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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.

  2. Injection dependent lifetime spectroscopy with a varying pulse length

    NASA Astrophysics Data System (ADS)

    Schüler, Nadine; Dornich, Kay; Niklas, Jürgen R.

    2014-02-01

    The versatile capabilities of MDP (microwave detected photoconductivity) measurements, facilitating injection dependent measurements with a varying exciting laser pulse width, are demonstrated. With these measurements new opportunities arise for the investigation of carrier dynamics in defects at different depths inside the sample. Additionally the possibilities to measure very thin layers are demonstrated. In this study several measurements onthin epitaxial layersare presented which demonstrate the numerous information that can be gained with injection and pulse dependent measurements.

  3. 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...

  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. Myofilament length dependent activation.

    PubMed

    de Tombe, Pieter P; Mateja, Ryan D; Tachampa, Kittipong; Ait Mou, Younss; Farman, Gerrie P; Irving, Thomas C

    2010-05-01

    The Frank-Starling law of the heart describes the interrelationship between end-diastolic volume and cardiac ejection volume, a regulatory system that operates on a beat-to-beat basis. The main cellular mechanism that underlies this phenomenon is an increase in the responsiveness of cardiac myofilaments to activating Ca(2+) ions at a longer sarcomere length, commonly referred to as myofilament length-dependent activation. This review focuses on what molecular mechanisms may underlie myofilament length dependency. Specifically, the roles of inter-filament spacing, thick and thin filament based regulation, as well as sarcomeric regulatory proteins are discussed. Although the "Frank-Starling law of the heart" constitutes a fundamental cardiac property that has been appreciated for well over a century, it is still not known in muscle how the contractile apparatus transduces the information concerning sarcomere length to modulate ventricular pressure development.

  6. Myofilament length dependent activation

    SciTech Connect

    de Tombe, Pieter P.; Mateja, Ryan D.; Tachampa, Kittipong; Mou, Younss Ait; Farman, Gerrie P.; Irving, Thomas C.

    2010-05-25

    The Frank-Starling law of the heart describes the interrelationship between end-diastolic volume and cardiac ejection volume, a regulatory system that operates on a beat-to-beat basis. The main cellular mechanism that underlies this phenomenon is an increase in the responsiveness of cardiac myofilaments to activating Ca{sup 2+} ions at a longer sarcomere length, commonly referred to as myofilament length-dependent activation. This review focuses on what molecular mechanisms may underlie myofilament length dependency. Specifically, the roles of inter-filament spacing, thick and thin filament based regulation, as well as sarcomeric regulatory proteins are discussed. Although the 'Frank-Starling law of the heart' constitutes a fundamental cardiac property that has been appreciated for well over a century, it is still not known in muscle how the contractile apparatus transduces the information concerning sarcomere length to modulate ventricular pressure development.

  7. 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

  8. Basic Business and Economics: Varied Activities Encourage Active Student Involvement.

    ERIC Educational Resources Information Center

    Baker, Robert Lee, Jr.

    1978-01-01

    Describes a variety of activities for the basic business classroom, such as having guest speakers, question-and-answer sessions, simulations, role playing, debates, small group work, field trips, games, and individualized instruction. Includes a report of business teachers' knowledge of and attitudes toward these activities. (MF)

  9. Evaluation of active appearance models in varying background conditions

    NASA Astrophysics Data System (ADS)

    Kowalski, Marek; Naruniec, Jacek

    2013-10-01

    In this paper we present an evaluation of the chosen versions of Active Appearance Models (AAM) in varying background conditions. Algorithms were tested on a subset of the CMU PIE database and chosen background im- ages. Our experiments prove, that the accuracy of those methods is strictly correlated with the used background, where the differences in the success rate differ even up to 50%.

  10. 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.

  11. 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.

  12. New exponential synchronization criteria for time-varying delayed neural networks with discontinuous activations.

    PubMed

    Cai, Zuowei; Huang, Lihong; Zhang, Lingling

    2015-05-01

    This paper investigates the problem of exponential synchronization of time-varying delayed neural networks with discontinuous neuron activations. Under the extended Filippov differential inclusion framework, by designing discontinuous state-feedback controller and using some analytic techniques, new testable algebraic criteria are obtained to realize two different kinds of global exponential synchronization of the drive-response system. Moreover, we give the estimated rate of exponential synchronization which depends on the delays and system parameters. The obtained results extend some previous works on synchronization of delayed neural networks not only with continuous activations but also with discontinuous activations. Finally, numerical examples are provided to show the correctness of our analysis via computer simulations. Our method and theoretical results have a leading significance in the design of synchronized neural network circuits involving discontinuous factors and time-varying delays.

  13. 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.

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

    PubMed

    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.

  15. 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.

  16. 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.

  17. Delay-dependent finite-time boundedness of a class of Markovian switching neural networks with time-varying delays.

    PubMed

    Zhong, Qishui; Cheng, Jun; Zhao, Yuqing

    2015-07-01

    In this paper, a novel method is developed for delay-dependent finite-time boundedness of a class of Markovian switching neural networks with time-varying delays. New sufficient condition for stochastic boundness of Markovian jumping neural networks is presented and proved by an newly augmented stochastic Lyapunov-Krasovskii functional and novel activation function conditions, the state trajectory remains in a bounded region of the state space over a given finite-time interval. Finally, a numerical example is given to illustrate the efficiency and less conservative of the proposed method.

  18. Isosurface extraction and view-dependent filtering from time-varying fields using Persistent Time-Octree (PTOT).

    PubMed

    Wang, Cong; Chiang, Yi-Jen

    2009-01-01

    We develop a new algorithm for isosurface extraction and view-dependent filtering from large time-varying fields, by using a novel Persistent Time-Octree (PTOT) indexing structure. Previously, the Persistent Octree (POT) was proposed to perform isosurface extraction and view-dependent filtering, which combines the advantages of the interval tree (for optimal searches of active cells) and of the Branch-On-Need Octree (BONO, forview-dependent filtering), but it only works for steady-state(i.e., single time step) data. For time-varying fields, a 4D version of POT, 4D-POT, was proposed for 4D isocontour slicing, where slicing on the time domain gives all active cells in the queried timestep and isovalue. However, such slicing is not output sensitive and thus the searching is sub-optimal. Moreover, it was not known how to support view-dependent filtering in addition to time-domain slicing.In this paper, we develop a novel Persistent Time-Octree (PTOT) indexing structure, which has the advantages of POT and performs 4D isocontour slicing on the time domain with an output-sensitive and optimal searching. In addition, when we query the same isovalue q over m consecutive time steps, there is no additional searching overhead (except for reporting the additionalactive cells) compared to querying just the first time step. Such searching performance for finding active cells is asymptotically optimal, with asymptotically optimal space and preprocessing time as well. Moreover, our PTOT supports view-dependent filtering in addition to time-domain slicing. We propose a simple and effective out-of-core scheme, where we integrate our PTOT with implicit occluders, batched occlusion queries and batched CUDA computing tasks, so that we can greatly reduce the I/O cost as well as increase the amount of data being concurrently computed in GPU.This results in an efficient algorithm for isosurface extraction with view-dependent filtering utilizing a state-of-the-art programmable GPUfor time-varying

  19. 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 future climate change

  20. 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.

  1. Resting Brain Activity Varies with Dream Recall Frequency Between Subjects

    PubMed Central

    Eichenlaub, Jean-Baptiste; Nicolas, Alain; Daltrozzo, Jérôme; Redouté, Jérôme; Costes, Nicolas; Ruby, Perrine

    2014-01-01

    Dreaming is still poorly understood. Notably, its cerebral underpinning remains unclear. Neuropsychological studies have shown that lesions in the temporoparietal junction (TPJ) and/or the white matter of the medial prefrontal cortex (MPFC) lead to the global cessation of dream reports, suggesting that these regions of the default mode network have key roles in the dreaming process (forebrain ‘dream-on' hypothesis). To test this hypothesis, we measured regional cerebral blood flow (rCBF) using [15O]H2O positron emission tomography in healthy subjects with high and low dream recall frequencies (DRFs) during wakefulness (rest) and sleep (rapid eye movement (REM) sleep, N2, and N3). Compared with Low recallers (0.5±0.3 dream recall per week in average), High recallers (5.2±1.4) showed higher rCBF in the TPJ during REM sleep, N3, and wakefulness, and in the MPFC during REM sleep and wakefulness. We demonstrate that the resting states of High recallers and Low recallers differ during sleep and wakefulness. It coheres with previous ERP results and confirms that a high/low DRF is associated with a specific functional organization of the brain. These results support the forebrain ‘dream-on' hypothesis and suggest that TPJ and MPFC are not only involved in dream recall during wakefulness but also have a role in dreaming during sleep (production and/or encoding). Increased activity in the TPJ and MPFC might promote the mental imagery and/or memory encoding of dreams. Notably, increased activity in TPJ might facilitate attention orienting toward external stimuli and promote intrasleep wakefulness, facilitating the encoding of the dreams in memory. PMID:24549103

  2. Resting brain activity varies with dream recall frequency between subjects.

    PubMed

    Eichenlaub, Jean-Baptiste; Nicolas, Alain; Daltrozzo, Jérôme; Redouté, Jérôme; Costes, Nicolas; Ruby, Perrine

    2014-06-01

    Dreaming is still poorly understood. Notably, its cerebral underpinning remains unclear. Neuropsychological studies have shown that lesions in the temporoparietal junction (TPJ) and/or the white matter of the medial prefrontal cortex (MPFC) lead to the global cessation of dream reports, suggesting that these regions of the default mode network have key roles in the dreaming process (forebrain 'dream-on' hypothesis). To test this hypothesis, we measured regional cerebral blood flow (rCBF) using [(15)O]H2O positron emission tomography in healthy subjects with high and low dream recall frequencies (DRFs) during wakefulness (rest) and sleep (rapid eye movement (REM) sleep, N2, and N3). Compared with Low recallers (0.5 ± 0.3 dream recall per week in average), High recallers (5.2 ± 1.4) showed higher rCBF in the TPJ during REM sleep, N3, and wakefulness, and in the MPFC during REM sleep and wakefulness. We demonstrate that the resting states of High recallers and Low recallers differ during sleep and wakefulness. It coheres with previous ERP results and confirms that a high/low DRF is associated with a specific functional organization of the brain. These results support the forebrain 'dream-on' hypothesis and suggest that TPJ and MPFC are not only involved in dream recall during wakefulness but also have a role in dreaming during sleep (production and/or encoding). Increased activity in the TPJ and MPFC might promote the mental imagery and/or memory encoding of dreams. Notably, increased activity in TPJ might facilitate attention orienting toward external stimuli and promote intrasleep wakefulness, facilitating the encoding of the dreams in memory.

  3. Energy dependence of hadronic activity

    NASA Astrophysics Data System (ADS)

    Gabriel, T. A.; Groom, D. E.; Job, P. K.; Mokhov, N. V.; Stevenson, G. R.

    1994-01-01

    Two features of high-energy hadronic cascades have long been known to shielding specialists: a) in a high-energy hadronic cascade in a given material (incident E ≳ 10 GeV), the relative abundance and spectrum of each hadronic species responsible for most of the energy deposition is independent of the energy or species of the incident hadron, and b) because π0 production bleeds off more and more energy into the electromagnetic sector as the energy of the incident hadron increases, the absolute level of this low-energy hadronic activity ( E ≲ 1 GeV) rises less rapidly than the incident energy, and in fact rises very nearly as a power of the incident energy. Both features are of great importance in hadron calorimetry, where it is the "universal spectrum" which makes possible the definition of an intrinsic {e}/{h}, and the increasing fraction of the energy going into π0's which leads to the energy dependence of {e}/{π}. We present evidence for the "universal spectrum," and use an induction argument and simulation results to demonstrate that the low-energy activity ss Em, with 0.80 ≲ m ≲ 0.85. The hadronic activity produced by incident pions is 15-20% less than that initiated by protons.

  4. 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

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

    PubMed

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

    2016-02-18

    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.

  6. 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.

  7. The tricks of the trait: neural implementation of personality varies with genotype-dependent serotonin levels.

    PubMed

    Hahn, Tim; Heinzel, Sebastian; Notebaert, Karolien; Dresler, Thomas; Reif, Andreas; Lesch, Klaus-Peter; Jakob, Peter M; Windmann, Sabine; Fallgatter, Andreas J

    2013-11-01

    Gray's Reinforcement Sensitivity Theory (RST) has developed into one of the most prominent personality theories of the last decades. The RST postulates a Behavioral Inhibition System (BIS) modulating the reaction to stimuli indicating aversive events. A number of psychiatric disorders including depression, anxiety disorders, and psychosomatic illnesses have been associated with extreme BIS responsiveness. In recent years, neuroimaging studies have implicated the amygdala-septo-hippocampal circuit as an important neural substrate of the BIS. However, the neurogenetic basis of the regulation of this behaviorally and clinically essential system remains unclear. Investigating the effects of two functional genetic polymorphisms (tryptophan hydroxylase-2, G-703T, and serotonin transporter, serotonin transporter gene-linked polymorphic region) in 89 human participants, we find significantly different patterns of associations between BIS scores and amygdala-hippocampus connectivity during loss anticipation for genotype groups regarding both polymorphisms. Specifically, the correlation between amygdala-hippocampus connectivity and Gray's trait anxiety scores is positive in individuals homozygous for the TPH2 G-allele, while carriers of at least one T-allele show a negative association. Likewise, individuals homozygous for the 5-HTTLPR L(A) variant display a positive association while carriers of the S/L(G) allele show a trend towards a negative association. Thus, we show converging evidence of different neural implementation of the BIS depending on genotype-dependent levels of serotonin. We provide evidence suggesting that genotype-dependent serotonin levels and thus putative changes in the efficiency of serotonergic neurotransmission might not only alter brain activation levels directly, but also more fundamentally impact the neural implementation of personality traits. We outline the direct clinical implications arising from this finding and discuss the complex interplay

  8. Temperature and Magnetic Field Dependence of Critical Current Density of YBCO with Varying Flux Pinning Additions (POSTPRINT)

    DTIC Science & Technology

    2010-03-01

    coverage corresponding to M phase 1 nm thickness was found to be necessary to increase compared to YBCO . The op- timal layer thickness for each M phase was...kept constant in this experiment: , Y211 0.8 nm , and [17]. Using the optimal M phase thickness, the YBCO layer was also systematically varied for...AFRL-RZ-WP-TP-2010-2083 TEMPERATURE AND MAGNETIC FIELD DEPENDENCE OF CRITICAL CURRENT DENSITY OF YBCO WITH VARYING FLUX PINNING ADDITIONS

  9. Occipital TMS has an activity-dependent suppressive effect

    PubMed Central

    Perini, Francesca; Cattaneo, Luigi; Carrasco, Marisa; Schwarzbach, Jens V.

    2012-01-01

    The effects of transcranial magnetic stimulation (TMS) vary depending on the brain state at the stimulation moment. Four mechanisms have been proposed to underlie these effects: (i) virtual lesion–TMS suppresses neural signals; (ii) preferential activation of less active neurons–TMS drives up activity in the stimulated area, but active neurons are saturating, (iii) noise generation–TMS adds random neuronal activity and its effect interacts with stimulus-intensity; (iv) noise generation–TMS adds random neuronal activity and its effect depends on TMS-intensity. Here we explore these hypotheses by investigating the effects of TMS on early visual cortex on the contrast response function while varying adaptation state of the observers. We tested human participants in an orientation discrimination task, in which performance is contingent upon contrast sensitivity. Before each trial, neuronal activation of visual cortex was altered through contrast adaptation to two flickering gratings. In a factorial design, with or without adaptation, a single TMS pulse was delivered simultaneously with targets of varying contrast. Adaptation decreased contrast sensitivity. The effect of TMS on performance was state-dependent: TMS decreased contrast sensitivity in the absence of adaptation but increased it after adaptation. None of the proposed mechanisms can account for the results in their entirety, in particular, for the facilitatory effect at intermediate to high contrasts after adaptation. We propose an alternative hypothesis: TMS effects are activity-dependent, so that TMS suppresses the most active neurons and thereby changes the balance between excitation and inhibition. PMID:22956826

  10. 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.

  11. 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…

  12. 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.

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

    PubMed

    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.

  14. 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.

  15. Does Apparent Stress Vary With Earthquake Size? Possible Mechanism of Artificial Size Dependency

    NASA Astrophysics Data System (ADS)

    Ide, S.; Beroza, G. C.; Prejean, S. G.; Ellsworth, W. L.

    2001-12-01

    The energy radiated from the seismic source (Es) has been estimated for a wide range of earthquake sizes. Many studies have found that the ratio between Es and seismic moment (apparent stress) increases as seismic moment increases. Es is distributed across a wide frequency band, reliable estimates require broadband recordings relative to the corner frequency. There are several possible mechanisms that could bias estimates of Es: 1) data bandwidth is too narrow, 2) a constant upper cutoff on the corner frequency affects event selection, and 3) unmodeled elastic/anelastic wave propagation effects may obscure source properties. We can attempt to account for 1) by estimating the missing energy based on the assumption of an omega-square spectral model. For 2) we know the minimum energy of missing events and can show where these events should be located in the moment-apparent stress relation. These two factors act to diminish the size dependency of apparent stress suggested by previous studies. For 3), we re-examined the data of Prejean and Ellsworth (2001) from a 2-km deep borehole in Long Valley Caldera, California. First, assuming an omega-square model with a constant Q, we determined the stress drop and apparent stress of 41 events (0.5 < Mw < 5.0). We find that some small events have small apparent stresses of about 0.003-0.03 MPa, and also find that these events have low stress drops of 0.01 to 0.1 MPa. Most larger events have both larger stress drops of 1-10 MPa and larger apparent stresses. This analysis supports the decline of Es with declining moment. It is natural that stress drop would have a strong relationship to the apparent stress---we find (apparent stress) = 0.3 x (stress drop)---since we assumed an omega-square model. Insofar as no systematic change in the spectral shape is observed with seismic moment in the data, it is unlikely that stress drop and apparent stress will have different dependencies on seismic moment. We also estimated stress drops

  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.

  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.

  20. Activity dependent CAM cleavage and neurotransmission

    PubMed Central

    Conant, Katherine; Allen, Megan; Lim, Seung T.

    2015-01-01

    Spatially localized proteolysis represents an elegant means by which neuronal activity dependent changes in synaptic structure, and thus experience dependent learning and memory, can be achieved. In vitro and in vivo studies suggest that matrix metalloproteinase and adamalysin activity is concentrated at the cell surface, and emerging evidence suggests that increased peri-synaptic expression, release and/or activation of these proteinases occurs with enhanced excitatory neurotransmission. Synaptically expressed cell adhesion molecules (CAMs) could therefore represent important targets for neuronal activity-dependent proteolysis. Several CAM subtypes are expressed at the synapse, and their cleavage can influence the efficacy of synaptic transmission through a variety of non-mutually exclusive mechanisms. In the following review, we discuss mechanisms that regulate neuronal activity-dependent synaptic CAM shedding, including those that may be calcium dependent. We also highlight CAM targets of activity-dependent proteolysis including neuroligin and intercellular adhesion molecule-5 (ICAM-5). We include discussion focused on potential consequences of synaptic CAM shedding, with an emphasis on interactions between soluble CAM cleavage products and specific pre- and post-synaptic receptors. PMID:26321910

  1. A semiparametrically efficient estimator of the time-varying effects for survival data with time-dependent treatment.

    PubMed

    Lin, Huazhen; Fei, Zhe; Li, Yi

    2016-09-01

    The timing of a time-dependent treatment-e.g., when to perform a kidney transplantation-is an important factor for evaluating treatment efficacy. A naïve comparison between the treated and untreated groups, while ignoring the timing of treatment, typically yields biased results that might favor the treated group because only patients who survive long enough will get treated. On the other hand, studying the effect of a time-dependent treatment is often complex, as it involves modeling treatment history and accounting for the possible time-varying nature of the treatment effect. We propose a varying-coefficient Cox model that investigates the efficacy of a time-dependent treatment by utilizing a global partial likelihood, which renders appealing statistical properties, including consistency, asymptotic normality and semiparametric efficiency. Extensive simulations verify the finite sample performance, and we apply the proposed method to study the efficacy of kidney transplantation for end-stage renal disease patients in the U.S. Scientific Registry of Transplant Recipients (SRTR).

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

    PubMed Central

    Marshall, Charles R.; Quental, Tiago B.

    2016-01-01

    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

  3. Event-Based H∞ State Estimation for Time-Varying Stochastic Dynamical Networks With State- and Disturbance-Dependent Noises.

    PubMed

    Sheng, Li; Wang, Zidong; Zou, Lei; Alsaadi, Fuad E

    2016-07-20

    In this paper, the event-based finite-horizon H∞ state estimation problem is investigated for a class of discrete time-varying stochastic dynamical networks with state- and disturbance-dependent noises [also called (x,v)-dependent noises]. An event-triggered scheme is proposed to decrease the frequency of the data transmission between the sensors and the estimator, where the signal is transmitted only when certain conditions are satisfied. The purpose of the problem addressed is to design a time-varying state estimator in order to estimate the network states through available output measurements. By employing the completing-the-square technique and the stochastic analysis approach, sufficient conditions are established to ensure that the error dynamics of the state estimation satisfies a prescribed H∞ performance constraint over a finite horizon. The desired estimator parameters can be designed via solving coupled backward recursive Riccati difference equations. Finally, a numerical example is exploited to demonstrate the effectiveness of the developed state estimation scheme.

  4. 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

    2016-04-05

    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).

  5. 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,…

  6. 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'.

  7. Time-varying spectral power of resting-state fMRI networks reveal cross-frequency dependence in dynamic connectivity

    PubMed Central

    Yaesoubi, Maziar; Miller, Robyn L.; Calhoun, Vince D.

    2017-01-01

    Brain oscillations and synchronicity among brain regions (brain connectivity) have been studied in resting-state (RS) and task-induced settings. RS-connectivity which captures brain functional integration during an unconstrained state is shown to vary with the frequency of oscillations. Indeed, high temporal resolution modalities have demonstrated both between and cross-frequency connectivity spanning across frequency bands such as theta and gamma. Despite high spatial resolution, functional magnetic resonance imaging (fMRI) suffers from low temporal resolution due to modulation with slow-varying hemodynamic response function (HRF) and also relatively low sampling rate. This limits the range of detectable frequency bands in fMRI and consequently there has been no evidence of cross-frequency dependence in fMRI data. In the present work we uncover recurring patterns of spectral power in network timecourses which provides new insight on the actual nature of frequency variation in fMRI network activations. Moreover, we introduce a new measure of dependence between pairs of rs-fMRI networks which reveals significant cross-frequency dependence between functional brain networks specifically default-mode, cerebellar and visual networks. This is the first strong evidence of cross-frequency dependence between functional networks in fMRI and our subject group analysis based on age and gender supports usefulness of this observation for future clinical applications. PMID:28192457

  8. Design of delay-dependent state estimator for discrete-time recurrent neural networks with interval discrete and infinite-distributed time-varying delays.

    PubMed

    Liao, Chin-Wen; Lu, Chien-Yu

    2011-06-01

    The state estimation problem for discrete-time recurrent neural networks with both interval discrete and infinite-distributed time-varying delays is studied in this paper, where interval discrete time-varying delay is in a given range. The activation functions are assumed to be globally Lipschitz continuous. A delay-dependent condition for the existence of state estimators is proposed based on new bounding techniques. Via solutions to certain linear matrix inequalities, general full-order state estimators are designed that ensure globally asymptotic stability. The significant feature is that no inequality is needed for seeking upper bounds for the inner product between two vectors, which can reduce the conservatism of the criterion by employing the new bounding techniques. Two illustrative examples are given to demonstrate the effectiveness and applicability of the proposed approach.

  9. Finite-time state-dependent Riccati equation for time-varying nonaffine systems: rigid and flexible joint manipulator control.

    PubMed

    Korayem, M H; Nekoo, S R

    2015-01-01

    This article investigates finite-time optimal and suboptimal controls for time-varying systems with state and control nonlinearities. The state-dependent Riccati equation (SDRE) controller was the main framework. A finite-time constraint imposed on the equation changes it to a differential equation, known as the state-dependent differential Riccati equation (SDDRE) and this equation was applied to the problem reported in this study that provides general formulation and stability analysis. The following four solution methods were developed for solving the SDDRE; backward integration, state transition matrix (STM) and the Lyapunov based method. In the Lyapunov approach, both positive and negative definite solutions to related SDRE were used to provide suboptimal gain for the SDDRE. Finite-time suboptimal control is applied for robotic manipulator, as finite-time constraint strongly decreases state error and operation time. General state-dependent coefficient (SDC) parameterizations for rigid and flexible joint arms (prismatic or revolute joints) are introduced. By including nonlinear control inputs in the formulation, the actuator׳s limits can be inserted directly to the state-space equation of a manipulator. A finite-time SDRE was implemented on a 6R manipulator both in theory and experimentally. And a reduced 3R arm was modeled and tested as a flexible joint robot (FJR). Evaluations of load carrying capacity and operation time were investigated to assess the capability of this approach, both of which showed significant improvement.

  10. Quantifying Time-Varying Multiunit Neural Activity Using Entropy-Based Measures

    PubMed Central

    Choi, Young-Seok; Koenig, Matthew A.; Jia, Xiaofeng

    2011-01-01

    Modern microelectrode arrays make it possible to simultaneously record population neural activity. However, methods to analyze multiunit activity (MUA), which reflects the aggregate spiking activity of a population of neurons, have remained underdeveloped in comparison to those used for studying single unit activity (SUA). In scenarios where SUA is hard to record and maintain or is not representative of brain’s response, MUA is informative in deciphering the brain’s complex time-varying response to stimuli or to clinical insults. Here, we present two quantitative methods of analysis of the time-varying dynamics of MUA without spike detection. These methods are based on the multiresolution discrete wavelet transform (DWT) of an envelope of MUA (eMUA) followed by information theoretic measures: multiresolution entropy (MRE) and the multiresolution Kullback–Leibler distance (MRKLD).We test the proposed quantifiers on both simulated and experimental MUA recorded from rodent cortex in an experimental model of global hypoxic–ischemic brain injury. First, our results validate the use of the eMUA as an alternative to detecting and analyzing transient and complex spike activity. Second, the MRE and MRKLD are shown to respond to dynamic changes due to the brain’s response to global injury and to identify the transient changes in the MUA. PMID:20460201

  11. Reduced risk of breast cancer associated with recreational physical activity varies by HER2 status

    PubMed Central

    Ma, Huiyan; Xu, Xinxin; Ursin, Giske; Simon, Michael S; Marchbanks, Polly A; Malone, Kathleen E; Lu, Yani; McDonald, Jill A; Folger, Suzanne G; Weiss, Linda K; Sullivan-Halley, Jane; Deapen, Dennis M; Press, Michael F; Bernstein, Leslie

    2015-01-01

    Convincing epidemiologic evidence indicates that physical activity is inversely associated with breast cancer risk. Whether this association varies by the tumor protein expression status of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), or p53 is unclear. We evaluated the effects of recreational physical activity on risk of invasive breast cancer classified by the four biomarkers, fitting multivariable unconditional logistic regression models to data from 1195 case and 2012 control participants in the population-based Women’s Contraceptive and Reproductive Experiences Study. Self-reported recreational physical activity at different life periods was measured as average annual metabolic equivalents of energy expenditure [MET]-hours per week. Our biomarker-specific analyses showed that lifetime recreational physical activity was negatively associated with the risks of ER-positive (ER+) and of HER2-negative (HER2−) subtypes (both Ptrend ≤ 0.04), but not with other subtypes (all Ptrend > 0.10). Analyses using combinations of biomarkers indicated that risk of invasive breast cancer varied only by HER2 status. Risk of HER2–breast cancer decreased with increasing number of MET-hours of recreational physical activity in each specific life period examined, although some trend tests were only marginally statistically significant (all Ptrend ≤ 0.06). The test for homogeneity of trends (HER2– vs. HER2+ ) reached statistical significance only when evaluating physical activity during the first 10 years after menarche (Phomogeneity = 0.03). Our data suggest that physical activity reduces risk of invasive breast cancers that lack HER2 overexpression, increasing our understanding of the biological mechanisms by which physical activity acts. PMID:25924995

  12. Reduced risk of breast cancer associated with recreational physical activity varies by HER2 status.

    PubMed

    Ma, Huiyan; Xu, Xinxin; Ursin, Giske; Simon, Michael S; Marchbanks, Polly A; Malone, Kathleen E; Lu, Yani; McDonald, Jill A; Folger, Suzanne G; Weiss, Linda K; Sullivan-Halley, Jane; Deapen, Dennis M; Press, Michael F; Bernstein, Leslie

    2015-07-01

    Convincing epidemiologic evidence indicates that physical activity is inversely associated with breast cancer risk. Whether this association varies by the tumor protein expression status of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), or p53 is unclear. We evaluated the effects of recreational physical activity on risk of invasive breast cancer classified by the four biomarkers, fitting multivariable unconditional logistic regression models to data from 1195 case and 2012 control participants in the population-based Women's Contraceptive and Reproductive Experiences Study. Self-reported recreational physical activity at different life periods was measured as average annual metabolic equivalents of energy expenditure [MET]-hours per week. Our biomarker-specific analyses showed that lifetime recreational physical activity was negatively associated with the risks of ER-positive (ER+) and of HER2-negative (HER2-) subtypes (both Ptrend  ≤ 0.04), but not with other subtypes (all Ptrend  > 0.10). Analyses using combinations of biomarkers indicated that risk of invasive breast cancer varied only by HER2 status. Risk of HER2-breast cancer decreased with increasing number of MET-hours of recreational physical activity in each specific life period examined, although some trend tests were only marginally statistically significant (all Ptrend  ≤ 0.06). The test for homogeneity of trends (HER2- vs. HER2+ ) reached statistical significance only when evaluating physical activity during the first 10 years after menarche (Phomogeneity  = 0.03). Our data suggest that physical activity reduces risk of invasive breast cancers that lack HER2 overexpression, increasing our understanding of the biological mechanisms by which physical activity acts.

  13. State-dependent differential Riccati equation to track control of time-varying systems with state and control nonlinearities.

    PubMed

    Korayem, M H; Nekoo, S R

    2015-07-01

    This work studies an optimal control problem using the state-dependent Riccati equation (SDRE) in differential form to track for time-varying systems with state and control nonlinearities. The trajectory tracking structure provides two nonlinear differential equations: the state-dependent differential Riccati equation (SDDRE) and the feed-forward differential equation. The independence of the governing equations and stability of the controller are proven along the trajectory using the Lyapunov approach. Backward integration (BI) is capable of solving the equations as a numerical solution; however, the forward solution methods require the closed-form solution to fulfill the task. A closed-form solution is introduced for SDDRE, but the feed-forward differential equation has not yet been obtained. Different ways of solving the problem are expressed and analyzed. These include BI, closed-form solution with corrective assumption, approximate solution, and forward integration. Application of the tracking problem is investigated to control robotic manipulators possessing rigid or flexible joints. The intention is to release a general program for automatic implementation of an SDDRE controller for any manipulator that obeys the Denavit-Hartenberg (D-H) principle when only D-H parameters are received as input data.

  14. 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

  15. 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.

  16. Nonlinearly Activated Neural Network for Solving Time-Varying Complex Sylvester Equation.

    PubMed

    Li, Shuai; Li, Yangming

    2013-10-28

    The Sylvester equation is often encountered in mathematics and control theory. For the general time-invariant Sylvester equation problem, which is defined in the domain of complex numbers, the Bartels-Stewart algorithm and its extensions are effective and widely used with an O(n³) time complexity. When applied to solving the time-varying Sylvester equation, the computation burden increases intensively with the decrease of sampling period and cannot satisfy continuous realtime calculation requirements. For the special case of the general Sylvester equation problem defined in the domain of real numbers, gradient-based recurrent neural networks are able to solve the time-varying Sylvester equation in real time, but there always exists an estimation error while a recently proposed recurrent neural network by Zhang et al [this type of neural network is called Zhang neural network (ZNN)] converges to the solution ideally. The advancements in complex-valued neural networks cast light to extend the existing real-valued ZNN for solving the time-varying real-valued Sylvester equation to its counterpart in the domain of complex numbers. In this paper, a complex-valued ZNN for solving the complex-valued Sylvester equation problem is investigated and the global convergence of the neural network is proven with the proposed nonlinear complex-valued activation functions. Moreover, a special type of activation function with a core function, called sign-bi-power function, is proven to enable the ZNN to converge in finite time, which further enhances its advantage in online processing. In this case, the upper bound of the convergence time is also derived analytically. Simulations are performed to evaluate and compare the performance of the neural network with different parameters and activation functions. Both theoretical analysis and numerical simulations validate the effectiveness of the proposed method.

  17. p53-dependent delayed effects of radiation vary according to time of irradiation of p53 + / - mice.

    PubMed

    Okazaki, Ryuji; Ootsuyama, Akira

    2014-01-01

    We previously reported that in p53 (+ / -) mice that had been given a whole-body dose of 3 Gy at 8 weeks of age, p53-dependent delayed effects of radiation, as manifested in T-cell receptor (TCR) variant fractions (VF) instability in mouse splenocytes, were biphasic, namely, induction of TCR-VF mutation reappeared at 44 weeks. The manifestation of the delayed effects and the measures of biological markers varied according to the timing of irradiation. We also reported that the decrease in function of the p53 gene was related to the effects of a delayed mutation. In the present study, we investigated the functions and mutations of the p53 gene in old age for p53 (+ / -) mice following irradiation at various ages. p53 (+ / -) mice were given a whole-body dose of 3 Gy at 8, 28 or 40 weeks of age. There were significant differences for all variables tested at 8 weeks of age. This was similarly the case for mice irradiated at 28 weeks of age, in which there were also significant differences in TCR VF and the percentage of apoptosis. In mice irradiated at 40 weeks of age, there were significant differences for all considered variables except for the p53 allele. We demonstrated that the different patterns of delayed mutation of the p53 gene at 56 weeks of age depended on the age at which mice had undergone 3-Gy whole-body irradiation. Our conclusions are limited to variation in p53-dependent delayed effects according to the time of irradiation.

  18. Nonlinear parametrically excited vibration and active control of gear pair system with time-varying characteristic

    NASA Astrophysics Data System (ADS)

    Liu, Shuang; Wang, Jin-Jin; Liu, Jin-Jie; Li, Ya-Qian

    2015-10-01

    In the present work, we investigate the nonlinear parametrically excited vibration and active control of a gear pair system involving backlash, time-varying meshing stiffness and static transmission error. Firstly, a gear pair model is established in a strongly nonlinear form, and its nonlinear vibration characteristics are systematically investigated through different approaches. Several complicated phenomena such as period doubling bifurcation, anti period doubling bifurcation and chaos can be observed under the internal parametric excitation. Then, an active compensation controller is designed to suppress the vibration, including the chaos. Finally, the effectiveness of the proposed controller is verified numerically. Project supported by the National Natural Science Foundation of China (Grant No. 61104040), the Natural Science Foundation of Hebei Province, China (Grant No. E2012203090), and the University Innovation Team of Hebei Province Leading Talent Cultivation Project, China (Grant No. LJRC013).

  19. 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.

  20. 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

  1. Flatness-based active disturbance rejection control for linear systems with unknown time-varying coefficients

    NASA Astrophysics Data System (ADS)

    Huang, Congzhi; Sira-Ramírez, Hebertt

    2015-12-01

    A flatness-based active disturbance rejection control approach is proposed to deal with the linear systems with unknown time-varying coefficients and external disturbances. By selecting appropriate nominal values for the parameters of the system, all the deviation between the nominal and actual dynamics of the controlled process, as well as all the external disturbances can be viewed as a total disturbance. Based on the accurately estimated total disturbance with the aid of the proposed extended state observer, a linear proportional derivative feedback control law taking into account the derivatives of the desired output is designed to eliminate the effect of the total disturbance on the system performance. Finally, the load frequency control problem of a single-area power system with non-reheated unit is employed as an illustrative example to demonstrate the effectiveness of the proposed approach.

  2. Outcome-dependent sampling for longitudinal binary response data based on a time-varying auxiliary variable.

    PubMed

    Schildcrout, Jonathan S; Mumford, Sunni L; Chen, Zhen; Heagerty, Patrick J; Rathouz, Paul J

    2012-09-28

    Outcome-dependent sampling (ODS) study designs are commonly implemented with rare diseases or when prospective studies are infeasible. In longitudinal data settings, when a repeatedly measured binary response is rare, an ODS design can be highly efficient for maximizing statistical information subject to resource limitations that prohibit covariate ascertainment of all observations. This manuscript details an ODS design where individual observations are sampled with probabilities determined by an inexpensive, time-varying auxiliary variable that is related but is not equal to the response. With the goal of validly estimating marginal model parameters based on the resulting biased sample, we propose a semi-parametric, sequential offsetted logistic regressions (SOLR) approach. The SOLR strategy first estimates the relationship between the auxiliary variable and the response and covariate data by using an offsetted logistic regression analysis where the offset is used to adjust for the biased design. Results from the auxiliary variable model are then combined with the known or estimated sampling probabilities to formulate a second offset that is used to correct for the biased design in the ultimate target model relating the longitudinal binary response to covariates. Because the target model offset is estimated with SOLR, we detail asymptotic standard error estimates that account for uncertainty associated with the auxiliary variable model. Motivated by an analysis of the BioCycle Study (Gaskins et al., Effect of daily fiber intake on reproductive function: the BioCycle Study. American Journal of Clinical Nutrition 2009; 90(4): 1061-1069) that aims to describe the relationship between reproductive health (determined by luteinizing hormone levels) and fiber consumption, we examine properties of SOLR estimators and compare them with other common approaches.

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

    PubMed

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

    2010-08-01

    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

  4. Controlling the antibacterial activity of CuSn thin films by varying the contents of Sn

    NASA Astrophysics Data System (ADS)

    Kang, Yujin; Park, Juyun; Kim, Dong-Woo; Kim, Hakjun; Kang, Yong-Cheol

    2016-12-01

    We investigated antibacterial activity of CuSn thin films against Gram positive Staphylococcus aureus (S. aureus). CuSn thin films with different Cu to Sn ratios were deposited on Si(100) by radio frequency (RF) magnetron sputtering method using Cu and Sn metal anodes. The film thickness was fixed at 200 nm by varying the sputtering time and RF power on the metal targets. The antibacterial test was conducted in various conditions such as different contact times and Cu to Sn ratios in the CuSn films. The antibacterial activities of CuSn thin films increased as the ratio of Cu and the contact time between the film and bacteria suspension increased execpt in the case of CuSn-83. The oxidation states of Cu and Sn and the chemical composition of CuSn thin films before and after the antibacterial test were investigated by X-ray photoelectron spectroscopy (XPS). When the contact time was fixed, the Cu species was further oxidized as the RF power on Cu target increased. The intensity of Sn 3d decreased with increasing Cu ratio. When the sample was fixed, the peak intensity of Sn 3d decreased as the contact time increased due to the permeation of Sn into the cell.

  5. 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

  6. Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment.

    PubMed

    De Foubert, G; Carney, S L; Robinson, C S; Destexhe, E J; Tomlinson, R; Hicks, C A; Murray, T K; Gaillard, J P; Deville, C; Xhenseval, V; Thomas, C E; O'Neill, M J; Zetterström, T S C

    2004-01-01

    Recent studies indicate that brain-derived neurotrophic factor (BDNF) may be implicated in the clinical action of antidepressant drugs. Repeated (2-3 weeks) administration of antidepressant drugs increases BDNF gene expression. The onset of this response as well as concomitant effects on the corresponding BDNF protein is however, unclear. The present study investigated the effects of acute and chronic administration of the selective serotonin reuptake inhibitor, fluoxetine (10mg/kg p.o.), upon regional rat brain levels of BDNF mRNA and protein expression. To improve the clinical significance of the study, fluoxetine was administered orally and mRNA and protein levels were determined ex vivo using the techniques of in situ hybridisation histochemistry and immunocytochemistry respectively. Direct measurement of BDNF protein was also carried out using enzyme-linked immunosorbent assay (ELISA). Four days of once daily oral administration of fluoxetine induced decreases in BDNF mRNA (hippocampus, medial habenular and paraventricular thalamic nuclei). Whilst 7 days of treatment showed a non-significant increase in BDNF mRNA, there were marked and region-specific increases following 14 days of treatment. BDNF protein levels remained unaltered until 21 days of fluoxetine treatment, when the numbers of BDNF immunoreactive cells were increased, reaching significance in the pyramidal cell layer of CA1 and CA3 regions of Ammon's horn (CA1 and CA3) but not in the other sub-regions of the hippocampus. Indicative of the highly regional change within the hippocampus, the ELISA method failed to demonstrate significant up-regulation at 21 days, measuring levels of BDNF protein in the whole hippocampus. In contrast to the detected time dependent and biphasic response of the BDNF gene, activity-regulated, cytoskeletal-associated protein (Arc) mRNA showed a gradual increase during the 14-day course of treatment. The results presented here show that BDNF is expressed differentially

  7. Activity-Dependent Model for Neuronal Avalanches

    NASA Astrophysics Data System (ADS)

    de Arcangelis, L.

    Networks of living neurons represent one of the most fascinating systems of modern biology. If the physical and chemical mechanisms at the basis of the functioning of a single neuron are quite well understood, the collective behavior of a system of many neurons is an extremely intriguing subject. Crucial ingredient of this complex behavior is the plasticity property of the network, namely the capacity to adapt and evolve depending on the level of activity. This plastic ability is believed, nowadays, to be at the basis of learning and memory in real brains. This fundamental problem in neurobiology has recently shown a number of features in common to other complex systems. These features mainly concern the morphology of the network, namely the spatial organization of the established connections, and a novel kind of neuronal activity. Experimental data have, in fact, shown that electrical information propagates in a cortex slice via an avalanche mode. Both features have been found in other problems in the context of the physics of complex systems and successful models have been developed to describe their behavior. In this contribution, we apply a statistical mechanical model to describe the complex activity in a neuronal network. The network is chosen to have a number of connections in long range, as found for neurons in vitro. The model implements the main physiological properties of living neurons and is able to reproduce recent experimental results. The numerical power spectra for electrical activity reproduces also the power law behavior measured in an EEG of man resting with the eyes closed.

  8. Polar polycyclic aromatic compounds from different coal types show varying mutagenic potential, EROD induction and bioavailability depending on coal rank.

    PubMed

    Meyer, Wiebke; Seiler, Thomas-Benjamin; Schwarzbauer, Jan; Püttmann, Wilhelm; Hollert, Henner; Achten, Christine

    2014-10-01

    Investigations of the bioavailability and toxicity of polycyclic aromatic compounds (PAC) have rarely considered the heterogeneity of coals and the impact of more polar PAC besides polycyclic aromatic hydrocarbons (PAH). Earlier, we investigated the toxicity of eight heterogeneous coals and their extracts. In the present study, the hazard potential with respect to mechanism-specific toxicity of polar fractions of dichloromethane extracts from coals was studied. Polar extract fractions of all coal types except for anthracite induced EROD activity (determined in RTL-W1 cells), independent of coal type (Bio-TEQs between 23 ± 16 and 52 ± 22 ng/g). The polar fractions of all bituminous coal extracts revealed mutagenic activity (determined using the Ames Fluctuation test). No significant mutation induction was detected for the polar extract fractions from the lignite, sub-bituminous coal and anthracite samples, which indicates a higher dependency on coal type for polar PAC here. Additionally, information on bioavailability was derived from a bioaccumulation test using the deposit-feeding oligochaete Lumbriculus variegatus which was exposed for 28 days to ground coal samples. Despite the high toxic potential of most coal extracts and a reduced biomass of Lumbriculus in bituminous coal samples, bioaccumulation of PAH and mortality after 28 days were found to be low. Limited bioaccumulation of PAH (up to 3.6 ± 3.8 mg/kg EPA-PAH) and polar PAC were observed for all coal samples. A significant reduction of Lumbriculus biomass was observed in the treatments containing bituminous coals (from 0.019 ± 0.004 g to 0.046 ± 0.011 g compared to 0.080 ± 0.025 g per replicate in control treatments). We conclude that bioavailability of native PAC from coals including polar PAC is low for all investigated coal types. In comparison to lignite, sub-bituminous coals and anthracite, the bioavailability of PAC from bituminous coals is slightly increased.

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

    PubMed

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

    2012-09-18

    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.

  10. 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

  11. EMG Activity of Selected Trunk and Hip Muscles During a Squat Lift: Effect of Varying the Lumbar Posture

    DTIC Science & Technology

    1990-01-01

    DIXC hLE O.. 1990 Thesis/i " EMG Activity of Selected Trunk and Hip Muscles During a Squat Lift: Effect of Varying the Lumbar Posture N Jim Vakos...1990 01-1’ ABSTRACT OF THESIS EMG ACTIVITY OF SELECTED TRUNK AND HIP MUSCLES DURING A SQUAT LIFT: EFFECT OF VARYING THE LUMBAR POSTURE - The...electromyographic ( EMG ) activity of selected hip and trunk muscles was recorded during a squat lift and the effects of two different lumbar spine postures were

  12. A new iterative linear integral isoconversional method for the determination of the activation energy varying with the conversion degree.

    PubMed

    Cai, Junmeng; Chen, Siyu

    2009-10-01

    The conventional linear integral isoconversional methods may lead to important errors in the determination of the activation energy when the significant variation of the activation energy with the conversion degree occurs. Vyazovkin proposed an advanced nonlinear isoconversional method, which allows the activation energy to be accurately determined [Vyazovkin, J Comput Chem 2001, 22, 178]. However, the use of the Vyazovkin method raises the problem of the time-consuming minimization without derivatives. A new iterative linear integral isoconversional method for the determination of the activation energy as a function of the conversion degree has been proposed, which is capable of providing valid values of the activation energy even if the latter strongly varies with the conversion degree. Also, the new method leads to the correct values of the activation energy in much less time than the Vyazovkin method. The application of the new method is illustrated by processing of theoretically simulated data of a strongly varying activation energy process.

  13. 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.

