Digital integrated protection system: Quantitative methods for dependability evaluation

International Nuclear Information System (INIS)

Krotoff, H.; Benski, C.

1986-01-01

The inclusion of programmed digital techniques in the SPIN system provides the used with the capability of performing sophisticated processing operations. However, it causes the quantitative evaluation of the overall failure probabilities to become somewhat more intricate by reason that: A single component may be involved in several functions; Self-tests may readily be incorporated for the purpose of monitoring the dependable operation of the equipment at all times. This paper describes the methods as implemented by MERLIN GERIN for the purpose of evaluating: The probabilities for the protective actions not to be initiated (dangerous failures); The probabilities for such protective actions to be initiated accidentally. Although the communication is focused on the programmed portion of the SPIN (UAIP) it will also deal with the evaluation performed within the scope of study works that do not exclusively cover the UAIPs

Quantitative analysis of the Ca2+‐dependent regulation of delayed rectifier K+ current I Ks in rabbit ventricular myocytes

Science.gov (United States)

Bartos, Daniel C.; Morotti, Stefano; Ginsburg, Kenneth S.; Grandi, Eleonora

2017-01-01

Key points [Ca2+]i enhanced rabbit ventricular slowly activating delayed rectifier K+ current (I Ks) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol.Rabbit ventricular rapidly activating delayed rectifier K+ current (I Kr) amplitude and voltage dependence were unaffected by high [Ca2+]i.When measuring or simulating I Ks during an action potential, I Ks was not different during a physiological Ca2+ transient or when [Ca2+]i was buffered to 500 nm. Abstract The slowly activating delayed rectifier K+ current (I Ks) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca2+ ([Ca2+]i) and β‐adrenergic receptor (β‐AR) stimulation modulate I Ks amplitude and kinetics, but details of these important I Ks regulators and their interaction are limited. We assessed the [Ca2+]i dependence of I Ks in steady‐state conditions and with dynamically changing membrane potential and [Ca2+]i during an AP. I Ks was recorded from freshly isolated rabbit ventricular myocytes using whole‐cell patch clamp. With intracellular pipette solutions that controlled free [Ca2+]i, we found that raising [Ca2+]i from 100 to 600 nm produced similar increases in I Ks as did β‐AR activation, and the effects appeared additive. Both β‐AR activation and high [Ca2+]i increased maximally activated tail I Ks, negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well‐established mathematical model of the rabbit myocyte. In both AP‐clamp experiments and simulations, I Ks recorded during a normal physiological Ca2+ transient was similar to I Ks measured with [Ca2+]i clamped at 500–600 nm. Thus, our study provides novel quantitative data as to how physiological [Ca2+]i regulates I Ks amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca2+]i, in the submembrane or junctional cleft

Quantitative Structure-Activity Relationships and Docking Studies of Calcitonin Gene-Related Peptide Antagonists

DEFF Research Database (Denmark)

Jenssen, Håvard; Mehrabian, Mohadeseh; Kyani, Anahita

2012-01-01

Defining the role of calcitonin gene-related peptide in migraine pathogenesis could lead to the application of calcitonin gene-related peptide antagonists as novel migraine therapeutics. In this work, quantitative structure-activity relationship modeling of biological activities of a large range...... of calcitonin gene-related peptide antagonists was performed using a panel of physicochemical descriptors. The computational studies evaluated different variable selection techniques and demonstrated shuffling stepwise multiple linear regression to be superior over genetic algorithm-multiple linear regression....... The linear quantitative structure-activity relationship model revealed better statistical parameters of cross-validation in comparison with the non-linear support vector regression technique. Implementing only five peptide descriptors into this linear quantitative structure-activity relationship model...

The temperature dependence of the BK channel activity - kinetics, thermodynamics, and long-range correlations.

Science.gov (United States)

Wawrzkiewicz-Jałowiecka, Agata; Dworakowska, Beata; Grzywna, Zbigniew J

2017-10-01

Large-conductance, voltage dependent, Ca 2+ -activated potassium channels (BK) are transmembrane proteins that regulate many biological processes by controlling potassium flow across cell membranes. Here, we investigate to what extent temperature (in the range of 17-37°C with ΔT=5°C step) is a regulating parameter of kinetic properties of the channel gating and memory effect in the series of dwell-time series of subsequent channel's states, at membrane depolarization and hyperpolarization. The obtained results indicate that temperature affects strongly the BK channels' gating, but, counterintuitively, it exerts no effect on the long-range correlations, as measured by the Hurst coefficient. Quantitative differences between dependencies of appropriate channel's characteristics on temperature are evident for different regimes of voltage. Examining the characteristics of BK channel activity as a function of temperature allows to estimate the net activation energy (E act ) and changes of thermodynamic parameters (ΔH, ΔS, ΔG) by channel opening. Larger E act corresponds to the channel activity at membrane hyperpolarization. The analysis of entropy and enthalpy changes of closed to open channel's transition suggest the entropy-driven nature of the increase of open state probability during voltage activation and supports the hypothesis about the voltage-dependent geometry of the channel vestibule. Copyright © 2017 Elsevier B.V. All rights reserved.

Quantitative modeling of the ionospheric response to geomagnetic activity

Directory of Open Access Journals (Sweden)

T. J. Fuller-Rowell

Full Text Available A physical model of the coupled thermosphere and ionosphere has been used to determine the accuracy of model predictions of the ionospheric response to geomagnetic activity, and assess our understanding of the physical processes. The physical model is driven by empirical descriptions of the high-latitude electric field and auroral precipitation, as measures of the strength of the magnetospheric sources of energy and momentum to the upper atmosphere. Both sources are keyed to the time-dependent TIROS/NOAA auroral power index. The output of the model is the departure of the ionospheric F region from the normal climatological mean. A 50-day interval towards the end of 1997 has been simulated with the model for two cases. The first simulation uses only the electric fields and auroral forcing from the empirical models, and the second has an additional source of random electric field variability. In both cases, output from the physical model is compared with F-region data from ionosonde stations. Quantitative model/data comparisons have been performed to move beyond the conventional "visual" scientific assessment, in order to determine the value of the predictions for operational use. For this study, the ionosphere at two ionosonde stations has been studied in depth, one each from the northern and southern mid-latitudes. The model clearly captures the seasonal dependence in the ionospheric response to geomagnetic activity at mid-latitude, reproducing the tendency for decreased ion density in the summer hemisphere and increased densities in winter. In contrast to the "visual" success of the model, the detailed quantitative comparisons, which are necessary for space weather applications, are less impressive. The accuracy, or value, of the model has been quantified by evaluating the daily standard deviation, the root-mean-square error, and the correlation coefficient between the data and model predictions. The modeled quiet-time variability, or standard

Quantitative modeling of the ionospheric response to geomagnetic activity

Directory of Open Access Journals (Sweden)

T. J. Fuller-Rowell

2000-07-01

Full Text Available A physical model of the coupled thermosphere and ionosphere has been used to determine the accuracy of model predictions of the ionospheric response to geomagnetic activity, and assess our understanding of the physical processes. The physical model is driven by empirical descriptions of the high-latitude electric field and auroral precipitation, as measures of the strength of the magnetospheric sources of energy and momentum to the upper atmosphere. Both sources are keyed to the time-dependent TIROS/NOAA auroral power index. The output of the model is the departure of the ionospheric F region from the normal climatological mean. A 50-day interval towards the end of 1997 has been simulated with the model for two cases. The first simulation uses only the electric fields and auroral forcing from the empirical models, and the second has an additional source of random electric field variability. In both cases, output from the physical model is compared with F-region data from ionosonde stations. Quantitative model/data comparisons have been performed to move beyond the conventional "visual" scientific assessment, in order to determine the value of the predictions for operational use. For this study, the ionosphere at two ionosonde stations has been studied in depth, one each from the northern and southern mid-latitudes. The model clearly captures the seasonal dependence in the ionospheric response to geomagnetic activity at mid-latitude, reproducing the tendency for decreased ion density in the summer hemisphere and increased densities in winter. In contrast to the "visual" success of the model, the detailed quantitative comparisons, which are necessary for space weather applications, are less impressive. The accuracy, or value, of the model has been quantified by evaluating the daily standard deviation, the root-mean-square error, and the correlation coefficient between the data and model predictions. The modeled quiet-time variability, or standard

Review of Department of Defense Education Activity (DODEA) Schools. Volume II: Quantitative Analysis of Educational Quality

National Research Council Canada - National Science Library

Anderson, Lowell

2000-01-01

This volume compiles, and presents in integrated form, IDA's quantitative analysis of educational quality provided by DoD's dependent schools, It covers the quantitative aspects of volume I in greater...

Comparison of conventional, model-based quantitative planar, and quantitative SPECT image processing methods for organ activity estimation using In-111 agents

International Nuclear Information System (INIS)

He, Bin; Frey, Eric C

2006-01-01

Accurate quantification of organ radionuclide uptake is important for patient-specific dosimetry. The quantitative accuracy from conventional conjugate view methods is limited by overlap of projections from different organs and background activity, and attenuation and scatter. In this work, we propose and validate a quantitative planar (QPlanar) processing method based on maximum likelihood (ML) estimation of organ activities using 3D organ VOIs and a projector that models the image degrading effects. Both a physical phantom experiment and Monte Carlo simulation (MCS) studies were used to evaluate the new method. In these studies, the accuracies and precisions of organ activity estimates for the QPlanar method were compared with those from conventional planar (CPlanar) processing methods with various corrections for scatter, attenuation and organ overlap, and a quantitative SPECT (QSPECT) processing method. Experimental planar and SPECT projections and registered CT data from an RSD Torso phantom were obtained using a GE Millenium VH/Hawkeye system. The MCS data were obtained from the 3D NCAT phantom with organ activity distributions that modelled the uptake of 111 In ibritumomab tiuxetan. The simulations were performed using parameters appropriate for the same system used in the RSD torso phantom experiment. The organ activity estimates obtained from the CPlanar, QPlanar and QSPECT methods from both experiments were compared. From the results of the MCS experiment, even with ideal organ overlap correction and background subtraction, CPlanar methods provided limited quantitative accuracy. The QPlanar method with accurate modelling of the physical factors increased the quantitative accuracy at the cost of requiring estimates of the organ VOIs in 3D. The accuracy of QPlanar approached that of QSPECT, but required much less acquisition and computation time. Similar results were obtained from the physical phantom experiment. We conclude that the QPlanar method, based

Limitations for qualitative and quantitative neutron activation analysis using reactor neutrons

International Nuclear Information System (INIS)

El-Abbady, W.H.; El-Tanahy, Z.H.; El-Hagg, A.A.; Hassan, A.M.

1999-01-01

In this work, the most important limitations for qualitative and quantitative analysis using reactor neutrons for activation are reviewed. Each limitation is discussed using different examples of activated samples. Photopeak estimation, nuclear reactions interference and neutron flux measurements are taken into consideration. Solutions for high accuracy evaluation in neutron activation analysis applications are given. (author)

Quantitative Activities for Introductory Astronomy

Science.gov (United States)

Keohane, Jonathan W.; Bartlett, J. L.; Foy, J. P.

2010-01-01

We present a collection of short lecture-tutorial (or homework) activities, designed to be both quantitative and accessible to the introductory astronomy student. Each of these involves interpreting some real data, solving a problem using ratios and proportionalities, and making a conclusion based on the calculation. Selected titles include: "The Mass of Neptune” "The Temperature on Titan” "Rocks in the Early Solar System” "Comets Hitting Planets” "Ages of Meteorites” "How Flat are Saturn's Rings?” "Tides of the Sun and Moon on the Earth” "The Gliese 581 Solar System"; "Buckets in the Rain” "How Hot, Bright and Big is Betelgeuse?” "Bombs and the Sun” "What Forms Stars?” "Lifetimes of Cars and Stars” "The Mass of the Milky” "How Old is the Universe?” "Is The Universe Speeding up or Slowing Down?"

Quantitative Index and Abnormal Alarm Strategy Using Sensor-Dependent Vibration Data for Blade Crack Identification in Centrifugal Booster Fans.

Science.gov (United States)

Chen, Jinglong; Sun, Hailiang; Wang, Shuai; He, Zhengjia

2016-05-09

Centrifugal booster fans are important equipment used to recover blast furnace gas (BFG) for generating electricity, but blade crack faults (BCFs) in centrifugal booster fans can lead to unscheduled breakdowns and potentially serious accidents, so in this work quantitative fault identification and an abnormal alarm strategy based on acquired historical sensor-dependent vibration data is proposed for implementing condition-based maintenance for this type of equipment. Firstly, three group dependent sensors are installed to acquire running condition data. Then a discrete spectrum interpolation method and short time Fourier transform (STFT) are applied to preliminarily identify the running data in the sensor-dependent vibration data. As a result a quantitative identification and abnormal alarm strategy based on compound indexes including the largest Lyapunov exponent and relative energy ratio at the second harmonic frequency component is proposed. Then for validation the proposed blade crack quantitative identification and abnormality alarm strategy is applied to analyze acquired experimental data for centrifugal booster fans and it has successfully identified incipient blade crack faults. In addition, the related mathematical modelling work is also introduced to investigate the effects of mistuning and cracks on the vibration features of centrifugal impellers and to explore effective techniques for crack detection.

Quantitative Index and Abnormal Alarm Strategy Using Sensor-Dependent Vibration Data for Blade Crack Identification in Centrifugal Booster Fans

Directory of Open Access Journals (Sweden)

Jinglong Chen

2016-05-01

Full Text Available Centrifugal booster fans are important equipment used to recover blast furnace gas (BFG for generating electricity, but blade crack faults (BCFs in centrifugal booster fans can lead to unscheduled breakdowns and potentially serious accidents, so in this work quantitative fault identification and an abnormal alarm strategy based on acquired historical sensor-dependent vibration data is proposed for implementing condition-based maintenance for this type of equipment. Firstly, three group dependent sensors are installed to acquire running condition data. Then a discrete spectrum interpolation method and short time Fourier transform (STFT are applied to preliminarily identify the running data in the sensor-dependent vibration data. As a result a quantitative identification and abnormal alarm strategy based on compound indexes including the largest Lyapunov exponent and relative energy ratio at the second harmonic frequency component is proposed. Then for validation the proposed blade crack quantitative identification and abnormality alarm strategy is applied to analyze acquired experimental data for centrifugal booster fans and it has successfully identified incipient blade crack faults. In addition, the related mathematical modelling work is also introduced to investigate the effects of mistuning and cracks on the vibration features of centrifugal impellers and to explore effective techniques for crack detection.

Temperature-dependent solute segregation in dilute Cu-Be under self-ion irradiation: a quantitative revision

International Nuclear Information System (INIS)

Koch, R.

1993-01-01

A reinvestigation of experimental data on solute precipitation behaviour in a Cu-1.35 at.%Be alloy subjected to Cu-ion irradiation has been carried out with regard to its strong dependence on the irradiation temperature in the range 400-700 K. A rate equation formalism presented in 1985 to describe the defect kinetics via mixed dumbbell formation and diffusion has been modified to take account of the redissolution of precipitated solutes into the matrix due to thermal vacancies. On the basis of the derived model this effect is shown to cause the observed reduction and disappearance of precipitation at high temperatures. Dumbbell dissociation and defect recombination with thermal vacancies become effective at still higher temperatures. The low-temperature decrease in precipitation is explained quantitatively by a marked change from the sink to the recombination case for point-defect annihilation. Moreover the whole temperature regime of precipitation is shown to shift to higher temperatures with increasing displacement rate. Both values of the activation enthalpies for migration and dissociation of the interstitial complex are given by analytical expressions and correspond to earlier estimates. (Author)

Acceptability criteria for linear dependence in validating UV-spectrophotometric methods of quantitative determination in forensic and toxicological analysis

Directory of Open Access Journals (Sweden)

L. Yu. Klimenko

2014-08-01

Full Text Available Introduction. This article is the result of authors’ research in the field of development of the approaches to validation of quantitative determination methods for purposes of forensic and toxicological analysis and devoted to the problem of acceptability criteria formation for validation parameter «linearity/calibration model». The aim of research. The purpose of this paper is to analyse the present approaches to acceptability estimation of the calibration model chosen for method description according to the requirements of the international guidances, to form the own approaches to acceptability estimation of the linear dependence when carrying out the validation of UV-spectrophotometric methods of quantitative determination for forensic and toxicological analysis. Materials and methods. UV-spectrophotometric method of doxylamine quantitative determination in blood. Results. The approaches to acceptability estimation of calibration models when carrying out the validation of bioanalytical methods is stated in international papers, namely «Guidance for Industry: Bioanalytical method validation» (U.S. FDA, 2001, «Standard Practices for Method Validation in Forensic Toxicology» (SWGTOX, 2012, «Guidance for the Validation of Analytical Methodology and Calibration of Equipment used for Testing of Illicit Drugs in Seized Materials and Biological Specimens» (UNODC, 2009 and «Guideline on validation of bioanalytical methods» (ЕМА, 2011 have been analysed. It has been suggested to be guided by domestic developments in the field of validation of analysis methods for medicines and, particularly, by the approaches to validation methods in the variant of the calibration curve method for forming the acceptability criteria of the obtained linear dependences when carrying out the validation of UV-spectrophotometric methods of quantitative determination for forensic and toxicological analysis. The choice of the method of calibration curve is

Quantitative assessment of integrated phrenic nerve activity.

Science.gov (United States)

Nichols, Nicole L; Mitchell, Gordon S

2016-06-01

Integrated electrical activity in the phrenic nerve is commonly used to assess within-animal changes in phrenic motor output. Because of concerns regarding the consistency of nerve recordings, activity is most often expressed as a percent change from baseline values. However, absolute values of nerve activity are necessary to assess the impact of neural injury or disease on phrenic motor output. To date, no systematic evaluations of the repeatability/reliability have been made among animals when phrenic recordings are performed by an experienced investigator using standardized methods. We performed a meta-analysis of studies reporting integrated phrenic nerve activity in many rat groups by the same experienced investigator; comparisons were made during baseline and maximal chemoreceptor stimulation in 14 wild-type Harlan and 14 Taconic Sprague Dawley groups, and in 3 pre-symptomatic and 11 end-stage SOD1(G93A) Taconic rat groups (an ALS model). Meta-analysis results indicate: (1) consistent measurements of integrated phrenic activity in each sub-strain of wild-type rats; (2) with bilateral nerve recordings, left-to-right integrated phrenic activity ratios are ∼1.0; and (3) consistently reduced activity in end-stage SOD1(G93A) rats. Thus, with appropriate precautions, integrated phrenic nerve activity enables robust, quantitative comparisons among nerves or experimental groups, including differences caused by neuromuscular disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

KAUST Repository

Jolivet, Renaud

2015-02-26

Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain’s metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging.

Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

Science.gov (United States)

Jolivet, Renaud; Coggan, Jay S.; Allaman, Igor; Magistretti, Pierre J.

2015-01-01

Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain’s metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging. PMID:25719367

Multi-timescale modeling of activity-dependent metabolic coupling in the neuron-glia-vasculature ensemble.

Directory of Open Access Journals (Sweden)

Renaud Jolivet

2015-02-01

Full Text Available Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS are still debated. To address this question, we developed a detailed biophysical model of the brain's metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging.

ACTIVATION REACTION ON THE ELECTROENCEPHALOGRAM IN SUBSTANCE DEPENDENT PATIENTS: LINKS TO ADDICTION STUDIES AND PSYCHOLOGICAL FACTORS AND CHANGES IN NEUROFEEDBACK TRAINING

Directory of Open Access Journals (Sweden)

M. e Melnikov

2014-01-01

Full Text Available Depth of activation reaction (α-activity suppression during the eyes-opening task is considered to be an important quantitative characteristic of α-band brainwaves. Activation reaction was assessed from O1 and O2 leads in 31 male substance dependent subjects. In 7 cases it was measured twice: before and after α- or β-brainwave biofeedback training. The correlations were found between grade of α suppression in eyes-opening task and attitude towards disease and treatment, personality maturity, and level of pathological personality traits. Activation reaction was significantly improved by α-training and non-significantly diminished after β-1-training.

A novel quantitative model of cell cycle progression based on cyclin-dependent kinases activity and population balances.

Science.gov (United States)

Pisu, Massimo; Concas, Alessandro; Cao, Giacomo

2015-04-01

Cell cycle regulates proliferative cell capacity under normal or pathologic conditions, and in general it governs all in vivo/in vitro cell growth and proliferation processes. Mathematical simulation by means of reliable and predictive models represents an important tool to interpret experiment results, to facilitate the definition of the optimal operating conditions for in vitro cultivation, or to predict the effect of a specific drug in normal/pathologic mammalian cells. Along these lines, a novel model of cell cycle progression is proposed in this work. Specifically, it is based on a population balance (PB) approach that allows one to quantitatively describe cell cycle progression through the different phases experienced by each cell of the entire population during its own life. The transition between two consecutive cell cycle phases is simulated by taking advantage of the biochemical kinetic model developed by Gérard and Goldbeter (2009) which involves cyclin-dependent kinases (CDKs) whose regulation is achieved through a variety of mechanisms that include association with cyclins and protein inhibitors, phosphorylation-dephosphorylation, and cyclin synthesis or degradation. This biochemical model properly describes the entire cell cycle of mammalian cells by maintaining a sufficient level of detail useful to identify check point for transition and to estimate phase duration required by PB. Specific examples are discussed to illustrate the ability of the proposed model to simulate the effect of drugs for in vitro trials of interest in oncology, regenerative medicine and tissue engineering. Copyright © 2015 Elsevier Ltd. All rights reserved.

Voltage Dependence of a Neuromodulator-Activated Ionic Current123

Science.gov (United States)

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

Nicotine Dependence, Physical Activity, and Sedentary Behavior among Adult Smokers.

Science.gov (United States)

Loprinzi, Paul D; Walker, Jerome F

2015-03-01

Research has previously demonstrated an inverse association between smoking status and physical activity; however, few studies have examined the association between nicotine dependence and physical activity or sedentary behavior. This study examined the association between nicotine dependence and accelerometer-determined physical activity and sedentary behavior. Data from the 2003-2006 National Health and Nutrition Examination Survey (NHANES) were used. A total of 851 adult (≥20 years) smokers wore an accelerometer for ≥4 days and completed the Fagerstrom Test for Nicotine Dependence scale. Regression models were used to examine the association between nicotine dependence and physical activity/sedentary behavior. After adjusting for age, gender, race-ethnicity, poverty level, hypertension, emphysema, bronchitis, body mass index (BMI), cotinine, and accelerometer wear time, smokers 50 + years of age with greater nicotine dependence engaged in more sedentary behavior (β = 11.4, P = 0.02) and less light-intensity physical activity (β = -9.6, P = 0.03) and moderate-to-vigorous physical activity (MVPA; β = -0.14, P = 0.003) than their less nicotine dependent counterparts. Older adults who are more nicotine dependent engage in less physical activity (both MVPA and light-intensity) and more sedentary behavior than their less nicotine dependent counterparts.

Reward salience and risk aversion underlie differential ACC activity in substance dependence.

Science.gov (United States)

Alexander, William H; Fukunaga, Rena; Finn, Peter; Brown, Joshua W

2015-01-01

The medial prefrontal cortex, especially the dorsal anterior cingulate cortex (ACC), has long been implicated in cognitive control and error processing. Although the association between ACC and behavior has been established, it is less clear how ACC contributes to dysfunctional behavior such as substance dependence. Evidence from neuroimaging studies investigating ACC function in substance users is mixed, with some studies showing disengagement of ACC in substance dependent individuals (SDs), while others show increased ACC activity related to substance use. In this study, we investigate ACC function in SDs and healthy individuals performing a change signal task for monetary rewards. Using a priori predictions derived from a recent computational model of ACC, we find that ACC activity differs between SDs and controls in factors related to reward salience and risk aversion between SDs and healthy individuals. Quantitative fits of a computational model to fMRI data reveal significant differences in best fit parameters for reward salience and risk preferences. Specifically, the ACC in SDs shows greater risk aversion, defined as concavity in the utility function, and greater attention to rewards relative to reward omission. Furthermore, across participants risk aversion and reward salience are positively correlated. The results clarify the role that ACC plays in both the reduced sensitivity to omitted rewards and greater reward valuation in SDs. Clinical implications of applying computational modeling in psychiatry are also discussed.

Zinc-ion-dependent acid phosphatase exhibits magnesium-ion-dependent myo-inositol-1-phosphatase activity.

Science.gov (United States)

Fujimoto, S; Okano, I; Tanaka, Y; Sumida, Y; Tsuda, J; Kawakami, N; Shimohama, S

1996-06-01

We have purified bovine brain Zn(2+)-dependent acid phosphatase (Zn(2+)-APase), which requires Zn2+ ions to hydrolyze the substrate p-nitrophenyl phosphate (pNPP) in an acidic environment. The substrate specificity and metal requirement of Zn(2+)-APase at a physiological pH was also studied. The enzyme exhibited hydrolytic activity on myo-inositol-1- and -2-monophosphates, 2'-adenosine monophosphate, 2'-guanosine monophosphate, and the alpha- and beta-glycerophosphates, glucose-1-phosphate, and fructose-6-phosphate in 50 mM Tris-HCl buffer (pH 7.4) in the presence of Mg2+ ions, but not on pNPP and phosphotyrosine. Zn2+, Mn2+ and Co2+ ions were less effective for activation. Among the above substrates, myo-inositol-1-phosphate was the most susceptible to hydrolysis by the enzyme in the presence of 3 mM Mg2+ ions. The enzyme exhibited an optimum pH at around 8 for myo-inositol-1-phosphate in the presence of 3 mM Mg2+ ions. The Mg(2+)-dependent myo-inositol-1-phosphatase activity of the enzyme was significantly inhibited by Li+ ions. The Zn(2+)-dependent p-nitrophenyl phosphatase activity and Mg(2+)-dependent myo-inositol-1-phosphatase activity of the purified enzyme fraction exhibited similar behavior on Sephadex G-100 and Mono Q colomns. These findings suggest that Zn(2+)-APase also exhibits Mg(2+)-dependent myo-inositol-1-phosphatase activity under physiological conditions.

Activity-dependent modulation of neural circuit synaptic connectivity

Directory of Open Access Journals (Sweden)

Charles R Tessier

2009-07-01

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

Quantitative proteomic characterization of redox-dependent post-translational modifications on protein cysteines

Energy Technology Data Exchange (ETDEWEB)

Duan, Jicheng; Gaffrey, Matthew J.; Qian, Wei-Jun

2017-01-01

Protein cysteine thiols play a crucial role in redox signaling, regulation of enzymatic activity and protein function, and maintaining redox homeostasis in living systems. The unique chemical reactivity of thiol groups makes cysteine susceptible to oxidative modifications by reactive oxygen and nitrogen species to form a broad array of reversible and irreversible protein post-translational modifications (PTMs). The reversible modifications in particular are one of the major components of redox signaling and are involved in regulation of various cellular processes under physiological and pathological conditions. The biological significance of these redox PTMs in health and diseases has been increasingly recognized. Herein, we review the recent advances of quantitative proteomic approaches for investigating redox PTMs in complex biological systems, including the general considerations of sample processing, various chemical or affinity enrichment strategies, and quantitative approaches. We also highlight a number of redox proteomic approaches that enable effective profiling of redox PTMs for addressing specific biological questions. Although some technological limitations remain, redox proteomics is paving the way towards a better understanding of redox signaling and regulation in human health and diseases.

Neurotrophin release by neurotrophins: Implications for activity-dependent neuronal plasticity

OpenAIRE

Canossa, Marco; Griesbeck, Oliver; Berninger, Benedikt; Campana, Gabriele; Kolbeck, Roland; Thoenen, Hans

1997-01-01

Neurotrophins, secreted in an activity-dependent manner, are thought to be involved in the activity-dependent refinement of synaptic connections. Here we demonstrate that in hippocampal neurons and the rat pheochromocytoma cell line PC12 application of exogenous neurotrophins induces secretion of neurotrophins, an effect that is mediated by the activation of tyrosine kinase neurotrophin receptors (Trks). Like activity-dependent secretion of neurotrophins, neurotrophin-induced neurotrophin sec...

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

International Nuclear Information System (INIS)

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

2011-01-01

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)-α-stimulated monocytes to endothelial cells and suppressed the TNF-α induced expression of intercellular cell adhesion molecule-1. Puerarin also inhibited the TNF-α-induced nuclear factor-κB activation, which was attenuated by pretreatment with N 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: ► Puerarin induced the phosphorylation of eNOS and the production of NO. ► Puerarin activated eNOS through ER-dependent PI3-kinase and Ca 2+ -dependent AMPK. ► Puerarin-induced NO was involved in the inhibition of NF-kB activation. ► Puerarin may help for prevention of vascular dysfunction and diabetes.

Calculation of Quantitative Structure-Activity Relationship Descriptors of Artemisinin Derivatives

Directory of Open Access Journals (Sweden)

Jambalsuren Bayarmaa

2008-06-01

Full Text Available Quantitative structure-activity relationships are based on the construction of predictive models using a set of known molecules and associated activity value. This accurate methodology, developed with adequate mathematical and computational tools, leads to a faster, cheaper and more comprehensive design of new products, reducing the experimental synthesis and testing on animals. Preparation of the QSAR models of artemisinin derivatives was carried out by the genetic function algorithm (GFA method for 91 molecules. The results show some relationships to the observed antimalarial activities of the artemisinin derivatives. The most statistically signi fi cant regression equation obtained from the fi nal GFA relates to two molecular descriptors.

