, that are the molecular-genomic and neural basis ofmemory, learning, consciousness, and behavior change. We recommend that the next step in investigating the efficacy of therapeutic hypnosis will be in partnering with neuroscientists to explore the possibilities and limitations of utilizing the activity-dependent approaches to hypnotic induction and the general waking trance in facilitating activity-dependent gene expression and brain plasticity. PMID:18998388

  17. The cross-sectional area of the gluteus maximus muscle varies according to habitual exercise loading: Implications for activity-related and evolutionary studies.

    PubMed

    Niinimäki, Sirpa; Härkönen, Laura; Nikander, Riku; Abe, Shinya; Knüsel, Christopher; Sievänen, Harri

    2016-04-01

    Greater size of the gluteus maximus muscle in humans compared to non-human primates has been considered an indication of its function in bipedal posture and gait, especially running capabilities. Our aim was to find out how the size of the gluteus maximus muscle varies according to sports while controlling for variation in muscle strength and body weight. Data on gluteus maximus muscle cross-sectional area (MCA) were acquired from magnetic resonance images of the hip region of female athletes (N=91), and physically active controls (N=20). Dynamic muscle force was measured as counter movement jump and isometric knee extension force as leg press. Five exercise loading groups were created: high impact (triple-jumpers and high-jumpers), odd impact (soccer and squash players), high magnitude (power-lifters), repetitive impact (endurance runners) and repetitive non-impact (swimmers) loadings. Individuals in high impact, odd impact or high-magnitude loading groups had greater MCA compared to those of controls, requiring powerful hip extension, trunk stabilization in rapid directional change and high explosive muscle force. Larger body size and greater muscle strength were associated with larger MCA. An increase in dynamic force was associated with larger MCA, but the strength of this relationship varied with body weight. Thus, gluteal adaptation in humans promotes powerful lower limb movements required in sprinting and rapid changes in direction, as well as maintenance and stabilization of an erect trunk which also provides a platform for powerful motions of the upper limbs. These movements have likely evolved to facilitate food acquisition, including hunting. PMID:26384568

  18. Irritant activation of epithelial cells is mediated via protease-dependent EGFR activation.

    PubMed

    White, Kellie J; Maffei, Vincent J; Newton-West, Marvin; Swerlick, Robert A

    2011-02-01

    Although numerous studies have examined in vivo and in vitro effects of irritants, most focused on events developing hours to days after exposure. Molecular events occurring immediately after skin contact remain incompletely defined. Characterization of early events could lead to the identification of key molecular signals necessary for the production of inflammatory mediators responsible for the signs and symptoms of irritant contact dermatitis (ICD). HaCaT cells treated with sodium lauryl sulfate (SLS), a model irritant, were used to examine early molecular events of ICD. Western analysis showed SLS-mediated induction of early growth response-1 (egr-1), a transcription factor capable of regulating hallmarks of ICD such as angiogenesis, hyperproliferation, and inflammation. Additionally, de novo egr-1 expression was commensurate with transcriptional activation of egr-1 mRNA and heteronuclear RNA. Use of pharmacological inhibitors demonstrated that SLS-induced egr-1 was dependent on MEK1/p44/42 ERK, but not on p38 or JNK signaling. The EGFR inhibitor PD168393 and the metalloprotease inhibitor TAPI-2 both inhibited SLS-induced egr-1. Finally, small interfering RNA silencing of the EGFR diminished SLS-induced egr-1 mRNA. These studies suggest a role of the EGFR in SLS signaling as well as a, to our knowledge, previously unreported association between ICD and EGFR induction of egr-1. PMID:20981109

  19. Level-dependent auditory tuning: Transducer-based active processes in hearing and best-frequency shifts.

    PubMed

    Nadrowski, Björn; Göpfert, Martin C

    2009-01-01

    Ears boost their sensitivity by means of active, force-generating processes that augment the minute vibrations induced by soft sounds. These processes can alter auditory frequency-tuning in a level-dependent way. In the antennal hearing organ of Drosophila, for example, the active process shifts the best frequency (BF) of the antennal sound receiver when the sound intensity is varied, tuning the receiver to conspecific songs. Here we show that this level-dependent tuning can be reproduced by an active transduction model as proposed for vertebrate hair cells and the Drosophila ear. We further show that the direction of the frequency shift depends on the system to which the molecular modules for auditory transduction connect: If this system is mass-less such as the sensory hair bundles of bullfrog saccular hair cells, the BF of the displacement response will increase as the sound intensity declines. Conversely, BF will decrease with declining intensity if the transduction modules couple to inertial systems such as the fly's antennal sound receiver or cupulae in the fish lateral line. PMID:19704854

  20. Effect of amines as activators on the alcohol-oxidizing activity of pyrroloquinoline quinone-dependent quinoprotein alcohol dehydrogenase.

    PubMed

    Takeda, Kouta; Ishida, Takuya; Igarashi, Kiyohiko; Samejima, Masahiro; Nakamura, Nobuhumi; Ohno, Hiroyuki

    2014-01-01

    Pyrroloquinoline quinone-dependent quinoprotein alcohol dehydrogenases (PQQ-ADH) require ammonia or primary amines as activators in in vitro assays with artificial electron acceptors. We found that PQQ-ADH from Pseudomonas putida KT2440 (PpADH) was activated by various primary amines, di-methylamine, and tri-methylamine. The alcohol oxidation activity of PpADH was strongly enhanced and the affinity for substrates was also improved by pentylamine as an activator. PMID:25229857

  1. Role of activity-dependent BDNF expression in hippocampal-prefrontal cortical regulation of behavioral perseverance.

    PubMed

    Sakata, Kazuko; Martinowich, Keri; Woo, Newton H; Schloesser, Robert J; Jimenez, Dennisse V; Ji, Yuanyuan; Shen, Liya; Lu, Bai

    2013-09-10

    Activity-dependent gene transcription, including that of the brain-derived neurotrophic factor (Bdnf) gene, has been implicated in various cognitive functions. We previously demonstrated that mutant mice with selective disruption of activity-dependent BDNF expression (BDNF-KIV mice) exhibit deficits in GABA-mediated inhibition in the prefrontal cortex (PFC). Here, we show that disruption of activity-dependent BDNF expression impairs BDNF-dependent late-phase long-term potentiation (L-LTP) in CA1, a site of hippocampal output to the PFC. Interestingly, early-phase LTP and conventional L-LTP induced by strong tetanic stimulation were completely normal in BDNF-KIV mice. In parallel, attenuation of activity-dependent BDNF expression significantly impairs spatial memory reversal and contextual memory extinction, two executive functions that require intact hippocampal-PFC circuitry. In contrast, spatial and contextual memory per se were not affected. Thus, activity-dependent BDNF expression in the hippocampus and PFC may contribute to cognitive and behavioral flexibility. These results suggest distinct roles for different forms of L-LTP and provide a link between activity-dependent BDNF expression and behavioral perseverance, a hallmark of several psychiatric disorders. PMID:23980178

  2. Activation of factor XII-dependent pathways in human plasma by hematin and protoporphyrin.

    PubMed Central

    Becker, C G; Wagner, M; Kaplan, A P; Silverberg, M; Grady, R W; Liem, H; Muller-Eberhard, U

    1985-01-01

    Intravenous administration of hematin is effective in the treatment of acute exacerbations of the inducible porphyrias. In the course of such treatment, coagulopathies have occurred that are characterized by prolongation of prothrombin time, partial thromboplastin time, and formation of fibrin split products. In experiments in vitro with normal human plasma, we observed that hematin and protoporphyrin activated Factor XII-dependent pathways of coagulation and fibrinolysis, and that they generated kallikrein activity. Incubation of protoporphyrin with purified Factor XII resulted in activation as measured by amidolysis of a chromogenic substrate. Neither coproporphyrin, uroporphyrin, delta-aminolevulinic acid, porphobilinogen, or bilirubin activated Factor XII-dependent pathways. Exposure of serum containing added uroporphyrin, coproporphyrin, and protoporphyrin, but not hematin, to ultraviolet light (405 nm) resulted in activation of the classical pathway of the complement system. On the other hand, exposure of plasma containing uroporphyrin or coproporphyrin to ultraviolet light did not result in activation of Factor XII-dependent pathways. PMID:4031058

  3. Impaired activity-dependent FMRP translation and enhanced mGluR-dependent LTD in Fragile X premutation mice.

    PubMed

    Iliff, Adam J; Renoux, Abigail J; Krans, Amy; Usdin, Karen; Sutton, Michael A; Todd, Peter K

    2013-03-15

    Fragile X premutation-associated disorders, including Fragile X-associated Tremor Ataxia Syndrome, result from unmethylated CGG repeat expansions in the 5' untranslated region (UTR) of the FMR1 gene. Premutation-sized repeats increase FMR1 transcription but impair rapid translation of the Fragile X mental retardation protein (FMRP), which is absent in Fragile X Syndrome (FXS). Normally, FMRP binds to RNA and regulates metabotropic glutamate receptor (mGluR)-mediated synaptic translation, allowing for dendritic synthesis of several proteins. FMRP itself is also synthesized at synapses in response to mGluR activation. However, the role of activity-dependent translation of FMRP in synaptic plasticity and Fragile X-premutation-associated disorders is unknown. To investigate this question, we utilized a CGG knock-in mouse model of the Fragile X premutation with 120-150 CGG repeats in the mouse Fmr1 5' UTR. These mice exhibit increased Fmr1 mRNA production but impaired FMRP translational efficiency, leading to a modest reduction in basal FMRP expression. Cultured hippocampal neurons and synaptoneurosomes derived from CGG KI mice demonstrate impaired FMRP translation in response to the group I mGluR agonist 3,5-dihydroxyphenylglycine. Electrophysiological analysis reveals enhanced mGluR-mediated long-term depression (mGluR-LTD) at CA3-CA1 synapses in acute hippocampal slices prepared from CGG KI mice relative to wild-type littermates, similar to Fmr1 knockout mice. However, unlike mGluR-LTD in mice completely lacking FMRP, mGluR-LTD in CGG knock-in mice remains dependent on new protein synthesis. These studies demonstrate partially overlapping synaptic plasticity phenotypes in mouse models of FXS and Fragile X premutation disorders and support a role for activity-dependent synthesis of FMRP in enduring forms of synaptic plasticity. PMID:23250915

  4. "Exercise Dependence"--A Problem or Natural Result of High Activity?

    ERIC Educational Resources Information Center

    Phelan, Suzanne; Bond, Dale S.; Lang, Wei; Jordan, Dustin; Wing, Rena R.

    2011-01-01

    Objectives: To compare physical activity (PA) and exercise dependence (ED) in 267 weight-loss maintainers (WLM) and 213 normal-weight (NW) controls. Methods: PA and ED assessed via accelerometery and the Exercise Dependence Questionnaire. Results: WLM had higher PA levels and ED scores than those of NW (P less than 0.0001). WLM status (P = 0.006)…

  5. 75 FR 80114 - Agency Information Collection (Status of Dependents Questionnaire) Activity Under OMB Review

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-21

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF VETERANS AFFAIRS Agency Information Collection (Status of Dependents Questionnaire) Activity Under OMB Review... INFORMATION: Title: Status of Dependents Questionnaire, VA Form 21-0538. OMB Control Number: 2900-0500....

  6. Rat long-chain acyl-CoA synthetase mRNA, protein, and activity vary in tissue distribution and in response to diet.

    PubMed

    Mashek, Douglas G; Li, Lei O; Coleman, Rosalind A

    2006-09-01

    Distinct isoforms of long-chain acyl-CoA synthetases (ACSLs) may partition fatty acids toward specific metabolic cellular pathways. For each of the five members of the rat ACSL family, we analyzed tissue mRNA distributions, and we correlated the mRNA, protein, and activity of ACSL1 and ACSL4 after fasting and refeeding a 69% sucrose diet. Not only did quantitative real-time PCR analyses reveal unique tissue expression patterns for each ACSL isoform, but expression varied markedly in different adipose depots. Fasting increased ACSL4 mRNA abundance in liver, muscle, and gonadal and inguinal adipose tissues, and refeeding decreased ACSL4 mRNA. A similar pattern was observed for ACSL1, but both fasting and refeeding decreased ACSL1 mRNA in gonadal adipose. Fasting also decreased ACSL3 and ACSL5 mRNAs in liver and ACSL6 mRNA in muscle. Surprisingly, in nearly every tissue measured, the effects of fasting and refeeding on the mRNA abundance of ACSL1 and ACSL4 were discordant with changes in protein abundance. These data suggest that the individual ACSL isoforms are distinctly regulated across tissues and show that mRNA expression may not provide useful information about isoform function. They further suggest that translational or posttranslational modifications are likely to contribute to the regulation of ACSL isoforms. PMID:16772660

  7. Variability of Mass Dependence of Auroral Acceleration Processes with Solar Activity

    NASA Technical Reports Server (NTRS)

    Ghielmetti, Arthur G.

    1997-01-01

    The objectives of this investigation are to improve understanding of the mass dependent variability of the auroral acceleration processes and so to clarify apparent discrepancies regarding the altitude and local time variations with solar cycle by investigating: (1) the global morphological relationships between auroral electric field structures and the related particle signatures under varying conditions of solar activity, and (2) the relationships between the electric field structures and particle signatures in selected events that are representative of the different conditions occurring during a solar cycle. The investigation is based in part on the Lockheed UFI data base of UpFlowing Ion (UFI) events in the 5OO eV to 16keV energy range and associated electrons in the energy range 7O eV to 24 keV. This data base was constructed from data acquired by the ion mass spectrometer on the S3-3 satellite in the altitude range of I to 1.3 Re. The launch of the POLAR spacecraft in early 1996 and successful operation of its TIMAS ion mass spectrometer has provided us with data from within the auroral acceleration regions during the current solar minimum. The perigee of POLAR is at about 1 Re, comparable to that of S3-3. The higher sensitivity and time resolution of TIMAS compared to the ion mass spectrometer on S3-3 together with its wider energy range, 15 eV to 33 keV, facilitate more detailed studies of upflowing ions.

  8. Myoelectric activity of the small intestine during morphine dependence and withdrawal in rats

    SciTech Connect

    Kuperman, D.A.; Sninsky, C.A.; Lynch, D.F.

    1987-04-01

    The authors investigated (1) the effect of morphine dependence on the migrating myoelectric complex (MMC) of the small intestine, (2) whether bacterial overgrowth developed in morphine-dependent rats, and (3) the effect of naloxone and methylbromide naltrexone, a peripheral opioid antagonist, on the MMC in morphine-naive and morphine-dependent rats. They also evaluated intestinal motility during naloxone-induced withdrawal in animals pretreated with clonidine. Intestinal myoelectric activity was monitored by four indwelling electrodes in unanesthetized, fasted rats. D-(/sup 14/C)xylose breath tests were performed before and after morphine-pellet implantation to evaluate the presence of bacterial overgrowth of the small intestine. Naloxone had no effect on myoelectric activity of the small intestine in morphine-naive rats. Cycling activity fronts were present in morphine-dependent animals, but there was a significant prolongation of activity front periodicity and slowing of the propagation velocity. No significant increase in /sup 14/CO/sub 2/ excretion was noted in the morphine-dependent rats. They conclude from their studies that (1) myoelectric activity of the small intestine develops incomplete tolerance to morphine; (2) bacterial overgrowth is not a feature of morphine dependence in the rat; (3) alterations of intestinal myoelectric activity are a component of the opiate withdrawal syndrome, and they appear at least partially mediated by a peripheral mechanism that can be suppressed by an ..cap alpha../sub 2/-adrenergic agonist.

  9. Mapping neural circuits with activity-dependent nuclear import of a transcription factor.

    PubMed

    Masuyama, Kaoru; Zhang, Yi; Rao, Yi; Wang, Jing W

    2012-03-01

    Abstract: Nuclear factor of activated T cells (NFAT) is a calcium-responsive transcription factor. We describe here an NFAT-based neural tracing method-CaLexA (calcium-dependent nuclear import of LexA)-for labeling active neurons in behaving animals. In this system, sustained neural activity induces nuclear import of the chimeric transcription factor LexA-VP16-NFAT, which in turn drives green fluorescent protein (GFP) reporter expression only in active neurons. We tested this system in Drosophila and found that volatile sex pheromones excite specific neurons in the olfactory circuit. Furthermore, complex courtship behavior associated with multi-modal sensory inputs activated neurons in the ventral nerve cord. This method harnessing the mechanism of activity-dependent nuclear import of a transcription factor can be used to identify active neurons in specific neuronal population in behaving animals. PMID:22236090

  10. Assessing visual requirements for social context-dependent activation of the songbird song system

    PubMed Central

    Hara, Erina; Kubikova, Lubica; Hessler, Neal A.; Jarvis, Erich D.

    2008-01-01

    Social context has been shown to have a profound influence on brain activation in a wide range of vertebrate species. Best studied in songbirds, when males sing undirected song, the level of neural activity and expression of immediate early genes (IEGs) in several song nuclei is dramatically higher or lower than when they sing directed song to other birds, particularly females. This differential social context-dependent activation is independent of auditory input and is not simply dependent on the motor act of singing. These findings suggested that the critical sensory modality driving social context-dependent differences in the brain could be visual cues. Here, we tested this hypothesis by examining IEG activation in song nuclei in hemispheres to which visual input was normal or blocked. We found that covering one eye blocked visually induced IEG expression throughout both contralateral visual pathways of the brain, and reduced activation of the contralateral ventral tegmental area, a non-visual midbrain motivation-related area affected by social context. However, blocking visual input had no effect on the social context-dependent activation of the contralateral song nuclei during female-directed singing. Our findings suggest that individual sensory modalities are not direct driving forces for the social context differences in song nuclei during singing. Rather, these social context differences in brain activation appear to depend more on the general sense that another individual is present. PMID:18826930

  11. Cholesterol ester hydrolase in pig liver is activated by cyclic AMP-dependent protein kinase

    SciTech Connect

    Chen, J.J.S.; Dubin, E.; Margolis, S.

    1986-05-01

    To examine whether hepatic neutral cholesterol ester hydrolase (CEH) is regulated by phosphorylation, the authors have assayed CEH activity from pig liver cytosol by measuring /sup 14/C-oleate release from labeled cholesteryl oleate at pH 7.4. When pig liver cytosol was incubated with 2 mM Mg and 0.5 mM ATP, CEH activity was increased (141 +/- 8% of control, mean +/- SEM). Addition of 25..mu..M cyclic AMP (cAMP) further activated CEH activity (164 +/- 4% of control) as compared to incubation with Mg and ATP (p < 0.02). In the presence of 5 mM EDTA or in the absence of either Mg or ATP, no activation of CEH was observed. The activation was completely abolished by further incubation of activated cytosol with E. coli alkaline phosphatase. Activation of CEH activity was partially prevented by the addition of protein kinase inhibitor (p < 0.02) and this effect was completely reversed in the presence of exogenous cAMP-dependent protein kinase (p < 0.05). To examine further the role of the cAMP-dependent protein kinase, CEH activity was purified 240-fold by 35% (NH/sub 4/)/sub 2/SO/sub 4/ precipitation and Sepharose 4B chromatography. Incubation of partially purified CEH fractions with Mg, ATP and cAMP did not increase CEH activity. Addition of exogenous cAMP-dependent protein kinase activated CEH activity of partially purified fractions. The authors observations indicate that pig liver CEH is activated by phosphorylation mediated by cAMP-dependent protein kinase.

  12. Ionizing Radiation Induces Macrophage Foam Cell Formation and Aggregation Through JNK-Dependent Activation of CD36 Scavenger Receptors

    SciTech Connect

    Katayama, Ikuo; Hotokezaka, Yuka; Matsuyama, Toshifumi; Sumi, Tadateru; Nakamura, Takashi

    2008-03-01

    Purpose: Irradiated arteries of cancer patients can be associated with atherosclerosis-like lesions containing cholesterol-laden macrophages (foam cells). Endothelial cell damage by irradiation does not completely explain the foam cell formation. We investigated the possible underlying mechanisms for ionizing radiation (IR)-induced foam cell formation. Methods and Materials: Human peripheral blood monocytes were activated by macrophage colony-stimulating factor and then treated with varying doses of IR in vitro in the absence of endothelial cells. Scavenger receptor expression and foam cell formation of IR-treated macrophages were investigated in the presence or absence of oxidized low-density lipoprotein. We also assessed the importance of mitogen-activated protein kinase activity in the macrophage colony-stimulating factor-activated human monocytes (macrophages) for the foam cell formation. Results: We found that IR treatment of macrophage colony-stimulating factor-activated human peripheral blood monocytes resulted in the enhanced expression of CD36 scavenger receptors and that cholesterol accumulated in the irradiated macrophages with resultant foam cell formation in the presence of oxidized low-density lipoprotein. Furthermore, when cultured on collagen gels, human macrophages formed large foam cell aggregates in response to IR. Antibodies against CD36 inhibited the IR-induced foam cell formation and aggregation, indicating that the IR-induced foam cell formation and the subsequent aggregation are dependent on functional CD36. In addition, we found that IR of human macrophages resulted in c-Jun N-terminal kinase activation and that c-Jun N-terminal kinase inhibition suppressed IR-induced CD36 expression and the subsequent foam cell formation and aggregation. Conclusion: Taken together, these results suggest that IR-induced foam cell formation is mediated by c-Jun N-terminal kinase-dependent CD36 activation.

  13. Evaluation of NAD(P)-Dependent Dehydrogenase Activities in Neutrophilic Granulocytes by the Bioluminescent Method.

    PubMed

    Savchenko, A A

    2015-09-01

    Bioluminescent method for measurements of the neutrophilic NAD(P)-dependent dehydrogenases (lactate dehydrogenase, NAD-dependent malate dehydrogenase, NADP-dependent decarboxylating malate dehydrogenase, NAD-dependent isocitrate dehydrogenase, and glucose- 6-phosphate dehydrogenase) is developed. The sensitivity of the method allows minimization of the volume of biological material for measurements to 104 neutrophils per analysis. The method is tried in patients with diffuse purulent peritonitis. Low levels of NADPH synthesis enzymes and high levels of enzymes determining the substrate flow by the Krebs cycle found in these patients can lead to attenuation of functional activity of cells. PMID:26468025

  14. Regulation of active site coupling in glutamine-dependent NAD[superscript +] synthetase

    SciTech Connect

    LaRonde-LeBlanc, Nicole; Resto, Melissa; Gerratana, Barbara

    2009-05-21

    NAD{sup +} is an essential metabolite both as a cofactor in energy metabolism and redox homeostasis and as a regulator of cellular processes. In contrast to humans, Mycobacterium tuberculosis NAD{sup +} biosynthesis is absolutely dependent on the activity of a multifunctional glutamine-dependent NAD{sup +} synthetase, which catalyzes the ATP-dependent formation of NAD{sup +} at the synthetase domain using ammonia derived from L-glutamine in the glutaminase domain. Here we report the kinetics and structural characterization of M. tuberculosis NAD{sup +} synthetase. The kinetics data strongly suggest tightly coupled regulation of the catalytic activities. The structure, the first of a glutamine-dependent NAD{sup +} synthetase, reveals a homooctameric subunit organization suggesting a tight dependence of catalysis on the quaternary structure, a 40-{angstrom} intersubunit ammonia tunnel and structural elements that may be involved in the transfer of information between catalytic sites.

  15. The cleaved cytoplasmic tail of polycystin-1 regulates Src-dependent STAT3 activation.

    PubMed

    Talbot, Jeffrey J; Song, Xuewen; Wang, Xiaofang; Rinschen, Markus M; Doerr, Nicholas; LaRiviere, Wells B; Schermer, Bernhard; Pei, York P; Torres, Vicente E; Weimbs, Thomas

    2014-08-01

    Polycystin-1 (PC1) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer and activator of transcription 3) was shown to be activated in cyst-lining cells in ADPKD and PKD mouse models and may drive renal cyst growth, but the mechanisms leading to persistent STAT3 activation are unknown. A proteolytic fragment of PC1 corresponding to the cytoplasmic tail, PC1-p30, is overexpressed in ADPKD. Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Src-dependent activation of STAT3 by tyrosine phosphorylation. The PC1-p30-mediated activation of Src/STAT3 was independent of JAK family kinases and insensitive to the STAT3 inhibitor suppressor of cytokine signaling 3. Signaling by the EGF receptor (EGFR) or cAMP amplified the activation of Src/STAT3 by PC1-p30. Expression of PC1-p30 changed the cellular response to cAMP signaling. In the absence of PC1-p30, cAMP dampened EGFR- or IL-6-dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src-dependent activation of STAT3. In the polycystic kidney (PCK) rat model, activation of STAT3 in renal cystic cells depended on vasopressin receptor 2 (V2R) signaling, which increased cAMP levels. Genetic inhibition of vasopressin expression or treatment with a pharmacologic V2R inhibitor strongly suppressed STAT3 activation and reduced renal cyst growth. These results suggest that PC1, via its cleaved cytoplasmic tail, integrates signaling inputs from EGFR and cAMP, resulting in Src-dependent activation of STAT3 and a proliferative response. PMID:24578126

  16. GATA Factor Regulation in Excess Nitrogen Occurs Independently of Gtr-Ego Complex-Dependent TorC1 Activation

    PubMed Central

    Tate, Jennifer J.; Georis, Isabelle; Rai, Rajendra; Vierendeels, Fabienne; Dubois, Evelyne; Cooper, Terrance G.

    2015-01-01

    The TorC1 protein kinase complex is a central component in a eukaryotic cell’s response to varying nitrogen availability, with kinase activity being stimulated in nitrogen excess by increased intracellular leucine. This leucine-dependent TorC1 activation requires functional Gtr1/2 and Ego1/3 complexes. Rapamycin inhibition of TorC1 elicits nuclear localization of Gln3, a GATA-family transcription activator responsible for the expression of genes encoding proteins required to transport and degrade poor nitrogen sources, e.g., proline. In nitrogen-replete conditions, Gln3 is cytoplasmic and Gln3-mediated transcription minimal, whereas in nitrogen limiting or starvation conditions, or after rapamycin treatment, Gln3 is nuclear and transcription greatly increased. Increasing evidence supports the idea that TorC1 activation may not be as central to nitrogen-responsive intracellular Gln3 localization as envisioned previously. To test this idea directly, we determined whether Gtr1/2- and Ego1/3-dependent TorC1 activation also was required for cytoplasmic Gln3 sequestration and repressed GATA factor-mediated transcription by abolishing the Gtr-Ego complex proteins. We show that Gln3 is sequestered in the cytoplasm of gtr1Δ, gtr2Δ, ego1Δ, and ego3Δ strains either long term in logarithmically glutamine-grown cells or short term after refeeding glutamine to nitrogen-limited or -starved cells; GATA factor−dependent transcription also was minimal. However, in all but a gtr1Δ, nuclear Gln3 localization in response to nitrogen limitation or starvation was adversely affected. Our data demonstrate: (i) Gtr-Ego-dependent TorC1 activation is not required for cytoplasmic Gln3 sequestration in nitrogen-rich conditions; (ii) a novel Gtr-Ego-TorC1 activation-independent mechanism sequesters Gln3 in the cytoplasm; (iii) Gtr and Ego complex proteins participate in nuclear Gln3-Myc13 localization, heretofore unrecognized functions for these proteins; and (iv) the importance of

  17. DREAM Controls the On/Off Switch of Specific Activity-Dependent Transcription Pathways

    PubMed Central

    Mellström, Britt; Sahún, Ignasi; Ruiz-Nuño, Ana; Murtra, Patricia; Gomez-Villafuertes, Rosa; Savignac, Magali; Oliveros, Juan C.; Gonzalez, Paz; Kastanauskaite, Asta; Knafo, Shira; Zhuo, Min; Higuera-Matas, Alejandro; Errington, Michael L.; Maldonado, Rafael; DeFelipe, Javier; Jefferys, John G. R.; Bliss, Tim V. P.; Dierssen, Mara

    2014-01-01

    Changes in nuclear Ca2+ homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K+ channel interacting protein 3), is a Ca2+-binding protein that binds DNA and represses transcription in a Ca2+-dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca2+-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Using genome-wide analysis, we show that DREAM regulates the expression of specific activity-dependent transcription factors in the hippocampus, including Npas4, Nr4a1, Mef2c, JunB, and c-Fos. Furthermore, DREAM regulates its own expression, establishing an autoinhibitory feedback loop to terminate activity-dependent transcription. Ablation of DREAM does not modify activity-dependent transcription because of gene compensation by the other KChIP family members. The expression of daDREAM in the forebrain resulted in a complex phenotype characterized by loss of recurrent inhibition and enhanced long-term potentiation (LTP) in the dentate gyrus and impaired learning and memory. Our results indicate that DREAM is a major master switch transcription factor that regulates the on/off status of specific activity-dependent gene expression programs that control synaptic plasticity, learning, and memory. PMID:24366545

  18. Nerve growth factor enhances the CRE-dependent transcriptional activity activated by nobiletin in PC12 cells.

    PubMed

    Takito, Jiro; Kimura, Junko; Kajima, Koji; Uozumi, Nobuyuki; Watanabe, Makoto; Yokosuka, Akihito; Mimaki, Yoshihiro; Nakamura, Masanori; Ohizumi, Yasushi

    2016-07-01

    Prevention and treatment of Alzheimer disease are urgent problems for elderly people in developed countries. We previously reported that nobiletin, a poly-methoxylated flavone from the citrus peel, improved the symptoms in various types of animal models of memory loss and activated the cAMP responsive element (CRE)-dependent transcription in PC12 cells. Nobiletin activated the cAMP/PKA/MEK/Erk/MAPK signaling pathway without using the TrkA signaling activated by nerve growth factor (NGF). Here, we examined the effect of combination of nobiletin and NGF on the CRE-dependent transcription in PC12 cells. Although NGF alone had little effect on the CRE-dependent transcription, NGF markedly enhanced the CRE-dependent transcription induced by nobiletin. The NGF-induced enhancement was neutralized by a TrkA antagonist, K252a. This effect of NGF was effective on the early signaling event elicited by nobiletin. These results suggested that there was crosstalk between NGF and nobiletin signaling in activating the CRE-dependent transcription in PC12 cells. PMID:27128150

  19. Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways.

    PubMed

    Hanno-Iijima, Yoko; Tanaka, Masami; Iijima, Takatoshi

    2015-01-01

    Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses. PMID:26241953

  20. Irofulven induces replication-dependent CHK2 activation related to p53 status1

    PubMed Central

    Wang, Yutian; Wiltshire, Timothy; Senft, Jamie; Reed, Eddie; Wang, Weixin

    2007-01-01

    CHK2 and p53 are frequently mutated in human cancers. CHK2 is known to phosphorylate and stabilize p53. CHK2 has also been implicated in DNA repair and apoptosis induction. However, whether p53 affects CHK2 activation and whether CHK2 activation modulates chemosensitivity are unclear. In this study, we found that in response to the DNA damage agent, irofulven, CHK2 activation, rather than its expression, is inversely correlated to p53 status. Irofulven inhibits DNA replication and induces chromosome aberrations (breaks and radials) and p53-dependent cell cycle arrest. Pretreatment of cells with the DNA polymerase inhibitor, aphidicolin, resulted in reduction of irofulven-induced CHK2 activation and foci formation, indicating that CHK2 activation by irofulven is replication-dependent. Furthermore, by using ovarian cancer cell lines expressing dominant-negative CHK2 and CHK2-knockout HCT116 cells, we found that CHK2 activation contributes to the control of S and G2/M cell cycle arrests, but not chemosensitivity to irofulven. Overall, this study demonstrates that in response to irofulven-induced DNA damage, the activation of CHK2 is dependent on DNA replication and related to p53 status. By controlling cell cycle arrest and DNA replication, p53 affects CHK2 activation. CHK2 activation contributes to cell cycle arrest, but not chemosensitivity. PMID:17118344

  1. Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory.