  14. Occipital transcranial magnetic stimulation has an activity-dependent suppressive effect.

    PubMed

    Perini, Francesca; Cattaneo, Luigi; Carrasco, Marisa; Schwarzbach, Jens V

    2012-09-05

    The effects of transcranial magnetic stimulation (TMS) vary depending on the brain state at the stimulation moment. Four mechanisms have been proposed to underlie these effects: (1) virtual lesion--TMS suppresses neural signals; (2) preferential activation of less active neurons--TMS drives up activity in the stimulated area, but active neurons are saturating; (3) noise generation--TMS adds random neuronal activity, and its effect interacts with stimulus intensity; and (4) noise generation--TMS adds random neuronal activity, and its effect depends on TMS intensity. Here we explore these hypotheses by investigating the effects of TMS on early visual cortex by assessing the contrast response function while varying the adaptation state of the observers. We tested human participants in an orientation discrimination task, in which performance is contingent upon contrast sensitivity. Before each trial, neuronal activation of visual cortex was altered through contrast adaptation to two flickering gratings. In a factorial design, with or without adaptation, a single TMS pulse was delivered simultaneously with targets of varying contrast. Adaptation decreased contrast sensitivity. The effect of TMS on performance was state dependent: TMS decreased contrast sensitivity in the absence of adaptation but increased it after adaptation. None of the proposed mechanisms can account for the results in their entirety, in particular, for the facilitatory effect at intermediate to high contrasts after adaptation. We propose an alternative hypothesis: TMS effects are activity dependent, so that TMS suppresses the most active neurons and thereby changes the balance between excitation and inhibition.

  15. Use of a lag differential reinforcement contingency to increase varied selections of classroom activities.

    PubMed

    Cammilleri, Anthony P; Hanley, Gregory P

    2005-01-01

    The present study evaluated the effects of a lag differential reinforcement contingency on 2 students' activity selections using reversal designs. Results showed that the lag contingency was responsible for promoting increased novel selections, engagement in diverse activities, and greater progress with respect to programmed academic activities.

  16. Use of a Lag Differential Reinforcement Contingency to Increase Varied Selections of Classroom Activities

    ERIC Educational Resources Information Center

    Cammilleri, Anthony P.; Hanley, Gregory P.

    2005-01-01

    The present study evaluated the effects of a lag differential reinforcement contingency on 2 students' activity selections using reversal designs. Results showed that the lag contingency was responsible for promoting increased novel selections, engagement in diverse activities, and greater progress with respect to programmed academic activities.

  17. 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…

  18. Biodegradation of an Organophosphate Chemical Warfare Agent Simulant by Activated Sludge with Varying Solid Retention Times

    DTIC Science & Technology

    2013-03-21

    coefficient close to that of VX, which may yield similar sorption kinetics between the two. Walters (2013) found that sorption of malathion to the activated...weapons in the activated sludge or under what conditions this removal is optimal. This study examined the fate of malathion , a surrogate compound for...activated sludge process in wastewater treatment facilities. Results show that a constant influent of malathion will be removed from the effluent

  19. 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...

  20. Spotlight on the Underdogs—An Analysis of Underrepresented Alternaria Mycotoxins Formed Depending on Varying Substrate, Time and Temperature Conditions

    PubMed Central

    Zwickel, Theresa; Kahl, Sandra M.; Klaffke, Horst; Rychlik, Michael; Müller, Marina E. H.

    2016-01-01

    Alternaria (A.) is a genus of widespread fungi capable of producing numerous, possibly health-endangering Alternaria toxins (ATs), which are usually not the focus of attention. The formation of ATs depends on the species and complex interactions of various environmental factors and is not fully understood. In this study the influence of temperature (7 °C, 25 °C), substrate (rice, wheat kernels) and incubation time (4, 7, and 14 days) on the production of thirteen ATs and three sulfoconjugated ATs by three different Alternaria isolates from the species groups A. tenuissima and A. infectoria was determined. High-performance liquid chromatography coupled with tandem mass spectrometry was used for quantification. Under nearly all conditions, tenuazonic acid was the most extensively produced toxin. At 25 °C and with increasing incubation time all toxins were formed in high amounts by the two A. tenuissima strains on both substrates with comparable mycotoxin profiles. However, for some of the toxins, stagnation or a decrease in production was observed from day 7 to 14. As opposed to the A. tenuissima strains, the A. infectoria strain only produced low amounts of ATs, but high concentrations of stemphyltoxin III. The results provide an essential insight into the quantitative in vitro AT formation under different environmental conditions, potentially transferable to different field and storage conditions. PMID:27869760

  1. Methanol emissions from maize: Ontogenetic dependence to varying light conditions and guttation as an additional factor constraining the flux

    NASA Astrophysics Data System (ADS)

    Mozaffar, A.; Schoon, N.; Digrado, A.; Bachy, A.; Delaplace, P.; du Jardin, P.; Fauconnier, M.-L.; Aubinet, M.; Heinesch, B.; Amelynck, C.

    2017-03-01

    Because of its high abundance and long lifetime compared to other volatile organic compounds in the atmosphere, methanol (CH3OH) plays an important role in atmospheric chemistry. Even though agricultural crops are believed to be a large source of methanol, emission inventories from those crop ecosystems are still scarce and little information is available concerning the driving mechanisms for methanol production and emission at different developmental stages of the plants/leaves. This study focuses on methanol emissions from Zea mays L. (maize), which is vastly cultivated throughout the world. Flux measurements have been performed on young plants, almost fully grown leaves and fully grown leaves, enclosed in dynamic flow-through enclosures in a temperature and light-controlled environmental chamber. Strong differences in the response of methanol emissions to variations in PPFD (Photosynthetic Photon Flux Density) were noticed between the young plants, almost fully grown and fully grown leaves. Moreover, young maize plants showed strong emission peaks following light/dark transitions, for which guttation can be put forward as a hypothetical pathway. Young plants' average daily methanol fluxes exceeded by a factor of 17 those of almost fully grown and fully grown leaves when expressed per leaf area. Absolute flux values were found to be smaller than those reported in the literature, but in fair agreement with recent ecosystem scale flux measurements above a maize field of the same variety as used in this study. The flux measurements in the current study were used to evaluate the dynamic biogenic volatile organic compound (BVOC) emission model of Niinemets and Reichstein. The modelled and measured fluxes from almost fully grown leaves were found to agree best when a temperature and light dependent methanol production function was applied. However, this production function turned out not to be suitable for modelling the observed emissions from the young plants

  2. 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

  3. Enzymatic activity of a mine soil varies according to vegetation cover and level of compost applied.

    PubMed

    de Varennes, Amerilis; Abreu, Maria Manuela; Qu, Guiwei; Cunha-Queda, Cristina

    2010-01-01

    We applied three doses of compost from mixed municipal solid waste (0, 15, and 30 g kg(-1) of soil) to a soil developed on pyrite mine wastes. Part of the soil was planted with young Erica australis L. collected at the mine; part was fertilized with N-P-K-Mg and sown with Dactylis glomerata L .Bare soil without mineral fertilization was included in the experiment, as well. Compost application to bare soil increased pH, provided plant nutrients, and enhanced the activity of the six soil enzymes tested. Growth of D. glomerata, and E. australis was stimulated in compost-amended soil compared with unamended controls. The presence of D. glomerata led to the greatest activities of soil acid phosphatase, beta-glucosidase, and cellulase compared with bare soil or with soil with E. australis. The presence of E. australis increased the activities of protease and cellulase in amended soil, compared with control, but it impaired dehydrogenase, fl-glucosidase, and acid phosphatase activities. These negative impacts probably derived from phenolic compounds known to be released from roots of this species. The survival strategy of this species seems to include a small need for P in the shoots, and the release of exudates that impair microbial activity and P cycling.

  4. Effects of activated sludge on the degradation of chlorate in soils under varying environmental conditions.

    PubMed

    Jiang, Chunxiao; Li, Huashou; Lin, Chuxia

    2009-03-15

    Incubation experiments were conducted to examine the effects of activated sludge on degradation of chlorate in soils. The results show that application of activated sludge could significantly promote the decomposition of soil chlorate though the degradation rate of chlorate did not necessarily increase with increasing application rate of the sludge. The effectiveness of activated sludge on soil chlorate degradation was significantly affected by temperature, moisture content and pH. There is a tendency that the rate of chlorate decomposition increased with increasing temperature and moisture content until optimal values of temperature and moisture content were reached. This can be attributed to the enhanced activity of chlorate-reducing microorganisms in hot and more reducing soil conditions. Soil pH also had important controls on the decomposition of chlorate. The experimental results demonstrate that neutral pH more favoured the degradation of soil chlorate, compared to either acidic or alkaline pH. While soil organic matter content could affect chlorate decomposition, its impact on the effectiveness of activated sludge on chlorate degradation was minor. This study has implications for developing cost-effective techniques for remediating chlorate-contaminated soils, particularly in the longan-producing countries.

  5. Lipid Dependent Mechanisms of Protein Pump Activity

    DTIC Science & Technology

    1989-05-23

    properties which result form the colligative interactions of many lipid molecules. Important materials properties include . . . i I I II II I i I 1 the...d identify by olock number) *This project is aime at investigating if a lipid elastic property , known as the spontaneous radius of curvature Ro’, is...a regulated membrane property and if its value modulates membrane protein activity. Specific aims reported on here include: 1) Correlation of ion pump

  6. DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain.

    PubMed

    Valu, K K; Gourdie, T A; Boritzki, T J; Gravatt, G L; Baguley, B C; Wilson, W R; Wakelin, L P; Woodgate, P D; Denny, W A

    1990-11-01

    Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability. The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons. Relationships were sought between chain length and biological properties. Within each series, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue. The in vivo antitumor activities of the compounds depended to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive. However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not. Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.

  7. Music Activity Reports by Music Teachers with Varying Training in Orff Schulwerk

    ERIC Educational Resources Information Center

    Sogin, David W.; Wang, Cecilia Chu

    2008-01-01

    The purpose of this study was to examine music activities occurring in the music classroom of teachers who received different levels of training in Orff Schulwerk. The subjects (N = 49) were teachers participating in three training levels at a summer Orff Schulwerk certification program in a university in the USA. Teachers were asked to report the…

  8. 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…

  9. 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…

  10. Cutaneous immune activity varies with physiological state in female house sparrows (Passer domesticus).

    PubMed

    Martin, L B; Han, P; Kwong, J; Hau, M

    2006-01-01

    Many vertebrates show seasonality in immune defenses, perhaps because of trade-offs with other physiological processes. Trade-offs between reproduction and immune function have been well studied, but how other life cycle events such as molt affect immune function remains unclear. Here, we hypothesize that one possible explanation is that accumulative dissociated processes (e.g., resource deficits generated over the long term by physiological processes) can have delayed effects on immune activity. To test this hypothesis, we compared cutaneous immune responses in groups of captive female house sparrows (Passer domesticus) photoperiodically induced into six different life cycle stages. We predicted that if delayed trade-offs occur, immune activity would be reduced after a mature life state was reached (e.g., postmolt) and not just compromised when other tissues were actively growing (instantaneous trade-off). We found evidence for both types of trade-offs: immune responses were weakest in sparrows that had just completed postnuptial molt, but they were also weak in birds growing reproductive tissues or feathers. Birds in mature reproductive states or light molt had strong immune responses comparable with birds in a nonbreeding/nonmolting state. Altogether, our results indicate that immune activity in female house sparrows can be influenced by both instantaneous and delayed trade-offs.

  11. 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.

  12. Varying responses of vegetation activity to climate changes on the Tibetan Plateau grassland.

    PubMed

    Cong, Nan; Shen, Miaogen; Yang, Wei; Yang, Zhiyong; Zhang, Gengxin; Piao, Shilong

    2017-02-28

    Vegetation activity on the Tibetan Plateau grassland has been substantially enhanced as a result of climate change, as revealed by satellite observations of vegetation greenness (i.e., the normalized difference vegetation index, NDVI). However, little is known about the temporal variations in the relationships between NDVI and temperature and precipitation, and understanding this is essential for predicting how future climate change would affect vegetation activity. Using NDVI data and meteorological records from 1982 to 2011, we found that the inter-annual partial correlation coefficient between growing season (May-September) NDVI and temperature (RNDVI-T) in a 15-year moving window for alpine meadow showed little change, likely caused by the increasing RNDVI-T in spring (May-June) and autumn (September) and decreasing RNDVI-T in summer (July-August). Growing season RNDVI-T for alpine steppe increased slightly, mainly due to increasing RNDVI-T in spring and autumn. The partial correlation coefficient between growing season NDVI and precipitation (RNDVI-P) for alpine meadow increased slightly, mainly in spring and summer, and RNDVI-P for alpine steppe increased, mainly in spring. Moreover, RNDVI-T for the growing season was significantly higher in those 15-year windows with more precipitation for alpine steppe. RNDVI-P for the growing season was significantly higher in those 15-year windows with higher temperature, and this tendency was stronger for alpine meadow than for alpine steppe. These results indicate that the impact of warming on vegetation activity of Tibetan Plateau grassland is more positive (or less negative) during periods with more precipitation and that the impact of increasing precipitation is more positive (or less negative) during periods with higher temperature. Such positive effects of the interactions between temperature and precipitation indicate that the projected warmer and wetter future climate will enhance vegetation activity of Tibetan

  13. Varying responses of vegetation activity to climate changes on the Tibetan Plateau grassland

    NASA Astrophysics Data System (ADS)

    Cong, Nan; Shen, Miaogen; Yang, Wei; Yang, Zhiyong; Zhang, Gengxin; Piao, Shilong

    2017-02-01

    Vegetation activity on the Tibetan Plateau grassland has been substantially enhanced as a result of climate change, as revealed by satellite observations of vegetation greenness (i.e., the normalized difference vegetation index, NDVI). However, little is known about the temporal variations in the relationships between NDVI and temperature and precipitation, and understanding this is essential for predicting how future climate change would affect vegetation activity. Using NDVI data and meteorological records from 1982 to 2011, we found that the inter-annual partial correlation coefficient between growing season (May-September) NDVI and temperature (RNDVI-T) in a 15-year moving window for alpine meadow showed little change, likely caused by the increasing RNDVI-T in spring (May-June) and autumn (September) and decreasing RNDVI-T in summer (July-August). Growing season RNDVI-T for alpine steppe increased slightly, mainly due to increasing RNDVI-T in spring and autumn. The partial correlation coefficient between growing season NDVI and precipitation (RNDVI-P) for alpine meadow increased slightly, mainly in spring and summer, and RNDVI-P for alpine steppe increased, mainly in spring. Moreover, RNDVI-T for the growing season was significantly higher in those 15-year windows with more precipitation for alpine steppe. RNDVI-P for the growing season was significantly higher in those 15-year windows with higher temperature, and this tendency was stronger for alpine meadow than for alpine steppe. These results indicate that the impact of warming on vegetation activity of Tibetan Plateau grassland is more positive (or less negative) during periods with more precipitation and that the impact of increasing precipitation is more positive (or less negative) during periods with higher temperature. Such positive effects of the interactions between temperature and precipitation indicate that the projected warmer and wetter future climate will enhance vegetation activity of Tibetan

  14. 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

    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.

  15. 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.

  16. 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.

  17. Ribosome-dependent activation of stringent control

    PubMed Central

    Gordiyenko, Yuliya; Ramakrishnan, V.

    2016-01-01

    In order to survive, bacteria continually sense, and respond to, environmental fluctuations. Stringent control represents a key bacterial stress response to nutrient starvation1,2 that leads to a rapid and comprehensive reprogramming of metabolic and transcriptional patterns3. In general, transcription of genes for growth and proliferation are down-regulated, while those important for survival and virulence are favored4. Amino acid starvation is sensed by depletion of the aminoacyl-tRNA pools5, which results in accumulation of ribosomes stalled with non-aminoacylated (uncharged) tRNA in the ribosomal A-site6,7. RelA is recruited to stalled ribosomes, and activated to synthesize a hyperphosphorylated guanosine analog, (p)ppGpp8, which acts as a pleiotropic second messenger. However, structural information for how RelA recognizes stalled ribosomes and discriminates against aminoacylated tRNAs is missing. Here, we present the electron cryo-microscopy (cryo-EM) 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 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 where 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

  18. Physical activity, subjective sleep quality and time in bed do not vary by moon phase in German adolescents.

    PubMed

    Smith, Maia P; Standl, Marie; Schulz, Holger; Heinrich, Joachim

    2016-12-08

    Lunar periodicity in human biology and behaviour, particularly sleep, has been reported. However, estimated relationships vary in direction (more or less sleep with full moon) if they exist at all, and studies tend to be so small that there is potential for confounding by weekly or monthly cycles. Lunar variation in physical activity has been posited as a driver of this relationship, but is likewise not well studied. We explore the association between lunar cycle, sleep and physical activity in a population-based sample of 1411 Germans age 14-17 years (46% male). Physical activity (daily minutes moderate-to-vigorous activity) was objectively assessed by accelerometry for a total of 8832 days between 2011 and 2014. At the same time, time in bed (h) and subjective sleep quality (1-6) were diaried each morning. In models corrected for confounding, we found that lunar phase was not significantly associated with physical activity, subjective sleep quality or time in bed in either sex, regardless of season. Observed relationships varied randomly in direction between models, suggesting artefact. Thus, this large, objectively-measured and well-controlled population of adolescents displayed no lunar periodicity in objective physical activity, subjective sleep quality or time in bed.

  19. Asymptotic theory of time-varying social networks with heterogeneous activity and tie allocation.

    PubMed

    Ubaldi, Enrico; Perra, Nicola; Karsai, Márton; Vezzani, Alessandro; Burioni, Raffaella; Vespignani, Alessandro

    2016-10-24

    The dynamic of social networks is driven by the interplay between diverse mechanisms that still challenge our theoretical and modelling efforts. Amongst them, two are known to play a central role in shaping the networks evolution, namely the heterogeneous propensity of individuals to i) be socially active and ii) establish a new social relationships with their alters. Here, we empirically characterise these two mechanisms in seven real networks describing temporal human interactions in three different settings: scientific collaborations, Twitter mentions, and mobile phone calls. We find that the individuals' social activity and their strategy in choosing ties where to allocate their social interactions can be quantitatively described and encoded in a simple stochastic network modelling framework. The Master Equation of the model can be solved in the asymptotic limit. The analytical solutions provide an explicit description of both the system dynamic and the dynamical scaling laws characterising crucial aspects about the evolution of the networks. The analytical predictions match with accuracy the empirical observations, thus validating the theoretical approach. Our results provide a rigorous dynamical system framework that can be extended to include other processes shaping social dynamics and to generate data driven predictions for the asymptotic behaviour of social networks.

  20. Asymptotic theory of time-varying social networks with heterogeneous activity and tie allocation

    NASA Astrophysics Data System (ADS)

    Ubaldi, Enrico; Perra, Nicola; Karsai, Márton; Vezzani, Alessandro; Burioni, Raffaella; Vespignani, Alessandro

    2016-10-01

    The dynamic of social networks is driven by the interplay between diverse mechanisms that still challenge our theoretical and modelling efforts. Amongst them, two are known to play a central role in shaping the networks evolution, namely the heterogeneous propensity of individuals to i) be socially active and ii) establish a new social relationships with their alters. Here, we empirically characterise these two mechanisms in seven real networks describing temporal human interactions in three different settings: scientific collaborations, Twitter mentions, and mobile phone calls. We find that the individuals’ social activity and their strategy in choosing ties where to allocate their social interactions can be quantitatively described and encoded in a simple stochastic network modelling framework. The Master Equation of the model can be solved in the asymptotic limit. The analytical solutions provide an explicit description of both the system dynamic and the dynamical scaling laws characterising crucial aspects about the evolution of the networks. The analytical predictions match with accuracy the empirical observations, thus validating the theoretical approach. Our results provide a rigorous dynamical system framework that can be extended to include other processes shaping social dynamics and to generate data driven predictions for the asymptotic behaviour of social networks.

  1. Brain regional networks active during the mismatch negativity vary with paradigm.

    PubMed

    MacLean, Shannon E; Blundon, Elizabeth G; Ward, Lawrence M

    2015-08-01

    We used independent component analysis (ICA) of high-density EEG recordings coupled with single dipole fitting to identify the dominant brain regions active during the MMN in two different versions of a passive oddball paradigm: a simple, monotic, frequency-deviant paradigm and a more complex, dichotic, frequency-deviant paradigm with deviants occurring in either ear alone or in both ears at the same time. In both paradigms we found brain regional sources in the temporal and frontal cortices active during the MMN period, consistent with some previous studies. In the simpler paradigm, the scalp-potential variance during the earlier (70-120 ms) MMN was mostly accounted for by a wide array of temporal, frontal, and parietal sources. In the more complex paradigm, however, a generator in the prefrontal cortex accounted for a substantial amount of the variance of the scalp potential during the somewhat later MMN period (120-200 ms). These findings are consistent with a more nuanced view of the MMN and its generators than has been held in the past.

  2. Asymptotic theory of time-varying social networks with heterogeneous activity and tie allocation

    PubMed Central

    Ubaldi, Enrico; Perra, Nicola; Karsai, Márton; Vezzani, Alessandro; Burioni, Raffaella; Vespignani, Alessandro

    2016-01-01

    The dynamic of social networks is driven by the interplay between diverse mechanisms that still challenge our theoretical and modelling efforts. Amongst them, two are known to play a central role in shaping the networks evolution, namely the heterogeneous propensity of individuals to i) be socially active and ii) establish a new social relationships with their alters. Here, we empirically characterise these two mechanisms in seven real networks describing temporal human interactions in three different settings: scientific collaborations, Twitter mentions, and mobile phone calls. We find that the individuals’ social activity and their strategy in choosing ties where to allocate their social interactions can be quantitatively described and encoded in a simple stochastic network modelling framework. The Master Equation of the model can be solved in the asymptotic limit. The analytical solutions provide an explicit description of both the system dynamic and the dynamical scaling laws characterising crucial aspects about the evolution of the networks. The analytical predictions match with accuracy the empirical observations, thus validating the theoretical approach. Our results provide a rigorous dynamical system framework that can be extended to include other processes shaping social dynamics and to generate data driven predictions for the asymptotic behaviour of social networks. PMID:27774998

  3. 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

  4. Voltage Dependence of a Neuromodulator-Activated Ionic Current.

    PubMed

    Gray, Michael; Golowasch, Jorge

    2016-01-01

    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 Ca(2+), but that, in conditions of low Ca(2+), 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 Ca(2+)/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.

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

    PubMed Central

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

    2016-01-01

    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

  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.

  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. Delay-dependent fuzzy static output feedback control for discrete-time fuzzy stochastic systems with distributed time-varying delays.

    PubMed

    Xia, ZhiLe; Li, JunMin; Li, JiangRong

    2012-11-01

    This paper is concerned with the delay-dependent H(∞) fuzzy static output feedback control scheme for discrete-time Takagi-Sugeno (T-S) fuzzy stochastic systems with distributed time-varying delays. To begin with, the T-S fuzzy stochastic system is transformed to an equivalent switching fuzzy stochastic system. Then, based on novel matrix decoupling technique, improved free-weighting matrix technique and piecewise Lyapunov-Krasovskii function (PLKF), a new delay-dependent H(∞) fuzzy static output feedback controller design approach is first derived for the switching fuzzy stochastic system. Some drawbacks existing in the previous papers such as matrix equalities constraint, coordinate transformation, the same output matrices, diagonal structure constraint on Lyapunov matrices and BMI problem have been eliminated. Since only a set of LMIs is involved, the controller parameters can be solved directly by the Matlab LMI toolbox. Finally, two examples are provided to illustrate the validity of the proposed method.

  9. Synapse Maturation by Activity-Dependent Ectodomain Shedding of SIRPα

    PubMed Central

    Toth, Anna B.; Terauchi, Akiko; Zhang, Lily Y.; Johnson-Venkatesh, Erin M.; Larsen, David J.; Sutton, Michael A.; Umemori, Hisashi

    2013-01-01

    Formation of appropriate synaptic connections is critical for proper functioning of the brain. After initial synaptic differentiation, active synapses are stabilized by neural activity-dependent signals to establish functional synaptic connections. However, the molecular mechanisms underlying activity-dependent synapse maturation remain to be elucidated. Here we show that activity-dependent ectodomain shedding of SIRPα mediates presynaptic maturation. Two target-derived molecules, FGF22 and SIRPα, sequentially organize the glutamatergic presynaptic terminals during the initial synaptic differentiation and synapse maturation stages, respectively, in the mouse hippocampus. SIRPα drives presynaptic maturation in an activity-dependent fashion. Remarkably, neural activity cleaves the extracellular domain of SIRPα, and the shed ectodomain, in turn, promotes the maturation of the presynaptic terminal. This process involves CaM kinase, matrix metalloproteinases, and the presynaptic receptor CD47. Finally, SIRPα-dependent synapse maturation has significant impacts on synaptic function and plasticity. Thus, ectodomain shedding of SIRPα is an activity-dependent trans-synaptic mechanism for the maturation of functional synapses. PMID:24036914

  10. Multistability of neural networks with discontinuous non-monotonic piecewise linear activation functions and time-varying delays.

    PubMed

    Nie, Xiaobing; Zheng, Wei Xing

    2015-05-01

    This paper is concerned with the problem of coexistence and dynamical behaviors of multiple equilibrium points for neural networks with discontinuous non-monotonic piecewise linear activation functions and time-varying delays. The fixed point theorem and other analytical tools are used to develop certain sufficient conditions that ensure that the n-dimensional discontinuous neural networks with time-varying delays can have at least 5(n) equilibrium points, 3(n) of which are locally stable and the others are unstable. The importance of the derived results is that it reveals that the discontinuous neural networks can have greater storage capacity than the continuous ones. Moreover, different from the existing results on multistability of neural networks with discontinuous activation functions, the 3(n) locally stable equilibrium points obtained in this paper are located in not only saturated regions, but also unsaturated regions, due to the non-monotonic structure of discontinuous activation functions. A numerical simulation study is conducted to illustrate and support the derived theoretical results.

  11. The Regulation of Skeletal Muscle Active Hyperemia: The Differential Role of Adenosine in Muscles of Varied Fiber Types

    DTIC Science & Technology

    1986-04-21

    0.2 Hz and three mnscles ~;timulated to contract at 0.4 Hz during BADA infuston. These m~tabolites were also mea~•1red in two muscles contractin ~ at...APR 1986 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE The Regulation of Skeletal Muscle Active Hyperemia: The Differential...Role of Adenosine in Muscles of Varied Fiber Types 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER

  12. Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation.

    PubMed

    Flores, Carmen E; Nikonenko, Irina; Mendez, Pablo; Fritschy, Jean-Marc; Tyagarajan, Shiva K; Muller, Dominique

    2015-01-06

    Maintaining a proper balance between excitation and inhibition is essential for the functioning of neuronal networks. However, little is known about the mechanisms through which excitatory activity can affect inhibitory synapse plasticity. Here we used tagged gephyrin, one of the main scaffolding proteins of the postsynaptic density at GABAergic synapses, to monitor the activity-dependent adaptation of perisomatic inhibitory synapses over prolonged periods of time in hippocampal slice cultures. We find that learning-related activity patterns known to induce N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation and transient optogenetic activation of single neurons induce within hours a robust increase in the formation and size of gephyrin-tagged clusters at inhibitory synapses identified by correlated confocal electron microscopy. This inhibitory morphological plasticity was associated with an increase in spontaneous inhibitory activity but did not require activation of GABAA receptors. Importantly, this activity-dependent inhibitory plasticity was prevented by pharmacological blockade of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), it was associated with an increased phosphorylation of gephyrin on a site targeted by CaMKII, and could be prevented or mimicked by gephyrin phospho-mutants for this site. These results reveal a homeostatic mechanism through which activity regulates the dynamics and function of perisomatic inhibitory synapses, and they identify a CaMKII-dependent phosphorylation site on gephyrin as critically important for this process.

  13. 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.

  14. 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

  15. RNA-Dependent RNA Polymerase Activity in Influenza Virions

    PubMed Central

    Penhoet, Edward; Miller, Henry; Doyle, Michael; Blatti, Stanley

    1971-01-01

    An RNA-dependent RNA polymerase activity has been detected in purified preparations of influenza virus. In contrast to the replicase activity induced in influenza-infected cells, the virion-associated enzyme has an absolute requirement for Mn++. Most of the RNA synthesized in vitro is complementary to virion RNA. PMID:5288388

  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. Activity-dependent dendritic release of BDNF and biological consequences

    PubMed Central

    Kuczewski, Nicola; Porcher, Christophe; Lessmann, Volkmar; Medina, Igor; Gaiarsa, Jean-Luc

    2009-01-01

    Network construction and reorganization is modulated by the level and pattern of synaptic activity generated in the nervous system. During the past decades, neurotrophins, and in particular brain-derived neurotrophic factor (BDNF), have emerged as attractive candidates for linking synaptic activity and brain plasticity. Thus, neurotrophin expression and secretion are under the control of activity-dependent mechanisms and, besides their classical role in supporting neuronal survival neurotrophins, modulate nearly all key steps of network construction from neuronal migration to experience-dependent refinement of local connections. In this paper, we provide an overview of recent findings showing that BDNF can serve as a target-derived messenger for activity-dependent synaptic plasticity and development at the single cell level. PMID:19156544

  18. Novel structurally varied N-alkyl 1,4-dihydropyridines as ABCB1 inhibitors: structure-activity relationships, biological activity and first bioanalytical evaluation.

    PubMed

    Hilgeroth, Andreas; Baumert, Christiane; Coburger, Claudius; Seifert, Marianne; Krawczyk, Sören; Hempel, Cornelius; Neubauer, Felix; Krug, Martin; Molnár, Josef; Lage, Hermann

    2013-06-01

    Series of structurally varied N-alkyl 1,4-dihydropyridines and novel benzo-annelated derivatives as 1,4- dihydroquinolines have been characterized as ABCB1 inhibitors. Structure-activity relationships (SARs) are discussed. Cytotoxic activities of selected compounds have been determined. A first bioanalysis of ABCB1 substrate properties has been carried out in a cell-based model. Compounds with highest ABCB1 inhibiting activities were no substrates of ABCB1 and not transported by the efflux pump, thus profiling the new ABCB1 inhibitors.

  19. Prediction of satellite orbits contraction due to diurnally varying oblate atmosphere and altitude-dependent scale height using KS canonical elements

    NASA Astrophysics Data System (ADS)

    Raj, Xavier James; Sharma, Ram Krishan

    2009-09-01

    A new non-singular analytical theory for the motion of near-Earth satellite orbits with the air drag effect is developed in terms of uniformly regular KS canonical elements. Diurnally varying oblate atmosphere is considered with variation in density scale height dependent on altitude. The series expansion method is utilized to generate the analytical solutions and terms up to fourth-order terms in eccentricity and c (a small parameter dependent on the flattening of the atmosphere) are retained. Only two of the nine equations are solved analytically to compute the state vector and change in energy at the end of each revolution, due to symmetry in the equations of motion. The important drag perturbed orbital parameters: semi-major axis and eccentricity are obtained up to 500 revolutions, with the present analytical theory and by numerical integration over a wide range of perigee height, eccentricity and inclination. The differences between the two are found to be very less. A comparison between the theories generated with terms up to third- and fourth-order terms in c and e shows an improvement in the computation of the orbital parameters semi-major axis and eccentricity, up to 9%. The theory can be effectively used for the re-entry of the near-Earth objects, which mainly decay due to atmospheric drag.

  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. 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.

  2. Task-dependent activations of human auditory cortex during spatial discrimination and spatial memory tasks.

    PubMed

    Rinne, Teemu; Koistinen, Sonja; Talja, Suvi; Wikman, Patrik; Salonen, Oili

    2012-02-15

    In the present study, we applied high-resolution functional magnetic resonance imaging (fMRI) of the human auditory cortex (AC) and adjacent areas to compare activations during spatial discrimination and spatial n-back memory tasks that were varied parametrically in difficulty. We found that activations in the anterior superior temporal gyrus (STG) were stronger during spatial discrimination than during spatial memory, while spatial memory was associated with stronger activations in the inferior parietal lobule (IPL). We also found that wide AC areas were strongly deactivated during the spatial memory tasks. The present AC activation patterns associated with spatial discrimination and spatial memory tasks were highly similar to those obtained in our previous study comparing AC activations during pitch discrimination and pitch memory (Rinne et al., 2009). Together our previous and present results indicate that discrimination and memory tasks activate anterior and posterior AC areas differently and that this anterior-posterior division is present both when these tasks are performed on spatially invariant (pitch discrimination vs. memory) or spatially varying (spatial discrimination vs. memory) sounds. These results also further strengthen the view that activations of human AC cannot be explained only by stimulus-level parameters (e.g., spatial vs. nonspatial stimuli) but that the activations observed with fMRI are strongly dependent on the characteristics of the behavioral task. Thus, our results suggest that in order to understand the functional structure of AC a more systematic investigation of task-related factors affecting AC activations is needed.

  3. Chloride dependence of hyperpolarization-activated chloride channel gates

    PubMed Central

    Pusch, Michael; Jordt, Sven-Eric; Stein, Valentin; Jentsch, Thomas J

    1999-01-01

    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.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.With all these channels, reducing [Cl−]i shifted activation to more negative voltages and reduced the maximal activation at most negative voltages.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.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.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−.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

  4. 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…

  5. 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.

  6. 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

  7. Arrhenius temperature dependence of in vitro tissue plasminogen activator thrombolysis

    NASA Astrophysics Data System (ADS)

    Shaw, George J.; Dhamija, Ashima; Bavani, Nazli; Wagner, Kenneth R.; Holland, Christy K.

    2007-06-01

    Stroke is a devastating disease and a leading cause of death and disability. Currently, the only FDA approved therapy for acute ischemic stroke is the intravenous administration of the thrombolytic medication, recombinant tissue plasminogen activator (tPA). However, this treatment has many contraindications and can have dangerous side effects such as intra-cerebral hemorrhage. These treatment limitations have led to much interest in potential adjunctive therapies, such as therapeutic hypothermia (T <= 35 °C) and ultrasound enhanced thrombolysis. Such interest may lead to combining these therapies with tPA to treat stroke, however little is known about the effects of temperature on the thrombolytic efficacy of tPA. In this work, we measure the temperature dependence of the fractional clot mass loss Δm(T) resulting from tPA exposure in an in vitro human clot model. We find that the temperature dependence is well described by an Arrhenius temperature dependence with an effective activation energy Eeff of 42.0 ± 0.9 kJ mole-1. Eeff approximates the activation energy of the plasminogen-to-plasmin reaction of 48.9 kJ mole-1. A model to explain this temperature dependence is proposed. These results will be useful in predicting the effects of temperature in future lytic therapies.

  8. 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

  9. A network model for activity-dependent sleep regulation.

    PubMed

    Roy, Sandip; Krueger, James M; Rector, David M; Wan, Yan

    2008-08-07

    We develop and characterize a dynamical network model for activity-dependent sleep regulation. Specifically, in accordance with the activity-dependent theory for sleep, we view organism sleep as emerging from the local sleep states of functional units known as cortical columns; these local sleep states evolve through integration of local activity inputs, loose couplings with neighboring cortical columns, and global regulation (e.g. by the circadian clock). We model these cortical columns as coupled or networked activity-integrators that transition between sleep and waking states based on thresholds on the total activity. The model dynamics for three canonical experiments (which we have studied both through simulation and system-theoretic analysis) match with experimentally observed characteristics of the cortical-column network. Most notably, assuming connectedness of the network graph, our model predicts the recovery of the columns to a synchronized state upon temporary overstimulation of a single column and/or randomization of the initial sleep and activity-integration states. In analogy with other models for networked oscillators, our model also predicts the possibility for such phenomena as mode-locking.

  10. Surface modification of CoCr alloy using varying concentrations of phosphoric and phosphonoacetic acids: albumin and fibrinogen adsorption, platelet adhesion, activation, and aggregation studies.

    PubMed

    Thiruppathi, Eagappanath; Larson, Mark K; Mani, Gopinath

    2015-01-01

    CoCr alloy is commonly used in various cardiovascular medical devices for its excellent physical and mechanical properties. However, the formation of blood clots on the alloy surfaces is a serious concern. This research is focused on the surface modification of CoCr alloy using varying concentrations (1, 25, 50, 75, and 100 mM) of phosphoric acid (PA) and phosphonoacetic acid (PAA) to generate various surfaces with different wettability, chemistry, and roughness. Then, the adsorption of blood plasma proteins such as albumin and fibrinogen and the adhesion, activation, and aggregation of platelets with the various surfaces generated were investigated. Contact angle analysis showed PA and PAA coatings on CoCr provided a gradient of hydrophilic surfaces. FTIR showed PA and PAA were covalently bound to CoCr surface and formed different bonding configurations depending on the concentrations of coating solutions used. AFM showed the formation of homogeneous PA and PAA coatings on CoCr. The single and dual protein adsorption studies showed that the amount of albumin and fibrinogen adsorbed on the alloy surfaces strongly depend on the type of PA and PAA coatings prepared by different concentrations of coating solutions. All PA coated CoCr showed reduced platelet adhesion and activation when compared to control CoCr. Also, 75 and 100 mM PA-CoCr showed reduced platelet aggregation. For PAA coated CoCr, no significant difference in platelet adhesion and activation was observed between PAA coated CoCr and control CoCr. Thus, this study demonstrated that CoCr can be surface modified using PA for potentially reducing the formation of blood clots and improving the blood compatibility of the alloy.

  11. Network-dependent modulation of brain activity during sleep.

    PubMed

    Watanabe, Takamitsu; Kan, Shigeyuki; Koike, Takahiko; Misaki, Masaya; Konishi, Seiki; Miyauchi, Satoru; Miyahsita, Yasushi; Masuda, Naoki

    2014-09-01

    Brain activity dynamically changes even during sleep. A line of neuroimaging studies has reported changes in functional connectivity and regional activity across different sleep stages such as slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. However, it remains unclear whether and how the large-scale network activity of human brains changes within a given sleep stage. Here, we investigated modulation of network activity within sleep stages by applying the pairwise maximum entropy model to brain activity obtained by functional magnetic resonance imaging from sleeping healthy subjects. We found that the brain activity of individual brain regions and functional interactions between pairs of regions significantly increased in the default-mode network during SWS and decreased during REM sleep. In contrast, the network activity of the fronto-parietal and sensory-motor networks showed the opposite pattern. Furthermore, in the three networks, the amount of the activity changes throughout REM sleep was negatively correlated with that throughout SWS. The present findings suggest that the brain activity is dynamically modulated even in a sleep stage and that the pattern of modulation depends on the type of the large-scale brain networks.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. Allosteric activation of apicomplexan calcium-dependent protein kinases

    SciTech Connect

    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

    2015-08-24

    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.

  18. Allosteric activation of apicomplexan calcium-dependent protein kinases

    DOE PAGES

    Ingram, Jessica R.; Knockenhauer, Kevin E.; Markus, Benedikt M.; ...

    2015-08-24

    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,more » 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.« less

  19. Breaking the Meyer-Overton rule: predicted effects of varying stiffness and interfacial activity on the intrinsic potency of anesthetics.

    PubMed Central

    Cantor, R S

    2001-01-01

    Exceptions to the Meyer-Overton rule are commonly cited as evidence against indirect, membrane-mediated mechanisms of general anesthesia. However, another interpretation is possible within the context of an indirect mechanism in which solubilization of an anesthetic in the membrane causes a redistribution of lateral pressures in the membrane, which in turn shifts the conformational equilibrium of membrane proteins such as ligand-gated ion channels. It is suggested that compounds of different stiffness and interfacial activity have different intrinsic potencies, i.e., they cause widely different redistributions of the pressure profile (and thus different effects on protein conformational equilibria) per unit concentration of the compound in the membrane. Calculations incorporating the greater stiffness of perfluoromethylenic chains and the large interfacial attraction of hydroxyl groups predict the higher intrinsic potency of short alkanols than alkanes, the cutoffs in potency of alkanes and alkanols and the much shorter cutoffs for their perfluorinated analogues. Both effects, increased stiffness and interfacial activity, are present in unsaturated hydrocarbon solutes, and the intrinsic potencies are predicted to depend on the magnitude of both effects and on the number and locations of multiple bonds within the molecule. Most importantly, the intrinsic potencies of polymeric alkanols with regularly spaced hydroxyl groups are predicted to rise with increasing chain length, without cutoff; such molecules should serve to distinguish unambiguously between indirect mechanisms and direct binding mechanisms of anesthesia. PMID:11325730

  20. 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

  1. 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.

  2. 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.

  3. Aven-dependent activation of ATM following DNA damage

    PubMed Central

    Guo, Jessie Yanxiang; Yamada, Ayumi; Kajino, Taisuke; Wu, Judy Qiju; Tang, Wanli; Freel, Christopher D.; Feng, Junjie; Chau, B. Nelson; Wang, Michael Zhuo; Margolis, Seth; Yoo, Hae Yong; Wang, Xiao-Fan; Dunphy, William G.; Irusta, Pablo M.; Hardwick, J. Marie; Kornbluth, Sally

    2009-01-01

    Summary Background In response to DNA damage, cells either undergo cell cycle arrest or apoptosis, depending on the extent of damage and the cell’s capacity for DNA repair. Cell cycle arrest induced by double-stranded DNA breaks depends on activation of the ataxia-telangiectasia (ATM) protein kinase, which phosphorylates cell cycle effectors such as Chk2 and p53 to inhibit cell cycle progression. ATM is recruited to double stranded DNA breaks by a complex of sensor proteins including Mre11/Rad50/Nbs1, resulting in autophosphorylation, monomerization, and activation of ATM kinase. Results In characterizing Aven protein, a previously reported apoptotic inhibitor, we have found that Aven can function as an ATM activator to inhibit G2/M progression. Aven bound to ATM and Aven overexpression in cycling Xenopus egg extracts prevented mitotic entry and induced phosphorylation of ATM and its substrates. Immunodepletion of endogenous Aven allowed mitotic entry even in the presence of damaged DNA, and RNAi-mediated knock-down of Aven in human cells prevented autophosphorylation of ATM at an activating site (S1981) in response to DNA damage. Interestingly, Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM following DNA damage is enhanced by ATM-mediated Aven phosphorylation. Conclusions These results identify Aven as a new ATM activator and describe a positive feedback loop operating between Aven and ATM. In aggregate, these findings place Aven, a known apoptotic inhibitor, as a critical transducer of the DNA damage signal. PMID:18571408

  4. 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.

  5. Role of BDNF epigenetics in activity-dependent neuronal plasticity.

    PubMed

    Karpova, Nina N

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is a key mediator of the activity-dependent processes in the brain that have a major impact on neuronal development and plasticity. Impaired control of neuronal activity-induced BDNF expression mediates the pathogenesis of various neurological and psychiatric disorders. Different environmental stimuli, such as the use of pharmacological compounds, physical and learning exercises or stress exposure, lead to activation of specific neuronal networks. These processes entail tight temporal and spatial transcriptional control of numerous BDNF splice variants through epigenetic mechanisms. The present review highlights recent findings on the dynamic and long-term epigenetic programming of BDNF gene expression by the DNA methylation, histone-modifying and microRNA machineries. The review also summarizes the current knowledge on the activity-dependent BDNF mRNA trafficking critical for rapid local regulation of BDNF levels and synaptic plasticity. Current data open novel directions for discovery of new promising therapeutic targets for treatment of neuropsychiatric disorders. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

  6. The magnitudes of hyperpolarization-activated and low-voltage-activated potassium currents co-vary in neurons of the ventral cochlear nucleus.

    PubMed

    Cao, Xiao-Jie; Oertel, Donata

    2011-08-01

    In the ventral cochlear nucleus (VCN), neurons have hyperpolarization-activated conductances, which in some cells are enormous, that contribute to the ability of neurons to convey acoustic information in the timing of their firing by decreasing the input resistance and speeding-up voltage changes. Comparisons of the electrophysiological properties of neurons in the VCN of mutant mice that lack the hyperpolarization-activated cyclic nucleotide-gated channel α subunit 1 (HCN1(-/-)) (Nolan et al. 2003) with wild-type controls (HCN1(+/+)) and with outbred ICR mice reveal that octopus, T stellate, and bushy cells maintain their electrophysiological distinctions in all strains. Hyperpolarization-activated (I(h)) currents were smaller and slower, input resistances were higher, and membrane time constants were longer in HCN1(-/-) than in HCN1(+/+) in octopus, bushy, and T stellate cells. There were significant differences in the average magnitudes of I(h), input resistances, and time constants between HCN1(+/+) and ICR mice, but the resting potentials did not differ between strains. I(h) is opposed by a low-voltage-activated potassium (I(KL)) current in bushy and octopus cells, whose magnitudes varied widely between neuronal types and between strains. The magnitudes of I(h) and I(KL) were correlated across neuronal types and across mouse strains. Furthermore, these currents balanced one another at the resting potential in individual cells. The magnitude of I(h) and I(KL) is linked in bushy and octopus cells and varies not only between HCN1(-/-) and HCN1(+/+) but also between "wild-type" strains of mice, raising the question to what extent the wild-type strains reflect normal mice.

  7. The magnitudes of hyperpolarization-activated and low-voltage-activated potassium currents co-vary in neurons of the ventral cochlear nucleus

    PubMed Central

    Cao, Xiao-Jie

    2011-01-01

    In the ventral cochlear nucleus (VCN), neurons have hyperpolarization-activated conductances, which in some cells are enormous, that contribute to the ability of neurons to convey acoustic information in the timing of their firing by decreasing the input resistance and speeding-up voltage changes. Comparisons of the electrophysiological properties of neurons in the VCN of mutant mice that lack the hyperpolarization-activated cyclic nucleotide-gated channel α subunit 1 (HCN1−/−) (Nolan et al. 2003) with wild-type controls (HCN1+/+) and with outbred ICR mice reveal that octopus, T stellate, and bushy cells maintain their electrophysiological distinctions in all strains. Hyperpolarization-activated (Ih) currents were smaller and slower, input resistances were higher, and membrane time constants were longer in HCN1−/− than in HCN1+/+ in octopus, bushy, and T stellate cells. There were significant differences in the average magnitudes of Ih, input resistances, and time constants between HCN1+/+ and ICR mice, but the resting potentials did not differ between strains. Ih is opposed by a low-voltage-activated potassium (IKL) current in bushy and octopus cells, whose magnitudes varied widely between neuronal types and between strains. The magnitudes of Ih and IKL were correlated across neuronal types and across mouse strains. Furthermore, these currents balanced one another at the resting potential in individual cells. The magnitude of Ih and IKL is linked in bushy and octopus cells and varies not only between HCN1−/− and HCN1+/+ but also between “wild-type” strains of mice, raising the question to what extent the wild-type strains reflect normal mice. PMID:21562186

  8. 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.