Quantitative Phase-Field Approach for Simulating Grain Growth in Anisotropic Systems with Arbitrary Inclination and Misorientation Dependence

International Nuclear Information System (INIS)

Moelans, N.; Blanpain, B.; Wollants, P.

2008-01-01

A phase-field approach for quantitative simulations of grain growth in anisotropic systems is introduced, together with a new methodology to derive appropriate model parameters that reproduce given misorientation and inclination dependent grain boundary energy and mobility in the simulations. The proposed model formulation and parameter choice guarantee a constant diffuse interface width and consequently give high controllability of the accuracy in grain growth simulations

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

Energy Technology Data Exchange (ETDEWEB)

Hwang, Yong Pil; Kim, Hyung Gyun [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Hien, Tran Thi [College of Pharmacy, Chosun University, Gwangju (Korea, Republic of); Jeong, Myung Ho [Heart Research Center, Chonnam National University Hospital, Gwangju (Korea, Republic of); Jeong, Tae Cheon, E-mail: taecheon@ynu.ac.kr [College of Pharmacy, Yeungnam University, Gyungsan (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

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.

Cerebral Metabolic Rate of Oxygen (CMRO2 ) Mapping by Combining Quantitative Susceptibility Mapping (QSM) and Quantitative Blood Oxygenation Level-Dependent Imaging (qBOLD).

Science.gov (United States)

Cho, Junghun; Kee, Youngwook; Spincemaille, Pascal; Nguyen, Thanh D; Zhang, Jingwei; Gupta, Ajay; Zhang, Shun; Wang, Yi

2018-03-07

To map the cerebral metabolic rate of oxygen (CMRO 2 ) by estimating the oxygen extraction fraction (OEF) from gradient echo imaging (GRE) using phase and magnitude of the GRE data. 3D multi-echo gradient echo imaging and perfusion imaging with arterial spin labeling were performed in 11 healthy subjects. CMRO 2 and OEF maps were reconstructed by joint quantitative susceptibility mapping (QSM) to process GRE phases and quantitative blood oxygen level-dependent (qBOLD) modeling to process GRE magnitudes. Comparisons with QSM and qBOLD alone were performed using ROI analysis, paired t-tests, and Bland-Altman plot. The average CMRO 2 value in cortical gray matter across subjects were 140.4 ± 14.9, 134.1 ± 12.5, and 184.6 ± 17.9 μmol/100 g/min, with corresponding OEFs of 30.9 ± 3.4%, 30.0 ± 1.8%, and 40.9 ± 2.4% for methods based on QSM, qBOLD, and QSM+qBOLD, respectively. QSM+qBOLD provided the highest CMRO 2 contrast between gray and white matter, more uniform OEF than QSM, and less noisy OEF than qBOLD. Quantitative CMRO 2 mapping that fits the entire complex GRE data is feasible by combining QSM analysis of phase and qBOLD analysis of magnitude. © 2018 International Society for Magnetic Resonance in Medicine.

Defect evolution in cosmology and condensed matter quantitative analysis with the velocity-dependent one-scale model

CERN Document Server

Martins, C J A P

2016-01-01

This book sheds new light on topological defects in widely differing systems, using the Velocity-Dependent One-Scale Model to better understand their evolution. Topological defects – cosmic strings, monopoles, domain walls or others - necessarily form at cosmological (and condensed matter) phase transitions. If they are stable and long-lived they will be fossil relics of higher-energy physics. Understanding their behaviour and consequences is a key part of any serious attempt to understand the universe, and this requires modelling their evolution. The velocity-dependent one-scale model is the only fully quantitative model of defect network evolution, and the canonical model in the field. This book provides a review of the model, explaining its physical content and describing its broad range of applicability.

Passion and dependency in online shopping activities.

Science.gov (United States)

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.

Quantitative genetic activity graphical profiles for use in chemical evaluation

Energy Technology Data Exchange (ETDEWEB)

Waters, M.D. [Environmental Protection Agency, Washington, DC (United States); Stack, H.F.; Garrett, N.E.; Jackson, M.A. [Environmental Health Research and Testing, Inc., Research Triangle Park, NC (United States)

1990-12-31

A graphic approach, terms a Genetic Activity Profile (GAP), was developed to display a matrix of data on the genetic and related effects of selected chemical agents. The profiles provide a visual overview of the quantitative (doses) and qualitative (test results) data for each chemical. Either the lowest effective dose or highest ineffective dose is recorded for each agent and bioassay. Up to 200 different test systems are represented across the GAP. Bioassay systems are organized according to the phylogeny of the test organisms and the end points of genetic activity. The methodology for producing and evaluating genetic activity profile was developed in collaboration with the International Agency for Research on Cancer (IARC). Data on individual chemicals were compiles by IARC and by the US Environmental Protection Agency (EPA). Data are available on 343 compounds selected from volumes 1-53 of the IARC Monographs and on 115 compounds identified as Superfund Priority Substances. Software to display the GAPs on an IBM-compatible personal computer is available from the authors. Structurally similar compounds frequently display qualitatively and quantitatively similar profiles of genetic activity. Through examination of the patterns of GAPs of pairs and groups of chemicals, it is possible to make more informed decisions regarding the selection of test batteries to be used in evaluation of chemical analogs. GAPs provided useful data for development of weight-of-evidence hazard ranking schemes. Also, some knowledge of the potential genetic activity of complex environmental mixtures may be gained from an assessment of the genetic activity profiles of component chemicals. The fundamental techniques and computer programs devised for the GAP database may be used to develop similar databases in other disciplines. 36 refs., 2 figs.

Light-dependent electrogenic activity of cyanobacteria.

Directory of Open Access Journals (Sweden)

John M Pisciotta

2010-05-01

Full Text Available Cyanobacteria account for 20-30% of Earth's primary photosynthetic productivity and convert solar energy into biomass-stored chemical energy at the rate of approximately 450 TW [1]. These single-cell microorganisms are resilient predecessors of all higher oxygenic phototrophs and can be found in self-sustaining, nitrogen-fixing communities the world over, from Antarctic glaciers to the Sahara desert [2].Here we show that diverse genera of cyanobacteria including biofilm-forming and pelagic strains have a conserved light-dependent electrogenic activity, i.e. the ability to transfer electrons to their surroundings in response to illumination. Naturally-growing biofilm-forming photosynthetic consortia also displayed light-dependent electrogenic activity, demonstrating that this phenomenon is not limited to individual cultures. Treatment with site-specific inhibitors revealed the electrons originate at the photosynthetic electron transfer chain (P-ETC. Moreover, electrogenic activity was observed upon illumination only with blue or red but not green light confirming that P-ETC is the source of electrons. The yield of electrons harvested by extracellular electron acceptor to photons available for photosynthesis ranged from 0.05% to 0.3%, although the efficiency of electron harvesting likely varies depending on terminal electron acceptor.The current study illustrates that cyanobacterial electrogenic activity is an important microbiological conduit of solar energy into the biosphere. The mechanism responsible for electrogenic activity in cyanobacteria appears to be fundamentally different from the one exploited in previously discovered electrogenic bacteria, such as Geobacter, where electrons are derived from oxidation of organic compounds and transported via a respiratory electron transfer chain (R-ETC [3], [4]. The electrogenic pathway of cyanobacteria might be exploited to develop light-sensitive devices or future technologies that convert solar

Prenatal and adult androgen activities in alcohol dependence.

Science.gov (United States)

Lenz, B; Mühle, C; Braun, B; Weinland, C; Bouna-Pyrrou, P; Behrens, J; Kubis, S; Mikolaiczik, K; Muschler, M-R; Saigali, S; Sibach, M; Tanovska, P; Huber, S E; Hoppe, U; Eichler, A; Heinrich, H; Moll, G H; Engel, A; Goecke, T W; Beckmann, M W; Fasching, P A; Müller, C P; Kornhuber, J

2017-07-01

Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Finding Biomass Degrading Enzymes Through an Activity-Correlated Quantitative Proteomics Platform (ACPP)

Science.gov (United States)

Ma, Hongyan; Delafield, Daniel G.; Wang, Zhe; You, Jianlan; Wu, Si

2017-04-01

The microbial secretome, known as a pool of biomass (i.e., plant-based materials) degrading enzymes, can be utilized to discover industrial enzyme candidates for biofuel production. Proteomics approaches have been applied to discover novel enzyme candidates through comparing protein expression profiles with enzyme activity of the whole secretome under different growth conditions. However, the activity measurement of each enzyme candidate is needed for confident "active" enzyme assignments, which remains to be elucidated. To address this challenge, we have developed an Activity-Correlated Quantitative Proteomics Platform (ACPP) that systematically correlates protein-level enzymatic activity patterns and protein elution profiles using a label-free quantitative proteomics approach. The ACPP optimized a high performance anion exchange separation for efficiently fractionating complex protein samples while preserving enzymatic activities. The detected enzymatic activity patterns in sequential fractions using microplate-based assays were cross-correlated with protein elution profiles using a customized pattern-matching algorithm with a correlation R-score. The ACPP has been successfully applied to the identification of two types of "active" biomass-degrading enzymes (i.e., starch hydrolysis enzymes and cellulose hydrolysis enzymes) from Aspergillus niger secretome in a multiplexed fashion. By determining protein elution profiles of 156 proteins in A. niger secretome, we confidently identified the 1,4-α-glucosidase as the major "active" starch hydrolysis enzyme (R = 0.96) and the endoglucanase as the major "active" cellulose hydrolysis enzyme (R = 0.97). The results demonstrated that the ACPP facilitated the discovery of bioactive enzymes from complex protein samples in a high-throughput, multiplexing, and untargeted fashion.

Impact of the Qualitative and Quantitative Aspects of Human Activity on the Ecosystem: Demonstration through the Use of Ecological Footprint Approach

Directory of Open Access Journals (Sweden)

Makram GAALICHE

2012-12-01

Full Text Available This article aims to show that the impact of human activities on the ecosystem, measured by the Ecological Footprint, depends on the qualitative and quantitative aspects of the population. Indeed, we confirmed our hypothesis by an empirical analysis on Tunisia, where it was revealed that the increase in its Ecological Footprint, is attributed mainly to massive consumption of goods, bad land management by building horizontal, and to a lesser extent, to the presence of polluting employments. The results suggest the adoption of targeted policies, according to the specific characteristics of population.

Field dependence-independence and participation in physical activity by college students.

Science.gov (United States)

Liu, Wenhao

2006-06-01

Field-independent individuals, compared with field-dependent individuals, have higher sports potential and advantages in sport-related settings. Little research, however, has been conducted on the association of field dependence-independence and participation in physical activity. The study examined this association for college students who participated in physical activities in and beyond physical education classes. The Group Embedded Figures Test distinguished 40 field-dependent from 40 field-independent participants. Activity logs during one semester showed that field-independent participants were significantly more physically active and their physical activity behaviors were more sport-related than those of field-dependent participants.

Angle-dependent XPS study of the mechanisms of 'high-low temperature' activation of GaAs photocathode

International Nuclear Information System (INIS)

Du Xiaoqing; Chang Benkang

2005-01-01

The surface chemical compositions, atomic concentration percentage and layer thickness after 'high-temperature' single-step activation and 'high-low temperature' two-step activation were obtained using quantitative analysis of angle-dependent X-ray photoelectron spectroscopy (XPS). It was found that compared to single-step activation, the thickness of GaAs-O interface barrier had a remarkable decrease, the degree of As-O bond became much smaller and the Ga-O bond became dominating, and at the same time the thickness of (Cs, O) layer also had a deduction while the ratio of Cs to O had no change after two-step activation. The measured spectral response curves showed that a increase of 29% of sensitivity had been obtained after two-step activation. To explore the inherent mechanisms of influences of the evolution of GaAs(Cs, O) surface layers on photoemission, surface electric barrier models based on the experimental results were built. By calculation of electron escape probability it was found that the decrease of thickness of GaAs-O interface barrier and (Cs, O) layer is the main reasons, which explained why higher sensitivity is achieved after two-step activation than single-step activation

A simplified method for quantitative assessment of the relative health and safety risk of environmental management activities

International Nuclear Information System (INIS)

Eide, S.A.; Smith, T.H.; Peatross, R.G.; Stepan, I.E.

1996-09-01

This report presents a simplified method to assess the health and safety risk of Environmental Management activities of the US Department of Energy (DOE). The method applies to all types of Environmental Management activities including waste management, environmental restoration, and decontamination and decommissioning. The method is particularly useful for planning or tradeoff studies involving multiple conceptual options because it combines rapid evaluation with a quantitative approach. The method is also potentially applicable to risk assessments of activities other than DOE Environmental Management activities if rapid quantitative results are desired

Characterization of ubiquitination dependent dynamics in growth factor receptor signaling by quantitative proteomics

DEFF Research Database (Denmark)

Akimov, Vyacheslav; Rigbolt, Kristoffer T G; Nielsen, Mogens M

2011-01-01

Protein ubiquitination is a dynamic reversible post-translational modification that plays a key role in the regulation of numerous cellular processes including signal transduction, endocytosis, cell cycle control, DNA repair and gene transcription. The conjugation of the small protein ubiquitin...... investigating ubiquitination on a proteomic scale, mainly due to the inherited complexity and heterogeneity of ubiquitination. We describe here a quantitative proteomics strategy based on the specificity of ubiquitin binding domains (UBDs) and Stable Isotope Labeling by Amino acids in Cell culture (SILAC...... as ubiquitination-dependent events in signaling pathways. In addition to a detailed seven time-point profile of EGFR ubiquitination over 30 minutes of ligand stimulation, our data determined prominent involvement of Lysine-63 ubiquitin branching in EGF signaling. Furthermore, we found two centrosomal proteins, PCM1...

Quantitative structure-activity relationship (QSAR) for insecticides: development of predictive in vivo insecticide activity models.

Science.gov (United States)

Naik, P K; Singh, T; Singh, H

2009-07-01

Quantitative structure-activity relationship (QSAR) analyses were performed independently on data sets belonging to two groups of insecticides, namely the organophosphates and carbamates. Several types of descriptors including topological, spatial, thermodynamic, information content, lead likeness and E-state indices were used to derive quantitative relationships between insecticide activities and structural properties of chemicals. A systematic search approach based on missing value, zero value, simple correlation and multi-collinearity tests as well as the use of a genetic algorithm allowed the optimal selection of the descriptors used to generate the models. The QSAR models developed for both organophosphate and carbamate groups revealed good predictability with r(2) values of 0.949 and 0.838 as well as [image omitted] values of 0.890 and 0.765, respectively. In addition, a linear correlation was observed between the predicted and experimental LD(50) values for the test set data with r(2) of 0.871 and 0.788 for both the organophosphate and carbamate groups, indicating that the prediction accuracy of the QSAR models was acceptable. The models were also tested successfully from external validation criteria. QSAR models developed in this study should help further design of novel potent insecticides.

A biology-based approach for quantitative structure-activity relationships (QSARs) in ecotoxicity.

NARCIS (Netherlands)

Jager, T.; Kooijman, S.A.L.M.

2009-01-01

Quantitative structure-activity relationships (QSARs) for ecotoxicity can be used to fill data gaps and limit toxicity testing on animals. QSAR development may additionally reveal mechanistic information based on observed patterns in the data. However, the use of descriptive summary statistics for

Quantitative and qualitative analysis of telomerase activity in benign and malignant thyroid tissues

International Nuclear Information System (INIS)

Zheng Rongxiu; Fang Peihua; Tan Jian; Lu Mei; Li Yigong

2002-01-01

Objective: To study the status of telomerase activity during the development of thyroid tumors, and to determine whether telomerase activity can be used clinically as a molecular marker in the differential diagnosis of thyroid cancer. Methods: Telomerase activity was measured in 37 thyroid carcinomas, 33 benign thyroid lesions and 30 normal thyroid tissue samples by means of a modified TRAP-PCR. The assay was also applied to 15 fine needle aspirates (FNAs) of thyroid carcinomas to test its sensitivity. Results: Thirty-one of 37 thyroid carcinomas (83.8%), 7 of 33 benign thyroid lesions (21.2%), and 4 of 30 adjacent normal thyroid tissue samples expressed telomerase activity, 15 FNAs also had positive telomerase activity, just as their corresponding tissue specimens. The quantitative analysis showed that the telomerase activity was significantly higher in thyroid carcinomas than that in benign thyroid tissue samples. And medullary carcinomas and anaplastic carcinomas had higher levels of telomerase activity than papillary carcinomas. Conclusions: Telomerase activity is a good marker for thyroid carcinomas. The quantitative TRAP-PCR might have more potential application in the differential diagnosis of tumors and the estimation of tumor progression and prognosis. And this sensitive assay could become a useful new modality for supplementing microscopic cytopathology in the detection of cancer cells in small tissue samples and FNAs

Correlation analysis between bone density measured by quantitative CT and blood sugar level of aged patients with non-insulin-dependent diabetes mellitus

International Nuclear Information System (INIS)

Wang Guizhi; Liang Ping; Qiao Junhua; Liu Chunyan

2008-01-01

Objective: To approach the correlation between the bone density measured by quantitative CT and the blood sugar level of the aged patients with non-insulin-dependent diabetes mellitus, and observe the effects of the blood sugar level on the bone density. Methods: The lumbar bone densities and the blood sugar levels of 160 aged patients with non-insulin-dependent diabetes mellitus (hyperglycemia group 80 cases, euglycemia group 80 cases ) and the healthy aged people (80 cases) were detected by quantitative CT and serum biochemical detection; the correlation between the blood sugar level and the bone density and the osteoporosis occurrence status of aged people in various groups were analyzed. Results: The bone density in the non-insulin-dependent diabetes and hyperglycemia group was lower than those in normal (control) group and non-insulin-dependent diabetes and euglycemia group (P<0.05); the morbility of osteoporosis in the non-insulin-dependent diabetes and hyperglycemia group was higher than those in normal (control) group and non-insulin-dependent diabetes and euglycemia group (P<0.05); negative correlation was found between the bone density and the blood sugar level (aged male group: r=-0.7382, P=0.0013; aged female group: r=-0.8343, P=0.0007). Conclusion: The blood sugar level affects the bone density of the aged patients with non-insulin-dependent diabetes mellitus; the higher the blood sugar level, the lower the bone density. The non-insulin-dependent diabetes aged patients with hyperglycemia have the liability of osteoporosis. (authors)

Quantitative structure-activity relationships for green algae growth inhibition by polymer particles.

NARCIS (Netherlands)

Nolte, Tom M; Peijnenburg, Willie J G M; Hendriks, A Jan; van de Meent, Dik

After use and disposal of chemical products, many types of polymer particles end up in the aquatic environment with potential toxic effects to primary producers like green algae. In this study, we have developed Quantitative Structure-Activity Relationships (QSARs) for a set of highly structural

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

Science.gov (United States)

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

2015-01-01

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

Quantitative research.

Science.gov (United States)

Watson, Roger

2015-04-01

This article describes the basic tenets of quantitative research. The concepts of dependent and independent variables are addressed and the concept of measurement and its associated issues, such as error, reliability and validity, are explored. Experiments and surveys – the principal research designs in quantitative research – are described and key features explained. The importance of the double-blind randomised controlled trial is emphasised, alongside the importance of longitudinal surveys, as opposed to cross-sectional surveys. Essential features of data storage are covered, with an emphasis on safe, anonymous storage. Finally, the article explores the analysis of quantitative data, considering what may be analysed and the main uses of statistics in analysis.

Quantitative chromatography in the analysis of labelled compounds 1. Quantitative paper chromotography of amino acids by A spot comparison technique

International Nuclear Information System (INIS)

Barakat, M.F.; Farag, A.N.; El-Gharbawy, A.A.

1974-01-01

For the determination of the specific activity of labelled compounds separated by paper sheet chromatography, it was found essential to perfect the quantitative aspect of the paper chromatographic technique. Actually, so far paper chromatography has been used as a separation tool mainly and its use in quantification of the separated materials is by far less studied. In the present work, the quantitative analysis of amino acids by paper sheet chromatography has been carried out by methods, depending on the use of the relative spot area values for correcting the experimental data obtained. The results obtained were good and reproducible. The main advantage of the proposed technique is its extreme simplicity. No complicated equipment of procedures are necessary

Quantitative assessment of target dependence of pion fluctuation in ...

Indian Academy of Sciences (India)

journal of. December 2012 physics pp. 1395–1405. Quantitative assessment ... The analysis reveals the erratic behaviour of the produced pions signifying ..... authors (Sitaram Pal) gratefully acknowledges the financial help from the University.

Quantitative Determination of Telomerase Activity in Breast Cancer and Benign Breast Diseases

Czech Academy of Sciences Publication Activity Database

Šimíčková, M.; Nekulová, M.; Pecen, Ladislav; Černoch, M.; Vagundová, M.; Pačovský, Z.

2001-01-01

Roč. 48, č. 4 (2001), s. 267-273 ISSN 0028-2685 R&D Projects: GA MZd NM17 Institutional research plan: AV0Z1030915 Keywords : telomerase activity * quantitative analysis * breast cancer * benign breast diseases * prognisis Subject RIV: BA - General Mathematics Impact factor: 0.637, year: 2001

A cellular system for quantitation of vitamin K cycle activity: structure-activity effects on vitamin K antagonism by warfarin metabolites

Science.gov (United States)

Haque, Jamil A.; McDonald, Matthew G.; Kulman, John D.

2014-01-01

Warfarin and other 4-hydroxycoumarins inhibit vitamin K epoxide reductase (VKOR) by depleting reduced vitamin K that is required for posttranslational modification of vitamin K–dependent clotting factors. In vitro prediction of the in vivo potency of vitamin K antagonists is complicated by the complex multicomponent nature of the vitamin K cycle. Here we describe a sensitive assay that enables quantitative analysis of γ-glutamyl carboxylation and its antagonism in live cells. We engineered a human embryonic kidney (HEK) 293–derived cell line (HEK 293-C3) to express a chimeric protein (F9CH) comprising the Gla domain of factor IX fused to the transmembrane and cytoplasmic regions of proline-rich Gla protein 2. Maximal γ-glutamyl carboxylation of F9CH required vitamin K supplementation, and was dose-dependently inhibited by racemic warfarin at a physiologically relevant concentration. Cellular γ-glutamyl carboxylation also exhibited differential VKOR inhibition by warfarin enantiomers (S > R) consistent with their in vivo potencies. We further analyzed the structure-activity relationship for inhibition of γ-glutamyl carboxylation by warfarin metabolites, observing tolerance to phenolic substitution at the C-5 and especially C-6, but not C-7 or C-8, positions on the 4-hydroxycoumarin nucleus. After correction for in vivo concentration and protein binding, 10-hydroxywarfarin and warfarin alcohols were predicted to be the most potent inhibitory metabolites in vivo. PMID:24297869

Diurnal variation in glycogen phosphorylase activity in rat liver. A quantitative histochemical study

NARCIS (Netherlands)

Frederiks, W. M.; Marx, F.; Bosch, K. S.

1987-01-01

The diurnal variations of the glycogen content and of glycogen phosphorylase activity in periportal and pericentral areas of rat liver parenchyma have been analyzed in periodic acid Schiff (PAS)-stained cryostat sections using quantitative microdensitometry. Glycogen content and phosphorylase

Nicotine dependence, physical activity, and sedentary behavior among adult smokers

OpenAIRE

Paul D Loprinzi; Jerome F Walker

2015-01-01

Background: Research has previously demonstrated an inverse association between smoking status and physical activity; however, few studies have examined the association between nicotine dependence and physical activity or sedentary behavior. Aim: This study examined the association between nicotine dependence and accelerometer-determined physical activity and sedentary behavior. Materials and Methods: Data from the 2003-2006 National Health and Nutrition Examination Survey (NHANES) were used....

Quantitative Collection and Enzymatic Activity of Glucose Oxidase Nanotubes Fabricated by Templated Layer-by-Layer Assembly.

Science.gov (United States)

Zhang, Shouwei; Demoustier-Champagne, Sophie; Jonas, Alain M

2015-08-10

We report on the fabrication of enzyme nanotubes in nanoporous polycarbonate membranes via the layer-by-layer (LbL) alternate assembly of polyethylenimine (PEI) and glucose oxidase (GOX), followed by dissolution of the sacrificial template in CH2Cl2, collection, and final dispersion in water. An adjuvant-assisted filtration methodology is exploited to extract quantitatively the nanotubes without loss of activity and morphology. Different water-soluble CH2Cl2-insoluble adjuvants are tested for maximal enzyme activity and nanotube stability; whereas NaCl disrupts the tubes by screening electrostatic interactions, the high osmotic pressure created by fructose also contributes to loosening the nanotubular structures. These issues are solved when using neutral, high molar mass dextran. The enzymatic activity of intact free nanotubes in water is then quantitatively compared to membrane-embedded nanotubes, showing that the liberated nanotubes have a higher catalytic activity in proportion to their larger exposed surface. Our study thus discloses a robust and general methodology for the fabrication and quantitative collection of enzymatic nanotubes and shows that LbL assembly provides access to efficient enzyme carriers for use as catalytic swarming agents.

A quantitative structure-activity relationship to predict efficacy of granular activated carbon adsorption to control emerging contaminants.

Science.gov (United States)

Kennicutt, A R; Morkowchuk, L; Krein, M; Breneman, C M; Kilduff, J E

2016-08-01

A quantitative structure-activity relationship was developed to predict the efficacy of carbon adsorption as a control technology for endocrine-disrupting compounds, pharmaceuticals, and components of personal care products, as a tool for water quality professionals to protect public health. Here, we expand previous work to investigate a broad spectrum of molecular descriptors including subdivided surface areas, adjacency and distance matrix descriptors, electrostatic partial charges, potential energy descriptors, conformation-dependent charge descriptors, and Transferable Atom Equivalent (TAE) descriptors that characterize the regional electronic properties of molecules. We compare the efficacy of linear (Partial Least Squares) and non-linear (Support Vector Machine) machine learning methods to describe a broad chemical space and produce a user-friendly model. We employ cross-validation, y-scrambling, and external validation for quality control. The recommended Support Vector Machine model trained on 95 compounds having 23 descriptors offered a good balance between good performance statistics, low error, and low probability of over-fitting while describing a wide range of chemical features. The cross-validated model using a log-uptake (qe) response calculated at an aqueous equilibrium concentration (Ce) of 1 μM described the training dataset with an r(2) of 0.932, had a cross-validated r(2) of 0.833, and an average residual of 0.14 log units.

Quantitative structure-activity relationship of some 1-benzylbenzimidazole derivatives as antifungal agents

Directory of Open Access Journals (Sweden)

Podunavac-Kuzmanović Sanja O.

2007-01-01

Full Text Available In the present study, the antifungal activity of some 1-benzylbenzimidazole derivatives against yeast Saccharomyces cerevisiae was investigated. The tested benzimidazoles displayed in vitro antifungal activity and minimum inhibitory concentration (MIC was determined for all the compounds. Quantitative structure-activity relationship (QSAR has been used to study the relationships between the antifungal activity and lipophilicity parameter, logP, calculated by using CS Chem-Office Software version 7.0. The results are discussed on the basis of statistical data. The best QSAR model for prediction of antifungal activity of the investigated series of benzimidazoles was developed. High agreement between experimental and predicted inhibitory values was obtained. The results of this study indicate that the lipophilicity parameter has a significant effect on antifungal activity of this class of compounds, which simplify design of new biologically active molecules.

NK Cell Receptor/H2-Dk–Dependent Host Resistance to Viral Infection Is Quantitatively Modulated by H2 q Inhibitory Signals

Science.gov (United States)

Fodil-Cornu, Nassima; Loredo-Osti, J. Concepción; Vidal, Silvia M.

2011-01-01

The cytomegalovirus resistance locus Cmv3 has been linked to an epistatic interaction between two loci: a Natural Killer (NK) cell receptor gene and the major histocompatibility complex class I (MHC-I) locus. To demonstrate the interaction between Cmv3 and H2k, we generated double congenic mice between MA/My and BALB.K mice and an F2 cross between FVB/N (H-2q) and BALB.K (H2k) mice, two strains susceptible to mouse cytomegalovirus (MCMV). Only mice expressing H2k in conjunction with Cmv3MA/My or Cmv3FVB were resistant to MCMV infection. Subsequently, an F3 cross was carried out between transgenic FVB/H2-Dk and MHC-I deficient mice in which only the progeny expressing Cmv3FVB and a single H2-Dk class-I molecule completely controlled MCMV viral loads. This phenotype was shown to be NK cell–dependent and associated with subsequent NK cell proliferation. Finally, we demonstrated that a number of H2q alleles influence the expression level of H2q molecules, but not intrinsic functional properties of NK cells; viral loads, however, were quantitatively proportional to the number of H2q alleles. Our results support a model in which H-2q molecules convey Ly49-dependent inhibitory signals that interfere with the action of H2-Dk on NK cell activation against MCMV infection. Thus, the integration of activating and inhibitory signals emanating from various MHC-I/NK cell receptor interactions regulates NK cell–mediated control of viral load. PMID:21533075

76 FR 9637 - Proposed Information Collection (Veteran Suicide Prevention Online Quantitative Surveys) Activity...

Science.gov (United States)

2011-02-18

... Collection (Veteran Suicide Prevention Online Quantitative Surveys) Activity: Comment Request AGENCY... prevention of suicide among Veterans and their families. DATES: Written comments and recommendations on the.... Abstract: VA's top priority is the prevention of Veterans suicide. It is imperative to reach these at-risk...