    PubMed

    Doll, Caleb A; Broadie, Kendal

    2015-04-01

    The activity-dependent refinement of neural circuit connectivity during critical periods of brain development is essential for optimized behavioral performance. We hypothesize that this mechanism is defective in fragile X syndrome (FXS), the leading heritable cause of intellectual disability and autism spectrum disorders. Here, we use optogenetic tools in the Drosophila FXS disease model to test activity-dependent dendritogenesis in two extrinsic neurons of the mushroom body (MB) learning and memory brain center: (1) the input projection neuron (PN) innervating Kenyon cells (KCs) in the MB calyx microglomeruli and (2) the output MVP2 neuron innervated by KCs in the MB peduncle. Both input and output neuron classes exhibit distinctive activity-dependent critical period dendritic remodeling. MVP2 arbors expand in Drosophila mutants null for fragile X mental retardation 1 (dfmr1), as well as following channelrhodopsin-driven depolarization during critical period development, but are reduced by halorhodopsin-driven hyperpolarization. Optogenetic manipulation of PNs causes the opposite outcome--reduced dendritic arbors following channelrhodopsin depolarization and expanded arbors following halorhodopsin hyperpolarization during development. Importantly, activity-dependent dendritogenesis in both neuron classes absolutely requires dfmr1 during one developmental window. These results show that dfmr1 acts in a neuron type-specific activity-dependent manner for sculpting dendritic arbors during early-use, critical period development of learning and memory circuitry in the Drosophila brain. PMID:25804740

  2. Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory

    PubMed Central

    Doll, Caleb A.; Broadie, Kendal

    2015-01-01

    The activity-dependent refinement of neural circuit connectivity during critical periods of brain development is essential for optimized behavioral performance. We hypothesize that this mechanism is defective in fragile X syndrome (FXS), the leading heritable cause of intellectual disability and autism spectrum disorders. Here, we use optogenetic tools in the Drosophila FXS disease model to test activity-dependent dendritogenesis in two extrinsic neurons of the mushroom body (MB) learning and memory brain center: (1) the input projection neuron (PN) innervating Kenyon cells (KCs) in the MB calyx microglomeruli and (2) the output MVP2 neuron innervated by KCs in the MB peduncle. Both input and output neuron classes exhibit distinctive activity-dependent critical period dendritic remodeling. MVP2 arbors expand in Drosophila mutants null for fragile X mental retardation 1 (dfmr1), as well as following channelrhodopsin-driven depolarization during critical period development, but are reduced by halorhodopsin-driven hyperpolarization. Optogenetic manipulation of PNs causes the opposite outcome – reduced dendritic arbors following channelrhodopsin depolarization and expanded arbors following halorhodopsin hyperpolarization during development. Importantly, activity-dependent dendritogenesis in both neuron classes absolutely requires dfmr1 during one developmental window. These results show that dfmr1 acts in a neuron type-specific activity-dependent manner for sculpting dendritic arbors during early-use, critical period development of learning and memory circuitry in the Drosophila brain. PMID:25804740

  3. SHP-2 phosphatase activity is required for PECAM-1-dependent cell motility.

    PubMed

    Zhu, Jing-Xu; Cao, Gaoyuan; Williams, James T; Delisser, Horace M

    2010-10-01

    Platelet endothelial cell adhesion molecule-1 (PECAM-1) has been implicated in endothelial cell motility during angiogenesis. Although there is evidence that SHP-2 plays a role in PECAM-1-dependent cell motility, the molecular basis of the activity of SHP-2 in this process has not been defined. To investigate the requirement of SHP-2 in PECAM-1-dependent cell motility, studies were done in which various constructs of SHP-2 were expressed in cell transfectants expressing PECAM-1. We observed that the levels of PECAM-1 tyrosine phosphorylation and SHP-2 association with PECAM-1 were significantly increased in cells expressing a phosphatase-inactive SHP-2 mutant, suggesting that the level of PECAM-1 tyrosine phosphorylation, and thus SHP-2 binding are regulated in part by bound, catalytically active SHP-2. We subsequently found that expression of PECAM-1 stimulated wound-induced migration and the formation of filopodia (a morphological feature of motile cells). These activities were associated with increased mitogen-activated protein kinase (MAPK) activation and the dephosphorylation of paxillin (an event implicated in the activation of MAPK). The phosphatase-inactive SHP-2 mutant, however, suppressed these PECAM-1-dependent phenomena, whereas the activity of PECAM-1 expressing cells was not altered by expression of wild-type SHP-2 or SHP-2 in which the scaffold/adaptor function had been disabled. Pharmacological inhibition of SHP-2 phosphatase activity also suppressed PECAM-1-dependent motility. Furthermore, PECAM-1 expression also stimulates tube formation, but none of the SHP-2 constructs affected this process. These findings therefore suggest a model for the involvement of SHP-2 in PECAM-1-dependent motility in which SHP-2, recruited by its interaction with PECAM-1, targets paxillin to ultimately activate the MAPK pathway and downstream events required for cell motility. PMID:20631249

  4. Dietary sugar promotes systemic TOR activation in Drosophila through AKH-dependent selective secretion of Dilp3

    PubMed Central

    Kim, Jung; Neufeld, Thomas P.

    2015-01-01

    Secreted ligands of the insulin family promote cell growth and maintain sugar homeostasis. Insulin release is tightly regulated in response to dietary conditions, but how insulin producing cells (IPCs) coordinate their responses to distinct nutrient signals is unclear. Here, we show that regulation of insulin secretion in Drosophila larvae has been segregated into distinct branches: whereas amino acids promote secretion of Drosophila insulin-like peptide 2 (Dilp2), circulating sugars promote selective release of Dilp3. Dilp3 is uniquely required for sugar-mediated activation of TOR signaling and suppression of autophagy in the larval fat body. Sugar levels are not sensed directly by the IPCs, but rather by the adipokinetic hormone (AKH)-producing cells of the corpora cardiaca, and we demonstrate that AKH signaling is required in the IPCs for sugar-dependent Dilp3 release. Thus, IPCs integrate multiple cues to regulate secretion of distinct insulin subtypes under varying nutrient conditions. PMID:25882208

  5. Osthole inhibits histamine-dependent itch via modulating TRPV1 activity

    PubMed Central

    Yang, Niu-Niu; Shi, Hao; Yu, Guang; Wang, Chang-Ming; Zhu, Chan; Yang, Yan; Yuan, Xiao-Lin; Tang, Min; Wang, Zhong-li; Gegen, Tana; He, Qian; Tang, Kehua; Lan, Lei; Wu, Guan-Yi; Tang, Zong-Xiang

    2016-01-01

    Osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson, has long been used in China as an antipruritic herbal medicine; however, the antipruitic mechanism of osthole is unknown. We studied the molecular mechanism of osthole in histamine-dependent itch by behavioral test, Ca2+ imaging, and electrophysiological experiments. First, osthole clearly remitted the scratching behaviors of mice induced with histamine, HTMT, and VUF8430. Second, in cultured dorsal root ganglion (DRG) neurons, osthole showed a dose-dependent inhibitory effect to histamine. On the same neurons, osthole also decreased the response to capsaicin and histamine. In further tests, the capsaicin-induced inward currents were inhibited by osthole. These results revealed that osthole inhibited histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how osthole exerts anti-pruritus effects and suggests that osthole may be a useful treatment medicine for histamine-dependent itch. PMID:27160770

  6. ENVIRONMENTAL DEPENDENCE OF OTHER GALAXY PROPERTIES FOR THE SAME STAR FORMATION ACTIVITIES

    SciTech Connect

    Deng Xinfa; Bei Yang; He Jizhou; Tang Xiaoxun

    2010-01-01

    Using two volume-limited Main galaxy samples of the Sloan Digital Sky Survey Data Release 6 above and below the value of M*, we have investigated the environmental dependence of other galaxy properties for the same star formation activities. Only in the luminous passive class, a strong environmental dependence of the g - r color is observed, but the environmental dependence of other properties in this class is very weak. In other classes, we can conclude that the local density dependence of luminosity, g - r color, concentration index ci, and morphologies for star-forming galaxies and passive ones is much weaker than that obtained in the volume-limited Main galaxy samples. This suggests that star formation activity is a galaxy property very predictive of the local environment. In addition, we also note that passive galaxies are more luminous, redder, highly concentrated, and preferentially 'early type'.

  7. Osthole inhibits histamine-dependent itch via modulating TRPV1 activity.

    PubMed

    Yang, Niu-Niu; Shi, Hao; Yu, Guang; Wang, Chang-Ming; Zhu, Chan; Yang, Yan; Yuan, Xiao-Lin; Tang, Min; Wang, Zhong-Li; Gegen, Tana; He, Qian; Tang, Kehua; Lan, Lei; Wu, Guan-Yi; Tang, Zong-Xiang

    2016-01-01

    Osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson, has long been used in China as an antipruritic herbal medicine; however, the antipruitic mechanism of osthole is unknown. We studied the molecular mechanism of osthole in histamine-dependent itch by behavioral test, Ca(2+) imaging, and electrophysiological experiments. First, osthole clearly remitted the scratching behaviors of mice induced with histamine, HTMT, and VUF8430. Second, in cultured dorsal root ganglion (DRG) neurons, osthole showed a dose-dependent inhibitory effect to histamine. On the same neurons, osthole also decreased the response to capsaicin and histamine. In further tests, the capsaicin-induced inward currents were inhibited by osthole. These results revealed that osthole inhibited histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how osthole exerts anti-pruritus effects and suggests that osthole may be a useful treatment medicine for histamine-dependent itch. PMID:27160770

  8. A new era for functional labeling of neurons: activity-dependent promoters have come of age.

    PubMed

    Kawashima, Takashi; Okuno, Hiroyuki; Bito, Haruhiko

    2014-01-01

    Genetic labeling of neurons with a specific response feature is an emerging technology for precise dissection of brain circuits that are functionally heterogeneous at the single-cell level. While immediate early gene mapping has been widely used for decades to identify brain regions which are activated by external stimuli, recent characterization of the promoter and enhancer elements responsible for neuronal activity-dependent transcription have opened new avenues for live imaging of active neurons. Indeed, these advancements provided the basis for a growing repertoire of novel experiments to address the role of active neuronal networks in cognitive behaviors. In this review, we summarize the current literature on the usage and development of activity-dependent promoters and discuss the future directions of this expanding new field. PMID:24795570

  9. A new era for functional labeling of neurons: activity-dependent promoters have come of age

    PubMed Central

    Kawashima, Takashi; Okuno, Hiroyuki; Bito, Haruhiko

    2014-01-01

    Genetic labeling of neurons with a specific response feature is an emerging technology for precise dissection of brain circuits that are functionally heterogeneous at the single-cell level. While immediate early gene mapping has been widely used for decades to identify brain regions which are activated by external stimuli, recent characterization of the promoter and enhancer elements responsible for neuronal activity-dependent transcription have opened new avenues for live imaging of active neurons. Indeed, these advancements provided the basis for a growing repertoire of novel experiments to address the role of active neuronal networks in cognitive behaviors. In this review, we summarize the current literature on the usage and development of activity-dependent promoters and discuss the future directions of this expanding new field. PMID:24795570

  10. Non-Cell-Autonomous Mechanism of Activity-Dependent Neurotransmitter Switching

    PubMed Central

    Guemez-Gamboa, Alicia; Xu, Lin; Meng, Da; Spitzer, Nicholas C.

    2014-01-01

    SUMMARY Activity-dependent neurotransmitter switching engages genetic programs regulating transmitter synthesis but the mechanism by which activity is transduced is unknown. We suppressed activity in single neurons in the embryonic spinal cord to determine whether glutamate-GABA switching is cell-autonomous. Transmitter respecification did not occur, suggesting that it is homeostatically regulated by the level of activity in surrounding neurons. Graded increase in the number of silenced neurons in cultures led to graded decrease in the number of neurons expressing GABA, supporting non-cell-autonomous transmitter switching. We found that BDNF is expressed in the spinal cord during the period of transmitter respecification and that spike activity causes release of BDNF. Activation of TrkB receptors triggers a signaling cascade involving JNK-mediated activation of cJun that regulates tlx3, a glutamate/GABA selector gene, accounting for calcium-spike-BDNF-dependent transmitter switching. Our findings identify a molecular mechanism for activity-dependent respecification of neurotransmitter phenotype in developing spinal neurons. PMID:24908484

  11. Dense small molecule labeling enables activator-dependent STORM by proximity mapping.

    PubMed

    Chen, Ye; Gu, Min; Gunning, Peter W; Russell, Sarah M

    2016-09-01

    Stochastic optical reconstruction microscopy (STORM) enables high-resolution imaging, but multi-channel 3D imaging is problematic because of chromatic aberrations and alignment errors. The use of activator-dependent STORM in which spectrally distinct activators can be coupled with a single reporter can circumvent such issues. However, the standard approach of linking activators and reporters to a single antibody molecule is hampered by low labeling density and the large size of the antibody. We proposed that small molecule labels might enable activator-dependent STORM if the reporter or activator were linked to separate small molecules that bound within 3.5 nm of each other. This would greatly increase the labeling density and therefore improve resolution. We tested various mixtures of phalloidin- or mCling-conjugated fluorophore to demonstrate this feasibility. The specific activation was dependent on the choice of activator, its density, a matching activating laser and its power. In addition to providing an effective means of multi-channel 3D STORM imaging, this method also provides information about the local proximity between labels, potentially enabling super-resolved mapping of the conformation of the labeled structures. PMID:27246003

  12. HIPK2 kinase activity depends on cis-autophosphorylation of its activation loop.

    PubMed

    Saul, Vera V; de la Vega, Laureano; Milanovic, Maja; Krüger, Marcus; Braun, Thomas; Fritz-Wolf, Karin; Becker, Katja; Schmitz, M Lienhard

    2013-02-01

    The multitude of mechanisms regulating the activity of protein kinases includes phosphorylation of amino acids contained in the activation loop. Here we show that the serine/threonine kinase HIPK2 (homeodomain-interacting protein kinase 2) is heavily modified by autophosphorylation, which occurs by cis-autophosphorylation at the activation loop and by trans-autophosphorylation at other phosphorylation sites. Cis-autophosphorylation of HIPK2 at Y354 and S357 in the activation loop is essential for its kinase function and the binding to substrates and the interaction partner Pin1. HIPK2 activation loop phosphorylation is also required for its biological activity as a regulator of gene expression and cell proliferation. Phosphorylation of HIPK2 at Y354 alone is not sufficient for full HIPK2 activity, which is in marked contrast to some dual-specificity tyrosine-phosphorylated and regulated kinases where tyrosine phosphorylation is absolutely essential. This study shows that differential phosphorylation of HIPK2 provides a mechanism for controlling and specifying the signal output from this kinase. PMID:23000554

  13. Varying constants quantum cosmology

    SciTech Connect

    Leszczyńska, Katarzyna; Balcerzak, Adam; Dabrowski, Mariusz P. E-mail: abalcerz@wmf.univ.szczecin.pl

    2015-02-01

    We discuss minisuperspace models within the framework of varying physical constants theories including Λ-term. In particular, we consider the varying speed of light (VSL) theory and varying gravitational constant theory (VG) using the specific ansätze for the variability of constants: c(a) = c{sub 0} a{sup n} and G(a)=G{sub 0} a{sup q}. We find that most of the varying c and G minisuperspace potentials are of the tunneling type which allows to use WKB approximation of quantum mechanics. Using this method we show that the probability of tunneling of the universe ''from nothing'' (a=0) to a Friedmann geometry with the scale factor a{sub t} is large for growing c models and is strongly suppressed for diminishing c models. As for G varying, the probability of tunneling is large for G diminishing, while it is small for G increasing. In general, both varying c and G change the probability of tunneling in comparison to the standard matter content (cosmological term, dust, radiation) universe models.

  14. Quantitative manganese tract tracing: dose-dependent and activity-independent terminal labelling in the mouse visual system.

    PubMed

    Lowe, Andrew S; Thompson, Ian D; Sibson, Nicola R

    2008-10-01

    At concentrations sufficient for visualisation using MRI, manganese (Mn) is believed to behave as a calcium analogue. This study examines different concentrations of Mn for enhanced MR tract tracing. The premise of activity-dependent axonal transport was also examined by partial or complete blockade of retinal ganglion cell activity. Quantitative T(1) maps and semi-quantitative normalised signal intensities in the superior colliculi facilitated assessment of applied intraocular concentrations and activity dependence, respectively. Varying the concentration of applied Mn revealed a non-monotonic profile, with optimal, unfavourable and undesirable effects noted: 25 mM proved optimal, showing a maximal decrease in T(1), whereas 400 mM was associated with no terminal-field enhancement. The estimated vitreal concentration for optimal transport of Mn (2 mM) is substantially lower than that used in previous studies of the mouse. Both the partial blockade of inputs to 50% of retinal ganglion cells by a mGluR6 glutamate agonist and the complete blockade of all retinal ganglion cell activity with tetrodotoxin failed to decrease the relative enhancement in the superior colliculus. The failure to prevent axonal transport of Mn by blocking activity (and therefore theoretically the intracellular influx) appeared to be paradoxical. The optimal vitreal concentration of Mn has previously been shown to facilitate massive intracellular uptake of Mn, competitively blocking calcium, and 1 mM Mn blocks neurotransmission pre-synaptically. These results suggest that, at concentrations required for optimal Mn-enhanced MRI tract tracing in the visual system of the mouse, the uptake and transport of Mn may be dominated by passive mechanisms, which may also block neurotransmission. PMID:18613265

  15. Glucocorticoids activate the ATP-ubiquitin-dependent proteolytic system in skeletal muscle during fasting

    NASA Technical Reports Server (NTRS)

    Wing, S. S.; Goldberg, A. L.; Goldberger, A. L. (Principal Investigator)

    1993-01-01

    Glucocorticoids are essential for the increase in protein breakdown in skeletal muscle normally seen during fasting. To determine which proteolytic pathway(s) are activated upon fasting, leg muscles from fed and fasted normal rats were incubated under conditions that block or activate different proteolytic systems. After food deprivation (1 day), the nonlysosomal ATP-dependent process increased by 250%, as shown in experiments involving depletion of muscle ATP. Also, the maximal capacity of the lysosomal process increased 60-100%, but no changes occurred in the Ca(2+)-dependent or the residual energy-independent proteolytic processes. In muscles from fasted normal and adrenalectomized (ADX) rats, the protein breakdown sensitive to inhibitors of the lysosomal or Ca(2+)-dependent pathways did not differ. However, the ATP-dependent process was 30% slower in muscles from fasted ADX rats. Administering dexamethasone to these animals or incubating their muscles with dexamethasone reversed this defect. During fasting, when the ATP-dependent process rises, muscles show a two- to threefold increase in levels of ubiquitin (Ub) mRNA. However, muscles of ADX animals failed to show this response. Injecting dexamethasone into the fasted ADX animals increased muscle Ub mRNA within 6 h. Thus glucocorticoids activate the ATP-Ub-dependent proteolytic pathway in fasting apparently by enhancing the expression of components of this system such as Ub.

  16. Activity-dependent upregulation of presynaptic kainate receptors at immature CA3-CA1 synapses.

    PubMed

    Clarke, Vernon R J; Molchanova, Svetlana M; Hirvonen, Teemu; Taira, Tomi; Lauri, Sari E

    2014-12-10

    Presynaptic kainate-type glutamate receptors (KARs) regulate glutamate release probability and short-term plasticity in various areas of the brain. Here we show that long-term depression (LTD) in the area CA1 of neonatal rodent hippocampus is associated with an upregulation of tonic inhibitory KAR activity, which contributes to synaptic depression and causes a pronounced increase in short-term facilitation of transmission. This increased KAR function was mediated by high-affinity receptors and required activation of NMDA receptors, nitric oxide (NO) synthetase, and postsynaptic calcium signaling. In contrast, KAR activity was irreversibly downregulated in response to induction of long-term potentiation in a manner that depended on activation of the TrkB-receptor of BDNF. Both tonic KAR activity and its plasticity were restricted to early stages of synapse development and were lost in parallel with maturation of the network due to ongoing BDNF-TrkB signaling. These data show that presynaptic KARs are targets for activity-dependent modulation via diffusible messengers NO and BDNF, which enhance and depress tonic KAR activity at immature synapses, respectively. The plasticity of presynaptic KARs in the developing network allows nascent synapses to shape their response to incoming activity. In particular, upregulation of KAR function after LTD allows the synapse to preferentially pass high-frequency afferent activity. This can provide a potential rescue from synapse elimination by uncorrelated activity and also increase the computational dynamics of the developing CA3-CA1 circuitry. PMID:25505341

  17. Dependence of Quiet Time Geomagnetic Activity Seasonal Variation on the Solar Magnetic Polarity

    NASA Astrophysics Data System (ADS)

    Oh, Suyeon

    2013-03-01

    The geomagnetic activity shows the semiannual variation stronger in vernal and autumnal equinoxes than in summer and winter solstices. The semiannual variation has been explained by three main hypotheses such as Axial hypothesis, Equinoctial hypothesis, and Russell-McPherron Effect. Many studies using the various geomagnetic indices have done to support three main hypotheses. In recent, Oh & Yi (2011) examined the solar magnetic polarity dependency of the geomagnetic storm occurrence defined by Dst index. They reported that there is no dependency of the semiannual variation on the sign of the solar polar fields. This study examines the solar magnetic polarity dependency of quiet time geomagnetic activity. Using Dxt index (Karinen & Mursula 2005) and Dcx index (Mursula & Karinen 2005) which are recently suggested, in addition to Dst index, we analyze the data of three-year at each solar minimum for eight solar cycles since 1932. As a result, the geomagnetic activity is stronger in the period that the solar magnetic polarity is anti-parallel with the Earth's magnetic polarity. There exists the difference between vernal and autumnal equinoxes regarding the solar magnetic polarity dependency. However, the difference is not statistically significant. Thus, we conclude that there is no solar magnetic polarity dependency of the semiannual variation for quiet time geomagnetic activity.

  18. Isolation of an activator-dependent, promoter-specific chromatin remodeling factor

    PubMed Central

    Ehrensberger, Andreas H.; Kornberg, Roger D.

    2011-01-01

    Repressed PHO5 gene chromatin, isolated from yeast in the native state, was remodeled by yeast extract in a gene activator-dependent, ATP-dependent manner. The product of the reaction bore the hallmark of the process in vivo, the selective removal of promoter nucleosomes, without effect on open reading frame nucleosomes. Fractionation of the extract identified a single protein, chromodomain helicase DNA binding protein 1 (Chd1), capable of the remodeling activity. Deletion of the CHD1 gene in an isw1Δ pho80Δ strain abolished PHO5 gene expression, demonstrating the relevance of the remodeling reaction in vitro to the process in vivo. PMID:21646535

  19. Isolation of an activator-dependent, promoter-specific chromatin remodeling factor.

    PubMed

    Ehrensberger, Andreas H; Kornberg, Roger D

    2011-06-21

    Repressed PHO5 gene chromatin, isolated from yeast in the native state, was remodeled by yeast extract in a gene activator-dependent, ATP-dependent manner. The product of the reaction bore the hallmark of the process in vivo, the selective removal of promoter nucleosomes, without effect on open reading frame nucleosomes. Fractionation of the extract identified a single protein, chromodomain helicase DNA binding protein 1 (Chd1), capable of the remodeling activity. Deletion of the CHD1 gene in an isw1Δ pho80Δ strain abolished PHO5 gene expression, demonstrating the relevance of the remodeling reaction in vitro to the process in vivo. PMID:21646535

  20. Restorative Care’s Effect on Activities of Daily Living Dependency in Long-stay Nursing Home Residents

    PubMed Central

    Talley, Kristine M. C.; Wyman, Jean F.; Savik, Kay; Kane, Robert L.; Mueller, Christine; Zhao, Hong

    2015-01-01

    Purpose of the Study: (a) Identify the prevalence of nursing homes providing Medicare supported restorative care programs and of long stay participants, (b) compare characteristics between restorative care participants and nonparticipants, and (c) assess restorative care’s effect on change in activities of daily living (ADL) dependency. Design and Methods: Longitudinal analysis of Minimum Data Set assessments linked to the 2004 National Nursing Home Survey using a sample of 7,735 residents, age ≥ 65 years living in 1,097 nursing homes for at least 6 months. Receipt of any restorative care was used as a time varying predictor to estimate change in ADL dependency over 18 months using linear mixed models. Results: The sample was 75% female, 89% non-Hispanic White, with a mean age of 85±8, and average length of stay of 3.2±3.4 years. Most nursing homes had restorative care programs (67%), but less than one-third of long-stay residents participated. After controlling for resident and nursing home characteristics, the predicted mean ADL dependency score (range 0–28) at baseline was 18 for restorative care participants and 14 for nonparticipants. Over 18 months, ADL dependency increased 1 point for both participants and nonparticipants (p = .12). Implications: A minority of long-stay residents participated in Medicare supported restorative care programs despite their availability and potential benefits. Even though participants had greater vulnerability for deterioration in physical, mental, and functional health than nonparticipants, both groups had similar rates of ADL decline. Future research is needed to determine if providing restorative care to less dependent long-stay residents is effective. PMID:26055785

  1. Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKKβ-dependent AMPK activation.

    PubMed

    Xu, Yuan; Xu, Yazhou; Wang, Yurong; Wang, Yunjie; He, Ling; Jiang, Zhenzhou; Huang, Zhangjian; Liao, Hong; Li, Jia; Saavedra, Juan M; Zhang, Luyong; Pang, Tao

    2015-11-01

    Brain inflammation plays an important role in the pathophysiology of many psychiatric and neurological diseases. During brain inflammation, microglia cells are activated, producing neurotoxic molecules and neurotrophic factors depending on their pro-inflammatory M1 and anti-inflammatory M2 phenotypes. It has been demonstrated that Angiotensin II type 1 receptor blockers (ARBs) ameliorate brain inflammation and reduce M1 microglia activation. The ARB telmisartan suppresses glutamate-induced upregulation of inflammatory genes in cultured primary neurons. We wished to clarify whether telmisartan, in addition, prevents microglia activation through polarization to an anti-inflammatory M2 phenotype. We found that telmisartan promoted M2 polarization and reduced M1 polarization in LPS-stimulated BV2 and primary microglia cells, effects partially dependent on PPARγ activation. The promoting effects of telmisartan on M2 polarization, were attenuated by an AMP-activated protein kinase (AMPK) inhibitor or AMPK knockdown, indicating that AMPK activation participates on telmisartan effects. Moreover, in LPS-stimulated BV2 cells, telmisartan enhancement of M2 gene expression was prevented by the inhibitor STO-609 and siRNA of calmodulin-dependent protein kinase kinase β (CaMKKβ), an upstream kinase of AMPK. Furthermore, telmisartan enhanced brain AMPK activation and M2 gene expression in a mouse model of LPS-induced neuroinflammation. In addition, telmisartan reduced the LPS-induced sickness behavior in this in vivo model, and this effect was prevented by prior administration of an AMPK inhibitor. Our results indicate that telmisartan can be considered as a novel AMPK activator, suppressing microglia activation by promoting M2 polarization. Telmisartan may provide a novel, safe therapeutic approach to treat brain disorders associated with enhanced inflammation. PMID:26188187

  2. FEF-microstimulation causes task-dependent modulation of occipital fMRI activity.

    PubMed

    Premereur, Elsie; Janssen, Peter; Vanduffel, Wim

    2013-02-15

    Electrical microstimulation of FEF (FEF-EM) modulates neuronal activity in area V4 (Moore and Armstrong, 2003) and elicits functional magnetic resonance imaging (fMRI) activations in visual cortex in a bottom-up dependent manner (Ekstrom et al., 2008). Here we test the hypothesis that FEF-EM-induced modulations of fMRI activity are also function of task demands, which would suggest top-down dependent gating of FEF signals in early visual cortex. We scanned two monkeys performing a visually guided saccade task; a passive fixation task with a very similar visual display; and a passive fixation task without peripheral dots. We found increased effects of FEF-EM on fMRI-activity in visual cortex during saccades compared to fixation, indicating that the FEF-EM induced modulation is task-dependent. Finally, the effect of FEF-EM is mainly present in voxels which were less activated by visual stimuli in the absence of electrical stimulation. Our results show that the FEF-EM-induced pattern of activation in early visual cortex is topographically specific and more pronounced during increased task demands. These results fit with models suggesting that FEF is an important source modulating activity in early sensory cortex and that these influences can be enhanced by coincident bottom-up or top-down signals. PMID:23186918

  3. Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin

    PubMed Central

    Wong, Yu-Hui; Lee, Chia-Ming; Xie, Wenjun; Cui, Bianxiao; Poo, Mu-ming

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) is known to modulate synapse development and plasticity, but the source of synaptic BDNF and molecular mechanisms regulating BDNF release remain unclear. Using exogenous BDNF tagged with quantum dots (BDNF-QDs), we found that endocytosed BDNF-QDs were preferentially localized to postsynaptic sites in the dendrite of cultured hippocampal neurons. Repetitive neuronal spiking induced the release of BDNF-QDs at these sites, and this process required activation of glutamate receptors. Down-regulating complexin 1/2 (Cpx1/2) expression eliminated activity-induced BDNF-QD secretion, although the overall activity-independent secretion was elevated. Among eight synaptotagmin (Syt) isoforms examined, down-regulation of only Syt6 impaired activity-induced BDNF-QD secretion. In contrast, activity-induced release of endogenously synthesized BDNF did not depend on Syt6. Thus, neuronal activity could trigger the release of endosomal BDNF from postsynaptic dendrites in a Cpx- and Syt6-dependent manner, and endosomes containing BDNF may serve as a source of BDNF for activity-dependent synaptic modulation. PMID:26216953

  4. Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin.

    PubMed

    Wong, Yu-Hui; Lee, Chia-Ming; Xie, Wenjun; Cui, Bianxiao; Poo, Mu-ming

    2015-08-11

    Brain-derived neurotrophic factor (BDNF) is known to modulate synapse development and plasticity, but the source of synaptic BDNF and molecular mechanisms regulating BDNF release remain unclear. Using exogenous BDNF tagged with quantum dots (BDNF-QDs), we found that endocytosed BDNF-QDs were preferentially localized to postsynaptic sites in the dendrite of cultured hippocampal neurons. Repetitive neuronal spiking induced the release of BDNF-QDs at these sites, and this process required activation of glutamate receptors. Down-regulating complexin 1/2 (Cpx1/2) expression eliminated activity-induced BDNF-QD secretion, although the overall activity-independent secretion was elevated. Among eight synaptotagmin (Syt) isoforms examined, down-regulation of only Syt6 impaired activity-induced BDNF-QD secretion. In contrast, activity-induced release of endogenously synthesized BDNF did not depend on Syt6. Thus, neuronal activity could trigger the release of endosomal BDNF from postsynaptic dendrites in a Cpx- and Syt6-dependent manner, and endosomes containing BDNF may serve as a source of BDNF for activity-dependent synaptic modulation. PMID:26216953

  5. Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors.

    PubMed

    Mu, Yuanyue; Otsuka, Takeshi; Horton, April C; Scott, Derek B; Ehlers, Michael D

    2003-10-30

    Activity-dependent targeting of NMDA receptors (NMDARs) is a key feature of synapse formation and plasticity. Although mechanisms for rapid trafficking of glutamate receptors have been identified, the molecular events underlying chronic accumulation or loss of synaptic NMDARs have remained unclear. Here we demonstrate that activity controls NMDAR synaptic accumulation by regulating forward trafficking at the endoplasmic reticulum (ER). ER export is accelerated by the alternatively spliced C2' domain of the NR1 subunit and slowed by the C2 splice cassette. This mRNA splicing event at the C2/C2' site is activity dependent, with C2' variants predominating upon activity blockade and C2 variants abundant with increased activity. The switch to C2' accelerates NMDAR forward trafficking by enhancing recruitment of nascent NMDARs to ER exit sites via binding of a divaline motif within C2' to COPII coats. These results define a novel pathway underlying activity-dependent targeting of glutamate receptors, providing an unexpected mechanistic link between activity, mRNA splicing, and membrane trafficking during excitatory synapse modification. PMID:14642281

  6. Human chorionic gonadotropin: Different glycoforms and biological activity depending on its source of production.

    PubMed

    Fournier, Thierry

    2016-06-01

    and hCG-H might represent a serum marker of implantation and early trophoblast invasion. In conclusion, hCG is the major pregnancy glycoprotein hormone, whose maternal concentration and glycan structure change all along pregnancy. Depending on its source of production, glycoforms of hCG display different biological activities and functions that are essential for pregnancy outcome. PMID:27177499

  7. Orally Active Metabotropic Glutamate Subtype 2 Receptor Positive Allosteric Modulators: Structure-Activity Relationships and Assessment in a Rat Model of Nicotine Dependence

    PubMed Central

    Sidique, Shyama; Dhanya, Raveendra-Panickar; Sheffler, Douglas J.; Nickols, Hilary Highfield; Yang, Li; Dahl, Russell; Mangravita-Novo, Arianna; Smith, Layton H.; D’Souza, Manoranjan S.; Semenova, Svetlana; Conn, P. Jeffrey; Markou, Athina; Cosford, Nicholas D. P.