  9. Neuronal activity-dependent membrane traffic at the neuromuscular junction

    PubMed Central

    Miana-Mena, Francisco Javier; Roux, Sylvie; Benichou, Jean-Claude; Osta, Rosario; Brûlet, Philippe

    2002-01-01

    During development and also in adulthood, synaptic connections are modulated by neuronal activity. To follow such modifications in vivo, new genetic tools are designed. The nontoxic C-terminal fragment of tetanus toxin (TTC) fused to a reporter gene such as LacZ retains the retrograde and transsynaptic transport abilities of the holotoxin itself. In this work, the hybrid protein is injected intramuscularly to analyze in vivo the mechanisms of intracellular and transneuronal traffics at the neuromuscular junction (NMJ). Traffic on both sides of the synapse are strongly dependent on presynaptic neural cell activity. In muscle, a directional membrane traffic concentrates β-galactosidase-TTC hybrid protein into the NMJ postsynaptic side. In neurons, the probe is sorted across the cell to dendrites and subsequently to an interconnected neuron. Such fusion protein, sensitive to presynaptic neuronal activity, would be extremely useful to analyze morphological changes and plasticity at the NMJ. PMID:11880654

  10. 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

  11. 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

  12. Functionally diverse biotin-dependent enzymes with oxaloacetate decarboxylase activity.

    PubMed

    Lietzan, Adam D; St Maurice, Martin

    2014-02-15

    Biotin-dependent enzymes catalyze carboxylation, decarboxylation and transcarboxylation reactions that participate in the primary metabolism of a wide range of organisms. In all cases, the overall reaction proceeds via two half reactions that take place in physically distinct active sites. In the first half-reaction, a carboxyl group is transferred to the 1-N' of a covalently tethered biotin cofactor. The tethered carboxybiotin intermediate subsequently translocates to a second active site where the carboxyl group is either transferred to an acceptor substrate or, in some bacteria and archaea, is decarboxylated to biotin and CO2 in order to power the export of sodium ions from the cytoplasm. A homologous carboxyltransferase domain is found in three enzymes that catalyze diverse overall reactions: carbon fixation by pyruvate carboxylase, decarboxylation and sodium transport by the biotin-dependent oxaloacetate decarboxylase complex, and transcarboxylation by transcarboxylase from Propionibacterium shermanii. Over the past several years, structural data have emerged which have greatly advanced the mechanistic description of these enzymes. This review assembles a uniform description of the carboxyltransferase domain structure and catalytic mechanism from recent studies of pyruvate carboxylase, oxaloacetate decarboxylase and transcarboxylase, three enzymes that utilize an analogous carboxyltransferase domain to catalyze the biotin-dependent decarboxylation of oxaloacetate.

  13. E region electric field dependence of the solar activity

    NASA Astrophysics Data System (ADS)

    Denardini, C. M.; Moro, J.; Resende, L. C. A.; Chen, S. S.; Schuch, N. J.; Costa, J. E. R.

    2015-10-01

    We have being studying the zonal and vertical E region electric field components inferred from the Doppler shifts of type 2 echoes (gradient drift irregularities) detected with the 50 MHz backscatter coherent radar set at São Luis, Brazil (SLZ, 2.3°S, 44.2°W) during the solar cycle 24. In this report we present the dependence of the vertical and zonal components of this electric field with the solar activity, based on the solar flux F10.7. For this study we consider the geomagnetically quiet days only (Kp ≤ 3+). A magnetic field-aligned-integrated conductivity model was developed for proving the conductivities, using the IRI-2007, the MISIS-2000, and the IGRF-11 models as input parameters for ionosphere, neutral atmosphere, and Earth magnetic field, respectively. The ion-neutron collision frequencies of all the species are combined through the momentum transfer collision frequency equation. The mean zonal component of the electric field, which normally ranged from 0.19 to 0.35 mV/m between the 8 and 18 h (LT) in the Brazilian sector, show a small dependency with the solar activity. Whereas the mean vertical component of the electric field, which normally ranges from 4.65 to 10.12 mV/m, highlights the more pronounced dependency of the solar flux.

  14. Selenium-dependent antitumor immunomodulating activity of polysaccharides from roots of A. membranaceus.

    PubMed

    Li, Shuang; Bian, Fuling; Yue, Ling; Jin, Hua; Hong, Zongguo; Shu, Guangwen

    2014-08-01

    Roots of Astragalus membranaceus (Fish.) Bge. var. mongholicus (Bge.) Hsiao (A. membranaceus) have been long used as an auxiliary reagent supporting cancer treatment. Here, we compared the chemical composition and antitumor immunomodulating activity of polysaccharides from roots of A. membranaceus (PAMs) from five major habitats in Inner Mongolia, PR China. We revealed that compositions of monosaccharides and amino acids were comparable among PAMs from different habitats. However, amounts of selenium varied widely in roots of A. membranaceus and PAMs. PAMs selenium-dependently repressed the in vivo proliferation of transplanted H22 ascitic hepatoma and S180 sarcoma cells with low toxic impacts on tumor-bearing mice. Selenium-containing PAMs ameliorated host CD4+ T cell apoptosis and serum cytokine dysregulation induced by tumor transplantation, leading to the enhancement of cytotoxic activities of natural killer and CD8+ T cells. Moreover, PAMs also selenium-dependently improved the phagocytotic function of intra-abdominal macrophages and suppressed M2-like polarization of tumor-associated macrophages. These data suggested that the selenium content varies in the roots of A. membranaceus and PAMs from different geographical origins dramatically and selenium is an important contributor to the antitumor immunomodulation activities of PAMs.

  15. 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

  16. Contraction of Satellite Orbits using K-S Elements in an Oblate Diurnally varying Atmosphere with Scale Height dependent on Altitude

    NASA Astrophysics Data System (ADS)

    Nair, L.; Sharma, R.

    Accurate orbit prediction of the near-Earth satellites is an important requirement for re-entry and orbital lifetime estimates. Since the Earth's atmosphere is non- stationary and does not possess spherical symmetry and varies, in general, considerably during the lifetime of a satellite, therefore, the selection of an appropriate atmospheric model has great significance in the study of the perturbations of satellite motion caused by air drag. The non -spherical nature of the atmosphere is primarily due to Earth's gravitational field and the heating of the illuminated part of the Earth's atmosphere by the Sun results in a deformation in the upper atmosphere and the atmospheric density at a given distance from the center of the Earth depends upon the geographic latitude and longitude, and on the Sun's location in the celestial sphere. Though the numerical integration methods generate more accurate ephemeris of a satellite with respect to any complex force model, the analytical solutions are very useful for qu alitative analysis as they represent a manifold of solutions for a large domain of initial conditions. A number of analytical solutions of artificial satellite motion in an atmosphere which consider the non-sphericity of the distribution of the atmospheric density, are available in the literature. Two important contributions on the problem of the Earth's satellite motion in which diurnal and atmospheric oblateness effects are treated in combination, are by Santora (1975) and Swinerd &Boulton (1982). Santora's analytical solution for changes due to drag in the semi- major axis (a), x = a e and argument of perigee (É), e being the eccentricity of the orbit, during a revolution is up to first-order in e and second-order in c ( a small parameter dependent on the flattening of the atmosphere). Swinerd &Boulton and Boulton -1983 (for change in argument of perigee) theory is up to third-order terms in e and c. In both the theories, the variation of density scale

  17. Structural basis for proteolysis-dependent activation of the poliovirus RNA-dependent RNA polymerase

    PubMed Central

    Thompson, Aaron A; Peersen, Olve B

    2004-01-01

    The active RNA-dependent RNA polymerase of poliovirus, 3Dpol, is generated by cleavage of the 3CDpro precursor protein, a protease that has no polymerase activity despite containing the entire polymerase domain. By intentionally disrupting a known and persistent crystal packing interaction, we have crystallized the poliovirus polymerase in a new space group and solved the complete structure of the protein at 2.0 Å resolution. It shows that the N-terminus of fully processed 3Dpol is buried in a surface pocket where it makes hydrogen bonds that act to position Asp238 in the active site. Asp238 is an essential residue that selects for the 2′ OH group of substrate rNTPs, as shown by a 2.35 Å structure of a 3Dpol–GTP complex. Mutational, biochemical, and structural data further demonstrate that 3Dpol activity is exquisitely sensitive to mutations at the N-terminus. This sensitivity is the result of allosteric effects where the structure around the buried N-terminus directly affects the positioning of Asp238 in the active site. PMID:15306852

  18. Dynamic activity dependence of in vivo normal knee kinematics.

    PubMed

    Moro-oka, Taka-aki; Hamai, Satoshi; Miura, Hiromasa; Shimoto, Takeshi; Higaki, Hidehiko; Fregly, Benjamin J; Iwamoto, Yukihide; Banks, Scott A

    2008-04-01

    Dynamic knee kinematics were analyzed for normal knees in three activities, including two different types of maximum knee flexion. Continuous X-ray images of kneel, squat, and stair climb motions were taken using a large flat panel detector. CT-derived bone models were used for model registration-based 3D kinematic measurement. Three-dimensional joint kinematics and contact locations were determined using three methods: bone-fixed coordinate systems, interrogation of CT-based bone model surfaces, and interrogation of MR-based articular cartilage model surfaces. The femur exhibited gradual external rotation throughout the flexion range. Tibiofemoral contact exhibited external rotation, with contact locations translating posterior while maintaining 15 degrees to 20 degrees external rotation from 20 degrees to 80 degrees of flexion. From 80 degrees to maximum flexion, contact locations showed a medial pivot pattern. Kinematics based on bone-fixed coordinate systems differed from kinematics based on interrogation of CT and MR surfaces. Knee kinematics varied significantly by activity, especially in deep flexion. No posterior subluxation occurred for either femoral condyle in maximum knee flexion. Normal knees accommodate a range of motions during various activities while maintaining geometric joint congruency.

  19. Regional variation in myofilament length-dependent activation.

    PubMed

    Cazorla, Olivier; Lacampagne, Alain

    2011-07-01

    The Frank-Starling law is an important regulatory mechanism of the heart that links the end-diastolic volume with the systolic ejection fraction. This beat-to-beat regulation of the heart, underlined at the cellular level by higher myofilament calcium sensitivity at longer sarcomere length, is known as length-dependent activation or stretch sensitization of activation. However, the heart is structurally and functionally heterogeneous and asymmetrical. Specifically, contractile properties are not uniform within the left ventricle partly due to transmural differences in action potential waveforms and calcium homeostasis. The present review will focus on the role of the contractile machinery in the transmural contractile heterogeneity and its adaptation to changes in muscle strain. The expression of different myosin isoforms, the level of titin-based passive tension, and thin and thick sarcomeric regulatory proteins are considered to explain the regional cellular contractile properties. Finally, the importance of transmural heterogeneity of length-dependent activation and the consequences of its modification on the heart mechanics are discussed. Despite extensive research since the characterization of the Frank-Starling law, the molecular mechanisms by which strain information is transduced to the contractile machinery have not been fully determined yet.

  20. Nitric oxide mediates local activity-dependent excitatory synapse development.

    PubMed

    Nikonenko, Irina; Nikonenko, Alexander; Mendez, Pablo; Michurina, Tatyana V; Enikolopov, Grigori; Muller, Dominique

    2013-10-29

    Learning related paradigms play an important role in shaping the development and specificity of synaptic networks, notably by regulating mechanisms of spine growth and pruning. The molecular events underlying these synaptic rearrangements remain poorly understood. Here we identify NO signaling as a key mediator of activity-dependent excitatory synapse development. We find that chronic blockade of NO production in vitro and in vivo interferes with the development of hippocampal and cortical excitatory spine synapses. The effect results from a selective loss of activity-mediated spine growth mechanisms and is associated with morphological and functional alterations of remaining synapses. These effects of NO are mediated by a cGMP cascade and can be reproduced or prevented by postsynaptic expression of vasodilator-stimulated phosphoprotein phospho-mimetic or phospho-resistant mutants. In vivo analyses show that absence of NO prevents the increase in excitatory synapse density induced by environmental enrichment and interferes with the formation of local clusters of excitatory synapses. We conclude that NO plays an important role in regulating the development of excitatory synapses by promoting local activity-dependent spine-growth mechanisms.

  1. New cell-based assay indicates dependence of antioxidant biological activity on the origin of reactive oxygen species.

    PubMed

    Dimitrov, Martin D; Pesheva, Margarita G; Venkov, Pencho V

    2013-05-08

    The mobility of the Ty1 transposon in Saccharomyces cerevisiae was found to vary proportionally with the level of ROS generated in cells, which provides the possibility to determine antioxidant activity by changes in a cellular process instead of using chemical reactions. The study of propolis, royal jelly, and honey with the newly developed Ty1antiROS test reveals an inverse exponential dependence of antioxidant activity on increased concentrations. This dependence can be transformed to proportional by changing the source of ROS: instead of cell-produced to applied as hydrogen peroxide. The different test responses are not due to excess of added hydrogen peroxide, as evidenced by the exponential dependence found by usage of yap1Δ tester cells accumulating cell-generated ROS. Results indicate that the activity of antioxidants to oxidative radicals depends on the origin of ROS, and this activity is elevated for cell-generated ROS compared to ROS added as reagents in the assay.

  2. Activation of cyclin A-dependent protein kinases during apoptosis.

    PubMed Central

    Meikrantz, W; Gisselbrecht, S; Tam, S W; Schlegel, R

    1994-01-01

    Apoptosis was induced in S-phase-arrested HeLa cells by staurosporine, caffeine, 6-dimethylaminopurine, and okadaic acid, agents that activate M-phase-promoting factor and induce premature mitosis in similarly treated hamster cell lines. Addition of these agents to asynchronously growing HeLa cells or to cells arrested in early G1 phase with lovastatin had little or no effect. S-phase arrest also promoted tumor necrosis factor alpha-induced apoptosis, eliminating the normal requirement for simultaneous cycloheximide treatment. For all of the apoptosis-inducing agents tested, the appearance of condensed chromatin was accompanied by 2- to 7-fold increases in cyclin A-associated histone H1 kinase activity, levels approximating the mitotic value. Where examined, both Cdc2 and Cdk2, the catalytic subunits known to associate with cyclin A, were activated. Stable overexpression of bcl-2 suppressed the apoptosis-inducing activity of all agents tested and reduced the amount of Cdc2 and Cdk2 in the nucleus, suggesting a possible mechanism by which bcl-2 inhibits the chromatin condensation characteristic of apoptosis. These findings suggest that at least one of the biochemical steps required for mitosis, activation of cyclin A-dependent protein kinases, is also an important event during apoptosis. Images PMID:8170983

  3. A microfluidic device for evaluating the dynamics of the metabolism-dependent antioxidant activity of nutrients.

    PubMed

    Lee, Jungwoo; Choi, Jong-ryul; Ha, Sang Keun; Choi, Inwook; Lee, Seung Hwan; Kim, Donghyun; Choi, Nakwon; Sung, Jong Hwan

    2014-08-21

    Various food components are known for their health-promoting effects. However, their biochemical effects are generally evaluated in vitro, and their actual in vivo effect can vary significantly, depending on their metabolic profiles. To evaluate the effect of the liver metabolism on the antioxidant activity, we have developed a two-compartment microfluidic system that integrates the dynamics of liver metabolism and the subsequent antioxidant activity of food components. In the first compartment of the device, human liver enzyme fractions were immobilized inside a poly(ethylene glycol) diacrylate (PEGDA) hydrogel to mimic the liver metabolism. The radical scavenging activity was evaluated by the change of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) absorbance in the second compartment. Reaction engineering and fluid mechanics principles were used to develop a simplified analytical model and a more complex finite element model, which were used to design the chip and determine the optimal flow conditions. For real-time measurements of the reaction on a chip, we developed a custom-made photospectrometer system with an LED light source. The developed microfluidic system showed a linear and dose-dependent antioxidant activity in response to increasing concentration of flavonoid. We also compared the antioxidant activity of flavonoid after various liver metabolic reactions. This microfluidic system can serve as a novel in vitro platform for predicting the antioxidant activity of various food components in a more physiologically realistic manner, as well as for studying the mechanism of action of such food components.

  4. Activity-Dependent Neuronal Model on Complex Networks

    PubMed Central

    de Arcangelis, Lucilla; Herrmann, Hans J.

    2012-01-01

    Neuronal avalanches are a novel mode of activity in neuronal networks, experimentally found in vitro and in vivo, and exhibit a robust critical behavior: these avalanches are characterized by a power law distribution for the size and duration, features found in other problems in the context of the physics of complex systems. We present a recent model inspired in self-organized criticality, which consists of an electrical network with threshold firing, refractory period, and activity-dependent synaptic plasticity. The model reproduces the critical behavior of the distribution of avalanche sizes and durations measured experimentally. Moreover, the power spectra of the electrical signal reproduce very robustly the power law behavior found in human electroencephalogram (EEG) spectra. We implement this model on a variety of complex networks, i.e., regular, small-world, and scale-free and verify the robustness of the critical behavior. PMID:22470347

  5. 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.

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

    NASA Astrophysics Data System (ADS)

    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, 10-23m3 ), 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.

  7. Degrasyn activates proteasomal-dependent degradation of c-Myc.

    PubMed

    Bartholomeusz, Geoffrey; Talpaz, Moshe; Bornmann, William; Kong, Ling-Yuan; Donato, Nicholas J

    2007-04-15

    c-Myc is a highly unstable transcription factor whose deregulation and increased expression are associated with cancer. Degrasyn, a small synthetic molecule, induces rapid degradation of c-Myc protein in MM-1 multiple myeloma and other tumor cell lines. Destruction of c-Myc by degrasyn requires the presence of a region of c-Myc between amino acid residues 316 and 378 that has not previously been associated with c-Myc stability. Degrasyn-induced degradation of c-Myc depends on proteasomes but is independent of the degron regions previously shown to be important for ubiquitin-mediated targeting and proteasomal destruction of the protein. Degrasyn-dependent c-Myc proteolysis is not mediated by any previously identified c-Myc regulatory mechanism, does not require new protein synthesis, and does not depend on the nuclear localization of c-Myc. Degrasyn reduced c-Myc levels in A375 melanoma cells and in A375 tumors in nude mice, and this activity correlated with tumor growth inhibition. Together, these results suggest that degrasyn reduces the stability of c-Myc in vitro and in vivo through a unique signaling process that uses c-Myc domains not previously associated with c-Myc regulation.

  8. Cholesterol-dependent hemolytic activity of Passiflora quadrangularis leaves.

    PubMed

    Yuldasheva, L N; Carvalho, E B; Catanho, M-T J A; Krasilnikov, O V

    2005-07-01

    Plants used in traditional medicine are rich sources of hemolysins and cytolysins, which are potential bactericidal and anticancer drugs. The present study demonstrates for the first time the presence of a hemolysin in the leaves of Passiflora quadrangularis L. This hemolysin is heat stable, resistant to trypsin treatment, has the capacity to froth, and acts very rapidly. The hemolysin activity is dose-dependent, with a slope greater than 1 in a double-logarithmic plot. Polyethylene glycols of high molecular weight were able to reduce the rate of hemolysis, while liposomes containing cholesterol completely inhibited it. In contrast, liposomes containing phosphatidylcholine were ineffective. The Passiflora hemolysin markedly increased the conductance of planar lipid bilayers containing cholesterol but was ineffective in cholesterol-free bilayers. Successive extraction of the crude hemolysin with n-hexane, chloroform, ethyl acetate, and n-butanol resulted in a 10-fold purification, with the hemolytic activity being recovered in the n-butanol fraction. The data suggest that membrane cholesterol is the primary target for this hemolysin and that several hemolysin molecules form a large transmembrane water pore. The properties of the Passiflora hemolysin, such as its frothing ability, positive color reaction with vanillin, selective extraction with n-butanol, HPLC profile, cholesterol-dependent membrane susceptibility, formation of a stable complex with cholesterol, and rapid erythrocyte lysis kinetics indicate that it is probably a saponin.

  9. Parthanatos Mediates AIMP2 Activated Age Dependent Dopaminergic Neuronal Loss

    PubMed Central

    Lee, Yunjong; Karuppagounder, Senthilkumar S.; Shin, Joo-Ho; Lee, Yun-Il; Ko, Han Seok; Swing, Debbie; Jiang, Haisong; Kang, Sung-Ung; Lee, Byoung Dae; Kang, Ho Chul; Kim, Donghoon; Tessarollo, Lino; Dawson, Valina L.; Dawson, Ted M.

    2013-01-01

    The defining pathogenic feature of Parkinson’s disease is the age dependent loss of dopaminergic neurons. Mutations and inactivation of parkin, an ubiquitin E3 ligase, cause Parkinson’s disease through accumulation of pathogenic substrates. Here we show that transgenic overexpression of the parkin substrate, aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2) leads to a selective, age-dependent progressive loss of dopaminergic neurons via activation of poly(ADP-ribose) polymerase-1 (PARP1). AIMP2 accumulation in vitro and in vivo results in PARP1 overactivation and dopaminergic cell toxicity via direct association of these proteins in the nucleus providing a new path to PARP1 activation other than DNA damage. Inhibition of PARP1 through gene deletion or drug inhibition reverses behavioral deficits and protects in vivo against dopamine neuron death in AIMP2 transgenic mice. These data indicate that brain permeable PARP inhibitors could be effective in delaying or preventing disease progression in Parkinson’s disease. PMID:23974709

  10. Chk2 Activation and Phosphorylation-Dependent Oligomerization

    PubMed Central

    Xu, Xingzhi; Tsvetkov, Lyuben M.; Stern, David F.

    2002-01-01

    The tumor suppressor gene CHK2 encodes a versatile effector serine/threonine kinase involved in responses to DNA damage. Chk2 has an amino-terminal SQ/TQ cluster domain (SCD), followed by a forkhead-associated (FHA) domain and a carboxyl-terminal kinase catalytic domain. Mutations in the SCD or FHA domain impair Chk2 checkpoint function. We show here that autophosphorylation of Chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably ATM or ATR. Both SQ/TQ sites and non-SQ/TQ sites within the Chk2 SCD can be phosphorylated by active Chk2. Amino acid substitutions in the SCD and the FHA domain impair auto- and trans-kinase activities of Chk2. Chk2 forms oligomers that minimally require the FHA domain of one Chk2 molecule and the SCD within another Chk2 molecule. Chk2 oligomerization in vivo increases after DNA damage, and when damage is induced by gamma irradiation, this increase requires ATM. Chk2 oligomerization is phosphorylation dependent and can occur in the absence of other eukaryotic proteins. Chk2 can cross-phosphorylate another Chk2 molecule in an oligomeric complex. Induced oligomerization of a Chk2 chimera in vivo concomitant with limited DNA damage augments Chk2 kinase activity. These results suggest that Chk2 oligomerization regulates Chk2 activation, signal amplification, and transduction in DNA damage checkpoint pathways. PMID:12024051

  11. Temporal dependence of cysteine protease activation following excitotoxic hippocampal injury.

    PubMed

    Berry, J N; Sharrett-Field, L J; Butler, T R; Prendergast, M A

    2012-10-11

    Excitotoxic insults can lead to intracellular signaling cascades that contribute to cell death, in part by activation of proteases, phospholipases, and endonucleases. Cysteine proteases, such as calpains, are calcium (Ca(2+))-activated enzymes which degrade cytoskeletal proteins, including microtubule-associated proteins, tubulin, and spectrin, among others. The current study used the organotypic hippocampal slice culture model to examine whether pharmacologic inhibition of cysteine protease activity inhibits N-methyl-D-aspartate- (NMDA-) induced excitotoxic (20 μM NMDA) cell death and changes in synaptophysin immunoreactivity. Significant NMDA-induced cytotoxicity (as measured by propidium iodide [PI] uptake) was found in the CA1 region of the hippocampus at all timepoints examined (24, 72, 120 h), an effect significantly attenuated by co-exposure to the selective NMDA receptor antagonist DL-2-Amino-5-phosphonopentanoic acid (APV), but not MDL-28170, a potent cysteine protease inhibitor. Results indicated sparing of NMDA-induced loss of the synaptic vesicular protein synaptophysin in all regions of the hippocampus by MDL-28170, though only at early timepoints after injury. These results suggest Ca(2+)-dependent recruitment of cysteine proteases within 24h of excitotoxic insult, but activation of alternative cellular degrading mechanisms after 24h. Further, these data suggest that synaptophysin may be a substrate for calpains and related proteases.

  12. Energy-Dependent Electron Activated Dissociation of Metal-Adducted Permethylated Oligosaccharides

    PubMed Central

    Yu, Xiang; Huang, Yiqun; Lin, Cheng; Costello, Catherine E.

    2013-01-01

    The effects of varying the electron energy and cationizing agents on electron activated dissociation (ExD) of metal-adducted oligosaccharides were explored, using permethylated maltoheptaose as the model system. Across the examined range of electron energy, the metal-adducted oligosaccharide exhibited several fragmentation processes, including electron capture dissociation (ECD) at low energies, hot-ECD at intermediate energies, and electronic excitation dissociation (EED) at high energies. The dissociation threshold depended on the metal charge carrier(s), whereas the types and sequence spans of product ions were influenced by the metal-oligosaccharide binding pattern. Theoretical modeling contributed insight into the metal-dependent behavior of carbohydrates during low-energy ECD. When ExD was applied to a permethylated high mannose N-linked glycan, EED provided more structural information than either collision-induced dissociation (CID) or low-energy ECD, thus demonstrating its potential for oligosaccharide linkage analysis. PMID:22881449

  13. Disaster Preparedness Among Active Duty Navy, Retirees, Veterans, and Dependents

    PubMed Central

    Annis, Heather; Jacoby, Irving; DeMers, Gerard

    2016-01-01

    Background With the increase in natural and manmade disasters, preparedness remains a vital area of concern. Despite attempts by government and non-government agencies to stress the importance of preparedness, national levels of preparedness remain unacceptably low. A goal of commands and installations is to ensure that US Navy beneficiaries are well prepared for disasters. This is especially critical in active service members to meet mission readiness requirements in crisis settings. Objective To evaluate active duty personnel, dependents, veterans, and retirees regarding disaster preparedness status. Methods The authors conducted an anonymous 29-question survey for US Navy active duty, dependents, veterans and retirees of the Greater San Diego Region evaluating actual basic disaster readiness as determined by FEMA standards of 3-day minimum supply of emergency stores and equipment. Descriptive statistics and regression analysis were used to analyze data. Results 1150 surveys were returned and analyzed. 983 were sufficiently complete for logistic regression analysis with 394 responding “Yes” to having a 72-hour disaster kit (40.1%) while 589 had “No” as a response (59.9%). Conclusion The surveyed population is no more prepared than the general public though surveyed beneficiaries overall are at upper range of preparedness. Lower income and levels of education were associated with lack of preparedness, whereas training in disaster preparedness or having been affected by disasters increased the likelihood of being adequately prepared. Unlike results seen in the general public, those with chronic healthcare needs in our surveyed population were more, rather than less likely to be prepared and those with minor children were less likely, rather than more likely to be prepared. Duty status was assessed and only veterans were significantly more likely than most to be prepared. PMID:26903142

  14. Sex-dependent differences in voluntary physical activity.

    PubMed

    Rosenfeld, Cheryl S

    2017-01-02

    Numbers of overweight and obese individuals are increasing in the United States and globally, and, correspondingly, the associated health care costs are rising dramatically. More than one-third of children are currently considered obese with a predisposition to type 2 diabetes, and it is likely that their metabolic conditions will worsen with age. Physical inactivity has also risen to be the leading cause of many chronic, noncommunicable diseases (NCD). Children are more physically inactive now than they were in past decades, which may be due to intrinsic and extrinsic factors. In rodents, the amount of time engaged in spontaneous activity within the home cage is a strong predictor of later adiposity and weight gain. Thus, it is important to understand primary motivators stimulating physical activity (PA). There are normal sex differences in PA levels in rodents and humans. The perinatal environment can induce sex-dependent differences in PA disturbances. This Review considers the current evidence for sex differences in PA in rodents and humans. The rodent studies showing that early exposure to environmental chemicals can shape later adult PA responses are discussed. Next, whether there are different motivators stimulating exercise in male vs. female humans are examined. Finally, the brain regions, genes, and pathways that modulate PA in rodents, and possibly by translation in humans, are described. A better understanding of why each sex remains physically active through the life span could open new avenues for preventing and treating obesity in children and adults. © 2016 Wiley Periodicals, Inc.

  15. An Automated Method for Extracting Spatially Varying Time-Dependent Quantities from an ALEGRA Simulation Using VisIt Visualization Software

    DTIC Science & Technology

    2014-07-01

    Visualization software such as VisIt presents an alternative method to examine data through the use of EXODUS databases.3 In addition, VisIt...extracting transient quantities that vary spatially from an EXODUS database using a VisIt macro written in the Python programming language. 2...Graphics; Sandia National Laboratories: Albuquerque, NM, September 1991. Revised April 1994. 3 Schoof, L. A.; Yarberry, V. R. EXODUS II: A Finite

  16. Reasons for smoking cessation attempts among Japanese male smokers vary by nicotine dependence level: a cross-sectional study after the 2010 tobacco tax increase

    PubMed Central

    Tanihara, Shinichi; Momose, Yoshito

    2015-01-01

    Objectives To examine the association between smoking cessation attempts during the previous 12 months, motivators to quit smoking and nicotine dependence levels among current male smokers after Japan's massive 2010 tobacco tax increase. Design Cross-sectional study. Setting A self-reported questionnaire about smoking habits, nicotine dependence levels and factors identified as motivators to quit smoking was administered to 9378 employees working at a company located in Fukuoka Prefecture in Japan (as of 1 October 2011). Participants A total of 2251 male current smokers 20–69 years old. Primary and secondary outcome measures Nicotine dependence level assessed by Fagerström Test for Cigarette Dependence (FTCD), smoking cessation attempts during the previous 12 months and motivators for smoking cessation. Results The proportion of current smokers who had attempted to quit smoking within the previous 12 months was 40.6%. Nicotine dependence level of current smokers was negatively associated with cessation attempts during the previous 12 months. Motivators for smoking cessation differed by nicotine dependence levels. ‘The rise in cigarette prices since October 2010’ as a smoking cessation motivator increased significantly at the medium nicotine dependence level (OR 1.44, 95% CI 1.09 to 1.90); however, this association was not statistically significant for individuals with high nicotine dependence (OR 1.24, 95% CI 0.80 to 1.92). ‘Feeling unhealthy’ was significantly negatively associated for medium (OR 0.42, 95% CI 0.27 to 0.65) and high (OR 0.31, 95% CI 0.14 to 0.71) nicotine dependence levels. Trend associations assessed by assigning ordinal numbers to total FTCD score for those two motivators were statistically significant. Conclusions The efficacy of smoking cessation strategies can be improved by considering the target group's nicotine dependence level. For smokers with medium and high nicotine dependence levels, more effective strategies aimed

  17. Presenilin-dependent γ-secretase activity modulates thymocyte development

    PubMed Central

    Doerfler, Petra; Shearman, Mark S.; Perlmutter, Roger M.

    2001-01-01

    In neuronal cells, presenilin-dependent γ-secretase activity cleaves amyloid precursor proteins to release Aβ peptides, and also catalyzes the release of the intracellular domain of the transmembrane receptor Notch. Accumulation of aberrant Aβ peptides appears to be causally related to Alzheimer's disease. Inhibition of Aβ peptide production is therefore a potential target for therapeutic intervention. Notch proteins play an important role in cell fate determination in many different organisms and at different stages of development, for example in mammalian T cell development. We therefore addressed whether structurally diverse γ-secretase inhibitors impair Notch function by studying thymocyte development in murine fetal thymic organ cultures. Here we show that high concentrations of the most potent inhibitors blocked thymocyte development at the most immature stage. In contrast, lower concentrations or less potent inhibitors impaired differentiation at a later stage, most notably suppressing the development of CD8 single-positive T cells. These phenotypes are consistent with an impairment of Notch signaling by γ-secretase inhibitors and define a strict Notch dose dependence of consecutive stages during thymocyte development. PMID:11470902

  18. Presence of diadenosine 5',5''' -P1, P4-tetraphosphate (Ap4A) in mamalian cells in levels varying widely with proliferative activity of the tissue: a possible positive "pleiotypic activator".

    PubMed Central

    Rapaport, E; Zamecnik, P C

    1976-01-01

    An accurate assay of diadenosine 5',5'''- P1,P4-tetraphosphate [A(5') pppp(5')A], which was shown to be formed in vitro in the backreaction of the amino acid activation step, has been developed in various cell lines in culture and in normal mouse liver or hepatoma in vivo. Use of radioactive labeling of acid-soluble nucleotides to high specific activity followed by chromatographic separation techniques yielded levels of Ap4A varying from 5 to 0.05 muM (from 30 pmol/mg of protein to 0.15 pmol), depending on the doubling time of the cell line or the proliferative state of the cells. The levels of Ap4A incells is inversely related to their doubling time, varying from 0.1 X 10(-4) of the cellular ATP levels in slowly growing cells to 20 X 10(-4) of the ATP levels of cells with rapid doubling times. The steady-state levels of ATP of different cell lines, although showing some fluctuations, are not related to the doubling time of the cells. Arrest of cellular proliferation by serum deprivation or amino acid starvation, which does not alter the cellular ATP levels more than 2-fold, does nevertheless cause a decrease of 30 to 50-fold in the Ap4A levels. Inhibition of protein synthesis by pactamycin or puromycin, or inhibition of DNA synthesis by hydroxyurea, leads to a more dramatic decrease of 50 to 100-fold in intracellular Ap4A levels. The metabolic lability of Ap4A is also demonstrated by its rapid depletion after decreases in the ATP/ADP ratio. The possibility of Ap4A being a metabolic "signal nucleotide" that is formed at the onset of protein synthesis and is active in positive growth regulation (positive pleiotypic activation) is discussed. PMID:1069282

  19. Regulated O2 activation in flavin-dependent monooxygenases.

    PubMed

    Frederick, Rosanne E; Mayfield, Jeffery A; DuBois, Jennifer L

    2011-08-17

    Flavin-dependent monooxygenases (FMOs) are involved in important biosynthetic pathways in diverse organisms, including production of the siderophores used for the import and storage of essential iron in serious pathogens. We have shown that the FMO from Aspergillus fumigatus, an ornithine monooxygenase (Af-OMO), is mechanistically similar to its well-studied distant homologues from mammalian liver. The latter are highly promiscuous in their choice of substrates, while Af-OMO is unusually specific. This presents a puzzle: how do Af-OMO and other FMOs of the biosynthetic classes achieve such specificity? We have discovered substantial enhancement in the rate of O(2) activation in Af-OMO in the presence of L-arginine, which acts as a small molecule regulator. Such protein-level regulation could help explain how this and related biosynthetic FMOs manage to couple O(2) activation and substrate hydroxylation to each other and to the appropriate cellular conditions. Given the essentiality of Fe to Af and the avirulence of the Af-OMO gene knock out, inhibitors of Af-OMO are likely to be drug targets against this medically intractable pathogen.

  20. Modeling the Effects of Varying the Capacitance, Resistance, Temperature, and Frequency Dependence for HTS Josephson Junctions, DC SQUIDs and DC bi-SQUIDS

    DTIC Science & Technology

    2014-09-01

    loop areas between a = 0.52 and a = 1.52, and use only nearest neighbor coupling with M = 0.001. The top left image is the voltage over time of the...RESULTS First, we varied the frequency and held i c3 and !0 constant with only nearest neighbor coupling for M = 0.001 (see Figure 40). Here, x e (f) is the...Program at SSC Pacific funded this Applied Research project. . This is a work of the United States Government and therefore is not

  1. Glycosylation-dependent activation of epithelial sodium channel by solnatide.

    PubMed

    Shabbir, Waheed; Tzotzos, Susan; Bedak, Minela; Aufy, Mohammad; Willam, Anita; Kraihammer, Martin; Holzner, Alexander; Czikora, Istvan; Scherbaum-Hazemi, Parastoo; Fischer, Hendrik; Pietschmann, Helmut; Fischer, Bernhard; Lucas, Rudolf; Lemmens-Gruber, Rosa

    2015-12-15

    Dysfunction of the epithelial sodium channel (ENaC), which regulates salt and water homeostasis in epithelia, causes several human pathological conditions, including pulmonary oedema. This is a potentially lethal complication of acute lung injury at least partially caused by dysfunctional alveolar liquid clearance, which in turn impairs alveolar gas exchange. Solnatide (named TIP-peptide, AP301), a 17 residue peptide mimicking the lectin-like domain of TNF has been shown to activate ENaC in several experimental animal models of acute lung injury and is being evaluated as a potential therapy for pulmonary oedema. The peptide has recently completed phase 1 and 2a clinical trials. In this study, we identify a glycosylation-dependent mechanism that preserves ENaC function and expression. Since our previous data suggested that the pore-forming subunits of ENaC are essential for maximal current activation by solnatide, we performed single- and multi-N-glycosylation site mutations in αN232,293,312,397,511Q- and δN166,211,384Q-subunits, in order to identify crucial residues for interaction with solnatide within the extracellular loop of the channel. Additionally, we generated αL576X and αN232,293,312,397,511Q,L576X deletion mutants of ENaC-α, since we have previously demonstrated that the carboxy terminal domain of this subunit is also involved in its interaction with solnatide. In cells expressing αN232,293,312,397,511Q,L576Xβγ-hENaC or δN166,311,384Q,D552Xβγ-hENaC activation by solnatide, as measured in whole cell patch clamp mode, was completely abolished, whereas it was attenuated in αL576Xβγ-hENaC- and δD552Xβγ-hENaC-expressing cells. Taken together, our findings delineate an N-glycan dependent interaction between the TIP-peptide and ENaC leading to normalization of both sodium and fluid absorption in oedematous alveoli to non-oedematous levels.

  2. Binding Activity Prediction of Cyclin-Dependent Inhibitors.

    PubMed

    Saha, Indrajit; Rak, Benedykt; Bhowmick, Shib Sankar; Maulik, Ujjwal; Bhattacharjee, Debotosh; Koch, Uwe; Lazniewski, Michal; Plewczynski, Dariusz

    2015-07-27

    The Cyclin-Dependent Kinases (CDKs) are the core components coordinating eukaryotic cell division cycle. Generally the crystal structure of CDKs provides information on possible molecular mechanisms of ligand binding. However, reliable and robust estimation of ligand binding activity has been a challenging task in drug design. In this regard, various machine learning techniques, such as Support Vector Machine, Naive Bayesian classifier, Decision Tree, and K-Nearest Neighbor classifier, have been used. The performance of these heterogeneous classification techniques depends on proper selection of features from the data set. This fact motivated us to propose an integrated classification technique using Genetic Algorithm (GA), Rotational Feature Selection (RFS) scheme, and Ensemble of Machine Learning methods, named as the Genetic Algorithm integrated Rotational Ensemble based classification technique, for the prediction of ligand binding activity of CDKs. This technique can automatically find the important features and the ensemble size. For this purpose, GA encodes the features and ensemble size in a chromosome as a binary string. Such encoded features are then used to create diverse sets of training points using RFS in order to train the machine learning method multiple times. The RFS scheme works on Principal Component Analysis (PCA) to preserve the variability information of the rotational nonoverlapping subsets of original data. Thereafter, the testing points are fed to the different instances of trained machine learning method in order to produce the ensemble result. Here accuracy is computed as a final result after 10-fold cross validation, which also used as an objective function for GA to maximize. The effectiveness of the proposed classification technique has been demonstrated quantitatively and visually in comparison with different machine learning methods for 16 ligand binding CDK docking and rescoring data sets. In addition, the best possible features

  3. Voltage-dependent potassium channels in activated rat microglia.

    PubMed Central

    Nörenberg, W; Gebicke-Haerter, P J; Illes, P

    1994-01-01

    1. Voltage-dependent currents of untreated (proliferating) and lipopolysaccharide (LPS)-treated rat microglial cells in culture were recorded using the whole-cell patch-clamp technique. 2. Membrane potentials showed prominent peaks at -35 mV and -70 mV. Membrane potentials of LPS-treated cells alternated between the two values. This may be due to a negative slope region of the I-V relation resulting in two zero current potentials. 3. From a holding potential of -70 mV, hyperpolarizing steps evoked an inwardly rectifying current both in proliferating and in LPS-treated cells, while depolarizing steps below -50 mV evoked an outwardly rectifying current only in LPS-treated microglia. The currents were K+ selective, as indicated by their reversal potential of approximately 0 mV in symmetric K+ concentrations (150 mM both intra- and extracellularly) and the reversal potential of the outward tail currents of approximately -90 mV at a normal extracellular K+ concentration (4.5 mM). 4. The activation of the outward current could be fitted by Hodgkin-Huxley-type n4 kinetics. The time constant of activation depended on voltage. 5. The inactivation of the inward and outward currents could be fitted by a single exponential. The time constant of the inward current inactivation was dependent on voltage, whereas the time constant of the outward current inactivation was virtually independent of voltage, except near the threshold of activation. Recovery of the outward from inactivation was slow and could be fitted by two exponentials. Responses to depolarizing steps were stable at 0.125 Hz, but greatly decreased from the first to the second pulse at 1 Hz. 6. The inactivation of the inward, but not of the outward, current disappeared in a low Na(+)-containing medium (5 mM). The inward current was selectively inhibited by extracellular Cs+ and Ba2+. The outward current was selectively inhibited by Cd2+, 4-aminopyridine and charybdotoxin. Replacement of intracellular K+ by an

  4. Tracing the Physical Conditions in Active Galactic Nuclei with Time-Dependent Chemistry

    NASA Astrophysics Data System (ADS)

    Meijerink, Rowin; Spaans, Marco; Kamp, Inga; Aresu, Giambattista; Thi, Wing-Fai; Woitke, Peter

    2013-10-01

    We present an extension of the code ProDiMo that allows for a modeling of processes pertinent to active galactic nuclei and to an ambient chemistry that is time dependent. We present a proof-of-concept and focus on a few astrophysically relevant species, e.g., H+, H2+, and H3+; C+ and N+; C and O; CO and H2O; OH+, H2O+, and H3O+; and HCN and HCO+. We find that the freeze-out of water is strongly suppressed and that this affects the bulk of the oxygen and carbon chemistry occurring in the active galactic nucleus (AGN). The commonly used AGN tracer HCN/HCO+ is strongly time-dependent, with ratios that vary over orders of magnitude for times longer than 104 years. Through Atacama large millimeter array observations this ratio can be used to probe how the narrow-line region evolves under large fluctuations in the supermassive black hole accretion rate. Strong evolutionary trends, on time scales of 104-108 years are also found in species such as H3O+, CO, and H2O. These reflect, respectively, time-dependent effects in the ionization balance, the transient nature of the production of molecular gas, and the freeze-out/sublimation of water.

  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

    2015-08-06

    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).

  6. 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

  7. Spatially and Temporally Varying Associations between Temporary Outmigration and Natural Resource Availability in Resource-Dependent Rural Communities in South Africa: A Modeling Framework

    PubMed Central

    Leyk, Stefan; Maclaurin, Galen J.; Hunter, Lori M.; Nawrotzki, Raphael; Twine, Wayne; Collinson, Mark; Erasmus, Barend

    2012-01-01

    Migration-environment models tend to be aspatial within chosen study regions, although associations between temporary outmigration and environmental explanatory variables likely vary across the study space. This research extends current approaches by developing migration models considering spatial non-stationarity and temporal variation – through examination of the migration-environment association at nested geographic scales (i.e. whole-population, village, and subvillage) within a specific study site. Demographic survey data from rural South Africa, combined with indicators of natural resource availability from satellite imagery, are employed in a nested modeling approach that brings out distinct patterns of spatial variation in model associations derived at finer geographic scales. Given recent heightened public and policy concern with the human migratory implications of climate change, we argue that consideration of spatial variability adds important nuance to scientific understanding of the migration-environment association. PMID:23008525

  8. 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

  9. 77 FR 24268 - Agency Information Collection (Dependents' Application for VA Educational Benefits) Activity...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-23

    ... AFFAIRS Agency Information Collection (Dependents' Application for VA Educational Benefits) Activity Under... INFORMATION: Title: Dependents' Application for VA Educational Benefits (Under Provisions of Chapters 33 and... spouses and children of veterans or servicemembers to apply for Survivors' and Dependents'...

  10. 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.

  11. 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

  12. 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.

  13. Substrate Activation in Flavin-Dependent Thymidylate Synthase

    PubMed Central

    2015-01-01

    Thymidylate is a critical DNA nucleotide that has to be synthesized in cells de novo by all organisms. Flavin-dependent thymidylate synthase (FDTS) catalyzes the final step in this de novo production of thymidylate in many human pathogens, but it is absent from humans. The FDTS reaction proceeds via a chemical route that is different from its human enzyme analogue, making FDTS a potential antimicrobial target. The chemical mechanism of FDTS is still not understood, and the two most recently proposed mechanisms involve reaction intermediates that are unusual in pyrimidine biosynthesis and biology in general. These mechanisms differ in the relative timing of the reaction of the flavin with the substrate. The consequence of this difference is significant: the intermediates are cationic in one case and neutral in the other, an important consideration in the construction of mechanism-based enzyme inhibitors. Here we test these mechanisms via chemical trapping of reaction intermediates, stopped-flow, and substrate hydrogen isotope exchange techniques. Our findings suggest that an initial activation of the pyrimidine substrate by reduced flavin is required for catalysis, and a revised mechanism is proposed on the basis of previous and new data. These findings and the newly proposed mechanism add an important piece to the puzzle of the mechanism of FDTS and suggest a new class of intermediates that, in the future, may serve as targets for mechanism-based design of FDTS-specific inhibitors. PMID:25025487

  14. KIF4 motor regulates activity-dependent neuronal survival by suppressing PARP-1 enzymatic activity.

    PubMed

    Midorikawa, Ryosuke; Takei, Yosuke; Hirokawa, Nobutaka

    2006-04-21

    In brain development, apoptosis is a physiological process that controls the final numbers of neurons. Here, we report that the activity-dependent prevention of apoptosis in juvenile neurons is regulated by kinesin superfamily protein 4 (KIF4), a microtubule-based molecular motor. The C-terminal domain of KIF4 is a module that suppresses the activity of poly (ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme known to maintain cell homeostasis by repairing DNA and serving as a transcriptional regulator. When neurons are stimulated by membrane depolarization, calcium signaling mediated by CaMKII induces dissociation of KIF4 from PARP-1, resulting in upregulation of PARP-1 activity, which supports neuron survival. After dissociation from PARP-1, KIF4 enters into the cytoplasm from the nucleus and moves to the distal part of neurites in a microtubule-dependent manner. We suggested that KIF4 controls the activity-dependent survival of postmitotic neurons by regulating PARP-1 activity in brain development.