76 FR 27384 - Agency Information Collection Activity (Veteran Suicide Prevention Online Quantitative Surveys...

Science.gov (United States)

2011-05-11

... Collection Activity (Veteran Suicide Prevention Online Quantitative Surveys) Under OMB Review AGENCY.... Abstract: VA's top priority is the prevention of Veterans suicide. It is imperative to reach these at-risk... families' awareness of VA's suicide prevention and mental health support services. In addition, the surveys...

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

Science.gov (United States)

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.

Quantitative Measurement of Physical Activity in Acute Ischemic Stroke and Transient Ischemic Attack

DEFF Research Database (Denmark)

Strømmen, Anna Maria; Christensen, Thomas; Jensen, Kai

2014-01-01

BACKGROUND AND PURPOSE: The purpose of this study was to quantitatively measure and describe the amount and pattern of physical activity in patients within the first week after acute ischemic stroke and transient ischemic attack using accelerometers. METHODS: A total of 100 patients with acute is...

Rethinking the Numerate Citizen: Quantitative Literacy and Public Issues

Directory of Open Access Journals (Sweden)

Ander W. Erickson

2016-07-01

Full Text Available Does a citizen need to possess quantitative literacy in order to make responsible decisions on behalf of the public good? If so, how much is enough? This paper presents an analysis of the quantitative claims made on behalf of ballot measures in order to better delineate the role of quantitative literacy for the citizen. I argue that this role is surprisingly limited due to the contextualized nature of quantitative claims that are encountered outside of a school setting. Instead, rational dependence, or the reasoned dependence on the knowledge of others, is proposed as an educational goal that can supplement quantitative literacy and, in so doing, provide a more realistic plan for informed evaluations of quantitative claims.

Chemical Variability and Biological Activities of Brassica rapa var. rapifera Parts Essential Oils Depending on Geographic Variation and Extraction Technique.

Science.gov (United States)

Saka, Boualem; Djouahri, Abderrahmane; Djerrad, Zineb; Terfi, Souhila; Aberrane, Sihem; Sabaou, Nasserdine; Baaliouamer, Aoumeur; Boudarene, Lynda

2017-06-01

In the present work, the Brassica rapa var. rapifera parts essential oils and their antioxidant and antimicrobial activities were investigated for the first time depending on geographic origin and extraction technique. Gas-chromatography (GC) and GC/mass spectrometry (MS) analyses showed several constituents, including alcohols, aldehydes, esters, ketones, norisoprenoids, terpenic, nitrogen and sulphur compounds, totalizing 38 and 41 compounds in leaves and root essential oils, respectively. Nitrogen compounds were the main volatiles in leaves essential oils and sulphur compounds were the main volatiles in root essential oils. Qualitative and quantitative differences were found among B. rapa var. rapifera parts essential oils collected from different locations and extracted by hydrodistillation and microwave-assisted hydrodistillation techniques. Furthermore, our findings showed a high variability for both antioxidant and antimicrobial activities. The highlighted variability reflects the high impact of plant part, geographic variation and extraction technique on chemical composition and biological activities, which led to conclude that we should select essential oils to be investigated carefully depending on these factors, in order to isolate the bioactive components or to have the best quality of essential oil in terms of biological activities and preventive effects in food. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

The cell biology of T-dependent B cell activation

DEFF Research Database (Denmark)

Owens, T; Zeine, R

1989-01-01

The requirement that CD4+ helper T cells recognize antigen in association with class II Major Histocompatibility Complex (MHC) encoded molecules constrains T cells to activation through intercellular interaction. The cell biology of the interactions between CD4+ T cells and antigen-presenting cells...... includes multipoint intermolecular interactions that probably involve aggregation of both polymorphic and monomorphic T cell surface molecules. Such aggregations have been shown in vitro to markedly enhance and, in some cases, induce T cell activation. The production of T-derived lymphokines that have been...... implicated in B cell activation is dependent on the T cell receptor for antigen and its associated CD3 signalling complex. T-dependent help for B cell activation is therefore similarly MHC-restricted and involves T-B intercellular interaction. Recent reports that describe antigen-independent B cell...

Symptoms of exercise dependence and physical activity in students.

Science.gov (United States)

MacLaren, Vance V; Best, Lisa A

2007-12-01

Health professionals recognize the benefits of moderate physical activity and encourage clients to engage in some form of activity on a regular basis. In spite of these recognized benefits, there are growing concerns that some may exercise at levels detrimental to health. The term exercise dependence refers to those individuals whose extreme exercise schedules interfere with their social, occupational, and family lives. The purpose of this study was to examine the relationship between weekly exercise habits and scores on the Exercise Dependence Questionnaire in a sample of undergraduate students (213 women and 79 men). Overall, participants who reported high activity scored higher than those reporting low activity on subscales measuring interference with family and social life, positive reward, withdrawal, exercise for social reasons, exercise for health reasons, and stereotyped behavior.

Quantitative Analysis of Bone Scintigrams at the Korle-Bu Teaching Hospital

International Nuclear Information System (INIS)

Huguette, E.Y.Y.

2012-01-01

Qualitative method of diagnosis has been the traditional means of diagnosing bone tumours at the Nuclear Medicine Department of the Korle-Bu Teaching Hospital over the years. Although this method is commendable, a more accurate diagnostic means is the quantitative approach. Study on ninety-five patients undergoing bone scans has been performed quantitatively using image J. The patients were administered with activity ranging from 15 to 30 mCi depending on their weights, and were then scanned with an installed e.Cam SPECT system. A 256 x 1024 matrix size was used in acquiring the bone scans. Quantitative analyses performed with the image J, revealed that uptake levels in all selected body parts were higher for metastatic tumours compared to non-metastatic tumours. The average normalised uptake in the recorded metastatic cases was 1.37332 cts/mm 2 /mCi and the corresponding uptake in the non-metastatic cases was 0.85230 cts/mm 2 /mCi. The relative higher uptake in metastatic tumours is attributed to high osteoblastic activity and blood flow in metastatic cases compared to non-metastatic cases. Quantitative assessment of bone scintigrams is recommended for its high accuracy and quicker means of diagnosing.(author)

Quantitative differences in think tank dissemination activities in Germany, Denmark and the UK

DEFF Research Database (Denmark)

Kelstrup, Jesper Dahl

2017-01-01

in a quantitative design which compares publications, events and newspaper mentionings of samples of think tanks from a coordinated (Germany), liberal (UK) and mixed (Denmark) system in 2012. The analysis indicates that think tanks in the UK have the highest level of dissemination on all three activities when...

Telomerase Activity Detected by Quantitative Assay in Bladder Carcinoma and Exfoliated Cells in Urine

Directory of Open Access Journals (Sweden)

Roberta Fedriga

2001-01-01

Full Text Available Early diagnosis is one of the most determining factors for patient survival. The detection of telomerase activity is a potentially promising tool in the diagnosis of bladder and other types of cancer due to the high expression of this enzyme in tumor cells. We carried out a quantitative evaluation of telomerase activity in urine samples in an attempt to determine a cut-off capable of identifying cancer patients. Telomerase activity was quantified by fluorescence TRAP assay in urine from 50 healthy volunteers and in urine and bioptic tumor samples from 56 previously untreated bladder cancer patients and expressed in arbitrary enzymatic units (AEU. Telomerase activity in urine ranged from 0 to 106 AEU (median 0 in healthy donors and from 0 to 282 AEU (median 87 in patients with cancer. A telomerase expression higher than the cut off value determined by receiver operating characteristic (ROC analysis was observed in 78% of cases, regardless of tumor grade and in 71% (15/21 of cases of nonassessable or negative cytology. The quantitative analysis of telomerase activity in urine enabled us to define cut-off values characterized by different sensitivity and specificity. Cytologic and telomerase determination, used sequentially, enabled us to detect about 90% of tumors.

Quantitative size-dependent structure and strain determination of CdSe nanoparticles using atomic pair distribution function analysis

Energy Technology Data Exchange (ETDEWEB)

Masadeh, A S; Bozin, E S; Farrow, C L; Paglia, G; Juhas, P; Billinge, S J. L.; Karkamkar, A; Kanatzidis, M G [Department of Physics and Astronomy, Michigan State University, East Lansing, Michigan 48824-1116 (United States); Department of Chemistry, Michigan State University, East Lansing, Michigan 48824-1116 (United States)

2007-09-15

The size-dependent structure of CdSe nanoparticles, with diameters ranging from 2 to 4 nm, has been studied using the atomic pair distribution function (PDF) method. The core structure of the measured CdSe nanoparticles can be described in terms of the wurtzite atomic structure with extensive stacking faults. The density of faults in the nanoparticles is {approx}50%. The diameter of the core region was extracted directly from the PDF data and is in good agreement with the diameter obtained from standard characterization methods, suggesting that there is little surface amorphous region. A compressive strain was measured in the Cd-Se bond length that increases with decreasing particle size being 0.5% with respect to bulk CdSe for the 2 nm diameter particles. This study demonstrates the size-dependent quantitative structural information that can be obtained even from very small nanoparticles using the PDF approach.

A Quantitative, Time-Dependent Model of Oxygen Isotopes in the Solar Nebula: Step one

Science.gov (United States)

Nuth, J. A.; Paquette, J. A.; Farquhar, A.; Johnson, N. M.

2011-01-01

The remarkable discovery that oxygen isotopes in primitive meteorites were fractionated along a line of slope I rather than along the typical slope 0,52 terrestrial fractionation line occurred almost 40 years ago, However, a satisfactory, quantitative explanation for this observation has yet to be found, though many different explanations have been proposed, The first of these explanations proposed that the observed line represented the final product produced by mixing molecular cloud dust with a nucleosynthetic component, rich in O-16, possibly resulting from a nearby supernova explosion, Donald Clayton suggested that Galactic Chemical Evolution would gradually change the oxygen isotopic composition of the interstellar grain population by steadily producing O-16 in supernovae, then producing the heavier isotopes as secondary products in lower mass stars, Thiemens and collaborators proposed a chemical mechanism that relied on the availability of additional active rotational and vibrational states in otherwise-symmetric molecules, such as CO2, O3 or SiO2, containing two different oxygen isotopes and a second, photochemical process that suggested that differential photochemical dissociation processes could fractionate oxygen , This second line of research has been pursued by several groups, though none of the current models is quantitative,

Cation dependency of the hydrolytic activity of activated bovine Protein C

International Nuclear Information System (INIS)

Hill, K.A.W.

1986-01-01

The hydrolytic activity of activated bovine plasma Protein C (APC) is dependent upon monovalent or divalent cations. The kinetics of APC activity were examined with a variety of monovalent and divalent cations, and significant differences were observed. Similar studies were performed with des(1-41, light chain)APC (GDAPC), from which all γ-carboxyglutamic acid residues have been removed. These studies provided useful information concerning the cation dependency. Divalent cations apparently stimulate APC and GDAPC kinetic activity through association at a single γ-carboxyglutamic acid-independent high affinity binding site. A Mn(II) binding site of this nature of GDAPC was determined by EPR spectroscopy, to possess a dissociation constant of 53 +/- 8 uM. Monovalent cations stimulate GDAPC activity through association at an apparently single binding site that is distinct from the divalent cation site. The monovalent cation , Tl(I), was determined, by 205 Tl(I) NMR spectroscopy, to bind to APC and GDAPC with dissociation constants of 16 +/- 8 mM and 32+/- 11 mM, respectively. Both NMR and EPR spectroscopy have been utilized to estimate topographical relationships between divalent cation sites, monovalent cation sites, and the active site of GDAPC. By observing the paramagnetic effects of either Mn(II) or an active site directed spin-label on the longitudinal relaxation rates of Tl(I) nuclei bound to this enzyme, the average interatomic distance between Mn(II) and Tl(I) was calculated to be 8.3 +/- 0.3 A, and the average distance between Tl(I) and the spin-label free electron was estimated to be 3.8 +/- 0.2 A

Nicotine dependence matters: examining longitudinal association between smoking and physical activity among Canadian adults.

Science.gov (United States)

Azagba, Sunday; Asbridge, Mark

2013-11-01

A number of studies point to the inverse relationship between physical activity and smoking; however, none has examined the role of nicotine dependence in physical activity participation among smokers. This study examined whether levels of nicotine dependence modify the association between leisure time physical activity and smoking status. The study used longitudinal data on 6795 adults from the Canadian National Population Health Survey (2004-2010). Generalized estimating equations were used to examine the association between physical activity, smoking, and nicotine dependence. We found that nicotine dependent smokers were significantly less likely to be physically active compared to non-smokers. Specifically, using the Fagerstrom Test for Nicotine Dependence, nicotine dependent smokers (OR 0.65, 95% CI 0.55-0.76) were less likely to be physically active while no significant difference was found for non-dependent smokers (OR 0.90, 95% CI 0.80-1.02) compared to non-smokers. Nicotine dependence matters in shaping engagement in physical activity among daily smokers. Efforts directed at promoting smoking cessation through nicotine dependence treatment intervention may provide additional benefits to health and well-being through an increased participation in physical activity. © 2013.

Spontaneous appetence for wheel-running: a model of dependency on physical activity in rat.

Science.gov (United States)

Ferreira, Anthony; Lamarque, Stéphanie; Boyer, Patrice; Perez-Diaz, Fernando; Jouvent, Roland; Cohen-Salmon, Charles

2006-12-01

According to human observations of a syndrome of physical activity dependence and its consequences, we tried to examine if running activity in a free activity paradigm, where rats had a free access to activity wheel, may present a valuable animal model for physical activity dependence and most generally to behavioral dependence. The pertinence of reactivity to novelty, a well-known pharmacological dependence predictor was also tested. Given the close linkage observed in human between physical activity and drugs use and abuse, the influence of free activity in activity wheels on reactivity to amphetamine injection and reactivity to novelty were also assessed. It appeared that (1) free access to wheel may be used as a valuable model for physical activity addiction, (2) two populations differing in activity amount also differed in dependence to wheel-running. (3) Reactivity to novelty did not appeared as a predictive factor for physical activity dependence (4) activity modified novelty reactivity and (5) subjects who exhibited a high appetence to wheel-running, presented a strong reactivity to amphetamine. These results propose a model of dependency on physical activity without any pharmacological intervention, and demonstrate the existence of individual differences in the development of this addiction. In addition, these data highlight the development of a likely vulnerability to pharmacological addiction after intense and sustained physical activity, as also described in man. This model could therefore prove pertinent for studying behavioral dependencies and the underlying neurobiological mechanisms. These results may influence the way psychiatrists view behavioral dependencies and phenomena such as doping in sport or addiction to sport itself.

Quantitative analysis of contrast-enhanced ultrasonography of the bowel wall can predict disease activity in inflammatory bowel disease

Energy Technology Data Exchange (ETDEWEB)

Romanini, Laura, E-mail: laura.romanini@libero.it [Department of Radiology, Spedali Civili di Brescia, P.le Spedali Civili, 1, 25123 Brescia (Italy); Passamonti, Matteo, E-mail: matteopassamonti@gmail.com [Department of Radiology-AO Provincia di Lodi, Via Fissiraga, 15, 26900 Lodi (Italy); Navarria, Mario, E-mail: navarria.mario@tiscali.it [Department of Radiology-ASL Vallecamonica-Sebino, Via Manzoni 142, 25040 Esine, BS (Italy); Lanzarotto, Francesco, E-mail: francesco.lanzarotto@spedalicivili.brescia.it [Department of Gastroenterology, Spedali Civili di Brescia, P.le Spedali Civili, 1, 25123 Brescia (Italy); Villanacci, Vincenzo, E-mail: villanac@alice.it [Department of Pathology, Spedali Civili di Brescia, P.le Spedali Civili, 1, 25123 Brescia (Italy); Grazioli, Luigi, E-mail: radiologia1@spedalicivili.brescia.it [Department of Radiology, Spedali Civili di Brescia, P.le Spedali Civili, 1, 25123 Brescia (Italy); Calliada, Fabrizio, E-mail: fabrizio.calliada@gmail.com [Department of Radiology, University of Pavia, Viale Camillo Golgi 19, 27100 Pavia (Italy); Maroldi, Roberto, E-mail: rmaroldi@gmail.com [Department of Radiology, University of Brescia, P.le Spedali Civili, 1, 25123 Brescia (Italy)

2014-08-15

Purpose: To evaluate the accuracy of quantitative analysis of bowel wall enhancement in inflammatory bowel disease (IBD) with contrast enhanced ultrasound (CEUS) by comparing the results with vascular density in a biopsy sample from the same area of the intestinal tract, and to determine the usefulness of this analysis for the prediction of disease activity. Materials and methods: This prospective study was approved by our institute's ethics committee and all patients gave written informed consent. We enrolled 33 consecutive adult patients undergoing colonoscopy and biopsy for IBD. All patients underwent CEUS and the results were quantitatively analyzed. Vessel count per high-power field on biopsy specimens was compared with colonoscopy, baseline ultrasonography, and CEUS findings, and with analysis of peak intensity, time to peak, regional blood volume, mean transit time, and regional blood flow. Results in patients with high and low vascular density were compared using Fisher's test, t-test, Pearson's correlation test, and receiver operating characteristic curve (ROC) analysis. Cutoff values were determined using ROC analysis, and sensitivity and specificity were calculated. Results: High vascular density (>265 vessels per field) on histological examination was significantly correlated with active disease on colonoscopy, baseline ultrasonography, and CEUS (p < .0001). Quantitative analysis showed a higher enhancement peak, a shorter time to peak enhancement, a higher regional blood flow and regional blood volume in patients with high vascular density than in those with low vascular density. Cutoff values to distinguish between active and inactive disease were identified for peak enhancement (>40.5%), and regional blood flow (>54.8 ml/min). Conclusion: Quantitative analysis of CEUS data correlates with disease activity as determined by vascular density. Quantitative parameters of CEUS can be used to predict active disease with high sensitivity and

Quantitative analysis of contrast-enhanced ultrasonography of the bowel wall can predict disease activity in inflammatory bowel disease

International Nuclear Information System (INIS)

Romanini, Laura; Passamonti, Matteo; Navarria, Mario; Lanzarotto, Francesco; Villanacci, Vincenzo; Grazioli, Luigi; Calliada, Fabrizio; Maroldi, Roberto

2014-01-01

Purpose: To evaluate the accuracy of quantitative analysis of bowel wall enhancement in inflammatory bowel disease (IBD) with contrast enhanced ultrasound (CEUS) by comparing the results with vascular density in a biopsy sample from the same area of the intestinal tract, and to determine the usefulness of this analysis for the prediction of disease activity. Materials and methods: This prospective study was approved by our institute's ethics committee and all patients gave written informed consent. We enrolled 33 consecutive adult patients undergoing colonoscopy and biopsy for IBD. All patients underwent CEUS and the results were quantitatively analyzed. Vessel count per high-power field on biopsy specimens was compared with colonoscopy, baseline ultrasonography, and CEUS findings, and with analysis of peak intensity, time to peak, regional blood volume, mean transit time, and regional blood flow. Results in patients with high and low vascular density were compared using Fisher's test, t-test, Pearson's correlation test, and receiver operating characteristic curve (ROC) analysis. Cutoff values were determined using ROC analysis, and sensitivity and specificity were calculated. Results: High vascular density (>265 vessels per field) on histological examination was significantly correlated with active disease on colonoscopy, baseline ultrasonography, and CEUS (p < .0001). Quantitative analysis showed a higher enhancement peak, a shorter time to peak enhancement, a higher regional blood flow and regional blood volume in patients with high vascular density than in those with low vascular density. Cutoff values to distinguish between active and inactive disease were identified for peak enhancement (>40.5%), and regional blood flow (>54.8 ml/min). Conclusion: Quantitative analysis of CEUS data correlates with disease activity as determined by vascular density. Quantitative parameters of CEUS can be used to predict active disease with high sensitivity and

Quantitative Structure Activity Relationship of Cinnamaldehyde Compounds against Wood-Decaying Fungi

Directory of Open Access Journals (Sweden)

Dongmei Yang

2016-11-01

Full Text Available Cinnamaldehyde, of the genius Cinnamomum, is a major constituent of the bark of the cinnamon tree and possesses broad-spectrum antimicrobial activity. In this study, we used best multiple linear regression (BMLR to develop quantitative structure activity relationship (QSAR models for cinnamaldehyde derivatives against wood-decaying fungi Trametes versicolor and Gloeophyllun trabeum. Based on the two optimal QSAR models, we then designed and synthesized two novel cinnamaldehyde compounds. The QSAR models exhibited good correlation coefficients: R2Tv = 0.910 for Trametes versicolor and R2Gt = 0.926 for Gloeophyllun trabeum. Small errors between the experimental and calculated values of two designed compounds indicated that these two QSAR models have strong predictability and stability.

Making College Count: An Examination of Quantitative Reasoning Activities in Higher Education

Directory of Open Access Journals (Sweden)

Louis M. Rocconi

2013-07-01

Full Text Available Findings from national studies along with more frequent calls from those who employ college graduates suggest an urgent need for colleges and universities to increase opportunities for students to develop quantitative reasoning (QR skills. To address this issue, the current study examines the relationship between the frequency of QR activities during college and student and institutional characteristics, as well as whether students at institutions with an emphasis on QR (at least one QR course requirement for all students report more QR activity. Results show that gender, race-ethnicity, major, full-time status, first-generation status, age, institutional enrollment size, and institutional control are related to the frequency of QR activities. Findings also suggest that such activities are indeed more common among institutions that emphasize QR.

Great red spot dependence on solar activity

International Nuclear Information System (INIS)

Schatten, K.H.

1979-01-01

A new inquiry has been made into the question of whether Jupiter's Great Red Spot shows a solar activity dependence. From 1892 to 1947 a clear correlation was present. A dearth of sightings in the seventeenth century, along with the Maunder Minimum, further supports the relation. An anticorrelation, however, from l948 to l967 removed support for such an effect. The old observations have reexamined and recent observations have also been studied. The author reexamines this difficult question and suggests a possible physical mechanism for a Sun-Jovian weather relation. Prinn and Lewis' conversion reaction of Phosphine gas to triclinic red phosphorous crystals is a reaction dependent upon solar radiation. It may explain the dependence found, as well as the striking appearance of the Great Red Spot in the UV

NK cell receptor/H2-Dk-dependent host resistance to viral infection is quantitatively modulated by H2q inhibitory signals.

Science.gov (United States)

Fodil-Cornu, Nassima; Loredo-Osti, J Concepción; Vidal, Silvia M

2011-04-01

The cytomegalovirus resistance locus Cmv3 has been linked to an epistatic interaction between two loci: a Natural Killer (NK) cell receptor gene and the major histocompatibility complex class I (MHC-I) locus. To demonstrate the interaction between Cmv3 and H2(k), we generated double congenic mice between MA/My and BALB.K mice and an F(2) cross between FVB/N (H-2(q)) and BALB.K (H2(k)) mice, two strains susceptible to mouse cytomegalovirus (MCMV). Only mice expressing H2(k) in conjunction with Cmv3(MA/My) or Cmv3(FVB) were resistant to MCMV infection. Subsequently, an F(3) cross was carried out between transgenic FVB/H2-D(k) and MHC-I deficient mice in which only the progeny expressing Cmv3(FVB) and a single H2-D(k) class-I molecule completely controlled MCMV viral loads. This phenotype was shown to be NK cell-dependent and associated with subsequent NK cell proliferation. Finally, we demonstrated that a number of H2(q) alleles influence the expression level of H2(q) molecules, but not intrinsic functional properties of NK cells; viral loads, however, were quantitatively proportional to the number of H2(q) alleles. Our results support a model in which H-2(q) molecules convey Ly49-dependent inhibitory signals that interfere with the action of H2-D(k) on NK cell activation against MCMV infection. Thus, the integration of activating and inhibitory signals emanating from various MHC-I/NK cell receptor interactions regulates NK cell-mediated control of viral load.

Scintigraphic quantitation of gastrointestinal motor activity and transport: Oesophagus and stomach

International Nuclear Information System (INIS)

Stacher, G.; Bergmann, H.

1992-01-01

For the recognition and characterisation of oesophageal motor disorders, manometry represents the most reliable tool but yields no information on bolus transport. The transport can be quantitated by radionuclide techniques. The patient is positioned supine beneath a gamma-camera and instructed to swallow a radiolabelled bolus in a single gulp. Using a marker over the cricoid and the activity in the stomach as landmarks, regions of interest are drawn representing the upper, middle and lower third of the oesophagus and the gastric fundus. Activity-time curves enable one to recognise the clearance patterns in these regions. In combination, manometric and radionuclide transit studies recognise a higher number of motor disorders than either procedure alone. Radionuclide methods also are the most reliable and sensitive to quantitate gastric emptying. Procedure, meal size and composition as well as patient position must be standardised and correction techniques applied. The emptying of solid and liquid meal constituents can be evaluated concomitantly. Solids start to empty only after a lag phase of varying extent. With semi-solid meals, which are emptied at the same rate as solid meals of identical composition in the postlag phase, the recording time can be considerably shorter. Besides gastric emptying, the amplitude, frequency and propagation velocity of antral contractions can be recorded using serial images of short frame time and specially devised analytic techniques. (orig.)

Scintigraphic quantitation of gastrointestinal motor activity and transport: Oesophagus and stomach

Energy Technology Data Exchange (ETDEWEB)

Stacher, G.; Bergmann, H. (Vienna Univ. (Austria). Psychiatrische Klinik Vienna Univ. (Austria). 1. Chirurgische Klinik Ludwig-Boltzmann-Institut fuer Nuklearmedizin, Vienna (Austria))

1992-09-01

For the recognition and characterisation of oesophageal motor disorders, manometry represents the most reliable tool but yields no information on bolus transport. The transport can be quantitated by radionuclide techniques. The patient is positioned supine beneath a gamma-camera and instructed to swallow a radiolabelled bolus in a single gulp. Using a marker over the cricoid and the activity in the stomach as landmarks, regions of interest are drawn representing the upper, middle and lower third of the oesophagus and the gastric fundus. Activity-time curves enable one to recognise the clearance patterns in these regions. In combination, manometric and radionuclide transit studies recognise a higher number of motor disorders than either procedure alone. Radionuclide methods also are the most reliable and sensitive to quantitate gastric emptying. Procedure, meal size and composition as well as patient position must be standardised and correction techniques applied. The emptying of solid and liquid meal constituents can be evaluated concomitantly. Solids start to empty only after a lag phase of varying extent. With semi-solid meals, which are emptied at the same rate as solid meals of identical composition in the postlag phase, the recording time can be considerably shorter. Besides gastric emptying, the amplitude, frequency and propagation velocity of antral contractions can be recorded using serial images of short frame time and specially devised analytic techniques. (orig.).

Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

Directory of Open Access Journals (Sweden)

Mark R. Hutchinson

2007-01-01

Full Text Available This review will introduce the concept of toll-like receptor (TLR–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward. Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine level of analysis. Moreover, a novel antagonism of TLR4 by (+- and (˗-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia and unwanted (tolerance, dependence, and reward actions of opioids, thereby improving the safety and efficacy of their use.

Localization and stretch-dependence of lung elastase activity in development and compensatory growth.

Science.gov (United States)

Young, Sarah Marie; Liu, Sheng; Joshi, Rashika; Batie, Matthew R; Kofron, Matthew; Guo, Jinbang; Woods, Jason C; Varisco, Brian Michael

2015-04-01

Synthesis and remodeling of the lung matrix is necessary for primary and compensatory lung growth. Because cyclic negative force is applied to developing lung tissue during the respiratory cycle, we hypothesized that stretch is a critical regulator of lung matrix remodeling. By using quantitative image analysis of whole-lung and whole-lobe elastin in situ zymography images, we demonstrated that elastase activity increased twofold during the alveolar stage of postnatal lung morphogenesis in the mouse. Remodeling was restricted to alveolar walls and ducts and was nearly absent in dense elastin band structures. In the mouse pneumonectomy model of compensatory lung growth, elastase activity increased threefold, peaking at 14 days postpneumonectomy and was higher in the accessory lobe compared with other lobes. Remodeling during normal development and during compensatory lung growth was different with increased major airway and pulmonary arterial remodeling during development but not regeneration, and with homogenous remodeling throughout the parenchyma during development, but increased remodeling only in subpleural regions during compensatory lung growth. Left lung wax plombage prevented increased lung elastin during compensatory lung growth. To test whether the adult lung retains an innate capacity to remodel elastin, we developed a confocal microscope-compatible stretching device. In ex vivo adult mouse lung sections, lung elastase activity increased exponentially with strain and in peripheral regions of lung more than in central regions. Our study demonstrates that lung elastase activity is stretch-dependent and supports a model in which externally applied forces influence the composition, structure, and function of the matrix during periods of alveolar septation. Copyright © 2015 the American Physiological Society.

Abscisic acid-dependent multisite phosphorylation regulates the activity of a transcription activator AREB1.