    2012-01-01

    Compounds that modulate metabotropic glutamate subtype 2 (mGlu2) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu2 receptor positive allosteric modulators (PAMs). The effects of N-substitution (R1) and substitutions on the aryl ring (R2) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu2 receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans. PMID:23009245

  8. Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation.

    PubMed

    Schwalm, Céline; Jamart, Cécile; Benoit, Nicolas; Naslain, Damien; Prémont, Christophe; Prévet, Jérémy; Van Thienen, Ruud; Deldicque, Louise; Francaux, Marc

    2015-08-01

    In humans, nutrient deprivation and extreme endurance exercise both activate autophagy. We hypothesized that cumulating fasting and cycling exercise would potentiate activation of autophagy in skeletal muscle. Well-trained athletes were divided into control (n = 8), low-intensity (LI, n = 8), and high-intensity (HI, n = 7) exercise groups and submitted to fed and fasting sessions. Muscle biopsy samples were obtained from the vastus lateralis before, at the end, and 1 h after a 2 h LI or HI bout of exercise. Phosphorylation of ULK1(Ser317) was higher after exercise (P < 0.001). In both the fed and the fasted states, LC3bII protein level and LC3bII/I were decreased after LI and HI (P < 0.05), while p62/SQSTM1 was decreased only 1 h after HI (P < 0.05), indicating an increased autophagic flux after HI. The autophagic transcriptional program was also activated, as evidenced by the increased level of LC3b, p62/SQSTM1, GabarapL1, and Cathepsin L mRNAs observed after HI but not after LI. The increased autophagic flux after HI exercise could be due to increased AMP-activated protein kinase α (AMPKα) activity, as both AMPKα(Thr172) and ACC(Ser79) had a higher phosphorylation state after HI (P < 0.001). In summary, the most effective strategy to activate autophagy in human skeletal muscle seems to rely on exercise intensity more than diet. PMID:25957282

  9. Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys.

    PubMed

    Negus, S S; Mello, N K; Blough, B E; Baumann, M H; Rothman, R B

    2007-02-01

    Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine- and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse

  10. The functional subunit of a dimeric transcription activator protein depends on promoter architecture.

    PubMed Central

    Zhou, Y; Pendergrast, P S; Bell, A; Williams, R; Busby, S; Ebright, R H

    1994-01-01

    In Class I CAP-dependent promoters, the DNA site for CAP is located upstream of the DNA site for RNA polymerase. In Class II CAP-dependent promoters, the DNA site for CAP overlaps the DNA site for RNA polymerase, replacing the -35 site. We have used an 'oriented heterodimers' approach to identify the functional subunit of CAP at two Class I promoters having different distances between the DNA sites for CAP and RNA polymerase [CC(-61.5) and CC(-72.5)] and at one Class II promoter [CC(-41.5)]. Our results indicate that transcription activation at Class I promoters, irrespective of the distance between the DNA sites for CAP and RNA polymerase, requires the activating region of the promoter-proximal subunit of CAP. In striking contrast, our results indicate that transcription activation at Class II promoters requires the activating region of the promoter-distal subunit of CAP. Images PMID:7925296

  11. Exploiting Innate Immune Cell Activation of a Copper-Dependent Antimicrobial Agent during Infection

    PubMed Central

    Festa, Richard A.; Helsel, Marian E.; Franz, Katherine J.; Thiele, Dennis J.

    2014-01-01

    SUMMARY Recalcitrant microbial infections demand new therapeutic options. Here we present an approach that exploits two prongs of the host immune cell antimicrobial response: the oxidative burst and the compartmentalization of copper (Cu) within phagolysosomes. The prochelator QBP is a nontoxic protected form of 8-hydroxyquinoline (8HQ) in which a pinanediol boronic ester blocks metal ion coordination by 8HQ. QBP is deprotected via reactive oxygen species produced by activated macrophages, creating 8HQ and eliciting Cu-dependent killing of the fungal pathogen Cryptococcus neoformans in vitro and in mouse pulmonary infection. 8HQ ionophoric activity increases intracellular Cu, overwhelming the Cu-resistance mechanisms of C. neoformans to elicit fungal killing. The Cu-dependent antimicrobial activity of 8HQ against a spectrum of microbial pathogens suggests that this strategy may have broad utility. The conditional activation of Cu ionophores by innate immune cells intensifies the hostile antimicrobial environment and represents a promising approach to combat infectious disease. PMID:25088681

  12. Replication-dependent histone genes are actively transcribed in differentiating and aging retinal neurons.

    PubMed

    Banday, Abdul Rouf; Baumgartner, Marybeth; Al Seesi, Sahar; Karunakaran, Devi Krishna Priya; Venkatesh, Aditya; Congdon, Sean; Lemoine, Christopher; Kilcollins, Ashley M; Mandoiu, Ion; Punzo, Claudio; Kanadia, Rahul N

    2014-01-01

    In the mammalian genome, each histone family contains multiple replication-dependent paralogs, which are found in clusters where their transcription is thought to be coupled to the cell cycle. Here, we wanted to interrogate the transcriptional regulation of these paralogs during retinal development and aging. We employed deep sequencing, quantitative PCR, in situ hybridization (ISH), and microarray analysis, which revealed that replication-dependent histone genes were not only transcribed in progenitor cells but also in differentiating neurons. Specifically, by ISH analysis we found that different histone genes were actively transcribed in a subset of neurons between postnatal day 7 and 14. Interestingly, within a histone family, not all paralogs were transcribed at the same level during retinal development. For example, expression of Hist1h1b was higher embryonically, while that of Hist1h1c was higher postnatally. Finally, expression of replication-dependent histone genes was also observed in the aging retina. Moreover, transcription of replication-dependent histones was independent of rapamycin-mediated mTOR pathway inactivation. Overall, our data suggest the existence of variant nucleosomes produced by the differential expression of the replication-dependent histone genes across retinal development. Also, the expression of a subset of replication-dependent histone isotypes in senescent neurons warrants re-examining these genes as "replication-dependent." Thus, our findings underscore the importance of understanding the transcriptional regulation of replication-dependent histone genes in the maintenance and functioning of neurons. PMID:25486194

  13. pH-Dependent Metal Ion Toxicity Influences the Antibacterial Activity of Two Natural Mineral Mixtures

    PubMed Central

    Cunningham, Tanya M.; Koehl, Jennifer L.; Summers, Jack S.; Haydel, Shelley E.

    2010-01-01

    Background Recent studies have demonstrated that several mineral products sold for medicinal purposes demonstrate antimicrobial activity, but little is known about the physicochemical properties involved in antibacterial activity. Methodology/Principal Findings Using in vitro mineral suspension testing, we have identified two natural mineral mixtures, arbitrarily designated BY07 and CB07, with antibacterial activity against a broad-spectrum of bacterial pathogens. Mineral-derived aqueous leachates also exhibited antibacterial activity, revealing that chemical, not physical, mineral characteristics were responsible for the observed activity. The chemical properties essential for bactericidal activity against Escherichia coli were probed by testing antibacterial activity in the presence of metal chelators, the hydroxyl radical scavenger, thiourea, and varying pH levels. Chelation of the BY07 minerals with EDTA or desferrioxamine eliminated or reduced BY07 toxicity, respectively, suggesting a role of an acid-soluble metal species, particularly Fe3+ or other sequestered metal cations, in mineral toxicity. This conclusion was supported by NMR relaxation data, which indicated that BY07 and CB07 leachates contained higher concentrations of chemically accessible metal ions than leachates from non-bactericidal mineral samples. Conclusions/Significance We conclude that the acidic environment of the hydrated minerals significantly contributes to antibacterial activity by increasing the availability and toxicity of metal ions. These findings provide impetus for further investigation of the physiological effects of mineral products and their applications in complementary antibacterial therapies. PMID:20209160

  14. Volvariella volvacea lectin activates mouse T lymphocytes by a calcium dependent pathway.

    PubMed

    Sze, S C W; Ho, J C K; Liu, W K

    2004-08-15

    The immunomodulatory lectin, Volvariella volvacea lectin (VVL), isolated from the edible mushroom, Volvariella volvacea, has been shown to stimulate the expression of Th1 cytokines and the proliferative activity of mouse splenocytes (She et al. [1998]: Biochem Biophys Res Comm 247:106-111). In order to elucidate the mechanisms underlying these activities, we conducted a kinetic analysis of the early and late activation markers in mouse T lymphocytes: (1) flow cytometric analysis of calcium influx, (2) induction of activation molecules (CD25 and CD69), (3) expression and DNA-binding activity of the nuclear factor of activated T cells (NFAT), NFkappaB, and activation protein-1 (AP-1), (4) translational production of cytokines (interleukin-2 (IL-2) and interferon-gamma (IFNgamma)), and (5) cell proliferation by expression of proliferating cell nuclear antigen (PCNA) and tritiated thymidine incorporation. All results showed that VVL induced a rapid expression of CD69, CD25, NFAT, IL-2, and PCNA in a dose- and time-dependent manner, leading to lymphocyte proliferation. These effects brought about by VVL were more potent than those stimulated by equimolar concentrations of mitogenic lectin, concanavalin A (Con A). Cell activation and proliferation were mediated through a calcium-dependent pathway as demonstrated by a VVL-induced increase of intracellular calcium influx, and a proliferation inhibition by the Ca-dependent phosphatase calcineurin blocker-cyclosporin A (CsA). Taken all data together, VVL is a lectin which activates lymphocyte through successive calcium influx, nuclear localization of NFAT transcription factor, induction of activation markers, CD25 and CD69, intracellular cytokine production, and cell proliferation. PMID:15258902

  15. Activity-dependent hyperpolarization of EGABA is absent in cutaneous DRG neurons from inflamed rats

    PubMed Central

    Zhu, Yi; Zhang, Xiu-Lin; Gold, Michael S.

    2013-01-01

    A shift in GABAA signaling from inhibition to excitation in primary afferent neurons appears to contribute to the inflammation-induced increase in afferent input to the central nervous system (CNS). An activity-dependent depolarization of the GABA equilibrium potential (EGABA) has been described in CNS neurons which drives a shift in GABAA signaling from inhibition to excitation. The purpose of the present study was to determine if such an activity-dependent depolarization of EGABA occurs in primary afferents and whether the depolarization is amplified with persistent inflammation. Acutely dissociated retrogradely labeled cutaneous DRG neurons from naïve and inflamed rats were studied with gramicidin perforated patch recording. Rather than a depolarization, 200 action potentials delivered at 2 Hz resulted in a ~10 mV hyperpolarization of EGABA in cutaneous neurons from naïve rats. No such hyperpolarization was observed in neurons from inflamed rats. The shift in EGABA was not blocked by 10 µM bumetanide. Furthermore, because activity-dependent hyperpolarization of EGABA was fully manifest in the absence of HCO3− in the bath solution, this shift was not dependent on a change in HCO3−-Cl− exchanger activity, despite evidence of HCO3−-Cl− exchangers in DRG neurons that may contribute to the establishment of EGABA in the presence of HCO3−. While the mechanism underlying the activity-dependent hyperpolarization of EGABA has yet to be identified, because this mechanism appears to function as a form of feedback inhibition, facilitating GABA mediated inhibition of afferent activity, it may serve as a novel target for the treatment of inflammatory pain. PMID:24135545

  16. Improved AIOMFAC model parameterisation of the temperature dependence of activity coefficients for aqueous organic mixtures

    NASA Astrophysics Data System (ADS)

    Ganbavale, G.; Zuend, A.; Marcolli, C.; Peter, T.

    2014-06-01

    This study presents a new, improved parameterisation of the temperature dependence of activity coefficients in the AIOMFAC (Aerosol Inorganic-Organic Mixtures Functional groups Activity Coefficients) model applicable for aqueous as well as water-free organic solutions. For electrolyte-free organic and organic-water mixtures the AIOMFAC model uses a group-contribution approach based on UNIFAC (UNIversal quasi-chemical Functional-group Activity Coefficients). This group-contribution approach explicitly accounts for interactions among organic functional groups and between organic functional groups and water. The previous AIOMFAC version uses a simple parameterisation of the temperature dependence of activity coefficients, aimed to be applicable in the temperature range from ~275 to ~400 K. With the goal to improve the description of a wide variety of organic compounds found in atmospheric aerosols, we extend the AIOMFAC parameterisation for the functional groups carboxyl, hydroxyl, ketone, aldehyde, ether, ester, alkyl, aromatic carbon-alcohol, and aromatic hydrocarbon to atmospherically relevant low temperatures with the introduction of a new temperature dependence parameterisation. The improved temperature dependence parameterisation is derived from classical thermodynamic theory by describing effects from changes in molar enthalpy and heat capacity of a multicomponent system. Thermodynamic equilibrium data of aqueous organic and water-free organic mixtures from the literature are carefully assessed and complemented with new measurements to establish a comprehensive database, covering a wide temperature range (~190 to ~440 K) for many of the functional group combinations considered. Different experimental data types and their processing for the estimation of AIOMFAC model parameters are discussed. The new AIOMFAC parameterisation for the temperature dependence of activity coefficients from low to high temperatures shows an overall improvement of 25% in comparison to

  17. Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation.

    PubMed

    Loh, Liyen; Wang, Zhongfang; Sant, Sneha; Koutsakos, Marios; Jegaskanda, Sinthujan; Corbett, Alexandra J; Liu, Ligong; Fairlie, David P; Crowe, Jane; Rossjohn, Jamie; Xu, Jianqing; Doherty, Peter C; McCluskey, James; Kedzierska, Katherine

    2016-09-01

    Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to elicit potent immunity to a broad range of bacteria, mainly via the rapid production of inflammatory cytokines. Whether MAIT cells contribute to antiviral immunity is less clear. Here we asked whether MAIT cells produce cytokines/chemokines during severe human influenza virus infection. Our analysis in patients hospitalized with avian H7N9 influenza pneumonia showed that individuals who recovered had higher numbers of CD161(+)Vα7.2(+) MAIT cells in peripheral blood compared with those who succumbed, suggesting a possible protective role for this lymphocyte population. To understand the mechanism underlying MAIT cell activation during influenza, we cocultured influenza A virus (IAV)-infected human lung epithelial cells (A549) and human peripheral blood mononuclear cells in vitro, then assayed them by intracellular cytokine staining. Comparison of influenza-induced MAIT cell activation with the profile for natural killer cells (CD56(+)CD3(-)) showed robust up-regulation of IFNγ for both cell populations and granzyme B in MAIT cells, although the individual responses varied among healthy donors. However, in contrast to the requirement for cell-associated factors to promote NK cell activation, the induction of MAIT cell cytokine production was dependent on IL-18 (but not IL-12) production by IAV-exposed CD14(+) monocytes. Overall, this evidence for IAV activation via an indirect, IL-18-dependent mechanism indicates that MAIT cells are protective in influenza, and also possibly in any human disease process in which inflammation and IL-18 production occur. PMID:27543331

  18. Activity in a Cortical-Basal Ganglia Circuit for Song Is Required for Social Context-Dependent Vocal Variability

    PubMed Central

    Stepanek, Laurie

    2010-01-01

    Variability in adult motor output is important for enabling animals to respond to changing external conditions. Songbirds are useful for studying variability because they alter the amount of variation in their song depending on social context. When an adult zebra finch male sings to a female (“directed”), his song is highly stereotyped, but when he sings alone (“undirected”), his song varies across renditions. Lesions of the lateral magnocellular nucleus of the anterior nidopallium (LMAN), the output nucleus of a cortical-basal ganglia circuit for song, reduce song variability to that of the stereotyped “performance” state. However, such lesions not only eliminate LMAN's synaptic input to its targets, but can also cause structural or physiological changes in connected brain regions, and thus cannot assess whether the acute activity of LMAN is important for social modulation of adult song variability. To evaluate the effects of ongoing LMAN activity, we reversibly silenced LMAN in singing zebra finches by bilateral reverse microdialysis of the GABAA receptor agonist muscimol. We found that LMAN inactivation acutely reduced undirected song variability, both across and even within syllable renditions, to the level of directed song variability in all birds examined. Song variability returned to pre-muscimol inactivation levels after drug washout. However, unlike LMAN lesions, LMAN inactivation did not eliminate social context effects on song tempo in adult birds. These results indicate that the activity of LMAN neurons acutely and actively generates social context-dependent increases in adult song variability but that social regulation of tempo is more complex. PMID:20884763

  19. Isolation and Identification of Genes Activating Uas2-Dependent Adh2 Expression in Saccharomyces Cerevisiae

    PubMed Central

    Donoviel, M. S.; Young, E. T.

    1996-01-01

    Two cis-acting elements have been identified that act synergistically to regulate expression of the glucose-repressed alcohol dehydrogenase 2 (ADH2) gene. UAS1 is bound by the trans-activator Adr1p. UAS2 is thought to be the binding site for an unidentified regulatory protein. A genetic selection based on a UAS2-dependent ADH2 reporter was devised to isolate genes capable of activating UAS2-dependent transcription. One set of UAS2-dependent genes contained SPT6/CRE2/SSN20. Multicopy SPT6 caused improper expression of chromosomal ADH2. A second set of UAS2-dependent clones contained a previously uncharacterized open reading frame designated MEU1 (Multicopy Enhancer of UAS2). A frame shift mutation in MEU1 abolished its ability to activate UAS2-dependent gene expression. Multicopy MEU1 expression suppressed the constitutive ADH2 expression caused by cre2-1. Disruption of MEU1 reduced endogenous ADH2 expression about twofold but had no effect on cell viability or growth. No homologues of MEU1 were identified by low-stringency Southern hybridization of yeast genomic DNA, and no significant homologues were found in the sequence data bases. A MEU1/β-gal fusion protein was not localized to a particular region of the cell. MEU1 is linked to PPR1 on chromosome XII. PMID:8807288

  20. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2.

    PubMed

    Kim, Kimberly H; Kim, Woojin; Howard, Thomas P; Vazquez, Francisca; Tsherniak, Aviad; Wu, Jennifer N; Wang, Weishan; Haswell, Jeffrey R; Walensky, Loren D; Hahn, William C; Orkin, Stuart H; Roberts, Charles W M

    2015-12-01

    Human cancer genome sequencing has recently revealed that genes that encode subunits of SWI/SNF chromatin remodeling complexes are frequently mutated across a wide variety of cancers, and several subunits of the complex have been shown to have bona fide tumor suppressor activity. However, whether mutations in SWI/SNF subunits result in shared dependencies is unknown. Here we show that EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is essential in all tested cancer cell lines and xenografts harboring mutations of the SWI/SNF subunits ARID1A, PBRM1, and SMARCA4, which are several of the most frequently mutated SWI/SNF subunits in human cancer, but that co-occurrence of a Ras pathway mutation is correlated with abrogation of this dependence. Notably, we demonstrate that SWI/SNF-mutant cancer cells are primarily dependent on a non-catalytic role of EZH2 in the stabilization of the PRC2 complex, and that they are only partially dependent on EZH2 histone methyltransferase activity. These results not only reveal a shared dependency of cancers with genetic alterations in SWI/SNF subunits, but also suggest that EZH2 enzymatic inhibitors now in clinical development may not fully suppress the oncogenic activity of EZH2. PMID:26552009

  1. SWI/SNF mutant cancers depend upon catalytic and non–catalytic activity of EZH2

    PubMed Central

    Kim, Kimberly H.; Kim, Woojin; Howard, Thomas P.; Vazquez, Francisca; Tsherniak, Aviad; Wu, Jennifer N.; Wang, Weishan; Haswell, Jeffrey R.; Walensky, Loren D.; Hahn, William C.; Orkin, Stuart H.; Roberts, Charles W. M.

    2016-01-01

    Human cancer genome sequencing has recently revealed that genes encoding subunits of SWI/SNF chromatin remodeling complexes are frequently mutated across a wide variety of cancers, and several subunits of the complex have been shown to have bona fide tumor suppressor activity1. However, whether mutations in SWI/SNF subunits result in shared dependencies is unknown. Here we show that EZH2, a catalytic subunit of the Polycomb repressive complex 2 (PRC2), is essential in all tested cancer cell lines and xenografts harboring mutations of the SWI/SNF subunits ARID1A, PBRM1, and SMARCA4, which are several of the most frequently mutated SWI/SNF subunits in human cancer but that co–occurrence of a Ras pathway mutation correlates with abrogation of this dependence. Surprisingly, we demonstrate that SWI/SNF mutant cancer cells are primarily dependent upon a non–catalytic role of EZH2 in stabilization of the PRC2 complex, and only partially dependent on EZH2 histone methyltransferase activity. These results not only reveal a shared dependency of cancers with genetic alterations in SWI/SNF subunits, but also suggest that EZH2 enzymatic inhibitors now in clinical development may not fully suppress the oncogenic activity of EZH2. PMID:26552009

  2. Dependency of {gamma}-secretase complex activity on the structural integrity of the bilayer

    SciTech Connect

    Zhou, Hua; Zhou, Shuxia; Walian, Peter J.; Jap, Bing K.

    2010-11-12

    Research highlights: {yields} Partial solubilization of membranes with CHAPSO can increase {gamma}-secretase activity. {yields} Completely solubilized {gamma}-secretase is inactive. {yields} Purified {gamma}-secretase regains activity after reconstitution into lipid bilayers. {yields} A broad range of detergents can be used to successfully reconstitute {gamma}-secretase. -- Abstract: {gamma}-secretase is a membrane protein complex associated with the production of A{beta} peptides that are pathogenic in Alzheimer's disease. We have characterized the activity of {gamma}-secretase complexes under a variety of detergent solubilization and reconstitution conditions, and the structural state of proteoliposomes by electron microscopy. We found that {gamma}-secretase activity is highly dependent on the physical state or integrity of the membrane bilayer - partial solubilization may increase activity while complete solubilization will abolish it. The activity of well-solubilized {gamma}-secretase can be restored to near native levels when properly reconstituted into a lipid bilayer environment.

  3. A proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting.

    PubMed

    Byron, Adam; Askari, Janet A; Humphries, Jonathan D; Jacquemet, Guillaume; Koper, Ewa J; Warwood, Stacey; Choi, Colin K; Stroud, Matthew J; Chen, Christopher S; Knight, David; Humphries, Martin J

    2015-01-01

    Integrin activation, which is regulated by allosteric changes in receptor conformation, enables cellular responses to the chemical, mechanical and topological features of the extracellular microenvironment. A global view of how activation state converts the molecular composition of the region proximal to integrins into functional readouts is, however, lacking. Here, using conformation-specific monoclonal antibodies, we report the isolation of integrin activation state-dependent complexes and their characterization by mass spectrometry. Quantitative comparisons, integrating network, clustering, pathway and image analyses, define multiple functional protein modules enriched in a conformation-specific manner. Notably, active integrin complexes are specifically enriched for proteins associated with microtubule-based functions. Visualization of microtubules on micropatterned surfaces and live cell imaging demonstrate that active integrins establish an environment that stabilizes microtubules at the cell periphery. These data provide a resource for the interrogation of the global molecular connections that link integrin activation to adhesion signalling. PMID:25609142

  4. A proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting

    PubMed Central

    Byron, Adam; Askari, Janet A.; Humphries, Jonathan D.; Jacquemet, Guillaume; Koper, Ewa J.; Warwood, Stacey; Choi, Colin K.; Stroud, Matthew J.; Chen, Christopher S.; Knight, David; Humphries, Martin J.

    2015-01-01

    Integrin activation, which is regulated by allosteric changes in receptor conformation, enables cellular responses to the chemical, mechanical and topological features of the extracellular microenvironment. A global view of how activation state converts the molecular composition of the region proximal to integrins into functional readouts is, however, lacking. Here, using conformation-specific monoclonal antibodies, we report the isolation of integrin activation state-dependent complexes and their characterization by mass spectrometry. Quantitative comparisons, integrating network, clustering, pathway and image analyses, define multiple functional protein modules enriched in a conformation-specific manner. Notably, active integrin complexes are specifically enriched for proteins associated with microtubule-based functions. Visualization of microtubules on micropatterned surfaces and live cell imaging demonstrate that active integrins establish an environment that stabilizes microtubules at the cell periphery. These data provide a resource for the interrogation of the global molecular connections that link integrin activation to adhesion signalling. PMID:25609142

  5. Fatigue resistance of rat extraocular muscles does not depend on creatine kinase activity

    PubMed Central

    McMullen, Colleen A; Hayeß, Katrin; Andrade, Francisco H

    2005-01-01

    Background Creatine kinase (CK) links phosphocreatine, an energy storage system, to cellular ATPases. CK activity serves as a temporal and spatial buffer for ATP content, particularly in fast-twitch skeletal muscles. The extraocular muscles are notoriously fast and active, suggesting the need for efficient ATP buffering. This study tested the hypotheses that (1) CK isoform expression and activity in rat extraocular muscles would be higher, and (2) the resistance of these muscles to fatigue would depend on CK activity. Results We found that mRNA and protein levels for cytosolic and mitochondrial CK isoforms were lower in the extraocular muscles than in extensor digitorum longus (EDL). Total CK activity was correspondingly decreased in the extraocular muscles. Moreover, cytoskeletal components of the sarcomeric M line, where a fraction of CK activity is found, were downregulated in the extraocular muscles as was shown by immunocytochemistry and western blotting. CK inhibition significantly accelerated the development of fatigue in EDL muscle bundles, but had no major effect on the extraocular muscles. Searching for alternative ATP buffers that could compensate for the relative lack of CK in extraocular muscles, we determined that mRNAs for two adenylate kinase (AK) isoforms were expressed at higher levels in these muscles. Total AK activity was similar in EDL and extraocular muscles. Conclusion These data indicate that the characteristic fatigue resistance of the extraocular muscles does not depend on CK activity. PMID:16107216

  6. Ethanol-Induced Activation of ATP-Dependent Proton Extrusion in Elodea densa Leaves 1

    PubMed Central

    Marrè, Maria T.; Venegoni, Alberto; Moroni, Anna

    1992-01-01

    In Elodea densa leaves, ethanol up to 0.17 m stimulates H+ extrusion activity. This effect is strictly dependent on the presence of K+ in the medium and is suppressed by the presence of the plasmalemma H+-ATPase inhibitor vanadate. Stimulation of H+ extrusion is associated with (a) a decrease in cellular ATP level, (b) a marked hyperpolarization of transmembrane electrical potential, and (c) an increase in net K+ influx. These results suggest that ethanol-induced H+ extrusion is mediated by an activation of the plasma membrane ATP-dependent, electrogenic proton pump. This stimulating effect is associated with an increase of cell sap pH and of the capacity to take up the weak acid 5,5-dimethyloxazolidine-2,4-dione, which is interpretable as due to an increase of cytosolic pH. This indicates that the stimulation of H+ extrusion by ethanol does not depend on a cytosolic acidification by products of ethanol metabolism. The similarity of the effects of ethanol and those of photosynthesis on proton pump activity in E. densa leaves suggests that a common metabolic situation is responsible for the activation of the ATP-dependent H+-extruding mechanism. PMID:16653093

  7. Impact of Network Activity Levels on the Performance of Passive Network Service Dependency Discovery

    SciTech Connect

    Carroll, Thomas E.; Chikkagoudar, Satish; Arthur-Durett, Kristine M.

    2015-11-02

    Network services often do not operate alone, but instead, depend on other services distributed throughout a network to correctly function. If a service fails, is disrupted, or degraded, it is likely to impair other services. The web of dependencies can be surprisingly complex---especially within a large enterprise network---and evolve with time. Acquiring, maintaining, and understanding dependency knowledge is critical for many network management and cyber defense activities. While automation can improve situation awareness for network operators and cyber practitioners, poor detection accuracy reduces their confidence and can complicate their roles. In this paper we rigorously study the effects of network activity levels on the detection accuracy of passive network-based service dependency discovery methods. The accuracy of all except for one method was inversely proportional to network activity levels. Our proposed cross correlation method was particularly robust to the influence of network activity. The proposed experimental treatment will further advance a more scientific evaluation of methods and provide the ability to determine their operational boundaries.

  8. Biochemical Assays for Analyzing Activities of ATP-dependent Chromatin Remodeling Enzymes

    PubMed Central

    Chen, Lu; Ooi, Soon-Keat; Conaway, Joan W.; Conaway, Ronald C.

    2014-01-01

    Members of the SNF2 family of ATPases often function as components of multi-subunit chromatin remodeling complexes that regulate nucleosome dynamics and DNA accessibility by catalyzing ATP-dependent nucleosome remodeling. Biochemically dissecting the contributions of individual subunits of such complexes to the multi-step ATP-dependent chromatin remodeling reaction requires the use of assays that monitor the production of reaction products and measure the formation of reaction intermediates. This JOVE protocol describes assays that allow one to measure the biochemical activities of chromatin remodeling complexes or subcomplexes containing various combinations of subunits. Chromatin remodeling is measured using an ATP-dependent nucleosome sliding assay, which monitors the movement of a nucleosome on a DNA molecule using an electrophoretic mobility shift assay (EMSA)-based method. Nucleosome binding activity is measured by monitoring the formation of remodeling complex-bound mononucleosomes using a similar EMSA-based method, and DNA- or nucleosome-dependent ATPase activity is assayed using thin layer chromatography (TLC) to measure the rate of conversion of ATP to ADP and phosphate in the presence of either DNA or nucleosomes. Using these assays, one can examine the functions of subunits of a chromatin remodeling complex by comparing the activities of the complete complex to those lacking one or more subunits. The human INO80 chromatin remodeling complex is used as an example; however, the methods described here can be adapted to the study of other chromatin remodeling complexes. PMID:25407555

  9. Detection of NAD(P)H-dependent enzyme activity with dynamic luminescence quenching of terbium complexes.

    PubMed

    Ito, Hiroki; Terai, Takuya; Hanaoka, Kenjiro; Ueno, Tasuku; Komatsu, Toru; Nagano, Tetsuo; Urano, Yasuteru

    2015-05-14

    We discovered that positively charged terbium complexes bearing 1,4,7,10-tetraazacyclododecane functionalized with amide ligands are highly sensitive to dynamic luminescence quenching by NAD(P)H. We exploited this phenomenon to establish a general time-resolved luminescence-based assay platform for sensitive detection of NAD(P)H-dependent enzyme activities. PMID:25879812

  10. Activity-dependent fluorescent labeling of bacterial cells expressing the TOL pathway

    SciTech Connect

    William K. Keener; Mary E. Watwood

    2005-01-01

    3-Ethynylbenzoate functions as an activity-dependent, fluorogenic and chromogenic probe for Pseudomonas putida mt-2, which is known to degrade toluene via conversion to benzoate, followed by meta ring fission of the intermediate, catechol. This direct physiological analysis allows the fluorescent labeling of cells whose toluene-degrading enzymes have been induced by an aromatic substrate.

  11. Genome-wide identification and characterization of functional neuronal activity-dependent enhancers

    PubMed Central

    Malik, Athar N.; Vierbuchen, Thomas; Hemberg, Martin; Rubin, Alex A.; Ling, Emi; Couch, Cameron H.; Stroud, Hume; Spiegel, Ivo; Farh, Kyle Kai-How; Harmin, David A.; Greenberg, Michael E.