  15. Contextualized Approach to Language and Literacy (Project CALL): Capitalizing on Varied Activities and Contexts to Teach Early Literacy Skills

    ERIC Educational Resources Information Center

    Culatta, Barbara; Hall, Kendra; Kovarsky, Dana; Theadore, Geraldine

    2007-01-01

    In a federally funded early literacy project, various instructional activities were embedded into an array of classroom contexts to provide supplemental literacy instruction and to contrast children's engagement and participation in different contexts and participant structures. The study was conducted with English- and Spanish-speaking children…

  16. 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…

  17. Effect of using repurposed science-rich feature films with varying levels of student activity in middle grades science instruction

    NASA Astrophysics Data System (ADS)

    Cavanaugh, Terence William

    This study provided an initial investigation into the use of repurposed content-rich entertainment videos (versus traditional educational videos) presented in either an active or passive educational setting. Eight classes of seventh grade general science students (n = 361) were randomly assigned to one of four video treatment groups: (1) repurposed content-rich entertainment video in a passive setting, (2) repurposed content-rich entertainment video in an active setting, (3) traditional educational video in a passive setting, and (4) traditional educational video in an active setting. The subject matter of the videos focused on basic chemistry, scientific method, and the nature of life. The repurposed content-rich entertainment groups watched a StarTrek the Next Generation episode, and the traditional educational video groups watched videos from NASA and the Understanding Science Corporation. Students completed a knowledge-based pretest and an initial attitude survey prior to the treatment. During the treatment, all participants watched the videos, discussed the science content, and answered directed questions. Active setting groups discussed and answered questions during the video, while the passive setting groups discussed and answered questions after the video. The treatment period lasted approximately 135 minutes. Immediately following treatment, participants received a knowledge-based posttest and an attitude survey. Three weeks after treatment, retention tests and follow-up surveys were administered. Test and survey data were analyzed using single factor and repeated measures ANOVA followed by post hoc tests. Significant gains (p < 0.05) in test scores were found for repurposed content-rich entertainment video over traditional educational video groups. No significant differences were found in test scores between the active and passive setting groups. When the variables were combined, additional effects were noted. Specifically, significant differences were

  18. 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.

  19. DNA-directed alkylating agents. 1. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the reactivity of the mustard.

    PubMed

    Gourdie, T A; Valu, K K; Gravatt, G L; Boritzki, T J; Baguley, B C; Wakelin, L P; Wilson, W R; Woodgate, P D; Denny, W A

    1990-04-01

    A series of DNA-targeted aniline mustards have been prepared, and their chemical reactivity and in vitro and in vivo cytotoxicity have been evaluated and compared with that of the corresponding simple aniline mustards. The alkylating groups were anchored to the DNA-intercalating 9-aminoacridine chromophore by an alkyl chain of fixed length attached at the mustard 4-position through a link group X, while the corresponding simple mustards possessed an electronically identical small group at this position. The link group was varied to provide a series of compounds of similar geometry but widely differing mustard reactivity. Variation in biological activity should then largely be a consequence of this varying reactivity. Rates of mustard hydrolysis in the two series related only to the electronic properties of the link group, with attachment of the intercalating chromophore having no effect. The cytotoxicities of the simple mustards correlated well with group electronic properties (with a 200-300-fold range in IC50S). The corresponding DNA-targeted mustards were much more potent (up to 100-fold), but their IC50 values varied much less with linker group electronic properties. Most of the DNA-targeted mustards showed in vivo antitumor activity, being both more active and more dose-potent than either the corresponding untargeted mustards and chlorambucil. These results show that targeting alkylating agents to DNA by attachment to DNA-affinic units may be a useful strategy.

  20. 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

    2016-07-29

    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.

  1. 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

  2. History-dependent changes in entrainment of the activity rhythm in the Syrian hamster (Mesocricetus auratus).

    PubMed

    Chiesa, Juan J; Anglès-Pujolràs, Montserrat; Díez-Noguera, Antoni; Cambras, Trinitat

    2006-02-01

    The authors have studied the activity rhythm of Syrian hamsters exposed to square LD cycles with a 22-h period (T22) with the aim of testing the effects of the previous history on the rhythmic pattern. To do so, sequential changes of different lighting environments were established, followed by the same LD condition. Also, the protocol included T22 cycles with varying lighting contrasts to test the extent to which a computational model predicts experimental outcomes. At the beginning of the experiment, exposure to T22 with 300 lux and dim red light occurring respectively at photophase and scotophase (LD300/dim red) mainly generated relative coordination. Subsequent transfer to cycles with approximately 0.1-lux dim light during the scotophase (LD300/0.1) promoted entrainment to T22. However, a further reduction in light intensity to 10 lux during the photophase (LD10/0.1) generated weak and unstable T22 rhythms. When, after that, animals were transferred again to the initial LD300/dim red cycles, the amplitude of the rhythm still remained very low, and the phases were very unstable. Exposure to constant darkness partially restored the activity rhythm, and when, afterwards, the animals were submitted again to LD300/dim red cycles, a robust T22 rhythm appeared. The results demonstrate history-dependent changes in the hamster circadian system because the locomotor activity pattern under the same T22 cycle can show relative coordination or unstable or robust entrainment depending on the prior lighting condition. This suggests that the circadian system responds to environmental stimuli depending on its previous history. Moreover, computer simulations allow the authors to predict entrainment under LD300/0.1 cycles and indicate that most of the patterns observed in the animals due to the light in the scotophase can be explained by different degrees of coupling among the oscillators of the circadian system.

  3. 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.

  4. 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.

  5. Organ-dependent response in antioxidants, myoglobin and neuroglobin in goldfish (Carassius auratus) exposed to MC-RR under varying oxygen level.

    PubMed

    Okogwu, Okechukwu Idumah; Xie, Ping; Zhao, Yanyan; Fan, Huihui

    2014-10-01

    Cyanobacterial bloom, a common phenomenon nowadays often results in the depletion of dissolved oxygen (hypoxia) and releases microcystin-RR (MC-RR) in the water. Information on the combined effects of MC-RR and hypoxia on the goldfish is lacking, therefore, this study is aimed at evaluating the effect of two doses of MC-RR on the antioxidants and globin mRNA of goldfish under normoxia, hypoxia and reoxygenation. The result showed that MC-RR at both doses (50 and 200 μg kg(-1) body weight) significantly (p<0.05) induced superoxide dismutase activities in the liver and kidney but catalase activities and total antioxidant capacity were low in these organs during hypoxia and reoxygenation compared to normoxia and control. Myoglobin and neuroglobin mRNAs in MC-RR group were significantly induced in the brain only and are believed to protect the brain from oxidative damage. However, other organs were unprotected and extensive damage was observed in the liver cells. Our results clearly demonstrated that MC-RR and hypoxia-reoxygenation transitions were synergistically harmful to the goldfish and could impair its adaptation to hypoxia, especially during reoxygenation.

  6. Fluorosis varied treatment options

    PubMed Central

    Sherwood, I Anand

    2010-01-01

    Fluorosis has been reported way back in 1901. The treatment options for fluorosis are varied depending upon individual cases. This article comes from Madurai in India where its surrounding towns are fluorosis-prone zones. The purpose of this article is to report various treatment options available for dental fluorosis; this is the first time that complete full mouth rehabilitation for dental fluorosis is being reported. This article also dwells on the need for the dentists to be aware of their local indigenous pathologies to treat it in a better manner. PMID:20582220

  7. 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.

  8. 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.

  9. 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.

  10. Multistability of memristive Cohen-Grossberg neural networks with non-monotonic piecewise linear activation functions and time-varying delays.

    PubMed

    Nie, Xiaobing; Zheng, Wei Xing; Cao, Jinde

    2015-11-01

    The problem of coexistence and dynamical behaviors of multiple equilibrium points is addressed for a class of memristive Cohen-Grossberg neural networks with non-monotonic piecewise linear activation functions and time-varying delays. By virtue of the fixed point theorem, nonsmooth analysis theory and other analytical tools, some sufficient conditions are established to guarantee that such n-dimensional memristive Cohen-Grossberg neural networks can have 5(n) equilibrium points, among which 3(n) equilibrium points are locally exponentially stable. It is shown that greater storage capacity can be achieved by neural networks with the non-monotonic activation functions introduced herein than the ones with Mexican-hat-type activation function. In addition, unlike most existing multistability results of neural networks with monotonic activation functions, those obtained 3(n) locally stable equilibrium points are located both in saturated regions and unsaturated regions. The theoretical findings are verified by an illustrative example with computer simulations.

  11. Task dependence of decision- and choice-related activity in monkey oculomotor thalamus

    PubMed Central

    Costello, M. Gabriela; Zhu, Dantong; May, Paul J.

    2015-01-01

    Oculomotor signals circulate within putative recurrent feedback loops that include the frontal eye field (FEF) and the oculomotor thalamus (OcTh). To examine how OcTh contributes to visuomotor control, and perceptually informed saccadic choices in particular, neural correlates of perceptual judgment and motor selection in OcTh were evaluated and compared with those previously reported for FEF in the same subjects. Monkeys performed three tasks: a choice task in which perceptual decisions are urgent, a choice task in which identical decisions are made without time pressure, and a single-target, delayed saccade task. The OcTh yielded far fewer task-responsive neurons than the FEF, but across responsive pools, similar neuron types were found, ranging from purely visual to purely saccade related. Across such types, the impact of the perceptual information relevant to saccadic choices was qualitatively the same in FEF and OcTh. However, distinct from that in FEF, activity in OcTh was strongly task dependent, typically being most vigorous in the urgent task, less so in the easier choice task, and least in the single-target task. This was true for responsive and nonresponsive cells alike. Neurons with exclusively motor-related activity showed strong task dependence, fired less, and differed most patently from their FEF counterparts, whereas those that combined visual and motor activity fired most similarly to their FEF counterparts. The results suggest that OcTh activity is more distantly related to saccade production per se, because its degree of commitment to a motor choice varies markedly as a function of ongoing cognitive or behavioral demands. PMID:26467516

  12. Fyn phosphorylates AMPK to inhibit AMPK activity and AMP-dependent activation of autophagy

    PubMed Central

    Yamada, Eijiro; Okada, Shuichi; Bastie, Claire C.; Vatish, Manu; Nakajima, Yasuyo; Shibusawa, Ryo; Ozawa, Atsushi; Pessin, Jeffrey E.; Yamada, Masanobu

    2016-01-01

    We previously demonstrated that proto-oncogene Fyn decreased energy expenditure and increased metabolic phenotypes. Also Fyn decreased autophagy-mediated muscle mass by directly inhibiting LKB1 and stimulating STAT3 activities, respectively. AMPK, a downstream target of LKB1, was recently identified as a key molecule controlling autophagy. Here we identified that Fyn phosphorylates the α subunit of AMPK on Y436 and inhibits AMPK enzymatic activity without altering the assembly state of the AMPK heterotrimeric complex. As pro-inflammatory mediators are reported modulators of the autophagy processes, treatment with the pro-inflammatory cytokine TNFα resulted in 1) increased Fyn activity 2) stimulated Fyn-dependent AMPKα tyrosine phosphorylation and 3) decreased AICAR-dependent AMPK activation. Importantly, TNFα induced inhibition of autophagy was not observed when AMPKα was mutated on Y436. 4) These data demonstrate that Fyn plays an important role in relaying the effects of TNFα on autophagy and apoptosis via phosphorylation and inhibition of AMPK. PMID:27626315

  13. Non-conductive and miniature fiber-optic imaging system for real-time detection of neuronal activity in time-varying electromagnetic fields.

    PubMed

    Saito, Atsushi; Takahashi, Masayuki; Jimbo, Yasuhiko; Nakasono, Satoshi

    2017-01-15

    Establishing an appropriate threshold value for neuronal modulation by time-varying electromagnetic field (EMF) exposure is important for developing international guidelines to protect against the potential health effects, and to design a variety of medical devices. However, it is technically difficult to achieve real-time detection of neuronal activity under repetitive and long-term exposure to EMF. For this purpose, we developed a non-conductive, miniature, and flexible fiber-optic imaging system that does not affect the electromagnetic noise, induction heating, or vibration in a high-intensity and repetitive time-varying EMF exposure. Using the proposed system, we succeeded at real-time detection of spontaneous Ca(2+) oscillations in single neuronal and glial cells, as well as synchronized bursting activities of multiple neuronal networks at a micrometer-scale and millisecond-order spatiotemporal resolution during long-term EMF exposure (sinusoidal wave, 20kHz, 8.6mT, >30min). The results indicated that short-term (<5min) exposure-related neuronal modulation was not detectable; however, long-term (15-30min) exposure was observed to depress neuronal activities. In addition, the simultaneous and real-time recording of neuronal activity and the environmental temperature revealed that the neuronal modulation was accompanied by a 0.5-1°C rise in the temperature of the culture medium induced by the heat generation of exposure coils. These findings suggest that our real-time imaging system can be used for precise evaluation of the threshold values and clarification of the mechanisms of neuronal modulation induced by time-varying EMF exposure.

  14. Do Training Programs Work? An Assessment of Pharmacists Activities in the Field of Chemical Dependency.

    ERIC Educational Resources Information Center

    Brooks, Valerie G.; Brock, Tina Penick; Ahn, Jungeun

    2001-01-01

    Seeks to determine if pharmacists who attended a chemical dependency training program were performing more chemical dependency related activities. Results reveal that participants were more likely to perform the following activities: lecture to community groups about chemical dependency; participate in a pharmacists' recovery program; provide…

  15. Coexistence and local μ-stability of multiple equilibrium points for memristive neural networks with nonmonotonic piecewise linear activation functions and unbounded time-varying delays.

    PubMed

    Nie, Xiaobing; Zheng, Wei Xing; Cao, Jinde

    2016-12-01

    In this paper, the coexistence and dynamical behaviors of multiple equilibrium points are discussed for a class of memristive neural networks (MNNs) with unbounded time-varying delays and nonmonotonic piecewise linear activation functions. By means of the fixed point theorem, nonsmooth analysis theory and rigorous mathematical analysis, it is proven that under some conditions, such n-neuron MNNs can have 5(n) equilibrium points located in ℜ(n), and 3(n) of them are locally μ-stable. As a direct application, some criteria are also obtained on the multiple exponential stability, multiple power stability, multiple log-stability and multiple log-log-stability. All these results reveal that the addressed neural networks with activation functions introduced in this paper can generate greater storage capacity than the ones with Mexican-hat-type activation function. Numerical simulations are presented to substantiate the theoretical results.

  16. Ischemia Induced Neutrophil Activation and Diapedesis is Lipoxygenase Dependent.

    DTIC Science & Technology

    2007-11-02

    activity in mediating PMN activation and diapedesis . Anesthetized rabbits (n = 8) underwent 3 h of bilateral hindlimb ischemia. At 10 min of reperfusion...enhanced response of 337% to PMA stimulation. To study diapedesis , plasma collected at 10 min of reperfusion was introduced into plastic chambers taped...abolished PMN activation (51 +/- 12 fM DCF/cell) and ischemic plasma induced diapedesis into the plastic chamber (38 +/- 18 PMN/mm(exp 3)).

  17. Cytotoxic activity in children with insulin-dependent diabetes mellitus.

    PubMed

    Lorini, R; Moretta, A; Valtorta, A; d'Annunzio, G; Cortona, L; Vitali, L; Bozzola, M; Severi, F

    1994-02-01

    We determined the percentage of circulating natural killer (NK) cells, using the monoclonal antibodies anti-CD57 and anti-CD16, NK cytotoxic activity (lytic units/10(6)) and lymphokine-activated killer (LAK) activity in 25 IDDM patients aged 3-23 years, 12 with disease for < 1 year (Group I) and 13 with disease for > 3 years (Group II). Nine age-matched healthy subjects served as controls. The percentage of CD57+ cells was similar in IDDM patients and controls, while the percentage of CD16+ cells was lower in IDDM patients (P < 0.05) than in controls. NK cell cytotoxic activity was lower in IDDM patients than in controls (P < 0.01), in Group I and II compared with controls (P < 0.005). LAK activity was similar in IDDM patients and in controls. No correlation was found between NK cytotoxic activity and metabolic control, HLA typing, while a negative correlation was found between NK cytotoxic activity and insulin requirement (P < 0.05). The decreased NK cytotoxic activity observed in our patients, in particular in long-standing diabetics, with normal NK cell number, could be due to a qualitative defect of the NK cells, or to a deficient IL-2 and/or TNF-alpha production, or to a immunomodulatory or immunosuppressing effect of insulin.

  18. Insulin-Dependent Activation of MCH Neurons Impairs Locomotor Activity and Insulin Sensitivity in Obesity.

    PubMed

    Hausen, A Christine; Ruud, Johan; Jiang, Hong; Hess, Simon; Varbanov, Hristo; Kloppenburg, Peter; Brüning, Jens C

    2016-12-06

    Melanin-concentrating-hormone (MCH)-expressing neurons (MCH neurons) in the lateral hypothalamus (LH) are critical regulators of energy and glucose homeostasis. Here, we demonstrate that insulin increases the excitability of these neurons in control mice. In vivo, insulin promotes phosphatidylinositol 3-kinase (PI3K) signaling in MCH neurons, and cell-type-specific deletion of the insulin receptor (IR) abrogates this response. While lean mice lacking the IR in MCH neurons (IR(ΔMCH)) exhibit no detectable metabolic phenotype under normal diet feeding, they present with improved locomotor activity and insulin sensitivity under high-fat-diet-fed, obese conditions. Similarly, obesity promotes PI3 kinase signaling in these neurons, and this response is abrogated in IR(ΔMCH) mice. In turn, acute chemogenetic activation of MCH neurons impairs locomotor activity but not insulin sensitivity. Collectively, our experiments reveal an insulin-dependent activation of MCH neurons in obesity, which contributes via distinct mechanisms to the manifestation of impaired locomotor activity and insulin resistance.

  19. 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,...

  20. 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...

  1. Adolescent brain activation: dependence on sex, dietary satiation, and restraint.

    PubMed

    Varley-Campbell, Joanna L; Fulford, Jonathan; Moore, Melanie S; Williams, Craig A

    2017-03-30

    The study aimed to explore how both sex and dietary restraint impacts brain activation in response to visual food stimuli in young adolescents (12-13 years) under fed and fasted conditions. Food and non-food images were viewed by 15 boys and 14 girls, while functional magnetic resonance images were acquired. The adolescents were either fasted or in a satiated (fed) state following a randomized crossover study design. When satiation state was not considered, girls showed significantly greater brain activity than boys in regions associated with executive function and decision making, working memory, and self-awareness. In contrast, when either fasted or fed states were considered separately, boys showed significantly increased brain activity in regions linked to executive function, self-awareness, and decision making than the girls. When fasted, compared to unrestrained eaters, restrained individuals showed heightened activation in regions connected to executive function and decision making, with areas associated with self-assessment showing increased activity for unrestrained eaters relative to restrained under fed conditions. These findings highlight important differences in adolescent brain activity and support further investigations to gain greater insight into how these differences might evolve with age.

  2. Modeling spontaneous activity in the developing spinal cord using activity-dependent variations of intracellular chloride.

    PubMed

    Marchetti, Cristina; Tabak, Joel; Chub, Nikolai; O'Donovan, Michael J; Rinzel, John

    2005-04-06

    We investigated how spontaneous activity is generated in developing, hyperexcitable networks. We focused our study on the embryonic chick spinal cord, a preparation that exhibits rhythmic discharge on multiple timescales: slow episodes (lasting minutes) and faster intraepisode cycling (approximately 1 Hz frequency). For this purpose, we developed a mean field model of a recurrent network with slow chloride dynamics and a fast depression variable. We showed that the model, in addition to providing a biophysical mechanism for the slow dynamics, was able to account for the experimentally observed activity. The model made predictions on how interval and duration of episodes are affected when changing chloride-mediated synaptic transmission or chloride flux across cell membrane. These predictions guided experiments, and the model results were compared with experimental data obtained with electrophysiological recordings. We found agreement when transmission was affected through changes in synaptic conductance and good qualitative agreement when chloride flux was varied through changes in external chloride concentration or in the rate of the Na+-K+-2Cl- cotransporter. Furthermore, the model made predictions about the time course of intracellular chloride concentration and chloride reversal potential and how these are affected by changes in synaptic conductance. Based on the comparison between modeling and experimental results, we propose that chloride dynamics could be an important mechanism in rhythm generation in the developing chick spinal cord.

  3. Charge dependent photodynamic activity of alanine based zinc phthalocyanines.

    PubMed

    Wang, Ao; Li, Yejing; Zhou, Lin; Yuan, Linxin; Lu, Shan; Lin, Yun; Zhou, Jiahong; Wei, Shaohua

    2014-12-01

    In this paper, to minimize the effects of different structure, three alanine-based zinc phthalocyanines (Pcs) of differing charges were engineered and synthesized with the same basic structure. On this premise, the relationship between nature of charge and photodynamic activity was studied. Besides, further verification and explanation of some inconsistent results were also carried out. The results showed that charge can influence the aggregation state, singlet oxygen generation ability and cellular uptake of Pcs, thereby affecting their photodynamic activity. In addition, the biomolecules inside cells may interact with Pcs of differing charges, which can also influence the aggregation state and singlet oxygen generation of the Pcs, and then influence the relationship between nature of charge and photodynamic activity.

  4. Batch and column adsorption of herbicide fluroxypyr on different types of activated carbons from water with varied degrees of hardness and alkalinity.

    PubMed

    Pastrana-Martínez, L M; López-Ramón, M V; Fontecha-Cámara, M A; Moreno-Castilla, C

    2010-02-01

    There has been little research into the effects of the water hardness and alkalinity of surface waters on the adsorption of herbicides on activated carbons. The aim of this study was to determine the influence of these water characteristics on fluroxypyr adsorption on different activated carbons. At low fluroxypyr surface concentrations, the amount adsorbed from distilled water was related to the surface hydrophobicity. Surface area of carbons covered by fluroxypyr molecules ranged from 60 to 65%. Variations in fluroxypyr solubility with water hardness and alkalinity showed a salting-in effect. Calcium, magnesium and bicarbonate ions were adsorbed to a varied extent on the activated carbons. The presence of fluroxypyr in solution decreased their adsorption due to a competition effect. K(F) from the Freundlich equation linearly increased with water hardness due to salt-screened electrostatic repulsions between charged fluroxypyr molecules. The amount adsorbed from distilled water was largest at high fluroxypyr solution concentrations, because there was no competition between inorganic ions and fluroxypyr molecules. The column breakthrough volume and the amount adsorbed at breakthrough were smaller in tap versus distilled water. Carbon consumption was lower with activated carbon cloth than with the use of granular activated carbon.

  5. Calcium-dependent activation of mitochondrial metabolism in mammalian cells

    PubMed Central

    Gaspers, Lawrence D.; Thomas, Andrew P.

    2008-01-01

    Endogenous fluorophores provide a simple, but elegant means to investigate the relationship between agonist-evoked Ca2+ signals and the activation of mitochondrial metabolism. In this article, we discuss the methods and strategies to measure cellular pyridine nucleotide and flavoprotein fluorescence alone or in combination with Ca2+-sensitive indicators. These methods were developed using primary cultured hepatocytes and neurons, which contain relatively high levels of endogenous fluorophores and robust metabolic responses. Nevertheless, these methods are amendable to a wide variety of primary cell types and cell lines that maintain active mitochondrial metabolism. PMID:18854213

  6. Task-dependent Modulations of Prefrontal and Hippocampal Activity during Intrinsic Word Production

    PubMed Central

    Whitney, Carin; Weis, Susanne; Krings, Timo; Huber, Walter; Grossman, Murray; Kircher, Tilo

    2009-01-01

    Functional imaging studies of single word production have consistently reported activation of the lateral prefrontal and cingulate cortex. Its contribution has been shown to be sensitive to task demands, which can be manipulated by the degree of response specification. Compared with classical verbal fluency, free word association relies less on response restrictions but to a greater extent on associative binding processes, usually subserved by the hippocampus. To elucidate the relevance of the frontal and medial-temporal areas during verbal retrieval tasks, we applied varying degrees of response specification. During fMRI data acquisition, 18 subjects performed a free verbal association (FVA), a semantic verbal fluency (SVF) task, and a phonological verbal fluency (PVF) task. Externally guided word production served as a baseline condition to control for basic articulatory and reading processes. As expected, increased brain activity was observed in the left lateral and bilateral medial frontal cortices for SVF and PVF. The anterior cingulate gyrus was the only structure common to both fluency tasks in direct comparison to the less restricted FVA task. The hippocampus was engaged during associative and semantic retrieval. Interestingly, hippocampal activity was selectively evident during FVA in direct comparison to SVF when it was controlled for stimulus–response relations. The current data confirm the role of the left prefrontal–cingulate network in constrained word production. Hippocampal activity during spontaneous word production is a novel finding and seems to be dependent on the retrieval process (free vs. constrained) rather than the variety of stimulus–response relationships that is involved. PMID:18578599

  7. 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

  8. 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.

  9. 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…

  10. Instruction-based response activation depends on task preparation.

    PubMed

    Liefooghe, Baptist; De Houwer, Jan; Wenke, Dorit

    2013-06-01

    An increasing number of studies have demonstrated that a response in one task can be activated automatically on the basis merely of instructed stimulus-response (S-R) mappings belonging to another task. Such instruction-based response activations are considered to be evidence for the formation of S-R associations on the basis of the S-R mappings for an upcoming, but not yet executed, task. A crucial but somewhat neglected assumption is that instructed S-R associations are formed only under conditions that impose a sufficient degree of task preparation. Accordingly, in the present study we investigated the relation between task preparation and the instruction-based task-rule congruency effect, which is an index of response activation on the basis of instructions. The results from two experiments demonstrated that merely instructed S-R mappings of a particular task only elicit instruction-based response activations when that task is prepared for to a sufficient degree. Implications are discussed for the representation of instructed S-R mappings in working memory.

  11. Dependence of heating rates of thermal activation on thermal activation characteristics of 110 °C TL peak of quartz: A simulation approach

    NASA Astrophysics Data System (ADS)

    Oniya, Ebenezer O.

    2015-10-01

    This work was undertaken to investigate heating rates effect of thermal activation on the thermal activation characteristic (TAC) by a way of numerical simulation of an existing model. This was done by monitoring charge distributions among trapping states (electron and hole traps), both immediately after thermal activation and after irradiation of test dose. Previously observed 'early activation' and 'late activation' of TACs have been numerically observed in this work by following the exact experimental procedures of varying heating rates of thermal activation that produced them. Indirect thermal transfer signal from high temperature-TL peak at the end of thermal activation was observed to also contribute to the sensitization in the TACs, apart from the popular pre-dose effect. This contribution to the TACs from indirect thermal transfer signal from high temperature-TL peak increases with heating rate utilised for thermal activation. Recombination rate of evicted electron from high temperature-TL peak with holes during the thermal activation resulted into (i) increased sensitization with heating rates of thermal activation and (ii) direct dependence of temperature at glow-peak maximum intensity (Tm) of high temperature TL peak and heating rates of thermal activation on the peak position of the TACs peak. The impact of the electrons loss to recombination during the short irradiation increases with the heating rates of the thermal activation. The overall results have been employed to shed more light on the pre-dose phenomenon and its applications in dating.

  12. Varying DNA base-pair size in subangstrom increments: evidence for a loose, not large, active site in low-fidelity Dpo4 polymerase.

    PubMed

    Mizukami, Shin; Kim, Tae Woo; Helquist, Sandra A; Kool, Eric T

    2006-03-07

    We describe the first systematic test of steric effects in the active site of a Y-family DNA polymerase, Dpo4. It has been hypothesized that low-fidelity repair polymerases in this family more readily accept damaged or mismatched base pairs because of a sterically more open active site, which might place lower geometric constraints on the incipient pair. We have tested the origin of low fidelity by use of five nonpolar thymidine analogues that vary in size by a total of 1.0 A over the series. The efficiency and fidelity of base-pair synthesis was measured by steady-state kinetics for single-nucleotide insertions. Analogues were examined both as incoming deoxynucleoside triphosphate (dNTP) derivatives and as template bases. The results showed that Dpo4 preferred to pair the thymidine shape mimics with adenine and, surprisingly, the preferred size was at the center of the range, the same optimum size as recently found for the high-fidelity Klenow fragment (Kf) of Escherichia coli DNA Pol I. However, the size preference with Dpo4 was quite small, varying by a factor of only 30-35 from most to least efficient thymidine analogue. This is in marked contrast to Kf, which showed a rigid size preference, varying by 1100-fold from best to worst. The fidelity for the non-hydrogen-bonding analogues in pairing with A over T, C, or G was much lower in Dpo4 than in the previous high-fidelity enzyme. The data establish that, unlike Kf, Dpo4 has very low steric selectivity and that steric effects alone cannot explain the fidelity (albeit low) that Dpo4 has for a correct base pair; the findings suggest that hydrogen bonds may be important in determining the fidelity of this enzyme. The results suggest that the low steric selectivity of this enzyme is the result of a conformationally flexible or loose active site that adapts with small energetic cost to different base-pair sizes (as measured by the glycosidic C1'-C1' distance), rather than a spatially large active site.

  13. 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).

  14. 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...

  15. Cytokine dependent and independent iNKT cell activation

    PubMed Central

    Reilly, Emma C.; Wands, Jack R.; Brossay, Laurent

    2010-01-01

    Invariant NKT (iNKT) cells have been extensively studied throughout the last decade due to their ability to polarize and amplify the downstream immune response. Only recently however, have the various mechanisms underlying NKT cell activation begun to unfold. iNKT cells have the ability to respond as innate immune cells with minimal TCR involvement as well as through direct TCR recognition of glycolipid antigens. Additionally, the existence of several subsets of iNKT cells creates the potential for other unique pathways, which are not yet clearly defined. Here we provide an overview of the known mechanisms of invariant NKT cell activation, focusing on cytokine driven pathways and the resulting cytokine responses. PMID:20554220

  16. Nitrogen-dependent calcineurin activation in the yeast Hansenula polymorpha.

    PubMed

    Rodríguez, Celia; Galindo, Luis R; Siverio, José M

    2013-04-01

    Non-preferred nitrogen sources, unlike preferred ones, raised total cell Ca(2+) content and expression of ENA1, a very well-known calcineurin-regulated gene. This indicates calcineurin activation is regulated by nitrogen source. Nitrogen catabolite repression (NCR) and nitrate induction mechanisms, both regulating nitrate assimilation in Hansenula polymorpha, are controlled by calcineurin. Concerning NCR, lack of calcineurin (cnb1 mutant) decreased nitrate-assimilation gene expression, levels of the transcription factor Gat1 and growth in several nitrogen sources. We found that the role of calcineurin in NCR was mediated by Crz1 via Gat1. Regarding nitrate induction, calcineurin also affects the levels of transcription factors Gat2 and Yna2 involved in this process. We conclude that Ca(2+) and calcineurin play a central role in nitrogen signalling and assimilation. Thus, the nitrogen source modulates Ca(2+) content and calcineurin activation. Calcineurin in turn regulates nitrogen assimilation genes.

  17. Screening of solvent dependent antibacterial activity of Prunus domestica.

    PubMed

    Yaqeen, Zahra; Naqvi, Naim-ul-Hasan; Sohail, Tehmina; Rehman, Zakir-ur; Fatima, Nudrat; Imran, Hina; Rehman, Atiqur

    2013-03-01

    Fruit of Prunus domestica was extracted in ethanol. The ethanol extract was further extracted with two solvents ethyl acetate and chloroform. The crude ethanol extract and two fractions (ethyl acetate and chloroform) were screened for their antibacterial activity using the agar well diffusion method .They were tested against nine bacteria; five Gram positive bacteria (Staphylococcus aureus, Streptococcuc intermedius, Bacillus cereus, Bacillus pumilus) and four Gram negative bacteria (Eschrichia coli, Proteus mirabilis Shigella flexneri, Salmonella typhi and Klebsiela pneumoniae). The susceptibility of microorganisms to all three fractions was compared with each other and with standard antibiotic (Ampicillin) Among all fractions ethyl acetate exhibited highest antibacterial activity (average zone of inhibition 34.57mm ± 1.3) while ethyl alcohol exhibited least antibacterial activity (average zone of inhibition 17.42mm ± 3.3). Minimum inhibitory concentration of ethanol, ethyl acetate and chloroform fractions was found in the range of 78 μ g/ml to 2500 μ gl/ml against gram positive and gram negative bacteria.

  18. 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.

  19. 75 FR 61251 - Proposed Information Collection (Statement of Dependency of Parent(s)) Activity: Comment Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-04

    ... AFFAIRS Proposed Information Collection (Statement of Dependency of Parent(s)) Activity: Comment Request... solicits comments on the information needed to establish a claimant's parents' dependency. DATES: Written... techniques or the use of other forms of information technology. Title: Statement of Dependency of...

  20. 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.

  1. Age dependent changes in tissue glutathione depleting activity of ethanol

    SciTech Connect

    Makar, A.B.; Currie, R.B.

    1986-03-01

    Hepatic glutathione (GSH) plays a major role in protecting the liver against the toxic effects of a variety of chemicals. Decreased GSH can increase liver susceptibility to the toxic actions of such agents. The purpose of this study was to examine whether age or the feeding status of animals alter the steady-state hepatic GSH concentrations. The authors also tested the ability of ethanol to lower GSH under these conditions. Male Sprague-Dawley rats between 3 and 34 weeks of age were used. Animals designed fasted were allowed water, but no food for the 24 hours preceding sacrifice. Six hours before sacrifice, ethanol or saline was injected i.p. The rats were always sacrificed between 12:00 noon and 1:00 P.M. to avoid the effects of diurnal variation of tissue GSH. Glutathione concentrations were determined in the liver using Ellman's reagent. Results indicated that the steady-state hepatic GSH in fed rats increased as a function of age, whereas fasted rats showed minimal changes. The ability of ethanol to lower hepatic GSH also increased with age. In 3 week old rats, GSH decreased 22% while in 34 week old rats it decreased 52%. The authors conclude that both the steady-state concentration of GSH and the GSH-lowering ability of ethanol are highly dependent on the age of as well as on the feeding status of rats.

  2. 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

  3. Regulation of spine and synapse formation by activity-dependent intracellular signaling pathways

    PubMed Central

    Saneyoshi, Takeo; Fortin, Dale A; Soderling, Thomas R

    2010-01-01

    Formation of the human brain during embryonic and postnatal development is an extraordinarily complex process resulting at maturity in billions of neurons with trillions of specialized connections called synapses. These synapses, composed of a varicosity or bouton from a presynaptic neuron that communicates with a dendritic spine of the postsynaptic neuron, comprise the neural network that is essential for complex behavioral phenomena and cognition. Inappropriate synapse formation or structure is thought to underlie several developmental neuropathologies. Even in the mature CNS, alterations in synapse structure and function continues to be a very dynamic process that is foundational to learning and memory as well as other adaptive abilities of the brain. This synaptic plasticity in mature neurons, which is often triggered by certain patterns of neural activity, is again multifaceted and involves post-translational modifications (e.g. phosphorylation) and subcellular relocalization or trafficking (endocytosis/exocytosis) of existing synaptic proteins, initiation of protein synthesis from existing mRNAs localized in dendrites or spines, and triggering of new gene transcription in the nucleus. These various cellular processes support varying temporal components of synaptic plasticity that begin within 1–2 min but can persist for hours to days. This review will give a critical assessment of activity-dependent molecular modulations of synapses reported over the past couple years. Owing to space limitations, it will focus on mammalian excitatory (i.e. glutamatergic) synapses and will not consider several activity-independent signaling pathways (e.g. ephrinB receptor) that also modulate spine and synapse formation [1,2]. PMID:19896363

  4. 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.

  5. Population Pharmacokinetic Model for Docetaxel in Patients with Varying Degrees of Liver Function: Incorporating Cytochrome P450 3A Activity Measurements

    PubMed Central

    Hooker, AC; ten Tije, AJ; Carducci, MA; Weber, J; Garrett-Mayer, E; Gelderblom, H; McGuire, WP; Verweij, J; Karlsson, MO; Baker, SD

    2011-01-01

    The relationship between cytochrome P4503A4 (CYP3A4) activity and docetaxel clearance in patients with varying degrees of liver function (LF) was evaluated. Docetaxel 40, 50, or 75 mg/m2 was administered to 85 patients with advanced cancer; 23 of 77 evaluable patients had abnormalities in liver function tests. Baseline CYP3A activity was assessed using the erythromycin breath test (ERMBT). Pharmacokinetic studies and toxicity assessments were performed during cycle 1 of therapy and population modeling was performed using NONMEM. Docetaxel unbound clearance was lower (317 vs. 470 L/h) and more variable in patients with liver function abnormalities compared to patients with normal LF. Covariates evaluated accounted for 83% of variability on clearance in patients with liver dysfunction, with CYP3A4 activity accounting for 47% of variation; covariates accounted for only 23% of variability in patients with normal LF. The clinical utility of the ERMBT may be in identifying safe docetaxel doses for patients with LF abnormalities. PMID:18183036

  6. Transcription activation by the siderophore sensor Btr is mediated by ligand-dependent stimulation of promoter clearance

    PubMed Central

    Gaballa, Ahmed; MacLellan, Shawn; Helmann, John D.

    2012-01-01

    Bacterial transcription factors often function as DNA-binding proteins that selectively activate or repress promoters, although the biochemical mechanisms vary. In most well-understood examples, activators function by either increasing the affinity of RNA polymerase (RNAP) for the target promoter, or by increasing the isomerization of the initial closed complex to the open complex. We report that Bacillus subtilis Btr, a member of the AraC family of activators, functions principally as a ligand-dependent activator of promoter clearance. In the presence of its co-activator, the siderophore bacillibactin (BB), the Btr:BB complex enhances productive transcription, while having only modest effects on either RNAP promoter association or the production of abortive transcripts. Btr binds to two direct repeat sequences adjacent to the −35 region; recognition of the downstream motif is most important for establishing a productive interaction between the Btr:BB complex and RNAP. The resulting Btr:BB dependent increase in transcription enables the production of the ferric-BB importer to be activated by the presence of its cognate substrate. PMID:22210890

  7. Temporal relationships between ceramide production, caspase activation and mitochondrial dysfunction in cell lines with varying sensitivity to anti-Fas-induced apoptosis.

    PubMed Central

    Rodriguez-Lafrasse, C; Alphonse, G; Broquet, P; Aloy, M T; Louisot, P; Rousson, R

    2001-01-01

    To clarify the chronology of events leading to anti-Fas-induced apoptosis, and the mechanisms of resistance to this death effector, we compared the response kinetics of three tumour cell lines that display varying sensitivity to anti-Fas (based on levels of apoptosis), in terms of ceramide release, mitochondrial function and the caspase-activation pathway. In the highly sensitive Jurkat cell line, early caspase-8 activation, observed from 2 h after treatment, was chronologically associated with an acute depletion of glutathione and the cleavage of caspase-3 and poly-ADP ribosyl polymerase (PARP), followed by a progressive fall in the mitochondrial transmembrane potential (Delta(psi)m), between 4 and 48 h after treatment. Ceramide levels began to increase 2 h after the addition of anti-Fas (with no increase during the first hour), and increased continuously to 640% of control cells at 48 h. In the moderately sensitive SCC61 adherent cells, comparable results were observed, though with lower levels of ceramide and a delay in the response kinetics, with apoptotic cells becoming flotant. Finally, despite early cleavage of caspase-8 at 2 h, and a sustained level of activation until 48 h, no apoptotic response was observed in anti-Fas-resistant SQ20B cells. This was confirmed by a lack of ceramide generation and mitochondrial changes, and by the absence of any detectable cleavage of caspase-3 or PARP. Inhibition of caspase processing, and amplification of endogenous ceramide signalling by pharmacological agents, allowed us to establish the order of cellular events, locating ceramide release after caspase-8 activation and before caspase-3 activation, and demonstrating a direct involvement for ceramide release in mitochondrial dysfunction. Furthermore, these experiments provide strong arguments for the role of endogenous ceramide as a key executor of apoptosis, rather than as a consequence of membrane alterations. PMID:11439090

  8. 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.

  9. Average characteristics and activity dependence of the subauroral polarization stream

    NASA Astrophysics Data System (ADS)

    Foster, J. C.; Vo, H. B.

    2002-12-01

    Data from the Millstone Hill incoherent scatter radar taken over two solar cycles (1979-2000) are examined to determine the average characteristics of the disturbance convection electric field in the midlatitude ionosphere. Radar azimuth scans provide a regular database of ionospheric plasma convection observations spanning auroral and subauroral latitudes, and these scans have been examined for all local times and activity conditions.We examine the occurrence and characteristics of a persistent secondary westward convection peak which lies equatorward of the auroral two-cell convection. Individual scans and average patterns of plasma flow identify and characterize this latitudinally broad and persistent subauroral polarization stream (SAPS), which spans the nightside from dusk to the early morning sector for all Kp greater than 4. Premidnight, the SAPS westward convection lies equatorward of L = 4 (60° invariant latitude, Λ), spans 3°-5° of latitude, and has an average peak amplitude of >900 m/s. In the predawn sector, SAPS is seen as a region of antisunward convection equatorward of L = 3 (55° Λ), spanning ˜3° of latitude, with an average peak amplitude of 400 m/s.

  10. Shape-dependent photocatalytic activities of bismuth subcarbonate nanostructures.

    PubMed

    Tang, Jiale; Cheng, Gang; Zhou, Huamin; Yang, Hao; Lu, Zhong; Chen, Rong

    2012-05-01

    Different shaped bismuth subcarbonate ((BiO)2CO3) nanostructures including irregular nanoplates, relatively uniform nanoplates and nanocubes were prepared and characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV-vis diffuse reflection spectroscopy (DRS) and nitrogen adsorption. The photocatalytic performance of the as-synthesized (BiO)2CO3 nanostructures on the degradation of Rhodamine B (RhB), methyl orange (MO) and methyl blue (MB) were evaluated under UV-vis light irradiation (modeling sunlight). The photocatalysis tests showed that all the different (BiO)2CO3 nanostructures displayed enhanced photodegradation performance compared with commercial (BiO)2CO3. The irregular (BiO)2CO3 nanoplates exhibited the highest photocatalytic activity on the degradation of different organic dyes. (BiO)2CO3 nanosturctures exhibited the different capacity to bleach the three organic dyes, which might be attributed to their different molecular structures. This work may provide a potential photocatalyst for the environmental pollutants treatments.

  11. Activity-dependent modulation of gonadotrophin-releasing hormone neurone activity by acute oestradiol.

    PubMed

    Romanò, Nicola; Herbison, Allan E

    2012-10-01

    Oestradiol (E₂) exerts potent feedback actions upon gonadotrophin-releasing hormone (GnRH) neurones and part of this feedback action may occur through the rapid action of E₂. Using a transgenic GnRH-Pericam mouse line that allows real-time intracellular calcium concentrations ([Ca²⁺](i)) to be monitored in adult GnRH neurones in a brain slice preparation, we examined the acute effects of 100 pM-100 nM E₂ on [Ca²⁺](i) transients in spontaneously active GnRH neurones. Approximately 30% of GnRH neurones exhibit spontaneous [Ca²⁺](i) transients at a frequency greater than two transients/15 min in adult female mice. In these cells, treatment with an incremental 1, 10, 100 nM E₂ protocol or 100 pM E₂ alone resulted in the suppression or complete cessation of [Ca²⁺](i) transients in 15 of 18 (83%) GnRH neurones. This effect was mimicked by E₂ bound to albumin, suggesting a membrane site of action, and was maintained in oestrogen receptor β knockout mice, indicating that this receptor is not essential for the rapid suppression of [Ca²⁺](i) transients. These findings contrast with those GnRH neurones exhibiting very few or no [Ca²⁺](i) transients (< 2 transients/15 min) that exhibit the opposite response of being activated by acute E₂. A series of dual calcium-cell-attached electrical recordings showed that [Ca²⁺](i) transients were associated with GnRH neurone burst firing and that E₂ suppression or activation of [Ca²⁺](i) transients was mirrored by a depression or initiation of burst firing. Taken together, these studies demonstrate that the acute actions of E₂ on GnRH neurones are critically dependent upon their pattern of burst firing.

  12. 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

  13. Transcriptional activities of methanogens and methanotrophs vary with methane emission flux in rice soils under chronic nutrient constraints of phosphorus and potassium

    NASA Astrophysics Data System (ADS)

    Sheng, Rong; Chen, Anlei; Zhang, Miaomiao; Whiteley, Andrew S.; Kumaresan, Deepak; Wei, Wenxue

    2016-12-01

    Nutrient status in soil is crucial for the growth and development of plants which indirectly or directly affect the ecophysiological functions of resident soil microorganisms. Soil methanogens and methanotrophs can be affected by soil nutrient availabilities and plant growth, which in turn modulate methane (CH4) emissions. Here, we assessed whether deficits in soil-available phosphorus (P) and potassium (K) modulated the activities of methanogens and methanotrophs in a long-term (20 year) experimental system involving limitation in either one or both nutrients. Results showed that a large amount of CH4 was emitted from paddy soil at rice tillering stage (flooding) while CH4 flux was minimum at ripening stage (drying). Compared to soils amended with NPK fertiliser treatment, the soils without P input significantly reduced methane flux rates, whereas those without K input did not. Under P limitation, methanotroph transcript copy number significantly increased in tandem with a decrease in methanogen transcript abundance, suggesting that P-deficiency-induced changes in soil physio-chemical properties, in tandem with rice plant growth, might constrain the activity of methanogens, whereas the methanotrophs might be adaptive to this soil environment. In contrast, lower transcript abundance of both methanogen and methanotrophs were observed in K-deficient soils. Assessments of community structures based upon transcripts indicated that soils deficient in P induced greater shifts in the active methanotrophic community than K-deficient soils, while similar community structures of active methanogens were observed in both treatments. These results suggested that the population dynamics of methanogens and methanotrophs could vary along with the changes in plant growth states and soil properties induced by nutrient deficiency.

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

    PubMed

    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(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 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.

  15. 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.