Science.gov (United States)

Furihata, Takashi; Maruyama, Kyonoshin; Fujita, Yasunari; Umezawa, Taishi; Yoshida, Riichiro; Shinozaki, Kazuo; Yamaguchi-Shinozaki, Kazuko

2006-02-07

bZIP-type transcription factors AREBs/ABFs bind an abscisic acid (ABA)-responsive cis-acting element named ABRE and transactivate downstream gene expression in Arabidopsis. Because AREB1 overexpression could not induce downstream gene expression, activation of AREB1 requires ABA-dependent posttranscriptional modification. We confirmed that ABA activated 42-kDa kinase activity, which, in turn, phosphorylated Ser/Thr residues of R-X-X-S/T sites in the conserved regions of AREB1. Amino acid substitutions of R-X-X-S/T sites to Ala suppressed transactivation activity, and multiple substitution of these sites resulted in almost complete suppression of transactivation activity in transient assays. In contrast, substitution of the Ser/Thr residues to Asp resulted in high transactivation activity without exogenous ABA application. A phosphorylated, transcriptionally active form was achieved by substitution of Ser/Thr in all conserved R-X-X-S/T sites to Asp. Transgenic plants overexpressing the phosphorylated active form of AREB1 expressed many ABA-inducible genes, such as RD29B, without ABA treatment. These results indicate that the ABA-dependent multisite phosphorylation of AREB1 regulates its own activation in plants.

Tip-Enhanced Raman Voltammetry: Coverage Dependence and Quantitative Modeling.

Science.gov (United States)

Mattei, Michael; Kang, Gyeongwon; Goubert, Guillaume; Chulhai, Dhabih V; Schatz, George C; Jensen, Lasse; Van Duyne, Richard P

2017-01-11

Electrochemical atomic force microscopy tip-enhanced Raman spectroscopy (EC-AFM-TERS) was employed for the first time to observe nanoscale spatial variations in the formal potential, E 0' , of a surface-bound redox couple. TERS cyclic voltammograms (TERS CVs) of single Nile Blue (NB) molecules were acquired at different locations spaced 5-10 nm apart on an indium tin oxide (ITO) electrode. Analysis of TERS CVs at different coverages was used to verify the observation of single-molecule electrochemistry. The resulting TERS CVs were fit to the Laviron model for surface-bound electroactive species to quantitatively extract the formal potential E 0' at each spatial location. Histograms of single-molecule E 0' at each coverage indicate that the electrochemical behavior of the cationic oxidized species is less sensitive to local environment than the neutral reduced species. This information is not accessible using purely electrochemical methods or ensemble spectroelectrochemical measurements. We anticipate that quantitative modeling and measurement of site-specific electrochemistry with EC-AFM-TERS will have a profound impact on our understanding of the role of nanoscale electrode heterogeneity in applications such as electrocatalysis, biological electron transfer, and energy production and storage.

Space-Time Dependent Transport, Activation, and Dose Rates for Radioactivated Fluids.

Science.gov (United States)

Gavazza, Sergio

Two methods are developed to calculate the space - and time-dependent mass transport of radionuclides, their production and decay, and the associated dose rates generated from the radioactivated fluids flowing through pipes. The work couples space- and time-dependent phenomena, treated as only space- or time-dependent in the open literature. The transport and activation methodology (TAM) is used to numerically calculate space- and time-dependent transport and activation of radionuclides in fluids flowing through pipes exposed to radiation fields, and volumetric radioactive sources created by radionuclide motions. The computer program Radionuclide Activation and Transport in Pipe (RNATPA1) performs the numerical calculations required in TAM. The gamma ray dose methodology (GAM) is used to numerically calculate space- and time-dependent gamma ray dose equivalent rates from the volumetric radioactive sources determined by TAM. The computer program Gamma Ray Dose Equivalent Rate (GRDOSER) performs the numerical calculations required in GAM. The scope of conditions considered by TAM and GAM herein include (a) laminar flow in straight pipe, (b)recirculating flow schemes, (c) time-independent fluid velocity distributions, (d) space-dependent monoenergetic neutron flux distribution, (e) space- and time-dependent activation process of a single parent nuclide and transport and decay of a single daughter radionuclide, and (f) assessment of space- and time-dependent gamma ray dose rates, outside the pipe, generated by the space- and time-dependent source term distributions inside of it. The methodologies, however, can be easily extended to include all the situations of interest for solving the phenomena addressed in this dissertation. A comparison is made from results obtained by the described calculational procedures with analytical expressions. The physics of the problems addressed by the new technique and the increased accuracy versus non -space and time-dependent methods

Quantitative Structure – Antioxidant Activity Relationships of Flavonoid Compounds

Directory of Open Access Journals (Sweden)

Károly Héberger

2004-12-01

Full Text Available A quantitative structure – antioxidant activity relationship (QSAR study of 36 flavonoids was performed using the partial least squares projection of latent structures (PLS method. The chemical structures of the flavonoids have been characterized by constitutional descriptors, two-dimensional topological and connectivity indices. Our PLS model gave a proper description and a suitable prediction of the antioxidant activities of a diverse set of flavonoids having clustering tendency.

Quantitative measurement of maritime sediment movement using radioactive tracers

International Nuclear Information System (INIS)

Makovski, E.; Grissener, G.

1967-01-01

The quantitative method described in the paper involves burying appropriate detectors over a given area of the sea bottom, the detectors being connected to recording equipment which is itself buried in the sediment or situated on the shore. Detectors arranged in this way are covered by a certain layer of radioactive sediment whose activity is proportional to its mass. Before the labelled sediments are removed, their initial activity is measured, and then, as the covering is removed, measurements are made of the gradual decrease in activity corresponding to loss of the surface layer of the bottom deposit area under investigation, expressed in g/cm 2 . The tracers used in the investigations discussed were natural ones such as sea with 31 Si and artificial ones such as activated fragments of sodium glass (with a 6.5% admixture of Fe 2 O 3 ) with 24 Na . The proportional dependence of activity on mass has been confirmed for both tracers; this is an essential point for a tracer intended for quantitative measurements. This proportionality is very well maintained if a sample of highly active sediment is introduced into a large mass of inactive sediments (10 -2 - 10 -3 ). The concluding section describes the advantages of this method as a possible way of using radioisotopes with a short half-life and a low total activity of the order of a few millicuries. (author)

Cultural differences in human brain activity: a quantitative meta-analysis.

Science.gov (United States)

Han, Shihui; Ma, Yina

2014-10-01

Psychologists have been trying to understand differences in cognition and behavior between East Asian and Western cultures within a single cognitive framework such as holistic versus analytic or interdependent versus independent processes. However, it remains unclear whether cultural differences in multiple psychological processes correspond to the same or different neural networks. We conducted a quantitative meta-analysis of 35 functional MRI studies to examine cultural differences in brain activity engaged in social and non-social processes. We showed that social cognitive processes are characterized by stronger activity in the dorsal medial prefrontal cortex, lateral frontal cortex and temporoparietal junction in East Asians but stronger activity in the anterior cingulate, ventral medial prefrontal cortex and bilateral insula in Westerners. Social affective processes are associated with stronger activity in the right dorsal lateral frontal cortex in East Asians but greater activity in the left insula and right temporal pole in Westerners. Non-social processes induce stronger activity in the left inferior parietal cortex, left middle occipital and left superior parietal cortex in East Asians but greater activations in the right lingual gyrus, right inferior parietal cortex and precuneus in Westerners. The results suggest that cultural differences in social and non-social processes are mediated by distinct neural networks. Moreover, East Asian cultures are associated with increased neural activity in the brain regions related to inference of others' mind and emotion regulation whereas Western cultures are associated with enhanced neural activity in the brain areas related to self-relevance encoding and emotional responses during social cognitive/affective processes. Copyright © 2014 Elsevier Inc. All rights reserved.

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

Science.gov (United States)

Zhang, Yili; Golowasch, Jorge

2011-11-01

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 Ca(2+) 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 Ca(2+) concentration, a Ca(2+) uptake regulation mechanism that is directly targeted by neuromodulator-activated signaling pathways, and variability in the Ca(2+) concentration sensing signaling pathway can account for the observed changes in neuronal activity. Our conclusions are all amenable to experimental analysis.

NPM1 directs PIDDosome-dependent caspase-2 activation in the nucleolus.

Science.gov (United States)

Ando, Kiyohiro; Parsons, Melissa J; Shah, Richa B; Charendoff, Chloé I; Paris, Sheré L; Liu, Peter H; Fassio, Sara R; Rohrman, Brittany A; Thompson, Ruth; Oberst, Andrew; Sidi, Samuel; Bouchier-Hayes, Lisa

2017-06-05

The PIDDosome (PIDD-RAIDD-caspase-2 complex) is considered to be the primary signaling platform for caspase-2 activation in response to genotoxic stress. Yet studies of PIDD-deficient mice show that caspase-2 activation can proceed in the absence of PIDD. Here we show that DNA damage induces the assembly of at least two distinct activation platforms for caspase-2: a cytoplasmic platform that is RAIDD dependent but PIDD independent, and a nucleolar platform that requires both PIDD and RAIDD. Furthermore, the nucleolar phosphoprotein nucleophosmin (NPM1) acts as a scaffold for PIDD and is essential for PIDDosome assembly in the nucleolus after DNA damage. Inhibition of NPM1 impairs caspase-2 processing, apoptosis, and caspase-2-dependent inhibition of cell growth, demonstrating that the NPM1-dependent nucleolar PIDDosome is a key initiator of the caspase-2 activation cascade. Thus we have identified the nucleolus as a novel site for caspase-2 activation and function. © 2017 Ando et al.

Quantitative genetic methods depending on the nature of the phenotypic trait.

Science.gov (United States)

de Villemereuil, Pierre

2018-01-24

A consequence of the assumptions of the infinitesimal model, one of the most important theoretical foundations of quantitative genetics, is that phenotypic traits are predicted to be most often normally distributed (so-called Gaussian traits). But phenotypic traits, especially those interesting for evolutionary biology, might be shaped according to very diverse distributions. Here, I show how quantitative genetics tools have been extended to account for a wider diversity of phenotypic traits using first the threshold model and then more recently using generalized linear mixed models. I explore the assumptions behind these models and how they can be used to study the genetics of non-Gaussian complex traits. I also comment on three recent methodological advances in quantitative genetics that widen our ability to study new kinds of traits: the use of "modular" hierarchical modeling (e.g., to study survival in the context of capture-recapture approaches for wild populations); the use of aster models to study a set of traits with conditional relationships (e.g., life-history traits); and, finally, the study of high-dimensional traits, such as gene expression. © 2018 New York Academy of Sciences.

The Stress-Dependent Activation Parameters for Dislocation Nucleation in Molybdenum Nanoparticles.

Science.gov (United States)

Chachamovitz, Doron; Mordehai, Dan

2018-03-02

Many specimens at the nanoscale are pristine of dislocations, line defects which are the main carriers of plasticity. As a result, they exhibit extremely high strengths which are dislocation-nucleation controlled. Since nucleation is a thermally activated process, it is essential to quantify the stress-dependent activation parameters for dislocation nucleation in order to study the strength of specimens at the nanoscale and its distribution. In this work, we calculate the strength of Mo nanoparticles in molecular dynamics simulations and we propose a method to extract the activation free-energy barrier for dislocation nucleation from the distribution of the results. We show that by deforming the nanoparticles at a constant strain rate, their strength distribution can be approximated by a normal distribution, from which the activation volumes at different stresses and temperatures are calculated directly. We found that the activation energy dependency on the stress near spontaneous nucleation conditions obeys a power-law with a critical exponent of approximately 3/2, which is in accordance with critical exponents found in other thermally activated processes but never for dislocation nucleation. Additionally, significant activation entropies were calculated. Finally, we generalize the approach to calculate the activation parameters for other driving-force dependent thermally activated processes.

Mapping Protein-Protein Interactions by Quantitative Proteomics

DEFF Research Database (Denmark)

Dengjel, Joern; Kratchmarova, Irina; Blagoev, Blagoy

2010-01-01

spectrometry (MS)-based proteomics in combination with affinity purification protocols has become the method of choice to map and track the dynamic changes in protein-protein interactions, including the ones occurring during cellular signaling events. Different quantitative MS strategies have been used...... to characterize protein interaction networks. In this chapter we describe in detail the use of stable isotope labeling by amino acids in cell culture (SILAC) for the quantitative analysis of stimulus-dependent dynamic protein interactions.......Proteins exert their function inside a cell generally in multiprotein complexes. These complexes are highly dynamic structures changing their composition over time and cell state. The same protein may thereby fulfill different functions depending on its binding partners. Quantitative mass...

Lateral dimension-dependent antibacterial activity of graphene oxide sheets.

Science.gov (United States)

Liu, Shaobin; Hu, Ming; Zeng, Tingying Helen; Wu, Ran; Jiang, Rongrong; Wei, Jun; Wang, Liang; Kong, Jing; Chen, Yuan

2012-08-21

Graphene oxide (GO) is a promising precursor to produce graphene-family nanomaterials for various applications. Their potential health and environmental impacts need a good understanding of their cellular interactions. Many factors may influence their biological interactions with cells, and the lateral dimension of GO sheets is one of the most relevant material properties. In this study, a model bacterium, Escherichia coli ( E. coli ), was used to evaluate the antibacterial activity of well-dispersed GO sheets, whose lateral size differs by more than 100 times. Our results show that the antibacterial activity of GO sheets toward E. coli cells is lateral size dependent. Larger GO sheets show stronger antibacterial activity than do smaller ones, and they have different time- and concentration-dependent antibacterial activities. Large GO sheets lead to most cell loss after 1 h incubation, and their concentration strongly influences antibacterial activity at relative low concentration (oxidation capacity toward glutathione is similar, consistent with X-ray photoelectron spectroscopy and ultraviolet-visible absorption spectroscopy results. This suggests the lateral size-dependent antibacterial activity of GO sheets is caused by neither their aggregation states, nor oxidation capacity. Atomic force microscope analysis of GO sheets and cells shows that GO sheets interact strongly with cells. Large GO sheets more easily cover cells, and cells cannot proliferate once fully covered, resulting in the cell viability loss observed in the followed colony counting test. In contrast, small GO sheets adhere to the bacterial surfaces, which cannot effectively isolate cells from environment. This study highlights the importance of tailoring the lateral dimension of GO sheets to optimize the application potential with minimal risks for environmental health and safety.

Quantitative analysis of HGF and EGF-dependent phosphotyrosine signaling networks

DEFF Research Database (Denmark)

Hammond, Dean E; Hyde, Russell; Kratchmarova, Irina

2010-01-01

549 lung adenocarcinoma cells with EGF or HGF. In total, we obtained quantitative information for 274 proteins, which respond to either or both stimuli by >1.5 fold changes in enrichment, following immuno-precipitation with antiphosphotyrosine antibodies. The data reveal a high degree of overlap...

Dependence of PERT endpoint on endogenous lipase activity.

Science.gov (United States)

Gao, Wen-Yi; Mulberg, Andrew E

2014-11-01

To clarify and to understand the potential for misinterpretation of change in fecal fat quantitation during pancreatic enzyme replacement therapy (PERT) trials for treatment of exocrine pancreatic insufficiency. Analysis of clinical trials submitted to the U.S. Food and Drug Administration (FDA) for approval of PERT that enrolled 123 cystic fibrosis adult and pediatric patients treated with Creon, Pertzye, Ultresa, and Zenpep. The CFA% defines lipase activity as a percentage of converting substrate of "Total Daily Dietary Fat Intake." PERT trials performed to date have modified the definition to converting the "Shared Daily Fat Intake," generating "Partial CFA" for the exogenous lipase: the higher the activity of coexisting endogenous lipase, the lower the "Partial CFA" of exogenous measured. This review shows that "Partial CFA" is not CFA. Enrollment of patients with low HPLA during treatment may improve the interpretability of "Partial CFA" measured by PERT trials.

Device-dependent activity estimation and decay correction of radionuclide mixtures with application to Tc-94m PET studies

International Nuclear Information System (INIS)

Smith, Mark F.; Daube-Witherspoon, Margaret E.; Plascjak, Paul S.; Szajek, Lawrence P.; Carson, Richard E.; Everett, James R.; Green, Shielah L.; Territo, Paul R.; Balaban, Robert S.; Bacharach, Stephen L.; Eckelman, William C.

2001-01-01

Multi-instrument activity estimation and decay correction techniques were developed for radionuclide mixtures, motivated by the desire for accurate quantitation of Tc-94m positron emission tomography (PET) studies. Tc-94m and byproduct Tc isotopes were produced by proton irradiation of enriched Mo-94 and natural Mo targets. Mixture activities at the end of bombardment were determined with a calibrated high purity germanium detector. The activity fractions of the greatest mixture impurities relative to 100% for Tc-94m averaged 10.0% (Tc-94g) and 3.3% (Tc-93) for enriched targets and 10.1% (Tc-94g), 11.0% (Tc-95), 255.8% (Tc-96m), and 7.2% (Tc-99m) for natural targets. These radioisotopes have different half-lives (e.g., 52.5 min for Tc-94m, 293 min for Tc-94g), positron branching ratios (e.g., 0.72 for Tc-94m, 0.11 for Tc-94g) and gamma ray emissions for themselves and their short-lived, excited Mo daughters. This complicates estimation of injected activity with a dose calibrator, in vivo activity with PET and blood sample activity with a gamma counter. Decay correction using only the Tc-94m half-life overestimates activity and is inadequate. For this reason analytic formulas for activity estimation and decay correction of radionuclide mixtures were developed. Isotope-dependent sensitivity factors for a PET scanner, dose calibrator, and gamma counter were determined using theoretical sensitivity models and fits of experimental decay curves to sums of exponentials with fixed decay rates. For up to 8 h after the end of bombardment with activity from enriched and natural Mo targets, decay-corrected activities were within 3% of the mean for three PET studies of a uniform cylinder, within 3% of the mean for six dose calibrator decay studies, and within 6% of the mean for four gamma counter decay studies. Activity estimation and decay correction for Tc-94m mixtures enable routine use of Tc-94m in quantitative PET, as illustrated by application to a canine Tc-94m sestamibi

Microfluorometric mithramycin assay for quantitating the effects of immunotoxicants on lymphocyte activation

International Nuclear Information System (INIS)

Quattrone, A.J.; Ranney, D.F.

1981-01-01

A semiautomated, microfluorometric assay has been developed for the detection of toxicant-induced changes in lymphocyte DNA content at standard intervals after mitogen activation. DNA is quantitated by solubilizing the cells and determining the fluorescence enhancement that results from formation of the highly specific mithramycin:DNA adduct. The limit of detection is 0.21 μg (30,000 resting cell equivalents) per microliter well. Correlation with the less sensitive, nonautomatable, diphenylamine DNA assay give a correlation coefficient r = 0.91. Prototype substances representative of true immunotoxicants (prostaglandin E 2 ) and common interfering substances (thymidine at 14 M) have been tested. The latter substance produces false positive results in the standard [ 3 H] thymidine assay. The mithramycin assay does not inappropriately detect this interfering substance. It has the characteristics of a highly specific, accurate technique of screening and quantitating immunotoxic drugs, agents, and mediators in patient sera and other complex biological fluids

Activity-dependent neurorehabilitation beyond physical trainings: "mental exercise" through mirror neuron activation

OpenAIRE

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

2015-01-01

The activity dependent brain repair mechanism has been widely adopted in many types of neurorehabilitation. The activity leads to target specific and non-specific beneficial effects in different brain regions, such as the releasing of neurotrophic factors, modulation of the cytokines and generation of new neurons in adult hood. However physical exercise program clinically are limited to some of the patients with preserved motor functions; while many patients suffered from paralysis cannot mak...

Improving quantitative dosimetry in (177)Lu-DOTATATE SPECT by energy window-based scatter corrections

DEFF Research Database (Denmark)

de Nijs, Robin; Lagerburg, Vera; Klausen, Thomas L

2014-01-01

and the activity, which depends on the collimator type, the utilized energy windows and the applied scatter correction techniques. In this study, energy window subtraction-based scatter correction methods are compared experimentally and quantitatively. MATERIALS AND METHODS: (177)Lu SPECT images of a phantom...... technique, the measured ratio was close to the real ratio, and the differences between spheres were small. CONCLUSION: For quantitative (177)Lu imaging MEGP collimators are advised. Both energy peaks can be utilized when the ESSE correction technique is applied. The difference between the calculated...

Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen*

Science.gov (United States)

Kozlov, Sergei V.; Waardenberg, Ashley J.; Engholm-Keller, Kasper; Arthur, Jonathan W.; Graham, Mark E.; Lavin, Martin

2016-01-01

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

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

Science.gov (United States)

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

2014-01-01

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

Curcumin Regulates Low-Linear Energy Transfer γ-Radiation-Induced NFκB-Dependent Telomerase Activity in Human Neuroblastoma Cells

International Nuclear Information System (INIS)

Aravindan, Natarajan; Veeraraghavan, Jamunarani; Madhusoodhanan, Rakhesh; Herman, Terence S.; Natarajan, Mohan

2011-01-01

Purpose: We recently reported that curcumin attenuates ionizing radiation (IR)-induced survival signaling and proliferation in human neuroblastoma cells. Also, in the endothelial system, we have demonstrated that NFκB regulates IR-induced telomerase activity (TA). Accordingly, we investigated the effect of curcumin in inhibiting IR-induced NFκB-dependent hTERT transcription, TA, and cell survival in neuroblastoma cells. Methods and Materials: SK-N-MC or SH-SY5Y cells exposed to IR and treated with curcumin (10-100 nM) with or without IR were harvested after 1 h through 24 h. NFκB-dependent regulation was investigated either by luciferase reporter assays using pNFκB-, pGL3-354-, pGL3-347-, or pUSE-IκBα-Luc, p50/p65, or RelA siRNA-transfected cells. NFκB activity was analyzed using an electrophoretic mobility shift assay and hTERT expression using the quantitative polymerase chain reaction. TA was determined using the telomerase repeat amplification protocol assay and cell survival using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium bromide and clonogenic assay. Results: Curcumin profoundly inhibited IR-induced NFκB. Consequently, curcumin significantly inhibited IR-induced TA and hTERT mRNA at all points investigated. Furthermore, IR-induced TA is regulated at the transcriptional level by triggering telomerase reverse transcriptase (TERT) promoter activation. Moreover, NFκB becomes functionally activated after IR and mediates TA upregulation by binding to the κB-binding region in the promoter region of the TERT gene. Consistently, elimination of the NFκB-recognition site on the telomerase promoter or inhibition of NFκB by the IκBα mutant compromises IR-induced telomerase promoter activation. Significantly, curcumin inhibited IR-induced TERT transcription. Consequently, curcumin inhibited hTERT mRNA and TA in NFκB overexpressed cells. Furthermore, curcumin enhanced the IR-induced inhibition of cell survival. Conclusions: These results

A Quantitative Structure-Activity Relationships (QSAR Study of Piperine Based Derivatives with Leishmanicidal Activity

Directory of Open Access Journals (Sweden)

Edilson Beserra Alencar Filho

2017-04-01

Full Text Available Leishmaniasis is a parasitic disease which represents a serious public health problem in developing countries. It is considered a neglected tropical disease, for which there is little initiative in the search for therapeutic alternatives by pharmaceutical industry. Natural products remain a great source of inspiration for obtaining bioactive molecules. In 2010, Singh and co-workers published the synthesis and in vitro biological activity of piperoyl-aminoacid conjugates, as well as of piperine, against cellular cultures of Leishmania donovani. The piperine is an alkaloid isolated from Piper nigrum that has many activities described in the literature. In this work, we present a Quantitative Structure-Activity Study of piperine derivatives tested by Singh and co-workers, aiming to highlight important molecular features for leishmanicidal activity, obtaining a mathematical model to predict the activity of new analogs. Compounds were submitted to a geometry optimization computational procedure at semiempirical level of quantum theory. Molecular descriptors for the set of compounds were calculated by E-Dragon online plataform, followed by a variable selection procedure using Ordered Predictors Selection algorithm. Validation parameters obtained showed that a good QSAR model, based on multiple linear regression, was obtained (R2 = 0.85; Q2 = 0.69, and the following conclusions regarding the structure-activity relationship were elucidated: Compounds with electronegative atoms on different substituent groups of analogs, absence of unsaturation on lateral chain, presence of ester instead of carboxyl, and large volumes (due the presence of additional aromatic rings trends to increase the activity against promastigote forms of leishmania. DOI: http://dx.doi.org/10.17807/orbital.v9i1.893

Qualitative and Quantitative Characteristics of Selected Bacterial Groups

Science.gov (United States)

Roszak, Dorota; Gałęcka, Mirosława; Cichy, Wojciech; Szachta, Patrycja

2016-01-01

The aim of the study was evaluation of qualitative and quantitative changes in bacterial ecosystem in 109 children with inflammatory bowel diseases. Stools obtained from patients were analysed for selected bacteria and concentration of faecal inflammatory markers (calprotectin, lactoferrin, M2-PK). The number of selected microorganisms depends on the level of clinical activity of disease and is correlated with faecal concentration of inflammatory markers. Differences in microflora disturbance, observed in patients with Crohn’s disease and ulcerative colitis, may suggest different causes of development of both pathologies.

[Flexibility of cognitive activity depends on its context].

Science.gov (United States)

Kostandov, É A

2010-01-01

The main purpose of this survey is to explain the importance of set-shifting for a flexible cognitive activity. Working memory overload may result in set-shifting slowdown, i.e., in a more rigid set and in a less flexible cognitive activity. This effect displays itself in an increase of erroneous perceptions of external stimuli. Set rigidity level also depends on the cognitive activity context (i.e., on the type of external stimuli the person has to deal with). We analyzed EEG-coherence function and induced synchronization/desynchronization responses in theta (4-7 Hz) and low alpha (8-10 Hz) bands. Basing on these data, we discuss the role of tonic and phasic forms of cortico-hippocampal and fronto-thalamic systems' activation in cognitive activity flexibility.

Arrhenius temperature dependence of in vitro tissue plasminogen activator thrombolysis

International Nuclear Information System (INIS)

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

2007-01-01

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 deg. 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 E eff of 42.0 ± 0.9 kJ mole -1 . E eff 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

Arrhenius temperature dependence of in vitro tissue plasminogen activator thrombolysis

Energy Technology Data Exchange (ETDEWEB)

Shaw, George J [Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769 (United States); Dhamija, Ashima [Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769 (United States); Bavani, Nazli [Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769 (United States); Wagner, Kenneth R [Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769 (United States); Holland, Christy K [Department of Biomedical Engineering, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769 (United States)

2007-06-07

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 deg. 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 {delta}m(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 E{sub eff} of 42.0 {+-} 0.9 kJ mole{sup -1}. E{sub eff} approximates the activation energy of the plasminogen-to-plasmin reaction of 48.9 kJ mole{sup -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.

Levels of plasminogen activator inhibitor type 1 and urokinase plasminogen activator receptor in non-small cell lung cancer as measured by quantitative ELISA and semiquantitative immunohistochemistry

DEFF Research Database (Denmark)

Pappot, Helle; Skov, Birgit Guldhammer; Pyke, Charles

1997-01-01

The components of the plasminogen activation system have been reported to have prognostic impact in several cancer types, e.g. breast-, colon-, gastric- and lung cancer. Most of these studies have used quantification by enzyme-linked immunosorbent assay (ELISA) on tumour tissue extracts. However......, results in non-small cell lung cancer (NSCLC) studies obtained by quantitative ELISA and semiquantitative immunohistochemistry differ. If the prognostic value of the components of the plasminogen activation system is to be exploited clinically in the future, it is important to choose an easy and valid...... methodology. In the present study we investigated levels of plasminogen activator inhibitor type 1 (PAI-I) and urokinase plasminogen activator receptor (uPAR), as quantitated by ELISA in tumour extracts from 64 NSCLC patients (38 squamous cell carcinomas, 26 adenocarcinomas), and compared them to staining...

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

Science.gov (United States)

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.

Qualitative and quantitative measurement of human brain activity using pixel subtraction algorithm

International Nuclear Information System (INIS)

Lee, Jin Myoung; Jeong, Gwang Woo; Kim, Hyung Joong; Cho, Seong Hoon; Kang, Heoung Keun; Seo, Jeong Jin; Park, Seung Jin

2004-01-01

quantification method showed an average error of 0.334±0.007 (%). Thus, the manual counting method gave less accurate quantitative information on brain activation than the FALBA program. The FALBA program is capable of providing accurate quantitative results, including the identification of the brain activation region and lateralization index with respect to the functional and anatomical areas. Also, the processing time was dramatically shortened in comparison with the manual counting method

Qualitative and quantitative measurement of human brain activity using pixel subtraction algorithm

Energy Technology Data Exchange (ETDEWEB)

Lee, Jin Myoung; Jeong, Gwang Woo; Kim, Hyung Joong; Cho, Seong Hoon; Kang, Heoung Keun; Seo, Jeong Jin; Park, Seung Jin [School of Medicine, Chonnam National Univ., Kwangju (Korea, Republic of)

2004-08-01

manual quantification method showed an average error of 0.334{+-}0.007 (%). Thus, the manual counting method gave less accurate quantitative information on brain activation than the FALBA program. The FALBA program is capable of providing accurate quantitative results, including the identification of the brain activation region and lateralization index with respect to the functional and anatomical areas. Also, the processing time was dramatically shortened in comparison with the manual counting method.

A simulation of orientation dependent, global changes in camera sensitivity in ECT

International Nuclear Information System (INIS)

Bieszk, J.A.; Hawman, E.G.; Malmin, R.E.