    2015-01-01

    SUMMARY Experience-dependent gene transcription is required for nervous system development and function. However, the DNA regulatory elements that control this program of gene expression are not well defined. Here we characterize the enhancers that function across the genome to mediate activity-dependent transcription in mouse cortical neurons. We find that the subset of enhancers enriched for monomethylation of histone H3 lysine 4 (H3K4me1) and binding of the transcriptional co-activator CREBBP (CBP) that shows increased acetylation of histone H3 lysine 27 (H3K27ac) upon membrane depolarization of cortical neurons functions to regulate activity-dependent transcription. A subset of these enhancers appears to require binding of FOS, which previously was thought to bind primarily to promoters. These findings suggest that FOS functions at enhancers to control activity-dependent gene programs that are critical for nervous system function and provide a resource of functional cis-regulatory elements that may give insight into the genetic variants that contribute to brain development and disease. PMID:25195102

  12. Deletion of phenylalanine 508 causes attenuated phosphorylation-dependent activation of CFTR chloride channels.

    PubMed

    Wang, F; Zeltwanger, S; Hu, S; Hwang, T C

    2000-05-01

    In cell-attached patches stimulated with cAMP agonists, the single-channel open probability (Po) of the phenylalanine 508-deleted cystic fibrosis transmembrane conductance regulator (DeltaF508-CFTR) channel, the most common disease-associated mutation in cystic fibrosis, was abnormally low (a functional defect). To investigate the mechanism for the poor response of DeltaF508-CFTR to cAMP stimulation, we examined, in excised inside-out patches, protein kinase A (PKA)-dependent phosphorylation activation and ATP-dependent gating of wild-type (WT) and DeltaF508-CFTR channels expressed in NIH3T3 mouse fibroblasts. For WT-CFTR, the activation time course of CFTR channel current upon addition of PKA and ATP followed a sigmoidal function with time constants that decreased as [PKA] was increased. The curvilinear relationship between [PKA] and the apparent activation rate suggests an incremental phosphorylation-dependent activation of CFTR at multiple phosphorylation sites. The time course of PKA-dependent activation of DeltaF508-CFTR channel current also followed a sigmoidal function, but the rate of activation was at least 7-fold slower than that with WT channels. This result suggests that deletion of phenylalanine 508 causes attenuated PKA-dependent phosphorylation of the CFTR chloride channel. Once DeltaF508-CFTR channels were maximally activated with PKA, the mutant channel and WT channel had indistinguishable steady-state Po values, ATP dose-response relationships and single-channel kinetics, indicating that DeltaF508-CFTR is not defective in ATP-dependent gating. By measuring whole-cell current density, we compared the number of functional channels in WT- and DeltaF508-CFTR cell membrane. Our data showed that the estimated channel density for DeltaF508-CFTR was approximately 10-fold lower than that for WT-CFTR, but the cAMP-dependent whole-cell current density differed by approximately 200-fold. We thus conclude that the functional defect (a decrease in Po) of Delta

  13. Deletion of phenylalanine 508 causes attenuated phosphorylation-dependent activation of CFTR chloride channels

    PubMed Central

    Wang, Fei; Zeltwanger, Shawn; Hu, Shenghui; Hwang, Tzyh-Chang

    2000-01-01

    In cell-attached patches stimulated with cAMP agonists, the single-channel open probability (Po) of the phenylalanine 508-deleted cystic fibrosis transmembrane conductance regulator (ΔF508-CFTR) channel, the most common disease-associated mutation in cystic fibrosis, was abnormally low (a functional defect). To investigate the mechanism for the poor response of ΔF508-CFTR to cAMP stimulation, we examined, in excised inside-out patches, protein kinase A (PKA)-dependent phosphorylation activation and ATP-dependent gating of wild-type (WT) and ΔF508-CFTR channels expressed in NIH3T3 mouse fibroblasts.For WT-CFTR, the activation time course of CFTR channel current upon addition of PKA and ATP followed a sigmoidal function with time constants that decreased as [PKA] was increased. The curvilinear relationship between [PKA] and the apparent activation rate suggests an incremental phosphorylation-dependent activation of CFTR at multiple phosphorylation sites.The time course of PKA-dependent activation of ΔF508-CFTR channel current also followed a sigmoidal function, but the rate of activation was at least 7-fold slower than that with WT channels. This result suggests that deletion of phenylalanine 508 causes attenuated PKA-dependent phosphorylation of the CFTR chloride channel.Once ΔF508-CFTR channels were maximally activated with PKA, the mutant channel and WT channel had indistinguishable steady-state Po values, ATP dose-response relationships and single-channel kinetics, indicating that ΔF508-CFTR is not defective in ATP-dependent gating.By measuring whole-cell current density, we compared the number of functional channels in WT- and ΔF508-CFTR cell membrane. Our data showed that the estimated channel density for ΔF508-CFTR was ∼10-fold lower than that for WT-CFTR, but the cAMP-dependent whole-cell current density differed by ∼200-fold. We thus conclude that the functional defect (a decrease in Po) of ΔF508-CFTR is as important as the trafficking defect (a

  14. Activity-dependent regulation of NMDA receptors in substantia nigra dopaminergic neurones.

    PubMed

    Wild, Angela R; Jones, Susan; Gibb, Alasdair J

    2014-02-15

    N-Methyl-d-aspartate receptors (NMDARs) are Ca(2+)-permeable glutamate receptors that play a critical role in synaptic plasticity and promoting cell survival. However, overactive NMDARs can trigger cell death signalling pathways and have been implicated in substantia nigra pars compacta (SNc) pathology in Parkinson's disease. Calcium ion influx through NMDARs recruits Ca(2+)-dependent proteins that can regulate NMDAR activity. The surface density of NMDARs can also be regulated dynamically in response to receptor activity via Ca(2+)-independent mechanisms. We have investigated the activity-dependent regulation of NMDARs in SNc dopaminergic neurones. Repeated whole-cell agonist applications resulted in a decline in the amplitude of NMDAR currents (current run-down) that was use dependent and not readily reversible. Run-down was reduced by increasing intracellular Ca(2+) buffering or by reducing Ca(2+) influx but did not appear to be mediated by the same regulatory proteins that cause Ca(2+)-dependent run-down in hippocampal neurones. The NMDAR current run-down may be mediated in part by a Ca(2+)-independent mechanism, because intracellular dialysis with a dynamin-inhibitory peptide reduced run-down, suggesting a role for clathrin-mediated endocytosis in the regulation of the surface density of receptors. Synaptic NMDARs were also subject to current run-down during repeated low-frequency synaptic stimulation in a Ca(2+)-dependent but dynamin-independent manner. Thus, we report, for the first time, regulation of NMDARs in SNc dopaminergic neurones by changes in intracellular Ca(2+) at both synaptic and extrasynaptic sites and provide evidence for activity-dependent changes in receptor trafficking. These mechanisms may contribute to intracellular Ca(2+) homeostasis in dopaminergic neurones by limiting Ca(2+) influx through the NMDAR. PMID:24344168

  15. 3D Traction Stresses Activate Protease-Dependent Invasion of Cancer Cells

    PubMed Central

    Aung, Aereas; Seo, Young N.; Lu, Shaoying; Wang, Yingxiao; Jamora, Colin; del Álamo, Juan C.; Varghese, Shyni

    2014-01-01

    Cell invasion and migration that occurs, for example, in cancer metastasis is rooted in the ability of cells to navigate through varying levels of physical constraint exerted by the extracellular matrix. Cancer cells can invade matrices in either a protease-independent or a protease-dependent manner. An emerging critical component that influences the mode of cell invasion is the traction stresses generated by the cells in response to the physicostructural properties of the extracellular matrix. In this study, we have developed a reference-free quantitative assay for measuring three-dimensional (3D) traction stresses generated by cells during the initial stages of invasion into matrices exerting varying levels of mechanical resistance. Our results show that as cells encounter higher mechanical resistance, a larger fraction of them shift to protease-mediated invasion, and this process begins at lower values of cell invasion depth. On the other hand, the compressive stress generated by the cells at the onset of protease-mediated invasion is found to be independent of matrix stiffness, suggesting that 3D traction stress is a key factor in triggering protease-mediated cancer cell invasion. At low 3D compressive traction stresses, cells utilize bleb formation to indent the matrix in a protease independent manner. However, at higher stress values, cells utilize invadopodia-like structures to mediate protease-dependent invasion into the 3D matrix. The critical value of compressive traction stress at the transition from a protease-independent to a protease-dependent mode of invasion is found to be ∼165 Pa. PMID:25468332

  16. Plasminogen-Dependent Matriptase Activation Accelerates Plasmin Generation by Differentiating Primary Human Keratinocytes.

    PubMed

    Chen, Ya-Wen; Yin, Shi; Lai, Ying-Jung J; Johnson, Michael D; Lin, Chen-Yong

    2016-06-01

    Pericellular plasmin generation, an important pathophysiological process, can be initiated and accelerated by the autoactivation of the type 2 transmembrane serine protease matriptase and subsequent activation of urokinase plasminogen activator. The link between matriptase and plasminogen was initially thought to be one-directional: from matriptase, through plasminogen activator, to plasminogen. However, in the current study, we now show that primary human keratinocytes that are undergoing calcium-induced differentiation can rapidly activate matriptase in response to serum treatment via a mechanism dependent on intracellular calcium, protein kinase C, and phosphatidylinositol 3-kinases-based signaling. The serum factor, responsible for the induction of matriptase zymogen activation, was shown to be plasminogen. A sub-pM concentration of plasminogen (but not plasmin) acting at the cell surface is sufficient to induce matriptase activation, suggesting high potency and specificity of the induction. After matriptase zymogen activation, a proportion of active matriptase is shed into extracellular milieu and returns to the cell surface to accelerate plasmin generation. The ability of plasminogen to induce matriptase zymogen activation and the subsequent acceleration of plasmin generation by active matriptase reveals a feed-forward mechanism that allows differentiating human keratinocytes to rapidly and robustly activate pericellular proteolysis. PMID:26872599

  17. Quantifying the lifetime circadian rhythm of physical activity: a covariate-dependent functional approach

    PubMed Central

    Xiao, Luo; Huang, Lei; Schrack, Jennifer A.; Ferrucci, Luigi; Zipunnikov, Vadim; Crainiceanu, Ciprian M.

    2015-01-01

    Objective measurement of physical activity using wearable devices such as accelerometers may provide tantalizing new insights into the association between activity and health outcomes. Accelerometers can record quasi-continuous activity information for many days and for hundreds of individuals. For example, in the Baltimore Longitudinal Study on Aging physical activity was recorded every minute for 773 adults for an average of 7 days per adult. An important scientific problem is to separate and quantify the systematic and random circadian patterns of physical activity as functions of time of day, age, and gender. To capture the systematic circadian pattern, we introduce a practical bivariate smoother and two crucial innovations: (i) estimating the smoothing parameter using leave-one-subject-out cross validation to account for within-subject correlation and (ii) introducing fast computational techniques that overcome problems both with the size of the data and with the cross-validation approach to smoothing. The age-dependent random patterns are analyzed by a new functional principal component analysis that incorporates both covariate dependence and multilevel structure. For the analysis, we propose a practical and very fast trivariate spline smoother to estimate covariate-dependent covariances and their spectra. Results reveal several interesting, previously unknown, circadian patterns associated with human aging and gender. PMID:25361695

  18. Small activating RNA binds to the genomic target site in a seed-region-dependent manner

    PubMed Central

    Meng, Xing; Jiang, Qian; Chang, Nannan; Wang, Xiaoxia; Liu, Chujun; Xiong, Jingwei; Cao, Huiqing; Liang, Zicai

    2016-01-01

    RNA activation (RNAa) is the upregulation of gene expression by small activating RNAs (saRNAs). In order to investigate the mechanism by which saRNAs act in RNAa, we used the progesterone receptor (PR) gene as a model, established a panel of effective saRNAs and assessed the involvement of the sense and antisense strands of saRNA in RNAa. All active saRNAs had their antisense strand effectively incorporated into Ago2, whereas such consistency did not occur for the sense strand. Using a distal hotspot for saRNA targeting at 1.6-kb upstream from the PR transcription start site, we further established that gene activation mediated by saRNA depended on the complementarity of the 5′ region of the antisense strand, and that such activity was largely abolished by mutations in this region of the saRNA. We found markedly reduced RNAa effects when we created mutations in the genomic target site of saRNA PR-1611, thus providing evidence that RNAa depends on the integrity of the DNA target. We further demonstrated that this saRNA bound the target site on promoter DNA. These results demonstrated that saRNAs work via an on-site mechanism by binding to target genomic DNA in a seed-region-dependent manner, reminiscent of miRNA-like target recognition. PMID:26873922

  19. A structural view of ligand-dependent activation in thermoTRP channels

    PubMed Central

    Steinberg, Ximena; Lespay-Rebolledo, Carolyne; Brauchi, Sebastian

    2014-01-01

    Transient Receptor Potential (TRP) proteins are a large family of ion channels, grouped into seven sub-families. Although great advances have been made regarding the activation and modulation of TRP channel activity, detailed molecular mechanisms governing TRP channel gating are still needed. Sensitive to electric, chemical, mechanical, and thermal cues, TRP channels are tightly associated with the detection and integration of sensory input, emerging as a model to study the polymodal activation of ion channel proteins. Among TRP channels, the temperature-activated kind constitute a subgroup by itself, formed by Vanilloid receptors 1–4, Melastatin receptors 2, 4, 5, and 8, TRPC5, and TRPA1. Some of the so-called “thermoTRP” channels participate in the detection of noxious stimuli making them an interesting pharmacological target for the treatment of pain. However, the poor specificity of the compounds available in the market represents an important obstacle to overcome. Understanding the molecular mechanics underlying ligand-dependent modulation of TRP channels may help with the rational design of novel synthetic analgesics. The present review focuses on the structural basis of ligand-dependent activation of TRPV1 and TRPM8 channels. Special attention is drawn to the dissection of ligand-binding sites within TRPV1, PIP2-dependent modulation of TRP channels, and the structure of natural and synthetic ligands. PMID:24847275

  20. Hippocampal glucocorticoid receptor activation enhances voltage-dependent Ca2+ conductances: relevance to brain aging.

    PubMed Central

    Kerr, D S; Campbell, L W; Thibault, O; Landfield, P W

    1992-01-01

    Glucocorticoids (GCs) activate several biochemical/molecular processes in the hippocampus through two receptor types. In addition, GCs influence cognitive behaviors and hippocampal neural activity and can also increase the rate of aging-dependent cell loss in the hippocampus. However, the ionic mechanisms through which GCs modulate hippocampal neuronal function are not well understood. We report here direct evidence that activation of cytosolic steroid receptors, specifically of the type II GC receptor, can enhance voltage-dependent Ca2+ conductances in brain neurons. Ca2+ current was assessed by current-clamp measures of Ca2+ action potentials and by sharp electrode voltage-clamp analyses of voltage-sensitive currents in cesium-, tetrodotoxin-, and tetraethylammonium-treated CA1 neurons in hippocampal slices. Both Ca2+ action potentials and voltage-activated Ca2+ currents (N- and L-like) were increased by 2-hr exposure to the synthetic GC receptor agonist, RU 28362. This effect of RU 28362 was blocked by coincubation with cycloheximide, indicating that the GC receptor-Ca2+ channel interaction depends on de novo protein synthesis. Dysregulated calcium homeostasis is also viewed as a candidate mechanism in brain aging. Thus, present results are consistent with the hypothesis that excessive GC-receptor activation and resultant increased Ca2+ influx may be two sequential phases of a brain-aging process that results initially in impairment of function and eventually in neuronal loss. PMID:1528857

  1. Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α

    PubMed Central

    Zhu, Τao; Liang, Chen; Li, Dongdong; Tian, Miaomiao; Liu, Sanxiong; Gao, Guanjun; Guan, Ji-Song

    2016-01-01

    Activity-dependent transcription is critical for the regulation of long-term synaptic plasticity and plastic rewiring in the brain. Here, we report that the transcription of neurexin1α (nrxn1α), a presynaptic adhesion molecule for synaptic formation, is regulated by transient neuronal activation. We showed that 10 minutes of firing at 50 Hz in neurons repressed the expression of nrxn1α for 24 hours in a primary cortical neuron culture through a transcriptional repression mechanism. By performing a screening assay using a synthetic zinc finger protein (ZFP) to pull down the proteins enriched near the nrxn1α promoter region in vivo, we identified that Ash1L, a histone methyltransferase, is enriched in the nrxn1α promoter. Neuronal activity triggered binding of Ash1L to the promoter and enriched the histone marker H3K36me2 at the nrxn1α promoter region. Knockout of Ash1L in mice completely abolished the activity-dependent repression of nrxn1α. Taken together, our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning. PMID:27229316

  2. Multifractal features of magnetospheric dynamics and their dependence on solar activity

    NASA Astrophysics Data System (ADS)

    Gopinath, Sumesh

    2016-09-01

    In the present study, novel wavelet leaders (WL) based multifractal analysis has been used to get a better knowledge of the self-organization phenomena inherent in complex magnetospheric dynamics during disturbance and quiescent periods, focusing mainly on the intermittent features of auroral electrojet (AE) index. The results derived from the analysis certainly exhibit the phase transition property of magnetosphere system with respect to variabilities in the driving conditions. By using the novel WL method, solar activity dependence/independence of intermittency of magnetospheric proxies such as AE, SYM-H and Dst indices have been compared. The results indicate that the multifractality of AE index does not follow the solar activity cycle while intermittent features of SYM-H and Dst indices show high degree of solar activity dependence. This shows that along with the external solar wind perturbations, certain complex phenomena of internal origin also significantly modulate the dynamics of geomagnetic fluctuations in the auroral region.

  3. Lactate racemase is a nickel-dependent enzyme activated by a widespread maturation system

    PubMed Central

    Desguin, Benoît; Goffin, Philippe; Viaene, Eric; Kleerebezem, Michiel; Martin-Diaconescu, Vlad; Maroney, Michael J; Declercq, Jean-Paul; Soumillion, Patrice; Hols, Pascal

    2014-01-01

    Racemases catalyze the inversion of stereochemistry in biological molecules, giving the organism the ability to use both isomers. Among them, lactate racemase remains unexplored due to its intrinsic instability and lack of molecular characterization. Here we determine the genetic basis of lactate racemization in Lactobacillus plantarum. We show that, unexpectedly, the racemase is a nickel-dependent enzyme with a novel α/β fold. In addition, we decipher the process leading to an active enzyme, which involves the activation of the apo-enzyme by a single nickel-containing maturation protein that requires preactivation by two other accessory proteins. Genomic investigations reveal the wide distribution of the lactate racemase system among prokaryotes, showing the high significance of both lactate enantiomers in carbon metabolism. The even broader distribution of the nickel-based maturation system suggests a function beyond activation of the lactate racemase and possibly linked with other undiscovered nickel-dependent enzymes. PMID:24710389

  4. Developmental and activity-dependent plasticity of filiform hair receptors in the locust

    PubMed Central

    Pflüger, Hans-Joachim; Wolf, Harald

    2013-01-01

    A group of wind sensitive filiform hair receptors on the locust thorax and head makes contact onto a pair of identified interneuron, A4I1. The hair receptors' central nervous projections exhibit pronounced structural dynamics during nymphal development, for example, by gradually eliminating their ipsilateral dendritic field while maintaining the contralateral one. These changes are dependent not only on hormones controlling development but on neuronal activity as well. The hair-to-interneuron system has remarkably high gain (close to 1) and makes contact to flight steering muscles. During stationary flight in front of a wind tunnel, interneuron A4I1 is active in the wing beat rhythm, and in addition it responds strongly to stimulation of sensory hairs in its receptive field. A role of the hair-to-interneuron in flight steering is thus suggested. This system appears suitable for further study of developmental and activity-dependent plasticity in a sensorimotor context with known connectivity patterns. PMID:23986712

  5. Phospho-dependent Accumulation of GABABRs at Presynaptic Terminals after NMDAR Activation.

    PubMed

    Hannan, Saad; Gerrow, Kim; Triller, Antoine; Smart, Trevor G

    2016-08-16

    Here, we uncover a mechanism for regulating the number of active presynaptic GABAB receptors (GABABRs) at nerve terminals, an important determinant of neurotransmitter release. We find that GABABRs gain access to axon terminals by lateral diffusion in the membrane. Their relative accumulation is dependent upon agonist activation and the presence of the two distinct sushi domains that are found only in alternatively spliced GABABR1a subunits. Following brief activation of NMDA receptors (NMDARs) using glutamate, GABABR diffusion is reduced, causing accumulation at presynaptic terminals in a Ca(2+)-dependent manner that involves phosphorylation of GABABR2 subunits at Ser783. This signaling cascade indicates how synaptically released glutamate can initiate, via a feedback mechanism, increased levels of presynaptic GABABRs that limit further glutamate release and excitotoxicity. PMID:27498877

  6. Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner

    PubMed Central

    Schafer, Dorothy P; Lehrman, Emily K; Kautzman, Amanda G; Koyama, Ryuta; Mardinly, Alan R; Yamasaki, Ryo; Ransohoff, Richard M; Greenberg, Michael E; Barres, Ben A; Stevens, Beth

    2012-01-01

    SUMMARY Microglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses. PMID:22632727

  7. Structures of apicomplexan calcium-dependent protein kinases reveal mechanism of activation by calcium

    SciTech Connect

    Wernimont, Amy K; Artz, Jennifer D.; Jr, Patrick Finerty; Lin, Yu-Hui; Amani, Mehrnaz; Allali-Hassani, Abdellah; Senisterra, Guillermo; Vedadi, Masoud; Tempel, Wolfram; Mackenzie, Farrell; Chau, Irene; Lourido, Sebastian; Sibley, L. David; Hui, Raymond

    2010-09-21

    Calcium-dependent protein kinases (CDPKs) have pivotal roles in the calcium-signaling pathway in plants, ciliates and apicomplexan parasites and comprise a calmodulin-dependent kinase (CaMK)-like kinase domain regulated by a calcium-binding domain in the C terminus. To understand this intramolecular mechanism of activation, we solved the structures of the autoinhibited (apo) and activated (calcium-bound) conformations of CDPKs from the apicomplexan parasites Toxoplasma gondii and Cryptosporidium parvum. In the apo form, the C-terminal CDPK activation domain (CAD) resembles a calmodulin protein with an unexpected long helix in the N terminus that inhibits the kinase domain in the same manner as CaMKII. Calcium binding triggers the reorganization of the CAD into a highly intricate fold, leading to its relocation around the base of the kinase domain to a site remote from the substrate binding site. This large conformational change constitutes a distinct mechanism in calcium signal-transduction pathways.

  8. Epidermal cell growth-dependent arylhydrocarbon-hydroxylase (AHH) activity in vitro.

    PubMed

    Thiele, B; Merk, H F; Bonnekoh, B; Mahrle, G; Steigleder, G K

    1987-01-01

    Cytochrome P-450-dependent arylhydrocarbon-hydroxylase (AHH) activity and inducibility by benzanthracene (BA) was measured in cultured guinea pig and human epidermal cells. Basal AHH-activity (AHHb) in guinea pig epidermal cells was much higher than in human epidermal cells. AHHb in guinea pig epidermal cells was directly related to the labeling index and decreased to the original level between the 5th and 7th day of cell culturing. On the other hand, the induction-ratio of AHH reached its maximum level when the number of cells began to rise (proliferation phase) and remained high at day 7 of the cell culture. These results suggest a cell growth dependent activity and inducibility of carcinogen-metabolizing enzymes, such as AHH, in isolated epidermal cells. PMID:3435181

  9. Goal- and retrieval-dependent activity in the striatum during memory recognition.

    PubMed

    Clos, Mareike; Schwarze, Ulrike; Gluth, Sebastian; Bunzeck, Nico; Sommer, Tobias

    2015-06-01

    The striatum has been associated with successful memory retrieval but the precise functional link still remains unclear. One hypothesis is that striatal activity reflects an active evaluation process of the retrieval outcome dependent on the current behavioral goals rather than being a consequence of memory reactivation. We have recently shown that the striatum also correlates with confidence in memory recognition, which could reflect high subjective value ascribed to high certainty decisions. To examine whether striatal activity during memory recognition reflects subjective value indeed, we conducted an fMRI study using a recognition memory paradigm in which the participants rated not only the recognition confidence but also indicated the pleasantness associated with the previous memory retrieval. The results demonstrated a high positive correlation between confidence and pleasantness both on the behavioral and brain activation level particularly in the striatum. As almost all of variance in the striatal confidence signal could be explained by experienced pleasantness, this part of the striatal memory recognition response probably corresponds to greater subjective value of high confidence responses. While perceived oldness was also strongly correlated with striatal activity, this activation pattern was clearly distinct from that associated with confidence and pleasantness and thus could not be explained by higher subjective value to detect "old" items. Together, these results show that at least two independent processes contribute to striatal activation in recognition memory: a more flexible evaluation response dependent on context and goals captured by memory confidence and a potentially retrieval-related response captured by perceived oldness. PMID:25868676

  10. Climbing Fiber Regulation of Spontaneous Purkinje Cell Activity and Cerebellum-Dependent Blink Responses123

    PubMed Central

    Bengtsson, Fredrik

    2016-01-01

    Abstract It has been known for a long time that GABAergic Purkinje cells in the cerebellar cortex, as well as their target neurons in the cerebellar nuclei, are spontaneously active. The cerebellar output will, therefore, depend on how input is integrated into this spontaneous activity. It has been shown that input from climbing fibers originating in the inferior olive controls the spontaneous activity in Purkinje cells. While blocking climbing fiber input to the Purkinje cells causes a dramatic increase in the firing rate, increased climbing fiber activity results in reduced Purkinje cell activity. However, the exact calibration of this regulation has not been examined systematically. Here we examine the relation between climbing fiber stimulation frequency and Purkinje cell activity in unanesthetized decerebrated ferrets. The results revealed a gradual suppression of Purkinje cell activity, starting at climbing fiber stimulation frequencies as low as 0.5 Hz. At 4 Hz, Purkinje cells were completely silenced. This effect lasted an average of 2 min after the stimulation rate was reduced to a lower level. We also examined the effect of sustained climbing fiber stimulation on overt behavior. Specifically, we analyzed conditioned blink responses, which are known to be dependent on the cerebellum, while stimulating the climbing fibers at different frequencies. In accordance with the neurophysiological data, the conditioned blink responses were suppressed at stimulation frequencies of ≥4 Hz. PMID:26839917

  11. What Lies Beneath: Antibody Dependent Natural Killer Cell Activation by Antibodies to Internal Influenza Virus Proteins.

    PubMed

    Vanderven, Hillary A; Ana-Sosa-Batiz, Fernanda; Jegaskanda, Sinthujan; Rockman, Steven; Laurie, Karen; Barr, Ian; Chen, Weisan; Wines, Bruce; Hogarth, P Mark; Lambe, Teresa; Gilbert, Sarah C; Parsons, Matthew S; Kent, Stephen J

    2016-06-01

    The conserved internal influenza proteins nucleoprotein (NP) and matrix 1 (M1) are well characterised for T cell immunity, but whether they also elicit functional antibodies capable of activating natural killer (NK) cells has not been explored. We studied NP and M1-specific ADCC activity using biochemical, NK cell activation and killing assays with plasma from healthy and influenza-infected subjects. Healthy adults had antibodies to M1 and NP capable of binding dimeric FcγRIIIa and activating NK cells. Natural symptomatic and experimental influenza infections resulted in a rise in antibody dependent NK cell activation post-infection to the hemagglutinin of the infecting strain, but changes in NK cell activation to M1 and NP were variable. Although antibody dependent killing of target cells infected with vaccinia viruses expressing internal influenza proteins was not detected, opsonising antibodies to NP and M1 likely contribute to an antiviral microenvironment by stimulating innate immune cells to secrete cytokines early in infection. We conclude that effector cell activating antibodies to conserved internal influenza proteins are common in healthy and influenza-infected adults. Given the significance of such antibodies in animal models of heterologous influenza infection, the definition of their importance and mechanism of action in human immunity to influenza is essential. PMID:27428437

  12. Differential Activity-Dependent Secretion of Brain-Derived Neurotrophic Factor from Axon and Dendrite

    PubMed Central

    Matsuda, Naoto; Lu, Hui; Fukata, Yuko; Noritake, Jun; Gao, Hongfeng; Mukherjee, Sujay; Nemoto, Tomomi; Fukata, Masaki

    2009-01-01

    Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival and differentiation during development and for synaptic function and plasticity in the mature brain. BDNF-containing vesicles are widely distributed and bidirectionally transported in neurons, and secreted BDNF can act on both presynaptic and postsynaptic cells. Activity-dependent BDNF secretion from neuronal cultures has been reported, but it remains unknown where the primary site of BDNF secretion is and whether neuronal activity can trigger BDNF secretion from axons and dendrites with equal efficacy. Using BDNF fused with pH-sensitive green fluorescent protein to visualize BDNF secretion, we found that BDNF-containing vesicles exhibited markedly different properties of activity-dependent exocytic fusion at the axon and dendrite of cultured hippocampal neurons. Brief spiking activity triggered a transient fusion pore opening, followed by immediate retrieval of vesicles without dilation of the fusion pore, resulting in very little BDNF secretion at the axon. On the contrary, the same brief spiking activity induced “full-collapse” vesicle fusion and substantial BDNF secretion at the dendrite. However, full vesicular fusion with BDNF secretion could occur at the axon when the neuron was stimulated by prolonged high-frequency activity, a condition neurons may encounter during epileptic discharge. Thus, activity-dependent axonal secretion of BDNF is highly restricted as a result of incomplete fusion of BDNF-containing vesicles, and normal neural activity induces BDNF secretion from dendrites, consistent with the BDNF function as a retrograde factor. Our study also revealed a novel mechanism by which differential exocytosis of BDNF-containing vesicles may regulate BDNF–TrkB signaling between connected neurons. PMID:19906967

  13. Temperature dependence of the activity of polyphenol peroxidases and polyphenol oxidases in modern and buried soils

    NASA Astrophysics Data System (ADS)

    Yakushev, A. V.; Kuznetsova, I. N.; Blagodatskaya, E. V.; Blagodatsky, S. A.

    2014-05-01

    Under conditions of the global climate warming, the changes in the reserves of soil humus depend on the temperature sensitivities of polyphenol peroxidases (PPPOs) and polyphenol oxidases (PPOs). They play an important role in lignin decomposition, mineralization, and humus formation. The temperature dependence of the potential enzyme activity in modern and buried soils has been studied during incubation at 10 or 20°C. The experimental results indicate that it depends on the availability of the substrate and the presence of oxygen. The activity of PPOs during incubation in the absence of oxygen for two months decreases by 2-2.5 times, which is balanced by an increase in the activity of PPPOs by 2-3 times. The increase in the incubation temperature to 20°C and the addition of glucose accelerates this transition due to the more abrupt decrease in the activity of PPOs. The preincubation of the soil with glucose doubles the activity of PPPOs but has no significant effect on the activity of PPOs. The different effects of temperature on two groups of the studied oxidases and the possibility of substituting enzymes by those of another type under changing aeration conditions should be taken into consideration in predicting the effect of the climate warming on the mineralization of the soil organic matter. The absence of statistically significant differences in the enzymatic activity between the buried and modern soil horizons indicates the retention by the buried soil of some of its properties (soil memory) and the rapid restoration of high enzymatic activity during the preincubation.