  16. Phosphorylation of Complexin by PKA Regulates Activity-dependent Spontaneous Neurotransmitter Release and Structural Synaptic Plasticity

    PubMed Central

    Cho, Richard W.; Buhl, Lauren K.; Volfson, Dina; Tran, Adrienne; Li, Feng; Akbergenova, Yulia; Littleton, J. Troy

    2016-01-01

    Summary Synaptic plasticity is a fundamental feature of the nervous system that allows adaptation to changing behavioral environments. Most studies of synaptic plasticity have examined the regulated trafficking of postsynaptic glutamate receptors that generates alterations in synaptic transmission. Whether and how changes in the presynaptic release machinery contribute to neuronal plasticity is less clear. The SNARE complex mediates neurotransmitter release in response to presynaptic Ca++ entry. Here we show that the SNARE fusion clamp Complexin undergoes activity-dependent phosphorylation that alters the basic properties of neurotransmission in Drosophila. Retrograde signaling following stimulation activates PKA-dependent phosphorylation of the Complexin C-terminus that selectively and transiently enhances spontaneous release. Enhanced spontaneous release is required for activity-dependent synaptic growth. These data indicate that SNARE-dependent fusion mechanisms can be regulated in an activity-dependent manner and highlight the key role of spontaneous neurotransmitter release as a mediator of functional and structural plasticity. PMID:26590346

  17. 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

  18. 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

    2015-12-23

    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

  19. 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.

  20. 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

  1. Chicken embryo fibroblasts exposed to weak, time-varying magnetic fields share cell proliferation, adenosine deaminase activity, and membrane characteristics of transformed cells

    SciTech Connect

    Parola, A.H.; Porat, N.; Kiesow, L.A. )

    1993-01-01

    Chicken embryo fibroblasts (CEF) exposed to a sinusoidally varying magnetic field (SVMF) (100 Hz, 700 microT, for 24 h) showed a remarkable rise of segmental rotational relaxation rate of adenosine deaminase (ADA, EC 3.5.4.4) as determined by multifrequency phase fluorometry. Pyrene-labeled, small subunit ADA was applied to cultured (normal) CEF, which have available and abundant ADA complexing protein (ADCP) on their plasma membranes. Sine-wave-modulated fluorometry of the pyrene yielded a profile of phase angle vs. modulation frequency. In SVMF-treated cells and in Rous-sarcoma-virus (RSV) transformed cells the differential phase values at low modulation frequencies of the excitation are remarkably reduced. This effect is magnetic rather than thermal, because the temperature was carefully controlled and monitored; nevertheless to further check this matter we studied CEF, infected by the RSV-Ts68 temperature-sensitive mutant (36 degrees C transformed, 41 degrees C revertant). When grown at 36 degrees C in the SVMF, cells did not show the slightest trend towards reversion, as would be expected had there been local heating. Concomitant with the increased segmental rotational relaxation rate of ADA, there was a decrease in fluorescence lifetime and a slight, yet significant, increase in membrane lipid microfluidity. These biophysical observations prompted us to examine the effect of SVMF on cell proliferation and ADA activity (a malignancy marker): higher rates of cell proliferation and reduced specific activity of ADA were observed.

  2. 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.

  3. 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.

  4. Canid progesterone receptors lack activation function 3 domain-dependent activity.

    PubMed

    Gracanin, Ana; van Wolferen, Monique E; Sartorius, Carol A; Brenkman, Arjan B; Schoonen, Willem G; Mol, Jan A

    2012-12-01

    Progesterone regulates multiple behavioral, physiological, and pathological aspects of female reproductive biology through its two progesterone receptors (PRs), PR-B and the truncated PR-A. PR-B is necessary for mammary gland development in mice and, compared with PR-A, is overall a stronger transactivator of target genes due to an additional activation function 3 (AF3) domain. In dogs, known for their high sensitivity to progesterone-induced mammary cancer, the PR-B function was studied. Canine PR (cPR)-B appeared to contain multiple mutations within AF3 core sequence motifs and lacks N-terminal ligand-independent posttranslational modifications. Consequently, cPR-B has a weak transactivation potential on progesterone-responsive mouse mammary tumor virus-luc and progesterone response element 2-luc reporters transiently transfected in hamster, human, or canine cells and also on known target genes FKBP5 and SGK in doxycycline-inducible, stable transfected cPR-B in canine mammary cells. The cPR-B function was restored to the level of human PR-B by the replacement of canine AF3 domain with the human one. The lack of AF3 domain-dependent transcriptional activity was unique for canids (gray wolf, red fox, and raccoon dog) and not present in closely related caniform species (brown bear, gray seal, and domestic ferret). Despite the limited transactivation potential, canids develop normal mammary glands and frequently mammary tumors. Therefore, these results question the role of PR-B in breast cancer development and may explain unique features of canid reproduction.

  5. Electropositive charge in alpha-defensin bactericidal activity: functional effects of Lys-for-Arg substitutions vary with the peptide primary structure.

    PubMed

    Llenado, R Alan; Weeks, Colby S; Cocco, Melanie J; Ouellette, André J

    2009-11-01

    Cationic amino acids contribute to alpha-defensin bactericidal activity. Curiously, although Arg and Lys have equivalent electropositive charges at neutral pH, alpha-defensins contain an average of nine Arg residues per Lys residue. To investigate the role of high alpha-defensin Arg content, all Arg residues in mouse Paneth cell alpha-defensin cryptdin 4 (Crp4) and rhesus myeloid alpha-defensin 4 (RMAD-4) were replaced with Lys to prepare (R/K)-Crp4 and (R/K)-RMAD-4, respectively. Lys-for-Arg replacements in Crp4 attenuated bactericidal activity and slowed the kinetics of Escherichia coli ML35 cell permeabilization, and (R/K)-Crp4 required longer exposure times to reduce E. coli cell survival. In marked contrast, Lys substitutions in RMAD-4 improved microbicidal activity against certain bacteria and permeabilized E. coli more effectively. Therefore, Arg-->Lys substitutions attenuated activity in Crp4 but not in RMAD-4, and the functional consequences of Arg-->Lys replacements in alpha-defensins are dependent on the peptide primary structure. In addition, the bactericidal effects of (R/K)-Crp4 and (R/K)-RMAD-4 were more sensitive to inhibition by NaCl than those of the native peptides, suggesting that the high Arg content of alpha-defensins may be under selection to confer superior microbicidal function under physiologic conditions.

  6. NADP+-dependent glutamate dehydrogenase activity is impaired in mutants of Saccharomyces cerevisiae that lack aconitase.

    PubMed

    González, A; Rodríguez, L; Olivera, H; Soberón, M

    1985-10-01

    A mutant of Saccharomyces cerevisiae lacking aconitase did not grow on minimal medium (MM) and had five- to tenfold less NADP+-dependent glutamate dehydrogenase (GDH) activity than the wild-type, although its glutamine synthetase (GS) activity was still inducible. When this mutant was incubated with glutamate as the sole nitrogen source, the 2-oxoglutarate content rose, and the NADP+-dependent GDH activity increased. Furthermore, carbon-limited cultures showed a direct relation between NADP+-dependent GDH activity and the intracellular 2-oxoglutarate content. We propose that the low NADP+-dependent GDH activity found in the mutant was due to the lack of 2-oxoglutarate or some other intermediate of the tricarboxylic acid cycle.

  7. Acute response of hypophysiotropic thyrotropin releasing hormone neurons and thyrotropin release to behavioral paradigms producing varying intensities of stress and physical activity.

    PubMed

    Gutiérrez-Mariscal, Mariana; Sánchez, Edith; García-Vázquez, Arlene; Rebolledo-Solleiro, Daniela; Charli, Jean-Louis; Joseph-Bravo, Patricia

    2012-11-10

    The activity of the hypothalamus-pituitary-thyroid (HPT) axis is essential for energy homeostasis and is differentially modulated by physical and by psychological stress. Contradictory effects of stressful behavioral paradigms on TSH or thyroid hormone release are due to type, length and controllability of the stressor. We hypothesized that an additional determinant of the activity of the HPT axis is the energy demand due to physical activity. We thus evaluated the response of thyrotropin releasing hormone (TRH) neurons of the hypothalamic paraventricular nucleus (PVN) in Wistar male rats submitted to the elevated plus maze (EPM), the open field test (OFT), or restraint, and sacrificed within 1h after test completion; the response to OFT was compared during light (L) or dark (D) phases. Locomotion and anxiety behaviors were similar if animals were tested in L or D phases but their relation to the biochemical parameters differed. All paradigms increased serum corticosterone concentration; the levels of corticotropin releasing hormone receptor 1 and of glucocorticoid receptor (GR) mRNAs in the PVN were enhanced after restraint or OFT-L. Levels of proTRH mRNA increased in the PVN after exposure to EPM-L or OFT-D; serum levels of thyrotropin (TSH) and T(4) only after OFT-D. In contrast, restraint decreased TRH mRNA and serum TSH levels, while it increased TRH content in the mediobasal hypothalamus, implying reduced release. Expression of proTRH in the PVN varied proportionally to the degree of locomotion in OFT-D, while inversely to anxiety in the EPM-L, and to corticosterone in EPM-L and OFT-D. TRH mRNA levels were analyzed by in situ hybridization in the rostral, middle and caudal zones of the PVN in response to OFT-D; they increased in the middle PVN, where most TRH hypophysiotropic neurons reside; levels correlated positively with the velocity attained in the periphery of the OF and negatively, with anxiety. Variations of serum TSH levels correlated positively with

  8. Passive-submissive and active-emotional trait dependency: evidence for a two-factor model.

    PubMed

    Morgan, Theresa A; Clark, Lee Anna

    2010-08-01

    Dependency plays an important role in both normal and abnormal personality, but the construct remains loosely defined, both in clinical practice and the research literature. Moreover, although a number of measures purport to measure trait dependency, little agreement exists as to the structure of dependency within or across these instruments. Furthermore, what constitutes the low end of trait dependency remains unclear. Five hundred nine undergraduates completed a battery of 14 dependency scales and subscales, a subset of whom (n=322) also completed a broad measure of personality pathology (SNAP-2). Exploratory factor analysis of the dependency measures yielded two correlated factors-Passive-Submissive and Active-Emotional dependency-as well as a third, unrelated factor, Detachment/Autonomy, all with differential correlates to the pathological personality traits of the SNAP-2. Taken together, these data suggest a clear, 2-factor model for trait dependency that is distinct from detachment/autonomy.

  9. Activity-Dependent Callosal Axon Projections in Neonatal Mouse Cerebral Cortex

    PubMed Central

    Tagawa, Yoshiaki; Hirano, Tomoo

    2012-01-01

    Callosal axon projections are among the major long-range axonal projections in the mammalian brain. They are formed during the prenatal and early postnatal periods in the mouse, and their development relies on both activity-independent and -dependent mechanisms. In this paper, we review recent findings about the roles of neuronal activity in callosal axon projections. In addition to the well-documented role of sensory-driven neuronal activity, recent studies using in utero electroporation demonstrated an essential role of spontaneous neuronal activity generated in neonatal cortical circuits. Both presynaptic and postsynaptic neuronal activities are critically involved in the axon development. Studies have begun to reveal intracellular signaling pathway which works downstream of neuronal activity. We also review several distinct patterns of neuronal activity observed in the developing cerebral cortex, which might play roles in activity-dependent circuit construction. Such neuronal activity during the neonatal period can be disrupted by genetic factors, such as mutations in ion channels. It has been speculated that abnormal activity caused by such factors may affect activity-dependent circuit construction, leading to some developmental disorders. We discuss a possibility that genetic mutation in ion channels may impair callosal axon projections through an activity-dependent mechanism. PMID:23213574

  10. The effect of varying dietary starch and fat content on serum creatine kinase activity and substrate availability in equine polysaccharide storage myopathy.

    PubMed

    Ribeiro, W P; Valberg, S J; Pagan, J D; Gustavsson, B Essen

    2004-01-01

    The effect of dietary starch and fat content on serum creatine kinase (CK) activity and substrate availability was evaluated in 4 mares of Quarter Horse-related breeds with polysaccharide storage myopathy (PSSM). Four isocaloric diets ranging in digestible energy (DE) from 21.2% (diet A), 14.8% (B), 8.4% (C), to 3.9% (D) for starch, and 7.2% DE (diet A), 9.9% (B), to 12.7% DE (diet C and D) for fat were fed for 6-week periods (4 weeks with exercise) using a 4 X 4 Latin square design. Postprandial glucose and insulin responses were measured, and 4 hours postexercise, serum CK activity, glucose, insulin, free fatty acids (FFA), and beta-hydroxybutyrate (beta-HBA) were analyzed. Glycogen, glucose-6-phosphate, citrate synthase, 3-hydroxy-acyl-CoA dehydrogenase, lactate dehydrogenase as well as abnormal polysaccharide and lipid content were measured in middle gluteal muscle samples. Postprandial insulin and glucose response was higher for diet A versus D. Log CK activity was higher with diets A, B, and C versus D. Daily insulin was higher and FFA lower on diet A versus B, C, and D, whereas glucose varied only slightly with diet. Muscle oxidative capacity and lipid stores were low in PSSM horses and muscle glycogen and abnormal polysaccharide content high on both diets A and D. Individual variation occurred in the response of PSSM horses to diets differing in starch and fat content. However, for those horses with clinical manifestations of PSSM, a diet with <5% DE starch and >12% DE fat can reduce exertional rhabdomyolysis, potentially by increasing availability of FFA for muscle metabolism.

  11. Recovery of rhythmic activity in a central pattern generator: analysis of the role of neuromodulator and activity-dependent mechanisms

    PubMed Central

    Zhang, Yili; Golowasch, Jorge

    2015-01-01

    The pyloric network of decapods crustaceans can undergo dramatic rhythmic activity changes. Under normal conditions the network generates low frequency rhythmic activity that depends obligatorily on the presence of neuromodulatory input from the central nervous system. When this input is removed (decentralization) the rhythmic activity ceases. In the continued absence of this input, periodic activity resumes after a few hours in the form of episodic bursting across the entire network that later turns into stable rhythmic activity that is nearly indistinguishable from control (recovery). It has been proposed that an activity-dependent modification of ionic conductance levels in the pyloric pacemaker neuron drives the process of recovery of activity. Previous modeling attempts have captured some aspects of the temporal changes observed experimentally, but key features could not be reproduced. Here we examined a model in which slow activity-dependent regulation of ionic conductances and slower neuromodulator-dependent regulation of intracellular Ca2+ concentration reproduce all the temporal features of this recovery. Key aspects of these two regulatory mechanisms are their independence and their different kinetics. We also examined the role of variability (noise) in the activity-dependent regulation pathway and observe that it can help to reduce unrealistic constraints that were otherwise required on the neuromodulator-dependent pathway. We conclude that small variations in intracellular Ca2+ concentration, a Ca2+ uptake regulation mechanism that is directly targeted by neuromodulator-activated signaling pathways, and variability in the Ca2+ concentration sensing signaling pathway can account for the observed changes in neuronal activity. Our conclusions are all amenable to experimental analysis. PMID:21573963

  12. 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

  13. Gibberellic Acid Activates Chromatin-bound DNA-dependent RNA Polymerase in Wounded Potato Tuber Tissue 1

    PubMed Central

    Wielgat, Bernard; Kahl, Günter

    1979-01-01

    Chromatin-bound DNA-dependent RNA polymerases react upon wounding of white potato tuber tissues with an increase in activity, which is additionally enhanced to 300% in the presence of 0.1 micromolar gibberellic acid (GA3). 2,4-Dichlorophenoxyacetic acid is only weakly effective and indoleacetic acid not at all. Wounding and treatment with GA3 affect template availability of chromatin only slightly. The hormone has no effect on chromatin-bound RNA polymerases, if added in vitro. The enzymes from intact, wounded, and hormone-treated tissues possess similar characteristics: their activity is dependent on the presence of all four ribonucleotides and a divalent cation such as Mg2+ or Mn2+. However, the sensitivity of the enzymes from different preparations toward α-amanitin differs. Total RNA polymerase activity of chromatin was inhibited by α-amanitin to about 44% in intact, to about 22% in wounded, and only 15% in GA3-treated tissues. The relative activities of polymerases I and II were estimated by varying the (NH4)2SO4 and α-amanitin concentrations in the assay system. It is evident that GA3 preferentially stimulates polymerase I and hence ribosomal RNA synthesis. RNA polymerase II is but slightly affected by GA3. Nearest neighbor frequency analysis revealed that the RNA synthesized by the enzymes from the intact tuber is different from that of wounded or GA3-treated tissues. PMID:16661071

  14. Biochemical changes in the liver and gill of Cathorops spixii collected seasonally in two Brazilian estuaries under varying influences of anthropogenic activities.

    PubMed

    Azevedo, J S; Braga, E S; Silva de Assis, H C; Oliveira Ribeiro, C A

    2013-10-01

    In order to understand environmental health by the use of a bioindicator species in estuaries, biochemical responses observed in the catfish Cathorops spixii such as catalase (CAT), glutathione-S-transferase (GST), lipid peroxidation (LPO) and acetylcholinesterase (AChE) were evaluated in liver and muscle. Furthermore, histological changes were also verified in liver and gills preparations. Fish were collected in three sites of the Santos-São Vicente estuary located at São Paulo (Brazil), subjected to varying levels of inputs of pollutants. For a reference site, specimens were sampled at Cananéia estuary at southern coast of São Paulo, a region with low anthropogenic influence. In general, no significant seasonal differences in antioxidant enzymes and lipid peroxidation responses were found in the organisms from the Cananéia estuary. However, in the polluted estuary (Santos-São Vicente), biochemical responses were observed by increases in GST hydroperoxides and decreases in AChE activities in the summer. Inhibition of AChE expression in fish from different areas of the Santos-São Vicente estuary in the summer was also found and can indicate neurotoxic effects in these organisms. Histopathological observation of gill and liver showed severe lesions, such as lamellar fusion and necrosis.

  15. 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.

  16. "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)…

  17. 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....

  18. A Ca2+-stimulated, Mg2+-dependent ATPase activity in subcellular fractions from Schistosoma mansoni.

    PubMed

    Cunha, V M; de Souza, W; Noël, F

    1988-12-05

    A Ca2+-stimulated, Mg2+-dependent ATPase activity was found in subcellular fractions from Schistosoma mansoni. Its specific and relative activities were higher in the heterogeneous cuticle fraction and in the microsomal fraction. The K0.5 for ATPase activation by free Ca2+ was 0.2-0.5 microM. This is the first description of an ATPase activity stimulated by Ca2+ in the micromolar range in S. mansoni.

  19. 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.

  20. Fractal analysis and ionic dependence of endocytotic membrane activity of human breast cancer cells.

    PubMed

    Krasowska, Monika; Grzywna, Zbigniew J; Mycielska, Maria E; Djamgoz, Mustafa B A

    2009-10-01

    The endocytic membrane activities of two human breast cancer cell lines (MDA-MB-231 and MCF-7) of strong and weak metastatic potential, respectively, were studied in a comparative approach. Uptake of horseradish peroxidase was used to follow endocytosis. Dependence on ionic conditions and voltage-gated sodium channel (VGSC) activity were characterized. Fractal methods were used to analyze quantitative differences in vesicular patterning. Digital quantification showed that MDA-MB-231 cells took up more tracer (i.e., were more endocytic) than MCF-7 cells. For the former, uptake was totally dependent on extracellular Na(+) and partially dependent on extracellular and intracellular Ca(2+) and protein kinase activity. Analyzing the generalized fractal dimension (D(q )) and its Legendre transform f(alpha) revealed that under control conditions, all multifractal parameters determined had values greater for MDA-MB-231 compared with MCF-7 cells, consistent with endocytic/vesicular activity being more developed in the strongly metastatic cells. All fractal parameters studied were sensitive to the VGSC blocker tetrodotoxin (TTX). Some of the parameters had a "simple" dependence on VGSC activity, if present, whereby pretreatment with TTX reduced the values for the MDA-MB-231 cells and eliminated the differences between the two cell lines. For other parameters, however, there was a "complex" dependence on VGSC activity. The possible physical/physiological meaning of the mathematical parameters studied and the nature of involvement of VGSC activity in control of endocytosis/secretion are discussed.

  1. 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.

  2. 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.

  3. Glucocorticoid receptor activation lowers the threshold for NMDA-receptor-dependent homosynaptic long-term depression in the hippocampus through activation of voltage-dependent calcium channels.

    PubMed

    Coussens, C M; Kerr, D S; Abraham, W C

    1997-07-01

    The effects of the glucocorticoid receptor agonist RU-28362 on homosynaptic long-term depression (LTD) were examined in hippocampal slices obtained from adrenal-intact adult male rats. Field excitatory postsynaptic potentials were evoked by stimulation of the Schaffer collateral/commissural pathway and recorded in stratum radiatum of area CA1. Low-frequency stimulation (LFS) was delivered at LTD threshold (2 bouts of 600 pulses, 1 Hz, at baseline stimulation intensity). LFS of the Schaffer collaterals did not produce significant homosynaptic LTD in control slices. However, identical conditioning in the presence of the glucocorticoid receptor agonist RU-28362 (10 microM) produced a robust LTD, which was blocked by the selective glucocorticoid antagonist RU-38486. The LTD induced by glucocorticoid receptor activation was dependent on N-methyl-D-aspartate (NMDA) receptor activity, because the specific NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) blocked the facilitation. However, the facilitation of LTD was not due to a potentiation of the isolated NMDA receptor potential by RU-28362. The facilitation of LTD by RU-28362 was also blocked by coincubation of the L-type voltage-dependent calcium channel (VDCC) antagonist nimodipine. Selective activation of the L-type VDCCs by the agonist Bay K 8644 also facilitated LTD induction. Both nimodipine and D-AP5 were effective in blocking the facilitation of LTD by Bay K 8644. These results indicate that L-type VDCCs can contribute to NMDA-receptor-dependent LTD induction.

  4. Increased dependency of cardiac pacemaker activity on extracellular Ca after adrenergic blockade in the frog heart.

    PubMed

    Fukuda, Y

    1986-01-01

    The frog sinus venosus shows spontaneous regular pacemaker activity, even in the absence of extracellular Ca2+. When an alpha-adrenergic blocking agent (phentolamine) is applied, the rate of pacemaker activity, height of action potential, rate of slow diastolic depolarization, and the maximum diastolic potential become strongly dependent upon the extracellular Ca2+ concentration.

  5. Seroprevalence of Antibody-Mediated, Complement-Dependent Opsonophagocytic Activity against Neisseria meningitidis Serogroup B in England.

    PubMed

    Humphries, Holly E; Brookes, Charlotte; Allen, Lauren; Kuisma, Eeva; Gorringe, Andrew; Taylor, Stephen

    2015-05-01

    The correlate of protection for the licensure of meningococcal vaccines is serum bactericidal activity. However, evidence indicates that a complex situation and other mechanisms, such as antibody-mediated, complement-dependent opsonophagocytosis (OP), may play a role in protection and should be investigated in order to understand immunity to this disease. In this study, a high-throughput flow cytometric opsonophagocytic assay (OPA) was optimized. The assay measures the presence of killed fluorescently labeled Neisseria meningitidis within human granulocytes (differentiated HL60 cells) by flow cytometry, using IgG-depleted pooled human plasma as an exogenous source of complement. This method was found to be reliable and correlated with the results of an opsonophagocytic killing assay. The OPA was used to measure OP activity in 1,878 serum samples from individuals ranging from 0 to 99 years of age against N. meningitidis strain NZ98/254 (B:4:P1.7-2,4). The levels of OP activity in individual serum samples varied greatly. OP activity showed an initial peak in the 6- to 12-month age group corresponding to a peak in disease incidence. The OP activity dropped in childhood until the late teenage years, although there was still a higher percentage of individuals with OP activity than with protective bactericidal antibody titers. OP activity reached a peak in the 30- to 39-year age group and then declined. This later peak in OP activity did not coincide with the young adults in whom peak serum bactericidal activity and disease incidence occurred. The demonstration of OP activity when disease incidence is low and when protective bactericidal antibody titers are not detected may indicate a role for OP in protection from meningococcal disease in these age groups.

  6. Seroprevalence of Antibody-Mediated, Complement-Dependent Opsonophagocytic Activity against Neisseria meningitidis Serogroup B in England

    PubMed Central

    Brookes, Charlotte; Allen, Lauren; Kuisma, Eeva; Gorringe, Andrew; Taylor, Stephen

    2015-01-01

    The correlate of protection for the licensure of meningococcal vaccines is serum bactericidal activity. However, evidence indicates that a complex situation and other mechanisms, such as antibody-mediated, complement-dependent opsonophagocytosis (OP), may play a role in protection and should be investigated in order to understand immunity to this disease. In this study, a high-throughput flow cytometric opsonophagocytic assay (OPA) was optimized. The assay measures the presence of killed fluorescently labeled Neisseria meningitidis within human granulocytes (differentiated HL60 cells) by flow cytometry, using IgG-depleted pooled human plasma as an exogenous source of complement. This method was found to be reliable and correlated with the results of an opsonophagocytic killing assay. The OPA was used to measure OP activity in 1,878 serum samples from individuals ranging from 0 to 99 years of age against N. meningitidis strain NZ98/254 (B:4:P1.7-2,4). The levels of OP activity in individual serum samples varied greatly. OP activity showed an initial peak in the 6- to 12-month age group corresponding to a peak in disease incidence. The OP activity dropped in childhood until the late teenage years, although there was still a higher percentage of individuals with OP activity than with protective bactericidal antibody titers. OP activity reached a peak in the 30- to 39-year age group and then declined. This later peak in OP activity did not coincide with the young adults in whom peak serum bactericidal activity and disease incidence occurred. The demonstration of OP activity when disease incidence is low and when protective bactericidal antibody titers are not detected may indicate a role for OP in protection from meningococcal disease in these age groups. PMID:25739917

  7. Changes in the flavonoid and phenolic acid contents and antioxidant activity of red leaf lettuce (Lollo Rosso) due to cultivation under plastic films varying in ultraviolet transparency.

    PubMed

    García-Macías, Paulina; Ordidge, Matthew; Vysini, Eleni; Waroonphan, Saran; Battey, Nicholas H; Gordon, Michael H; Hadley, Paul; John, Philip; Lovegrove, Julie A; Wagstaffe, Alexandra

    2007-12-12

    Red leaf lettuce (Lollo Rosso) was grown under three types of plastic films that varied in transparency to UV radiation (designated as UV block, UV low, and UV window). Flavonoid composition was determined by high-performance liquid chromatography (HPLC), total phenolics by the Folin-Ciocalteu assay, and antioxidant capacity by the oxygen radical absorbance capacity (ORAC) assay. Exposure to increased levels of UV radiation during cultivation caused the leaves to redden and increased concentrations of total phenols and the main flavonoids, quercetin and cyanidin glycosides, as well as luteolin conjugates and phenolic acids. The total phenol content increased from 1.6 mg of gallic acid equivalents (GAE)/g of fresh weight (FW) for lettuce grown under UV block film to 2.9 and 3.5 mg of GAE/g of FW for lettuce grown under the UV low and UV window films. The antioxidant activity was also higher in lettuce exposed to higher levels of UV radiation with ORAC values of 25.4 and 55.1 micromol of Trolox equivalents/g of FW for lettuce grown under the UV block and UV window films, respectively. The content of phenolic acids, quantified as caffeic acid, was also different, ranging from 6.2 to 11.1 micromol/g of FW for lettuce cultivated under the lowest and highest UV exposure plastic films, respectively. Higher concentrations of the flavonoid glycosides were observed with increased exposure to UV radiation, as demonstrated by the concentrations of aglycones after hydrolysis, which were cyanidin (ranging from 165 to 793 microg/g), quercetin (ranging from 196 to 880 microg/g), and luteolin (ranging from 19 to 152 microg/g). The results demonstrate the potential of the use of UV-transparent plastic as a means of increasing beneficial flavonoid content of red leaf lettuce when the crop is grown in polytunnels.

  8. 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

  9. Sodium-dependent pH regulation in active sea urchin sperm.

    PubMed

    Bibring, T; Baxandall, J; Harter, C C

    1984-02-01

    Extracellular sodium ion is required for activation of motility and respiration in sea urchin sperm when semen is diluted in seawater. We have investigated the role of sodium ion in maintenance of sperm activity. Active sperm lose activity on transfer to sodium-free artificial seawater and can be reactivated with external Na+. Reactivation occurs in the range of Na+ concentration required for initial activation; ammonium can substitute for sodium in reactivation. Sperm withdrawn from sodium and sperm prior to activation share a characteristic morphology with straight or gently bent flagella. Activation of sperm by amines in the absence of Na+ is unstable. It is followed by a steady respiratory decline which is temporarily reversed by addition of more amine and stably reversed by addition of Na+. Measurements of intracellular pH indicate that the internal pH rises during amine activation. Internal reacidification occurs during the period of respiratory decline, and Na+ again elevates internal pH. Treatment with cyanide abolishes the reacidification, indicating that it depends on respiration. We conclude that the sodium requirement persists in active sperm; respiration-dependent production of H+ must be balanced by sodium-dependent H+ removal to maintain activity.

  10. Age-dependent arginine phosphokinase activity changes in male vestigial and wild-type Drosophila melanogaster.

    PubMed

    Baker, G T

    1975-01-01

    The activity of arginine phosphokinase, an important muscle enzyme in insects, was investigated with age in vestigial-winged and wild-type Drosophila melanogaster. Identical patterns of age-dependent activity changes were observed in the vestigial-winged flies as in the wild-type, even though vestigial-winged flies exhibit a 50% mortality approximately two thirds that of the wild-type as well as being incapable of flight. Results indicate that the age-dependent changes in arginine phosphokinase activity are intrinsically regulated within the cells of the flight muscle.

  11. Tamoxifen Dependent Interaction Between the Estrogen Receptor and a Novel P21 Activated Kinase

    DTIC Science & Technology

    2002-06-01

    AD Award Number: DAMDl7-01-1-0149 TITLE: Tamoxifen Dependent Interaction Between the Estrogen Receptor and a Novel P21 Activated Kinase PRINCIPAL...Tamoxifen Dependent Interaction Between the DAMD17-00-1-0114 Estrogen Receptor and a Novel P21 Activated Kinase 6. AUTHOR(S) Steven P. Balk, M.D., Ph.D. 7...Z, Karas RH, nisms of androgen receptor activation and function. J Mendelsohn ME, Shaul PW 1999 Estrogen receptor a Steroid Biochem Mol Biol 69:307

  12. Modeling of spontaneous activity in developing spinal cord using activity-dependent depression in an excitatory network.

    PubMed

    Tabak, J; Senn, W; O'Donovan, M J; Rinzel, J

    2000-04-15

    Spontaneous episodic activity is a general feature of developing neural networks. In the chick spinal cord, the activity comprises episodes of rhythmic discharge (duration 5-90 sec; cycle rate 0.1-2 Hz) that recur every 2-30 min. The activity does not depend on specialized connectivity or intrinsic bursting neurons and is generated by a network of functionally excitatory connections. Here, we develop an idealized, qualitative model of a homogeneous, excitatory recurrent network that could account for the multiple time-scale spontaneous activity in the embryonic chick spinal cord. We show that cycling can arise from the interplay between excitatory connectivity and fast synaptic depression. The slow episodic behavior is attributable to a slow activity-dependent network depression that is modeled either as a modulation of cellular excitability or as synaptic depression. Although the two descriptions share many features, the model with a slow synaptic depression accounts better for the experimental observations during blockade of excitatory synapses.

  13. Modulation of p47PHOX activity by site-specific phosphorylation: Akt-dependent activation of the NADPH oxidase

    PubMed Central

    Hoyal, Carolyn R.; Gutierrez, Abel; Young, Brandon M.; Catz, Sergio D.; Lin, Jun-Hsiang; Tsichlis, Philip N.; Babior, Bernard M.

    2003-01-01

    The leukocyte NADPH oxidase catalyzes the reduction of oxygen to O\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} \\begin{equation*}{\\mathrm{_{2}^{-}}}\\end{equation*}\\end{document} at the expense of NADPH. Extensive phosphorylation of the oxidase subunit p47PHOX occurs during the activation of the enzyme in intact cells. p47PHOX carrying certain serine-to-alanine mutations fails to support NADPH oxidase activity in intact cells, suggesting that the phosphorylation of specific serines on p47PHOX is required for the activation of the oxidase. Earlier studies with both intact cells and a kinase-dependent, cell-free system have suggested that protein kinase C can phosphorylate those serines of p47PHOX whose phosphorylation is necessary for its activity. Work with inhibitors suggested that a phosphatidylinositol 3-kinase-dependent pathway also can activate the oxidase. Phosphorylation of p47PHOX by Akt (protein kinase B), whose activation depends on phosphatidylinositol 3-kinase, could be the final step in such a pathway. We now find that Akt activates the oxidase in vitro by phosphorylating serines S304 and S328 of p47PHOX. These results suggest that Akt could participate in the activation of the leukocyte NADPH oxidase. PMID:12704229

  14. mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation.

    PubMed

    Moon, Jong-Seok; Hisata, Shu; Park, Mi-Ae; DeNicola, Gina M; Ryter, Stefan W; Nakahira, Kiichi; Choi, Augustine M K

    2015-07-07

    The mammalian target of rapamycin complex 1 (mTORC1) regulates activation of immune cells and cellular energy metabolism. Although glycolysis has been linked to immune functions, the mechanisms by which glycolysis regulates NLRP3 inflammasome activation remain unclear. Here, we demonstrate that mTORC1-induced glycolysis provides an essential mechanism for NLRP3 inflammasome activation. Moreover, we demonstrate that hexokinase 1 (HK1)-dependent glycolysis, under the regulation of mTORC1, represents a critical metabolic pathway for NLRP3 inflammasome activation. Downregulation of glycolysis by inhibition of Raptor/mTORC1 or HK1 suppressed both pro-IL-1β maturation and caspase-1 activation in macrophages in response to LPS and ATP. These results suggest that upregulation of HK1-dependent glycolysis by mTORC1 regulates NLRP3 inflammasome activation.

  15. 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.

  16. 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.

  17. Two Degradation Pathways of the p35 Cdk5 (Cyclin-dependent Kinase) Activation Subunit, Dependent and Independent of Ubiquitination.

    PubMed

    Takasugi, Toshiyuki; Minegishi, Seiji; Asada, Akiko; Saito, Taro; Kawahara, Hiroyuki; Hisanaga, Shin-ichi

    2016-02-26

    Cdk5 is a versatile protein kinase that is involved in various neuronal activities, such as the migration of newborn neurons, neurite outgrowth, synaptic regulation, and neurodegenerative diseases. Cdk5 requires the p35 regulatory subunit for activation. Because Cdk5 is more abundantly expressed in neurons compared with p35, the p35 protein levels determine the kinase activity of Cdk5. p35 is a protein with a short half-life that is degraded by proteasomes. Although ubiquitination of p35 has been previously reported, the degradation mechanism of p35 is not yet known. Here, we intended to identify the ubiquitination site(s) in p35. Because p35 is myristoylated at the N-terminal glycine, the possible ubiquitination sites are the lysine residues in p35. We mutated all 23 Lys residues to Arg (p35 23R), but p35 23R was still rapidly degraded by proteasomes at a rate similar to wild-type p35. The degradation of p35 23R in primary neurons and the Cdk5 activation ability of p35 23R suggested the occurrence of ubiquitin-independent degradation of p35 in physiological conditions. We found that p35 has the amino acid sequence similar to the ubiquitin-independent degron in the NKX3.1 homeodomain transcription factor. An Ala mutation at Pro-247 in the degron-like sequence made p35 stable. These results suggest that p35 can be degraded by two degradation pathways: ubiquitin-dependent and ubiquitin-independent. The rapid degradation of p35 by two different methods would be a mechanism to suppress the production of p25, which overactivates Cdk5 to induce neuronal cell death.

  18. Hypotonicity activates a voltage-dependent membrane conductance in N2a neuroblastoma cells.

    PubMed

    Taruno, Akiyuki; Marunaka, Yoshinori

    2017-03-04

    To maintain cellular and bodily homeostasis, cells respond to extracellular stimuli including osmotic stress by activating various ion channels, which have been implicated in many physiological and pathophysiological conditions. However, cellular osmosensory mechanisms remain elusive. Here, we report a novel voltage-dependent current in N2a cells activated by exposure to hypotonic stress. After a hypotonic challenge, N2a cells sequentially develop two distinct currents. The volume-regulated anion channel (VRAC) current emerges first and, after a delay, activation of a previously uncharacterized strongly outwardly rectifying current follows. The latter, delayed current (Id) is insensitive to NPPB, a nonspecific blocker of Cl(-) channels, and intracellular Mg(2+), which inhibits VRAC and swelling-activated TRPM3 and TRPM7 channels. Replacement of extracellular Na(+) with NMDG(+) reduces inward tail currents, suggesting that Id is mediated by cations. Finally, Id shows voltage-dependent activation with slow activation kinetics and half-maximal activation at +76 mV. These pharmacological and biophysical characteristics of Id are distinct from those of known osmotic cell swelling-activated ion channels. In conclusion, our data identify and characterize a novel osmotically-activated, voltage-dependent ion channel in N2a cells.

  19. Activity-Dependent Adenosine Release May Be Linked to Activation of Na+-K+ ATPase: An In Vitro Rat Study

    PubMed Central

    Sims, Robert Edward; Dale, Nicholas

    2014-01-01

    In the brain, extracellular adenosine increases as a result of neuronal activity. The mechanisms by which this occurs are only incompletely understood. Here we investigate the hypothesis that the Na+ influxes associated with neuronal signalling activate the Na+-K+ ATPase which, by consuming ATP, generates intracellular adenosine that is then released via transporters. By measuring adenosine release directly with microelectrode biosensors, we have demonstrated that AMPA-receptor evoked adenosine release in basal forebrain and cortex depends on extracellular Na+. We have simultaneously imaged intracellular Na+ and measured adenosine release. The accumulation of intracellular Na+ during AMPA receptor activation preceded adenosine release by some 90 s. By removing extracellular Ca2+, and thus preventing indiscriminate neuronal activation, we used ouabain to test the role of the Na+-K+ ATPase in the release of adenosine. Under conditions which caused a Na+ influx, brief applications of ouabain increased the accumulation of intracellular Na+ but conversely rapidly reduced extracellular adenosine levels. In addition, ouabain greatly reduced the amount of adenosine released during application of AMPA. Our data therefore suggest that activity of the Na+-K+ ATPase is directly linked to the efflux of adenosine and could provide a universal mechanism that couples adenosine release to neuronal activity. The Na+-K+ ATPase-dependent adenosine efflux is likely to provide adenosine-mediated activity-dependent negative feedback that will be important in many diverse functional contexts including the regulation of sleep. PMID:24489921

  20. Surfactin inducing mitochondria-dependent ROS to activate MAPKs, NF-κB and inflammasomes in macrophages for adjuvant activity.

    PubMed

    Gan, Ping; Gao, Zhenqiu; Zhao, Xiuyun; Qi, Gaofu

    2016-12-14

    Surfactin, a natural lipopeptide, can be used both as parenteral and non-parenteral adjuvant for eliciting immune response. However, the mechanisms that confer its adjuvant properties have not been fully explored. By staining with NHS-Rhodamine B labeled surfactin and Mito-Tracker Green, we found surfactin could penetrate into macrophages to bind with mitochondria, following induce ROS that could be inhibited by mitochondria-dependent ROS inhibitor. ROS enhanced p38 MAPK and JNK expression, as well their phorsphorylation, following activated NF-κB nuclear translocation in macrophages that was obviously inhibited by mitochondria-dependent ROS inhibitor. However, inhibition of ROS production only weakened p38 MAPK and JNK expression, but not their phosphorylation in macrophages. As a result, surfaction could activate NF-κB to release TNF-α by the mitochondria-dependent ROS signalling pathway. ROS also induced macrophages apoptosis to release endogenous danger signals, following activated inflammasomes of NLRP1, NLRP3, IPAF and AIM2 in vitro and only NLRP1 in vivo, as well caspase-1 and IL-1 in macrophages, which were significantly inhibited by pre-treatment with ROS inhibitors. Collectively, surfactin as a kind of non-pathogen-associated molecular patterns, modulates host innate immunity by multiple signalling pathways, including induction of mitochondria-dependent ROS, activating MAPKs and NF-κB, and inducing cell apoptosis to realease endogenous danger signals for activation of inflammasomes.

  1. Surfactin inducing mitochondria-dependent ROS to activate MAPKs, NF-κB and inflammasomes in macrophages for adjuvant activity

    PubMed Central

    Gan, Ping; Gao, Zhenqiu; Zhao, Xiuyun; Qi, Gaofu

    2016-01-01

    Surfactin, a natural lipopeptide, can be used both as parenteral and non-parenteral adjuvant for eliciting immune response. However, the mechanisms that confer its adjuvant properties have not been fully explored. By staining with NHS-Rhodamine B labeled surfactin and Mito-Tracker Green, we found surfactin could penetrate into macrophages to bind with mitochondria, following induce ROS that could be inhibited by mitochondria-dependent ROS inhibitor. ROS enhanced p38 MAPK and JNK expression, as well their phorsphorylation, following activated NF-κB nuclear translocation in macrophages that was obviously inhibited by mitochondria-dependent ROS inhibitor. However, inhibition of ROS production only weakened p38 MAPK and JNK expression, but not their phosphorylation in macrophages. As a result, surfaction could activate NF-κB to release TNF-α by the mitochondria-dependent ROS signalling pathway. ROS also induced macrophages apoptosis to release endogenous danger signals, following activated inflammasomes of NLRP1, NLRP3, IPAF and AIM2 in vitro and only NLRP1 in vivo, as well caspase-1 and IL-1 in macrophages, which were significantly inhibited by pre-treatment with ROS inhibitors. Collectively, surfactin as a kind of non-pathogen-associated molecular patterns, modulates host innate immunity by multiple signalling pathways, including induction of mitochondria-dependent ROS, activating MAPKs and NF-κB, and inducing cell apoptosis to realease endogenous danger signals for activation of inflammasomes. PMID:27966632

  2. Activation of polyomavirus DNA replication by yeast GAL4 is dependent on its transcriptional activation domains.

    PubMed Central

    Bennett-Cook, E R; Hassell, J A

    1991-01-01

    The polyomavirus replication origin contains transcriptional regulatory sequences. To determine how these elements function in DNA replication, and to learn whether a common mechanism underlies the activation of transcription and DNA replication, we tested whether a well-characterized transcriptional activator, yeast GAL4, was capable of stimulating DNA replication and transcription in the same mammalian cell line. We observed that GAL4 activated polyomavirus DNA replication in mouse cells when its binding site was juxtaposed to the late border of the polyomavirus origin core. Synergistic activation of DNA replication was achieved by multimerization of the GAL4 binding site. Analysis of GAL4 mutant proteins, GAL4 hybrid proteins and mutants of the latter revealed that the activation domains of these transcriptional activators were required to stimulate DNA replication. In agreement with previously published data, the activation domains of GAL4 were also required to enhance transcription in the same mouse cell line. These observations implicate transcriptional activators in Py DNA replication and suggest that similar mechanisms govern the activation of transcription and DNA replication. Images PMID:1849079

  3. Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone

    SciTech Connect

    Guo, Feng; Stanevich, Vitali; Wlodarchak, Nathan; Sengupta, Rituparna; Jiang, Li; Satyshur, Kenneth A.; Xing, Yongna

    2013-10-08

    Proper activation of protein phosphatase 2A (PP2A) catalytic subunit is central for the complex PP2A regulation and is crucial for broad aspects of cellular function. The crystal structure of PP2A bound to PP2A phosphatase activator (PTPA) and ATPγS reveals that PTPA makes broad contacts with the structural elements surrounding the PP2A active site and the adenine moiety of ATP. PTPA-binding stabilizes the protein fold of apo-PP2A required for activation, and orients ATP phosphoryl groups to bind directly to the PP2A active site. This allows ATP to modulate the metal-binding preferences of the PP2A active site and utilize the PP2A active site for ATP hydrolysis. In vitro, ATP selectively and drastically enhances binding of endogenous catalytic metal ions, which requires ATP hydrolysis and is crucial for acquisition of pSer/Thr-specific phosphatase activity. Furthermore, both PP2A- and ATP-binding are required for PTPA function in cell proliferation and survival. Our results suggest novel mechanisms of PTPA in PP2A activation with structural economy and a unique ATP-binding pocket that could potentially serve as a specific therapeutic target.

  4. 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

  5. Molecular mechanism of allosteric substrate activation in a thiamine diphosphate-dependent decarboxylase.

    PubMed

    Versées, Wim; Spaepen, Stijn; Wood, Martin D H; Leeper, Finian J; Vanderleyden, Jos; Steyaert, Jan

    2007-11-30

    Thiamine diphosphate-dependent enzymes are involved in a wide variety of metabolic pathways. The molecular mechanism behind active site communication and substrate activation, observed in some of these enzymes, has since long been an area of debate. Here, we report the crystal structures of a phenylpyruvate decarboxylase in complex with its substrates and a covalent reaction intermediate analogue. These structures reveal the regulatory site and unveil the mechanism of allosteric substrate activation. This signal transduction relies on quaternary structure reorganizations, domain rotations, and a pathway of local conformational changes that are relayed from the regulatory site to the active site. The current findings thus uncover the molecular mechanism by which the binding of a substrate in the regulatory site is linked to the mounting of the catalytic machinery in the active site in this thiamine diphosphate-dependent enzyme.

  6. Chronic Mild Stress Modulates Activity-Dependent Transcription of BDNF in Rat Hippocampal Slices.

    PubMed

    Molteni, Raffaella; Rossetti, Andrea C; Savino, Elisa; Racagni, Giorgio; Calabrese, Francesca

    2016-01-01

    Although activity-dependent transcription represents a crucial mechanism for long-lasting experience-dependent changes in the hippocampus, limited data exist on its contribution to pathological conditions. We aim to investigate the influence of chronic stress on the activity-dependent transcription of brain-derived neurotrophic factor (BDNF). The ex vivo methodology of acute stimulation of hippocampal slices obtained from rats exposed to chronic mild stress (CMS) was used to evaluate whether the adverse experience may alter activity-dependent BDNF gene expression. CMS reduces BDNF expression and that acute depolarization significantly upregulates total BDNF mRNA levels only in control animals, showing that CMS exposure may alter BDNF transcription under basal conditions and during neuronal activation. Moreover, while the basal effect of CMS on total BDNF reflects parallel modulations of all the transcripts examined, isoform-specific changes were found after depolarization. This different effect was also observed in the activation of intracellular signaling pathways related to the neurotrophin. In conclusion, our study discloses a functional alteration of BDNF transcription as a consequence of stress. Being the activity-regulated transcription a critical process in synaptic and neuronal plasticity, the different regulation of individual BDNF promoters may contribute to long-lasting changes, which are fundamental for the vulnerability of the hippocampus to stress-related diseases.

  7. 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.