1984-01-01

ECT promises the abilities to: 1) observe radioisotope distributions in a patient without the summation of overlying activity to reduce contrast, and 2) measure quantitatively these distributions to further and more accurately assess organ function. Ideally, camera-based ECT systems should have a performance that is independent of camera orientation or gantry angle. This study is concerned with ECT quantitation errors that can arise from angle-dependent variations of camera sensitivity. Using simulated phantoms representative of heart and liver sections, the effects of sensitivity changes on reconstructed images were assessed both visually and quantitatively based on ROI sums. The sinogram for each test image was simulated with 128 linear digitization and 180 angular views. The global orientation-dependent sensitivity was modelled by applying an angular sensitivity dependence to the sinograms of the test images. Four sensitivity variations were studied. Amplitudes of 0% (as a reference), 5%, 10%, and 25% with a cosθ dependence were studied as well as a cos2θ dependence with a 5% amplitude. Simulations were done with and without Poisson noise to: 1) determine trends in the quantitative effects as a function of the magnitude of the variation, and 2) to see how these effects are manifested in studies having statistics comparable to clinical cases. For the most realistic sensitivity variation (cosθ, 5% ampl.), the ROIs chosen in the present work indicated changes of <0.5% in the noiseless case and <5% for the case with Poisson noise. The effects of statistics appear to dominate any effects due to global, sinusoidal, orientation-dependent sensitivity changes in the cases studied

Dependency Defence and Dependency Analysis Guidance. Volume 2: Appendix 3-8. How to analyse and protect against dependent failures. Summary report of the Nordic Working Group on Common Cause Failure Analysis

International Nuclear Information System (INIS)

Johanson, Gunnar; Hellstroem, Per; Makamo, Tuomas; Bento, Jean-Pierre; Knochenhauer, Michael; Poern, Kurt

2003-10-01

The safety systems in Nordic nuclear power plants are characterised by substantial redundancy and/or diversification in safety critical functions, as well as by physical separation of critical safety systems, including their support functions. Viewed together with the evident additional fact, that the single failure criterion has been systematically applied in the design of safety systems, this means that the plant risk profile as calculated in existing PSA:s is usually strongly dominated by failures caused by dependencies resulting in the loss of more than one system sub. The overall objective with the working group is to support safety by studying potential and real CCF events, process statistical data and report conclusions and recommendations that can improve the understanding of these events eventually resulting in increased safety. The result is intended for application in NPP operation, maintenance, inspection and risk assessments. The NAFCS project is part of the activities of the Nordic PSA Group (NPSAG), and is financed jointly by the Nordic utilities and authorities. The work is divided into one quantitative and one qualitative part with the following specific objectives: Qualitative objectives-The goal with the qualitative analysis is to compile experience data and generate insights in terms of relevant failure mechanisms and effective CCF protection measures. The results shall be presented as a guide with checklists and recommendations on how to identify current CCF protection standard and improvement possibilities regarding CCF defences decreasing the CCF vulnerability. Quantitative objectives-The goal with the quantitative analysis is to prepare a Nordic C-book where quantitative insights as Impact Vectors and CCF parameters for different redundancy levels are presented. Uncertainties in CCF data shall be reduced as much as possible. The high redundancy systems sensitivity to CCF events demand a well structured quantitative analysis in support of

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

International Nuclear Information System (INIS)

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

1987-01-01

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-[ 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 14 CO 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 α 2 -adrenergic agonist

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

Energy Technology Data Exchange (ETDEWEB)

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.

Selective functional activity measurement of a PEGylated protein with a modification-dependent activity assay.

Science.gov (United States)

Weber, Alfred; Engelmaier, Andrea; Mohr, Gabriele; Haindl, Sonja; Schwarz, Hans Peter; Turecek, Peter L

2017-01-05

BAX 855 (ADYNOVATE) is a PEGylated recombinant factor VIII (rFVIII) that showed prolonged circulatory half-life compared to unmodified rFVIII in hemophilic patients. Here, the development and validation of a novel assay is described that selectively measures the activity of BAX 855 as cofactor for the serine protease factor IX, which actives factor X. This method type, termed modification-dependent activity assay, is based on PEG-specific capture of BAX 855 by an anti-PEG IgG preparation, followed by a chromogenic FVIII activity assay. The assay principle enabled sensitive measurement of the FVIII cofactor activity of BAX 855 down to the pM-range without interference by non-PEGylated FVIII. The selectivity of the capture step, shown by competition studies to primarily target the terminal methoxy group of PEG, also allowed assessment of the intactness of the attached PEG chains. Altogether, the modification-dependent activity not only enriches, but complements the group of methods to selectively, accurately, and precisely measure a PEGylated drug in complex biological matrices. In contrast to all other methods described so far, it allows measurement of the biological activity of the PEGylated protein. Data obtained demonstrate that this new method principle can be extended to protein modifications other than PEGylation and to a variety of functional activity assays. Copyright © 2016 Elsevier B.V. All rights reserved.

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

Science.gov (United States)

Hu, Xiaoyu; Huang, Fang; Szymusiak, Magdalena

2015-01-01

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

Going the distance: Memory and control processes in active dependency construction.

Science.gov (United States)

Wagers, Matthew W; Phillips, Colin

2014-01-01

Filler-gap dependencies make strong demands on working memory in language comprehension because they cannot always be immediately resolved. In a series of three reading-time studies, we test the idea that these demands can be decomposed into active maintenance processes and retrieval events. Results indicate that the fact that a displaced phrase exists and the identity of its basic syntactic category both immediately impact comprehension at potential gap sites. In contrast, specific lexical details of the displaced phrase show an immediate effect only for short dependencies and a much later effect for longer dependencies. We argue that coarse-grained information about the filler is actively maintained and is used to make phrase structure parsing decisions, whereas finer grained information is more quickly released from active maintenance and consequently has to be retrieved at the gap site.

Association between quantitative measures obtained using fluorescence-based methods and activity status of occlusal caries lesions in primary molars.

Science.gov (United States)

Novaes, Tatiane Fernandes; Reyes, Alessandra; Matos, Ronilza; Antunes-Pontes, Laura Regina; Marques, Renata Pereira de Samuel; Braga, Mariana Minatel; Diniz, Michele Baffi; Mendes, Fausto Medeiros

2017-05-01

Fluorescence-based methods (FBM) can add objectiveness to diagnosis strategy for caries. Few studies, however, have focused on the evaluation of caries activity. To evaluate the association between quantitative measures obtained with FBM, clinical parameters acquired from the patients, caries detection, and assessment of activity status in occlusal surfaces of primary molars. Six hundred and six teeth from 113 children (4-14 years) were evaluated. The presence of a biofilm, caries experience, and the number of active lesions were recorded. The teeth were assessed using FBM: DIAGNOdent pen (Lfpen) and Quantitative light-induced fluorescence (QLF). As reference standard, all teeth were evaluated using the ICDAS (International Caries Detection and Assessment System) associated with clinical activity assessments. Multilevel regressions compared the FBM values and evaluated the association between the FBM measures and clinical variables related to the caries activity. The measures from the FBM were higher in cavitated lesions. Only, ∆F values distinguished active and inactive lesions. The LFpen measures were higher in active lesions, at the cavitated threshold (56.95 ± 29.60). Following regression analyses, only the presence of visible biofilm on occlusal surfaces (adjusted prevalence ratio = 1.43) and ∆R values of the teeth (adjusted prevalence ratio = 1.02) were associated with caries activity. Some quantitative measures from FBM parameters are associated with caries activity evaluation, which is similar to the clinical evaluation of the presence of visible biofilm. © 2016 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Quantitative structure-activation barrier relationship modeling for Diels-Alder ligations utilizing quantum chemical structural descriptors.

Science.gov (United States)

Nandi, Sisir; Monesi, Alessandro; Drgan, Viktor; Merzel, Franci; Novič, Marjana

2013-10-30

In the present study, we show the correlation of quantum chemical structural descriptors with the activation barriers of the Diels-Alder ligations. A set of 72 non-catalysed Diels-Alder reactions were subjected to quantitative structure-activation barrier relationship (QSABR) under the framework of theoretical quantum chemical descriptors calculated solely from the structures of diene and dienophile reactants. Experimental activation barrier data were obtained from literature. Descriptors were computed using Hartree-Fock theory using 6-31G(d) basis set as implemented in Gaussian 09 software. Variable selection and model development were carried out by stepwise multiple linear regression methodology. Predictive performance of the quantitative structure-activation barrier relationship (QSABR) model was assessed by training and test set concept and by calculating leave-one-out cross-validated Q2 and predictive R2 values. The QSABR model can explain and predict 86.5% and 80% of the variances, respectively, in the activation energy barrier training data. Alternatively, a neural network model based on back propagation of errors was developed to assess the nonlinearity of the sought correlations between theoretical descriptors and experimental reaction barriers. A reasonable predictability for the activation barrier of the test set reactions was obtained, which enabled an exploration and interpretation of the significant variables responsible for Diels-Alder interaction between dienes and dienophiles. Thus, studies in the direction of QSABR modelling that provide efficient and fast prediction of activation barriers of the Diels-Alder reactions turn out to be a meaningful alternative to transition state theory based computation.

Quantitative PET of human urokinase-type plasminogen activator receptor with 64Cu-DOTA-AE105

DEFF Research Database (Denmark)

Persson, Morten; Madsen, Jacob; Østergaard, Søren

2012-01-01

Expression levels of the urokinase-type plasminogen activator receptor (uPAR) represent an established biomarker for poor prognosis in a variety of human cancers. The objective of the present study was to explore whether noninvasive PET can be used to perform a quantitative assessment of expressi...

Rapid and Quantitative Assay of Amyloid-Seeding Activity in Human Brains Affected with Prion Diseases.

Directory of Open Access Journals (Sweden)

Hanae Takatsuki

Full Text Available The infectious agents of the transmissible spongiform encephalopathies are composed of amyloidogenic prion protein, PrPSc. Real-time quaking-induced conversion can amplify very small amounts of PrPSc seeds in tissues/body fluids of patients or animals. Using this in vitro PrP-amyloid amplification assay, we quantitated the seeding activity of affected human brains. End-point assay using serially diluted brain homogenates of sporadic Creutzfeldt-Jakob disease patients demonstrated that 50% seeding dose (SD50 is reached approximately 10(10/g brain (values varies 10(8.79-10.63/g. A genetic case (GSS-P102L yielded a similar level of seeding activity in an autopsy brain sample. The range of PrPSc concentrations in the samples, determined by dot-blot assay, was 0.6-5.4 μg/g brain; therefore, we estimated that 1 SD50 unit was equivalent to 0.06-0.27 fg of PrPSc. The SD50 values of the affected brains dropped more than three orders of magnitude after autoclaving at 121°C. This new method for quantitation of human prion activity provides a new way to reduce the risk of iatrogenic prion transmission.

Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones

Directory of Open Access Journals (Sweden)

Reto Brun

2009-06-01

Full Text Available Prompted by results of our previous studies where we found high activity of some sesquiterpene lactones (STLs against Trypanosoma brucei rhodesiense (which causes East African sleeping sickness, we have now conducted a structure-(in-vitro-activity study on a set of 40 STLs against T. brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. Furthermore, cytotoxic activity against L6 rat skeletal myoblast cells was assessed. Some of the compounds possess high activity, especially against T. brucei (e.g. helenalin and some of its esters with IC50-values of 0.05-0.1 µM, which is about 10 times lower than their cytotoxic activity. It was found that all investigated antiprotozoal activities are significantly correlated with cytotoxicity and the major determinants for activity are a,b-unsaturated structural elements, also known to be essential for other biological activities of STLs. It was observed, however, that certain compounds are considerably more toxic against protozoa than against mammalian cells while others are more cytotoxic than active against the protozoa. A comparative QSAR analysis was therefore undertaken, in order to discern the antiparasitic activity of STLs against T. brucei and cytotoxicity. Both activities were found to depend to a large extent on the same structural elements and molecular properties. The observed variance in the biological data can be explained in terms of subtle variations in the relative influences of various molecular descriptors.

Frictional coefficient depending on active friction radius with BPV ...

African Journals Online (AJOL)

Frictional coefficient depending on active friction radius with BPV and BTV in automobile disc braking system. ... International Journal of Engineering, Science and Technology. Journal Home · ABOUT ... AJOL African Journals Online. HOW TO ...

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

Science.gov (United States)

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.

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

Science.gov (United States)

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)…

Fragment-based quantitative structure-activity relationship (FB-QSAR) for fragment-based drug design.

Science.gov (United States)

Du, Qi-Shi; Huang, Ri-Bo; Wei, Yu-Tuo; Pang, Zong-Wen; Du, Li-Qin; Chou, Kuo-Chen

2009-01-30

In cooperation with the fragment-based design a new drug design method, the so-called "fragment-based quantitative structure-activity relationship" (FB-QSAR) is proposed. The essence of the new method is that the molecular framework in a family of drug candidates are divided into several fragments according to their substitutes being investigated. The bioactivities of molecules are correlated with the physicochemical properties of the molecular fragments through two sets of coefficients in the linear free energy equations. One coefficient set is for the physicochemical properties and the other for the weight factors of the molecular fragments. Meanwhile, an iterative double least square (IDLS) technique is developed to solve the two sets of coefficients in a training data set alternately and iteratively. The IDLS technique is a feedback procedure with machine learning ability. The standard Two-dimensional quantitative structure-activity relationship (2D-QSAR) is a special case, in the FB-QSAR, when the whole molecule is treated as one entity. The FB-QSAR approach can remarkably enhance the predictive power and provide more structural insights into rational drug design. As an example, the FB-QSAR is applied to build a predictive model of neuraminidase inhibitors for drug development against H5N1 influenza virus. (c) 2008 Wiley Periodicals, Inc.

Power-dependent photocatalytic activity of ZnO

Energy Technology Data Exchange (ETDEWEB)

Chun, So Yeon; Han, Noh Soo; Jeong, Seong Hyun; Park, Seung Min; Song, Jae Kyu [Dept. of Chemistry, Kyung Hee University, Seoul (Korea, Republic of); Moon, Cheol Joo; Choi, Myong Yong [Dept. of Chemistry (BK21) and Research Institute of Natural Science, Gyeongsang NationalUniversity, Jinju (Korea, Republic of)

2017-03-15

the power-dependent photocatalytic activity of ZnO was examined for the photoreduction processes of Rh101 and AN in the presence of hole scavengers, where the fluorescence spectra were measured as a function of irradiation time and excitation intensity. The concentration of the reactants decreased, while the concentration of the products increased accordingly, which indicated the single-electron reduction process by electrons supplied from the conduction band of ZnO. Despite the single-electron process, the efficiency of the photoreaction depended nonlinearly on the excitation intensity, which was explained by the saturation of defect states in ZnO. The enhanced ratio of available electrons in ZnO led to a superlinear increase in the photoreduction efficiency, while the single-electron process linearly reflected the electrons available in ZnO.

Benefits of Exercise for the Quality of Life of Drug-Dependent Patients.

Science.gov (United States)

Giménez-Meseguer, Jorge; Tortosa-Martínez, Juan; de los Remedios Fernández-Valenciano, María

2015-01-01

This study combined quantitative and qualitative research methods to evaluate quality-of-life changes in drug-dependent patients after participation in a group-based exercise program. Quality of life (SF-36) and physical fitness (six-minute Walk Test, Timed Get Up and Go Test, and Chair Stand Test) were quantitatively determined in a group (n=37) of drug-dependent patients before and after a 12-week group exercise program (n=18) or routine care (n=19). Additionally, in-depth interviews were conducted at the end of the program with a subsample of 11 participants from the exercise group. Quantitative results showed improvements in fitness and different aspects of quality of life, such as physical function, mental health, vitality, social function, and general health perception. Qualitative results showed specific physical benefits (decreased injuries and muscle pain, decreased weight, and increased vitality with improvement in activities of daily living), psychological benefits (forgetting about everyday problems, improved mood, decreased stress and anxiety), social benefits, and a reduction in craving. The results of this study provide insight into the importance of exercise for the quality of life and recovery process of drug-dependent patients.

Quantitative assessment of motor functions post-stroke: Responsiveness of upper-extremity robotic measures and its task dependence.

Science.gov (United States)

Hussain, Asif; Budhota, Aamani; Contu, Sara; Kager, Simone; Vishwanath, Deshmukh A; Kuah, Christopher W K; Yam, Lester H L; Chua, Karen S G; Masia, Lorenzo; Campolo, Domenico

2017-07-01

Technology aided measures offer a sensitive, accurate and time-efflcient approach for the assessment of sensorimotor function after neurological impairment compared to standard clinical assessments. This preliminary study investigated the relationship between task definition and its effect on robotic measures using a planar, two degree of freedom, robotic-manipulator (H-Man). Four chronic stroke participants (49.5±11.95 years, 2 Female, FMA: 37.5±13.96) and eight healthy control participants (26.25± 4.70 years, 2 Female) participated in the study. Motor functions were evaluated using line tracing and circle tracing tasks with dominant and nondominant hand of healthy and affected vs. non affected hand of stroke participants. The results show significant dependence of quantitative measures on investigated tasks.

Abscisic acid-dependent multisite phosphorylation regulates the activity of a transcription activator AREB1

OpenAIRE

Furihata, Takashi; Maruyama, Kyonoshin; Fujita, Yasunari; Umezawa, Taishi; Yoshida, Riichiro; Shinozaki, Kazuo; Yamaguchi-Shinozaki, Kazuko

2006-01-01

bZIP-type transcription factors AREBs/ABFs bind an abscisic acid (ABA)-responsive cis-acting element named ABRE and transactivate downstream gene expression in Arabidopsis. Because AREB1 overexpression could not induce downstream gene expression, activation of AREB1 requires ABA-dependent posttranscriptional modification. We confirmed that ABA activated 42-kDa kinase activity, which, in turn, phosphorylated Ser/Thr residues of R-X-X-S/T sites in the conserved regions of AREB1. Amino acid subs...

Understanding Pre-Quantitative Risk in Projects

Science.gov (United States)

Cooper, Lynne P.

2011-01-01

Standard approaches to risk management in projects depend on the ability of teams to identify risks and quantify the probabilities and consequences of these risks (e.g., the 5 x 5 risk matrix). However, long before quantification does - or even can - occur, and long after, teams make decisions based on their pre-quantitative understanding of risk. These decisions can have long-lasting impacts on the project. While significant research has looked at the process of how to quantify risk, our understanding of how teams conceive of and manage pre-quantitative risk is lacking. This paper introduces the concept of pre-quantitative risk and discusses the implications of addressing pre-quantitative risk in projects.

Quantitative structure activity relationship (QSAR) of piperine analogs for bacterial NorA efflux pump inhibitors.

Science.gov (United States)

Nargotra, Amit; Sharma, Sujata; Koul, Jawahir Lal; Sangwan, Pyare Lal; Khan, Inshad Ali; Kumar, Ashwani; Taneja, Subhash Chander; Koul, Surrinder

2009-10-01

Quantitative structure activity relationship (QSAR) analysis of piperine analogs as inhibitors of efflux pump NorA from Staphylococcus aureus has been performed in order to obtain a highly accurate model enabling prediction of inhibition of S. aureus NorA of new chemical entities from natural sources as well as synthetic ones. Algorithm based on genetic function approximation method of variable selection in Cerius2 was used to generate the model. Among several types of descriptors viz., topological, spatial, thermodynamic, information content and E-state indices that were considered in generating the QSAR model, three descriptors such as partial negative surface area of the compounds, area of the molecular shadow in the XZ plane and heat of formation of the molecules resulted in a statistically significant model with r(2)=0.962 and cross-validation parameter q(2)=0.917. The validation of the QSAR models was done by cross-validation, leave-25%-out and external test set prediction. The theoretical approach indicates that the increase in the exposed partial negative surface area increases the inhibitory activity of the compound against NorA whereas the area of the molecular shadow in the XZ plane is inversely proportional to the inhibitory activity. This model also explains the relationship of the heat of formation of the compound with the inhibitory activity. The model is not only able to predict the activity of new compounds but also explains the important regions in the molecules in quantitative manner.

Quantitative traits and diversification.

Science.gov (United States)

FitzJohn, Richard G

2010-12-01

Quantitative traits have long been hypothesized to affect speciation and extinction rates. For example, smaller body size or increased specialization may be associated with increased rates of diversification. Here, I present a phylogenetic likelihood-based method (quantitative state speciation and extinction [QuaSSE]) that can be used to test such hypotheses using extant character distributions. This approach assumes that diversification follows a birth-death process where speciation and extinction rates may vary with one or more traits that evolve under a diffusion model. Speciation and extinction rates may be arbitrary functions of the character state, allowing much flexibility in testing models of trait-dependent diversification. I test the approach using simulated phylogenies and show that a known relationship between speciation and a quantitative character could be recovered in up to 80% of the cases on large trees (500 species). Consistent with other approaches, detecting shifts in diversification due to differences in extinction rates was harder than when due to differences in speciation rates. Finally, I demonstrate the application of QuaSSE to investigate the correlation between body size and diversification in primates, concluding that clade-specific differences in diversification may be more important than size-dependent diversification in shaping the patterns of diversity within this group.

Optimization of Bayesian Emission tomographic reconstruction for region of interest quantitation

International Nuclear Information System (INIS)

Qi, Jinyi

2003-01-01

Region of interest (ROI) quantitation is an important task in emission tomography (e.g., positron emission tomography and single photon emission computed tomography). It is essential for exploring clinical factors such as tumor activity, growth rate, and the efficacy of therapeutic interventions. Bayesian methods based on the maximum a posteriori principle (or called penalized maximum likelihood methods) have been developed for emission image reconstructions to deal with the low signal to noise ratio of the emission data. Similar to the filter cut-off frequency in the filtered backprojection method, the smoothing parameter of the image prior in Bayesian reconstruction controls the resolution and noise trade-off and hence affects ROI quantitation. In this paper we present an approach for choosing the optimum smoothing parameter in Bayesian reconstruction for ROI quantitation. Bayesian reconstructions are difficult to analyze because the resolution and noise properties are nonlinear and object-dependent. Building on the recent progress on deriving the approximate expressions for the local impulse response function and the covariance matrix, we derived simplied theoretical expressions for the bias, the variance, and the ensemble mean squared error (EMSE) of the ROI quantitation. One problem in evaluating ROI quantitation is that the truth is often required for calculating the bias. This is overcome by using ensemble distribution of the activity inside the ROI and computing the average EMSE. The resulting expressions allow fast evaluation of the image quality for different smoothing parameters. The optimum smoothing parameter of the image prior can then be selected to minimize the EMSE

Quantitation of fibroblast activation protein (FAP-specific protease activity in mouse, baboon and human fluids and organs

Directory of Open Access Journals (Sweden)

Fiona M. Keane

2014-01-01

Full Text Available The protease fibroblast activation protein (FAP is a specific marker of activated mesenchymal cells in tumour stroma and fibrotic liver. A specific, reliable FAP enzyme assay has been lacking. FAP's unique and restricted cleavage of the post proline bond was exploited to generate a new specific substrate to quantify FAP enzyme activity. This sensitive assay detected no FAP activity in any tissue or fluid of FAP gene knockout mice, thus confirming assay specificity. Circulating FAP activity was ∼20- and 1.3-fold less in baboon than in mouse and human plasma, respectively. Serum and plasma contained comparable FAP activity. In mice, the highest levels of FAP activity were in uterus, pancreas, submaxillary gland and skin, whereas the lowest levels were in brain, prostate, leukocytes and testis. Baboon organs high in FAP activity included skin, epididymis, bladder, colon, adipose tissue, nerve and tongue. FAP activity was greatly elevated in tumours and associated lymph nodes and in fungal-infected skin of unhealthy baboons. FAP activity was 14- to 18-fold greater in cirrhotic than in non-diseased human liver, and circulating FAP activity was almost doubled in alcoholic cirrhosis. Parallel DPP4 measurements concorded with the literature, except for the novel finding of high DPP4 activity in bile. The new FAP enzyme assay is the first to be thoroughly characterised and shows that FAP activity is measurable in most organs and at high levels in some. This new assay is a robust tool for specific quantitation of FAP enzyme activity in both preclinical and clinical samples, particularly liver fibrosis.

The effect of respiratory induced density variations on non-TOF PET quantitation in the lung

Science.gov (United States)

Holman, Beverley F.; Cuplov, Vesna; Hutton, Brian F.; Groves, Ashley M.; Thielemans, Kris

2016-04-01

Accurate PET quantitation requires a matched attenuation map. Obtaining matched CT attenuation maps in the thorax is difficult due to the respiratory cycle which causes both motion and density changes. Unlike with motion, little attention has been given to the effects of density changes in the lung on PET quantitation. This work aims to explore the extent of the errors caused by pulmonary density attenuation map mismatch on dynamic and static parameter estimates. Dynamic XCAT phantoms were utilised using clinically relevant 18F-FDG and 18F-FMISO time activity curves for all organs within the thorax to estimate the expected parameter errors. The simulations were then validated with PET data from 5 patients suffering from idiopathic pulmonary fibrosis who underwent PET/Cine-CT. The PET data were reconstructed with three gates obtained from the Cine-CT and the average Cine-CT. The lung TACs clearly displayed differences between true and measured curves with error depending on global activity distribution at the time of measurement. The density errors from using a mismatched attenuation map were found to have a considerable impact on PET quantitative accuracy. Maximum errors due to density mismatch were found to be as high as 25% in the XCAT simulation. Differences in patient derived kinetic parameter estimates and static concentration between the extreme gates were found to be as high as 31% and 14%, respectively. Overall our results show that respiratory associated density errors in the attenuation map affect quantitation throughout the lung, not just regions near boundaries. The extent of this error is dependent on the activity distribution in the thorax and hence on the tracer and time of acquisition. Consequently there may be a significant impact on estimated kinetic parameters throughout the lung.

The effect of respiratory induced density variations on non-TOF PET quantitation in the lung

International Nuclear Information System (INIS)

Holman, Beverley F; Cuplov, Vesna; Hutton, Brian F; Groves, Ashley M; Thielemans, Kris

2016-01-01

Accurate PET quantitation requires a matched attenuation map. Obtaining matched CT attenuation maps in the thorax is difficult due to the respiratory cycle which causes both motion and density changes. Unlike with motion, little attention has been given to the effects of density changes in the lung on PET quantitation. This work aims to explore the extent of the errors caused by pulmonary density attenuation map mismatch on dynamic and static parameter estimates. Dynamic XCAT phantoms were utilised using clinically relevant 18 F-FDG and 18 F-FMISO time activity curves for all organs within the thorax to estimate the expected parameter errors. The simulations were then validated with PET data from 5 patients suffering from idiopathic pulmonary fibrosis who underwent PET/Cine-CT. The PET data were reconstructed with three gates obtained from the Cine-CT and the average Cine-CT. The lung TACs clearly displayed differences between true and measured curves with error depending on global activity distribution at the time of measurement. The density errors from using a mismatched attenuation map were found to have a considerable impact on PET quantitative accuracy. Maximum errors due to density mismatch were found to be as high as 25% in the XCAT simulation. Differences in patient derived kinetic parameter estimates and static concentration between the extreme gates were found to be as high as 31% and 14%, respectively. Overall our results show that respiratory associated density errors in the attenuation map affect quantitation throughout the lung, not just regions near boundaries. The extent of this error is dependent on the activity distribution in the thorax and hence on the tracer and time of acquisition. Consequently there may be a significant impact on estimated kinetic parameters throughout the lung. (paper)

Quantitative Method of Measuring Metastatic Activity

Science.gov (United States)

Morrison, Dennis R. (Inventor)

1999-01-01

The metastatic potential of tumors can be evaluated by the quantitative detection of urokinase and DNA. The cell sample selected for examination is analyzed for the presence of high levels of urokinase and abnormal DNA using analytical flow cytometry and digital image analysis. Other factors such as membrane associated uroldnase, increased DNA synthesis rates and certain receptors can be used in the method for detection of potentially invasive tumors.

A Review of Recent Advances towards the Development of (Quantitative) Structure-Activity Relationships for Metallic Nanomaterials.

NARCIS (Netherlands)

Chen, Guangchao; Vijver, Martina G; Xiao, Yinlong; Peijnenburg, Willie J G M

2017-01-01

Gathering required information in a fast and inexpensive way is essential for assessing the risks of engineered nanomaterials (ENMs). The extension of conventional (quantitative) structure-activity relationships ((Q)SARs) approach to nanotoxicology, i.e., nano-(Q)SARs, is a possible solution. The

Network-dependent modulation of brain activity during sleep.

Science.gov (United States)

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. Copyright © 2014 Elsevier Inc. All rights reserved.

Antimicrobial activity of Algerian propolis in foodborne pathogens and its quantitative chemical composition

Directory of Open Access Journals (Sweden)

Neila Nedji

2014-12-01

Full Text Available Objective: To evaluate the antimicrobial activity of propolis samples collected from different regions of Algeria and their chemical composition. Methods: The antibacterial activity of ethanolic extract of Algerian propolis against Bacillus cereus (IPA, Staphylococcus aureus (ATCC25923R, Escherichia coli (ATCC25922 and Pseudomonas aeruginosa (ATCC27893R was evaluated by the disc diffusion method and determined as an equivalent of the inhibition zones diameters after incubation of the cultures at 37 °C for 24 h. The investigation of the polyphenol and flavonoid contents was done spectrophotometrically. Results: The ethanolic extract of Algerian propolis samples inhibited the growth of all examined microorganisms with the highest antimicrobial activity against the Gram-positive bacteria. Polyphenol and flavonoids contents were variable, depending on the propolis samples and a positive correlation between antimicrobial activity and chemical composition was observed. Conclusions: Antimicrobial activity, polyphenol and flavonoid contents were variable, depending on the propolis sample. The strong antimicrobial activity of Algerian propolis may be due to high total phenolic and flavonoid contents and this study suggests potential use of propolis in foods.