  14. Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors

    PubMed Central

    Tigerholm, Jenny; Petersson, Marcus E.; Obreja, Otilia; Lampert, Angelika; Carr, Richard; Schmelz, Martin

    2013-01-01

    Action potential initiation and conduction along peripheral axons is a dynamic process that displays pronounced activity dependence. In patients with neuropathic pain, differences in the modulation of axonal conduction velocity by activity suggest that this property may provide insight into some of the pathomechanisms. To date, direct recordings of axonal membrane potential have been hampered by the small diameter of the fibers. We have therefore adopted an alternative approach to examine the basis of activity-dependent changes in axonal conduction by constructing a comprehensive mathematical model of human cutaneous C-fibers. Our model reproduced axonal spike propagation at a velocity of 0.69 m/s commensurate with recordings from human C-nociceptors. Activity-dependent slowing (ADS) of axonal propagation velocity was adequately simulated by the model. Interestingly, the property most readily associated with ADS was an increase in the concentration of intra-axonal sodium. This affected the driving potential of sodium currents, thereby producing latency changes comparable to those observed for experimental ADS. The model also adequately reproduced post-action potential excitability changes (i.e., recovery cycles) observed in vivo. We performed a series of control experiments replicating blockade of particular ion channels as well as changing temperature and extracellular ion concentrations. In the absence of direct experimental approaches, the model allows specific hypotheses to be formulated regarding the mechanisms underlying activity-dependent changes in C-fiber conduction. Because ADS might functionally act as a negative feedback to limit trains of nociceptor activity, we envisage that identifying its mechanisms may also direct efforts aimed at alleviating neuronal hyperexcitability in pain patients. PMID:24371290

  15. Using Claims Data to Predict Dependency in Activities of Daily Living as a Proxy for Frailty

    PubMed Central

    Faurot, Keturah R.; Funk, Michele Jonsson; Pate, Virginia; Brookhart, M. Alan; Patrick, Amanda; Hanson, Laura C.; Castillo, Wendy Camelo; Stürmer, Til

    2014-01-01

    Purpose Estimating drug effectiveness and safety among older adults in population-based studies using administrative healthcare claims can be hampered by unmeasured confounding due to frailty. A claims-based algorithm that identifies patients likely to be dependent, a proxy for frailty, may improve confounding control. Our objective was to develop an algorithm to predict dependency in activities of daily living (ADL) in a sample of Medicare beneficiaries. Methods Community-dwelling respondents to the 2006 Medicare Current Beneficiary Survey, >65 years old, with Medicare Part A, B, home health, and hospice claims were included. ADL dependency was defined as needing help with bathing, eating, walking, dressing, toileting, or transferring. Potential predictors were demographics, ICD-9 diagnosis/procedure and durable medical equipment codes for frailty-associated conditions. Multivariable logistic regression was to predict ADL dependency. Cox models estimated hazard ratios for death as a function of observed and predicted ADL dependency. Results Of 6391 respondents, 57% were female, 88% white, and 38% were ≥80. The prevalence of ADL dependency was 9.5%. Strong predictors of ADL dependency were charges for a home hospital bed (OR=5.44, 95% CI=3.28–9.03) and wheelchair (OR=3.91, 95% CI=2.78–5.51). The c-statistic of the final model was 0.845. Model-predicted ADL dependency of 20% or greater was associated with a hazard ratio for death of 3.19 (95% CI: 2.78, 3.68). Conclusions An algorithm for predicting ADL dependency using healthcare claims was developed to measure some aspects of frailty. Accounting for variation in frailty among older adults could lead to more valid conclusions about treatment use, safety, and effectiveness. PMID:25335470

  16. Size-dependent regulation of synchronized activity in living neuronal networks

    NASA Astrophysics Data System (ADS)

    Yamamoto, Hideaki; Kubota, Shigeru; Chida, Yudai; Morita, Mayu; Moriya, Satoshi; Akima, Hisanao; Sato, Shigeo; Hirano-Iwata, Ayumi; Tanii, Takashi; Niwano, Michio

    2016-07-01

    We study the effect of network size on synchronized activity in living neuronal networks. Dissociated cortical neurons form synaptic connections in culture and generate synchronized spontaneous activity within 10 days in vitro. Using micropatterned surfaces to extrinsically control the size of neuronal networks, we show that synchronized activity can emerge in a network as small as 12 cells. Furthermore, a detailed comparison of small (˜20 cells), medium (˜100 cells), and large (˜400 cells) networks reveal that synchronized activity becomes destabilized in the small networks. A computational modeling of neural activity is then employed to explore the underlying mechanism responsible for the size effect. We find that the generation and maintenance of the synchronized activity can be minimally described by: (1) the stochastic firing of each neuron in the network, (2) enhancement in the network activity in a positive feedback loop of excitatory synapses, and (3) Ca-dependent suppression of bursting activity. The model further shows that the decrease in total synaptic input to a neuron that drives the positive feedback amplification of correlated activity is a key factor underlying the destabilization of synchrony in smaller networks. Spontaneous neural activity plays a critical role in cortical information processing, and our work constructively clarifies an aspect of the structural basis behind this.

  17. Size-dependent regulation of synchronized activity in living neuronal networks.

    PubMed

    Yamamoto, Hideaki; Kubota, Shigeru; Chida, Yudai; Morita, Mayu; Moriya, Satoshi; Akima, Hisanao; Sato, Shigeo; Hirano-Iwata, Ayumi; Tanii, Takashi; Niwano, Michio

    2016-07-01

    We study the effect of network size on synchronized activity in living neuronal networks. Dissociated cortical neurons form synaptic connections in culture and generate synchronized spontaneous activity within 10 days in vitro. Using micropatterned surfaces to extrinsically control the size of neuronal networks, we show that synchronized activity can emerge in a network as small as 12 cells. Furthermore, a detailed comparison of small (∼20 cells), medium (∼100 cells), and large (∼400 cells) networks reveal that synchronized activity becomes destabilized in the small networks. A computational modeling of neural activity is then employed to explore the underlying mechanism responsible for the size effect. We find that the generation and maintenance of the synchronized activity can be minimally described by: (1) the stochastic firing of each neuron in the network, (2) enhancement in the network activity in a positive feedback loop of excitatory synapses, and (3) Ca-dependent suppression of bursting activity. The model further shows that the decrease in total synaptic input to a neuron that drives the positive feedback amplification of correlated activity is a key factor underlying the destabilization of synchrony in smaller networks. Spontaneous neural activity plays a critical role in cortical information processing, and our work constructively clarifies an aspect of the structural basis behind this. PMID:27575164

  18. In vitro transcriptional activation by a metabolic intermediate: activation by Leu3 depends on alpha-isopropylmalate.

    PubMed

    Sze, J Y; Woontner, M; Jaehning, J A; Kohlhaw, G B

    1992-11-13

    In the absence of the leucine biosynthetic precursor alpha-isopropylmalate (alpha-IPM), the yeast LEU3 protein (Leu3p) binds DNA and acts as a transcriptional repressor in an in vitro extract. Addition of alpha-IPM resulted in a dramatic increase in Leu3p-dependent transcription. The presence of alpha-IPM was also required for Leu3p to compete effectively with another transcriptional activator, GAL4/VP16, for limiting transcription factors. Therefore, the addition of alpha-IPM appears to convert a transcriptional repressor into an activator. This represents an example in eukaryotes of direct transcriptional regulation by a small effector molecule. PMID:1439822

  19. Comparative Study of the Activity of Brain Behavioral Systems in Methamphetamine and Opiate Dependents

    PubMed Central

    Alemikhah, Marjan; Faridhosseini, Farhad; Kordi, Hassan; Rasouli-Azad, Morad; Shahini, Najmeh

    2016-01-01

    Background: Substance dependency is a major problem for the general health of a society. Different approaches have investigated the substance dependency in order to explain it. Gray’s reinforcement sensitivity theory (RST) is an advanced and important neuropsychological theory in this area. Objectives: The aim of this study was to compare three systems of the revised reinforcement sensitivity theory the behavioral activation system (r-BAS), the revised behavioral inhibition system (r-BIS), and the revised fight/flight/freezing system (r-FFFS) between patients dependent on methamphetamine and opiates, and a group of controls. Patients and Methods: This research was a causal-comparative study that was conducted in the first six months of 2012. The population of the study was males of Mashhad city, who were dependent on methamphetamine or opiates, and ruling out psychotic disorders and prominent Axis II. Twenty-five people were selected by the convenient sampling method. Also, 25 non-dependent people from the patients’ relatives were selected and matched for the variables of age, gender, and education to participate in this study. Participants were evaluated using a structured clinical interview (SCID) for DSM-IV, demographic questionnaire information, and a Jackson-5 questionnaire (2009). Data were analyzed by Chi-square, K-S, and independent t-test. Results: The methamphetamine dependent group had a higher sensitivity in the r-BAS, r-BIS, and the r-Fight and r-Freezing systems compared to the control group (P < 0.05). However, there was no significant difference in r-Flight between the two groups (P > 0.05). “The scores of r-BIS were also significantly higher in the methamphetamine-dependent group than the opioid-dependent and control groups. For the r-Fight variable, the methamphetamine-dependent group was higher than the opioid-dependent group”. Conclusions: The personality patterns of patients dependent on methamphetamines were different from the controls

  20. Long Lasting Protein Synthesis- and Activity-Dependent Spine Shrinkage and Elimination after Synaptic Depression

    PubMed Central

    Ramiro-Cortés, Yazmín; Israely, Inbal

    2013-01-01

    Neuronal circuits modify their response to synaptic inputs in an experience-dependent fashion. Increases in synaptic weights are accompanied by structural modifications, and activity dependent, long lasting growth of dendritic spines requires new protein synthesis. When multiple spines are potentiated within a dendritic domain, they show dynamic structural plasticity changes, indicating that spines can undergo bidirectional physical modifications. However, it is unclear whether protein synthesis dependent synaptic depression leads to long lasting structural changes. Here, we investigate the structural correlates of protein synthesis dependent long-term depression (LTD) mediated by metabotropic glutamate receptors (mGluRs) through two-photon imaging of dendritic spines on hippocampal pyramidal neurons. We find that induction of mGluR-LTD leads to robust and long lasting spine shrinkage and elimination that lasts for up to 24 hours. These effects depend on signaling through group I mGluRs, require protein synthesis, and activity. These data reveal a mechanism for long lasting remodeling of synaptic inputs, and offer potential insights into mental retardation. PMID:23951097

  1. Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus.

    PubMed

    Kim, Jynho; Kato, Masaki; Beachy, Philip A

    2009-12-22

    Stimulation by the extracellular Hedgehog (Hh) protein signal has been shown to alter ciliary localization of the mammalian Hh receptor components Smoothened (Smo) and Patched (Ptc), and mutations that disrupt the structure and function of the cilium also disrupt Hh-induced changes in gene expression. But how ciliary events affect gene expression in the nucleus is not known, and to address this question we have characterized the cellular trafficking of Gli2, the principal mediator of Hh-dependent transcriptional activation. From a combination of pharmacological and genetic manipulations we find in resting cells that both Gli2 and Smo appear to shuttle in and out of the cilium, with Gli2 but not Smo requiring intact cytoplasmic microtubules for ciliary entry and both requiring the ciliary retrograde motor, cytoplasmic dynein 2, for ciliary exit. We also find that changes in ciliary and nuclear trafficking of Gli2 are triggered by the Hh-dependent accumulation of activated Smo in the cilium, resulting in a shift from primarily cytoplasmic localization to accumulation at the distal tip of the cilium and within the nucleus. Gli2 thus functions as a dynamic monitor of Smo activity in the cilium and thereby links Hh pathway activation in the cilium to transcriptional activation in the nucleus. PMID:19996169

  2. Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent

    PubMed Central

    Bonenfant, Débora; Rubert, Joëlle; Vangrevelinghe, Eric; Scheufler, Clemens; Marque, Fanny; Régnier, Catherine H.; De Pover, Alain; Ryckelynck, Hugues; Bhagwat, Neha; Koppikar, Priya; Goel, Aviva; Wyder, Lorenza; Tavares, Gisele; Baffert, Fabienne; Pissot-Soldermann, Carole; Manley, Paul W.; Gaul, Christoph; Voshol, Hans; Levine, Ross L.; Sellers, William R.; Hofmann, Francesco; Radimerski, Thomas

    2016-01-01

    JAK inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type-I binding mode leads to an increase in JAK activation-loop phosphorylation, despite blockade of kinase function. Here we report that stabilizing the inactive state via type-II inhibition acts in the opposite manner, leading to a loss of activation-loop phosphorylation. We used X-ray crystallography to corroborate the binding mode and report for the first time the crystal structure of the JAK2 kinase domain in an inactive conformation. Importantly, JAK inhibitor-induced activation-loop phosphorylation requires receptor interaction, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation stabilized by a JAK inhibitor, hyperphosphorylation of the activation-loop may or may not be elicited. PMID:22684457

  3. A novel approach for reliable activity determination of ascorbic acid depending myrosinases.

    PubMed

    Kleinwächter, Maik; Selmar, Dirk

    2004-06-30

    Up to now, a wide array of methods for the determination of myrosinase activity has been described. These vary from the simple photometric estimation to highly sophisticated assays using radioactively labelled substrates. However, ascorbic acid--an effective activator of myrosinases--interferes with most of these enzyme tests. Unfortunately, in the past, such interferences were disregarded in many scientific examinations of myrosinases. Whereas such failings have less effects when the activation of myrosinases is not very distinctive, they are quite relevant in all cases where myrosinases are completely inactive in the absence of ascorbic acid. In this paper, the current methods for myrosinase determination are reviewed critically with special emphasis on putative interferences with ascorbic acid. Thereafter, an alternative and interference-free HPLC-based quantification method of the enzymatically produced glucose is presented. Due to the benzoylation of glucose, it becomes possible to quantify even those exiguous glucose concentrations, which are indispensable for correct determination of kinetic enzyme data in the presence of ascorbic acid. Using this new method, the activity of Tropaeolum majus myrosinase towards glucotropaeolin was analyzed. This enzyme shows a distinctive activation by ascorbic acid with maximal activation at a concentration of about 2 mM. PMID:15165756

  4. Structure-activity relationship study of angiotensin II analogs in terms of β-arrestin-dependent signaling to aldosterone production.

    PubMed

    Valero, Thairy Reyes; Sturchler, Emmanuel; Jafferjee, Malika; Rengo, Giuseppe; Magafa, Vassiliki; Cordopatis, Paul; McDonald, Patricia; Koch, Walter J; Lymperopoulos, Anastasios

    2016-04-01

    The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion induction, a steroid hormone that contributes to the pathology of postmyocardial infarction (MI) heart failure (HF), is mediated by both Gq/11 proteins and β-arrestins, both of which couple to the AngII type 1 receptors (AT1Rs) of adrenocortical zona glomerulosa (AZG) cells. Over the past several years, AngII analogs with increased selectivity ("bias") toward β-arrestin-dependent signaling at the AT1R have been designed and described, starting with SII, the gold-standard β-arrestin-"biased" AngII analog. In this study, we examined the relative potencies of an extensive series of AngII peptide analogs at relative activation of G proteins versus β-arrestins by the AT1R. The major structural difference of these peptides from SII was their varied substitutions at position 5, rather than position 4 of native AngII. Three of them were found biased for β-arrestin activation and extremely potent at stimulating aldosterone secretion in AZG cells in vitro, much more potent than SII in that regard. Finally, the most potent of these three ([Sar(1), Cys(Et)(5), Leu(8)]-AngII, CORET) was further examined in post-MI rats progressing to HF and overexpressing adrenal β-arrestin1 in vivo. Consistent with the in vitro studies, CORET was found to exacerbate the post-MI hyperaldosteronism, and, consequently, cardiac function of the post-MI animals in vivo. Finally, our data suggest that increasing the size of position 5 of the AngII peptide sequence results in directly proportional increases in AT1R-dependent β-arrestin activation. These findings provide important insights for AT1R pharmacology and future AngII-targeted drug development. PMID:27069636

  5. Striatal Volume Increases in Active Methamphetamine-Dependent Individuals and Correlation with Cognitive Performance

    PubMed Central

    Jan, Reem K.; Lin, Joanne C.; Miles, Sylvester W.; Kydd, Rob R.; Russell, Bruce R.

    2012-01-01

    The effect of methamphetamine (MA) dependence on the structure of the human brain has not been extensively studied, especially in active users. Previous studies reported cortical deficits and striatal gains in grey matter (GM) volume of abstinent MA abusers compared with control participants. This study aimed to investigate structural GM changes in the brains of 17 active MA-dependent participants compared with 20 control participants aged 18–46 years using voxel-based morphometry and region of interest volumetric analysis of structural magnetic resonance imaging data, and whether these changes might be associated with cognitive performance. Significant volume increases were observed in the right and left putamen and left nucleus accumbens of MA-dependent compared to control participants. The volumetric gain in the right putamen remained significant after Bonferroni correction, and was inversely correlated with the number of errors (standardised z-scores) on the Go/No-go task. MA-dependent participants exhibited cortical GM deficits in the left superior frontal and precentral gyri in comparison to control participants, although these findings did not survive correction for multiple comparisons. In conclusion, consistent with findings from previous studies of abstinent users, active chronic MA-dependent participants showed significant striatal enlargement which was associated with improved performance on the Go/No-go, a cognitive task of response inhibition and impulsivity. Striatal enlargement may reflect the involvement of neurotrophic effects, inflammation or microgliosis. However, since it was associated with improved cognitive function, it is likely to reflect a compensatory response to MA-induced neurotoxicity in the striatum, in order to maintain cognitive function. Follow-up studies are recommended to ascertain whether this effect continues to be present following abstinence. Several factors may have contributed to the lack of more substantial cortical and

  6. Integrin-Dependent Activation of the JNK Signaling Pathway by Mechanical Stress

    PubMed Central

    Kanger, Johannes S.; Subramaniam, Vinod; Martin-Blanco, Enrique

    2011-01-01

    Mechanical force is known to modulate the activity of the Jun N-terminal kinase (JNK) signaling cascade. However, the effect of mechanical stresses on JNK signaling activation has previously only been analyzed by in vitro detection methods. It still remains unknown how living cells activate the JNK signaling cascade in response to mechanical stress and what its functions are in stretched cells. We assessed in real-time the activity of the JNK pathway in Drosophila cells by Fluorescence Lifetime Imaging Microscopy (FLIM), using an intramolecular phosphorylation-dependent dJun-FRET (Fluorescence Resonance Energy Transfer) biosensor. We found that quantitative FRET-FLIM analysis and confocal microscopy revealed sustained dJun-FRET biosensor activation and stable morphology changes in response to mechanical stretch for Drosophila S2R+ cells. Further, these cells plated on different substrates showed distinct levels of JNK activity that associate with differences in cell morphology, integrin expression and focal adhesion organization. These data imply that alterations in the cytoskeleton and matrix attachments may act as regulators of JNK signaling, and that JNK activity might feed back to modulate the cytoskeleton and cell adhesion. We found that this dynamic system is highly plastic; at rest, integrins at focal adhesions and talin are key factors suppressing JNK activity, while multidirectional static stretch leads to integrin-dependent, and probably talin-independent, Jun sensor activation. Further, our data suggest that JNK activity has to coordinate with other signaling elements for the regulation of the cytoskeleton and cell shape remodeling associated with stretch. PMID:22180774

  7. Size-dependent catalytic activity and dynamics of gold nanoparticles at the single-molecule level.

    PubMed

    Zhou, Xiaochun; Xu, Weilin; Liu, Guokun; Panda, Debashis; Chen, Peng

    2010-01-13

    Nanoparticles are important catalysts for petroleum processing, energy conversion, and pollutant removal. As compared to their bulk counterparts, their often superior or new catalytic properties result from their nanometer size, which gives them increased surface-to-volume ratios and chemical potentials. The size of nanoparticles is thus pivotal for their catalytic properties. Here, we use single-molecule fluorescence microscopy to study the size-dependent catalytic activity and dynamics of spherical Au-nanoparticles under ambient solution conditions. By monitoring the catalysis of individual Au-nanoparticles of three different sizes in real time with single-turnover resolution, we observe clear size-dependent activities in both the catalytic product formation reaction and the product dissociation reaction. Within a model of classical thermodynamics, these size-dependent activities of Au-nanoparticles can be accounted for by the changes in the adsorption free energies of the substrate resazurin and the product resorufin because of the nanosize effect. We also observe size-dependent differential selectivity of the Au-nanoparticles between two parallel product dissociation pathways, with larger nanoparticles less selective between the two pathways. The particle size also strongly influences the surface-restructuring-coupled catalytic dynamics; both the catalysis-induced and the spontaneous dynamic surface restructuring occur more readily for smaller Au-nanoparticles due to their higher surface energies. Using a simple thermodynamic model, we analyze the catalysis- and size-dependent dynamic surface restructuring quantitatively; the results provide estimates on the activation energies and time scales of spontaneous dynamic surface restructuring that are fundamental to heterogeneous catalysis in both the nano- and the macro-scale. This study further exemplifies the power of the single-molecule approach in probing the intricate workings of nanoscale catalysts. PMID

  8. pH-dependent biotransformation of ionizable organic micropollutants in activated sludge.

    PubMed

    Gulde, Rebekka; Helbling, Damian E; Scheidegger, Andreas; Fenner, Kathrin

    2014-12-01

    Removal of micropollutants (MPs) during activated sludge treatment can mainly be attributed to biotransformation and sorption to sludge flocs, whereby the latter process is known to be of minor importance for polar organic micropollutants. In this work, we investigated the influence of pH on the biotransformation of MPs with cationic-neutral speciation in an activated sludge microbial community. We performed batch biotransformation, sorption control, and abiotic control experiments for 15 MPs with cationic-neutral speciation, one control MP with neutral-anionic speciation, and two neutral MPs at pHs 6, 7, and 8. Biotransformation rate constants corrected for sorption and abiotic processes were estimated from measured concentration time series with Bayesian inference. We found that biotransformation is pH-dependent and correlates qualitatively with the neutral fraction of the ionizable MPs. However, a simple speciation model based on the assumption that only the neutral species is efficiently taken up and biotransformed by the cells tends to overpredict the effect of speciation. Therefore, additional mechanisms such as uptake of the ionic species and other more complex attenutation mechanisms are discussed. Finally, we observed that the sorption coefficients derived from our control experiments were small and showed no notable pH-dependence. From this we conclude that pH-dependent removal of polar, ionizable organic MPs in activated sludge systems is less likely an effect of pH-dependent sorption but rather of pH-dependent biotransformation. The latter has the potential to cause marked differences in the removal of polar, ionizable MPs at different operational pHs during activated sludge treatment. PMID:25337862

  9. Energy and angular dependence of active-type personal dosemeter for high-energy neutron.

    PubMed

    Rito, Hirotaka; Yamauchi, Tomoya; Oda, Keiji

    2011-07-01

    In order to develop an active-type personal dosemeter having suitable sensitivity to high-energy neutrons, the characteristic response of silicon surface barrier detector has been investigated experimentally and theoretically. An agreement of the shape of pulse-height distribution, its change with radiator thickness and the relative sensitivity was confirmed between the calculated and experimental results for 14.8-MeV neutrons. The angular dependence was estimated for other neutron energies, and found that the angular dependence decreased with the incident energy. The reason was also discussed with regard to the radiator thickness relative to maximum range of recoil protons. PMID:21613268

  10. FIS-dependent trans activation of stable RNA operons of Escherichia coli under various growth conditions.

    PubMed Central

    Nilsson, L; Verbeek, H; Vijgenboom, E; van Drunen, C; Vanet, A; Bosch, L

    1992-01-01

    In Escherichia coli transcription of the tRNA operon thrU (tufB) and the rRNA operon rrnB is trans-activated by the protein FIS. This protein, which stimulates the inversion of various viral DNA segments, binds specifically to a cis-acting sequence (designated UAS) upstream of the promoter of thrU (tufB) and the P1 promoter of the rrnB operon. There are indications that this type of regulation is representative for the regulation of more stable RNA operons. In the present investigation we have studied UAS-dependent transcription activation of the thrU (tufB) operon in the presence and absence of FIS during a normal bacterial growth cycle and after a nutritional shift-up. In early log phase the expression of the operon rises steeply in wild-type cells, whereafter it declines. Concomitantly, a peak of the cellular FIS concentration is observed. Cells in the stationary phase are depleted of FIS. The rather abrupt increase of transcription activation depends on the nutritional quality of the medium. It is not seen in minimal medium. After a shift from minimal to rich medium, a peak of transcription activation and of FIS concentration is measured. This peak gets higher as the medium gets more strongly enriched. We conclude that a correlation between changes of the UAS-dependent activation of the thrU (tufB) operon and changes of the cellular FIS concentration under a variety of experimental conditions exists. This correlation strongly suggests that the production of FIS responds to environmental signals, thereby trans-activating the operon. Cells unable to produce FIS (fis cells) also show an increase of operon transcription in the early log phase and after a nutritional shift-up, albeit less pronounced than that wild-type cells. Presumably it is controlled by the ribosome feedback regulatory system. cis activation of the operon by the upstream activator sequence is apparent in the absence of FIS. This activation is constant throughout the entire growth cycle and is

  11. FIS-dependent trans activation of stable RNA operons of Escherichia coli under various growth conditions.

    PubMed

    Nilsson, L; Verbeek, H; Vijgenboom, E; van Drunen, C; Vanet, A; Bosch, L

    1992-02-01

    In Escherichia coli transcription of the tRNA operon thrU (tufB) and the rRNA operon rrnB is trans-activated by the protein FIS. This protein, which stimulates the inversion of various viral DNA segments, binds specifically to a cis-acting sequence (designated UAS) upstream of the promoter of thrU (tufB) and the P1 promoter of the rrnB operon. There are indications that this type of regulation is representative for the regulation of more stable RNA operons. In the present investigation we have studied UAS-dependent transcription activation of the thrU (tufB) operon in the presence and absence of FIS during a normal bacterial growth cycle and after a nutritional shift-up. In early log phase the expression of the operon rises steeply in wild-type cells, whereafter it declines. Concomitantly, a peak of the cellular FIS concentration is observed. Cells in the stationary phase are depleted of FIS. The rather abrupt increase of transcription activation depends on the nutritional quality of the medium. It is not seen in minimal medium. After a shift from minimal to rich medium, a peak of transcription activation and of FIS concentration is measured. This peak gets higher as the medium gets more strongly enriched. We conclude that a correlation between changes of the UAS-dependent activation of the thrU (tufB) operon and changes of the cellular FIS concentration under a variety of experimental conditions exists. This correlation strongly suggests that the production of FIS responds to environmental signals, thereby trans-activating the operon. Cells unable to produce FIS (fis cells) also show an increase of operon transcription in the early log phase and after a nutritional shift-up, albeit less pronounced than that wild-type cells. Presumably it is controlled by the ribosome feedback regulatory system. cis activation of the operon by the upstream activator sequence is apparent in the absence of FIS. This activation is constant throughout the entire growth cycle and is

  12. Loneliness in elderly individuals, level of dependence in activities of daily living (ADL) and influential factors.

    PubMed

    Hacihasanoğlu, Rabia; Yildirim, Arzu; Karakurt, Papatya

    2012-01-01

    This study has been carried out to investigate the level of loneliness, determine the level of dependence in the ADL and influential factors in the elderly people. This descriptive, cross-sectional study was conducted in 5 Family Healthcare Centers (FHC) located in central Erzincan, Turkey between March and June 2010. The data of the research was collected using a questionnaire that determined the descriptive and UCLA Loneliness Scale (UCLA-LS). Mean score of the UCLA-LS was determined as 51.59 ± 4.44. It was determined that 2% of the elderly ADL were completely dependent, 14.5% were semi-dependent. Factors such as being old, a widow/divorced, having a lower level of education and/or income, living alone, having a chronic disease, poor self-perceived health, lack of visits by relatives or acquaintances, dissatisfaction with the place of living, and being fully dependent while performing daily activities were determined as factors which increased the level of loneliness. Furthermore, factors such as being old, a female, a widow/divorced, living together with a daughter/son, having a chronic disease and poor self-perceived health were found to be influential in dependency. Elderly people who are alone and dependent in fulfilling their ADL should be monitored more closely. PMID:21514680

  13. Time-varying BRDFs.

    PubMed

    Sun, Bo; Sunkavalli, Kalyan; Ramamoorthi, Ravi; Belhumeur, Peter N; Nayar, Shree K

    2007-01-01

    The properties of virtually all real-world materials change with time, causing their bidirectional reflectance distribution functions (BRDFs) to be time varying. However, none of the existing BRDF models and databases take time variation into consideration; they represent the appearance of a material at a single time instance. In this paper, we address the acquisition, analysis, modeling, and rendering of a wide range of time-varying BRDFs (TVBRDFs). We have developed an acquisition system that is capable of sampling a material's BRDF at multiple time instances, with each time sample acquired within 36 sec. We have used this acquisition system to measure the BRDFs of a wide range of time-varying phenomena, which include the drying of various types of paints (watercolor, spray, and oil), the drying of wet rough surfaces (cement, plaster, and fabrics), the accumulation of dusts (household and joint compound) on surfaces, and the melting of materials (chocolate). Analytic BRDF functions are fit to these measurements and the model parameters' variations with time are analyzed. Each category exhibits interesting and sometimes nonintuitive parameter trends. These parameter trends are then used to develop analytic TVBRDF models. The analytic TVBRDF models enable us to apply effects such as paint drying and dust accumulation to arbitrary surfaces and novel materials. PMID:17356224

  14. Trim9 regulates activity-dependent fine-scale topography in Drosophila.

    PubMed

    Yang, Limin; Li, Ruonan; Kaneko, Takuya; Takle, Kendra; Morikawa, Rei K; Essex, Laura; Wang, Xin; Zhou, Jie; Emoto, Kazuo; Xiang, Yang; Ye, Bing

    2014-05-01

    Topographic projection of afferent terminals into 2D maps in the CNS is a general strategy used by the nervous system to encode the locations of sensory stimuli. In vertebrates, it is known that although guidance cues are critical for establishing a coarse topographic map, neural activity directs fine-scale topography between adjacent afferent terminals [1-4]. However, the molecular mechanism underlying activity-dependent regulation of fine-scale topography is poorly understood. Molecular analysis of the spatial relationship between adjacent afferent terminals requires reliable localization of the presynaptic terminals of single neurons as well as genetic manipulations with single-cell resolution in vivo. Although both requirements can potentially be met in Drosophila melanogaster [5, 6], no activity-dependent topographic system has been identified in flies [7]. Here we report a topographic system that is shaped by neuronal activity in Drosophila. With this system, we found that topographic separation of the presynaptic terminals of adjacent nociceptive neurons requires different levels of Trim9, an evolutionarily conserved signaling molecule [8-11]. Neural activity regulates Trim9 protein levels to direct fine-scale topography of sensory afferents. This study offers both a novel mechanism by which neural activity directs fine-scale topography of axon terminals and a new system to study this process at single-neuron resolution. PMID:24746793

  15. Procaspase-activating compound 1 induces a caspase-3-dependent cell death in cerebellar granule neurons

    SciTech Connect

    Aziz, Gulzeb; Akselsen, Oyvind W.; Hansen, Trond V.; Paulsen, Ragnhild E.

    2010-09-15

    Procaspase-activating compound 1, PAC-1, has been introduced as a direct activator of procaspase-3 and has been suggested as a therapeutic agent against cancer. Its activation of procaspase-3 is dependent on the chelation of zinc. We have tested PAC-1 and an analogue of PAC-1 as zinc chelators in vitro as well as their ability to activate caspase-3 and induce cell death in chicken cerebellar granule neuron cultures. These neurons are non-dividing, primary cells with normal caspase-3. The results reported herein show that PAC-1 chelates zinc, activates procaspase-3, and leads to caspase-3-dependent cell death in neurons, as the specific caspase-3-inhibitor Ac-DEVD-cmk inhibited both the caspase-3 activity and cell death. Thus, chicken cerebellar granule neurons is a suitable model to study mechanisms of interference with apoptosis of PAC-1 and similar compounds. Furthermore, the present study also raises concern about potential neurotoxicity of PAC-1 if used in cancer therapy.

  16. Cdc18/CDC6 activates the Rad3-dependent checkpoint in the fission yeast.

    PubMed

    Fersht, Naomi; Hermand, Damien; Hayles, Jacqueline; Nurse, Paul

    2007-01-01

    A screen for genes that can ectopically activate a Rad3-dependent checkpoint block over mitosis in fission yeast has identified the DNA replication initiation factor cdc18 (known as CDC6 in other organisms). Either a stabilized form of Cdc18, the Cdc18-T6A phosphorylation mutant, or overexpression of wild type Cdc18, activate the Rad3-dependent S-M checkpoint in the apparent absence of detectable replication structures and gross DNA damage. This cell cycle block relies on the Rad checkpoint pathway and requires Chk1 phosphorylation and activation. Unexpectedly, Cdc18-T6A induces changes in the mobility of Chromosome III, affecting the size of a restriction fragment containing rDNA repeats and producing aberrant nucleolar structures. Recombination events within the rDNA appear to contribute at least in part to the cell cycle delay. We propose that an elevated level of Cdc18 activates the Rad3-dependent checkpoint either directly or indirectly, and additionally causes expansion of the rDNA repeats on Chromosome III. PMID:17690116

  17. Hypoxia-ischemia or excitotoxin-induced tissue plasminogen activator- dependent gelatinase activation in mice neonate brain microvessels.