  8. Strings on a Violin: Location Dependence of Frequency Tuning in Active Dendrites

    PubMed Central

    Das, Anindita; Rathour, Rahul K.; Narayanan, Rishikesh

    2017-01-01

    Strings on a violin are tuned to generate distinct sound frequencies in a manner that is firmly dependent on finger location along the fingerboard. Sound frequencies emerging from different violins could be very different based on their architecture, the nature of strings and their tuning. Analogously, active neuronal dendrites, dendrites endowed with active channel conductances, are tuned to distinct input frequencies in a manner that is dependent on the dendritic location of the synaptic inputs. Further, disparate channel expression profiles and differences in morphological characteristics could result in dendrites on different neurons of the same subtype tuned to distinct frequency ranges. Alternately, similar location-dependence along dendritic structures could be achieved through disparate combinations of channel profiles and morphological characteristics, leading to degeneracy in active dendritic spectral tuning. Akin to strings on a violin being tuned to different frequencies than those on a viola or a cello, different neuronal subtypes exhibit distinct channel profiles and disparate morphological characteristics endowing each neuronal subtype with unique location-dependent frequency selectivity. Finally, similar to the tunability of musical instruments to elicit distinct location-dependent sounds, neuronal frequency selectivity and its location-dependence are tunable through activity-dependent plasticity of ion channels and morphology. In this morceau, we explore the origins of neuronal frequency selectivity, and survey the literature on the mechanisms behind the emergence of location-dependence in distinct forms of frequency tuning. As a coda to this composition, we present some future directions for this exciting convergence of biophysical mechanisms that endow a neuron with frequency multiplexing capabilities. PMID:28348519

  9. Temperature dependence of the Raman-active phonon frequencies in indium sulfide

    NASA Astrophysics Data System (ADS)

    Gasanly, N. M.; Özkan, H.; Aydinli, A.; Yilmaz, İ.

    1999-03-01

    The temperature dependence of the Raman-active mode frequencies in indium sulfide was measured in the range from 10 to 300 K. The analysis of the temperature dependence of the A g intralayer optical modes show that Raman frequency shift results from the change of harmonic frequency with volume expansion and anharmonic coupling to phonons of other branches. The pure-temperature contribution (phonon-phonon coupling) is due to three- and four-phonon processes.

  10. 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.

  11. Sodium Pumps Mediate Activity-Dependent Changes in Mammalian Motor Networks

    PubMed Central

    Picton, Laurence D.; Nascimento, Filipe; Broadhead, Matthew J.; Sillar, Keith T.

    2017-01-01

    Ubiquitously expressed sodium pumps are best known for maintaining the ionic gradients and resting membrane potential required for generating action potentials. However, activity- and state-dependent changes in pump activity can also influence neuronal firing and regulate rhythmic network output. Here we demonstrate that changes in sodium pump activity regulate locomotor networks in the spinal cord of neonatal mice. The sodium pump inhibitor, ouabain, increased the frequency and decreased the amplitude of drug-induced locomotor bursting, effects that were dependent on the presence of the neuromodulator dopamine. Conversely, activating the pump with the sodium ionophore monensin decreased burst frequency. When more “natural” locomotor output was evoked using dorsal-root stimulation, ouabain increased burst frequency and extended locomotor episode duration, whereas monensin slowed and shortened episodes. Decreasing the time between dorsal-root stimulation, and therefore interepisode interval, also shortened and slowed activity, suggesting that pump activity encodes information about past network output and contributes to feedforward control of subsequent locomotor bouts. Using whole-cell patch-clamp recordings from spinal motoneurons and interneurons, we describe a long-duration (∼60 s), activity-dependent, TTX- and ouabain-sensitive, hyperpolarization (∼5 mV), which is mediated by spike-dependent increases in pump activity. The duration of this dynamic pump potential is enhanced by dopamine. Our results therefore reveal sodium pumps as dynamic regulators of mammalian spinal motor networks that can also be affected by neuromodulatory systems. Given the involvement of sodium pumps in movement disorders, such as amyotrophic lateral sclerosis and rapid-onset dystonia parkinsonism, knowledge of their contribution to motor network regulation also has considerable clinical importance. SIGNIFICANCE STATEMENT The sodium pump is ubiquitously expressed and responsible

  12. Cardiac troponin I threonine 144: role in myofilament length dependent activation.

    PubMed

    Tachampa, Kittipong; Wang, Helen; Farman, Gerrie P; de Tombe, Pieter P

    2007-11-26

    Myofilament length-dependent activation is the main cellular mechanism responsible for the Frank-Starling law of the heart. All striated muscle display length-dependent activation properties, but it is most pronounced in cardiac muscle and least in slow skeletal muscle. Cardiac muscle expressing slow skeletal troponin (ssTn)I instead of cardiac troponin (cTn)I displays reduced myofilament length-dependent activation. The inhibitory region of troponin (Tn)I differs by a single residue, proline at position 112 in ssTnI versus threonine at position 144 in cTnI. Here we tested whether this substitution was important for myofilament length-dependent activation; using recombinant techniques, we prepared wild-type cTnI, ssTnI, and 2 mutants: cTnI(Thr>Pro) and ssTnI(Pro>Thr). Purified proteins were complexed with recombinant cardiac TnT/TnC and exchanged into skinned rat cardiac trabeculae. Force-Ca2+ relationships were determined to derive myofilament Ca2+ sensitivity (EC50) at 2 sarcomere lengths: 2.0 and 2.2 microm (n=7). Myofilament length-dependent activation was indexed as deltaEC50, the difference in EC50 between sarcomere lengths of 2.0 and 2.2 microm. Incorporation of ssTnI compared with cTnI into the cardiac sarcomere reduced deltaEC50 from 1.26+/-0.30 to 0.19+/-0.04 micromol/L. A similar reduction also could be observed when Tn contained cTnI(Thr>Pro) (deltaEC50=0.24+/-0.04 micromol/L), whereas the presence of ssTnI(Pro>Thr) increased deltaEC50 to 0.94+/-0.12 micromol/L. These results suggest that Thr144 in cardiac TnI modulates cardiac myofilament length-dependent activation.

  13. Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons

    PubMed Central

    Qiu, Jing; McQueen, Jamie; Bilican, Bilada; Dando, Owen; Magnani, Dario; Punovuori, Karolina; Selvaraj, Bhuvaneish T; Livesey, Matthew; Haghi, Ghazal; Heron, Samuel; Burr, Karen; Patani, Rickie; Rajan, Rinku; Sheppard, Olivia; Kind, Peter C; Simpson, T Ian; Tybulewicz, Victor LJ; Wyllie, David JA; Fisher, Elizabeth MC; Lowell, Sally; Chandran, Siddharthan; Hardingham, Giles E

    2016-01-01

    Evolutionary differences in gene regulation between humans and lower mammalian experimental systems are incompletely understood, a potential translational obstacle that is challenging to surmount in neurons, where primary tissue availability is poor. Rodent-based studies show that activity-dependent transcriptional programs mediate myriad functions in neuronal development, but the extent of their conservation in human neurons is unknown. We compared activity-dependent transcriptional responses in developing human stem cell-derived cortical neurons with those induced in developing primary- or stem cell-derived mouse cortical neurons. While activity-dependent gene-responsiveness showed little dependence on developmental stage or origin (primary tissue vs. stem cell), notable species-dependent differences were observed. Moreover, differential species-specific gene ortholog regulation was recapitulated in aneuploid mouse neurons carrying human chromosome-21, implicating promoter/enhancer sequence divergence as a factor, including human-specific activity-responsive AP-1 sites. These findings support the use of human neuronal systems for probing transcriptional responses to physiological stimuli or indeed pharmaceutical agents. DOI: http://dx.doi.org/10.7554/eLife.20337.001 PMID:27692071

  14. Molecular cloning and functional characterization of porcine DNA-dependent activator of IFN-regulatory factors (DAI).

    PubMed

    Xie, Lilan; Fang, Liurong; Wang, Dang; Luo, Rui; Cai, Kaimei; Chen, Huanchun; Xiao, Shaobo

    2010-03-01

    The DNA-dependent activator of IFN-regulatory factors (DAI) is a recently identified DNA sensor for intracellular DNA that triggers a signal for the production of type I IFN. Here we report the cloning and characterization of porcine DAI (poDAI). The full-length of poDAI encodes 439 amino acids, contains two N-terminal DNA-binding domains and shows similarity to mouse, rat, dog, monkey, human, horse and cattle counterparts ranging from 44% to 67%. poDAI mRNA expression was mainly detected in spleen, lung, kidney and small intestine. Over-expression of poDAI activated transcription factors IRF3 and NF-kappaB and induced IFN-beta in different porcine cell lines, but to varying degrees. Deletion mutant analysis revealed that both the DNA-binding domains and the C-terminus are required for full activation of IFN-beta. siRNA targeting poDAI significantly decreased poly(dAT:dAT)- or Pseudorabies virus (PRV)-induced IFN-beta activation. These results indicate that DAI is an important immuno-regulator of the porcine innate immune system.

  15. Distinct roles for Cav2.1–2.3 in activity-dependent synaptic dynamics

    PubMed Central

    Ricoy, Ulises M.

    2014-01-01

    Synaptic transmission throughout most of the CNS is steeply dependent on presynaptic calcium influx through the voltage-gated calcium channels Cav2.1–Cav2.3. In addition to triggering exocytosis, this calcium influx also recruits short-term synaptic plasticity. During the complex patterns of presynaptic activity that occur in vivo, several forms of plasticity combine to generate a synaptic output that is dynamic, in which the size of a given excitatory postsynaptic potential (EPSP) in response to a given spike depends on the short-term history of presynaptic activity. It remains unclear whether the different Cav2 channels play distinct roles in defining these synaptic dynamics and, if so, under what conditions different Cav2 family members most effectively determine synaptic output. We examined these questions by measuring the effects of calcium channel-selective toxins on synaptic transmission at the Schaffer collateral synapse in hippocampal slices from adult mice in response to both low-frequency stimulation and complex stimulus trains derived from in vivo recordings. Blockade of Cav2.1 had a greater inhibitory effect on synaptic transmission during low-frequency components of the stimulus train than on synaptic transmission during high-frequency components of the train, indicating that Cav2.1 had a greater fractional contribution to synaptic transmission at low frequencies than at high frequencies. Relative to Cav2.1, Cav2.2 had a disproportionately reduced contribution to synaptic transmission at frequencies >20 Hz, while Cav2.3 had a disproportionately increased contribution to synaptic transmission at frequencies >1 Hz. These activity-dependent effects of different Cav2 family members shape the filtering characteristics of GABAB receptor-mediated presynaptic inhibition. Thus different Cav2 channels vary in their coupling to synaptic transmission over different frequency ranges, with consequences for the frequency tuning of both synaptic dynamics and

  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.

  17. [Suicidal and personality characteristics of women married to men with alcohol dependence and suicidal activity].

    PubMed

    Merinov, A V; Shustov, D I

    2011-01-01

    The effect of the suicidal activity in men with alcohol dependence on suicidal indexes, personal-codependency and psychological specifics of their wives has been studied. It has been found that women married to suicidal men with alcohol dependence significantly more frequently demonstrate suicidal activity (a phenomenon of suicidal matrimonial comorbidity) compared to wives of "non-suicidal" men. They also reveal non-suicidal behavioral patterns more frequently and prosuicidal predictors are quite common in them. This contingent of women has high suicidal potential that needs special attention during the therapeutic work.

  18. Age-dependence of hepatic dimethylnitrosamine-demethylase activity in the rat.

    PubMed

    Davies, D L; Bryant, G M; Arcos, J C; Argus, M F

    1976-05-01

    The mixed-function oxidase which activates the carcinogen dimethylnitrosamine (DMN) was determined in the rat liver as a function of animal age. DMN-demethylase activity increased considerably at first to reach a maximum on day 29, and then substantially decreased to day 59; thereafter, enzyme activity remained essentially stable up to at least day 110. Pretreatment with 3-methylcholanthrene, which caused a pronounced decrease in this enzyme activity, did not affect the general shape of the age-dependence curve. The results suggest that rats between weaning and sexual maturity are more susceptible to the carcinogenic effects of pulse doses of DMN than are neonates or adult animals.

  19. Metacaspase 2 of Trypanosoma brucei is a calcium-dependent cysteine peptidase active without processing.

    PubMed

    Moss, Catherine X; Westrop, Gareth D; Juliano, Luiz; Coombs, Graham H; Mottram, Jeremy C

    2007-12-11

    Metacaspases are cysteine peptidases that are distantly related to the caspases, for which proteolytic processing is central to their activation. Here, we show that recombinant metacaspase 2 (MCA2) from Trypanosoma brucei has arginine/lysine-specific, Ca(2+)-dependent proteolytic activity. Autocatalytic processing of MCA2 occurred after Lys55 and Lys268; however, this was shown not to be required for the enzyme to be proteolytically active. The necessity of Ca(2+), but not processing, for MCA2 enzymatic activity clearly distinguishes MCA2 from the caspases and would be consistent with different physiological roles.

  20. 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.

  1. Macrophage Migration Inhibitory Factor Activates Hypoxia-Inducible Factor in a p53-Dependent Manner

    PubMed Central

    Oda, Seiko; Oda, Tomoyuki; Nishi, Kenichiro; Takabuchi, Satoshi; Wakamatsu, Takuhiko; Tanaka, Tomoharu; Adachi, Takehiko; Fukuda, Kazuhiko; Semenza, Gregg L.; Hirota, Kiichi

    2008-01-01

    Background Macrophage migration inhibitory factor (MIF) is not only a cytokine which has a critical role in several inflammatory conditions but also has endocrine and enzymatic functions. MIF is identified as an intracellular signaling molecule and is implicated in the process of tumor progression, and also strongly enhances neovascularization. Overexpression of MIF has been observed in tumors from various organs. MIF is one of the genes induced by hypoxia in an hypoxia-inducible factor 1 (HIF-1)-dependent manner. Methods/Principal Findings The effect of MIF on HIF-1 activity was investigated in human breast cancer MCF-7 and MDA-MB-231 cells, and osteosarcoma Saos-2 cells. We demonstrate that intracellular overexpression or extracellular administration of MIF enhances activation of HIF-1 under hypoxic conditions in MCF-7 cells. Mutagenesis analysis of MIF and knockdown of 53 demonstrates that the activation is not dependent on redox activity of MIF but on wild-type p53. We also indicate that the MIF receptor CD74 is involved in HIF-1 activation by MIF at least when MIF is administrated extracellularly. Conclusion/Significance MIF regulates HIF-1 activity in a p53-dependent manner. In addition to MIF's potent effects on the immune system, MIF is linked to fundamental processes conferring cell proliferation, cell survival, angiogenesis, and tumor invasiveness. This functional interdependence between MIF and HIF-1α protein stabilization and transactivation activity provide a molecular mechanism for promotion of tumorigenesis by MIF. PMID:18493321

  2. 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.

  3. Solar activity dependence of low-and mid-latitude ionosphere

    NASA Astrophysics Data System (ADS)

    Chen, Yiding; Liu, Libo; Wan, Weixing

    Solar activity dependence of low-and mid-latitude ionosphere is investigated using ionosonde and the ROCSAT-1 satellite (600 km) observations. The pattern in the solar activity varia-tion of the electron density shows significant local time, seasonal, latitudinal, and altitudinal dependences. Noontime NmF2 saturates with F107 in all seasons in low-latitude regions, while it saturates with F107 in equinoxes and local summer and linearly increases with F107 in local winter in mid-latitude regions. Nighttime NmF2 nearly increases with F107 linearly in equinox seasons and saturates with F107 in local summer, what is peculiar is that there is an amplifica-tion trend of nighttime NmF2 with F107 in local winter. We discussed the possible mechanisms which affect the solar activity variation trend of NmF2 and argued that the changes of neutral atmosphere and ionospheric dynamics are important for the solar activity variation trend of NmF2. Solar activity variations of the plasma density at 600 km present three kinds of patterns (linearity, amplification, and saturation), the pattern depends on local time, season, and lati-tude. That is different from the case at higher altitudes, e.g., 800 km, where the amplification trend prevails. In particular, saturation effect is found in the dip equator region at equinox sunset. Latitudinal distribution of the plasma density at 600 km also depends on local time, season, and solar activity level. Around sunset, a profound double-peak structure is found in the latitudinal distribution of the plasma density in solar maximum equinox and December solstice months. Solar activity dependence of the low-latitude topside ionosphere at 600 km is strongly related to the low-latitude dynamics processes.

  4. Requirements for intercistronic distance and level of eukaryotic initiation factor 2 activity in reinitiation on GCN4 mRNA vary with the downstream cistron.

    PubMed Central

    Grant, C M; Miller, P F; Hinnebusch, A G

    1994-01-01

    Translational control of the GCN4 gene in response to amino acid availability is mediated by four short open reading frames in the GCN4 mRNA leader (uORFs) and by phosphorylation of eukaryotic initiation factor 2 (eIF-2). We have proposed that reducing eIF-2 activity by phosphorylation of its alpha subunit or by a mutation in the eIF-2 recycling factor eIF-2B allows ribosomes which have translated the 5'-proximal uORF1 to bypass uORF2 to uORF4 and reinitiate at GCN4 instead. In this report, we present two lines of evidence that all ribosomes which synthesize GCN4 have previously translated uORF1, resumed scanning, and reinitiated at the GCN4 start site. First, GCN4 expression was abolished when uORF1 was elongated to make it overlap the beginning of the GCN4 coding region. Second, GCN4 expression was reduced as uORF1 was moved progressively closer to GCN4, decreasing to only 5% of the level seen in the absence of all uORFs when only 32 nucleotides separated uORF1 from GCN4. We additionally found that inserting small synthetic uORFs between uORF4 and GCN4 inhibited GCN4 expression under derepressing conditions, confirming the idea that reinitiation at GCN4 under conditions of diminished eIF-2 activity is proportional to the distance of the reinitiation site downstream from uORF1. While uORF4 and GCN4 appear to be equally effective at capturing ribosomes scanning downstream from the 5' cap of mRNA, these two ORFs differ greatly in their ability to capture reinitiating ribosomes scanning from uORF1. When the active form of eIF-2 is present at high levels, reinitiation appears to be much more efficient at uORF4 than at GCN4 when each is located very close to uORF1. Under conditions of reduced recycling of eIF-2, reinitiation at uORF4 is substantially suppressed, which allows ribosomes to reach the GCN4 start site; in contrast, reinitiation at GCN4 in constructs lacking uORF4 is unaffected by decreasing the level of eIF-2 activity. This last finding raises the

  5. The Effects of Methylphenidate on Cognitive Control in Active Methamphetamine Dependence Using Functional Magnetic Resonance Imaging

    PubMed Central

    Jan, Reem K.; Lin, Joanne C.; McLaren, Donald G.; Kirk, Ian J.; Kydd, Rob R.; Russell, Bruce R.

    2014-01-01

    Methamphetamine (MA) dependence is associated with cognitive deficits. Methylphenidate (MPH) has been shown to improve inhibitory control in healthy and cocaine-dependent subjects. This study aimed to understand the neurophysiological effects before and after acute MPH administration in active MA-dependent and control subjects. Fifteen MA-dependent and 18 control subjects aged 18–46 years were scanned using functional magnetic resonance imaging before and after either a single oral dose of MPH (18 mg) or placebo while performing a color-word Stroop task. Baseline accuracy was lower (p = 0.026) and response time (RT) was longer (p < 0.0001) for the incongruent compared to congruent condition, demonstrating the task probed cognitive control. Increased activation of the dorsolateral prefrontal cortex (DLPFC) and parietal cortex during the incongruent and Stroop effect conditions, respectively was observed in MA-dependent compared to control subjects (p < 0.05), suggesting the need to recruit neural resources within these regions for conflict resolution. Post- compared to pre-MPH treatment, increased RT and DLPFC activation for the Stroop effect were observed in MA-dependent subjects (p < 0.05). In comparison to MPH-treated controls and placebo-treated MA-dependent subjects, MPH-treated MA-dependent subjects showed decreased activation of parietal and occipital regions during the incongruent and Stroop effect conditions (p < 0.05). These findings suggest that in MA-dependent subjects, MPH facilitated increased recruitment of the DLPFC for Stroop conflict resolution, and a decreased need for recruitment of neural resources in parietal and occipital regions compared to the other groups, while maintaining a comparable level of task performance to that achieved pre-drug administration. Due to the small sample size, the results from this study are preliminary; however, they inform us about the effects of MPH on the neural correlates of cognitive

  6. 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.

  7. Consequences and utility of the zinc-dependent metalloprotease activity of anthrax lethal toxin.

    PubMed

    Bromberg-White, Jennifer; Lee, Chih-Shia; Duesbery, Nicholas

    2010-05-01

    Anthrax is caused by the gram-positive bacterium Bacillus anthracis. The pathogenesis of this disease is dependent on the presence of two binary toxins, edema toxin (EdTx) and lethal toxin (LeTx). LeTx, the major virulence factor contributing to anthrax, contains the effector moiety lethal factor (LF), a zinc-dependent metalloprotease specific for targeting mitogen-activated protein kinase kinases. This review will focus on the protease-specific activity and function of LF, and will include a discussion on the implications and consequences of this activity, both in terms of anthrax disease, and how this activity can be exploited to gain insight into other pathologic conditions.

  8. Activity-dependent signaling: influence on plasticity in circuits controlling fear-related behavior

    PubMed Central

    Hill, Julia L; Martinowich, Keri

    2015-01-01

    Fear regulation is impaired in anxiety and trauma-related disorders. Patients experience heightened fear expression and reduced ability to extinguish fear memories. Because fear regulation is abnormal in these disorders and extinction recapitulates current treatment strategies, understanding the underlying mechanisms is vital for developing new treatments. This is critical because although extinction-based exposure therapy is a mainstay of treatment, relapse is common. We examine recent findings describing changes in network activity and functional connectivity within limbic circuits during fear regulation, and explore how activity-dependent signaling contributes to the neural activity patterns that control fear and anxiety. We review the role of the prototypical activity-dependent molecule, brain-derived neurotrophic factor (BDNF), whose signaling has been critically linked to regulation of fear behavior. PMID:26485574

  9. Perturbed Length–Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations

    PubMed Central

    Sequeira, Vasco; Wijnker, Paul J.M.; Nijenkamp, Louise L.A.M.; Kuster, Diederik W.D.; Najafi, Aref; Witjas-Paalberends, E. Rosalie; Regan, Jessica A.; Boontje, Nicky; ten Cate, Folkert J.; Germans, Tjeerd; Carrier, Lucie; Sadayappan, Sakthivel; van Slegtenhorst, Marjon A.; Zaremba, Ruud; Foster, D. Brian; Murphy, Anne M.; Poggesi, Corrado; dos Remedios, Cris; Stienen, Ger J.M.; Ho, Carolyn Y.; Michels, Michelle; van der Velden, Jolanda

    2013-01-01

    Rationale High-myofilament Ca2+-sensitivity has been proposed as trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) based on in vitro and transgenic mice studies. However, myofilament Ca2+-sensitivity depends on protein phosphorylation and muscle length, and at present, data in human are scarce. Objective To investigate whether high-myofilament Ca2+-sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick- and thin-filament proteins. Methods and Results Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca2+-sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA)-targets compared with donors. After exogenous PKA treatment, myofilament Ca2+-sensitivity was either similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations, but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values. Conclusions High-myofilament Ca2+-sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA-targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via post-translational modifications other than PKA-hypophosphorylation or altered protein–protein interactions, and represents a

  10. Modulation of Rhythmic Activity in Mammalian Spinal Networks Is Dependent on Excitability State

    PubMed Central

    2017-01-01

    Neuromodulators play an important role in activating rhythmically active motor networks; however, what remains unclear are the network interactions whereby neuromodulators recruit spinal motor networks to produce rhythmic activity. Evidence from invertebrate systems has demonstrated that the effect of neuromodulators depends on the pre-existing state of the network. We explored how network excitation state affects the ability of dopamine to evoke rhythmic locomotor activity in the neonatal mouse isolated spinal cord. We found that dopamine can evoke unique patterns of motor activity that are dependent on the excitability state of motor networks. Different patterns of motor activity ranging from tonic, nonrhythmic activity to multirhythmic, nonlocomotor activity to locomotor activity were produced by altering global motor network excitability through manipulations of the extracellular potassium and bath NMDA concentration. A similar effect was observed when network excitation was manipulated during an unstable multirhythm evoked by a low concentration (15 µm) of 5-HT, suggesting that our results are not neuromodulator specific. Our data show in vertebrate systems that modulation is a two-way street and that modulatory actions are largely influenced by the network state. The level of network excitation can account for variability between preparations and is an additional factor to be considered when circuit elements are removed from the network. PMID:28144626

  11. Sodium Pumps Mediate Activity-Dependent Changes in Mammalian Motor Networks.

    PubMed

    Picton, Laurence D; Nascimento, Filipe; Broadhead, Matthew J; Sillar, Keith T; Miles, Gareth B

    2017-01-25

    Ubiquitously expressed sodium pumps are best known for maintaining the ionic gradients and resting membrane potential required for generating action potentials. However, activity- and state-dependent changes in pump activity can also influence neuronal firing and regulate rhythmic network output. Here we demonstrate that changes in sodium pump activity regulate locomotor networks in the spinal cord of neonatal mice. The sodium pump inhibitor, ouabain, increased the frequency and decreased the amplitude of drug-induced locomotor bursting, effects that were dependent on the presence of the neuromodulator dopamine. Conversely, activating the pump with the sodium ionophore monensin decreased burst frequency. When more "natural" locomotor output was evoked using dorsal-root stimulation, ouabain increased burst frequency and extended locomotor episode duration, whereas monensin slowed and shortened episodes. Decreasing the time between dorsal-root stimulation, and therefore interepisode interval, also shortened and slowed activity, suggesting that pump activity encodes information about past network output and contributes to feedforward control of subsequent locomotor bouts. Using whole-cell patch-clamp recordings from spinal motoneurons and interneurons, we describe a long-duration (∼60 s), activity-dependent, TTX- and ouabain-sensitive, hyperpolarization (∼5 mV), which is mediated by spike-dependent increases in pump activity. The duration of this dynamic pump potential is enhanced by dopamine. Our results therefore reveal sodium pumps as dynamic regulators of mammalian spinal motor networks that can also be affected by neuromodulatory systems. Given the involvement of sodium pumps in movement disorders, such as amyotrophic lateral sclerosis and rapid-onset dystonia parkinsonism, knowledge of their contribution to motor network regulation also has considerable clinical importance.

  12. High-throughput measurement of the Ca2+-dependent ATPase activity in COS microsomes.

    PubMed

    Vandecaetsbeek, Ilse; Holemans, Tine; Wuytack, Frank; Vangheluwe, Peter

    2014-08-01

    We provide a detailed procedure to determine the Ca(2+)-dependent ATPase activity in COS or HEK293 cells overexpressing a Ca(2+) pump. The ATPase activity is determined by the Baginsky method, which allows measurement of the steady-state production of inorganic phosphate (Pi). We have adapted this widely applied method into a sensitive, fast, and semi-high-throughput protocol suitable for use in a 96-well plate format.

  13. 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

  14. Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18–dependent activation

    PubMed Central

    Loh, Liyen; Wang, Zhongfang; Sant, Sneha; Koutsakos, Marios; Jegaskanda, Sinthujan; Liu, Ligong; Fairlie, David P.; Crowe, Jane; Rossjohn, Jamie; Xu, Jianqing; Doherty, Peter C.; Kedzierska, Katherine

    2016-01-01

    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

  15. 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

  16. Experience-dependent changes in human brain activation during contingency learning.

    PubMed

    Schlund, M W; Ortu, D

    2010-01-13

    Successful adaption requires learning to respond appropriately to cues associated with response-reinforcer contingencies. In this investigation, we used functional magnetic resonance imaging to characterize changes in frontal and limbic activation associated with learning under a positive reinforcement contingency. Imaging analyses identified linear and nonlinear changes in brain activation across nine reinforcement trials when response accuracy and reaction times were stable. The development of contingency control was generally associated with linear increases or inverted-U shaped changes in activation in superior, medial and orbitofrontal (OFC) regions, amygdala, insula and the medial temporal lobe. Linear decreases and U-shaped changes in activation were generally observed in parietal, occipital and cerebellar regions. Results highlighting linear increases in activation in superior, medial and OFC regions suggest involvement in the development of contingency control, even when behavior is stable. Results also highlighted a positive correlation between changes in OFC activation and amygdala activation. However, inspection of the correspondence between group changes and individual subject changes in OFC, amygdala and insula activation revealed that approximately half of subjects exhibited changes resembling group changes and the strength of the OFC-amygdala relationship varied markedly between subjects. Such disparities highlight a unique opportunity for exploring individual differences in regional sensitivity to contingency as well as improving experimental preparations to better highlight and control the effects of extraneous variables.

  17. Endothelium dependency of contractile activity differs in infant and adult vertebral arteries.

    PubMed Central

    Charpie, J R; Schreur, K D; Papadopoulos, S M; Webb, R C

    1994-01-01

    Contractions to serotonin (5-HT) and endothelin-1 (ET-1) in infant (0-2 yr) and adult (38-71 yr) vertebral arteries were examined in the presence of either the cyclooxygenase inhibitor indomethacin or NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide production. In addition, endothelium-dependent relaxations to acetylcholine were characterized in arteries contracted with agonist. The results showed that: (a) Contractions of infant arteries to 5-HT or ET-1 decreased to 44 +/- 8% and 27 +/- 13%, respectively, within 10 min. Indomethacin or removal of endothelium abolished this decreased response, whereas L-NMMA had no effect. (b) Adult arteries produced sustained contractions to 5-HT or ET-1 that were unaffected by indomethacin, endothelium denudation, or L-NMMA. (c) Endothelium-dependent relaxations to acetylcholine were greater in infant than adult arteries and were abolished by indomethacin (but not L-NMMA) in infants and L-NMMA (but not indomethacin) in adults. Thus, endothelium-dependent responses in infant arteries are attenuated because of increased prostaglandin activity not observed in adult tissues. Additionally, there is an age-dependent change in the primary mechanism responsible for acetylcholine-induced vasodilation. Apparently, endothelium dependency of acetylcholine-induced relaxation is highly dependent on cyclooxygenase activity in the infant vertebral artery, but in the adult artery, nitric oxide is linked to the vasodilator response. Images PMID:8132776

  18. Activity-dependent Protein Dynamics Define Interconnected Cores of Co-regulated Postsynaptic Proteins*

    PubMed Central

    Trinidad, Jonathan C.; Thalhammer, Agnes; Burlingame, Alma L.; Schoepfer, Ralf

    2013-01-01

    Synapses are highly dynamic structures that mediate cell–cell communication in the central nervous system. Their molecular composition is altered in an activity-dependent fashion, which modulates the efficacy of subsequent synaptic transmission events. Whereas activity-dependent trafficking of individual key synaptic proteins into and out of the synapse has been characterized previously, global activity-dependent changes in the synaptic proteome have not been studied. To test the feasibility of carrying out an unbiased large-scale approach, we investigated alterations in the molecular composition of synaptic spines following mass stimulation of the central nervous system induced by pilocarpine. We observed widespread changes in relative synaptic abundances encompassing essentially all proteins, supporting the view that the molecular composition of the postsynaptic density is tightly regulated. In most cases, we observed that members of gene families displayed coordinate regulation even when they were not known to physically interact. Analysis of correlated synaptic localization revealed a tightly co-regulated cluster of proteins, consisting of mainly glutamate receptors and their adaptors. This cluster constitutes a functional core of the postsynaptic machinery, and changes in its size affect synaptic strength and synaptic size. Our data show that the unbiased investigation of activity-dependent signaling of the postsynaptic density proteome can offer valuable new information on synaptic plasticity. PMID:23035237

  19. 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.

  20. 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.

  1. Discovery of bacterial NAD+-dependent DNA ligase inhibitors: optimization of antibacterial activity.

    PubMed

    Stokes, Suzanne S; Huynh, Hoan; Gowravaram, Madhusudhan; Albert, Robert; Cavero-Tomas, Marta; Chen, Brendan; Harang, Jenna; Loch, James T; Lu, Min; Mullen, George B; Zhao, Shannon; Liu, Ce-Feng; Mills, Scott D

    2011-08-01

    Optimization of adenosine analog inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. Antibacterial activity against Streptococcus pneumoniae and Staphylococcus aureus was improved by modification of the 2-position substituent on the adenine ring and 3'- and 5'-substituents on the ribose. Compounds with logD values 1.5-2.5 maximized potency and maintained drug-like physical properties.

  2. 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.

  3. Transcription factor Runx3 regulates interleukin-15-dependent natural killer cell activation.

    PubMed

    Levanon, Ditsa; Negreanu, Varda; Lotem, Joseph; Bone, Karen Rae; Brenner, Ori; Leshkowitz, Dena; Groner, Yoram

    2014-03-01

    Natural killer cells belong to the family of innate lymphoid cells comprising the frontline defense against infected and transformed cells. Development and activation of natural killer cells is highly dependent on interleukin-15 signaling. However, very little is known about the transcription program driving this process. The transcription factor Runx3 is highly expressed in natural killer cells, but its function in these cells is largely unknown. We show that loss of Runx3 impaired interleukin-15-dependent accumulation of mature natural killer cells in vivo and under culture conditions and pregnant Runx3(-/-) mice completely lack the unique population of interleukin-15-dependent uterine natural killer cells. Combined chromatin immunoprecipitation sequencing and differential gene expression analysis of wild-type versus Runx3-deficient in vivo activated splenic natural killer cells revealed that Runx3 cooperates with ETS and T-box transcription factors to drive the interleukin-15-mediated transcription program during activation of these cells. Runx3 functions as a nuclear regulator during interleukin-15-dependent activation of natural killer cells by regulating the expression of genes involved in proliferation, maturation, and migration. Similar studies with additional transcription factors will allow the construction of a more detailed transcriptional network that controls natural killer cell development and function.

  4. Ral mediates activity-dependent growth of postsynaptic membranes via recruitment of the exocyst

    PubMed Central

    Teodoro, Rita O; Pekkurnaz, Gulçin; Nasser, Abdullah; Higashi-Kovtun, Misao E; Balakireva, Maria; McLachlan, Ian G; Camonis, Jacques; Schwarz, Thomas L

    2013-01-01

    Remodelling neuronal connections by synaptic activity requires membrane trafficking. We present evidence for a signalling pathway by which synaptic activity and its consequent Ca2+ influx activate the small GTPase Ral and thereby recruit exocyst proteins to postsynaptic zones. In accord with the ability of the exocyst to direct delivery of post-Golgi vesicles, constitutively active Ral expressed in Drosophila muscle causes the exocyst to be concentrated in the region surrounding synaptic boutons and consequently enlarges the membrane folds of the postsynaptic plasma membrane (the subsynaptic reticulum, SSR). SSR growth requires Ral and the exocyst component Sec5 and Ral-induced enlargement of these membrane folds does not occur in sec5−/− muscles. Chronic changes in synaptic activity influence the plastic growth of this membrane in a manner consistent with activity-dependent activation of Ral. Thus, Ral regulation of the exocyst represents a control point for postsynaptic plasticity. This pathway may also function in mammals as expression of activated RalA in hippocampal neurons increases dendritic spine density in an exocyst-dependent manner and increases Sec5 in spines. PMID:23812009

  5. 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.

  6. A Model of Mercury's Magnetospheric Magnetic Field with Dependence on Magnetic Activity

    NASA Astrophysics Data System (ADS)

    Korth, H.; Tsyganenko, N. A.; Johnson, C. L.; Philpott, L. C.; Anderson, B. J.; Solomon, S. C.; McNutt, R. L., Jr.

    2015-12-01

    Accurate knowledge of Mercury's magnetospheric magnetic field is required to characterize the planet's internal field and the structure of the magnetosphere. We present the first model of Mercury's magnetospheric magnetic field that includes a dependence on magnetic activity. The model consists of individual modules for magnetic fields of internal origin, approximated by a dipole of magnitude 190 nT RM3, where RM is Mercury's radius, offset northward by 479 km along the spin axis, and of external origin resulting from currents flowing on the magnetopause boundary and in the cross-tail current sheet. The magnetic field is confined within a magnetopause shape derived from Magnetometer observations by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft and dependent on magnetic activity. The cross-tail current is prescribed having a disk shape near the planet and extending into a sheet at larger distances. The magnitude of the tail current, which also depends on magnetic activity, is fit to minimize the root-mean-square residual between the model magnetic field and the field within the magnetosphere observed by MESSENGER. The model was fit separately for magnetic field observations within distinct levels of magnetic activity. Linear fits of model parameters versus magnetic activity allows continuous scaling of the model to magnetic activity. The magnetic field contribution from each module is shielded individually by a scalar potential function, which was fit to minimize the root-mean-square normal magnetic field component at the magnetopause. The resulting model reproduces the dependence of the magnetospheric size and tail current intensity on magnetic activity, and allows more accurate characterization of the internal field.

  7. Ligand-dependent intersubunit association with the insulin receptor complex activates its intrinsic kinase activity

    SciTech Connect

    Boeni-Schnetzler, M.; Kaligian, A.; DelVecchio, R.; Pilch, P.F.

    1988-05-15

    Insulin receptor halves (..cap alpha beta..) were obtained upon selective reduction of the holoreceptor (..cap alpha../sub 2/..beta../sub 2/) and were isolated in concentrated form. Autophosphorylation of concentrated ..cap alpha beta.. receptor halves can be stimulated by insulin an average of 4.0-fold, whereas nonreduced holoreceptor can be stimulated 5.4-fold. If ..cap alpha beta.. half-receptors are immobilized on wheat germ agglutinin-agarose, no insulin-stimulated autophosphorylation is observed, whereas immobilized holoreceptor retains insulin responsiveness. Treatment of ..cap alpha beta.. half-receptors with glutathione in the presence of insulin results in reoxidation to the holoreceptor form (..cap alpha../sub 2/..beta../sub 2/) with an efficiency of 60-70% as visualized by immunoblotting, thus providing evidence that two ..cap alpha beta.. halves are in close physical proximity. This reoxidation reaction, which is evident prior to autophosphorylation, is rapid and strictly dependent on the presence of insulin, consistent with the hypothesis that insulin promotes the association of two ..cap alpha beta.. halves. Furthermore, the insulin-induced reoxidation reaction and the insulin-induced autophosphorylation show the same dose dependence suggesting that the noncovalent association of ..cap alpha beta.. half-receptors upon insulin binding is a prerequisite for insulin-stimulated autophosphorylation in concentrated ..gamma beta.. half-receptor preparations. If the ..cap alpha beta.. half-receptor forms are phosphorylated in the presence of an anti-phosphotyrosine antibody and separated from nonphosphorylated ..cap alpha beta.. receptors, we observe that the phosphorylated ..cap alpha beta.. receptor halves contain bound insulin.

  8. Composition-dependent electrocatalytic activity of AuPd alloy nanoparticles prepared via simultaneous sputter deposition into an ionic liquid.

    PubMed

    Hirano, Masanori; Enokida, Kazuki; Okazaki, Ken-ichi; Kuwabata, Susumu; Yoshida, Hisao; Torimoto, Tsukasa

    2013-05-21

    Homogeneously alloyed bimetallic particles of AuPd with an average size of ca. 2 nm were successfully prepared by simultaneous sputter deposition of Au and Pd in an ionic liquid in the absence of any additional stabilizing agents. The chemical composition of the AuPd alloy was tunable depending on the area fraction of Au plates in the Au-Pd binary targets for sputtering. The particles were immobilized on an HOPG surface by heat treatment along with the increase in the average size of particles from ca. 2 nm to ca. 7 nm. Ionic liquid species adsorbed on the as-prepared AuPd nanoparticle films on HOPG caused the prevention of electrocatalytic reactions, but repetition of potential sweep cycling in a basic aqueous solution removed the adsorbed ionic species, resulting in electrocatalytic oxidation of ethanol at the AuPd alloy nanoparticle-immobilized HOPG electrode. The electrocatalytic activity of AuPd nanoalloy particles varied upon changing the fraction of Au and Pd in the particles, and alloy particles having an Au fraction of ca. 0.61 exhibited the maximum activity against ethanol oxidation, being higher than the activity of the pure Pt surface.

  9. Volume-activated Cl(-)-independent and Cl(-)-dependent K+ pathways in trout red blood cells.

    PubMed Central

    Guizouarn, H; Harvey, B J; Borgese, F; Gabillat, N; Garcia-Romeu, F; Motais, R

    1993-01-01

    1. Swelling of trout erythrocytes can be induced either by addition of catecholamine to the cell suspension, thus promoting NaCl uptake via beta-adrenergic-stimulated Na(+)-H+ exchange (isotonic swelling) or by suspending red blood cells in a hypotonic medium (hypotonic swelling). In both cases cells tend to regulate their volume by losing K+, but the characteristics of the volume-activated K+ pathways are different: after hormonally induced swelling the K+ loss is strictly Cl- dependent; after hypotonic swelling the K+ loss is essentially Cl- independent. 2. In order to determine the nature of these volume regulatory pathways (i.e. whether the net K+ loss was conductive or was by electroneutral K(+)-H+ exchange or KCl co-transport), studies were performed to analyse ion fluxes and associated electrical phenomena. The cell membrane potential and intracellular ionic activities of volume-regulating and volume-static cells were measured by impalement with conventional microelectrodes and double-barrelled ion-sensitive microelectrodes. 3. The information gained from the electrical and ion flux studies leads to the conclusion that both Cl(-)-independent and Cl(-)-dependent K+ loss proceed via electrically silent pathways. 4. Experiments were designed to distinguish between electroneutral K(+)-H+ exchange or KCl co-transport. These were based upon the inhibition of Cl(-)-OH- exchange to evaluate the degree of coupling between K+ and Cl- (KCl stoichiometry, pH change). The experimental observations are consistent with the fact that both Cl(-)-independent and Cl(-)-dependent K+ loss are mediated by coupled K(+)-anion co-transport and not by K(+)-H+ exchange. 5. On the basis of previous data, we suggest that only one type of K(+)-anion co-transport exists in the cell membrane, for which the selectivity for anions varies according to the change in cellular ionic strength induced by swelling. PMID:8392575

  10. CREB is activated by UVC through a p38/HOG-1-dependent protein kinase.

    PubMed Central

    Iordanov, M; Bender, K; Ade, T; Schmid, W; Sachsenmaier, C; Engel, K; Gaestel, M; Rahmsdorf, H J; Herrlich, P

    1997-01-01

    Changes in environmental conditions such as the addition of growth factors or irradiation of cells in culture first affect immediate response genes. We have shown previously that short wavelength UV irradiation (UVC) elicits massive activation of several growth factor receptor-dependent pathways. At the level of the immediate response gene c-fos, these pathways activate the transcription factor complex serum response factor (SRF)-p62TCF which mediates part of the UV-induced transcriptional response. These studies have, however, suggested that more that one pathway is required for full UV responsiveness of c-fos. Using appropriate promoter mutations and dominant-negative cAMP response element (CRE)-binding protein (CREB), we now find that UVC-induced transcriptional activation depends also on the CRE at position -60 of the c-fos promoter and on the functionality of a CREB. Upon UV irradiation, CREB and ATF-1 are phosphorylated at serines 133 and 63, respectively, preceded by and dependent on activation of p38/RK/HOG-1 and of a p38/RK/HOG-1-dependent p108 CREB kinase. Although p90RSK1 and MAPKAP kinase 2 are also activated by UV, p90RSK1 does not, at least not decisively, participate in this signalling pathway to CREB and ATF-1 as it is not p38/RK/HOG-1 dependent, and CREB is a poor substrate for MAPKAP kinase 2 in vitro. On the basis of resistance to the growth factor receptor inhibitor suramin and of several types of cross-refractoriness experiments, the UVC-induced CREB/ATF-1 phosphorylation represents an as yet unrecognized route of UVC-induced signal transduction, independent of suramin-inhibitable growth factor receptors and different from the Erk 1,2-p62TCF pathway. PMID:9118940

  11. Sucrose increases calcium-dependent protein kinase and phosphatase activities in potato plants.

    PubMed

    Raíces, M; MacIntosh, G C; Ulloa, R M; Gargantini, P R; Vozza, N F; Téllez-Inón, M T

    2003-09-01

    The effect of sucrose on tuber formation, calcium-dependent protein kinase (CDPK) and phosphatase activities was analysed using in vitro cultured potato plants. In short treatments, sucrose induced CDPK and phosphatase activities. In long treatments, sucrose induced tuber formation in the absence of other tuber inducing stimuli. Sorbitol caused a minor increase in CDPK activity and affected plant morphology but did not induce tuber development. The addition of the protein kinase inhibitor Staurosporine precluded sucrose-induced tuberization. Altogether, our results suggest that phosphorylation/dephosphorylation events are involved in sucrose-induced tuber development.

  12. Synthesis and SAR study of modulators inhibiting tRXRα-dependent AKT activation

    PubMed Central

    Wang, Zhi-Gang; Chen, Liqun; Chen, Jiebo; Zheng, Jian-Feng; Gao, Weiwei; Zeng, Zhiping; Zhou, Hu; Zhang, Xiao-kun; Huang, Pei-Qiang; Su, Ying

    2013-01-01

    RXRα represents an intriguing and unique target for pharmacologic interventions. We recently showed that Sulindac and a designed analog could bind to RXRα and modulate its biological activity, including inhibition of the interaction of an N-terminally truncated RXRα (tRXRα) with the p85α regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K). Here we report the synthesis, testing and SAR of a series of novel analogs of Sulindac as potential modulators for inhibiting tRXRα-dependent AKT activation. A new compound 30 was identified to have improved biological activity. PMID:23434637

  13. LIGAND STRUCTURE-DEPENDENT ACTIVATION OF ESTROGEN RECEPTOR α/Sp BY ESTROGENS AND XENOESTROGENS

    PubMed Central

    Wu, Fei; Khan, Shaheen; Wu, Qian; Barhoumi, Rola; Burghardt, Robert; Safe, Stephen

    2008-01-01

    This study investigated the effects of E2, diethylstilbestrol (DES), antiestrogens, the phytoestrogen resveratrol, and the xenoestrogens octylphenol (OP), nonylphenol (NP), endosulfan, kepone, 2,3,4,5-tetrachlorobiphenyl-4-ol (HO-PCB-Cl4), bisphenol-A(BPA), and 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) on induction of luciferase activity in breast cancer cells transfected with a construct (pSp13) containing three tandem GC-rich Sp binding sites linked to luciferase and wild-type or variant ERα. The results showed that induction of luciferase activity was highly structure-dependent in both MCF-7 and MDA-MB-231 cells. Moreover, RNA interference assays using small inhibitory RNAs for Sp1, Sp3 and Sp4 also demonstrated structure-dependent differences in activation of ERα/Sp1, ERα/Sp3 and ERα/Sp4. These results demonstrate for the first time that various structural classes of ER ligands differentially activate wild-type and variant ERα/Sp-dependent transactivation, selectively use different Sp proteins, and exhibit selective ER modulator (SERM)-like activity. PMID:18400491

  14. 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

  15. Field dependence of the activation volumes in Co/Pd multilayered films

    NASA Astrophysics Data System (ADS)

    Ryu, Kwang-Su; Choe, Sug-Bong; Lee, Kyeong-Dong; Shin, Sung-Chul

    2007-09-01

    The field dependence of the activation volumes of nucleation and wall-motion processes in magnetization reversal of Co/Pd multilayers is presented, as observed using a magneto-optical Kerr-effect microscope capable of real-time domain imaging in a wide time range of 10-5-103 s. The analytic forms of the activation volumes are derived from a theoretical consideration of equilibrium conditions of the two typical domain evolution processes in a ferromagnetic film with uniaxial perpendicular anisotropy; the theory is shown to be in good agreement with the experimental results. It was found that the field dependence of the activation volumes can be characterized by the difference between the domain wall energy and the dipolar energy.