Quantitative Characterization of Major Hepatic UDP-Glucuronosyltransferase Enzymes in Human Liver Microsomes: Comparison of Two Proteomic Methods and Correlation with Catalytic Activity.

Science.gov (United States)

Achour, Brahim; Dantonio, Alyssa; Niosi, Mark; Novak, Jonathan J; Fallon, John K; Barber, Jill; Smith, Philip C; Rostami-Hodjegan, Amin; Goosen, Theunis C

2017-10-01

Quantitative characterization of UDP-glucuronosyltransferase (UGT) enzymes is valuable in glucuronidation reaction phenotyping, predicting metabolic clearance and drug-drug interactions using extrapolation exercises based on pharmacokinetic modeling. Different quantitative proteomic workflows have been employed to quantify UGT enzymes in various systems, with reports indicating large variability in expression, which cannot be explained by interindividual variability alone. To evaluate the effect of methodological differences on end-point UGT abundance quantification, eight UGT enzymes were quantified in 24 matched liver microsomal samples by two laboratories using stable isotope-labeled (SIL) peptides or quantitative concatemer (QconCAT) standard, and measurements were assessed against catalytic activity in seven enzymes ( n = 59). There was little agreement between individual abundance levels reported by the two methods; only UGT1A1 showed strong correlation [Spearman rank order correlation (Rs) = 0.73, P quantitative proteomic data should be validated against catalytic activity whenever possible. In addition, metabolic reaction phenotyping exercises should consider spurious abundance-activity correlations to avoid misleading conclusions. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Physical activity moderates the association between nicotine dependence and depression among U.S. smokers.

Science.gov (United States)

Loprinzi, Paul D; Walker, Jerome F; Kane, Christy; Cardinal, Bradley J

2014-01-01

Research demonstrates that nicotine dependence and depression are associated and that physical activity is effective in reducing depression symptoms. However, our understanding of the potential beneficial effects of physical activity on depression in current smokers is more limited. The purpose of this study was to examine whether physical activity moderates the association between nicotine dependence and depression in U.S. smokers. Cross-sectional. National Health and Nutrition Examination Survey 2005-2006. Four hundred forty-one current adult smokers. Participants wore an accelerometer for at least 4 days and completed questionnaires to assess nicotine dependence and depression. Effect modification and statistical interaction models were used. Both models were significant. With regard to the statistical interaction model, and after controlling for age, gender, race/ethnicity, education, comorbidity index, homocysteine, cotinine, total cholesterol, sedentary behavior, and vitamins C, D, and E, objectively measured physical activity moderated the association between nicotine dependence and depression (interaction variable: odds ratio = 3.43; 95% confidence interval: 1.02-11.51; p = .04). In this national sample of current smokers, physical activity moderated the association between nicotine dependence and depression. These results suggest that those individuals with nicotine dependence and who are less physically active are more likely to be depressed than what would be expected on the basis of the individual effects of nicotine and physical inactivity separately.

Dependency Defence and Dependency Analysis Guidance. Volume 1: Summary and Guidance (Appendix 1-2). How to analyse and protect against dependent failures. Summary report of the Nordic Working group on Common Cause Failure Analysis

International Nuclear Information System (INIS)

Johanson, Gunnar; Hellstroem, Per; Makamo, Tuomas; Bento, Jean-Pierre; Knochenhauer, Michael; Poern, Kurt

2003-10-01

The safety systems in Nordic nuclear power plants are characterised by substantial redundancy and/or diversification in safety critical functions, as well as by physical separation of critical safety systems, including their support functions. Viewed together with the evident additional fact, that the single failure criterion has been systematically applied in the design of safety systems, this means that the plant risk profile as calculated in existing PSA:s is usually strongly dominated by failures caused by dependencies resulting in the loss of more than one system sub. The overall objective with the working group is to support safety by studying potential and real CCF events, process statistical data and report conclusions and recommendations that can improve the understanding of these events eventually resulting in increased safety. The result is intended for application in NPP operation, maintenance, inspection and risk assessments. The NAFCS project is part of the activities of the Nordic PSA Group (NPSAG), and is financed jointly by the Nordic utilities and authorities. The work is divided into one quantitative and one qualitative part with the following specific objectives: Qualitative objectives-The goal with the qualitative analysis is to compile experience data and generate insights in terms of relevant failure mechanisms and effective CCF protection measures. The results shall be presented as a guide with checklists and recommendations on how to identify current CCF protection standard and improvement possibilities regarding CCF defences decreasing the CCF vulnerability. Quantitative objectives-The goal with the quantitative analysis is to prepare a Nordic C-book where quantitative insights as Impact Vectors and CCF parameters for different redundancy levels are presented. Uncertainties in CCF data shall be reduced as much as possible. The high redundancy systems sensitivity to CCF events demand a well structured quantitative analysis in support of

Design of cinnamaldehyde amino acid Schiff base compounds based on the quantitative structure–activity relationship

Science.gov (United States)

Hui Wang; Mingyue Jiang; Shujun Li; Chung-Yun Hse; Chunde Jin; Fangli Sun; Zhuo Li

2017-01-01

Cinnamaldehyde amino acid Schiff base (CAAS) is a new class of safe, bioactive compounds which could be developed as potential antifungal agents for fungal infections. To design new cinnamaldehyde amino acid Schiff base compounds with high bioactivity, the quantitative structure–activity relationships (QSARs) for CAAS compounds against Aspergillus niger (A. niger) and...

A framework for the quantitative assessment of climate change impacts on water-related activities at the basin scale

OpenAIRE

Anghileri, D.; Pianosi, F.; Soncini-Sessa, R.

2011-01-01

While quantitative assessment of the climate change impact on hydrology at the basin scale is quite addressed in the literature, extension of quantitative analysis to impact on the ecological, economic and social sphere is still limited, although well recognized as a key issue to support water resource planning and promote public participation. In this paper we propose a framework for assessing climate change impact on water-related activities at the basin scale. The specific features of our ...

Quantitation in planar renal scintigraphy: which μ value should be used?

International Nuclear Information System (INIS)

Hindie, E.; Jeanguillaume, C.; Galle, P.; Prigent, A.

1999-01-01

The attenuation coefficient value μ used by different authors for quantitation in planar renal scintigraphy varies greatly, from the theoretical value of 0.153 cm -1 (appropriate for scatter-free data) down to 0.099 cm -1 (empirical value assumed to compensate for both scatter and attenuation). For a 6-cm-deep kidney, such variations introduce up to 30% differences in absolute measurement of kidney activity. Using technetium-99m phantom studies, we determined the μ values that would yield accurate kidney activity quantitation for different energy windows corresponding to different amounts of scatter, and when using different image analysis approaches similar to those used in renal quantitation. With the 20% energy window, it was found that the μ value was strongly dependent on the size of the region of interest (ROI) and on whether background subtraction was performed: the μ value thus varied from 0.119 cm -1 (loose ROI, no background subtraction) to 0.150 cm -1 (kidney ROI and background subtraction). When using data from an energy window that could be considered scatter-free, the μ value became almost independent of the image analysis scheme. It is concluded that: (1) when performing background subtraction, which implicitly reduces the effect of scatter, the μ value to be used for accurate quantitation is close to the theoretical μ value; (2) if the acquired data were initially corrected for scatter, the appropriate μ value would then be the theoretical μ value, whatever the image analysis scheme. (orig.)

Online Activity Levels Are Related to Caffeine Dependency.

Science.gov (United States)

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.

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

Science.gov (United States)

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…

Neural electrical activity and neural network growth.

Science.gov (United States)

Gafarov, F M

2018-05-01

The development of central and peripheral neural system depends in part on the emergence of the correct functional connectivity in its input and output pathways. Now it is generally accepted that molecular factors guide neurons to establish a primary scaffold that undergoes activity-dependent refinement for building a fully functional circuit. However, a number of experimental results obtained recently shows that the neuronal electrical activity plays an important role in the establishing of initial interneuronal connections. Nevertheless, these processes are rather difficult to study experimentally, due to the absence of theoretical description and quantitative parameters for estimation of the neuronal activity influence on growth in neural networks. In this work we propose a general framework for a theoretical description of the activity-dependent neural network growth. The theoretical description incorporates a closed-loop growth model in which the neural activity can affect neurite outgrowth, which in turn can affect neural activity. We carried out the detailed quantitative analysis of spatiotemporal activity patterns and studied the relationship between individual cells and the network as a whole to explore the relationship between developing connectivity and activity patterns. The model, developed in this work will allow us to develop new experimental techniques for studying and quantifying the influence of the neuronal activity on growth processes in neural networks and may lead to a novel techniques for constructing large-scale neural networks by self-organization. Copyright © 2018 Elsevier Ltd. All rights reserved.

Induced mutations for quantitative traits in rice

International Nuclear Information System (INIS)

Chakrabarti, B.N.

1974-01-01

The characteristics and frequency of micro-mutations induced in quantitative traits by radiation treatment and the extent of heterozygotic effects of different recessive chlorophyll-mutant-genes on quantitative trait has been presented. Mutagenic treatments increased the variance for quantitative traits in all cases although the magnitude of increase varied depending on the treatment and the selection procedure adopted. The overall superiority of the chlorophyll-mutant heterozygotes over the corresponding wild homozygotes, as noted in consecutive two seasons, was not observed when these were grown at a high level of nitrogen fertiliser. (author)

Activity-Dependent Plasticity of Spike Pauses in Cerebellar Purkinje Cells

Directory of Open Access Journals (Sweden)

Giorgio Grasselli

2016-03-01

Full Text Available The plasticity of intrinsic excitability has been described in several types of neurons, but the significance of non-synaptic mechanisms in brain plasticity and learning remains elusive. Cerebellar Purkinje cells are inhibitory neurons that spontaneously fire action potentials at high frequencies and regulate activity in their target cells in the cerebellar nuclei by generating a characteristic spike burst-pause sequence upon synaptic activation. Using patch-clamp recordings from mouse Purkinje cells, we find that depolarization-triggered intrinsic plasticity enhances spike firing and shortens the duration of spike pauses. Pause plasticity is absent from mice lacking SK2-type potassium channels (SK2−/− mice and in occlusion experiments using the SK channel blocker apamin, while apamin wash-in mimics pause reduction. Our findings demonstrate that spike pauses can be regulated through an activity-dependent, exclusively non-synaptic, SK2 channel-dependent mechanism and suggest that pause plasticity—by altering the Purkinje cell output—may be crucial to cerebellar information storage and learning.

Statistical mechanics and the evolution of polygenic quantitative traits

NARCIS (Netherlands)

Barton, N.H.; De Vladar, H.P.

The evolution of quantitative characters depends on the frequencies of the alleles involved, yet these frequencies cannot usually be measured. Previous groups have proposed an approximation to the dynamics of quantitative traits, based on an analogy with statistical mechanics. We present a modified

Constructing bioactive peptides with pH-dependent activities.

Science.gov (United States)

Tu, Zhigang; Volk, Melanie; Shah, Khushali; Clerkin, Kevin; Liang, Jun F

2009-08-01

Many bioactive peptides are featured by their arginine and lysine rich contents. In this study, lysine and arginine residues in lytic peptides were selectively replaced by histidines. Although resulting histidine-containing lytic peptides had decreased activity, they did show pH-dependent cytotoxicity. The activity of the constructed histidine-containing lytic peptides increased 2-8 times as the solution pH changed from 7.4 to 5.5. More importantly, these histidine-containing peptides maintain the same cell killing mechanism as their parent peptides by causing cell lysis. Both the activity and pH-sensitivity of histidine-containing peptides are tunable by adjusting histidine substitution numbers and positions. This study has presented a general strategy to create bioactive peptides with desired pH-sensitivity to meet the needs of various applications such as cancer treatments.

Profiling Y561-dependent and -independent substrates of CSF-1R in epithelial cells.

Directory of Open Access Journals (Sweden)

Melodie L Knowlton

2010-10-01

Full Text Available Receptor tyrosine kinases (RTKs activate multiple downstream cytosolic tyrosine kinases following ligand stimulation. SRC family kinases (SFKs, which are recruited to activated RTKs through SH2 domain interactions with RTK autophosphorylation sites, are targets of many subfamilies of RTKs. To date, there has not been a systematic analysis of the downstream substrates of such receptor-activated SFKs. Here, we conducted quantitative mass spectrometry utilizing stable isotope labeling (SILAC analysis to profile candidate SRC-substrates induced by the CSF-1R tyrosine kinase by comparing the phosphotyrosine-containing peptides from cells expressing either CSF-1R or a mutant form of this RTK that is unable to bind to SFKs. This analysis identified previously uncharacterized changes in tyrosine phosphorylation induced by CSF-1R in mammary epithelial cells as well as a set of candidate substrates dependent on SRC recruitment to CSF-1R. Many of these candidates may be direct SRC targets as the amino acids flanking the phosphorylation sites in these proteins are similar to known SRC kinase phosphorylation motifs. The putative SRC-dependent proteins include known SRC substrates as well as previously unrecognized SRC targets. The collection of substrates includes proteins involved in multiple cellular processes including cell-cell adhesion, endocytosis, and signal transduction. Analyses of phosphoproteomic data from breast and lung cancer patient samples identified a subset of the SRC-dependent phosphorylation sites as being strongly correlated with SRC activation, which represent candidate markers of SRC activation downstream of receptor tyrosine kinases in human tumors. In summary, our data reveal quantitative site-specific changes in tyrosine phosphorylation induced by CSF-1R activation in epithelial cells and identify many candidate SRC-dependent substrates phosphorylated downstream of an RTK.

Are quantitative trait-dependent sampling designs cost-effective for analysis of rare and common variants?

Science.gov (United States)

Yilmaz, Yildiz E; Bull, Shelley B

2011-11-29

Use of trait-dependent sampling designs in whole-genome association studies of sequence data can reduce total sequencing costs with modest losses of statistical efficiency. In a quantitative trait (QT) analysis of data from the Genetic Analysis Workshop 17 mini-exome for unrelated individuals in the Asian subpopulation, we investigate alternative designs that sequence only 50% of the entire cohort. In addition to a simple random sampling design, we consider extreme-phenotype designs that are of increasing interest in genetic association analysis of QTs, especially in studies concerned with the detection of rare genetic variants. We also evaluate a novel sampling design in which all individuals have a nonzero probability of being selected into the sample but in which individuals with extreme phenotypes have a proportionately larger probability. We take differential sampling of individuals with informative trait values into account by inverse probability weighting using standard survey methods which thus generalizes to the source population. In replicate 1 data, we applied the designs in association analysis of Q1 with both rare and common variants in the FLT1 gene, based on knowledge of the generating model. Using all 200 replicate data sets, we similarly analyzed Q1 and Q4 (which is known to be free of association with FLT1) to evaluate relative efficiency, type I error, and power. Simulation study results suggest that the QT-dependent selection designs generally yield greater than 50% relative efficiency compared to using the entire cohort, implying cost-effectiveness of 50% sample selection and worthwhile reduction of sequencing costs.

Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation

International Nuclear Information System (INIS)

Park, Jeong Su; Kang, Dong Hoon; Lee, Da Hyun; Bae, Soo Han

2015-01-01

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

Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation

Energy Technology Data Exchange (ETDEWEB)

Park, Jeong Su [Severance Biomedical Science Institute (Korea, Republic of); Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Kang, Dong Hoon [Department of Life Science and Ewha Research Center for Systems Biology (Korea, Republic of); The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750 (Korea, Republic of); Lee, Da Hyun [Severance Biomedical Science Institute (Korea, Republic of); Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Bae, Soo Han, E-mail: soohanbae@yuhs.ac [Severance Biomedical Science Institute (Korea, Republic of); Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of)

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.

Quantitative functional scintigraphy of the salivary glands: A new method of interpreting and clinical results

International Nuclear Information System (INIS)

Schneider, P.; Trauring, G.; Haas, J.P.; Noodt, A.; Draf, W.

1984-01-01

Tc-99m pertechnetate is injected i.v. and the kinetics of the tracer in the salivary glands is analyzed using a gamma camera and a computer system. To visualize regional gland function, phase images as well as socalled gradient images are generated, which reflect the rate of tracer inflow and outflow. The time activity curves for the individual glands which are obtained with the ROI technique show an initial rise which reflects the pertechnetate uptake potential of the gland and is superimposed by background activity. After a standardized lemon juice dose the curve drops steeply, with the slope depending on the outflow potential of the gland and the background activity. In the past, attempts at quantifying the uptake and elimination functions have failed because of problems in allowing for the variable background component of the time activity curves, which normally amounts of about 60%. In 25 patients in whom one gland had been removed surgically the background activity was examined in terms of the time course and the regional pattern and a patient and gland-specific subtraction method was developed for visualizing the time activity curves of isolated glands devoid of any background activity and describing the uptake and elimination potentials in quantitative terms. Using this new method we evaluated 305 salivary gland scans. Normal ranges for the quantitative parameters were established and their reproducibility was examined. Unlike qualitative functional images of the salivary glands the new quantitative method offers accurate evidence of the extent of gland function and thus helps to decide wether a gland should be salvaged or not (conservative versus surgical treatment). However, quantitation does not furnish any clues on the benign or malignant nature of a tumor. (Author)

Striatal activation and frontostriatal connectivity during non-drug reward anticipation in alcohol dependence.

Science.gov (United States)

Becker, Alena; Kirsch, Martina; Gerchen, Martin Fungisai; Kiefer, Falk; Kirsch, Peter

2017-05-01

According to prevailing neurobiological theories of addiction, altered function in neural reward circuitry is a central mechanism of alcohol dependence. Growing evidence postulates that the ventral striatum (VS), as well as areas of the prefrontal cortex, contribute to the increased incentive salience of alcohol-associated cues, diminished motivation to pursue non-drug rewards and weakened strength of inhibitory cognitive control, which are central to addiction. The present study aims to investigate the neural response and functional connectivity underlying monetary, non-drug reward processing in alcohol dependence. We utilized a reward paradigm to investigate the anticipation of monetary reward in 32 alcohol-dependent inpatients and 35 healthy controls. Functional magnetic resonance imaging was used to measure task-related brain activation and connectivity. Alcohol-dependent patients showed increased activation of the VS during anticipation of monetary gain compared with healthy controls. Generalized psychophysiological interaction analyses revealed decreased functional connectivity between the VS and the dorsolateral prefrontal cortex in alcohol dependent patients relative to controls. Increased activation of the VS and reduced frontostriatal connectivity were associated with increased craving. These findings provide evidence that alcohol dependence is rather associated with disrupted integration of striatal and prefrontal processes than with a global reward anticipation deficit. © 2016 Society for the Study of Addiction.

Blood lactate clearance after maximal exercise depends on active recovery intensity.

Science.gov (United States)

Devlin, J; Paton, B; Poole, L; Sun, W; Ferguson, C; Wilson, J; Kemi, O J

2014-06-01

High-intensity exercise is time-limited by onset of fatigue, marked by accumulation of blood lactate. This is accentuated at maximal, all-out exercise that rapidly accumulates high blood lactate. The optimal active recovery intensity for clearing lactate after such maximal, all-out exercise remains unknown. Thus, we studied the intensity-dependence of lactate clearance during active recovery after maximal exercise. We constructed a standardized maximal, all-out treadmill exercise protocol that predictably lead to voluntary exhaustion and blood lactate concentration>10 mM. Next, subjects ran series of all-out bouts that increased blood lactate concentration to 11.5±0.2 mM, followed by recovery exercises ranging 0% (passive)-100% of the lactate threshold. Repeated measurements showed faster lactate clearance during active versus passive recovery (P40%>passive recovery, Pexercise clears accumulated blood lactate faster than passive recovery in an intensity-dependent manner, with maximum clearance occurring at active recovery of 80% of lactate threshold.

Quantitative structure-activity relationship modeling of the toxicity of organothiophosphate pesticides to Daphnia magna and Cyprinus carpio

NARCIS (Netherlands)

Zvinavashe, E.; Du, T.; Griff, T.; Berg, van den J.H.J.; Soffers, A.E.M.F.; Vervoort, J.J.M.; Murk, A.J.; Rietjens, I.

2009-01-01

Within the REACH regulatory framework in the EU, quantitative structure-activity relationships (QSAR) models are expected to help reduce the number of animals used for experimental testing. The objective of this study was to develop QSAR models to describe the acute toxicity of organothiophosphate

The profile of quantitative risk indicators in Krsko NPP

International Nuclear Information System (INIS)

Vrbanic, I.; Basic, I.; Bilic-Zabric, T.; Spiler, J.

2004-01-01

During the past decade strong initiative was observed which was aimed at incorporating information on risk into various aspects of operation of nuclear power plants. The initiative was observable in activities carried out by regulators as well as utilities and industry. It resulted in establishing the process, or procedure, which is often referred to as integrated decision making or risk informed decision making. In this process, engineering analyses and evaluations that are usually termed traditional and that rely on considerations of safety margins and defense in depth are supplemented by quantitative indicators of risk. Throughout the process, the plant risk was most commonly expressed in terms of likelihood of events involving damage to the reactor core and events with radiological releases to the environment. These became two commonly used quantitative indicators or metrics of plant risk (or, reciprocally, plant safety). They were evaluated for their magnitude (e.g. the expected number of events per specified time interval), as well as their profile (e.g. the types of contributing events). The information for quantitative risk indicators (to be used in risk informing process) is obtained from plant's probabilistic safety analyses or analyses of hazards. It is dependable on issues such as availability of input data or quality of model or analysis. Nuclear power plant Krsko has recently performed Periodic Safety Review, which was a good opportunity to evaluate and integrate the plant specific information on quantitative plant risk indicators and their profile. The paper discusses some aspects of quantitative plant risk profile and its perception.(author)

Improving quantitative structure-activity relationship models using Artificial Neural Networks trained with dropout.

Science.gov (United States)

Mendenhall, Jeffrey; Meiler, Jens

2016-02-01

Dropout is an Artificial Neural Network (ANN) training technique that has been shown to improve ANN performance across canonical machine learning (ML) datasets. Quantitative Structure Activity Relationship (QSAR) datasets used to relate chemical structure to biological activity in Ligand-Based Computer-Aided Drug Discovery pose unique challenges for ML techniques, such as heavily biased dataset composition, and relatively large number of descriptors relative to the number of actives. To test the hypothesis that dropout also improves QSAR ANNs, we conduct a benchmark on nine large QSAR datasets. Use of dropout improved both enrichment false positive rate and log-scaled area under the receiver-operating characteristic curve (logAUC) by 22-46 % over conventional ANN implementations. Optimal dropout rates are found to be a function of the signal-to-noise ratio of the descriptor set, and relatively independent of the dataset. Dropout ANNs with 2D and 3D autocorrelation descriptors outperform conventional ANNs as well as optimized fingerprint similarity search methods.

Identification and quantitation of signal molecule-dependent protein phosphorylation

KAUST Repository

Groen, Arnoud J.

2013-09-03

Phosphoproteomics is a fast-growing field that aims at characterizing phosphorylated proteins in a cell or a tissue at a given time. Phosphorylation of proteins is an important regulatory mechanism in many cellular processes. Gel-free phosphoproteome technique involving enrichment of phosphopeptide coupled with mass spectrometry has proven to be invaluable to detect and characterize phosphorylated proteins. In this chapter, a gel-free quantitative approach involving 15N metabolic labelling in combination with phosphopeptide enrichment by titanium dioxide (TiO2) and their identification by MS is described. This workflow can be used to gain insights into the role of signalling molecules such as cyclic nucleotides on regulatory networks through the identification and quantification of responsive phospho(proteins). © Springer Science+Business Media New York 2013.

QUAIL: A Quantitative Security Analyzer for Imperative Code

DEFF Research Database (Denmark)

Biondi, Fabrizio; Wasowski, Andrzej; Traonouez, Louis-Marie

2013-01-01

Quantitative security analysis evaluates and compares how effectively a system protects its secret data. We introduce QUAIL, the first tool able to perform an arbitrary-precision quantitative analysis of the security of a system depending on private information. QUAIL builds a Markov Chain model...... of the system’s behavior as observed by an attacker, and computes the correlation between the system’s observable output and the behavior depending on the private information, obtaining the expected amount of bits of the secret that the attacker will infer by observing the system. QUAIL is able to evaluate...... the safety of randomized protocols depending on secret data, allowing to verify a security protocol’s effectiveness. We experiment with a few examples and show that QUAIL’s security analysis is more accurate and revealing than results of other tools...

Validation of Quantitative Structure-Activity Relationship (QSAR Model for Photosensitizer Activity Prediction

Directory of Open Access Journals (Sweden)

Sharifuddin M. Zain

2011-11-01

Full Text Available Photodynamic therapy is a relatively new treatment method for cancer which utilizes a combination of oxygen, a photosensitizer and light to generate reactive singlet oxygen that eradicates tumors via direct cell-killing, vasculature damage and engagement of the immune system. Most of photosensitizers that are in clinical and pre-clinical assessments, or those that are already approved for clinical use, are mainly based on cyclic tetrapyrroles. In an attempt to discover new effective photosensitizers, we report the use of the quantitative structure-activity relationship (QSAR method to develop a model that could correlate the structural features of cyclic tetrapyrrole-based compounds with their photodynamic therapy (PDT activity. In this study, a set of 36 porphyrin derivatives was used in the model development where 24 of these compounds were in the training set and the remaining 12 compounds were in the test set. The development of the QSAR model involved the use of the multiple linear regression analysis (MLRA method. Based on the method, r2 value, r2 (CV value and r2 prediction value of 0.87, 0.71 and 0.70 were obtained. The QSAR model was also employed to predict the experimental compounds in an external test set. This external test set comprises 20 porphyrin-based compounds with experimental IC50 values ranging from 0.39 µM to 7.04 µM. Thus the model showed good correlative and predictive ability, with a predictive correlation coefficient (r2 prediction for external test set of 0.52. The developed QSAR model was used to discover some compounds as new lead photosensitizers from this external test set.

Phospho-dependent Accumulation of GABABRs at Presynaptic Terminals after NMDAR Activation.

Science.gov (United States)

Hannan, Saad; Gerrow, Kim; Triller, Antoine; Smart, Trevor G

2016-08-16

Here, we uncover a mechanism for regulating the number of active presynaptic GABAB receptors (GABABRs) at nerve terminals, an important determinant of neurotransmitter release. We find that GABABRs gain access to axon terminals by lateral diffusion in the membrane. Their relative accumulation is dependent upon agonist activation and the presence of the two distinct sushi domains that are found only in alternatively spliced GABABR1a subunits. Following brief activation of NMDA receptors (NMDARs) using glutamate, GABABR diffusion is reduced, causing accumulation at presynaptic terminals in a Ca(2+)-dependent manner that involves phosphorylation of GABABR2 subunits at Ser783. This signaling cascade indicates how synaptically released glutamate can initiate, via a feedback mechanism, increased levels of presynaptic GABABRs that limit further glutamate release and excitotoxicity. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Joint reconstruction of activity and attenuation in Time-of-Flight PET: A Quantitative Analysis.

Science.gov (United States)

Rezaei, Ahmadreza; Deroose, Christophe M; Vahle, Thomas; Boada, Fernando; Nuyts, Johan

2018-03-01

Joint activity and attenuation reconstruction methods from time of flight (TOF) positron emission tomography (PET) data provide an effective solution to attenuation correction when no (or incomplete/inaccurate) information on the attenuation is available. One of the main barriers limiting their use in clinical practice is the lack of validation of these methods on a relatively large patient database. In this contribution, we aim at validating the activity reconstructions of the maximum likelihood activity reconstruction and attenuation registration (MLRR) algorithm on a whole-body patient data set. Furthermore, a partial validation (since the scale problem of the algorithm is avoided for now) of the maximum likelihood activity and attenuation reconstruction (MLAA) algorithm is also provided. We present a quantitative comparison of the joint reconstructions to the current clinical gold-standard maximum likelihood expectation maximization (MLEM) reconstruction with CT-based attenuation correction. Methods: The whole-body TOF-PET emission data of each patient data set is processed as a whole to reconstruct an activity volume covering all the acquired bed positions, which helps to reduce the problem of a scale per bed position in MLAA to a global scale for the entire activity volume. Three reconstruction algorithms are used: MLEM, MLRR and MLAA. A maximum likelihood (ML) scaling of the single scatter simulation (SSS) estimate to the emission data is used for scatter correction. The reconstruction results are then analyzed in different regions of interest. Results: The joint reconstructions of the whole-body patient data set provide better quantification in case of PET and CT misalignments caused by patient and organ motion. Our quantitative analysis shows a difference of -4.2% (±2.3%) and -7.5% (±4.6%) between the joint reconstructions of MLRR and MLAA compared to MLEM, averaged over all regions of interest, respectively. Conclusion: Joint activity and attenuation

Neuromodulation of activity-dependent synaptic enhancement at crayfish neuromuscular junction.