    PubMed

    Omouendze, Priscilla L; Henry, Vincent J; Porte, Baptiste; Dupré, Nicolas; Carmeliet, Peter; Gonzalez, Bruno J; Marret, Stéphane; Leroux, Philippe

    2013-01-01

    Hypoxia-ischemia (HI) and excitotoxicity are validated causes of neonatal brain injuries and tissue plasminogen activator (t-PA) participates in the processes through proteolytic and receptor-mediated pathways. Brain microvascular endothelial cells from neonates in culture, contain and release more t-PA and gelatinases upon glutamate challenge than adult cells. We have studied t-PA to gelatinase (MMP-2 and MMP-9) activity links in HI and excitotoxicity lesion models in 5 day-old pups in wild type and in t-PA or its inhibitor (PAI-1) genes inactivated mice. Gelatinolytic activities were detected in SDS-PAGE zymograms and by in situ fluorescent DQ-gelatin microscopic zymographies. HI was achieved by unilateral carotid ligature followed by a 40 min hypoxia (8%O₂). Excitotoxic lesions were produced by intra parenchymal cortical (i.c.) injections of 10 µg ibotenate (Ibo). Gel zymograms in WT cortex revealed progressive extinction of MMP-2 and MMP-9 activities near day 15 or day 8 respectively. MMP-2 expression was the same in all strains while MMP-9 activity was barely detectable in t-PA⁻/⁻ and enhanced in PAI-1⁻/⁻ mice. HI or Ibo produced activation of MMP-2 activities 6 hours post-insult, in cortices of WT mice but not in t-PA⁻/⁻ mice. In PAI-1⁻/⁻ mice, HI or vehicle i.c. injection increased MMP-2 and MMP-9 activities. In situ zymograms using DQ-gelatin revealed vessel associated gelatinolytic activity in lesioned areas in PAI-1⁻/⁻ and in WT mice. In WT brain slices incubated ex vivo, glutamate (200 µM) induced DQ-gelatin activation in vessels. The effect was not detected in t-PA⁻/⁻ mice, but was restored by concomitant exposure to recombinant t-PA (20 µg/mL). In summary, neonatal brain lesion paradigms and ex vivo excitotoxic glutamate evoked t-PA-dependent gelatinases activation in vessels. Both MMP-2 and MMP-9 activities appeared t-PA-dependent. The data suggest that vascular directed protease inhibition may have neuroprotection

  18. Alterations of cytochrome P450-dependent monooxygenase activities in Eriocheir japonicus in response to water pollution.

    PubMed Central

    Ishizuka, M; Hoshi, H; Minamoto, N; Masuda, M; Kazusaka, A; Fujita, S

    1996-01-01

    Eriocheir japonicus, fresh-water crabs inhabiting rivers and estuaries in Japan, were investigated for cytochrome P450 (CYP)-dependent drug-metabolizing enzyme activities to see if these activities reflect the river pollution gradient. From the laboratory dose-response experiments, we found that the polycyclic aromatic hydrocarbon (PAH) 3-methylcholanthrene induced total CYP contents, ethoxycoumarin O-deethylase activity, and bunitrolol 4-hydroxylase activity in crab hepatopancreas. In the field studies, crabs collected from the river with the highest concentration of PAHs exhibited the highest levels of CYP, the highest activities of benzo[a]pyrene 3-hydroxylase, imipramine 2-hydroxylase, bunitrolol 4-hydroxylase, ethoxycoumarin O-deethylase, and the ability to metabolically activate benzo[a]pyrene, but erythromycin N-demethylase activity was not induced. The correlation between PAH levels and drug-metabolizing enzyme activities in female crabs were not as marked as in male crabs. The levels and activities of CYP did not appear to reflect the concentrations of organochlorines and polychlorinated biphenyl congeners (PCBs) studied in the fat of crab hepatopancreas. Images Figure 1. Figure 2. A Figure 2. B Figure 2. C Figure 3. Figure 4. A Figure 4. B Figure 5. A Figure 5. B Figure 5. C Figure 5. D Figure 5. E Figure 5. F Figure 6. PMID:8841764

  19. Selenium dependent glutathione-peroxidase (GSH-Px) activity in the retina of preterm human infants

    SciTech Connect

    Lane, H.; Hittner, H.; Barron, S.; Mehta, R.; Kretzer, F.

    1986-03-01

    GSH-Px activity was determined in the retina of 15 preterm human neonates with gestational ages of 17-28 weeks and birth weights of 120 to 960 g. GSH-Px activity was measured using the coupled assay. The infants survived from 0.5 to 9 hours after parturition. The retinas were removed within 3 hours of autopsy. Through electronmicroscopy, there was verification that the entire retina was removed and no contamination of other eye tissues occurred. After removal, the retinas were immediately dissolved in phosphate buffered pH 7.0 saline for assay of GSH-Px activity. The mean GSH-Px activity was 19.44 +/- 6.44 with a range of 11.1 to 32.8 units NAPH/sub 2/ oxidized/min/g protein. There was a negative correlation between birth weight and GSH-Px activity (r = -0.86) and between week of gestation and GSH-Px activity (r = -0.91). The neonatal retina GSH-Px activity was 2 to 15 times higher than found in adult retinas. Thus, this research demonstrates that selenium dependent GSH-Px activity is elevated in the preterm neonate's retina which indicates that retina GSH-Px activity may be an important antioxidation system in the premature neonate.

  20. Ras-dependent and -independent pathways target the mitogen-activated protein kinase network in macrophages.

    PubMed Central

    Büscher, D; Hipskind, R A; Krautwald, S; Reimann, T; Baccarini, M

    1995-01-01

    Mitogen-activated protein kinases (MAPKs) are activated upon a variety of extracellular stimuli in different cells. In macrophages, colony-stimulating factor 1 (CSF-1) stimulates proliferation, while bacterial lipopolysaccharide (LPS) inhibits cell growth and causes differentiation and activation. Both CSF-1 and LPS rapidly activate the MAPK network and induce the phosphorylation of two distinct ternary complex factors (TCFs), TCF/Elk and TCF/SAP. CSF-1, but not LPS, stimulated the formation of p21ras. GTP complexes. Expression of a dominant negative ras mutant reduced, but did not abolish, CSF-1-mediated stimulation of MEK and MAPK. In contrast, activation of the MEK kinase Raf-1 was Ras independent. Treatment with the phosphatidylcholine-specific phospholipase C inhibitor D609 suppressed LPS-mediated, but not CSF-1-mediated, activation of Raf-1, MEK, and MAPK. Similarly, down-regulation or inhibition of protein kinase C blocked MEK and MAPK induction by LPS but not that by CSF-1. Phorbol 12-myristate 13-acetate pretreatment led to the sustained activation of the Raf-1 kinase but not that of MEK and MAPK. Thus, activated Raf-1 alone does not support MEK/MAPK activation in macrophages. Phosphorylation of TCF/Elk but not that of TCF/SAP was blocked by all treatments that interfered with MAPK activation, implying that TCF/SAP was targeted by a MAPK-independent pathway. Therefore, CSF-1 and LPS target the MAPK network by two alternative pathways, both of which induce Raf-1 activation. The mitogenic pathway depends on Ras activity, while the differentiation signal relies on protein kinase C and phosphatidylcholine-specific phospholipase C activation. PMID:7799956

  1. Antioxidant Activity and Phenolic Content of Defatted Buckwheat (Fagopyrum esculentum Moench) Flour in Water or Ethanol Heated using Microwave Irradiation at Varying Temperatures

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Buckwheat (Fagopyrum esculentum) has potential to be a nutritionally beneficial crop due to its high phenolic content and antioxidant activity. We explored new technologies to enhance buckwheat phenolic content and antioxidant activity. Buckwheat achenes were ground and flour was extracted for 15 ...

  2. Experimental determination of the temperature dependence of water activities for a selection of aqueous organic solutions

    NASA Astrophysics Data System (ADS)

    Ganbavale, G.; Marcolli, C.; Krieger, U. K.; Zuend, A.; Stratmann, G.; Peter, T.

    2014-09-01

    This work presents experimental data of the temperature dependence of water activity in aqueous organic solutions relevant for tropospheric conditions (200-273 K). Water activity (aw) at low temperatures (T) is a crucial parameter for predicting homogeneous ice nucleation. We investigated temperature-dependent water activities, ice freezing and melting temperatures of solutions, and vapour pressures of a selection of atmospherically relevant aqueous organic systems. To measure aw over a wide composition range and with a focus on low temperatures, we use various aw measurement techniques and instruments: a dew point water activity meter, an electrodynamic balance (EDB), differential scanning calorimetry (DSC), and a setup to measure the total gas phase pressure at equilibrium over aqueous solutions. Water activity measurements were performed for aqueous multicomponent and multifunctional organic mixtures containing the functional groups typically found in atmospheric organic aerosols, such as hydroxyl, carboxyl, ketone, ether, ester, and aromatic groups. The aqueous organic systems studied at several fixed compositions over a considerable temperature range differ significantly in their temperature dependence. Aqueous organic systems of 1,4-butanediol and methoxyacetic acid show a moderate decrease in aw with decreasing temperature. The aqueous M5 system (a multicomponent system containing five different dicarboxylic acids) and aqueous 2-(2-ethoxyethoxy)ethanol solutions both show a strong increase of water activity with decreasing temperature at high solute concentrations for T < 270 K and T < 260 K, respectively. These measurements show that the temperature trend of aw can be reversed at low temperatures and that linear extrapolations of high-temperature data may lead to erroneous predictions. To avoid this, experimentally determined aw at low temperature are needed to improve thermodynamic models towards lower temperatures and for improved predictions of the ice

  3. Experimental determination of the temperature dependence of water activities for a selection of aqueous organic solutions

    NASA Astrophysics Data System (ADS)

    Ganbavale, G.; Marcolli, C.; Krieger, U. K.; Zuend, A.; Stratmann, G.; Peter, T.

    2014-05-01

    This work presents experimental data of the temperature dependence of water activity in aqueous organic solutions relevant for tropospheric conditions (200-273 K). Water activity (aw) at low temperatures (T) is a crucial parameter for predicting homogeneous ice nucleation. We investigated temperature dependent water activities, ice freezing and melting temperatures of solutions, and vapour pressures of a selection of atmospherically relevant aqueous organic systems. To measure aw over a wide composition range and with a focus on low temperatures, we use various aw measurement techniques and instruments: a dew point water activity meter, an electrodynamic balance (EDB), differential scanning calorimetry (DSC), and a setup to measure the total gas phase pressure at equilibrium over aqueous solutions. Water activity measurements were performed for aqueous multicomponent and multifunctional organic mixtures containing the functional groups typically found in atmospheric organic aerosols, such as hydroxyl, carboxyl, ketone, ether, ester, and aromatic groups. The aqueous organic systems studied at several fixed compositions over a considerable temperature range differ significantly in their temperature dependence. Aqueous organic systems of 1,4-butanediol and methoxyacetic acid show a moderate decrease in aw with decreasing temperature. The aqueous M5 system (a multicomponent system containing five different dicarboxylic acids) and aqueous 2-(2-ethoxyethoxy)ethanol solutions both show a strong increase of water activity with decreasing temperature at high solute concentrations for T<270 K and T<260 K, respectively. These measurements show that the temperature trend of aw can be reversed at low temperatures and that linear extrapolations of high temperature data may lead to erroneous predictions. To avoid this, experimentally determined aw at low temperature are needed to improve thermodynamic models towards lower temperatures and for improved predictions of the ice

  4. IL-1 beta-dependent regulation of C/EBP delta transcriptional activity.

    PubMed

    Svotelis, Amy; Doyon, Geneviève; Bernatchez, Gérald; Désilets, Antoine; Rivard, Nathalie; Asselin, Claude

    2005-03-11

    We have previously shown that the transcription factor C/EBP delta is involved in the intestinal inflammatory response. C/EBP delta regulates several inflammatory response genes, such as haptoglobin, in the rat intestinal epithelial cell line IEC-6 in response to IL-1. However, the different C/EBP delta domains involved in IL-1 beta-mediated transcriptional activation and the kinases implicated have not been properly defined. To address this, we determined the role of the p38 MAP kinase in the regulation of C/EBP delta transcriptional activity. The IL-1-dependent induction of the acute phase protein gene haptoglobin in IEC-6 cells was decreased in response to the p38 MAP kinase inhibitor SB203580, as determined by Northern blot. Transcriptional activity of C/EBP delta was repressed by the specific inhibitor of the p38 MAP kinase, as assessed by transient transfection assays. Mutagenesis studies and transient transfection assays revealed an important domain for transcriptional activation between amino acids 70 and 108. This domain overlapped with a docking site for the p38 MAP kinase, between amino acids 75 and 85, necessary to insure C/EBP delta phosphorylation. Deletion of this domain led to a decrease in basal transcriptional activity of C/EBP delta and in p300-dependent transactivation, as assessed by transient transfection assays, and in IL-1-dependent haptoglobin induction. This unusual arrangement of a kinase docking site within a transactivation domain may functionally be important for the regulation of C/EBP delta transcriptional activity. PMID:15694370

  5. Crystallographic dependence of CO activation on cobalt catalysts: HCP versus FCC.

    PubMed

    Liu, Jin-Xun; Su, Hai-Yan; Sun, Da-Peng; Zhang, Bing-Yan; Li, Wei-Xue

    2013-11-01

    Identifying the structure sensitivity of catalysts in reactions, such as Fischer-Tropsch synthesis from CO and H2 over cobalt catalysts, is an important yet challenging issue in heterogeneous catalysis. Based on a first-principles kinetic study, we find for the first time that CO activation on hexagonal close-packed (HCP) Co not only has much higher intrinsic activity than that of face centered-cubic (FCC) Co but also prefers a different reaction route, i.e., direct dissociation with HCP Co but H-assisted dissociation on the FCC Co. The origin is identified from the formation of various denser yet favorable active sites on HCP Co not available for FCC Co, due to their distinct crystallographic structure and morphology. The great dependence of the activity on the crystallographic structure and morphology of the catalysts revealed here may open a new avenue for better, stable catalysts with maximum mass-specific reactivity. PMID:24147726

  6. Phosphatidylinositol 3-kinase-dependent, MEK-independent proliferation in response to CaR activation

    SciTech Connect

    Bilderback, Tim R.; Lee, Fred; Auersperg, Nelly; Rodland, Karin D.

    2002-07-02

    Although ovarian surface epithelial (OSE) cells are responsible for the majority of ovarian tumors, we know relatively little about the pathway(s) that are responsible for regulating their proliferation. We found that phosphatidylinositol 3-kinase (PI3K) is activated in OSE cells in response to elevated extracellular calcium, and the PI3K inhibitors wortmannin and LY29004 inhibited ERK activation by approximately 75%, similar to effects of the MEK2 inhibitor PD98059. However, in assays of proliferation we found that PD98059 inhibited proliferation by approximately 50%, while wortmannin inhibited greater than 90% of the proliferative response to elevated calcium. Expression of a dominant negative PI3K totally inhibited ERK activation in response to calcium. These results demonstrate that ERK activation cannot account for the full proliferative effect of elevated calcium in OSE cells, and suggest the presence of an ERK independent, PI3K dependant component in the proliferative response.

  7. The activity of the TRP-like channel depends on its expression system

    PubMed Central

    Lev, Shaya; Katz, Ben; Minke, Baruch

    2012-01-01

    The Drosophila light activated TRP and TRPL channels have been a model for TRPC channel gating. Several gating mechanisms have been proposed following experiments conducted on photoreceptor and tissue cultured cells. However, conclusive evidence for any mechanism is still lacking. Here, we show that the Drosophila TRPL channel expressed in tissue cultured cells is constitutively active in S2 cells but is silent in HEK cells. Modulations of TRPL channel activity in different expression system by pharmacology or specific enzymes, which change the lipid content of the plasma membrane, resulted in conflicting effects. These findings demonstrate the difficulty in elucidating TRPC gating, as channel behavior is expression system dependent. However, clues on the gating mechanism may arise from understanding how different expression systems affect TRPC channel activation. PMID:22627924

  8. Astrocytes Modulate Neural Network Activity by Ca2+-Dependent Uptake of Extracellular K+

    PubMed Central

    Wang, Fushun; Smith, Nathan A.; Xu, Qiwu; Fujita, Takumi; Baba, Akemichi; Matsuda, Toshio; Takano, Takahiro; Bekar, Lane; Nedergaard, Maiken

    2012-01-01

    Astrocytes are electrically nonexcitable cells that display increases in cytosolic calcium ion (Ca2+) in response to various neurotransmitters and neuromodulators. However, the physiological role of astrocytic Ca2+ signaling remains controversial. We show here that astrocytic Ca2+ signaling ex vivo and in vivo stimulated the Na+,K+-ATPase (Na+- and K+-dependent adenosine triphosphatase), leading to a transient decrease in the extracellular potassium ion (K+) concentration. This in turn led to neuronal hyperpolarization and suppressed baseline excitatory synaptic activity, detected as a reduced frequency of excitatory postsynaptic currents. Synaptic failures decreased in parallel, leading to an increase in synaptic fidelity. The net result was that astrocytes, through active uptake of K+, improved the signal-to-noise ratio of synaptic transmission. Active control of the extracellular K+ concentration thus provides astrocytes with a simple yet powerful mechanism to rapidly modulate network activity. PMID:22472648

  9. Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo

    PubMed Central

    Cirrito, John R.; Kang, Jae-Eun; Lee, Jiyeon; Stewart, Floy R.; Verges, Deborah K.; Silverio, Luz M.; Bu, Guojun; Mennerick, Steven; Holtzman, David M.

    2008-01-01

    Aggregation of amyloid-β (Aβ) peptide into soluble and insoluble forms within the brain extracellular space is central to the pathogenesis of Alzheimer’s disease. Full length amyloid precursor protein (APP) is endocytosed from the cell surface into endosomes where it is cleaved to produce Aβ. Aβ is subsequently released into the brain interstitial fluid (ISF). We hypothesized that synaptic transmission results in more APP endocytosis, thereby increasing Aβ generation and release into the ISF. We found that inhibition of clathrin-mediated endocytosis immediately lowers ISF Aβ levels in vivo. Two distinct methods which increased synaptic transmission resulted in an elevation of ISF Aβ levels. Inhibition of endocytosis, however, prevented the activity-dependent increase in Aβ. We estimate that ~70% of ISF Aβ arises from endocytosis-associated mechanisms with the vast majority of this pool also dependent on synaptic activity. These findings have implications for AD pathogenesis and may provide insights into therapeutic intervention. PMID:18400162

  10. Upstream activation sequence-dependent alteration of chromatin structure and transcription activation of the yeast GAL1-GAL10 genes.

    PubMed Central

    Fedor, M J; Kornberg, R D

    1989-01-01

    Conversion of the positioned nucleosome array characteristic of the repressed GAL1-GAL10 promoter region to the more accessible conformation of the induced state was found to depend on the upstream activation sequence, GAL4 protein, a positive regulator of transcription, and galactose, the inducing agent. The effect of the GAL4 protein-upstream activation sequence complex on the structure of adjacent chromatin required no other promoter sequences. Although sequences protected by histones in the repressed state became more accessible to micrococcal nuclease and (methidiumpropyl-EDTA)iron(II) cleavage following induction of transcription, DNA-protein particles containing these sequences retained the electrophoretic mobility of nucleosomes, indicating that the promoter region can be associated with nucleosomes under conditions of transcription activation. Images PMID:2657404

  11. Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen.

    PubMed

    Kozlov, Sergei V; Waardenberg, Ashley J; Engholm-Keller, Kasper; Arthur, Jonathan W; Graham, Mark E; Lavin, Martin

    2016-03-01

    Ataxia-telangiectasia, mutated (ATM) protein plays a central role in phosphorylating a network of proteins in response to DNA damage. These proteins function in signaling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle checkpoints, initiating DNA repair, and regulating gene expression. ATM kinase can be activated by a variety of stimuli, including oxidative stress. Here, we confirmed activation of cytoplasmic ATM by autophosphorylation at multiple sites. Then we employed a global quantitative phosphoproteomics approach to identify cytoplasmic proteins altered in their phosphorylation state in control and ataxia-telangiectasia (A-T) cells in response to oxidative damage. We demonstrated that ATM was activated by oxidative damage in the cytoplasm as well as in the nucleus and identified a total of 9,833 phosphorylation sites, including 6,686 high-confidence sites mapping to 2,536 unique proteins. A total of 62 differentially phosphorylated peptides were identified; of these, 43 were phosphorylated in control but not in A-T cells, and 19 varied in their level of phosphorylation. Motif enrichment analysis of phosphopeptides revealed that consensus ATM serine glutamine sites were overrepresented. When considering phosphorylation events, only observed in control cells (not observed in A-T cells), with predicted ATM sites phosphoSerine/phosphoThreonine glutamine, we narrowed this list to 11 candidate ATM-dependent cytoplasmic proteins. Two of these 11 were previously described as ATM substrates (HMGA1 and UIMCI/RAP80), another five were identified in a whole cell extract phosphoproteomic screens, and the remaining four proteins had not been identified previously in DNA damage response screens. We validated the phosphorylation of three of these proteins (oxidative stress responsive 1 (OSR1), HDGF, and ccdc82) as ATM dependent after H2O2 exposure, and another protein (S100A11) demonstrated ATM-dependence

  12. Relocation of a Ca2+-dependent protein kinase activity during pollen tube reorientation

    PubMed Central

    Moutinho, A; Trewavas, AJ; Malho, R

    1998-01-01

    Pollen tube reorientation is a dynamic cellular event that is crucial for successful fertilization. We have shown previously that pollen tube orientation is regulated by cytosolic free calcium ([Ca2+]c). In this paper, we studied the activity of a Ca2+-dependent protein kinase during reorientation. The kinase activity was assayed in living cells by using confocal ratio imaging of BODIPY FL bisindolylmaleimide. We found that growing pollen tubes exhibited higher protein kinase activity in the apical region, whereas nongrowing cells showed uniform distribution. Modification of growth direction by diffusion of inhibitors/activators from a micropipette showed the spatial redistribution of kinase activity to predict the new growth orientation. Localized increases in [Ca2+]c induced by photolysis of caged Ca2+ that led to reorientation also increased kinase activity. Molecular and immunological assays suggest that this kinase may show some functional homology with protein kinase C. We suggest that the tip-localized gradient of kinase activity promotes Ca2+-mediated exocytosis and may act to regulate Ca2+ channel activity. PMID:9724696

  13. Interferon regulatory factor 7 is activated by a viral oncoprotein through RIP-dependent ubiquitination.

    PubMed

    Huye, Leslie E; Ning, Shunbin; Kelliher, Michelle; Pagano, Joseph S

    2007-04-01

    As a key mediator of type I interferon (IFN) (IFN-alpha/beta) responses, IFN regulatory factor 7 (IRF7) is essential to host immune defenses. Activation of IRF7 generally requires virus-induced C-terminal phosphorylation, which leads to its nuclear accumulation and activation of target genes. Here we use the Epstein-Barr virus (EBV) oncoprotein LMP1, which activates IRF7, to identify factors involved in IRF7 activation. We demonstrate for the first time that RIP activates IRF7 and that RIP and IRF7 interact under physiological conditions in EBV-positive Burkitt's lymphoma cells. We provide evidence that both RIP and IRF7 are ubiquitinated in these cells and that IRF7 preferentially interacts with ubiquitinated RIP. RIP is required for full activation of IRF7 by LMP1, with LMP1 stimulating the ubiquitination of RIP and its interaction with IRF7. Moreover, LMP1 stimulates RIP-dependent K63-linked ubiquitination of IRF7, which regulates protein function rather than proteasomal degradation of proteins. We suggest that RIP may serve as a general activator of IRF7, responding to and transmitting the signals from various stimuli, and that ubiquitination may be a general mechanism for enhancing the activity of IRF7. PMID:17296724

  14. Dependence of stem cell fate in Arabidopsis on a feedback loop regulated by CLV3 activity.

    PubMed

    Brand, U; Fletcher, J C; Hobe, M; Meyerowitz, E M; Simon, R

    2000-07-28

    The fate of stem cells in plant meristems is governed by directional signaling systems that are regulated by negative feedback. In Arabidopsis thaliana, the CLAVATA (CLV) genes encode the essential components of a negative, stem cell-restricting pathway. We used transgenic plants overexpressing CLV3 to show that meristem cell accumulation and fate depends directly on the level of CLV3 activity and that CLV3 signaling occurs exclusively through a CLV1/CLV2 receptor kinase complex. We also demonstrate that the CLV pathway acts by repressing the activity of the transcription factor WUSCHEL, an element of the positive, stem cell-promoting pathway. PMID:10915624

  15. Context-dependent olfactory learning monitored by activities of salivary neurons in cockroaches.

    PubMed

    Matsumoto, Chihiro Sato; Matsumoto, Yukihisa; Watanabe, Hidehiro; Nishino, Hiroshi; Mizunami, Makoto

    2012-01-01

    Context-dependent discrimination learning, a sophisticated form of nonelemental associative learning, has been found in many animals, including insects. The major purpose of this research is to establish a method for monitoring this form of nonelemental learning in rigidly restrained insects for investigation of underlying neural mechanisms. We report context-dependent olfactory learning (occasion-setting problem solving) of salivation, which can be monitored as activity changes of salivary neurons in immobilized cockroaches, Periplaneta americana. A group of cockroaches was trained to associate peppermint odor (conditioned stimulus, CS) with sucrose solution reward (unconditioned stimulus, US) while vanilla odor was presented alone without pairing with the US under a flickering light condition (1.0 Hz) and also trained to associate vanilla odor with sucrose reward while peppermint odor was presented alone under a steady light condition. After training, the responses of salivary neurons to the rewarded peppermint odor were significantly greater than those to the unrewarded vanilla odor under steady illumination and those to the rewarded vanilla odor was significantly greater than those to the unrewarded peppermint odor in the presence of flickering light. Similar context-dependent responses were observed in another group of cockroaches trained with the opposite stimulus arrangement. This study demonstrates context-dependent olfactory learning of salivation for the first time in any vertebrate and invertebrate species, which can be monitored by activity changes of salivary neurons in restrained cockroaches. PMID:21930226

  16. The dihydrolipoamide dehydrogenase of Aeromonas caviae ST exhibits NADH-dependent tellurite reductase activity.

    PubMed

    Castro, Miguel E; Molina, Roberto; Díaz, Waldo; Pichuantes, Sergio E; Vásquez, Claudio C

    2008-10-10

    Potassium tellurite (K(2)TeO(3)) is extremely toxic for most forms of life and only a limited number of organisms are naturally resistant to the toxic effects of this compound. Crude extracts prepared from the environmental isolate Aeromonas caviae ST catalize the in vitro reduction of TeO32- in a NADH-dependent reaction. Upon fractionation by ionic exchange column chromatography three major polypeptides identified as the E1, E2, and E3 components of the pyruvate dehydrogenase (PDH) complex were identified in fractions exhibiting tellurite-reducing activity. Tellurite reductase and pyruvate dehydrogenase activities co-eluted from a Sephadex gel filtration column. To determine which component(s) of the PDH complex has tellurite reductase activity, the A. caviae ST structural genes encoding for E1 (aceE), E2 (aceF), and E3 (lpdA) were independently cloned and expressed in Escherichia coli and their gene products purified. Results indicated that tellurite reductase activity lies almost exclusively in the E3 component, dihydrolipoamide dehydrogenase. The E3 component of the PDH complex from E. coli, Zymomonas mobilis, Streptococcus pneumoniae, and Geobacillus stearothermophilus also showed NADH-dependent tellurite reductase in vitro suggesting that this enzymatic activity is widely distributed among microorganisms. PMID:18675788

  17. Shape-dependent bactericidal activity of copper oxide nanoparticle mediated by DNA and membrane damage

    SciTech Connect

    Laha, Dipranjan; Pramanik, Arindam; Laskar, Aparna; Jana, Madhurya; Pramanik, Panchanan; Karmakar, Parimal

    2014-11-15

    Highlights: • Spherical and sheet shaped copper oxide nanoparticles were synthesized. • Physical characterizations of these nanoparticles were done by TEM, DLS, XRD, FTIR. • They showed shape dependent antibacterial activity on different bacterial strain. • They induced both membrane damage and ROS mediated DNA damage in bacteria. - Abstract: In this work, we synthesized spherical and sheet shaped copper oxide nanoparticles and their physical characterizations were done by the X-ray diffraction, fourier transform infrared spectroscopy, transmission electron microscopy and dynamic light scattering. The antibacterial activity of these nanoparticles was determined on both gram positive and gram negative bacterial. Spherical shaped copper oxide nanoparticles showed more antibacterial property on gram positive bacteria where as sheet shaped copper oxide nanoparticles are more active on gram negative bacteria. We also demonstrated that copper oxide nanoparticles produced reactive oxygen species in both gram negative and gram positive bacteria. Furthermore, they induced membrane damage as determined by atomic force microscopy and scanning electron microscopy. Thus production of and membrane damage are major mechanisms of the bactericidal activity of these copper oxide nanoparticles. Finally it was concluded that antibacterial activity of nanoparticles depend on physicochemical properties of copper oxide nanoparticles and bacterial strain.

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

    PubMed Central

    Sjöqvist, Marika; Antfolk, Daniel; Ferraris, Saima; Rraklli, Vilma; Haga, Cecilia; Antila, Christian; Mutvei, Anders; Imanishi, Susumu Y; Holmberg, Johan; Jin, Shaobo; Eriksson, John E; Lendahl, Urban; Sahlgren, Cecilia

    2014-01-01

    Activation of Notch signaling requires intracellular routing of the receptor, but the mechanisms controlling the distinct steps in the routing process is poorly understood. We identify PKCζ as a key regulator of Notch receptor intracellular routing. When PKCζ was inhibited in the developing chick central nervous system and in cultured myoblasts, Notch-stimulated cells were allowed to undergo differentiation. PKCζ phosphorylates membrane-tethered forms of Notch and regulates two distinct routing steps, depending on the Notch activation state. When Notch is activated, PKCζ promotes re-localization of Notch from late endosomes to the nucleus and enhances production of the Notch intracellular domain, which leads to increased Notch activity. In the non-activated state, PKCζ instead facilitates Notch receptor internalization, accompanied with increased ubiquitylation and interaction with the endosomal sorting protein Hrs. Collectively, these data identify PKCζ as a key regulator of Notch trafficking and demonstrate that distinct steps in intracellular routing are differentially modulated depending on Notch signaling status. PMID:24662486

  19. The impact of a parkinsonian lesion on dynamic striatal dopamine transmission depends on nicotinic receptor activation.

    PubMed

    Jennings, Katie A; Platt, Nicola J; Cragg, Stephanie J

    2015-10-01

    Dopamine function is disturbed in Parkinson's disease (PD), but whether and how release of dopamine from surviving neurons is altered has long been debated. Nicotinic acetylcholine receptors (nAChRs) on dopamine axons powerfully govern dopamine release and could be critical contributing factors. We revisited whether fundamental properties of dopamine transmission are changed in a parkinsonian brain and tested the potentially profound masking effects of nAChRs. Using real-time detection of dopamine in mouse striatum after a partial 6-hydroxydopamine lesion and under nAChR inhibition, we reveal that dopamine signals show diminished sensitivity to presynaptic activity. This effect manifested as diminished contrast between DA release evoked by the lowest versus highest frequencies. This reduced activity-dependence was underpinned by loss of short-term facilitation of dopamine release, consistent with an increase in release probability (Pr). With nAChRs active, the reduced activity-dependence of dopamine release after a parkinsonian lesion was masked. Consequently, moment-by-moment variation in activity of nAChRs may lead to dynamic co-variation in dopamine signal impairments in PD. PMID:26117304

  20. The impact of a parkinsonian lesion on dynamic striatal dopamine transmission depends on nicotinic receptor activation

    PubMed Central

    Jennings, Katie A.; Platt, Nicola J.; Cragg, Stephanie J.