  16. Activity-dependent facilitation of Synaptojanin and synaptic vesicle recycling by the Minibrain kinase

    PubMed Central

    Chen, Chun-Kan; Bregere, Catherine; Paluch, Jeremy; Lu, Jason; Dickman, Dion K.; Chang, Karen T.

    2014-01-01

    Phosphorylation has emerged as a crucial regulatory mechanism in the nervous system to integrate the dynamic signaling required for proper synaptic development, function, and plasticity, particularly during changes in neuronal activity. Here we present evidence that Minibrain (Mnb; also known as Dyrk1A), a serine/threonine kinase implicated in autism spectrum disorder and Down syndrome, is required presynaptically for normal synaptic growth and rapid synaptic vesicle endocytosis at the Drosophila neuromuscular junction (NMJ). We find that Mnb-dependent phosphorylation of synaptojanin (Synj) is required, in vivo, for complex endocytic protein interactions and to enhance Synj activity. Neuronal stimulation drives Mnb mobilization to endocytic zones and triggers Mnb-dependent phosphorylation of Synj. Our data identify Mnb as a synaptic kinase that promotes efficient synaptic vesicle recycling by dynamically calibrating Synj function at the Drosophila NMJ, and in turn endocytic capacity, to adapt to conditions of high synaptic activity. PMID:24977345

  17. Activity-dependent facilitation of Synaptojanin and synaptic vesicle recycling by the Minibrain kinase.

    PubMed

    Chen, Chun-Kan; Bregere, Catherine; Paluch, Jeremy; Lu, Jason F; Dickman, Dion K; Chang, Karen T

    2014-06-30

    Phosphorylation has emerged as a crucial regulatory mechanism in the nervous system to integrate the dynamic signalling required for proper synaptic development, function and plasticity, particularly during changes in neuronal activity. Here we present evidence that Minibrain (Mnb; also known as Dyrk1A), a serine/threonine kinase implicated in autism spectrum disorder and Down syndrome, is required presynaptically for normal synaptic growth and rapid synaptic vesicle endocytosis at the Drosophila neuromuscular junction (NMJ). We find that Mnb-dependent phosphorylation of Synaptojanin (Synj) is required, in vivo, for complex endocytic protein interactions and to enhance Synj activity. Neuronal stimulation drives Mnb mobilization to endocytic zones and triggers Mnb-dependent phosphorylation of Synj. Our data identify Mnb as a synaptic kinase that promotes efficient synaptic vesicle recycling by dynamically calibrating Synj function at the Drosophila NMJ, and in turn endocytic capacity, to adapt to conditions of high synaptic activity.

  18. Activity-dependent PSA expression regulates inhibitory maturation and onset of critical period plasticity.

    PubMed

    Di Cristo, Graziella; Chattopadhyaya, Bidisha; Kuhlman, Sandra J; Fu, Yu; Bélanger, Marie-Claude; Wu, Cai Zhi; Rutishauser, Urs; Maffei, Lamberto; Huang, Z Josh

    2007-12-01

    Functional maturation of GABAergic innervation in the developing visual cortex is regulated by neural activity and sensory inputs and in turn influences the critical period of ocular dominance plasticity. Here we show that polysialic acid (PSA), presented by the neural cell adhesion molecule, has a role in the maturation of GABAergic innervation and ocular dominance plasticity. Concentrations of PSA significantly decline shortly after eye opening in the adolescent mouse visual cortex; this decline is hindered by visual deprivation. The developmental and activity-dependent regulation of PSA expression is inversely correlated with the maturation of GABAergic innervation. Premature removal of PSA in visual cortex results in precocious maturation of perisomatic innervation by basket interneurons, enhanced inhibitory synaptic transmission, and earlier onset of ocular dominance plasticity. The developmental and activity-dependent decline of PSA expression therefore regulates the timing of the maturation of GABAergic inhibition and the onset of ocular dominance plasticity.

  19. 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.

  20. 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.

  1. Time-dependent activation of the semicarbazide-sensitive amine oxidase (SSAO) from ox lung microsomes.

    PubMed Central

    Lizcano, J M; Tipton, K F; Unzeta, M

    2000-01-01

    The activity of ox lung microsomal semicarbazide-sensitive amine oxidase (EC 1.4.3.6; SSAO) towards benzylamine increased 20-fold during incubation at 37 degrees C. After an initial lag-period, activation was first-order with time and complete after approx. 20 h. No significant changes in activity towards methylamine, histamine or 2-phenylethylamine were observed, although mixed-substrate experiments were consistent with the same enzyme being involved in the oxidation of all these substrates, both before and after time-dependent activation. The enzyme-tryptophan fluorescence increased on incubation at 37 degrees C in parallel with the increase in activity towards benzylamine. Treatment of the activated-enzyme preparation with 6 M guanidinium chloride followed by dialysis, caused both the activity towards benzylamine and the fluorescence to fall to that occurring before activation. However, incubation of this preparation at 37 degrees C resulted in increases in fluorescence and activity similar to those seen with the unactivated enzyme. Benzylamine oxidation was inhibited, uncompetitively with respect to oxygen, by high substrate concentrations but no such inhibition was observed with the other amines. Activation resulted in an increase in V(max) for benzylamine oxidation, with no significant alterations in the K(m) or the K(si) for high-substrate inhibition. Kinetic studies were consistent with sequential mechanisms being followed for the oxidation of both benzylamine and methylamine but the dependence on oxygen concentration was complex. These results might indicate that benzylamine follows a different reaction pathway from the other substrates, with substrate-specific activation involving a reaction step that is rate-limiting for benzylamine oxidation but not for the others. PMID:11042135

  2. Age-dependent changes in plasma and brain cholinesterase activities of house wrens and European starlings.

    PubMed

    Mayack, David T; Martin, Tim

    2003-07-01

    We determined age-dependent changes in plasma and brain cholinesterase (ChE) activity for two species of passerines: house wren (Troglodytes aedon) and European starling (Sturnus vulgaris, starling). In plasma from nestlings of both species, total ChE activity increased with age, acetycholinesterase (AChE, EC 3.1.1.7) activity declined rapidly immediately after hatching, and butyrylcholinesterase (BChE, EC 3.1.1.8) activity increased steadily. For both species, total ChE and BChE activities and the BChE:AChE ratio in plasma were significantly greater in adults than nestlings suggesting trends observed in nestlings continue post fledging. In older nestlings and adults, AChE activity in plasma was significantly greater and BChE:AChE ratio less in house wrens than starlings. For house wrens as compared with starlings, ChE activity in brain increased at a significantly greater rate with age in nestlings and was significantly greater in adults. However, ChE activity in brain was similar at fledging for both species suggesting that the increase in ChE in brain is more directly related to ontogeny than chronologic age in nestlings of passerines. For both species, ChE activity increased significantly with brain weight of nestlings but not adults. House wrens hold similar patterns of age-dependent change in ChE activity in common with starlings but also exhibit differences in AChE activity in plasma that should be considered as a factor potentially affecting their relative toxicologic response to ChE inhibitors.

  3. 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

  4. 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.

  5. Fast and slow activation of voltage-dependent ion channels in radish vacuoles.

    PubMed Central

    Gambale, F; Cantu, A M; Carpaneto, A; Keller, B U

    1993-01-01

    The molecular processes associated with voltage-dependent opening and closing (gating) of ion channels were investigated using a new preparation from plant cells, i.e., voltage and calcium-activated ion channels in radish root vacuoles. These channels display a main single channel conductance of approximately 90 pS and are characterized by long activation times lasting several hundreds of milliseconds. Here, we demonstrate that these channels have a second kinetically distinct activation mode which is characterized by even longer activation times. Different membrane potential protocols allowed to switch between the fast and the slow mode in a controlled and reversible manner. At transmembrane potentials of -100 mV, the ratio between the fast and slow activation time constant was around 1:5. Correspondingly, activation times lasting several seconds were observed in the slow mode. The molecular process controlling fast and slow activation may represent an effective modulator of voltage-dependent gating of ion channels in other plant and animal systems. PMID:7507716

  6. 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.

  7. 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

  8. 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

  9. Superresolution imaging reveals activity-dependent plasticity of axon morphology linked to changes in action potential conduction velocity.

    PubMed

    Chéreau, Ronan; Saraceno, G Ezequiel; Angibaud, Julie; Cattaert, Daniel; Nägerl, U Valentin

    2017-02-07

    Axons convey information to nearby and distant cells, and the time it takes for action potentials (APs) to reach their targets governs the timing of information transfer in neural circuits. In the unmyelinated axons of hippocampus, the conduction speed of APs depends crucially on axon diameters, which vary widely. However, it is not known whether axon diameters are dynamic and regulated by activity-dependent mechanisms. Using time-lapse superresolution microscopy in brain slices, we report that axons grow wider after high-frequency AP firing: synaptic boutons undergo a rapid enlargement, which is mostly transient, whereas axon shafts show a more delayed and progressive increase in diameter. Simulations of AP propagation incorporating these morphological dynamics predicted bidirectional effects on AP conduction speed. The predictions were confirmed by electrophysiological experiments, revealing a phase of slowed down AP conduction, which is linked to the transient enlargement of the synaptic boutons, followed by a sustained increase in conduction speed that accompanies the axon shaft widening induced by high-frequency AP firing. Taken together, our study outlines a morphological plasticity mechanism for dynamically fine-tuning AP conduction velocity, which potentially has wide implications for the temporal transfer of information in the brain.

  10. 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

  11. 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.

  12. 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.

  13. Dependence of cerebral-cortex activation in women on environmental factors

    NASA Astrophysics Data System (ADS)

    Pavlov, K. I.; Mukhin, V. N.; Kamenskaya, V. G.; Klimenko, V. M.

    2016-12-01

    The investigation of female physiological reactions to different meteorological conditions and space weather is relevant, since there are little experimental findings in this field. The purpose of this work is to determine how the level of cerebral-cortex activity in women depends on the meteorological and cosmophysical parameters of weather and space processes. We studied electroencephalograms (EEGs) recorded at rest in the sitting position and with eyes closed. We performed four series of measurements of brain bioelectrical activity from February to June 2013. We found that the level of cortical activity recorded by EEG changed significantly during these 6 months. Significant differences were detected between the cortical activity and the parameters of weather and space processes; namely, an increase in the air temperature and a decrease in the wind speed and cosmic-ray energy result in a decrease in the activity rate of the right occipital lobe.

  14. In the newborn hippocampus, neurotrophin-dependent survival requires spontaneous activity and integrin signaling

    PubMed Central

    Murase, Sachiko; Owens, David F.; McKay, Ronald D.

    2012-01-01

    The nervous system develops through a program that first produces neurons in excess and then eliminates as many as half in a specific period of early post-natal life. Neurotrophins are widely thought to regulate neuronal survival but this role has not been clearly defined in the central nervous system. Here we show that neurotrophins promote survival of young neurons by promoting spontaneous activity. Survival of hippocampal neurons in neonatal rat requires spontaneous activity that depends on the excitatory action of γ-aminobutyric acid (GABA). Neurotrophins facilitate recruitment of cultured neurons into active networks, and it is this activity, combined with integrin receptor signaling, that controls neuronal survival. In vivo, neurotrophins require integrin signaling to control neuron number. These data are the first to link the early excitatory action of GABA to the developmental death period and to assign an essential role for activity in neurotrophin-mediated survival that establishes appropriate networks. PMID:21613492

  15. Coordinated integrin activation by actin-dependent force during T-cell migration.

    PubMed

    Nordenfelt, Pontus; Elliott, Hunter L; Springer, Timothy A

    2016-10-10

    For a cell to move forward it must convert chemical energy into mechanical propulsion. Force produced by actin polymerization can generate traction across the plasma membrane by transmission through integrins to their ligands. However, the role this force plays in integrin activation is unknown. Here we show that integrin activity and cytoskeletal dynamics are reciprocally linked, where actin-dependent force itself appears to regulate integrin activity. We generated fluorescent tension-sensing constructs of integrin αLβ2 (LFA-1) to visualize intramolecular tension during cell migration. Using quantitative imaging of migrating T cells, we correlate tension in the αL or β2 subunit with cell and actin dynamics. We find that actin engagement produces tension within the β2 subunit to induce and stabilize an active integrin conformational state and that this requires intact talin and kindlin motifs. This supports a general mechanism where localized actin polymerization can coordinate activation of the complex machinery required for cell migration.

  16. Lysosome-Dependent Activation of Human Dendritic Cells by the Vaccine Adjuvant QS-21

    PubMed Central

    Welsby, Iain; Detienne, Sophie; N’Kuli, Francisca; Thomas, Séverine; Wouters, Sandrine; Bechtold, Viviane; De Wit, Dominique; Gineste, Romain; Reinheckel, Thomas; Elouahabi, Abdelatif; Courtoy, Pierre J.; Didierlaurent, Arnaud M.; Goriely, Stanislas

    2017-01-01

    The adjuvant properties of the saponin QS-21 have been known for decades. It is a component of the Adjuvant System AS01 that is used in several vaccine candidates. QS-21 strongly potentiates both cellular and humoral immune responses to purified antigens, yet how it activates immune cells is largely unknown. Here, we report that QS-21 directly activated human monocyte-derived dendritic cells (moDCs) and promoted a pro-inflammatory transcriptional program. Cholesterol-dependent QS-21 endocytosis followed by lysosomal destabilization and Syk kinase activation were prerequisites for this response. Cathepsin B, a lysosomal cysteine protease, was essential for moDC activation in vitro and contributed to the adjuvant effects of QS-21 in vivo. Collectively, these findings provide new insights into the pathways involved in the direct activation of antigen-presenting cells by a clinically relevant QS-21 formulation. PMID:28105029

  17. pH-dependent biotransformation of ionizable organic micropollutants in activated sludge.

    PubMed

    Gulde, Rebekka; Helbling, Damian E; Scheidegger, Andreas; Fenner, Kathrin

    2014-12-02

    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.

  18. Task-load-dependent activation of dopaminergic midbrain areas in the absence of reward.

    PubMed

    Boehler, Carsten N; Hopf, Jens-Max; Krebs, Ruth M; Stoppel, Christian M; Schoenfeld, Mircea A; Heinze, Hans-Jochen; Noesselt, Toemme

    2011-03-30

    Dopamine release in cortical and subcortical structures plays a central role in reward-related neural processes. Within this context, dopaminergic inputs are commonly assumed to play an activating role, facilitating behavioral and cognitive operations necessary to obtain a prospective reward. Here, we provide evidence from human fMRI that this activating role can also be mediated by task-demand-related processes and thus extends beyond situations that only entail extrinsic motivating factors. Using a visual discrimination task in which varying levels of task demands were precued, we found enhanced hemodynamic activity in the substantia nigra (SN) for high task demands in the absence of reward or similar extrinsic motivating factors. This observation thus indicates that the SN can also be activated in an endogenous fashion. In parallel to its role in reward-related processes, reward-independent activation likely serves to recruit the processing resources needed to meet enhanced task demands. Simultaneously, activity in a wide network of cortical and subcortical control regions was enhanced in response to high task demands, whereas areas of the default-mode network were deactivated more strongly. The present observations suggest that the SN represents a core node within a broader neural network that adjusts the amount of available neural and behavioral resources to changing situational opportunities and task requirements, which is often driven by extrinsic factors but can also be controlled endogenously.

  19. 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.

  20. 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

  1. Actin interaction and regulation of cyclin-dependent kinase 5/p35 complex activity.

    PubMed

    Xu, Jiqing; Tsutsumi, Koji; Tokuraku, Kiyotaka; Estes, Katherine A; Hisanaga, Shin-ichi; Ikezu, Tsuneya

    2011-01-01

    Cyclin-dependent kinase 5 (Cdk5) plays a critical role during neurodevelopment, synaptic plasticity, and neurodegeneration. Cdk5 activity depends on association with neuronal proteins p35 and p25, a proteolytic product of p35. Cdk5 regulates the actin cytoskeletal dynamics that are essential for neuronal migration, neuritic growth, and synaptogenesis. However, little is known about the interaction of actin and Cdk5 and its effect on neuronal Cdk5 activity. In a previous study, we observed that Cdk5/p35 activity is negatively correlated with co-immunoprecipitated F-actin (filamentous actin) amounts in the mouse brain, and suggested that F-actin inhibits the formation of the Cdk5/p35 complex [Journal of Neuroscience (2008) vol. 28, p. 14511]. The experiments reported here were undertaken to elucidate the relationship between actin and the formation of the Cdk5/p35 complex and its activity. Instead of an F-actin-mediated inhibition, we propose that G-actin (globular actin) in the F-actin preparations is responsible for inhibiting Cdk5/p35 and Cdk5/p25 kinase activity. We found that F-actin binds to p35 but not p25 or Cdk5. We have shown that G-actin binds directly to Cdk5 without disrupting the formation of the Cdk5/p35 or Cdk5/p25 complexes. G-actin potently suppressed Cdk5/p35 and Cdk5/p25 activity when either histone H1 or purified human tau protein were used as substrates, indicating a substrate-independent inhibitory effect of G-actin on Cdk5 activity. Finally, G-actin suppressed the activity of Cdk5 immunoprecipitated from wild type and p35-deficient mouse brain, suggesting that G-actin suppresses endogenous Cdk5 activity in a p35-independent manner. Together, these results suggest a novel mechanism of actin cytoskeletal regulation of Cdk5/p35 activity.

  2. 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.

  3. 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

  4. Activity-Dependent Degradation of Synaptic Vesicle Proteins Requires Rab35 and the ESCRT Pathway

    PubMed Central

    Sheehan, Patricia; Zhu, Mei; Beskow, Anne; Vollmer, Cyndel

    2016-01-01

    Synaptic vesicle (SV) pools must maintain a functional repertoire of proteins to efficiently release neurotransmitter. The accumulation of old or damaged proteins on SV membranes is linked to synaptic dysfunction and neurodegeneration. However, despite the importance of SV protein turnover for neuronal health, the molecular mechanisms underlying this process are largely unknown. Here, we have used dissociated rat hippocampal neurons to investigate the pathway for SV protein degradation. We find that neuronal activity drives the degradation of a subset of SV proteins and that the endosomal sorting complex required for transport (ESCRT) machinery and SV-associated GTPase Rab35 are key elements of this use-dependent degradative pathway. Specifically, neuronal activity induces Rab35 activation and binding to the ESCRT-0 protein Hrs, which we have identified as a novel Rab35 effector. These actions recruit the downstream ESCRT machinery to SV pools, thereby initiating SV protein degradation via the ESCRT pathway. Our findings show that the Rab35/ESCRT pathway facilitates the activity-dependent removal of specific proteins from SV pools, thereby maintaining presynaptic protein homeostasis. SIGNIFICANCE STATEMENT Synaptic transmission is mediated by the release of chemical neurotransmitters from synaptic vesicles (SVs). This tightly regulated process requires a functional pool of SVs, necessitating cellular mechanisms for removing old or damaged proteins that could impair SV cycling. Here, we show that a subset of SV proteins is degraded in an activity-dependent manner and that key steps in this degradative pathway are the activation of the small GTPase Rab35 and the subsequent recruitment of the endosomal sorting complex required for transport (ESCRT) machinery to SV pools. Further, we demonstrate that ESCRT-0 component Hrs is an effector of Rab35, thus providing novel mechanistic insight into the coupling of neuronal activity with SV protein degradation and the

  5. Calcium-dependent activation and autolysis of Arabidopsis metacaspase 2d.

    PubMed

    Watanabe, Naohide; Lam, Eric

    2011-03-25

    Metacaspases (MCPs) are members of a new family of cysteine proteases found in plants, fungi, and protozoa that are structurally related to metazoan caspases. Recent studies showed that plant MCPs are arginine/lysine-specific cysteine proteases with caspase-like processing activities in vitro and in vivo, and some of the plant type II MCPs exhibit Ca(2+) dependence for their endopeptidase activity in vitro. However, the mechanisms and biological relevance of Ca(2+) dependence and self-processing of plant MCPs remains unclear. Here we show that recombinant AtMCP2d, the most abundantly expressed member of Arabidopsis type II MCPs at the transcriptional level, exhibits a strict Ca(2+) dependence for its catalytic activation that is apparently mediated by intramolecular self-cleavage mechanism. However, rapid inactivation of AtMCP2d activity concomitant with Ca(2+)-induced self-processing at multiple internal sites was observed. Because active AtMCP2d can cleave its inactive form, intermolecular cleavage (autolysis) of AtMCP2d could also occur under our assay conditions. Ca(2+)-induced self-processing of recombinant AtMCP2d was found to correlate with the sequential appearance of at least six intermediates, including self-cleaved forms, during the proenzyme purification process. Six of these peptides were characterized, and the cleavage sites were mapped through N-terminal protein sequencing. Mutation analysis of AtMCP2d revealed that cleavage after Lys-225, which is a highly conserved residue among the six Arabidopsis type II MCPs, is critical for the catalytic activation by Ca(2+), and we demonstrate that this residue is essential for AtMCP2d activation of H(2)O(2)-induced cell death in yeast. Together, our results provide clues to understand the mode of regulation for this class of proteases.

  6. Quantifying the fingerprint descriptor dependence of structure-activity relationship information on a large scale.

    PubMed

    Dimova, Dilyana; Stumpfe, Dagmar; Bajorath, Jürgen

    2013-09-23

    It is well-known that different molecular representations, e.g., graphs, numerical descriptors, fingerprints, or 3D models, change the numerical results of molecular similarity calculations. Because the assessment of structure-activity relationships (SARs) requires similarity and potency comparisons of active compounds, this representation dependence inevitably also affects SAR analysis. But to what extent? How exactly does SAR information change when alternative fingerprints are used as descriptors? What is the proportion of active compounds with substantial changes in SAR information induced by different fingerprints? To provide answers to these questions, we have quantified changes in SAR information across many different compound classes using six different fingerprints. SAR profiling was carried out on 128 target-based data sets comprising more than 60,000 compounds with high-confidence activity annotations. A numerical measure of SAR discontinuity was applied to assess SAR information on a per compound basis. For ~70% of all test compounds, changes in SAR characteristics were detected when different fingerprints were used as molecular representations. Moreover, the SAR phenotype of ~30% of the compounds changed, and distinct fingerprint-dependent local SAR environments were detected. The fingerprints we compared were found to generate SAR models that were essentially not comparable. Atom environment and pharmacophore fingerprints produced the largest differences in compound-associated SAR information. Taken together, the results of our systematic analysis reveal larger fingerprint-dependent changes in compound-associated SAR information than would have been anticipated.

  7. Surface orientation dependence of the activation energy of S diffusion in bcc Fe

    NASA Astrophysics Data System (ADS)

    Barnard, P. E.; Terblans, J. J.; Swart, H. C.

    2015-11-01

    The formation of vacancies in the low-index orientations of bcc Fe was studied by a combined computational modelling and experimental investigation by making use of density functional theory (DFT), Auger electron spectroscopy (AES), time-of-flight secondary ion mass spectrometry (TOF-SIMS) and X-ray diffraction (XRD). Vacancies were considered to occur as a result of a Schottky defect forming in the bcc Fe lattice. This predicted a surface orientation dependence on the vacancy formation energy and consequently also on the activation energy of diffusion. Activation energies for the segregation of S in the Fe(1 0 0), Fe(1 1 0) and Fe(1 1 1) surface orientations were calculated by DFT modelling as 2.75 eV, 2.86 eV and 1.94 eV respectively. Simulations furthermore revealed a variation in the segregation kinetics of S as a result of the activation energy dependence on the surface orientation. Experimental data obtained by AES, TOF-SIMS and XRD confirmed this variation in the segregation kinetics of S segregation in different Fe orientations. This article provides compelling evidence for the formation of vacancies in bcc Fe to occur via the Schottky defect mechanism, which results in the orientation dependence for the activation energy of diffusion.

  8. Changes in Calcium-Dependent Protein Kinase Activity during in Vitro Tuberization in Potato.

    PubMed

    MacIntosh, G. C.; Ulloa, R. M.; Raices, M.; Tellez-Inon, M. T.

    1996-12-01

    A soluble Ca2+-dependent protein kinase (CDPK) was purified to homogeneity in potato (Solanum tuberosum L.) plants. Potato CDPK was strictly dependent on Ca2+ (one-half maximal activation 0.6 [mu]M) and phosphorylated a wide diversity of substrates, in which Syntide 2 was the best phosphate acceptor (Michaelis constant = 30 [mu]M). The kinase was inhibited by Ca2+-chelating agents, phenotiazine derivatives, and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (one-half maximal inhibition = 0.25 mM). Polyclonal antibodies directed against the regulatory region of the soybean CDPK recognized a 53-kD polypeptide. In an autophosphorylation assay, this same band was strongly labeled with [[gamma]-32P]ATP in the presence of Ca2+. CDPK activity was high in nontuberized plants, but increased 2.5-fold at the onset of tuber development and was reduced to one-half of its original activity when the tuber had completed formation. In the early stages of tuberization, Ca2+-dependent phosphorylation of endogenous targets (specific bands of 68, 51, and 46 kD) was observed. These polypeptides were not labeled in nontuberizing plants or in completely formed tubers, indicating that this phosphorylation is a stage-specific event. In addition, dephosphorylation of specific polypeptides was detected in tuberizing plants, suggesting the involvement of a phosphatase. Preincubation of crude extracts with phosphatase inhibitors rendered a 100% increase in CDPK activity.

  9. Alterations in activities of acid phosphatase, alkaline phosphatase, ATPase and ATP content in response to seasonally varying Pi status in okra (Abelmoschus esculentus).

    PubMed

    Sen, Supatra; Mukherji, S

    2004-04-01

    Phosphorus (P) is the second most important macronutrient for plant growth. Plants exhibit numerous physiological and metabolic adaptations in response to seasonal variations in phosphorus content. Activities of acid and alkaline phosphatases, ATPase and ATP content were studied in summer, rainy and winter seasons at two different developmental stages (28 and 58 days after sowing) in Okra. Activities of both acid and alkaline phosphatases increased manifold in winter to cope up with low phosphorus content. ATP content and ATPase activity were high in summer signifying an active metabolic period. Phosphorus deficiency is characterized by low ATP content and ATPase activity (which are in turn partly responsible for a drastic reduction in growth and yield) and enhanced activities of acid and alkaline phosphatases which increase the availability of P in P-deficient seasons.

  10. The equine arteritis virus induces apoptosis via caspase-8 and mitochondria-dependent caspase-9 activation.

    PubMed

    St-Louis, Marie-Claude; Archambault, Denis

    2007-10-10

    We have previously showed that equine arteritis virus (EAV), an arterivirus, induces apoptosis in vitro. To determine the caspase activation pathways involved in EAV-induced apoptosis, target cells were treated with peptide inhibitors of apoptosis Z-VAD-FMK (pan-caspase inhibitor), Z-IETD-FMK (caspase-8-specific inhibitor) or Z-LEHD-FMK (caspase-9-specific inhibitor) 4 h prior to infection with the EAV T1329 Canadian isolate. Significant inhibition of apoptosis was obtained with all peptide inhibitors used. Furthermore, apoptosis was inhibited in cells expressing the R1 subunit of herpes simplex virus type 2 ribonucleotide reductase (HSV2-R1) or hsp70, two proteins which are known to inhibit apoptosis associated with caspase-8 activation and cytochrome c release-dependent caspase-9 activation, respectively. Given the activation of Bid and the translocation of cytochrome c within the cytoplasm, the overall results indicate that EAV induces apoptosis initiated by caspase-8 activation and subsequent mitochondria-dependent caspase-9 activation.

  11. Drosophila factor 2, an RNA polymerase II transcript release factor, has DNA-dependent ATPase activity.

    PubMed

    Xie, Z; Price, D

    1997-12-12

    Drosophila factor 2 has been identified as a component of negative transcription elongation factor (N-TEF) that causes the release of RNA polymerase II transcripts in an ATP-dependent manner (Xie, Z. and Price D. H. (1996) J. Biol. Chem. 271, 11043-11046). We show here that the transcript release activity of factor 2 requires ATP or dATP and that adenosine 5'-O-(thiotriphosphate) (ATPgammaS), adenosine 5'-(beta,gamma-imino)triphosphate (AMP-PNP), or other NTPs do not support the activity. Factor 2 demonstrated a strong DNA-dependent ATPase activity that correlated with its transcript release activity. At 20 microg/ml DNA, the ATPase activity of factor 2 had an apparent Km(ATP) of 28 microM and an estimated Kcat of 140 min-1. Factor 2 caused the release of nascent transcripts associated with elongation complexes generated by RNA polymerase II on a dC-tailed template. Therefore, no other protein cofactors are required for the transcript release activity of factor 2. Using the dC-tailed template assay, it was found that renaturation of the template was required for factor 2 function.

  12. Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis.

    PubMed

    Jang, Mi-Hyeon; Bonaguidi, Michael A; Kitabatake, Yasuji; Sun, Jiaqi; Song, Juan; Kang, Eunchai; Jun, Heechul; Zhong, Chun; Su, Yijing; Guo, Junjie U; Wang, Marie Xun; Sailor, Kurt A; Kim, Ju-Young; Gao, Yuan; Christian, Kimberly M; Ming, Guo-li; Song, Hongjun

    2013-02-07

    Adult neurogenesis, the process of generating mature neurons from adult neural stem cells, proceeds concurrently with ongoing neuronal circuit activity and is modulated by various physiological and pathological stimuli. The niche mechanism underlying the activity-dependent regulation of the sequential steps of adult neurogenesis remains largely unknown. Here, we report that neuronal activity decreases the expression of secreted frizzled-related protein 3 (sFRP3), a naturally secreted Wnt inhibitor highly expressed by adult dentate gyrus granule neurons. Sfrp3 deletion activates quiescent radial neural stem cells and promotes newborn neuron maturation, dendritic growth, and dendritic spine formation in the adult mouse hippocampus. Furthermore, sfrp3 reduction is essential for activity-induced adult neural progenitor proliferation and the acceleration of new neuron development. Our study identifies sFRP3 as an inhibitory niche factor from local mature dentate granule neurons that regulates multiple phases of adult hippocampal neurogenesis and suggests an interesting activity-dependent mechanism governing adult neurogenesis via the acute release of tonic inhibition.

  13. Modification of thiamine pyrophosphate dependent enzyme activity by oxythiamine in Saccharomyces cerevisiae cells.

    PubMed

    Tylicki, Adam; Czerniecki, Jan; Dobrzyn, Pawel; Matanowska, Agnieszka; Olechno, Anna; Strumilo, Slawomir

    2005-10-01

    Oxythiamine is an antivitamin derivative of thiamine that after phosphorylation to oxythiamine pyro phosphate can bind to the active centres of thiamine-dependent enzymes. In the present study, the effect of oxythiamine on the viability of Saccharomyces cerevisiae and the activity of thiamine pyrophosphate dependent enzymes in yeast cells has been investigated. We observed a decrease in pyruvate decarboxylase specific activity on both a control and an oxythiamine medium after the first 6 h of culture. The cytosolic enzymes transketolase and pyruvate decarboxylase decreased their specific activity in the presence of oxythiamine but only during the beginning of the cultivation. However, after 12 h of cultivation, oxythiamine-treated cells showed higher specific activity of cytosolic enzymes. More over, it was established by SDS-PAGE that the high specific activity of pyruvate decarboxylase was followed by an increase in the amount of the enzyme protein. In contrast, the mitochondrial enzymes, pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes, were inhibited by oxythiamine during the entire experiment. Our results suggest that the observed strong decrease in growth rate and viability of yeast on medium with oxythiamine may be due to stronger inhibition of mitochondrial pyruvate dehydrogenase than of cytosolic enzymes.

  14. Temperature dependence of rapidly adapting mechanically activated currents in rat dorsal root ganglion neurons.

    PubMed

    Jia, Zhanfeng; Ling, Jennifer; Gu, Jianguo G

    2012-08-01

    Rapidly adapting mechanically activated channels (RA) are expressed on somatosensory neurons and thought to play a role in mechanical transduction. Because mechanical sensations can be significantly affected by temperatures, we examined thermal sensitivity of RA currents in cultured dorsal root ganglion (DRG) neurons to see if RA channel activity is highly temperature-dependent. RA currents were evoked from DRG neurons by membrane displacements and recorded by the whole-cell patch-clamp recording technique. We found that RA currents were significantly enhanced by warming temperatures from 22 to 32 °C and reduced by cooling temperatures from 24 to 14 °C. RA channel activation exhibited steep temperature-dependence with a large temperature coefficient (Q10>5) and a high activation energy (Ea>30 kcal/mol). We further showed that RA channel activation by mechanical stimulation led to membrane depolarization, which could result in action potential firing at 22 °C or 32 °C but not at 14 °C. Taken together, our results provide the measurements of thermal dynamics and activation energy of RA channels, and suggest that a high energy barrier is present for RA channels to open. These findings are in agreement with temperature sensitivity of mechanical sensations in mammals.

  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. Adrenodemedullation activates the Ca(2+)-dependent proteolysis in soleus muscles from rats exposed to cold.

    PubMed

    Manfredi, L H; Lustrino, D; Machado, J; Silveira, W A; Zanon, N M; Navegantes, L C; Kettelhut, I C

    2017-02-01

    Previous studies have shown that catecholamines in vivo and in vitro inhibit the activity of Ca(2+)-dependent proteolysis in skeletal muscles under basal conditions. In the present study we sought to investigate the role of catecholamines in regulating the Ca(2+)-dependent proteolysis in soleus and extensor digitorum longus (EDL) muscles from rats acutely exposed to cold. Overall proteolysis, the activity of proteolytic systems, protein levels and gene expression of different components of the calpain system were investigated in rats submitted to adrenodemedullation (ADMX) and exposed to cold for 24 h. ADMX drastically reduced plasma epinephrine and promoted an additional increase in the overall proteolysis, which was already increased by cold exposure. The rise in the rate of protein degradation in soleus muscles from adrenodemedullated cold-exposed rats was caused by the high activity of the Ca(2+)-dependent proteolysis, which was associated with the generation of a 145-kDa cleaved α-fodrin fragment, a typical calpain substrate, and lower protein levels and mRNA expression of calpastatin, the endogenous calpain inhibitor. Unlike that observed for soleus muscles, the cold-induced muscle proteolysis in EDL was not affected by ADMX. In isolated soleus muscle, clenbuterol, a selective β2-adrenoceptor agonist, reduced the basal Ca(2+)-dependent proteolysis and completely abolished the activation of this pathway by the cholinergic agonist carbachol. These data suggest that catecholamines released from the adrenal medulla inhibit cold-induced protein breakdown in soleus, and this antiproteolytic effect on the Ca(2+)-dependent proteolytic system is apparently mediated through expression of calpastatin, which leads to suppression of calpain activation.NEW & NOTEWORTHY Although many effects of the sympathetic nervous system on muscle physiology are known, the role of catecholamines in skeletal muscle protein metabolism has been scarcely studied. We suggest that

  17. PKC-dependent activation of human K2P18.1 K+ channels

    PubMed Central

    Rahm, Ann-Kathrin; Gierten, Jakob; Kisselbach, Jana; Staudacher, Ingo; Staudacher, Kathrin; Schweizer, Patrick A; Becker, Rüdiger; Katus, Hugo A; Thomas, Dierk

    2012-01-01

    BACKGROUND AND PURPOSE Two-pore-domain K+ channels (K2P) mediate K+ background currents that modulate the membrane potential of excitable cells. K2P18.1 (TWIK-related spinal cord K+ channel) provides hyperpolarizing background currents in neurons. Recently, a dominant-negative loss-of-function mutation in K2P18.1 has been implicated in migraine, and activation of K2P18.1 channels was proposed as a therapeutic strategy. Here we elucidated the molecular mechanisms underlying PKC-dependent activation of K2P18.1 currents. EXPERIMENTAL APPROACH Human K2P18.1 channels were heterologously expressed in Xenopus laevis oocytes, and currents were recorded with the two-electrode voltage clamp technique. KEY RESULTS Stimulation of PKC using phorbol 12-myristate-13-acetate (PMA) activated the hK2P18.1 current by 3.1-fold in a concentration-dependent fashion. The inactive analogue 4α-PMA had no effect on channel activity. The specific PKC inhibitors bisindolylmaleimide I, Ro-32-0432 and chelerythrine reduced PMA-induced channel activation indicating that PKC is involved in this effect of PMA. Selective activation of conventional PKC isoforms with thymeleatoxin (100 nM) did not reproduce K2P18.1 channel activation. Current activation by PMA was not affected by pretreatment with CsA (calcineurin inhibitor) or KT 5720 (PKA inhibitor), ruling out a significant contribution of calcineurin or cross-talk with PKA to the PKC-dependent hK2P18.1 activation. Finally, mutation of putative PKC phosphorylation sites did not prevent PMA-induced K2P18.1 channel activation. CONCLUSIONS AND IMPLICATIONS We demonstrated that activation of hK2P18.1 (TRESK) by PMA is mediated by PKC stimulation. Hence, PKC-mediated activation of K2P18.1 background currents may serve as a novel molecular target for migraine treatment. PMID:22168364

  18. Activation of transient receptor potential vanilloid 1 by lipoxygenase metabolites depends on PKC phosphorylation.

    PubMed

    Kumar, Rakesh; Hazan, Adina; Geron, Matan; Steinberg, Rebbeca; Livni, Lital; Matzner, Henry; Priel, Avi

    2017-03-01

    Peripheral neuronal activation by inflammatory mediators is a multifaceted physiological response that involves a multitude of regulated cellular functions. One key pathway that has been shown to be involved in inflammatory pain is Gq/GPCR, whose activation by inflammatory mediators is followed by the regulated response of the cation channel transient receptor potential vanilloid 1 (TRPV1). However, the mechanism that underlies TRPV1 activation downstream of the Gq/GPCR pathway has yet to be fully defined. In this study, we employ pharmacological and molecular biology tools to dissect this activation mechanism via perforated-patch recordings and calcium imaging of both neurons and a heterologous system. We showed that TRPV1 activity downstream of Gq/GPCR activation only produced a subdued current, which was noticeably different from the robust current that is typical of TRPV1 activation by exogenous stimuli. Moreover, we specifically demonstrated that 2 pathways downstream of Gq/GPCR signaling, namely endovanilloid production by lipoxygenases and channel phosphorylation by PKC, converge on TRPV1 to evoke a tightly regulated response. Of importance, we show that only when both pathways are acting on TRPV1 is the inflammatory-mediated response achieved. We propose that the requirement of multiple signaling events allows subdued TRPV1 activation to evoke regulated neuronal response during inflammation.-Kumar R., Hazan, A., Geron, M., Steinberg, R., Livni, L., Matzner, H., Priel, A. Activation of transient receptor potential vanilloid 1 by lipoxygenase metabolites depends on PKC phosphorylation.

  19. Antibacterial activity of pH-dependent biosynthesized silver nanoparticles against clinical pathogen.

    PubMed

    Chitra, Kethirabalan; Annadurai, Gurusamy

    2014-01-01

    Simple, nontoxic, environmental friendly method is employed for the production of silver nanoparticles. In this study the synthesized nanoparticles UV absorption band occurred at 400 nm because of the surface Plasmon resonance of silver nanoparticles. The pH of the medium plays important role in the synthesis of control shaped and sized nanoparticles. The colour intensity of the aqueous solution varied with pH. In this study, at pH 9, the colour of the aqueous solution was dark brown, whereas in pH 5 the colour was yellowish brown; the colour difference in the aqueous solution occurred due to the higher production of silver nanoparticles. The antibacterial activity of biosynthesized silver nanoparticles was carried out against E. coli. The silver nanoparticles synthesized at pH 9 showed maximum antibacterial activity at 50 μL.

  20. TNFα induces survival through the FLIP-L-dependent activation of the MAPK/ERK pathway

    PubMed Central

    Marques-Fernandez, F; Planells-Ferrer, L; Gozzelino, R; Galenkamp, K MO; Reix, S; Llecha-Cano, N; Lopez-Soriano, J; Yuste, V J; Moubarak, R S; Comella, J X

    2013-01-01

    Activation of tumor necrosis factor receptor-1 can trigger survival or apoptosis pathways. In many cellular models, including the neuronal cell model PC12, it has been demonstrated that inhibition of protein synthesis is sufficient to render cells sensitive to apoptosis induced by TNFα. The survival effect is linked to the translocation of the transcription factor nuclear factor-kappa B (NF-κB) to the nucleus and activation of survival-related genes such as FLICE-like inhibitory protein long form (FLIP-L) or IAPs. Nonetheless, we previously reported an NF-κB-independent contribution of Bcl-xL to cell survival after TNFα treatment. Here, we demonstrate that NF-κB-induced increase in FLIP-L expression levels is essential for mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) activation. We demonstrate that FLIP-L behaves as a Raf-1 activator through both protein–protein interaction and Raf-1 kinase activation, without the requirement of the classical Ras activation. Importantly, prevention of FLIP-L increase by NF-κB inhibition or knockdown of endogenous FLIP-L blocks MAPK/ERK activation after TNFα treatment. From a functional point of view, we show that inhibition of the MAPK/ERK pathway and the NF-κB pathway are equally relevant to render PC12 cells sensitive to cell death induced by TNFα. Apoptosis induced by TNFα under these conditions is dependent on jun nuclear kinase1/2 JNK1/2-dependent Bim upregulation. Therefore, we report a previously undescribed and essential role for MAPK/ERK activation by FLIP-L in the decision between cell survival and apoptosis upon TNFα stimulation. PMID:23412386

  1. Alternative Oxidase Activity in Tobacco Leaf Mitochondria (Dependence on Tricarboxylic Acid Cycle-Mediated Redox Regulation and Pyruvate Activation).

    PubMed

    Vanlerberghe, G. C.; Day, D. A.; Wiskich, J. T.; Vanlerberghe, A. E.; McIntosh, L.

    1995-10-01

    Transgenic Nicotiana tabacum (cv Petit Havana SR1) containing high levels of mitochondrial alternative oxidase (AOX) protein due to the introduction of a sense transgene(s) of Aox1, the nuclear gene encoding AOX, were used to investigate mechanisms regulating AOX activity. After purification of leaf mitochondria, a large proportion of the AOX protein was present as the oxidized (covalently associated and less active) dimer. High AOX activity in these mitochondria was dependent on both reduction of the protein by DTT (to the noncovalently associated and more active dimer) and its subsequent activation by certain [alpha]-keto acids, particularly pyruvate. Reduction of AOX to its more active form could also be mediated by intramitochondrial reducing power generated by the oxidation of certain tricarboxylic acid cycle substrates, most notably isocitrate and malate. Our evidence suggests that NADPH may be specifically required for AOX reduction. All of the above regulatory mechanisms applied to AOX in wild-type mitochondria as well. Transgenic leaves lacking AOX due to the introduction of an Aox1 antisense transgene or multiple sense transgenes were used to investigate the potential physiological significance of the AOX-regulatory mechanisms. Under conditions in which respiratory carbon metabolism is restricted by the capacity of mitochondrial electron transport, feed-forward activation of AOX by mitochondrial reducing power and pyruvate may act to prevent redirection of carbon metabolism, such as to fermentative pathways.

  2. 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 ...

  3. Cross bridge-dependent activation of contraction in cardiac myofibrils at low pH.

    PubMed

    Swartz, D R; Zhang, D; Yancey, K W

    1999-05-01

    Striated muscle contracts in the absence of calcium at low concentrations of MgATP ([MgATP]), and this has been termed rigor activation because rigor cross bridges attach and activate adjacent actin sites. This process is well characterized in skeletal muscle but not in cardiac muscle. Rigor cross bridges are also thought to increase calcium binding to troponin C and play a synergistic role in activation. We tested the hypothesis that cross bridge-dependent activation results in an increase in contractile activity at normal and low pH values. Myofibrillar ATPase activity was measured as a function of pCa and [MgATP] at pH 7.0, and the data showed that, at pCa values of >/=5.5, there was a biphasic relationship between activity and [MgATP]. Peak activity occurred at 10-50 microM MgATP, and [MgATP] for peak activity was lower with increased pCa. The ATPase activity of rat cardiac myofibrils as a function of [MgATP] at a pCa of 9.0 was measured at several pH levels (pH 5.4-7.0). The ATPase activity as a function of [MgATP] was biphasic with a maximum at 8-10 microM MgATP. Lower pH did not result in a substantial decrease in myofibrillar ATPase activity even at pH 5.4. The extent of shortening, as measured by Z-line spacing, was greatest at 8 microM MgATP and less at both lower and higher [MgATP], and this response was observed at all pH levels. These studies suggest that the peak ATPase activity associated with low [MgATP] was coupled to sarcomere shortening. These results support the hypothesis that cross bridge-dependent activation of contraction may be responsible for contracture in the ischemic heart.

  4. 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

  5. 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

  6. Local Interleukin-1-Driven Joint Pathology Is Dependent on Toll-Like Receptor 4 Activation

    PubMed Central

    Abdollahi-Roodsaz, Shahla; Joosten, Leo A.B.; Koenders, Marije I.; van den Brand, Ben T.; van de Loo, Fons A.J.; van den Berg, Wim B.