Science.gov (United States)

Qian, S M; Delaney, K R

1997-10-17

decay of ADSE by 5-HT was not accompanied by significant changes in the initial amplitude of activity-dependent components of enhancement 1.5 s after the train. Measurements of presynaptic [Ca2+] indicated that the time course of Ca2+ removal from the presynaptic terminals after trains was not altered by 5-HT. Changes in presynaptic action potential shape, resting membrane potential or postsynaptic impedance after trains cannot account for slower recovery of ADSE. Axonal injection of EDTA slows the removal of residual Ca2+ and the decay of synaptic augmentation after trains of action potentials (K.R. Delaney, D.W. Tank, A quantitative measure of the dependence of short-term synaptic enhancement on presynaptic residual calcium, J. Neurosci. 14 (1994) 5885-5902), but has little or no effect on the 5-HT-induced persistence of ADSE. This also suggests that the time course of ADSE in the presence of 5-HT is not determined primarily by residual Ca2+ removal kinetics. The slowing of ADSE recovery after trains by 5-HT reverses with washing in 5-HT-free saline along with the 5-HT-mediated enhancement of release.

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

Science.gov (United States)

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

2015-01-01

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

Xanthene derivatives increase glucose utilization through activation of LKB1-dependent AMP-activated protein kinase.

Directory of Open Access Journals (Sweden)

Yonghoon Kwon

Full Text Available 5' AMP-activated protein kinase (AMPK is a highly conserved serine-threonine kinase that regulates energy expenditure by activating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. Therefore AMPK activators are considered to be drug targets for treatment of metabolic diseases such as diabetes mellitus. To identify novel AMPK activators, we screened xanthene derivatives. We determined that the AMPK activators 9H-xanthene-9-carboxylic acid {2,2,2-trichloro-1-[3-(3-nitro-phenyl-thioureido]-ethyl}-amide (Xn and 9H-xanthene-9-carboxylic acid {2,2,2-trichloro-1-[3-(3-cyano-phenyl-thioureido]-ethyl}-amide (Xc elevated glucose uptake in L6 myotubes by stimulating translocation of glucose transporter type 4 (GLUT4. Treatment with the chemical AMPK inhibitor compound C and infection with dominant-negative AMPKa2-virus inhibited AMPK phosphorylation and glucose uptake in myotubes induced by either Xn or Xc. Of the two major upstream kinases of AMPK, we found that Xn and Xc showed LKB1 dependency by knockdown of STK11, an ortholog of human LKB1. Single intravenous administration of Xn and Xc to high-fat diet-induced diabetic mice stimulated AMPK phosphorylation of skeletal muscle and improved glucose tolerance. Taken together, these results suggest that Xn and Xc regulate glucose homeostasis through LKB1-dependent AMPK activation and that the compounds are potential candidate drugs for the treatment of type 2 diabetes mellitus.

Preliminary Phytochemical Screening, Quantitative Analysis of Alkaloids, and Antioxidant Activity of Crude Plant Extracts from Ephedra intermedia Indigenous to Balochistan.

Science.gov (United States)

Gul, Rahman; Jan, Syed Umer; Faridullah, Syed; Sherani, Samiullah; Jahan, Nusrat

2017-01-01

The aim of this study was to evaluate the antioxidant activity, screening the phytogenic chemical compounds, and to assess the alkaloids present in the E. intermedia to prove its uses in Pakistani folk medicines for the treatment of asthma and bronchitis. Antioxidant activity was analyzed by using 2,2-diphenyl-1-picryl-hydrazyl-hydrate assay. Standard methods were used for the identification of cardiac glycosides, phenolic compounds, flavonoids, anthraquinones, and alkaloids. High performance liquid chromatography (HPLC) was used for quantitative purpose of ephedrine alkaloids in E. intermedia . The quantitative separation was confirmed on Shimadzu 10AVP column (Shampack) of internal diameter (id) 3.0 mm and 50 mm in length. The extract of the solute in flow rate of 1 ml/min at the wavelength 210 nm and methanolic extract showed the antioxidant activity and powerful oxygen free radicals scavenging activities and the IC50 for the E. intermedia plant was near to the reference standard ascorbic acid. The HPLC method was useful for the quantitative purpose of ephedrine (E) and pseudoephedrine (PE) used for 45 samples of one species collected from central habitat in three districts (Ziarat, Shairani, and Kalat) of Balochistan. Results showed that average alkaloid substance in E. intermedia was as follows: PE (0.209%, 0.238%, and 0.22%) and E (0.0538%, 0.0666%, and 0.0514%).

Genotype modulates testosterone-dependent activity and reactivity in male mice.

Science.gov (United States)

Broida, J; Svare, B

1983-03-01

Adult castration significantly reduced the homecage locomotor activity of both inbred C57BL/6J and DBA/2J and outbred Rockland-Swiss (R-S) male mice. Castrated C57BL animals exhibited greater reductions in this behavior than did the other genotypes. Locomotor activity in a novel environment (reactivity) was also reduced by castration but only for inbred males. In both test situations, postcastration reductions in ambulation were prevented by implants of testosterone (T)-containing Silastic capsules. Thus, testicular hormones promote activity and reactivity in the male mouse in a genotype-dependent fashion.

Development and application of a quantitative multiplexed small GTPase activity assay using targeted proteomics.

Science.gov (United States)

Zhang, Cheng-Cheng; Li, Ru; Jiang, Honghui; Lin, Shujun; Rogalski, Jason C; Liu, Kate; Kast, Juergen

2015-02-06

Small GTPases are a family of key signaling molecules that are ubiquitously expressed in various types of cells. Their activity is often analyzed by western blot, which is limited by its multiplexing capability, the quality of isoform-specific antibodies, and the accuracy of quantification. To overcome these issues, a quantitative multiplexed small GTPase activity assay has been developed. Using four different binding domains, this assay allows the binding of up to 12 active small GTPase isoforms simultaneously in a single experiment. To accurately quantify the closely related small GTPase isoforms, a targeted proteomic approach, i.e., selected/multiple reaction monitoring, was developed, and its functionality and reproducibility were validated. This assay was successfully applied to human platelets and revealed time-resolved coactivation of multiple small GTPase isoforms in response to agonists and differential activation of these isoforms in response to inhibitor treatment. This widely applicable approach can be used for signaling pathway studies and inhibitor screening in many cellular systems.

A Novel Qualitative and Quantitative Biofilm Assay Based on 3D Soft Tissue

Directory of Open Access Journals (Sweden)

Bodil Hakonen

2014-01-01

Full Text Available The lack of predictable in vitro methods to analyze antimicrobial activity could play a role in the development of resistance to antibiotics. Current used methods analyze planktonic cells but for the method to be clinically relevant, biofilm in in vivo like conditions ought to be studied. Hence, our group has developed a qualitative and quantitative method with in vivo like 3D tissue for prediction of antimicrobial activity in reality. Devices (wound dressings were applied on top of Pseudomonas aeruginosa inoculated Muller-Hinton (MH agar or 3D synthetic soft tissues (SST and incubated for 24 hours. The antibacterial activity was then analyzed visually and by viable counts. On MH agar two out of three silver containing devices showed zone of inhibitions (ZOI and on SST, ZOI were detected for all three. Corroborating results were found upon evaluating the bacterial load in SST and shown to be silver concentration dependent. In conclusion, a novel method was developed combining visual rapid screening and quantitative evaluation of the antimicrobial activity in both tissue and devices. It uses tissue allowing biofilm formation thus mimicking reality closely. These conditions are essential in order to predict antimicrobial activity of medical devices in the task to prevent device related infections.

Glucocorticoids activate the ATP-ubiquitin-dependent proteolytic system in skeletal muscle during fasting

Science.gov (United States)

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.

Designing a Quantitative Structure-Activity Relationship for the ...

Science.gov (United States)

Toxicokinetic models serve a vital role in risk assessment by bridging the gap between chemical exposure and potentially toxic endpoints. While intrinsic metabolic clearance rates have a strong impact on toxicokinetics, limited data is available for environmentally relevant chemicals including nearly 8000 chemicals tested for in vitro bioactivity in the Tox21 program. To address this gap, a quantitative structure-activity relationship (QSAR) for intrinsic metabolic clearance rate was developed to offer reliable in silico predictions for a diverse array of chemicals. Models were constructed with curated in vitro assay data for both pharmaceutical-like chemicals (ChEMBL database) and environmentally relevant chemicals (ToxCast screening) from human liver microsomes (2176 from ChEMBL) and human hepatocytes (757 from ChEMBL and 332 from ToxCast). Due to variability in the experimental data, a binned approach was utilized to classify metabolic rates. Machine learning algorithms, such as random forest and k-nearest neighbor, were coupled with open source molecular descriptors and fingerprints to provide reasonable estimates of intrinsic metabolic clearance rates. Applicability domains defined the optimal chemical space for predictions, which covered environmental chemicals well. A reduced set of informative descriptors (including relative charge and lipophilicity) and a mixed training set of pharmaceuticals and environmentally relevant chemicals provided the best intr

Dependent Human Error Probability Assessment

International Nuclear Information System (INIS)

Simic, Z.; Mikulicic, V.; Vukovic, I.

2006-01-01

This paper presents an assessment of the dependence between dynamic operator actions modeled in a Nuclear Power Plant (NPP) PRA and estimate the associated impact on Core damage frequency (CDF). This assessment was done improve HEP dependencies implementation inside existing PRA. All of the dynamic operator actions modeled in the NPP PRA are included in this assessment. Determining the level of HEP dependence and the associated influence on CDF are the major steps of this assessment. A decision on how to apply the results, i.e., should permanent HEP model changes be made, is based on the resulting relative CDF increase. Some CDF increase was selected as a threshold based on the NPP base CDF value and acceptance guidelines from the Regulatory Guide 1.174. HEP dependence resulting in a CDF increase of > 5E-07 would be considered potential candidates for specific incorporation into the baseline model. The approach used to judge the level of dependence between operator actions is based on dependency level categories and conditional probabilities developed in the Handbook of Human Reliability Analysis with Emphasis on Nuclear Power Plant Applications NUREG/CR-1278. To simplify the process, NUREG/CR-1278 identifies five levels of dependence: ZD (zero dependence), LD (low dependence), MD (moderate dependence), HD (high dependence), and CD (complete dependence). NUREG/CR-1278 also identifies several qualitative factors that could be involved in determining the level of dependence. Based on the NUREG/CR-1278 information, Time, Function, and Spatial attributes were judged to be the most important considerations when determining the level of dependence between operator actions within an accident sequence. These attributes were used to develop qualitative criteria (rules) that were used to judge the level of dependence (CD, HD, MD, LD, ZD) between the operator actions. After the level of dependence between the various HEPs is judged, quantitative values associated with the

Quantitative fluorescence nanoscopy for cancer biomedicine

Science.gov (United States)

Huang, Tao; Nickerson, Andrew; Peters, Alec; Nan, Xiaolin

2015-08-01

Cancer is a major health threat worldwide. Options for targeted cancer therapy, however, are often limited, in a large part due to our incomplete understanding of how key processes including oncogenesis and drug response are mediated at the molecular level. New imaging techniques for visualizing biomolecules and their interactions at the nanometer and single molecule scales, collectively named fluorescence nanoscopy, hold the promise to transform biomedical research by providing direct mechanistic insight into cellular processes. We discuss the principles of quantitative single-molecule localization microscopy (SMLM), a subset of fluorescence nanoscopy, and their applications to cancer biomedicine. In particular, we will examine oncogenesis and drug resistance mediated by mutant Ras, which is associated with ~1/3 of all human cancers but has remained an intractable drug target. At ~20 nm spatial and single-molecule stoichiometric resolutions, SMLM clearly showed that mutant Ras must form dimers to activate its effector pathways and drive oncogenesis. SMLM further showed that the Raf kinase, one of the most important effectors of Ras, also forms dimers upon activation by Ras. Moreover, treatment of cells expressing wild type Raf with Raf inhibitors induces Raf dimer formation in a manner dependent on Ras dimerization. Together, these data suggest that Ras dimers mediate oncogenesis and drug resistance in tumors with hyperactive Ras and can potentially be targeted for cancer therapy. We also discuss recent advances in SMLM that enable simultaneous imaging of multiple biomolecules and their interactions at the nanoscale. Our work demonstrates the power of quantitative SMLM in cancer biomedicine.

Quantitative CT: technique dependence of volume estimation on pulmonary nodules

Science.gov (United States)

Chen, Baiyu; Barnhart, Huiman; Richard, Samuel; Colsher, James; Amurao, Maxwell; Samei, Ehsan

2012-03-01

Current estimation of lung nodule size typically relies on uni- or bi-dimensional techniques. While new three-dimensional volume estimation techniques using MDCT have improved size estimation of nodules with irregular shapes, the effect of acquisition and reconstruction parameters on accuracy (bias) and precision (variance) of the new techniques has not been fully investigated. To characterize the volume estimation performance dependence on these parameters, an anthropomorphic chest phantom containing synthetic nodules was scanned and reconstructed with protocols across various acquisition and reconstruction parameters. Nodule volumes were estimated by a clinical lung analysis software package, LungVCAR. Precision and accuracy of the volume assessment were calculated across the nodules and compared between protocols via a generalized estimating equation analysis. Results showed that the precision and accuracy of nodule volume quantifications were dependent on slice thickness, with different dependences for different nodule characteristics. Other parameters including kVp, pitch, and reconstruction kernel had lower impact. Determining these technique dependences enables better volume quantification via protocol optimization and highlights the importance of consistent imaging parameters in sequential examinations.

An Activity Promoting the Practice of Quantitative Literacy for Pre– and In–Service Teachers of Mathematics and Science

OpenAIRE

Timothy L. Sorey; Teri Willard; Duane Sholz

2010-01-01

The purpose of this article is to describe a hands-on, laboratory activity that provided pre-service teachers in mathematics and science methods courses, and also some in-service mathematics teachers, with the opportunity to exercise quantitative literacy (QL) skills. The focus of the activity is electrical resistance, more particularly the resistance (in ohms) that is painted on small resistors by the use of color-coded bands, one of which is a band for % error. The activity consists of four...

Quantitative Structure activity relationship and risk analysis of some pesticides in the cattle milk

OpenAIRE

Faqir Muhammad*, Ijaz Javed, Masood Akhtar1, Zia-ur-Rahman, Mian Muhammad Awais1, Muhammad Kashif Saleemi2 and Muhammad Irfan Anwar3

2012-01-01

Milk of cattle was collected from various localities of Faisalabad, Pakistan. Pesticides concentration was determined by HPLC using solid phase microextraction. The residue analysis revealed that about 40% milk samples were contaminated with pesticides. The mean±SE levels (ppm) of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.38±0.02, 0.26±0.02, 0.072±0.01 and 0.085±0.02, respectively. Quantitative structure activity relationship (QSAR) models were used to predict the residues...

Supported rhodium catalysts for ammonia-borane hydrolysis. Dependence of the catalytic activity on the highest occupied state of the single rhodium atoms

Energy Technology Data Exchange (ETDEWEB)

Wang, Liangbing; Li, Hongliang; Zhang, Wenbo; Zhao, Xiao; Qiu, Jianxiang; Li, Aowen; Zheng, Xusheng; Zeng, Jie [Hefei National Lab. for Physical Sciences at the Microscale, Key Lab. of Strongly-Coupled Quantum Matter Physics, Chinese Academy of Sciences, Hefei, Anhui(China); Department of Chemical Physics, University of Science and Technology of China, Hefei, Anhui (China); Hu, Zhenpeng [School of Physics, Nankai University, Tianjin (China); Si, Rui [Shanghai Synchrotron Radiation Facility, Shanghai Institute of Applied Physics, Chinese Academy of Sciences (China)

2017-04-18

Supported metal nanocrystals have exhibited remarkable catalytic performance in hydrogen generation reactions, which is influenced and even determined by their supports. Accordingly, it is of fundamental importance to determine the direct relationship between catalytic performance and metal-support interactions. Herein, we provide a quantitative profile for exploring metal-support interactions by considering the highest occupied state in single-atom catalysts. The catalyst studied consisted of isolated Rh atoms dispersed on the surface of VO{sub 2} nanorods. It was observed that the activation energy of ammonia-borane hydrolysis changed when the substrate underwent a phase transition. Mechanistic studies indicate that the catalytic performance depended directly on the highest occupied state of the single Rh atoms, which was determined by the band structure of the substrates. Other metal catalysts, even with non-noble metals, that exhibited significant catalytic activity towards NH{sub 3}BH{sub 3} hydrolysis were rationally designed by adjusting their highest occupied states. (copyright 2017 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim)

Visual characterization and quantitative measurement of artemisinin-induced DNA breakage

Energy Technology Data Exchange (ETDEWEB)

Cai Huaihong [Bionanotechnology Lab, and Department of Chemistry, Jinan University, Guangzhou 510632 (China); Yang Peihui [Bionanotechnology Lab, and Department of Chemistry, Jinan University, Guangzhou 510632 (China)], E-mail: typh@jnu.edu.cn; Chen Jianan [Bionanotechnology Lab, and Department of Chemistry, Jinan University, Guangzhou 510632 (China); Liang Zhihong [Experiment and Technology Center, Jinan University, Guangzhou 510632 (China); Chen Qiongyu [Institute of Genetic Engineering, Jinan University, Guangzhou 510632 (China); Cai Jiye [Bionanotechnology Lab, and Department of Chemistry, Jinan University, Guangzhou 510632 (China)], E-mail: tjycai@jnu.edu.cn

2009-05-01

DNA conformational change and breakage induced by artemisinin, a traditional Chinese herbal medicine, have been visually characterized and quantitatively measured by the multiple tools of electrochemistry, UV-vis absorption spectroscopy, atomic force microscopy (AFM), and DNA electrophoresis. Electrochemical and spectroscopic results confirm that artemisinin can intercalate into DNA double helix, which causes DNA conformational changes. AFM imaging vividly demonstrates uneven DNA strand breaking induced by QHS interaction. To assess these DNA breakages, quantitative analysis of the extent of DNA breakage has been performed by analyzing AFM images. Basing on the statistical analysis, the occurrence of DNA breaks is found to depend on the concentration of artemisinin. DNA electrophoresis further validates that the intact DNA molecules are unwound due to the breakages occur at the single strands. A reliable scheme is proposed to explain the process of artemisinin-induced DNA cleavage. These results can provide further information for better understanding the anticancer activity of artemisinin.

Synthesis, quantitative structure-property relationship study of novel fluorescence active 2-pyrazolines and application

Science.gov (United States)

Girgis, Adel S.; Basta, Altaf H.; El-Saied, Houssni; Mohamed, Mohamed A.; Bedair, Ahmad H.; Salim, Ahmad S.

2018-03-01

A variety of fluorescence-active fluorinated pyrazolines 13-33 was synthesized in good yields through cyclocondensation reaction of propenones 1-9 with aryl hydrazines 10-12. Some of the synthesized compounds provided promising fluorescence properties with quantum yield (Φ) higher than that of quinine sulfate (standard reference). Quantitative structure-property relationship studies were undertaken supporting the exhibited fluorescence properties and estimating the parameters governing properties. Five synthesized fluorescence-active pyrazolines (13, 15, 18, 19 and 23) with variable Φ were selected for treating two types of paper sheets (Fabriano and Bible paper). These investigated fluorescence compounds, especially compounds 19 and 23, provide improvements in strength properties of paper sheets. Based on the observed performance they can be used as markers in security documents.

The Quantitative Basis of the Arabidopsis Innate Immune System to Endemic Pathogens Depends on Pathogen Genetics.

Directory of Open Access Journals (Sweden)

Jason A Corwin

2016-02-01

Full Text Available The most established model of the eukaryotic innate immune system is derived from examples of large effect monogenic quantitative resistance to pathogens. However, many host-pathogen interactions involve many genes of small to medium effect and exhibit quantitative resistance. We used the Arabidopsis-Botrytis pathosystem to explore the quantitative genetic architecture underlying host innate immune system in a population of Arabidopsis thaliana. By infecting a diverse panel of Arabidopsis accessions with four phenotypically and genotypically distinct isolates of the fungal necrotroph B. cinerea, we identified a total of 2,982 genes associated with quantitative resistance using lesion area and 3,354 genes associated with camalexin production as measures of the interaction. Most genes were associated with resistance to a specific Botrytis isolate, which demonstrates the influence of pathogen genetic variation in analyzing host quantitative resistance. While known resistance genes, such as receptor-like kinases (RLKs and nucleotide-binding site leucine-rich repeat proteins (NLRs, were found to be enriched among associated genes, they only account for a small fraction of the total genes associated with quantitative resistance. Using publically available co-expression data, we condensed the quantitative resistance associated genes into co-expressed gene networks. GO analysis of these networks implicated several biological processes commonly connected to disease resistance, including defense hormone signaling and ROS production, as well as novel processes, such as leaf development. Validation of single gene T-DNA knockouts in a Col-0 background demonstrate a high success rate (60% when accounting for differences in environmental and Botrytis genetic variation. This study shows that the genetic architecture underlying host innate immune system is extremely complex and is likely able to sense and respond to differential virulence among pathogen

Nuclear cGMP-dependent kinase regulates gene expression via activity-dependent recruitment of a conserved histone deacetylase complex.

Directory of Open Access Journals (Sweden)

Yan Hao

2011-05-01

Full Text Available Elevation of the second messenger cGMP by nitric oxide (NO activates the cGMP-dependent protein kinase PKG, which is key in regulating cardiovascular, intestinal, and neuronal functions in mammals. The NO-cGMP-PKG signaling pathway is also a major therapeutic target for cardiovascular and male reproductive diseases. Despite widespread effects of PKG activation, few molecular targets of PKG are known. We study how EGL-4, the Caenorhabditis elegans PKG ortholog, modulates foraging behavior and egg-laying and seeks the downstream effectors of EGL-4 activity. Using a combination of unbiased forward genetic screen and proteomic analysis, we have identified a conserved SAEG-1/SAEG-2/HDA-2 histone deacetylase complex that is specifically recruited by activated nuclear EGL-4. Gene expression profiling by microarrays revealed >40 genes that are sensitive to EGL-4 activity in a SAEG-1-dependent manner. We present evidence that EGL-4 controls egg laying via one of these genes, Y45F10C.2, which encodes a novel protein that is expressed exclusively in the uterine epithelium. Our results indicate that, in addition to cytoplasmic functions, active EGL-4/PKG acts in the nucleus via a conserved Class I histone deacetylase complex to regulate gene expression pertinent to behavioral and physiological responses to cGMP. We also identify transcriptional targets of EGL-4 that carry out discrete components of the physiological response.

The quantitative basis of the Arabidopsis innate immune system to endemic pathogens depends on pathogen genetics

DEFF Research Database (Denmark)

Corwin, Jason A; Copeland, Daniel; Feusier, Julie

2016-01-01

The most established model of the eukaryotic innate immune system is derived from examples of large effect monogenic quantitative resistance to pathogens. However, many host-pathogen interactions involve many genes of small to medium effect and exhibit quantitative resistance. We used the Arabido......The most established model of the eukaryotic innate immune system is derived from examples of large effect monogenic quantitative resistance to pathogens. However, many host-pathogen interactions involve many genes of small to medium effect and exhibit quantitative resistance. We used....... cinerea, we identified a total of 2,982 genes associated with quantitative resistance using lesion area and 3,354 genes associated with camalexin production as measures of the interaction. Most genes were associated with resistance to a specific Botrytis isolate, which demonstrates the influence...... genes associated with quantitative resistance. Using publically available co-expression data, we condensed the quantitative resistance associated genes into co-expressed gene networks. GO analysis of these networks implicated several biological processes commonly connected to disease resistance...

Latitude dependence of long-term geomagnetic activity and its solar wind drivers

Energy Technology Data Exchange (ETDEWEB)

Myllys, M. [Helsinki Univ. (Finland). Dept. of Physics; Partamies, N. [Finnish Meteorological Institute, Helsinki (Finland); University Centre in Svalbard, Longyearbyen (Norway). Dept. of Arctic Geophysics; Juusola, L. [Finnish Meteorological Institute, Helsinki (Finland)

2015-09-01

To validate the usage of global indices in studies of geomagnetic activity, we have examined the latitude dependence of geomagnetic variations in Fennoscandia and Svalbard from 1994 to 2010. Daily standard deviation (SD) values of the horizontal magnetic field have been used as a measure of the ground magnetic disturbance level.We found that the timing of the geomagnetic minimum depends on the latitude region: corresponding to the minimum of sunspot cycle 22 (in 1996), the geomagnetic minimum occurred between the geomagnetic latitudes 57-61 in 1996 and at the latitudes 64-67 in 1997, which are the average auroral oval latitudes. During sunspot cycle 23, all latitude regions experienced the minimum in 2009, a year after the sunspot minimum. These timing differences are due to the latitude dependence of the 10 s daily SD on the different solar wind drivers. In the latitude region of 64-67 , the impact of the high-speed solar wind streams (HSSs) on the geomagnetic activity is the most pronounced compared to the other latitude groups, while in the latitude region of 57-61 , the importance of the coronal mass ejections (CMEs) dominates. The geomagnetic activity maxima during ascending solar cycle phases are typically caused by CME activity and occur especially in the oval and sub-auroral regions. The strongest geomagnetic activity occurs during the descending solar cycle phases due to a mixture of CME and HSS activity. Closer to the solar minimum, less severe geomagnetic activity is driven by HSSs and mainly visible in the poleward part of the auroral region. According to our study, however, the timing of the geomagnetic activity minima (and maxima) in different latitude bands is different, due to the relative importance of different solar wind drivers at different latitudes.

Latitude dependence of long-term geomagnetic activity and its solar wind drivers

International Nuclear Information System (INIS)

Myllys, M.

2015-01-01

To validate the usage of global indices in studies of geomagnetic activity, we have examined the latitude dependence of geomagnetic variations in Fennoscandia and Svalbard from 1994 to 2010. Daily standard deviation (SD) values of the horizontal magnetic field have been used as a measure of the ground magnetic disturbance level.We found that the timing of the geomagnetic minimum depends on the latitude region: corresponding to the minimum of sunspot cycle 22 (in 1996), the geomagnetic minimum occurred between the geomagnetic latitudes 57-61 in 1996 and at the latitudes 64-67 in 1997, which are the average auroral oval latitudes. During sunspot cycle 23, all latitude regions experienced the minimum in 2009, a year after the sunspot minimum. These timing differences are due to the latitude dependence of the 10 s daily SD on the different solar wind drivers. In the latitude region of 64-67 , the impact of the high-speed solar wind streams (HSSs) on the geomagnetic activity is the most pronounced compared to the other latitude groups, while in the latitude region of 57-61 , the importance of the coronal mass ejections (CMEs) dominates. The geomagnetic activity maxima during ascending solar cycle phases are typically caused by CME activity and occur especially in the oval and sub-auroral regions. The strongest geomagnetic activity occurs during the descending solar cycle phases due to a mixture of CME and HSS activity. Closer to the solar minimum, less severe geomagnetic activity is driven by HSSs and mainly visible in the poleward part of the auroral region. According to our study, however, the timing of the geomagnetic activity minima (and maxima) in different latitude bands is different, due to the relative importance of different solar wind drivers at different latitudes.

Evolution of the international workshops on quantitative structure-activity relationships (QSARs) in environmental toxicology.

Science.gov (United States)

Kaiser, K L E

2007-01-01

This presentation will review the evolution of the workshops from a scientific and personal perspective. From their modest beginning in 1983, the workshops have developed into larger international meetings, regularly held every two years. Their initial focus on the aquatic sphere soon expanded to include properties and effects on atmospheric and terrestrial species, including man. Concurrent with this broadening of their scientific scope, the workshops have become an important forum for the early dissemination of all aspects of qualitative and quantitative structure-activity research in ecotoxicology and human health effects. Over the last few decades, the field of quantitative structure/activity relationships (QSARs) has quickly emerged as a major scientific method in understanding the properties and effects of chemicals on the environment and human health. From substances that only affect cell membranes to those that bind strongly to a specific enzyme, QSARs provides insight into the biological effects and chemical and physical properties of substances. QSARs are useful for delineating the quantitative changes in biological effects resulting from minor but systematic variations of the structure of a compound with a specific mode of action. In addition, more holistic approaches are being devised that result in our ability to predict the effects of structurally unrelated compounds with (potentially) different modes of action. Research in QSAR environmental toxicology has led to many improvements in the manufacturing, use, and disposal of chemicals. Furthermore, it has led to national policies and international agreements, from use restrictions or outright bans of compounds, such as polychlorinated biphenyls (PCBs), mirex, and highly chlorinated pesticides (e.g. DDT, dieldrin) for the protection of avian predators, to alternatives for ozone-depleting compounds, to better waste treatment systems, to more powerful and specific acting drugs. Most of the recent advances

Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships (MCBIOS)

Science.gov (United States)

Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships Jie Liu1,2, Richard Judson1, Matthew T. Martin1, Huixiao Hong3, Imran Shah1 1National Center for Computational Toxicology (NCCT), US EPA, RTP, NC...

Quantitative structure-activity relationship modeling on in vitro endocrine effects and metabolic stability involving 26 selected brominated flame retardants

NARCIS (Netherlands)

Harju, M.; Hamers, T.; Kamstra, J.H.; Sonneveld, E.; Boon, J.P.