    2015-01-01

    Dopamine function is disturbed in Parkinson's disease (PD), but whether and how release of dopamine from surviving neurons is altered has long been debated. Nicotinic acetylcholine receptors (nAChRs) on dopamine axons powerfully govern dopamine release and could be critical contributing factors. We revisited whether fundamental properties of dopamine transmission are changed in a parkinsonian brain and tested the potentially profound masking effects of nAChRs. Using real-time detection of dopamine in mouse striatum after a partial 6-hydroxydopamine lesion and under nAChR inhibition, we reveal that dopamine signals show diminished sensitivity to presynaptic activity. This effect manifested as diminished contrast between DA release evoked by the lowest versus highest frequencies. This reduced activity-dependence was underpinned by loss of short-term facilitation of dopamine release, consistent with an increase in release probability (Pr). With nAChRs active, the reduced activity-dependence of dopamine release after a parkinsonian lesion was masked. Consequently, moment-by-moment variation in activity of nAChRs may lead to dynamic co-variation in dopamine signal impairments in PD. PMID:26117304

  1. Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

    SciTech Connect

    Zhang, Lianying; Ren, Xiao-Min; Wan, Bin; Guo, Liang-Hong

    2014-09-15

    Perfluorinated compounds (PFCs) have been shown to disrupt lipid metabolism and even induce cancer in rodents through activation of peroxisome proliferator-activated receptors (PPARs). Lines of evidence showed that PPARα was activated by PFCs. However, the information on the binding interactions between PPARγ and PFCs and subsequent alteration of PPARγ activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPARγ ligand binding domain (hPPARγ-LBD) and their activity on the receptor in cells were investigated. The results showed that the binding affinity was strongly dependent on their carbon number and functional group. For the eleven perfluorinated carboxylic acids (PFCAs), the binding affinity increased with their carbon number from 4 to 11, and then decreased slightly. The binding affinity of the three perfluorinated sulfonic acids (PFSAs) was stronger than their PFCA counterparts. No binding was detected for the two fluorotelomer alcohols (FTOHs). Circular dichroim spectroscopy showed that PFC binding induced distinctive structural change of the receptor. In dual luciferase reporter assays using transiently transfected Hep G2 cells, PFCs acted as hPPARγ agonists, and their potency correlated with their binding affinity with hPPARγ-LBD. Molecular docking showed that PFCs with different chain length bind with the receptor in different geometry, which may contribute to their differences in binding affinity and transcriptional activity. - Highlights: • Binding affinity between PFCs and PPARγ was evaluated for the first time. • The binding strength was dependent on fluorinated carbon chain and functional group. • PFC binding induced distinctive structural change of the receptor. • PFCs could act as hPPARγ agonists in Hep G2 cells.

  2. Activation of protein kinase C by lysophosphatidic acid: dependence on composition of phospholipid vesicles.

    PubMed Central

    Sando, J J; Chertihin, O I

    1996-01-01

    Lysophosphatidic acid (LPA) has attracted recent attention as a major serum-derived regulator implicated in responses to vascular injury and inflammation, in tumour invasiveness and in neuronal signalling and remodelling. Although the possibility of a specific G-protein-coupled LPA receptor protein has been suggested, characterization of such a receptor is lacking. Since LPA can activate protein kinase C (PKC) pathways in many cells and PKC activators mimic many LPA effects, the possibility of more direct LPA effects on PKC was investigated. Phosphatidylcholine (PC)/phosphatidylserine (PS)/diacylglycerol (DAG) lipid vesicles of defined acyl chain composition were used to activate the enzyme. At total concentrations of saturated PC/PS + DAG vesicles (2-3 mM) that provided maximal PKC activation, 1-10 mol % [18:1]-LPA led to a further approx. 2-fold activation of PKC alpha. At lower lipid concentrations, a greater increase was observed with LPA concentrations up to 16-20 mol %. Higher concentrations of LPA were inhibitory. The LPA activation of PKC was dependent on the presence of DAG, PS and Ca2+. [18:1]-Lysophosphatidylcholine produced similar PKC activation in PC/PS/DAG vesicles. [14:0]-LPA was less effective, and longer-chain saturated lysolipids were ineffective. In unsaturated PC/PS vesicles, very little to no effect of LPA was discernable. These results suggest that physiologically or pathologically relevant concentrations of LPA can contribute to PKC activation depending on the composition of the lipid membrane. We hypothesize that LPA may affect the formation of lipid domains that are recognized by the enzyme. PMID:8713089

  3. Single-trial estimation of stimulus and spike-history effects on time-varying ensemble spiking activity of multiple neurons: a simulation study

    NASA Astrophysics Data System (ADS)

    Shimazaki, Hideaki

    2013-12-01

    Neurons in cortical circuits exhibit coordinated spiking activity, and can produce correlated synchronous spikes during behavior and cognition. We recently developed a method for estimating the dynamics of correlated ensemble activity by combining a model of simultaneous neuronal interactions (e.g., a spin-glass model) with a state-space method (Shimazaki et al. 2012 PLoS Comput Biol 8 e1002385). This method allows us to estimate stimulus-evoked dynamics of neuronal interactions which is reproducible in repeated trials under identical experimental conditions. However, the method may not be suitable for detecting stimulus responses if the neuronal dynamics exhibits significant variability across trials. In addition, the previous model does not include effects of past spiking activity of the neurons on the current state of ensemble activity. In this study, we develop a parametric method for simultaneously estimating the stimulus and spike-history effects on the ensemble activity from single-trial data even if the neurons exhibit dynamics that is largely unrelated to these effects. For this goal, we model ensemble neuronal activity as a latent process and include the stimulus and spike-history effects as exogenous inputs to the latent process. We develop an expectation-maximization algorithm that simultaneously achieves estimation of the latent process, stimulus responses, and spike-history effects. The proposed method is useful to analyze an interaction of internal cortical states and sensory evoked activity.

  4. Hypoxia in Leishmania major skin lesions impairs the NO-dependent leishmanicidal activity of macrophages.

    PubMed

    Mahnke, Alexander; Meier, Robert J; Schatz, Valentin; Hofmann, Julian; Castiglione, Kirstin; Schleicher, Ulrike; Wolfbeis, Otto S; Bogdan, Christian; Jantsch, Jonathan

    2014-09-01

    Cure of infections with Leishmania major is critically dependent on the ability of macrophages to induce the type 2 nitic oxide (NO) synthase (NOS2) that produces high levels of NO in the presence of ample oxygen. Therefore, we analyzed the oxygen levels found in leishmanial skin lesions and their effect on the NOS2-dependent leishmanicidal activity of macrophages (MΦ). When L. major skin lesions of self-healing C57BL/6 mice reached their maximum size, the infected tissue displayed low oxygen levels (pO2∼21 Torr). MΦ activated under these oxygen tensions failed to produce sufficient amounts of NO to clear L. major. Nos2-deficient and hypoxic wild-type macrophages displayed a similar phenotype. Killing was restored when MΦ were reoxygenated or exposed to a NO donor. The resolution of the lesion in C57BL/6 mice was paralleled by an increase of lesional pO2. When mice were kept under normobaric hypoxia, this caused a persistent suppression of the lesional pO2 and a concurrent increase of the parasite load. In Nos2-deficient mice, there was no effect of atmospheric hypoxia. Low oxygen levels found at leishmanial skin lesions impaired the NOS2-dependent leishmanicidal activity of MΦ. Hence, tissue oxygenation represents an underestimated local milieu factor that participates in the persistence of Leishmania. PMID:24583949

  5. The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent

    PubMed Central

    te Velthuis, Aartjan J. W.; Arnold, Jamie J.; Cameron, Craig E.; van den Worm, Sjoerd H. E.; Snijder, Eric J.

    2010-01-01

    An RNA-dependent RNA polymerase (RdRp) is the central catalytic subunit of the RNA-synthesizing machinery of all positive-strand RNA viruses. Usually, RdRp domains are readily identifiable by comparative sequence analysis, but biochemical confirmation and characterization can be hampered by intrinsic protein properties and technical complications. It is presumed that replication and transcription of the ∼30-kb severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) RNA genome are catalyzed by an RdRp domain in the C-terminal part of nonstructural protein 12 (nsp12), one of 16 replicase subunits. However, thus far full-length nsp12 has proven refractory to expression in bacterial systems, which has hindered both the biochemical characterization of coronavirus RNA synthesis and RdRp-targeted antiviral drug design. Here, we describe a combined strategy involving bacterial expression of an nsp12 fusion protein and its in vivo cleavage to generate and purify stable SARS-CoV nsp12 (106 kDa) with a natural N-terminus and C-terminal hexahistidine tag. This recombinant protein possesses robust in vitro RdRp activity, as well as a significant DNA-dependent activity that may facilitate future inhibitor studies. The SARS-CoV nsp12 is primer dependent on both homo- and heteropolymeric templates, supporting the likeliness of a close enzymatic collaboration with the intriguing RNA primase activity that was recently proposed for coronavirus nsp8. PMID:19875418

  6. The Chromatin Remodeler CHD8 Is Required for Activation of Progesterone Receptor-Dependent Enhancers

    PubMed Central

    Giannopoulou, Eugenia G.; Soronellas, Daniel; Vázquez-Chávez, Elena; Vicent, Guillermo P.; Elemento, Olivier; Beato, Miguel; Reyes, José C.

    2015-01-01

    While the importance of gene enhancers in transcriptional regulation is well established, the mechanisms and the protein factors that determine enhancers activity have only recently begun to be unravelled. Recent studies have shown that progesterone receptor (PR) binds regions that display typical features of gene enhancers. Here, we show by ChIP-seq experiments that the chromatin remodeler CHD8 mostly binds promoters under proliferation conditions. However, upon progestin stimulation, CHD8 re-localizes to PR enhancers also enriched in p300 and H3K4me1. Consistently, CHD8 depletion severely impairs progestin-dependent gene regulation. CHD8 binding is PR-dependent but independent of the pioneering factor FOXA1. The SWI/SNF chromatin-remodelling complex is required for PR-dependent gene activation. Interestingly, we show that CHD8 interacts with the SWI/SNF complex and that depletion of BRG1 and BRM, the ATPases of SWI/SNF complex, impairs CHD8 recruitment. We also show that CHD8 is not required for H3K27 acetylation, but contributes to increase accessibility of the enhancer to DNaseI. Furthermore, CHD8 was required for RNAPII recruiting to the enhancers and for transcription of enhancer-derived RNAs (eRNAs). Taken together our data demonstrate that CHD8 is involved in late stages of PR enhancers activation. PMID:25894978

  7. Structural Basis for the Magnesium-Dependent Activation and Hexamerization of the Lon AAA+ Protease.

    PubMed

    Su, Shih-Chieh; Lin, Chien-Chu; Tai, Hui-Chung; Chang, Mu-Yueh; Ho, Meng-Ru; Babu, C Satheesan; Liao, Jiahn-Haur; Wu, Shih-Hsiung; Chang, Yuan-Chih; Lim, Carmay; Chang, Chung-I

    2016-05-01

    The Lon AAA+ protease (LonA) plays important roles in protein homeostasis and regulation of diverse biological processes. LonA behaves as a homomeric hexamer in the presence of magnesium (Mg(2+)) and performs ATP-dependent proteolysis. However, it is also found that LonA can carry out Mg(2+)-dependent degradation of unfolded protein substrate in an ATP-independent manner. Here we show that in the presence of Mg(2+) LonA forms a non-secluded hexameric barrel with prominent openings, which explains why Mg(2+)-activated LonA can operate as a diffusion-based chambered protease to degrade unstructured protein and peptide substrates efficiently in the absence of ATP. A 1.85 Å crystal structure of Mg(2+)-activated protease domain reveals Mg(2+)-dependent remodeling of a substrate-binding loop and a potential metal-binding site near the Ser-Lys catalytic dyad, supported by biophysical binding assays and molecular dynamics simulations. Together, these findings reveal the specific roles of Mg(2+) in the molecular assembly and activation of LonA. PMID:27041593

  8. Activity dependent therapies modulate the spinal changes that motoneurons suffer after a peripheral nerve injury.

    PubMed

    Arbat-Plana, Ariadna; Torres-Espín, Abel; Navarro, Xavier; Udina, Esther

    2015-01-01

    Injury of a peripheral nerve not only leads to target denervation, but also induces massive stripping of spinal synapses on axotomized motoneurons, with disruption of spinal circuits. Even when regeneration is successful, unspecific reinnervation and the limited reconnection of the spinal circuits impair functional recovery. The aim of this study was to describe the changes that axotomized motoneurons suffer after peripheral nerve injury and how activity-dependent therapies and neurotrophic factors can modulate these events. We observed a marked decrease in glutamatergic synapses, with a maximum peak at two weeks post-axotomy, which was only partially reversed with time. This decrease was accompanied by an increase in gephyrin immunoreactivity and a disintegration of perineuronal nets (PNNs) surrounding the motoneurons. Direct application of neurotrophins at the proximal stump was not able to reverse these effects. In contrast, activity-dependent treatment, in the form of treadmill running, reduced the observed destructuring of perineuronal nets and the loss of glutamatergic synapses two weeks after injury. These changes were proportional to the intensity of the exercise protocol. Blockade of sensory inputs from the homolateral hindlimb also reduced PNN immunoreactivity around intact motoneurons, and in that case treadmill running did not reverse that loss, suggesting that the effects of exercise on motoneuron PNN depend on increased sensory activity. Preservation of motoneuron PNN and reduction of synaptic stripping by exercise could facilitate the maintenance of the spinal circuitry and benefit functional recovery after peripheral nerve injury. PMID:25448160

  9. Working memory in preterm-born adults: load-dependent compensatory activity of the posterior default mode network.

    PubMed

    Daamen, Marcel; Bäuml, Josef G; Scheef, Lukas; Sorg, Christian; Busch, Barbara; Baumann, Nicole; Bartmann, Peter; Wolke, Dieter; Wohlschläger, Afra; Boecker, Henning

    2015-03-01

    Premature birth is associated with an increased risk of cognitive performance deficits that are dependent on working memory (WM) load in childhood. Less clear is whether preterm-born adults show similar WM impairments, or develop compensatory brain mechanisms that help to overcome prematurity-related functional deficits, for example, by a workload-dependent over-recruitment of WM-typical areas, and/or engagement of alternative brain networks. In this functional magnetic resonance imaging study, 73 adults born very preterm and/or with very low birth weight (VP/VLBW) and 73 term-born controls (CON, mean age: 26.5 years) performed a verbal N-Back paradigm with varying workload (0-back, 1-back, 2-back). Generally, both groups showed similar performance accuracy and task-typical patterns of brain activations (especially in fronto-cingulo-parietal, thalamic, and cerebellar areas) and deactivations (especially in mesial frontal and parietal aspects of the default mode network [DMN]). However, VP/VLBW adults showed significantly stronger deactivations (P < 0.05, cluster-level corrected) than CON in posterior DMN regions, including right ventral precuneus, and right parahippocampal areas (with adjacent cerebellar areas), which were specific for the most demanding 2-back condition. Consistent with a workload-dependent effect, VP/VLBW adults with stronger deactivations (1-back > 2-back) in the parahippocampal/cerebellar cluster also presented a greater slowing of response latencies with increasing WM load (2-back > 1-back), indicative of higher effort. In conclusion, VP/VLBW adults recruited similar anatomical networks as controls during N-back performance, but showed an enhanced suppression of posterior DMN regions during higher workload, which may reflect a temporary suppression of stimulus-independent thoughts that helps to maintain adequate task performance with increasing attentional demands. PMID:25413496

  10. Phase dependent photocatalytic activity of Ag loaded TiO2 films under sun light

    NASA Astrophysics Data System (ADS)

    Madhavi, V.; Kondaiah, P.; Shaik, Habibuddin; Rao, G. Mohan

    2016-02-01

    Well-crystallized anatase and mixed (anatase-rutile) phase TiO2 thin films were deposited by DC magnetron sputtering technique at various DC powers in the range of 80-140 W. Pure anatase phase was observed in the TiO2 films deposited at low power of 80 W. Films deposited at 120 W were composed of both anatase and rutile phases. At higher power of 140 W, the films are rutile dominated and the rutile percentage increased from 0 to 82% with increase of DC power. The same results of phase change were confirmed by Raman studies. The surface morphology of the TiO2 films showed that the density of the films increased with increase of sputter power. The optical band gap of the films varied from 3.35 to 3.14 eV with increase of DC power. The photocatalytic activity of the TiO2 films increased with increasing DC power up to 120 W and after that it decreases. We found that the TiO2 films deposited at 120 W with 48% of rutile phase, exhibited high photocatalytic activity (43% of degradation) under UV light compared with other TiO2 films. After loading the optimized Ag nanoparticles on the mixed phase TiO2 films, the photocatalytic activity shifted from UV to visible region with enhancement of photocatalytic activity (55% of degradation).

  11. Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation

    SciTech Connect

    Park, Jeong Su; Kang, Dong Hoon; Lee, Da Hyun; Bae, Soo Han

    2015-09-25

    Peroxisome proliferator-activated receptor α (PPARα) activates the β-oxidation of fatty acids in the liver. Fenofibrate is a potent agonist of PPARα and is used in the treatment of hyperlipidemia. Fenofibrate treatment often induces the production of intracellular reactive oxygen species (ROS), leading to cell death. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is an essential component of the defense mechanism against oxidative stress. However, the molecular mechanism underlying the regulation of the Nrf2-Keap1 pathway in fenofibrate-induced cell death is not known. In this study, we demonstrated that fenofibrate induces Keap1 degradation and Nrf2 activation. This fenofibrate-mediated Keap1 degradation is partly dependent on autophagy. Furthermore, fenofibrate-induced Keap1 degradation followed by Nrf2 activation is mainly mediated by p62, which functions as an adaptor protein in the autophagic pathway. Consistent with these findings, ablation of p62 increased fenofibrate-mediated apoptotic cell death associated with ROS accumulation. These results strongly suggest that p62 plays a crucial role in preventing fenofibrate-induced cell death. - Highlights: • Fenofibrate induces cell death by increasing ROS production. • The underlying defense mechanism against this effect is unknown. • Fenofibrate induces autophagy-dependent Keap1 degradation and Nrf2 activation. • This process is p62-dependent; lack of p62 enhanced fenofibrate-mediated apoptosis. • p62 plays a crucial role in preventing fenofibrate-induced cell death.

  12. VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

    SciTech Connect

    Garcia-Roman, Jonathan; Ibarra-Sanchez, Alfredo; Lamas, Monica; Gonzalez Espinosa, Claudia

    2010-10-15

    Research highlights: {yields} Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. {yields} CoCl{sub 2}-induced VEGF secretion in mast cells occurs by a Ca{sup 2+}-insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. {yields} Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits Fc{epsilon}RI-dependent anaphylactic degranulation in mast cells. {yields} Src family kinase Fyn activation after free radical production is necessary for hypoxia-induced VEGF secretion in mast cells. -- Abstract: Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl{sub 2}) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl{sub 2} promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl{sub 2}-induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle-associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl{sub 2}-induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl{sub 2} in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N-acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals-dependent

  13. Adiponectin Regulation of Stellate Cell Activation via PPARγ-Dependent and -Independent Mechanisms

    PubMed Central

    Shafiei, Mahnoush S.; Shetty, Shoba; Scherer, Philipp E.; Rockey, Don C.

    2011-01-01

    In this study, we elucidated the mechanism by which adiponectin modulates hepatic stellate cell activation and fibrogenesis. Adiponectin-overexpressing transgenic mice receiving thioacetamide were resistant to fibrosis, compared with controls. In contrast, adiponectin-null animals developed severe fibrosis. Expression of collagen α1(I) and α-smooth muscle actin (α-SMA) mRNAs were significantly lower in adiponectin-overexpressing mice, compared with controls. In wild-type stellate cells exposed to a lentivirus encoding adiponectin, expression of peroxisome proliferator-activated receptor-γ (PPARγ), SREBP1c, and CEBPα mRNAs was significantly increased (3.2-, 4.1-, and 2.2-fold, respectively; n = 3; P < 0.05, adiponectin virus versus control), consistent with possible activation of an adipogenic transcriptional program. Troglitazone, a PPARγ agonist, strongly suppressed up-regulation of collagen α1(I) and α-SMA mRNA in stellate cells isolated from wild-type mice; however, stellate cells from adiponectin-null animals failed to respond to troglitazone. Furthermore, in isolated stellate cells in which PPARγ was depleted using an adenovirus-Cre-recombinase system and in which adiponectin was also overexpressed, collagen α1(I) and α-SMA were significantly inhibited. We conclude that the PPARγ effect on stellate cell activation and the fibrogenic cascade appears to be adiponectin-dependent; however, the inhibitory effect of adiponectin on stellate cell activation was not dependent on PPARγ, suggesting the presence of PPARγ-dependent as well as independent pathways in stellate cells. PMID:21641391

  14. Involvement of aberrant cyclin-dependent kinase 5/p25 activity in experimental traumatic brain injury.

    PubMed

    Yousuf, Mohammad A; Tan, Chunfeng; Torres-Altoro, Melissa I; Lu, Fang-Min; Plautz, Erik; Zhang, Shanrong; Takahashi, Masaya; Hernandez, Adan; Kernie, Steven G; Plattner, Florian; Bibb, James A

    2016-07-01

    Traumatic brain injury (TBI) is associated with adverse effects on brain functions, including sensation, language, emotions and/or cognition. Therapies for improving outcomes following TBI are limited. A better understanding of the pathophysiological mechanisms of TBI may suggest novel treatment strategies to facilitate recovery and improve treatment outcome. Aberrant activation of cyclin-dependent kinase 5 (Cdk5) has been implicated in neuronal injury and neurodegeneration. Cdk5 is a neuronal protein kinase activated via interaction with its cofactor p35 that regulates numerous neuronal functions, including synaptic remodeling and cognition. However, conversion of p35 to p25 via Ca(2+) -dependent activation of calpain results in an aberrantly active Cdk5/p25 complex that is associated with neuronal damage and cell death. Here, we show that mice subjected to controlled cortical impact (CCI), a well-established experimental TBI model, exhibit increased p25 levels and consistently elevated Cdk5-dependent phosphorylation of microtubule-associated protein tau and retinoblastoma (Rb) protein in hippocampal lysates. Moreover, CCI-induced neuroinflammation as indicated by increased astrocytic activation and number of reactive microglia. Brain-wide conditional Cdk5 knockout mice (Cdk5 cKO) subjected to CCI exhibited significantly reduced edema, ventricular dilation, and injury area. Finally, neurophysiological recordings revealed that CCI attenuated excitatory post-synaptic potential field responses in the hippocampal CA3-CA1 pathway 24 h after injury. This neurophysiological deficit was attenuated in Cdk5 cKO mice. Thus, TBI induces increased levels of p25 generation and aberrant Cdk5 activity, which contributes to pathophysiological processes underlying TBI progression. Hence, selectively preventing aberrant Cdk5 activity may be an effective acute strategy to improve recovery from TBI. Traumatic brain injury (TBI) increases astrogliosis and microglial activation

  15. A novel light-dependent activation of DAGK and PKC in bovine photoreceptor nuclei.

    PubMed

    Natalini, Paola M; Mateos, Melina V; Ilincheta de Boschero, Mónica G; Giusto, Norma M

    2014-08-01

    In this work, we describe a selective light-dependent distribution of the lipid kinase 1,2-diacylglycerol kinase (EC 2.7.1.107, DAGK) and the phosphorylated protein kinase C alpha (pPKCα) in a nuclear fraction of photoreceptor cells from bovine retinas. A nuclear fraction enriched in small nuclei from photoreceptor cells (PNF), was obtained when a modified nuclear isolation protocol developed by our laboratory was used. We measured and compared DAGK activity as phosphatidic acid (PA) formation in PNF obtained from retinas exposed to light and in retinas kept in darkness using [γ-(32)P]ATP or [(3)H]DAG. In the absence of exogenous substrates and detergents, no changes in DAGK activity were observed. However, when DAGK activity assays were performed in the presence of exogenous substrates, such as stearoyl arachidonoyl glycerol (SAG) or dioleoyl glycerol (DOG), and different detergents (used to make different DAGK isoforms evident), we observed significant light effects on DAGK activity, suggesting the presence of several DAGK isoforms in PNF. Under conditions favoring DAGKζ activity (DOG, Triton X-100, dioleoyl phosphatidylserine and R59022) we observed an increase in PA formation in PNF from retinas exposed to light with respect to those exposed to darkness. In contrast, under conditions favoring DAGKɛ (SAG, octylglucoside and R59022) we observed a decrease in its activity. These results suggest different physiological roles of the above-mentioned DAGK isoforms. Western blot analysis showed that whereas light stimulation of bovine retinas increases DAGKζ nuclear content, it decreases DAGKɛ and DAGKβ content in PNF. The role of PIP2-phospholipase C in light-stimulated DAGK activity was demonstrated using U73122. Light was also observed to induce enhanced pPKCα content in PNF. The selective distribution of DAGKζ and ɛ in PNF could be a light-dependent mechanism that in vertebrate retina promotes selective DAG removal and PKC regulation. PMID:24950064

  16. GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation

    PubMed Central

    Shigeto, Makoto; Ramracheya, Reshma; Tarasov, Andrei I.; Cha, Chae Young; Chibalina, Margarita V.; Hastoy, Benoit; Philippaert, Koenraad; Reinbothe, Thomas; Rorsman, Nils; Salehi, Albert; Sones, William R.; Vergari, Elisa; Weston, Cathryn; Gorelik, Julia; Katsura, Masashi; Nikolaev, Viacheslav O.; Vennekens, Rudi; Zaccolo, Manuela; Galione, Antony; Johnson, Paul R.V.; Kaku, Kohei; Ladds, Graham; Rorsman, Patrik

    2015-01-01

    Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca2+ channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na+. The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na+-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca2+ from thapsigargin-sensitive Ca2+ stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells. PMID:26571400

  17. Rac1 Protein Regulates Glycogen Phosphorylase Activation and Controls Interleukin (IL)-2-dependent T Cell Proliferation*

    PubMed Central

    Arrizabalaga, Onetsine; Lacerda, Hadriano M.; Zubiaga, Ana M.; Zugaza, José L.

    2012-01-01

    Small GTPases of the Rho family have been implicated in important cellular processes such as cell migration and adhesion, protein secretion, and/or gene transcription. In the lymphoid system, these GTPases participate in the signaling cascades that are activated after engagement of antigen receptors. However, little is known about the role that Rho GTPases play in IL-2-mediated responses. Here, we show that IL-2 induces Rac1 activation in Kit 225 T cells. We identified by mass spectrometry the muscle isoform of glycogen phosphorylase (PYGM) as a novel Rac1 effector molecule in IL-2-stimulated cells. The interaction between the active form of Rac1 (Rac1-GTP) and PYGM was established directly through a domain comprising amino acids 191–270 of PYGM that exhibits significant homology with the Rac binding domain of PAK1. The integrity of this region was crucial for PYGM activation. Importantly, IL-2-dependent cellular proliferation was inhibited upon blocking both the activation of Rac1 and the activity of PYGM. These results reveal a new role for Rac1 in cell signaling, showing that this GTPase triggers T cell proliferation upon IL-2 stimulation by associating with PYGM and modulating its enzymatic activity. PMID:22337875

  18. RASA3 is a critical inhibitor of RAP1-dependent platelet activation

    PubMed Central

    Stefanini, Lucia; Paul, David S.; Robledo, Raymond F.; Chan, E. Ricky; Getz, Todd M.; Campbell, Robert A.; Kechele, Daniel O.; Casari, Caterina; Piatt, Raymond; Caron, Kathleen M.; Mackman, Nigel; Weyrich, Andrew S.; Parrott, Matthew C.; Boulaftali, Yacine; Adams, Mark D.; Peters, Luanne L.; Bergmeier, Wolfgang

    2015-01-01

    The small GTPase RAP1 is critical for platelet activation and thrombus formation. RAP1 activity in platelets is controlled by the GEF CalDAG-GEFI and an unknown regulator that operates downstream of the adenosine diphosphate (ADP) receptor, P2Y12, a target of antithrombotic therapy. Here, we provide evidence that the GAP, RASA3, inhibits platelet activation and provides a link between P2Y12 and activation of the RAP1 signaling pathway. In mice, reduced expression of RASA3 led to premature platelet activation and markedly reduced the life span of circulating platelets. The increased platelet turnover and the resulting thrombocytopenia were reversed by concomitant deletion of the gene encoding CalDAG-GEFI. Rasa3 mutant platelets were hyperresponsive to agonist stimulation, both in vitro and in vivo. Moreover, activation of Rasa3 mutant platelets occurred independently of ADP feedback signaling and was insensitive to inhibitors of P2Y12 or PI3 kinase. Together, our results indicate that RASA3 ensures that circulating platelets remain quiescent by restraining CalDAG-GEFI/RAP1 signaling and suggest that P2Y12 signaling is required to inhibit RASA3 and enable sustained RAP1-dependent platelet activation and thrombus formation at sites of vascular injury. These findings provide insight into the antithrombotic effect of P2Y12 inhibitors and may lead to improved diagnosis and treatment of platelet-related disorders. PMID:25705885

  19. Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation.

    PubMed

    Brennan, Todd V; Lin, Liwen; Brandstadter, Joshua D; Rendell, Victoria R; Dredge, Keith; Huang, Xiaopei; Yang, Yiping

    2016-01-01

    Heparan sulfate (HS) is an essential component of the extracellular matrix (ECM), which serves as a barrier to tumor invasion and metastasis. Heparanase promotes tumor growth by cleaving HS chains of proteoglycan and releasing HS-bound angiogenic growth factors and facilitates tumor invasion and metastasis by degrading the ECM. HS mimetics, such as PG545, have been developed as antitumor agents and are designed to suppress angiogenesis and metastasis by inhibiting heparanase and competing for the HS-binding domain of angiogenic growth factors. However, how PG545 exerts its antitumor effect remains incompletely defined. Here, using murine models of lymphoma, we determined that the antitumor effects of PG545 are critically dependent on NK cell activation and that NK cell activation by PG545 requires TLR9. We demonstrate that PG545 does not activate TLR9 directly but instead enhances TLR9 activation through the elevation of the TLR9 ligand CpG in DCs. Specifically, PG545 treatment resulted in CpG accumulation in the lysosomal compartment of DCs, leading to enhanced production of IL-12, which is essential for PG545-mediated NK cell activation. Overall, these results reveal that PG545 activates NK cells and that this activation is critical for the antitumor effect of PG545. Moreover, our findings may have important implications for improving NK cell-based antitumor therapies. PMID:26649979

  20. Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration

    PubMed Central

    Wakatsuki, Shuji; Furuno, Akiko; Ohshima, Makiko

    2015-01-01

    Oxidative stress is a well-known inducer of neuronal apoptosis and axonal degeneration. We previously showed that the E3 ubiquitin ligase ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B activation. We now demonstrate that oxidative stress serves as an activator of the ubiquitin ligase activity of ZNRF1 by inducing epidermal growth factor receptor (EGFR)–mediated phosphorylation at the 103rd tyrosine residue and that the up-regulation of ZNRF1 activity by oxidative stress leads to neuronal apoptosis and Wallerian degeneration. We also show that nicotinamide adenine dinucleotide phosphate–reduced oxidase activity is required for the EGFR-dependent phosphorylation-induced activation of ZNRF1 and resultant AKT degradation via the ubiquitin proteasome system to induce Wallerian degeneration. These results indicate the pathophysiological significance of the EGFR–ZNRF1 pathway induced by oxidative stress in the regulation of neuronal apoptosis and Wallerian degeneration. A deeper understanding of the regulatory mechanism for ZNRF1 catalytic activity via phosphorylation will provide a potential therapeutic avenue for neurodegeneration. PMID:26572622

  1. Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation

    PubMed Central

    Brennan, Todd V.; Lin, Liwen; Brandstadter, Joshua D.; Rendell, Victoria R.; Dredge, Keith; Huang, Xiaopei; Yang, Yiping

    2015-01-01

    Heparan sulfate (HS) is an essential component of the extracellular matrix (ECM), which serves as a barrier to tumor invasion and metastasis. Heparanase promotes tumor growth by cleaving HS chains of proteoglycan and releasing HS-bound angiogenic growth factors and facilitates tumor invasion and metastasis by degrading the ECM. HS mimetics, such as PG545, have been developed as antitumor agents and are designed to suppress angiogenesis and metastasis by inhibiting heparanase and competing for the HS-binding domain of angiogenic growth factors. However, how PG545 exerts its antitumor effect remains incompletely defined. Here, using murine models of lymphoma, we determined that the antitumor effects of PG545 are critically dependent on NK cell activation and that NK cell activation by PG545 requires TLR9. We demonstrate that PG545 does not activate TLR9 directly but instead enhances TLR9 activation through the elevation of the TLR9 ligand CpG in DCs. Specifically, PG545 treatment resulted in CpG accumulation in the lysosomal compartment of DCs, leading to enhanced production of IL-12, which is essential for PG545-mediated NK cell activation. Overall, these results reveal that PG545 activates NK cells and that this activation is critical for the antitumor effect of PG545. Moreover, our findings may have important implications for improving NK cell–based antitumor therapies. PMID:26649979

  2. Brain activations evoked by tactile stimulation varies with the intensity and not with number of receptive fields stimulated: An fMRI study

    NASA Astrophysics Data System (ADS)

    Ramirez Garzón, Y. T.; Pasaye, E. H.; Barrios, F. A.