    2009-01-01

    Toll-like receptors (TLRs) may contribute to the pathogenesis of chronic inflammatory destructive diseases through the recognition of endogenous ligands produced on either inflammation or degeneration of the extracellular matrix. The presence of endogenous TLR agonists has been reported in rheumatoid joints. In the present study, we investigated the significance of TLR2 and TLR4 activation by locally- produced endogenous ligands in the severity of joint inflammation and destruction. Local joint pathology independent of systemic immune activation was induced by overexpression of interleukin (IL)-1 and TNF in naive joints using adenoviral gene transfer. Here, we report that at certain doses, IL-1-induced local joint inflammation, cartilage proteoglycan depletion, and bone erosion are dependent on TLR4 activation, whereas TLR2 activation is not significantly involved. In comparison, tumor necrosis factor α-driven joint pathology seemed to be less dependent on TLR2 and TLR4. The severity of IL-1-induced bone erosion and irreversible cartilage destruction was markedly reduced in TLR4−/− mice, even though the degree of inflammation was similar, suggesting uncoupled processes. Furthermore, the expression of cathepsin K, a marker for osteoclast activity, induced by IL-1β was dependent on TLR4. Overexpression of IL-1β in the joint as well as ex vivo IL-1 stimulation of patellae provoked the release of endogenous TLR4 agonists capable of inducing TLR4-mediated cytokine production. These data emphasize the potential relevance of TLR4 activation in rheumatoid arthritis, particularly with respect to IL-1-mediated joint pathology. PMID:19834062

  7. 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

  8. Activity-dependent regulation of genes implicated in X-linked non-specific mental retardation.

    PubMed

    Boda, B; Mas, C; Muller, D

    2002-01-01

    X-linked forms of non-specific mental retardation are complex disorders, for which mutations in several genes have recently been identified. These include OPHN1, GDI1, PAK3, IL1RAPL, TM4SF2, FMR2 and RSK2. To investigate the mechanisms through which alterations of these gene products could result in cognitive impairment, we analyzed their expression using quantitative PCR technique in two in vitro models of activity-dependent gene regulation: kainate-induced seizures and long-term synaptic potentiation (LTP). We found that the level of expression of four genes, PAK3, IL1RAPL, RSK2 and TM4SF2, was significantly up-regulated following kainate treatment. Furthermore we observed a significant increase in mRNA levels of PAK3 and IL1RAPL following LTP induction. These results suggest a possible role for these four genes in activity-dependent brain plasticity.

  9. Activity-Dependent Plasticity and Gene Expression Modifications in the Adult CNS

    PubMed Central

    Carulli, Daniela; Foscarin, Simona; Rossi, Ferdinando

    2011-01-01

    Information processing, memory formation, or functional recovery after nervous system damage depend on the ability of neurons to modify their functional properties or their connections. At the cellular/molecular level, structural modifications of neural circuits are finely regulated by intrinsic neuronal properties and growth-regulatory cues in the extracellular milieu. Recently, it has become clear that stimuli coming from the external world, which comprise sensory inflow, motor activity, cognitive elaboration, or social interaction, not only provide the involved neurons with instructive information needed to shape connection patterns to sustain adaptive function, but also exert a powerful influence on intrinsic and extrinsic growth-related mechanisms, so to create permissive conditions for neuritic remodeling. Here, we present an overview of recent findings concerning the effects of experience on molecular mechanisms underlying CNS structural plasticity, both in physiological conditions and after damage, with particular focus on activity-dependent modulation of growth-regulatory genes and epigenetic modifications. PMID:22144945

  10. Activity-dependent signal changes in neurons by fiber-coupled microscopy

    NASA Astrophysics Data System (ADS)

    Sakurai, Takashi; Koida, Kowa

    2014-03-01

    To study neuronal functions in brain, we developed a higher resolution type fiber-coupled microscope (FCM), and measured the activity-dependent fluorescence intensity of the excitable cells over time. FCM was constructed by combining a fluorescence microscope with the high density type of fiber bundle, which consisted of 1.5 x 104 unit fiber in the assemble less than 0.5 mm tip. The spatial resolution was calculated to be 2.4 mm with the 5 mm focal depth. The activity-dependent Ca signals were detectable in each cell of either the pancreatic spheroids or the brain slices. The present FCM is very promising for detailed studies with the live imaging of signal molecules in the body at a single cell level.

  11. ZP3-dependent activation of sperm cation channels regulates acrosomal secretion during mammalian fertilization

    PubMed Central

    1996-01-01

    The sperm acrosome reaction is a Ca(2+)-dependent secretory event required for fertilization. Adhesion to the egg's zona pellucida promotes Ca2+ influx through voltage-sensitive channels, thereby initiating secretion. We used potentiometric fluorescent probes to determine the role of sperm membrane potential in regulating Ca2+ entry. ZP3, the glycoprotein agonist of the zona pellucida, depolarizes sperm membranes by activating a pertussis toxin-insensitive mechanism with the characteristics of a poorly selective cation channel. ZP3 also activates a pertussis toxin-sensitive pathway that produces a transient rise in internal pH. The concerted effects of depolarization and alkalinization open voltage-sensitive Ca2+ channels. These observations suggest that mammalian sperm utilize membrane potential-dependent signal transduction mechanisms and that a depolarization pathway is an upstream transducing element coupling adhesion to secretion during fertilization. PMID:8707844

  12. Suborganelle sensing of mitochondrial cAMP-dependent protein kinase activity.

    PubMed

    Agnes, Richard S; Jernigan, Finith; Shell, Jennifer R; Sharma, Vyas; Lawrence, David S

    2010-05-05

    A fluorescent sensor of protein kinase activity has been developed and used to characterize the compartmentalized location of cAMP-dependent protein kinase activity in mitochondria. The sensor functions via a phosphorylation-induced release of a quencher from a peptide-based substrate, producing a 150-fold enhancement in fluorescence. The quenching phenomenon transpires via interaction of the quencher with Arg residues positioned on the peptide substrate. Although the cAMP-dependent protein kinase is known to be present in mitochondria, the relative amount of enzyme positioned in the major compartments (outer membrane, intermembrane space, and the matrix) of the organelle is unclear. The fluorescent sensor developed in this study was used to reveal the relative matrix/intermembrane space/outer membrane (85:6:9) distribution of PKA in bovine heart mitochondria.

  13. INNATE IMMUNITY. Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.

    PubMed

    Gaudet, Ryan G; Sintsova, Anna; Buckwalter, Carolyn M; Leung, Nelly; Cochrane, Alan; Li, Jianjun; Cox, Andrew D; Moffat, Jason; Gray-Owen, Scott D

    2015-06-12

    Host recognition of pathogen-associated molecular patterns (PAMPs) initiates an innate immune response that is critical for pathogen elimination and engagement of adaptive immunity. Here we show that mammalian cells can detect and respond to the bacterial-derived monosaccharide heptose-1,7-bisphosphate (HBP). A metabolic intermediate in lipopolysaccharide biosynthesis, HBP is highly conserved in Gram-negative bacteria, yet absent from eukaryotic cells. Detection of HBP within the host cytosol activated the nuclear facto κB pathway in vitro and induced innate and adaptive immune responses in vivo. Moreover, we used a genome-wide RNA interference screen to uncover an innate immune signaling axis, mediated by phosphorylation-dependent oligomerization of the TRAF-interacting protein with forkhead-associated domain (TIFA) that is triggered by HBP. Thus, HBP is a PAMP that activates TIFA-dependent immunity to Gram-negative bacteria.

  14. 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

    2013-11-06

    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.

  15. The BLOC-1 Subunit Pallidin Facilitates Activity-Dependent Synaptic Vesicle Recycling

    PubMed Central

    Ma, Wenpei; Zhang, Shixing; Paluch, Jeremy; Guo, Wanlin

    2017-01-01

    Abstract Membrane trafficking pathways must be exquisitely coordinated at synaptic terminals to maintain functionality, particularly during conditions of high activity. We have generated null mutations in the Drosophila homolog of pallidin, a central subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), to determine its role in synaptic development and physiology. We find that Pallidin localizes to presynaptic microtubules and cytoskeletal structures, and that the stability of Pallidin protein is highly dependent on the BLOC-1 components Dysbindin and Blos1. We demonstrate that the rapidly recycling vesicle pool is not sustained during high synaptic activity in pallidin mutants, leading to accelerated rundown and slowed recovery. Following intense activity, we observe a loss of early endosomes and a concomitant increase in tubular endosomal structures in synapses without Pallidin. Together, our data reveal that Pallidin subserves a key role in promoting efficient synaptic vesicle recycling and re-formation through early endosomes during sustained activity. PMID:28317021

  16. Epileptiform Activity in Alcohol Dependent Patients and Possibilities of Its Indirect Measurement

    PubMed Central

    Bob, Petr; Jasova, Denisa; Bizik, Gustav; Raboch, Jiri

    2011-01-01

    Background Alcohol dependence during withdrawal and also in abstinent period in many cases is related to reduced inhibitory functions and kindling that may appear in the form of psychosensory symptoms similar to temporal lobe epilepsy frequently in conditions of normal EEG and without seizures. Because temporal lobe epileptic activity tend to spread between hemispheres, it is possible to suppose that measures reflecting interhemispheric information transfer such as electrodermal activity (EDA) might be related to the psychosensory symptoms. Methods and Findings We have performed measurement of bilateral EDA, psychosensory symptoms (LSCL-33) and alcohol craving (ACQ) in 34 alcohol dependent patients and 32 healthy controls. The results in alcohol dependent patients show that during rest conditions the psychosensory symptoms (LSCL-33) are related to EDA transinformation (PTI) between left and right EDA records (Spearman r = 0.44, p<0.01). Conclusions The result may present potentially useful clinical finding suggesting a possibility to indirectly assess epileptiform changes in alcohol dependent patients. PMID:21541318

  17. 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.

  18. 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.

  19. Dolphin changes in whistle structure with watercraft activity depends on their behavioral state.

    PubMed

    May-Collado, Laura J; Quiñones-Lebrón, Shakira G

    2014-04-01

    Dolphins rely on whistles to identify each other and to receive and convey information about their environment. Although capable of adjusting these signals with changing environments, there is little information on how dolphins acoustically respond to different watercraft activities and if this response depends on dolphin behavioral state. Bottlenose dolphin whistles were recorded in the presence of research and dolphin-watching boats. Dolphins emitted lower frequency and longer whistles when interacting with dolphin-watching boats, particularly during foraging activities. This study suggests that dolphin-watching boat traffic significantly hinders dolphin communication during important behavioral states.

  20. An Evolutionarily Conserved Mechanism for Activity-Dependent Visual Circuit Development

    PubMed Central

    Pratt, Kara G.; Hiramoto, Masaki; Cline, Hollis T.

    2016-01-01

    Neural circuit development is an activity-dependent process. This activity can be spontaneous, such as the retinal waves that course across the mammalian embryonic retina, or it can be sensory-driven, such as the activation of retinal ganglion cells (RGCs) by visual stimuli. Whichever the source, neural activity provides essential instruction to the developing circuit. Indeed, experimentally altering activity has been shown to impact circuit development and function in many different ways and in many different model systems. In this review, we contemplate the idea that retinal waves in amniotes, the animals that develop either in ovo or utero (namely reptiles, birds and mammals) could be an evolutionary adaptation to life on land, and that the anamniotes, animals whose development is entirely external (namely the aquatic amphibians and fish), do not display retinal waves, most likely because they simply don’t need them. We then review what is known about the function of both retinal waves and visual stimuli on their respective downstream targets, and predict that the experience-dependent development of the tadpole visual system is a blueprint of what will be found in future studies of the effects of spontaneous retinal waves on instructing development of retinorecipient targets such as the superior colliculus (SC) and the lateral geniculate nucleus. PMID:27818623

  1. 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.

  2. Cocaine dependent individuals with attenuated striatal activation during reinforcement learning are more susceptible to relapse.

    PubMed

    Stewart, Jennifer L; Connolly, Colm G; May, April C; Tapert, Susan F; Wittmann, Marc; Paulus, Martin P

    2014-08-30

    Cocaine-dependent individuals show altered brain activation during decision making. It is unclear, however, whether these activation differences are related to relapse vulnerability. This study tested the hypothesis that brain-activation patterns during reinforcement learning are linked to relapse 1 year later in individuals entering treatment for cocaine dependence. Subjects performed a Paper-Scissors-Rock task during functional magnetic resonance imaging (fMRI). A year later, we examined whether subjects had remained abstinent (n=15) or relapsed (n=15). Although the groups did not differ on demographic characteristics, behavioral performance, or lifetime substance use, abstinent patients reported greater motivation to win than relapsed patients. The fMRI results indicated that compared with abstinent individuals, relapsed users exhibited lower activation in (1) bilateral inferior frontal gyrus and striatum during decision making more generally; and (2) bilateral middle frontal gyrus and anterior insula during reward contingency learning in particular. Moreover, whereas abstinent patients exhibited greater left middle frontal and striatal activation to wins than losses, relapsed users did not demonstrate modulation in these regions as a function of outcome valence. Thus, individuals at high risk for relapse relative to those who are able to abstain allocate fewer neural resources to action-outcome contingency formation and decision making, as well as having less motivation to win on a laboratory-based task.

  3. Cocaine dependent individuals with attenuated striatal activation during reinforcement learning are more susceptible to relapse

    PubMed Central

    Stewart, Jennifer L.; Connolly, Colm G.; May, April C.; Tapert, Susan F.; Wittmann, Marc; Paulus, Martin P.

    2014-01-01

    Cocaine-dependent individuals show altered brain activation during decision making. It is unclear, however, whether these activation differences are related to relapse vulnerability. This study tested the hypothesis that brain-activation patterns during reinforcement learning are linked to relapse 1 year later in individuals entering treatment for cocaine dependence. Subjects performed a Paper-Scissors-Rock task during functional magnetic resonance imaging (fMRI). A year later, we examined whether subjects had remained abstinent (n=15) or relapsed (n=15). Although the groups did not differ on demographic characteristics, behavioral performance, or lifetime substance use, abstinent patients reported greater motivation to win than relapsed patients. The fMRI results indicated that compared with abstinent individuals, relapsed users exhibited lower activation in (1) bilateral inferior frontal gyrus and striatum during decision making more generally; and (2) bilateral middle frontal gyrus and anterior insula during reward contingency learning in particular. Moreover, whereas abstinent patients exhibited greater left middle frontal and striatal activation to wins than losses, relapsed users did not demonstrate modulation in these regions as a function of outcome valence. Thus, individuals at high risk for relapse relative to those who are able to abstain allocate fewer neural resources to action-outcome contingency formation and decision making, as well as having less motivation to win on a laboratory-based task. PMID:24862388

  4. 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.

  5. Phospholipase D activity couples plasma membrane endocytosis with retromer dependent recycling

    PubMed Central

    Thakur, Rajan; Panda, Aniruddha; Coessens, Elise; Raj, Nikita; Yadav, Shweta; Balakrishnan, Sruthi; Zhang, Qifeng; Georgiev, Plamen; Basak, Bishal; Pasricha, Renu; Wakelam, Michael JO; Ktistakis, Nicholas T; Raghu, Padinjat

    2016-01-01

    During illumination, the light-sensitive plasma membrane (rhabdomere) of Drosophila photoreceptors undergoes turnover with consequent changes in size and composition. However, the mechanism by which illumination is coupled to rhabdomere turnover remains unclear. We find that photoreceptors contain a light-dependent phospholipase D (PLD) activity. During illumination, loss of PLD resulted in an enhanced reduction in rhabdomere size, accumulation of Rab7 positive, rhodopsin1-containing vesicles (RLVs) in the cell body and reduced rhodopsin protein. These phenotypes were associated with reduced levels of phosphatidic acid, the product of PLD activity and were rescued by reconstitution with catalytically active PLD. In wild-type photoreceptors, during illumination, enhanced PLD activity was sufficient to clear RLVs from the cell body by a process dependent on Arf1-GTP levels and retromer complex function. Thus, during illumination, PLD activity couples endocytosis of RLVs with their recycling to the plasma membrane thus maintaining plasma membrane size and composition. DOI: http://dx.doi.org/10.7554/eLife.18515.001 PMID:27848911

  6. Activation of TRPV1 by Dietary Capsaicin Improves Endothelium-Dependent Vasorelaxation and Prevents Hypertension

    PubMed Central

    Yang, Dachun; Luo, Zhidan; Ma, Shuangtao; Wong, Wing Tak; Ma, Liqun; Zhong, Jian; He, Hongbo; Zhao, Zhigang; Cao, Tingbing; Yan, Zhencheng; Liu, Daoyan; Arendshorst, William J.; Huang, Yu; Tepel, Martin; Zhu, Zhiming

    2014-01-01

    SUMMARY Some plant-based diets lower the cardiometabolic risks and prevalence of hypertension. New evidence implies a role for the transient receptor potential vanilloid 1 (TRPV1) cation channel in the pathogenesis of cardiometabolic diseases. Little is known about impact of chronic TRPV1 activation on the regulation of vascular function and blood pressure. Here we report that chronic TRPV1 activation by dietary capsaicin increases the phosphorylation of protein kinase A (PKA) and eNOS and thus production of nitric oxide (NO) in endothelial cells, which is calcium dependent. TRPV1 activation by capsaicin enhances endothelium-dependent relaxation in wild-type mice, an effect absent in TRPV1-deficient mice. Long-term stimulation of TRPV1 can activate PKA, which contributes to increased eNOS phosphorylation, improves vasorelaxation, and lowers blood pressure in genetically hypertensive rats. We conclude that TRPV1 activation by dietary capsaicin improves endothelial function. TRPV1-mediated increase in NO production may represent a promising target for therapeutic intervention of hypertension. PMID:20674858

  7. Changes in brain activation in breast cancer patients depend on cognitive domain and treatment type

    PubMed Central

    Menning, Sanne; de Ruiter, Michiel B.; Veltman, Dick J.; Boogerd, Willem; Oldenburg, Hester S. A.; Reneman, Liesbeth

    2017-01-01

    Background Cognitive problems in breast cancer patients are common after systemic treatment, particularly chemotherapy. An increasing number of fMRI studies show altered brain activation in breast cancer patients after treatment, suggestive of neurotoxicity. Previous prospective fMRI studies administered a single cognitive task. The current study employed two task paradigms to evaluate whether treatment-induced changes depend on the probed cognitive domain. Methods Participants were breast cancer patients scheduled to receive systemic treatment (anthracycline-based chemotherapy +/- endocrine treatment, n = 28), or no systemic treatment (n = 24) and no-cancer controls (n = 31). Assessment took place before adjuvant treatment and six months after chemotherapy, or at similar intervals. Blood oxygen level dependent (BOLD) activation and performance were measured during an executive functioning task and an episodic memory task. Group-by-time interactions were analyzed using a flexible factorial design. Results Task performance did not differ between patient groups and did not change over time. Breast cancer patients who received systemic treatment, however, showed increased parietal activation compared to baseline with increasing executive functioning task load compared to breast cancer patients who did not receive systemic treatment. This hyperactivation was accompanied by worse physical functioning, higher levels of fatigue and more cognitive complaints. In contrast, in breast cancer patients who did not receive systemic treatment, parietal activation normalized over time compared to the other two groups. Conclusions Parietal hyperactivation after systemic treatment in the context of stable levels of executive task performance is compatible with a compensatory processing account of hyperactivation or maintain adequate performance levels. This over-recruitment of brain regions depends on the probed cognitive domain and may represent a response to decreased neural

  8. Size Dependent Platelet Subpopulations: Relationship of Platelet Volume to Ultrastructure Enzymatic Activity, and Function.

    DTIC Science & Technology

    1983-03-10

    of the present apheresis instruments to separate the larger more functional platelets from the smaller ones. The selective isolation of large... PLATELET VOLUME T. -(U) BOSTON UNIV MA SCHOOL OF I MEDICINE C B THOMPSON ET RL 10 MAR 83 BUSM-93-89 UNIIDN919CA89 /68 6ilfflfllflflflflll l...N00014-79-C-0168 TECHNICAL REPORT NO. 83-08 SIZE DEPENDENT PLATELET SUBPOPULATIONS: RELATIONSHIP OF PLATELET VOLUME TO ULTRASTRUCTURE. ENZYMATIC ACTIVITY

  9. Regulation of aPKC activity by Nup358 dependent SUMO modification

    PubMed Central

    Yadav, Santosh Kumar; Magre, Indrasen; Singh, Aditi; Khuperkar, Deepak; Joseph, Jomon

    2016-01-01

    Atypical PKC (aPKC) family members are involved in regulation of diverse cellular processes, including cell polarization. aPKCs are known to be activated by phosphorylation of specific threonine residues in the activation loop and turn motif. They can also be stimulated by interaction with Cdc42~GTP-Par6 complex. Here we report that PKCζ, a member of the aPKC family, is activated by SUMOylation. We show that aPKC is endogenously modified by SUMO1 and the nucleoporin Nup358 acts as its SUMO E3 ligase. Results from in vitro SUMOylation and kinase assays showed that the modification enhances the kinase activity of PKCζ by ~10-fold. By monitoring the phosphorylation of Lethal giant larvae (Lgl), a downstream target of aPKC, we confirmed these findings in vivo. Consistent with the function of Nup358 as a SUMO E3 ligase for aPKC, depletion of Nup358 attenuated the extent of SUMOylation and the activity of aPKC. Moreover, overexpression of the C-terminal fragment of Nup358 that possesses the E3 ligase activity enhanced SUMOylation of endogenous aPKC and its kinase activity. Collectively, our studies reveal a role for Nup358-dependent SUMOylation in the regulation of aPKC activity and provide a framework for understanding the role of Nup358 in cell polarity. PMID:27682244

  10. Activity dependent mechanisms of visual map formation--from retinal waves to molecular regulators.

    PubMed

    Assali, Ahlem; Gaspar, Patricia; Rebsam, Alexandra

    2014-11-01

    The refinement of neural connections requires activity-dependent mechanisms in addition to the genetic program initially establishing wiring diagrams. The well-understood organization of the visual system makes it an accessible model for analyzing the contribution of activity in the formation of connectivity. Prior to visual experience, patterned spontaneous activity in the form of retinal waves has an important role for the establishment of eye-specific and retinotopic maps by acting on the refinement of axon arborization. In the present review, which focuses on experimental data obtained in mice and ferrets, we highlight the features of retinal activity that are important for visual map formation and question whether synaptic release and Hebbian based competition rules apply to this system. Recent evidence using genetic tools that allowed the manipulation of different features of neural activity have clarified the controversy on whether activity is instructive or permissive for visual map formation. Furthermore, current evidence strongly suggests that different mechanisms are at play for different types of axons (ipsilateral vs. contralateral), maps (eye-specific vs. retinotopic) or targets. Many molecules that either modulate activity or are modulated by activity are important in the formation of the visual map, such as adenylate cyclase 1, serotonin, or molecules from the immune system. Finally, new players in the game include retrograde messengers signaling from the target cell to the retinal axons as well as microglia that could help to eliminate inappropriate synapses.

  11. Activation-Dependent Rapid Postsynaptic Clustering of Glycine Receptors in Mature Spinal Cord Neurons

    PubMed Central

    Eto, Kei; Murakoshi, Hideji; Watanabe, Miho; Hirata, Hiromi; Moorhouse, Andrew J.; Ishibashi, Hitoshi

    2017-01-01

    Abstract Inhibitory synapses are established during development but continue to be generated and modulated in strength in the mature nervous system. In the spinal cord and brainstem, presynaptically released inhibitory neurotransmitter dominantly switches from GABA to glycine during normal development in vivo. While presynaptic mechanisms of the shift of inhibitory neurotransmission are well investigated, the contribution of postsynaptic neurotransmitter receptors to this shift is not fully elucidated. Synaptic clustering of glycine receptors (GlyRs) is regulated by activation-dependent depolarization in early development. However, GlyR activation induces hyperpolarization after the first postnatal week, and little is known whether and how presynaptically released glycine regulates postsynaptic receptors in a depolarization-independent manner in mature developmental stage. Here we developed spinal cord neuronal culture of rodents using chronic strychnine application to investigate whether initial activation of GlyRs in mature stage could change postsynaptic localization of GlyRs. Immunocytochemical analyses demonstrate that chronic blockade of GlyR activation until mature developmental stage resulted in smaller clusters of postsynaptic GlyRs that could be enlarged upon receptor activation for 1 h in the mature stage. Furthermore, live cell-imaging techniques show that GlyR activation decreases its lateral diffusion at synapses, and this phenomenon is dependent on PKC, but neither Ca2+ nor CaMKII activity. These results suggest that the GlyR activation can regulate receptor diffusion and cluster size at inhibitory synapses in mature stage, providing not only new insights into the postsynaptic mechanism of shifting inhibitory neurotransmission but also the inhibitory synaptic plasticity in mature nervous system. PMID:28197549

  12. PKCα mediates acetylcholine-induced activation of TRPV4-dependent calcium influx in endothelial cells

    PubMed Central

    Adapala, Ravi K.; Talasila, Phani K.; Bratz, Ian N.; Zhang, David X.; Suzuki, Makoto; Meszaros, J. Gary

    2011-01-01

    Transient receptor potential vanilloid channel 4 (TRPV4) is a polymodally activated nonselective cationic channel implicated in the regulation of vasodilation and hypertension. We and others have recently shown that cyclic stretch and shear stress activate TRPV4-mediated calcium influx in endothelial cells (EC). In addition to the mechanical forces, acetylcholine (ACh) was shown to activate TRPV4-mediated calcium influx in endothelial cells, which is important for nitric oxide-dependent vasodilation. However, the molecular mechanism through which ACh activates TRPV4 is not known. Here, we show that ACh-induced calcium influx and endothelial nitric oxide synthase (eNOS) phosphorylation but not calcium release from intracellular stores is inhibited by a specific TRPV4 antagonist, AB-159908. Importantly, activation of store-operated calcium influx was not altered in the TRPV4 null EC, suggesting that TRPV4-dependent calcium influx is mediated through a receptor-operated pathway. Furthermore, we found that ACh treatment activated protein kinase C (PKC) α, and inhibition of PKCα activity by the specific inhibitor Go-6976, or expression of a kinase-dead mutant of PKCα but not PKCε or downregulation of PKCα expression by chronic 12-O-tetradecanoylphorbol-13-acetate treatment, completely abolished ACh-induced calcium influx. Finally, we found that ACh-induced vasodilation was inhibited by the PKCα inhibitor Go-6976 in small mesenteric arteries from wild-type mice, but not in TRPV4 null mice. Taken together, these findings demonstrate, for the first time, that a specific isoform of PKC, PKCα, mediates agonist-induced receptor-mediated TRPV4 activation in endothelial cells. PMID:21705673

  13. 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

  14. Region-related modular nerve-dependent motor activity in anorectum--cholinergic and nitrergic contribution to rat model.

    PubMed

    Stavreva, Galya; Radomirov, Radomir

    2012-01-01

    Disturbances of enteric nerve-mediated anorectal evacuation mechanisms have medical and social impact. The study aimed at further eliciting the contribution of cholinergic and nitrergic neurotransmission systems to modular nerve networks in different regions of Wistar rat anorectum. Electrical field stimulation (EFS, 0.8 ms, 40 V, 2, 5 or 10 Hz, 20 s), computerized mechanographic on-line setup and drugs were used to evaluate the motor responses of isolated rings from circular muscle of rectum (proximal, middle, and distal part), internal anal sphincter, and anal canal. Twitch-like frequency-dependent contractions, more pronounced in rectal preparations, characterized the modular motor responses of rectal circular muscle rings and anal canal. Depending on the frequency of stimulation, the motor activity of internal anal sphincter varied from deep long-lasting relaxation to initial short-lasting relaxation, followed by a contraction. Electrically-evoked responses of anorectal preparations were tetrodotoxin (0.1 microM)-sensitive. In the presence of atropine (0.3 microM) the contractions of rectal rings decreased, relaxation of internal anal sphincter increased and inhibition of the contractions of the anal canal occurred, followed by relaxation. During atropine treatment, NG-nitro-L-arginine (0.5 microM) increased the contractile responses and suppressed internal anal sphincter relaxations. L-arginine (0.5 microM) decreased the contractions and extended the relaxations of internal anal sphincter and anal canal. Our results suggest that cholinergic and nitrergic systems are not equally involved in modular nerve networks of various regions of anorectum. Cholinergic transmission is more expressed in distal rectum, underlying its contractile potency, while nitric oxide-dependent transmission(s) control the relaxation ability of the internal anal sphincter and anal canal.

  15. Characterization of quinol-dependent nitric oxide reductase from Geobacillus stearothermophilus: enzymatic activity and active site structure.

    PubMed

    Terasaka, Erina; Okada, Norihiro; Sato, Nozomi; Sako, Yoshihiko; Shiro, Yoshitsugu; Tosha, Takehiko

    2014-07-01

    Nitric oxide reductase (NOR) catalyzes the reduction of nitric oxide to generate nitrous oxide. We recently reported on the crystal structure of a quinol-dependent NOR (qNOR) from Geobacillus stearothermophilus [Y. Matsumoto, T. Tosha, A.V. Pisliakov, T. Hino, H. Sugimoto, S. Nagano, Y. Sugita and Y. Shiro, Nat. Struct. Mol. Biol. 19 (2012) 238-246], and suggested that a water channel from the cytoplasm, which is not observed in cytochrome c-dependent NOR (cNOR), functions as a pathway transferring catalytic protons. Here, we further investigated the functional and structural properties of qNOR, and compared the findings with those for cNOR. The pH optimum for the enzymatic reaction of qNOR was in the alkaline range, whereas Pseudomonas aeruginosa cNOR showed a higher activity at an acidic pH. The considerably slower reduction rate, and a correlation of the pH dependence for enzymatic activity and the reduction rate suggest that the reduction process is the rate-determining step for the NO reduction by qNOR, while the reduction rate for cNOR was very fast and therefore is unlikely to be the rate-determining step. A close examination of the heme/non-heme iron binuclear center by resonance Raman spectroscopy indicated that qNOR has a more polar environment at the binuclear center compared with cNOR. It is plausible that a water channel enhances the accessibility of the active site to solvent water, creating a more polar environment in qNOR. This structural feature could control certain properties of the active site, such as redox potential, which could explain the different catalytic properties of the two NORs. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.

  16. 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.

  17. Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.

    PubMed

    Li, Donghui; Dammer, Eric B; Sewer, Marion B

    2012-07-01

    In the human adrenal cortex, cortisol is synthesized from cholesterol by members of the cytochrome P450 superfamily and hydroxysteroid dehydrogenases. Both the first and last steps of cortisol biosynthesis occur in mitochondria. Based on our previous findings that activation of ACTH signaling changes the ratio of nicotinamide adenine dinucleotide (NAD) phosphate to reduced NAD phosphate in adrenocortical cells, we hypothesized that pyridine nucleotide metabolism may regulate the activity of the mitochondrial NAD(+)-dependent sirtuin (SIRT) deacetylases. We show that resveratrol increases the protein expression and half-life of P450 side chain cleavage enzyme (P450scc). The effects of resveratrol on P450scc protein levels and acetylation status are dependent on SIRT3 and SIRT5 expression. Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis. Finally, resveratrol also increases the protein expression of P450 11β, another mitochondrial enzyme required for cortisol biosynthesis. Collectively, this study identifies a role for NAD(+)-dependent SIRT deacetylase activity in regulating the expression of mitochondrial steroidogenic P450.

  18. Release activity-dependent control of vesicle endocytosis by the synaptic adhesion molecule N-cadherin.

    PubMed

    van Stegen, Bernd; Dagar, Sushma; Gottmann, Kurt

    2017-01-20

    At synapses in the mammalian brain, continuous information transfer requires the long-term maintenance of homeostatic coupling between exo- and endocytosis of synaptic vesicles. Because classical endocytosis is orders of magnitude slower than the millisecond-range exocytosis of vesicles, high frequency vesicle fusion could potentially compromise structural stability of synapses. However, the molecular mechanisms mediating the tight coupling of exo- and endocytosis are largely unknown. Here, we investigated the role of the transsynaptic adhesion molecules N-cadherin and Neuroligin1 in regulating vesicle exo- and endocytosis by using activity-induced FM4-64 staining and by using synaptophysin-pHluorin fluorescence imaging. The synaptic adhesion molecules N-cadherin and Neuroligin1 had distinct impacts on exo- and endocytosis at mature cortical synapses. Expression of Neuroligin1 enhanced vesicle release in a N-cadherin-dependent way. Most intriguingly, expression of N-cadherin enhanced both vesicle exo- and endocytosis. Further detailed analysis of N-cadherin knockout neurons revealed that the boosting of endocytosis by N-cadherin was largely dependent on preceding high levels of vesicle release activity. In summary, regulation of vesicle endocytosis was mediated at the molecular level by N-cadherin in a release activity-dependent manner. Because of its endocytosis enhancing function, N-cadherin might play an important role in the coupling of vesicle exo- and endocytosis.

  19. 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

  20. [Bacteria and viruses modulate FcεRI-dependent mast cell activity].

    PubMed

    Słodka, Aleksandra; Brzezińska-Błaszczyk, Ewa

    2013-03-08

    Undoubtedly, mast cells play a central role in allergic processes. Specific allergen cross-linking of IgE bound to the high affinity receptors (FcεRI) on the mast cell surface leads to the release of preformed mediators and newly synthesized mediators, i.e. metabolites of arachidonic acid and cytokines. More and more data indicate that bacteria and viruses can influence FcεRI-dependent mast cell activation. Some bacterial and viral components can reduce the surface expression of FcεRI. There are also findings that ligation of Toll-like receptors (TLRs) by bacterial or viral antigens can affect IgE-dependent mast cell degranulation and preformed mediator release as well as eicosanoid production. The synergistic interaction of TLR ligands and allergen can also modify cytokine synthesis by mast cells stimulated via FcεRI. Moreover, data suggest that specific IgE for bacterial or viral antigens can influence mast cell activity. What is more, some bacterial and viral components or some endogenous proteins produced during viral infection can act as superantigens by interacting with the VH3 domain of IgE. All these observations indicate that bacterial and viral infections modify the course of allergic diseases by affecting FcεRI-dependent mast cell activation

  1. Release activity-dependent control of vesicle endocytosis by the synaptic adhesion molecule N-cadherin

    PubMed Central

    van Stegen, Bernd; Dagar, Sushma; Gottmann, Kurt

    2017-01-01

    At synapses in the mammalian brain, continuous information transfer requires the long-term maintenance of homeostatic coupling between exo- and endocytosis of synaptic vesicles. Because classical endocytosis is orders of magnitude slower than the millisecond-range exocytosis of vesicles, high frequency vesicle fusion could potentially compromise structural stability of synapses. However, the molecular mechanisms mediating the tight coupling of exo- and endocytosis are largely unknown. Here, we investigated the role of the transsynaptic adhesion molecules N-cadherin and Neuroligin1 in regulating vesicle exo- and endocytosis by using activity-induced FM4–64 staining and by using synaptophysin-pHluorin fluorescence imaging. The synaptic adhesion molecules N-cadherin and Neuroligin1 had distinct impacts on exo- and endocytosis at mature cortical synapses. Expression of Neuroligin1 enhanced vesicle release in a N-cadherin-dependent way. Most intriguingly, expression of N-cadherin enhanced both vesicle exo- and endocytosis. Further detailed analysis of N-cadherin knockout neurons revealed that the boosting of endocytosis by N-cadherin was largely dependent on preceding high levels of vesicle release activity. In summary, regulation of vesicle endocytosis was mediated at the molecular level by N-cadherin in a release activity-dependent manner. Because of its endocytosis enhancing function, N-cadherin might play an important role in the coupling of vesicle exo- and endocytosis. PMID:28106089

  2. 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

  3. 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.

  4. 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.

  5. Nonlinear dose-dependent impact of D1 receptor activation on motor cortex plasticity in humans.

    PubMed

    Fresnoza, Shane; Paulus, Walter; Nitsche, Michael A; Kuo, Min-Fang

    2014-02-12

    The neuromodulator dopamine plays an important role in synaptic plasticity. The effects are determined by receptor subtype specificity, concentration level, and the kind of neuroplasticity induced. D1-like receptors have been proposed to be involved in cognitive processes via their impact on plasticity. Cognitive studies in humans and animals revealed a dosage-dependent effect of D1-like receptor activation on task performance. In humans, D1-like receptor activation re-establishes plasticity under D2 receptor block. However, a dosage-dependent effect has not been explored so far. To determine the impact of the amount of D1-like receptor activation on neuroplasticity in humans, we combined sulpiride, a selective D2 receptor antagonist, with the dopamine precursor l-DOPA (25, 100, and 200 mg) or applied placebo medication. The impact on plasticity induced by anodal and cathodal transcranial direct current stimulation (tDCS) was compared with the impact on plasticity induced by excitatory and inhibitory paired associative stimulation (PAS) at the primary motor cortex of healthy humans. Stimulation-generated cortical excitability alterations were monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. D1-like receptor activation produced an inverted U-shaped dose-response curve on plasticity induced by both facilitatory tDCS and PAS. For excitability-diminishing tDCS and PAS, aftereffects were abolished or converted trendwise into facilitation. These data extend findings of dose-dependent inverted U-shaped effects of D1 receptor activation on neuroplasticity of the motor cortex.

  6. 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

  7. Time Varying Feature Data

    NASA Astrophysics Data System (ADS)

    Echterhoff, J.; Simonis, I.; Atkinson, R.

    2012-04-01

    The infrastructure to gather, store and access information about our environment is improving and growing rapidly. The increasing amount of information allows us to get a better understanding of the current state of our environment, historical processes and to simulate and predict the future state of the environment. Finer grained spatial and temporal data and more reliable communications make it easier to model dynamic states and ephemeral features. The exchange of information within and across geospatial domains is facilitated through the use of harmonized information models. The Observations & Measurements (O&M) developed through OGC and standardised by ISO is an example of such a cross-domain information model. It is used in many domains, including meteorology, hydrology as well as the emergency management. O&M enables harmonized representation of common metadata that belong to the act of determining the state of a feature property, whether by sensors, simulations or humans. In addition to the resulting feature property value, information such as the result quality but especially the time that the result applies to the feature property can be represented. Temporal metadata is critical to modelling past and future states of a feature. The features, and the semantics of each property, are defined in domain specific Application Schema using the General Feature Model (GFM) from ISO 19109 and usually encoded following ISO 19136. However, at the moment these standards provide only limited support for the representation and handling of time varying feature data. Features like rivers, wildfires or gas plumes have a defined state - for example geographic extent - at any given point in time. To keep track of changes, a more complex model for example using time-series coverages is required. Furthermore, the representation and management of feature property value changes via the service interfaces defined by OGC and ISO - namely: WFS and WCS - would be rather complex

  8. 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.

  9. Dependence of Dbl and Dbs Transformation on MEK and NF-κB Activation

    PubMed Central

    Whitehead, Ian P.; Lambert, Que T.; Glaven, Judith A.; Abe, Karon; Rossman, Kent L.; Mahon, Gwendolyn M.; Trzaskos, James M.; Kay, Robert; Campbell, Sharon L.; Der, Channing J.

    1999-01-01

    Dbs was identified initially as a transforming protein and is a member of the Dbl family of proteins (>20 mammalian members). Here we show that Dbs, like its rat homolog Ost and the closely related Dbl, exhibited guanine nucleotide exchange activity for the Rho family members RhoA and Cdc42, but not Rac1, in vitro. Dbs transforming activity was blocked by specific inhibitors of RhoA and Cdc42 function, demonstrating the importance of these small GTPases in Dbs-mediated growth deregulation. Although Dbs transformation was dependent upon the structural integrity of its pleckstrin homology (PH) domain, replacement of the PH domain with a membrane localization signal restored transforming activity. Thus, the PH domain of Dbs (but not Dbl) may be important in modulating association with the plasma membrane, where its GTPase substrates reside. Both Dbs and Dbl activate multiple signaling pathways that include activation of the Elk-1, Jun, and NF-κB transcription factors and stimulation of transcription from the cyclin D1 promoter. We found that Elk-1 and NF-κB, but not Jun, activation was necessary for Dbl and Dbs transformation. Finally, we have observed that Dbl and Dbs regulated transcription from the cyclin D1 promoter in a NF-κB-dependent manner. Previous studies have dissociated actin cytoskeletal activity from the transforming potential of RhoA and Cdc42. These observations, when taken together with those of the present study, suggest that altered gene expression, and not actin reorganization, is the critical mediator of Dbl and Rho family protein transformation. PMID:10523665

  10. Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities.

    PubMed

    Kagawa, S; Natsuizaka, M; Whelan, K A; Facompre, N; Naganuma, S; Ohashi, S; Kinugasa, H; Egloff, A M; Basu, D; Gimotty, P A; Klein-Szanto, A J; Bass, A J; Wong, K-K; Diehl, J A; Rustgi, A K; Nakagawa, H

    2015-04-30

    Notch activity regulates tumor biology in a context-dependent and complex manner. Notch may act as an oncogene or a tumor-suppressor gene even within the same tumor type. Recently, Notch signaling has been implicated in cellular senescence. Yet, it remains unclear as to how cellular senescence checkpoint functions may interact with Notch-mediated oncogenic and tumor-suppressor activities. Herein, we used genetically engineered human esophageal keratinocytes and esophageal squamous cell carcinoma cells to delineate the functional consequences of Notch activation and inhibition along with pharmacological intervention and RNA interference experiments. When expressed in a tetracycline-inducible manner, the ectopically expressed activated form of Notch1 (ICN1) displayed oncogene-like characteristics inducing cellular senescence corroborated by the induction of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat and enlarged cell morphology and senescence-associated β-galactosidase activity. Notch-induced senescence involves canonical CSL/RBPJ-dependent transcriptional activity and the p16(INK4A)-Rb pathway. Loss of p16(INK4A) or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence but permitted ICN1 to facilitate anchorage-independent colony formation and xenograft tumor growth with increased cell proliferation and reduced squamous-cell differentiation. Moreover, Notch1 appears to mediate replicative senescence as well as transforming growth factor-β-induced cellular senescence in non-transformed cells and that HPV E6/E7 targets Notch1 for inactivation to prevent senescence, revealing a tumor-suppressor attribute of endogenous Notch1. In aggregate, cellular senescence checkpoint functions may influence dichotomous Notch activities in the neoplastic context.

  11. Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol

    PubMed Central

    Cao, Duanfang; Wang, Mingzhu; Qiu, Xiayang; Liu, Dongxiang; Jiang, Hualiang; Yang, Na; Xu, Rui-Ming

    2015-01-01

    Sirtuins with an extended N-terminal domain (NTD), represented by yeast Sir2 and human SIRT1, harbor intrinsic mechanisms for regulation of their NAD-dependent deacetylase activities. Elucidation of the regulatory mechanisms is crucial for understanding the biological functions of sirtuins and development of potential therapeutics. In particular, SIRT1 has emerged as an attractive therapeutic target, and the search for SIRT1-activating compounds (STACs) has been actively pursued. However, the effectiveness of a class of reported STACs (represented by resveratrol) as direct SIRT1 activators is under debate due to the complication involving the use of fluorogenic substrates in in vitro assays. Future efforts of SIRT1-based therapeutics necessitate the dissection of the molecular mechanism of SIRT1 stimulation. We solved the structure of SIRT1 in complex with resveratrol and a 7-amino-4-methylcoumarin (AMC)-containing peptide. The structure reveals the presence of three resveratrol molecules, two of which mediate the interaction between the AMC peptide and the NTD of SIRT1. The two NTD-bound resveratrol molecules are principally responsible for promoting tighter binding between SIRT1 and the peptide and the stimulation of SIRT1 activity. The structural information provides valuable insights into regulation of SIRT1 activity and should benefit the development of authentic SIRT1 activators. PMID:26109052

  12. 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

  13. Light-dependent activation of G proteins by two isoforms of chicken melanopsins.

    PubMed

    Torii, Masaki; Kojima, Daisuke; Nishimura, Akiyuki; Itoh, Hiroshi; Fukada, Yoshitaka

    2015-11-01

    In the chicken pineal gland, light stimuli trigger signaling pathways mediated by two different subtypes, Gt and G11. These G proteins may be activated by any of the three major pineal opsins, pinopsin, OPN4-1 and OPN4-2, but biochemical evidence for the coupling has been missing except for functional coupling between pinopsin and Gt. Here we investigated the relative expression levels and the functional difference among the three pineal opsins. In the chicken pineal gland, the pinopsin mRNA level was significantly more abundant than the others, of which the OPN4-2 mRNA level was higher than that of OPN4-1. In G protein activation assays, Gt was strongly activated by pinopsin in a light-dependent manner, being consistent with previous studies, and weakly activated by OPN4-2. Unexpectedly, illuminated OPN4-2 more efficiently activated G protein(s) that was endogenously expressed in HEK293T cells in culture. On the other hand, Gq, the closest analogue of G11, was activated only by OPN4-1 although the activity was relatively weak under these conditions. These results suggest that OPN4-1 and OPN4-2 couple with Gq and Gt, respectively. Two melanopsins, OPN4-1 and OPN4-2, appear to have acquired mutually different functions through the evolution.

  14. 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

  15. 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

  16. Erythropoietin alleviates hepatic insulin resistance via PPARγ-dependent AKT activation

    PubMed Central

    Ge, Zhijuan; Zhang, Pengzi; Hong, Ting; Tang, Sunyinyan; Meng, Ran; Bi, Yan; Zhu, Dalong

    2015-01-01

    Erythropoietin (EPO) has beneficial effects on glucose metabolism and insulin resistance. However, the mechanism underlying these effects has not yet been elucidated. This study aimed to investigate how EPO affects hepatic glucose metabolism. Here, we report that EPO administration promoted phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation in palmitic acid (PA)-treated HepG2 cells and in the liver of high-fat diet (HFD)-fed mice, whereas adenovirus-mediated silencing of the erythropoietin receptor (EPOR) blocked EPO-induced AKT signalling in HepG2 cells. Importantly, a peroxisome proliferator-activated receptor γ (PPARγ) antagonist and PPARγ small interfering RNA (siRNA) abrogated the EPO-induced increase in p-AKT in HepG2 cells. Lentiviral vector-mediated hepatic PPARγ silencing in HFD-fed C57BL/6 mice impaired EPO-mediated increases in glucose tolerance, insulin sensitivity and hepatic AKT activation. Furthermore, EPO activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signalling pathway, and AMPKα and SIRT1 knockdown each attenuated the EPO-induced PPARγ expression and deacetylation and PPARγ-dependent AKT activation in HepG2 cells. In summary, these findings suggest that PPARγ is involved in EPO/EPOR-induced AKT activation, and targeting the PPARγ/AKT pathway via EPO may have therapeutic implications for hepatic insulin resistance and type 2 diabetes. PMID:26643367

  17. GLP-1 stimulates