    2014-11-01

    Using functional Magnetic Resonance Imaging (fMRI) it is possible to study the functional anatomy of primary cortices. Cortical representations in the primary somatosensory cortex have shown discrepancies between activations related to the same body region in some studies; these differences have been more pronounced for lower limb representations. The aim of this study was to observe the influence of the tactile stimulus intensity in somatosensory cortical responses using fMRI. Based in the sensitivity and pain threshold of each subject, we used Von Frey filaments for stimulate 12 control subject in three receptive fields on the right thigh. One filament near to sensitivity threshold (VFS), other close to pain threshold (VFP) and one intermediate filament between the two previous thresholds (VFI). The tactile stimulation with VFS produced no activation on SI, while that the contralateral SI was activated by stimulation with VFI in 5 subjects and with the stimulation of VFP in all subjects. Second level statistical analysis showed significant differences between SI activations related to the stimulation with VFP and VFI (VFP > VFI), in the comparison between the applied different intensities, a small cluster of activation was observed on SI for the unique possible contrast (VFP > VFI). The time course per trial for each subject was extracted and averaged to extract the activation in the contralateral SI and compared across the stimulus modalities, between the sites of field receptive stimulated and the intensities used. The time course of tactile stimulus responses revealed a consistent single peak of activity per cycle (30 s), approximately 12 s after the onset of the stimulus, with exception of the VFI stimulation,_which showed the peak at 10 s. Thus, our results indicate that the cortical representation of a tactile stimulus with fMRI is modulated for the intensity of the stimulus applied.

  3. Quantitative structure-activity relationship models with receptor-dependent descriptors for predicting peroxisome proliferator-activated receptor activities of thiazolidinedione and oxazolidinedione derivatives.

    PubMed

    Lather, Viney; Kairys, Visvaldas; Fernandes, Miguel X

    2009-04-01

    A quantitative structure-activity relationship study has been carried out, in which the relationship between the peroxisome proliferator-activated receptor alpha and the peroxisome proliferator-activated receptor gamma agonistic activities of thiazolidinedione and oxazolidinedione derivatives and quantitative descriptors, V(site) calculated in a receptor-dependent manner is modeled. These descriptors quantify the volume occupied by the optimized ligands in regions that are either common or specific to the superimposed binding sites of the targets under consideration. The quantitative structure-activity relationship models were built by forward stepwise linear regression modeling for a training set of 27 compounds and validated for a test set of seven compounds, resulting in a squared correlation coefficient value of 0.90 for peroxisome proliferator-activated receptor alpha and of 0.89 for peroxisome proliferator-activated receptor gamma. The leave-one-out cross-validation and test set predictability squared correlation coefficient values for these models were 0.85 and 0.62 for peroxisome proliferator-activated receptor alpha and 0.89 and 0.50 for peroxisome proliferator-activated receptor gamma respectively. A dual peroxisome proliferator-activated receptor model has also been developed, and it indicates the structural features required for the design of ligands with dual peroxisome proliferator-activated receptor activity. These quantitative structure-activity relationship models show the importance of the descriptors here introduced in the prediction and interpretation of the compounds affinity and selectivity. PMID:19243388

  4. TRAIL activates JNK and NF-κB through RIP1-dependent and -independent pathways.

    PubMed

    Zhang, Laiqun; Dittmer, Martin R; Blackwell, Ken; Workman, Lauren M; Hostager, Bruce; Habelhah, Hasem

    2015-02-01

    The death receptor (DR) ligand TRAIL is being evaluated in clinical trials as an anti-cancer agent; however, many studies have found that TRAIL also enhances tumor progression by activating the NF-κB pathway in apoptosis-resistant cells. Although RIP1, cFLIP and caspase-8 have been implicated in TRAIL-induced JNK and NF-κB activation, underlying mechanisms are unclear. By examining the kinetics of pathway activation in TRAIL-sensitive lymphoma cells wild-type or deficient for RIP1, TRAF2, cIAP1/2 or HOIP, we report here that TRAIL induces two phases of JNK and NF-κB activation. The early phase is activated by TRAF2- and cIAP1-mediated ubiquitination of RIP1, whereas the delayed phase is induced by caspase-dependent activation of MEKK1 independent of RIP1 and TRAF2 expression. cFLIP overexpression promotes the early phase but completely suppresses the delayed phase of pathway activation in lymphoma cells, whereas Bcl-2 overexpression promotes both the early and delayed phases of the pathways. In addition, stable overexpression of cFLIP in RIP1- or TRAF2-deficient cells confers resistance to apoptosis, but fails to mediate NF-κB activation. HOIP is not essential for, but contributes to, TRAIL-induced NF-κB activation in cFLIP-overexpressing cells. These findings not only elucidate details of the mechanisms underlying TRAIL-induced JNK and NF-κB activation, but also clarify conflicting reports in the field. PMID:25446254

  5. Regional Brain Activity in Abstinent Methamphetamine Dependent Males Following Cue Exposure

    PubMed Central

    Malcolm, Robert; Myrick, Hugh; Li, Xingbao; Henderson, Scott; Brady, Kathleen T; George, Mark S; See, Ronald E

    2016-01-01

    Background Neuroimaging of drug-associated cue presentations has aided in understanding the neurobiological substrates of craving and relapse for cocaine, alcohol, and nicotine. However, imaging of cue-reactivity in methamphetamine addiction has been much less studied. Method Nine caucasian male methamphetamine-dependent subjects and nine healthy controls were scanned in a Phillips 3.0T MRI scan when they viewed a randomized presentation of visual cues of methamphetamine, neutral objects, and rest conditions. Functional Imaging data were analyzed with Statistical Parametric Mapping software 5 (SPM 5) Results Methamphetamine subjects had significant brain activation in the ventral striatum and medial frontal cortex in comparison to meth pictures and neutral pictures in healthy controls (p<0.005, threshold 15 voxels). Interestingly the ventral striatum activation significantly correlated with the days since the last use of meth (r=−0.76, p=0.017). No significant activity was found in healthy control group. Conclusion The preliminary data suggest that methamphetamine dependent subjects, when exposed to methamphetamine-associated visual cues, have increased brain activity in ventral striatum, caudate nucleus and medial frontal cortex which subserve craving, drug-seeking, and drug use. PMID:27314105

  6. NMDAR-dependent proteasome activity in the gustatory cortex is necessary for conditioned taste aversion.

    PubMed

    Rosenberg, Tali; Elkobi, Alina; Dieterich, Daniela C; Rosenblum, Kobi

    2016-04-01

    Taste information is processed in different brain structures in the mammalian brain, including the gustatory cortex (GC), which resides within the insular cortex. N-methyl-d-aspartate receptor (NMDAR) activity in the GC is necessary for the acquisition of conditioned taste aversion (CTA) but not positive novel taste learning. Previous studies have shown that taste memory consolidation requires intact protein synthesis in the GC. In addition, the direct involvement of translation initiation and elongation factors was documented in the GC during taste learning. However, protein expression is defined by protein synthesis, degradation, and localization. Protein degradation is critical for the consolidation and reconsolidation of other forms of learning, such as fear learning and addiction behavior, but its role in cortical-dependent learning is not clear. Here, we show for the first time that proteasome activity is specifically increased in the GC 4h following experiencing of a novel taste. This increase in proteasome activity was abolished by local administration to the GC of the NMDA antagonist, APV, as well as a CaMKII inhibitor, at the time of acquisition. In addition, local application of lactacystin, a proteasome inhibitor, resulted in impaired CTA, but not novel taste learning. These results suggest that NMDAR-dependent proteasome activity in the GC participates in the association process between novel taste experience and negative visceral sensation. PMID:26785229

  7. Context-dependent transcriptional interpretation of mitogen activated protein kinase signaling in the Drosophila embryo

    NASA Astrophysics Data System (ADS)

    Kim, Yoosik; Iagovitina, Antonina; Ishihara, Keisuke; Fitzgerald, Kate M.; Deplancke, Bart; Papatsenko, Dmitri; Shvartsman, Stanislav Y.

    2013-06-01

    Terminal regions of the Drosophila embryo are patterned by the localized activation of Mitogen Activated Protein Kinase (MAPK), which induces zygotic genes through relief of their repression by transcriptional repressor Capicua. The levels of MAPK activation at the anterior and posterior termini are close to each other, but the expression patterns of MAPK-target genes, such as zerknüllt (zen) and tailless (tll), display strong anterior-posterior (AP) asymmetry. This region-specific response to MAPK activation provides a clear example of context-dependent interpretation of inductive signaling, a common developmental effect that remains poorly understood. In the past, the AP asymmetry of zen expression was attributed to a mechanism that depends on MAPK substrate competition. We present data suggesting that the asymmetric expression of tll is generated by a different mechanism, based on feedforward control and multiple enhancers of the tll gene. A simple mathematical model of this mechanism correctly predicts how the wild-type expression pattern of tll changes in mutants affecting the anterior, dorsoventral, and terminal patterning systems and some of their direct targets.

  8. Shape-Dependent Biomimetic Inhibition of Enzyme by Nanoparticles and Their Antibacterial Activity.

    PubMed

    Cha, Sang-Ho; Hong, Jin; McGuffie, Matt; Yeom, Bongjun; VanEpps, J Scott; Kotov, Nicholas A

    2015-09-22

    Enzyme inhibitors are ubiquitous in all living systems, and their biological inhibitory activity is strongly dependent on their molecular shape. Here, we show that small zinc oxide nanoparticles (ZnO NPs)-pyramids, plates, and spheres-possess the ability to inhibit activity of a typical enzyme β-galactosidase (GAL) in a biomimetic fashion. Enzyme inhibition by ZnO NPs is reversible and follows classical Michaelis-Menten kinetics with parameters strongly dependent on their geometry. Diverse spectroscopic, biochemical, and computational experimental data indicate that association of GAL with specific ZnO NP geometries interferes with conformational reorganization of the enzyme necessary for its catalytic activity. The strongest inhibition was observed for ZnO nanopyramids and compares favorably to that of the best natural GAL inhibitors while being resistant to proteases. Besides the fundamental significance of this biomimetic function of anisotropic NPs, their capacity to serve as degradation-resistant enzyme inhibitors is technologically attractive and is substantiated by strong shape-specific antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), endemic for most hospitals in the world. PMID:26325486

  9. Blood Oxygen Level-Dependent Activation of the Primary Visual Cortex Predicts Size Adaptation Illusion

    PubMed Central

    Pooresmaeili, Arezoo; Arrighi, Roberto; Biagi, Laura; Morrone, Maria Concetta

    2016-01-01

    In natural scenes, objects rarely occur in isolation but appear within a spatiotemporal context. Here, we show that the perceived size of a stimulus is significantly affected by the context of the scene: brief previous presentation of larger or smaller adapting stimuli at the same region of space changes the perceived size of a test stimulus, with larger adapting stimuli causing the test to appear smaller than veridical and vice versa. In a human fMRI study, we measured the blood oxygen level-dependent activation (BOLD) responses of the primary visual cortex (V1) to the contours of large-diameter stimuli and found that activation closely matched the perceptual rather than the retinal stimulus size: the activated area of V1 increased or decreased, depending on the size of the preceding stimulus. A model based on local inhibitory V1 mechanisms simulated the inward or outward shifts of the stimulus contours and hence the perceptual effects. Our findings suggest that area V1 is actively involved in reshaping our perception to match the short-term statistics of the visual scene. PMID:24089504

  10. The Molecular Physiology of Activity-Dependent Bulk Endocytosis of Synaptic Vesicles

    PubMed Central

    Clayton, Emma L.; Cousin, Michael A.

    2010-01-01

    Central nerve terminals release neurotransmitter in response to a wide variety of stimuli. Since maintenance of neurotransmitter release is dependent on the continual supply of synaptic vesicles (SVs), nerve terminals possess an array of endocytosis modes to retrieve and recycle SV membrane and proteins. During mild stimulation conditions single SV retrieval modes such as clathrin-mediated endocytosis (CME) predominate. However during increased neuronal activity additional SV retrieval capacity is required, which is provided by activity-dependent bulk endocytosis (ADBE). ADBE is the dominant SV retrieval mechanism during elevated neuronal activity. It is a high capacity SV retrieval mode that is immediately triggered during such stimulation conditions. This review will summarise the current knowledge regarding the molecular mechanism of ADBE, including molecules required for its triggering and subsequent steps, including SV budding from bulk endosomes. The molecular relationship between ADBE and the SV reserve pool will also be discussed. It is becoming clear that an understanding of the molecular physiology of ADBE will be of critical importance in attempts to modulate both normal and abnormal synaptic function during intense neuronal activity. PMID:19765184

  11. Inhibition of Bak Activation by VDAC2 Is Dependent on the Bak Transmembrane Anchor*

    PubMed Central

    Lazarou, Michael; Stojanovski, Diana; Frazier, Ann E.; Kotevski, Aneta; Dewson, Grant; Craigen, William J.; Kluck, Ruth M.; Vaux, David L.; Ryan, Michael T.

    2010-01-01

    Bax and Bak are pro-apoptotic factors that are required for cell death by the mitochondrial or intrinsic pathway. Bax is found in an inactive state in the cytosol and upon activation is targeted to the mitochondrial outer membrane where it releases cytochrome c and other factors that cause caspase activation. Although Bak functions in the same way as Bax, it is constitutively localized to the mitochondrial outer membrane. In the membrane, Bak activation is inhibited by the voltage-dependent anion channel isoform 2 (VDAC2) by an unknown mechanism. Using blue native gel electrophoresis, we show that in healthy cells endogenous inactive Bak exists in a 400-kDa complex that is dependent on the presence of VDAC2. Activation of Bak is concomitant with its release from the 400-kDa complex and the formation of lower molecular weight species. Furthermore, substitution of the Bak transmembrane anchor with that of the mitochondrial outer membrane tail-anchored protein hFis1 prevents association of Bak with the VDAC2 complex and increases the sensitivity of cells to an apoptotic stimulus. Our results suggest that VDAC2 interacts with the hydrophobic tail of Bak to sequester it in an inactive state in the mitochondrial outer membrane, thereby raising the stimulation threshold necessary for permeabilization of the mitochondrial outer membrane and cell death. PMID:20851889

  12. Inhibition of Bak activation by VDAC2 is dependent on the Bak transmembrane anchor.

    PubMed

    Lazarou, Michael; Stojanovski, Diana; Frazier, Ann E; Kotevski, Aneta; Dewson, Grant; Craigen, William J; Kluck, Ruth M; Vaux, David L; Ryan, Michael T

    2010-11-19

    Bax and Bak are pro-apoptotic factors that are required for cell death by the mitochondrial or intrinsic pathway. Bax is found in an inactive state in the cytosol and upon activation is targeted to the mitochondrial outer membrane where it releases cytochrome c and other factors that cause caspase activation. Although Bak functions in the same way as Bax, it is constitutively localized to the mitochondrial outer membrane. In the membrane, Bak activation is inhibited by the voltage-dependent anion channel isoform 2 (VDAC2) by an unknown mechanism. Using blue native gel electrophoresis, we show that in healthy cells endogenous inactive Bak exists in a 400-kDa complex that is dependent on the presence of VDAC2. Activation of Bak is concomitant with its release from the 400-kDa complex and the formation of lower molecular weight species. Furthermore, substitution of the Bak transmembrane anchor with that of the mitochondrial outer membrane tail-anchored protein hFis1 prevents association of Bak with the VDAC2 complex and increases the sensitivity of cells to an apoptotic stimulus. Our results suggest that VDAC2 interacts with the hydrophobic tail of Bak to sequester it in an inactive state in the mitochondrial outer membrane, thereby raising the stimulation threshold necessary for permeabilization of the mitochondrial outer membrane and cell death. PMID:20851889

  13. Context-dependent transcriptional interpretation of mitogen activated protein kinase signaling in the Drosophila embryo

    PubMed Central

    Kim, Yoosik; Iagovitina, Antonina; Ishihara, Keisuke; Fitzgerald, Kate M.; Deplancke, Bart; Papatsenko, Dmitri; Shvartsman, Stanislav Y.

    2013-01-01

    Terminal regions of the Drosophila embryo are patterned by the localized activation of Mitogen Activated Protein Kinase (MAPK), which induces zygotic genes through relief of their repression by transcriptional repressor Capicua. The levels of MAPK activation at the anterior and posterior termini are close to each other, but the expression patterns of MAPK-target genes, such as zerknüllt (zen) and tailless (tll), display strong anterior-posterior (AP) asymmetry. This region-specific response to MAPK activation provides a clear example of context-dependent interpretation of inductive signaling, a common developmental effect that remains poorly understood. In the past, the AP asymmetry of zen expression was attributed to a mechanism that depends on MAPK substrate competition. We present data suggesting that the asymmetric expression of tll is generated by a different mechanism, based on feedforward control and multiple enhancers of the tll gene. A simple mathematical model of this mechanism correctly predicts how the wild-type expression pattern of tll changes in mutants affecting the anterior, dorsoventral, and terminal patterning systems and some of their direct targets. PMID:23822503

  14. Activity-dependent transmission and integration control the timescales of auditory processing at an inhibitory synapse.

    PubMed

    Ammer, Julian J; Siveke, Ida; Felmy, Felix

    2015-06-15

    To capture the context of sensory information, neural networks must process input signals across multiple timescales. In the auditory system, a prominent change in temporal processing takes place at an inhibitory GABAergic synapse in the dorsal nucleus of the lateral lemniscus (DNLL). At this synapse, inhibition outlasts the stimulus by tens of milliseconds, such that it suppresses responses to lagging sounds, and is therefore implicated in echo suppression. Here, we untangle the cellular basis of this inhibition. We demonstrate with in vivo whole-cell patch-clamp recordings in Mongolian gerbils that the duration of inhibition increases with sound intensity. Activity-dependent spillover and asynchronous release translate the high presynaptic firing rates found in vivo into a prolonged synaptic output in acute slice recordings. A key mechanism controlling the inhibitory time course is the passive integration of the hyperpolarizing inhibitory conductance. This prolongation depends on the synaptic conductance amplitude. Computational modeling shows that this prolongation is a general mechanism and relies on a non-linear effect caused by synaptic conductance saturation when approaching the GABA reversal potential. The resulting hyperpolarization generates an efficient activity-dependent suppression of action potentials without affecting the threshold or gain of the input-output function. Taken together, the GABAergic inhibition in the DNLL is adjusted to the physiologically relevant duration by passive integration of inhibition with activity-dependent synaptic kinetics. This change in processing timescale combined with the reciprocal connectivity between the DNLLs implements a mechanism to suppress the distracting localization cues of echoes and helps to localize the initial sound source reliably. PMID:26004766

  15. Activation of Ca2+-dependent K+ channels in human B lymphocytes by anti-immunoglobulin.

    PubMed Central

    MacDougall, S L; Grinstein, S; Gelfand, E W

    1988-01-01

    Many mammalian cell types exhibit Ca2+-dependent K+ channels, and activation of these channels by increasing intracellular calcium generally leads to a hyperpolarization of the plasma membrane. Their presence in B lymphocytes is as yet uncertain. Crosslinking Ig on the surface of B lymphocytes is known to increase the level of free cytoplasmic calcium ([Ca2+]i). However, rather than hyperpolarization, a depolarization has been reported to occur after treatment of B lymphocytes with anti-Ig. To determine if Ca2+-dependent K+ channels are present in B lymphocytes, and to examine the relationship between intracellular free calcium and membrane potential, we monitored [Ca2+]i by means of indo-1 and transmembrane potential using bis(1,3-diethylthiobarbituric)trimethine oxonol in human tonsillar B cells activated by anti-IgM. Treatment with anti-IgM induced a biphasic increase in [Ca2+]i and a simultaneous hyperpolarization. A similar hyperpolarization was induced by ionomycin, a Ca2+ ionophore. Delaying the development of the [Ca2+]i response by increasing the cytoplasmic Ca2+-buffering power delayed the hyperpolarization. Conversely, eliminating the sustained phase of the [Ca2+]i response by omission of external Ca2+ abolished the prolonged hyperpolarization. In fact, a sizable Na+-dependent depolarization was unmasked. This study demonstrates that in human B lymphocytes, Ca2+-dependent K+ channels can be activated by crosslinking of surface IgM. Moreover, it is likely that, by analogy with voltage-sensitive Ca2+ channels, Na+ can permeate through these ligand-gated Ca2+ "channels" in the absence of extracellular Ca2+. PMID:2448342

  16. Long-range signaling in growing neurons after local elevation of cyclic AMP-dependent activity

    PubMed Central

    1994-01-01

    Cyclic AMP-dependent activity at the growth cone or the soma of cultured Xenopus spinal neurons was elevated by local extracellular perfusion of the neuron with culture medium containing 8-bromoadenosine 3',5'-cyclic monophosphate (8-br-cAMP) or forskolin. During local perfusion of one of the growth cones of multipolar neurons with these drugs, the perfused growth cone showed further extension, while the distant, unperfused growth cones were inhibited in their growth. Local perfusion of the growth cone with culture medium or local perfusion with 8-br-cAMP at a cell-free region 100 microns away from the growth cone did not produce any effect on the extension of the growth cone. Reduced extension of all growth cones was observed when the perfusion with 8-br-cAMP was restricted to the soma. The distant inhibitory effect does not depend on the growth of the perfused growth cone since local coperfusion of the growth cone with 8-br-cAMP and colchicine inhibited growth on both perfused and unperfused growth cones, while local perfusion with colchicine alone inhibited only the perfused growth cone. The distant inhibitory effect was abolished when the perfusion of 8-br-cAMP was carried out together with kinase inhibitor H- 8, suggesting the involvement of cAMP-dependent protein kinase and/or its downstream factors in the long-range inhibitory signaling. Uniform exposure of the entire neuron to bath-applied 8-br-cAMP, however, led to enhanced growth activity at all growth cones. Thus, local elevation of cAMP-dependent activity produces long-range and opposite effects on distant parts of the neuron, and a cytosolic gradient of second messengers may produce effects distinctly different from those following uniform global elevation of the messenger, leading to differential growth regulation at different regions of the same neuron. PMID:7798321

  17. Supplementation with Sodium Selenite and Selenium-Enriched Microalgae Biomass Show Varying Effects on Blood Enzymes Activities, Antioxidant Response, and Accumulation in Common Barbel (Barbus barbus)

    PubMed Central

    Kouba, Antonín; Velíšek, Josef; Stará, Alžběta; Masojídek, Jiří; Kozák, Pavel

    2014-01-01

    Yearling common barbel (Barbus barbus L.) were fed four purified casein-based diets for 6 weeks in outdoor cages. Besides control diet, these were supplemented with 0.3 mg kg−1 dw selenium (Se) from sodium selenite, or 0.3 and 1.0 mg kg−1 from Se-enriched microalgae biomass (Chlorella), a previously untested Se source for fish. Fish mortality, growth, Se accumulation in muscle and liver, and activity of selected enzymes in blood plasma, muscle, liver, and intestine were evaluated. There was no mortality, and no differences in fish growth, among groups. Se concentrations in muscle and liver, activity of alanine aminotransferase and creatine kinase in blood plasma, glutathione reductase (GR) in muscle, and GR and catalase in muscle and liver suggested that selenium from Se-enriched Chlorella is more readily accumulated and biologically active while being less toxic than sodium selenite. PMID:24772422

  18. Supplementation with sodium selenite and selenium-enriched microalgae biomass show varying effects on blood enzymes activities, antioxidant response, and accumulation in common barbel (Barbus barbus).

    PubMed

    Kouba, Antonín; Velíšek, Josef; Stará, Alžběta; Masojídek, Jiří; Kozák, Pavel

    2014-01-01

    Yearling common barbel (Barbus barbus L.) were fed four purified casein-based diets for 6 weeks in outdoor cages. Besides control diet, these were supplemented with 0.3 mg kg(-1) dw selenium (Se) from sodium selenite, or 0.3 and 1.0 mg kg(-1) from Se-enriched microalgae biomass (Chlorella), a previously untested Se source for fish. Fish mortality, growth, Se accumulation in muscle and liver, and activity of selected enzymes in blood plasma, muscle, liver, and intestine were evaluated. There was no mortality, and no differences in fish growth, among groups. Se concentrations in muscle and liver, activity of alanine aminotransferase and creatine kinase in blood plasma, glutathione reductase (GR) in muscle, and GR and catalase in muscle and liver suggested that selenium from Se-enriched Chlorella is more readily accumulated and biologically active while being less toxic than sodium selenite. PMID:24772422

  19. The activity of lysosomal exoglycosidases in serum of alcohol-dependent men supplemented with borage oil enriched with vitamin E.

    PubMed

    Zaniewska, Agnieszka; Borzym-Kluczyk, Malgorzata; Szajda, Slawomir D; Romatowski, Jacek; Gil, Andrzej; Knas, Malgorzata; Dobryniewski, Jacek; Zwierz, Krzysztof

    2009-08-01

    The aim of this study was to determine the activity of the lysosomal exoglycosidases: alpha-mannosidase (MAN), alpha-fucosidase (FUC), and beta-glucuronidase (GLUCUR) in serum of alcohol-dependent men supplemented and not supplemented with borage oil enriched with vitamin E. Serum was collected from eight social drinkers and 16 alcohol-dependent men after a drinking period. The activity of exoglycosidases and the concentration of protein in serum were determined. The increase in specific activity of MAN and GLUCUR was significant in serum of alcohol-dependent men both not supplemented and supplemented with borage oil enriched with vitamin E, in comparison with the specific activity in serum of social drinkers. In serum of alcohol-dependent men treated with borage oil enriched with vitamin E, specific activity of MAN and GLUCUR fluctuated in comparison with alcohol-dependent men not supplemented. Specific activity of FUC in serum of alcohol-dependent men both not supplemented and supplemented with borage oil enriched with vitamin E showed a tendency to increase, in comparison with social drinkers. Specific activity of FUC had a tendency to decrease in serum of alcohol-dependent men supplemented with borage oil enriched with vitamin E, in comparison with alcohol-dependent men not supplemented. Thus, supplementation of alcohol-dependent men after a long-lasting drinking period with borage oil and vitamin E did not change the rate of catabolism of the oligosaccharide chains of glycoconjugates, as evaluated by serum activity of exoglycosidases. PMID:19735195

  20. Varying electric charge in multiscale spacetimes

    NASA Astrophysics Data System (ADS)

    Calcagni, Gianluca; Magueijo, João; Fernández, David Rodríguez

    2014-01-01

    We derive the covariant equations of motion for Maxwell field theory and electrodynamics in multiscale spacetimes with weighted Laplacian. An effective spacetime-dependent electric charge of geometric origin naturally emerges from the theory, thus giving rise to a varying fine-structure constant. The theory is compared with other varying-coupling models, such as those with a varying electric charge or varying speed of light. The theory is also confronted with cosmological observations, which can place constraints on the characteristic scales in the multifractional measure. We note that the model considered here is fundamentally different from those previously proposed in the literature, either of the varying-e or varying-c persuasion.

  1. Adult house fly (Diptera: Muscidae) activity and age of females near varying levels of (Z)-9-tricosene on a southern California dairy.

    PubMed

    Butler, Sarah M; Mullens, Bradley A

    2010-10-01

    The number of adult male and female house flies, Musca domestica L. (Diptera: Muscidae), near varying levels of (Z)-9-tricosene alone (5, 50, or 100 micdrol) or combined (50 microl) with sugar was determined using conical screened traps on a dairy in southern California. Overall, significantly more males than females were collected in the traps. Significantly more flies (male and female) were collected in traps with (Z)-9-tricosene. There were no significant differences among doses of (Z)-9-tricosene alone, but numbers of both sexes were significantly higher in traps baited with (Z)-9-tricosene and sugar compared with the 5- and 50-microl doses without sugar. The age of female flies collected in traps was determined by pterin analysis. Mean female ages ranged from 94.7 to 99.6 degree-days (6.3-6.8 d of age) and did not differ significantly among treatments. Dissections of a subset of females from each treatment determined that collected females were primarily nongravid (86.3%). Proportions of gravid females that were collected did not differ among treatments. PMID:21061998

  2. Dihydromyricetin promotes hepatocellular carcinoma regression via a p53 activation-dependent mechanism

    NASA Astrophysics Data System (ADS)

    Zhang, Qingyu; Liu, Jie; Liu, Bin; Xia, Juan; Chen, Nianping; Chen, Xiaofeng; Cao, Yi; Zhang, Chen; Lu, Caijie; Li, Mingyi; Zhu, Runzhi

    2014-04-01

    The development of antitumor chemotherapy drugs remains a key goal for oncologists, and natural products provide a vast resource for anti-cancer drug discovery. In the current study, we found that the flavonoid dihydromyricetin (DHM) exhibited antitumor activity against liver cancer cells, including primary cells obtained from hepatocellular carcinoma (HCC) patients. In contrast, DHM was not cytotoxic to immortalized normal liver cells. Furthermore, DHM treatment resulted in the growth inhibition and remission of xenotransplanted tumors in nude mice. Our results further demonstrated that this antitumor activity was caused by the activation of the p53-dependent apoptosis pathway via p53 phosphorylation at serine (15Ser). Moreover, our results showed that DHM plays a dual role in the induction of cell death when administered in combination with cisplatin, a common clinical drug that kills primary hepatoma cells but not normal liver cells.

  3. Structures of apicomplexan calcium-dependent protein kinases reveal mechanism of activation by calcium

    PubMed Central

    Wernimont, Amy K.; Artz, Jennifer D.; Finerty, Patrick; Lin, Y.; Amani, Mehrnaz; Allali-Hassani, Abdellah; Senisterra, Guillermo; Vedadi, Masoud; Tempel, Wolfram; Mackenzie, Farrell; Chau, Irene; Lourido, Sebastian; Sibley, L. David; Hui, Raymond

    2013-01-01

    Calcium-dependent protein kinases (CDPKs) play pivotal roles in the calcium-signaling pathway in plants, ciliates and apicomplexan parasites, and comprise a CaMK-like kinase domain regulated by a calcium-binding domain in the C-terminus. To understand this intramolecular mechanism of activation, we solved the structures of the autoinhibited (apo) and activated (calcium-bound) conformations of CDPKs from the apicomplexan parasites Toxoplasma gondii and Cryptosporidium parvum. In the apo form, the C-terminal CDPK activation domain (CAD) resembles a calmodulin protein with an unexpected long helix in the N-terminus that inhibits the kinase domain in the same manner as CaMKII. Calcium binding triggers the reorganization of the CAD into a highly intricate fold, leading to its relocation around the base of the kinase domain to a site remote from the substrate-binding site. This large conformational change constitutes a distinct mechanism in calcium signal transduction pathways. PMID:20436473

  4. Specific Inhibition of Cyclin-dependent Kinase 5 Activity Induces Motor Neuron Development in vivo

    PubMed Central

    Kanungo, Jyotshnabala; Zheng, Ya-Li; Amin, Niranjana D.; Kaur, Sukhbir; Ramchandran, Ramani; Pant, Harish C.

    2009-01-01

    Cyclin-dependent kinase 5 (cdk5) is a ubiquitous protein activated by specific activators, p35 and p39. Cdk5 regulates neuronal migration, differentiation, axonogenesis, synaptic transmission and apoptosis. However, its role in motor neuron development remains unexplored. Here, using gain and loss-of-function analyses