2007-01-01

In this work, quantitative structure-activity relationships (QSARs) were developed to aid human and environmental risk assessment processes for brominated flame retardants (BFRs). Brominated flame retardants, such as the high-production-volume chemicals polybrominated diphenyl ethers (PBDEs),

In Vivo Quantitative Study of Sized-Dependent Transport and Toxicity of Single Silver Nanoparticles Using Zebrafish Embryos

Science.gov (United States)

Lee, Kerry J.; Browning, Lauren M.; Nallathamby, Prakash D.; Desai, Tanvi; Cherukui, Pavan K.; Xu, Xiao-Hong Nancy

2012-01-01

Nanomaterials possess distinctive physicochemical properties (e.g., small sizes, high surface area-to-volume ratios) and promise a wide variety of applications, ranging from design of high quality consumer products to effective disease diagnosis and therapy. These properties can lead to toxic effects, potentially hindering advance in nanotechnology. In this study, we have synthesized and characterized purified and stable (non-aggregation) silver nanoparticles (Ag NPs, 41.6±9.1 nm in average diameters), and utilized early-developing (cleavage-stage) zebrafish embryos (critical aquatic and eco- species) as in vivo model organisms to probe diffusion and toxicity of Ag NPs. We found that single Ag NPs (30–72 nm diameters) passively diffused into the embryos through chorionic pores via random Brownian motion and stayed inside the embryos throughout their entire development (120 hours-post-fertilization, hpf). Dose and size dependent toxic effects of the NPs on embryonic development were observed, showing the possibility of tuning biocompatibility and toxicity of the NPs. At lower concentrations of the NPs (≤ 0.02 nM), 75–91% of embryos developed to normal zebrafish. At the higher concentrations of NPs (≥ 0.20 nM), 100% of embryos became dead. At the concentrations in between (0.02–0.2 nM), embryos developed to various deformed zebrafish. Number and sizes of individual Ag NPs embedded in tissues of normal and deformed zebrafish at 120 hpf were quantitatively analyzed, showing deformed zebrafish with higher number of larger NPs than normal zebrafish, and size-dependent nanotoxicity. By comparing with our previous studies of smaller Ag NPs (11.6±3.5 nm), the results further demonstrate striking size-dependent nanotoxicity that, at the same molar concentration, the larger Ag NPs (41.6±9.1 nm) are more toxic than the smaller Ag NPs (11.6±3.5 nm). PMID:22486336

Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling.

Science.gov (United States)

Vlot, Anna H C; de Witte, Wilhelmus E A; Danhof, Meindert; van der Graaf, Piet H; van Westen, Gerard J P; de Lange, Elizabeth C M

2017-12-04

Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D ) and the target dissociation rate constant on target and tissue selectivity. The K D values of CB1 ligands in the ChEMBL database are predicted by QSAR random forest (RF) modeling for the CB1 receptor and known off-targets (TRPV1, mGlu5, 5-HT1a). Of these CB1 ligands, rimonabant, CP-55940, and Δ 8 -tetrahydrocanabinol, one of the active ingredients of cannabis, were selected for simulations of target occupancy for CB1, TRPV1, mGlu5, and 5-HT1a in three brain regions, to illustrate the principles of the combined PBPK-QSAR modeling. Our combined PBPK and target binding modeling demonstrated that the optimal values of the K D and k off for target and tissue selectivity were dependent on target concentration and tissue distribution kinetics. Interestingly, if the target concentration is high and the perfusion of the target site is low, the optimal K D value is often not the lowest K D value, suggesting that optimization towards high drug-target affinity can decrease the benefit-risk ratio. The presented integrative structure-pharmacokinetic-pharmacodynamic modeling provides an improved understanding of tissue and target selectivity.

State-dependent, bidirectional modulation of neural network activity by endocannabinoids.

Science.gov (United States)

Piet, Richard; Garenne, André; Farrugia, Fanny; Le Masson, Gwendal; Marsicano, Giovanni; Chavis, Pascale; Manzoni, Olivier J

2011-11-16

The endocannabinoid (eCB) system and the cannabinoid CB1 receptor (CB1R) play key roles in the modulation of brain functions. Although actions of eCBs and CB1Rs are well described at the synaptic level, little is known of their modulation of neural activity at the network level. Using microelectrode arrays, we have examined the role of CB1R activation in the modulation of the electrical activity of rat and mice cortical neural networks in vitro. We find that exogenous activation of CB1Rs expressed on glutamatergic neurons decreases the spontaneous activity of cortical neural networks. Moreover, we observe that the net effect of the CB1R antagonist AM251 inversely correlates with the initial level of activity in the network: blocking CB1Rs increases network activity when basal network activity is low, whereas it depresses spontaneous activity when its initial level is high. Our results reveal a complex role of CB1Rs in shaping spontaneous network activity, and suggest that the outcome of endogenous neuromodulation on network function might be state dependent.

Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

Energy Technology Data Exchange (ETDEWEB)

Zhang, Lianying [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China); College of Life Science, Dezhou University, Dezhou 253023 (China); Ren, Xiao-Min; Wan, Bin [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China); Guo, Liang-Hong, E-mail: LHGuo@rcees.ac.cn [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China)

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.

Quantitative diffusion characteristics of the human brain depend on MRI sequence parameters

International Nuclear Information System (INIS)

Wilson, M.; Blumhardt, L.D.; Morgan, P.S.

2002-01-01

Quantitative diffusion-weighted MRI has been applied to the study of neurological diseases, including multiple sclerosis, where the molecular self-diffusion coefficient D has been measured in both lesions and normal-appearing white matter. Histograms of D have been used as a novel measure of the ''lesion load'', with potential applications that include the monitoring of efficacy in new treatment trials. However different ways of measuring D may affect its value, making comparison between different centres and research groups impossible. We aimed to assess the effect, if any, of using two different MRI sequences on the value of D. We studied 13 healthy volunteers, using two different quantitative diffusion sequences (including different b max values and gradient applications). Maps of D were analysed using both regions of interest (ROI) in white matter and ''whole brain'' histograms, and compared between the two sequences. In addition, we studied three standardised test liquids (with known values of D) using both sequences. Histograms from the two sequences had different distributions, with a greater spread and higher peak position from the sequence with lower b max . This greater spread of D was also evident in the white matter and test liquid ROI. ''Limits of agreement'' analysis demonstrated that the differences could be clinically relevant, despite significant correlations between the sequences obtained using simple rank methods. We conclude that different quantitative diffusion sequences are unlikely to produce directly comparable values of D, particularly if different b max values are used. In addition, the use of inappropriate statistical tests may give false impressions of close agreement. Standardisation of methods for the measurement of D are required if these techniques are to become useful tools, for example in monitoring changes in the disease burden of multiple sclerosis. (orig.)

Quantitative diffusion characteristics of the human brain depend on MRI sequence parameters

Energy Technology Data Exchange (ETDEWEB)

Wilson, M.; Blumhardt, L.D. [University of Nottingham, Department of Neurology, Royal Preston Hospital, Preston (United Kingdom); Morgan, P.S. [Division of Academic Radiology, Queens Medical Centre, Nottingham (United Kingdom)

2002-07-01

Quantitative diffusion-weighted MRI has been applied to the study of neurological diseases, including multiple sclerosis, where the molecular self-diffusion coefficient D has been measured in both lesions and normal-appearing white matter. Histograms of D have been used as a novel measure of the ''lesion load'', with potential applications that include the monitoring of efficacy in new treatment trials. However different ways of measuring D may affect its value, making comparison between different centres and research groups impossible. We aimed to assess the effect, if any, of using two different MRI sequences on the value of D. We studied 13 healthy volunteers, using two different quantitative diffusion sequences (including different b{sub max} values and gradient applications). Maps of D were analysed using both regions of interest (ROI) in white matter and ''whole brain'' histograms, and compared between the two sequences. In addition, we studied three standardised test liquids (with known values of D) using both sequences. Histograms from the two sequences had different distributions, with a greater spread and higher peak position from the sequence with lower b{sub max}. This greater spread of D was also evident in the white matter and test liquid ROI. ''Limits of agreement'' analysis demonstrated that the differences could be clinically relevant, despite significant correlations between the sequences obtained using simple rank methods. We conclude that different quantitative diffusion sequences are unlikely to produce directly comparable values of D, particularly if different b{sub max} values are used. In addition, the use of inappropriate statistical tests may give false impressions of close agreement. Standardisation of methods for the measurement of D are required if these techniques are to become useful tools, for example in monitoring changes in the disease burden of multiple sclerosis. (orig.)

Quantitative phosphoproteomic analysis of postmortem muscle development

DEFF Research Database (Denmark)

Huang, Honggang

Meat quality development is highly dependent on postmortem (PM) metabolism and rigor mortis development in PM muscle. PM glycometabolism and rigor mortis fundamentally determine most of the important qualities of raw meat, such as ultimate pH, tenderness, color and water-holding capacity. Protein...... phosphorylation is known to play essential roles on regulating metabolism, contraction and other important activities in muscle systems. However, protein phosphorylation has rarely been systematically explored in PM muscle in relation to meat quality. In this PhD project, both gel-based and mass spectrometry (MS......)-based quantitative phosphoproteomic strategies were employed to analyze PM muscle with the aim to intensively characterize the protein phosphorylation involved in meat quality development. Firstly, gel-based phosphoproteomic studies were performed to analyze the protein phosphorylation in both sarcoplasmic proteins...

Quantitative activation patterns of cerebral blood flow during mental stimulation after intravenous injection of sup(195m)Au

International Nuclear Information System (INIS)

Lindner, P.; Nickel, O.

1983-01-01

A previously reported theory for quantitative cerebral blood flow measurement for nondiffusible radiotracers has been applied to patients after stroke and to volunteers undergoing a mental stimulation exercise. Quantitative measurements of cerebral blood flow pattern in p-a and lateral projections of the brain are obtained using the short lived (30s) isotope sup(195m)Au from the recently developed generator. The energy spectrum of the eluate from the generator shows two strong photon peaks, one at an energy level of 68 KeV and a second at 262 KeV. The low-energy peak is suitable for perfusion studies of the cerebral hemispheres in lateral projection, being without ''look through'' effect. The high-energy level is good for studies in p-a-projection. Studies last less than 1 min and can be repeated after 3 min. Parametric images for quantitative regional cerebral blood flow can be generated, in which the avascular region following stroke can be detected. Quantitative activation patterns of cerebral blood flow during mental stimulation can be generated. The results show that it is possible to measure cerebral blood-flow patterns not only with freely diffusible indicators like Xenon but also with nondiffusible indicators. (orig.)

Quantitative Evaluation of Stomatal Cytoskeletal Patterns during the Activation of Immune Signaling in Arabidopsis thaliana.

Directory of Open Access Journals (Sweden)

Masaki Shimono

Full Text Available Historically viewed as primarily functioning in the regulation of gas and water vapor exchange, it is now evident that stomata serve an important role in plant immunity. Indeed, in addition to classically defined functions related to cell architecture and movement, the actin cytoskeleton has emerged as a central component of the plant immune system, underpinning not only processes related to cell shape and movement, but also receptor activation and signaling. Using high resolution quantitative imaging techniques, the temporal and spatial changes in the actin microfilament array during diurnal cycling of stomatal guard cells has revealed a highly orchestrated transition from random arrays to ordered bundled filaments. While recent studies have demonstrated that plant stomata close in response to pathogen infection, an evaluation of stimulus-induced changes in actin cytoskeletal dynamics during immune activation in the guard cell, as well as the relationship of these changes to the function of the actin cytoskeleton and stomatal aperture, remains undefined. In the current study, we employed quantitative cell imaging and hierarchical clustering analyses to define the response of the guard cell actin cytoskeleton to pathogen infection and the elicitation of immune signaling. Using this approach, we demonstrate that stomatal-localized actin filaments respond rapidly, and specifically, to both bacterial phytopathogens and purified pathogen elicitors. Notably, we demonstrate that higher order temporal and spatial changes in the filament array show distinct patterns of organization during immune activation, and that changes in the naïve diurnal oscillations of guard cell actin filaments are perturbed by pathogens, and that these changes parallel pathogen-induced stomatal gating. The data presented herein demonstrate the application of a highly tractable and quantifiable method to assign transitions in actin filament organization to the activation of

Control of neuropeptide expression by parallel activity-dependent pathways in caenorhabditis elegans

DEFF Research Database (Denmark)

Rojo Romanos, Teresa; Petersen, Jakob Gramstrup; Pocock, Roger

2017-01-01

Monitoring of neuronal activity within circuits facilitates integrated responses and rapid changes in behavior. We have identified a system in Caenorhabditis elegans where neuropeptide expression is dependent on the ability of the BAG neurons to sense carbon dioxide. In C. Elegans, CO 2 sensing...... is predominantly coordinated by the BAG-expressed receptor-type guanylate cyclase GCY-9. GCY-9 binding to CO 2 causes accumulation of cyclic GMP and opening of the cGMP-gated TAX-2/TAX-4 cation channels; provoking an integrated downstream cascade that enables C. Elegans to avoid high CO 2. Here we show that c...... that expression of flp-19::GFP is controlled in parallel to GCY-9 by the activity-dependent transcription factor CREB (CRH-1) and the cAMP-dependent protein kinase (KIN-2) signaling pathway. We therefore show that two parallel pathways regulate neuropeptide gene expression in the BAG sensory neurons: the ability...

Age-dependent regulation of ERF-VII transcription factor activity in Arabidopsis thaliana.

Science.gov (United States)

Giuntoli, Beatrice; Shukla, Vinay; Maggiorelli, Federica; Giorgi, Federico M; Lombardi, Lara; Perata, Pierdomenico; Licausi, Francesco

2017-10-01

The Group VII Ethylene Responsive Factors (ERFs-VII) RAP2.2 and RAP2.12 have been mainly characterized with regard to their contribution as activators of fermentation in plants. However, transcriptional changes measured in conditions that stabilize these transcription factors exceed the mere activation of this biochemical pathway, implying additional roles performed by the ERF-VIIs in other processes. We evaluated gene expression in transgenic Arabidopsis lines expressing a stabilized form of RAP2.12, or hampered in ERF-VII activity, and identified genes affected by this transcriptional regulator and its homologs, including some involved in oxidative stress response, which are not universally induced under anaerobic conditions. The contribution of the ERF-VIIs in regulating this set of genes in response to chemically induced or submergence-stimulated mitochondria malfunctioning was found to depend on the plant developmental stage. A similar age-dependent mechanism also restrained ERF-VII activity upon the core-hypoxic genes, independently of the N-end rule pathway, which is accounted for the control of the anaerobic response. To conclude, this study shed new light on a dual role of ERF-VII proteins under submergence: as positive regulators of the hypoxic response and as repressors of oxidative-stress related genes, depending on the developmental stage at which plants are challenged by stress conditions. © 2017 John Wiley & Sons Ltd.

Quantitative autoradiography - a method of radioactivity measurement

International Nuclear Information System (INIS)

Treutler, H.C.; Freyer, K.

1988-01-01

In the last years the autoradiography has been developed to a quantitative method of radioactivity measurement. Operating techniques of quantitative autoradiography are demonstrated using special standard objects. Influences of irradiation quality, of backscattering in sample and detector materials, and of sensitivity and fading of the detectors are considered. Furthermore, questions of quantitative evaluation of autoradiograms are dealt with, and measuring errors are discussed. Finally, some practical uses of quantitative autoradiography are demonstrated by means of the estimation of activity distribution in radioactive foil samples. (author)

Quantitative Ability as Correlates of Students' Academic ...

African Journals Online (AJOL)

Nekky Umera

The introduction of quantitative topics into the secondary school economics curriculum has ... since the quality of education at any level is highly dependent on the quality and dedication of ..... Ibadan: Constellations Books 466-481. Anderson ...

The Application of the Photographic Plate to the Quantitative Determination of Activities by Track Counts

International Nuclear Information System (INIS)

Broda, E.

1946-01-01

This report was written by E. Broda at the Cavendish Laboratory (Cambridge) in August 1946 and is about the application of the photographic plate to the quantitative determination of activities by track counts. This report includes the experiment description and the discussion of the results and consists of 4 parts: 1) Introduction 2) Estimation of Concentrations 3) The uptake of U in different conditions 4) The upper limits of the fission Cross sections of Bi and Pb. (nowak)

The Application of the Photographic Plate to the Quantitative Determination of Activities by Track Counts

Energy Technology Data Exchange (ETDEWEB)

Broda, E.

1946-07-01

This report was written by E. Broda at the Cavendish Laboratory (Cambridge) in August 1946 and is about the application of the photographic plate to the quantitative determination of activities by track counts. This report includes the experiment description and the discussion of the results and consists of 4 parts: 1) Introduction 2) Estimation of Concentrations 3) The uptake of U in different conditions 4) The upper limits of the fission Cross sections of Bi and Pb. (nowak)

Constitutive NADPH-dependent electron transferase activity of the Nox4 dehydrogenase domain.

Science.gov (United States)

Nisimoto, Yukio; Jackson, Heather M; Ogawa, Hisamitsu; Kawahara, Tsukasa; Lambeth, J David

2010-03-23

NADPH oxidase 4 (Nox4) is constitutively active, while Nox2 requires the cytosolic regulatory subunits p47(phox) and p67(phox) and activated Rac with activation by phorbol 12-myristate 13-acetate (PMA). This study was undertaken to identify the domain on Nox4 that confers constitutive activity. Lysates from Nox4-expressing cells exhibited constitutive NADPH- but not NADH-dependent hydrogen peroxide production with a K(m) for NADPH of 55 +/- 10 microM. The concentration of Nox4 in cell lysates was estimated using Western blotting and allowed calculation of a turnover of approximately 200 mol of H(2)O(2) min(-1) (mol of Nox4)(-1). A chimeric protein (Nox2/4) consisting of the Nox2 transmembrane (TM) domain and the Nox4 dehydrogenase (DH) domain showed H(2)O(2) production in the absence of cytosolic regulatory subunits. In contrast, chimera Nox4/2, consisting of the Nox4 TM and Nox2 DH domains, exhibited PMA-dependent activation that required coexpression of regulatory subunits. Nox DH domains from several Nox isoforms were purified and evaluated for their electron transferase activities. Nox1 DH, Nox2 DH, and Nox5 DH domains exhibited barely detectable activities toward artificial electron acceptors, while the Nox4 DH domain exhibited significant rates of reduction of cytochrome c (160 min(-1), largely superoxide dismutase-independent), ferricyanide (470 min(-1)), and other electron acceptors (artificial dyes and cytochrome b(5)). Rates were similar to those observed for H(2)O(2) production by the Nox4 holoenzyme in cell lysates. The activity required added FAD and was seen with NADPH but not NADH. These results indicate that the Nox4 DH domain exists in an intrinsically activated state and that electron transfer from NADPH to FAD is likely to be rate-limiting in the NADPH-dependent reduction of oxygen by holo-Nox4.

PEG-b-PCL polymeric nano-micelle inhibits vascular angiogenesis by activating p53-dependent apoptosis in zebrafish.

Science.gov (United States)

Zhou, Tian; Dong, Qinglei; Shen, Yang; Wu, Wei; Wu, Haide; Luo, Xianglin; Liao, Xiaoling; Wang, Guixue

Micro/nanoparticles could cause adverse effects on cardiovascular system and increase the risk for cardiovascular disease-related events. Nanoparticles prepared from poly(ethylene glycol) (PEG)- b -poly( ε -caprolactone) (PCL), namely PEG- b -PCL, a widely studied biodegradable copolymer, are promising carriers for the drug delivery systems. However, it is unknown whether polymeric PEG- b -PCL nano-micelles give rise to potential complications of the cardiovascular system. Zebrafish were used as an in vivo model to evaluate the effects of PEG- b -PCL nano-micelle on cardiovascular development. The results showed that PEG- b -PCL nano-micelle caused embryo mortality as well as embryonic and larval malformations in a dose-dependent manner. To determine PEG- b -PCL nano-micelle effects on embryonic angiogenesis, a critical process in zebrafish cardiovascular development, growth of intersegmental vessels (ISVs) and caudal vessels (CVs) in flk1-GFP transgenic zebrafish embryos using fluorescent stereomicroscopy were examined. The expression of fetal liver kinase 1 (flk1), an angiogenic factor, by real-time quantitative polymerase chain reaction (qPCR) and in situ whole-mount hybridization were also analyzed. PEG- b -PCL nano-micelle decreased growth of ISVs and CVs, as well as reduced flk1 expression in a concentration-dependent manner. Parallel to the inhibitory effects on angiogenesis, PEG- b -PCL nano-micelle exposure upregulated p53 pro-apoptotic pathway and induced cellular apoptosis in angiogenic regions by qPCR and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay. This study further showed that inhibiting p53 activity, either by pharmacological inhibitor or RNA interference, could abrogate the apoptosis and angiogenic defects caused by PEG- b -PCL nano-micelles, indicating that PEG- b -PCL nano-micelle inhibits angiogenesis by activating p53-mediated apoptosis. This study indicates that polymeric PEG- b -PCL nano-micelle could

Quantitative evaluation of hidden defects in cast iron components using ultrasound activated lock-in vibrothermography.

Science.gov (United States)

Montanini, R; Freni, F; Rossi, G L

2012-09-01

This paper reports one of the first experimental results on the application of ultrasound activated lock-in vibrothermography for quantitative assessment of buried flaws in complex cast parts. The use of amplitude modulated ultrasonic heat generation allowed selective response of defective areas within the part, as the defect itself is turned into a local thermal wave emitter. Quantitative evaluation of hidden damages was accomplished by estimating independently both the area and the depth extension of the buried flaws, while x-ray 3D computed tomography was used as reference for sizing accuracy assessment. To retrieve flaw's area, a simple yet effective histogram-based phase image segmentation algorithm with automatic pixels classification has been developed. A clear correlation was found between the thermal (phase) signature measured by the infrared camera on the target surface and the actual mean cross-section area of the flaw. Due to the very fast cycle time (<30 s/part), the method could potentially be applied for 100% quality control of casting components.

Similar expression patterns of bestrophin-4 and cGMP dependent Ca2+-activated chloride channel activity in the vasculature

DEFF Research Database (Denmark)

Bouzinova, Elena V.; Larsen, Per; Matchkov, Vladimir

2008-01-01

(abstract by Matchkov et. al) that siRNA mediated downregulation of bestrophin-4 is associated with the disappearance of a recently demonstrated2 cGMP-dependent Ca2+-activated Cl- current in vascular smooth muscle cells (SMCs). Here we study the distribution of bestrophin-4-and cGMP dependent Cl- channel...... expressed epitope) Western blot detected a ~65 kDa band in cell lysates from rat mesenteric small arteries and aorta, which was not seen in pulmonary arteries and when preincubated with the immunizing peptide. The distribution of bestrophin-4 mRNA and protein has a pattern similar to the cGMP-dependent Cl......- current in SMCs of different origins. Immunohistochemistry identified bestrophin-4 both in endothelial and SMCs of the vascular tree in the brain, heart, kidney and mesentery, but not in the lungs. We suggest that bestrophin-4 is important for the cGMP dependent, Ca2+ activated Cl- conductance in many...

PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design.

Science.gov (United States)

Norinder, U; Högberg, T

1992-04-01

The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.

Latent transforming growth factor beta1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiation

Science.gov (United States)

Ehrhart, E. J.; Segarini, P.; Tsang, M. L.; Carroll, A. G.; Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

1997-01-01

The biological activity of transforming growth factor beta1 (TGF-beta) is controlled by its secretion as a latent complex in which it is noncovalently associated with latency-associated peptide (LAP). Activation is the extracellular process in which TGF-beta is released from LAP, and is considered to be a primary regulatory control. We recently reported rapid and persistent changes in TGF-beta immunoreactivity in conjunction with extracellular matrix remodeling in gamma-irradiated mouse mammary gland. Our hypothesis is that these specific changes in immunoreactivity are indicative of latent TGF-beta activation. In the present study, we determined the radiation dose response and tested whether a functional relationship exists between radiation-induced TGF-beta and collagen type III remodeling. After radiation exposures as low as 0.1 Gy, we detected increased TGF-beta immunoreactivity in the mammary epithelium concomitant with decreased LAP immunostaining, which are events consistent with activation. Quantitative image analysis demonstrated a significant (P=0.0005) response at 0.1 Gy without an apparent threshold and a linear dose response to 5 Gy. However, in the adipose stroma, loss of LAP demonstrated a qualitative threshold at 0.5 Gy. Loss of LAP paralleled induction of collagen III immunoreactivity in this tissue compartment. We tested whether TGF-beta mediates collagen III expression by treating animals with TGF-beta panspecific monoclonal antibody, 1D11.16, administered i.p. shortly before irradiation. Radiation-induced collagen III staining in the adipose stroma was blocked in an antibody dose-dependent manner, which persisted through 7 days postirradiation. RNase protection assay revealed that radiation-induced elevation of total gland collagen III mRNA was also blocked by neutralizing antibody treatment. These data provide functional confirmation of the hypothesis that radiation exposure leads to latent TGF-beta activation, support our interpretation of the

Non-linear quantitative structure-activity relationship for adenine derivatives as competitive inhibitors of adenosine deaminase

International Nuclear Information System (INIS)

Sadat Hayatshahi, Sayyed Hamed; Abdolmaleki, Parviz; Safarian, Shahrokh; Khajeh, Khosro

2005-01-01

Logistic regression and artificial neural networks have been developed as two non-linear models to establish quantitative structure-activity relationships between structural descriptors and biochemical activity of adenosine based competitive inhibitors, toward adenosine deaminase. The training set included 24 compounds with known k i values. The models were trained to solve two-class problems. Unlike the previous work in which multiple linear regression was used, the highest of positive charge on the molecules was recognized to be in close relation with their inhibition activity, while the electric charge on atom N1 of adenosine was found to be a poor descriptor. Consequently, the previously developed equation was improved and the newly formed one could predict the class of 91.66% of compounds correctly. Also optimized 2-3-1 and 3-4-1 neural networks could increase this rate to 95.83%

Activation of Peripheral κ-Opioid Receptors Normalizes Caffeine Effects Modified in Nicotine-Dependent Rats during Nicotine Withdrawal.

Science.gov (United States)

Sudakov, S K; Bogdanova, N G

2016-10-01

The study examined the effect of peripheral (intragastric) ICI-204,448, an agonist of gastric κ-opioid receptors, on the psychostimulating and anxiolytic effects of caffeine in nicotinedependent rats at the stage of nicotine withdrawal. In these rats, the effects of caffeine (10 mg/kg) were perverted. In nicotine-dependent rats, caffeine produced an anxiolytic effect accompanied by pronounced stimulation of motor activity, in contrast to anxiogenic effect induced by caffeine in intact rats without nicotine dependence. During nicotine withdrawal, nicotine-dependent rats demonstrated enhanced sensitivity to nicotine. Intragastric administration of κ-opioid receptor agonist ICI-204,448 normalized the effect of caffeine in nicotinedependent rats. We have previously demonstrated that activation of peripheral κ-opioid receptors inhibited central κ-opioid activity and eliminated manifestations of nicotine withdrawal syndrome in nicotine-dependent rats, e.g. metabolism activation, stimulation of motor activity, and enhancement of food consumption. In its turn, inhibition of central κ-opioid structures activates the brain adenosine system, which can attenuate the caffeine-induced effects in nicotine-dependent rats.

A new sensitive and quantitative HTLV-I-mediated cell fusion assay in T cells

International Nuclear Information System (INIS)

Pare, Marie-Eve; Gauthier, Sonia; Landry, Sebastien; Sun Jiangfeng; Legault, Eric; Leclerc, Denis; Tanaka, Yuetsu; Marriott, Susan J.; Tremblay, Michel J.; Barbeau, Benoit

2005-01-01

Similar to several other viruses, human T cell leukemia virus type I (HTLV-I) induces the formation of multinucleated giant cells (also known as syncytium) when amplified in tissue culture. These syncytia result from the fusion of infected cells with uninfected cells. Due to the intrinsic difficulty of infecting cells with cell-free HTLV-I virions, syncytium formation has become an important tool in the study of HTLV-I infection and transmission. Since most HTLV-I-based cell fusion assays rely on the use of non-T cells, the aim of this study was to optimize a new HTLV-I-induced cell fusion assay in which HTLV-I-infected T cell lines are co-cultured with T cells that have been transfected with an HTLV-I long terminal repeat (LTR) luciferase reporter construct. We demonstrate that co-culture of various HTLV-I-infected T cells with different transfected T cell lines resulted in induction of luciferase activity. Cell-to-cell contact and expression of the viral gp46 envelope protein was crucial for this induction while other cell surface proteins (including HSC70) did not have a significant effect. This quantitative assay was shown to be very sensitive. In this assay, the cell fusion-mediated activation of NF-κB and the HTLV-I LTR occurred through previously described Tax-dependent signaling pathways. This assay also showed that cell fusion could activate Tax-inducible cellular promoters. These results thus demonstrate that this new quantitative HTLV-I-dependent cell fusion assay is versatile, highly sensitive, and can provide an important tool to investigate cellular promoter activation and intrinsic signaling cascades that modulate cellular gene expression

Using quantitative structure-activity relationships (QSAR) to predict toxic endpoints for polycyclic aromatic hydrocarbons (PAH).

Science.gov (United States)

Bruce, Erica D; Autenrieth, Robin L; Burghardt, Robert C; Donnelly, K C; McDonald, Thomas J

2008-01-01

Quantitative structure-activity relationships (QSAR) offer a reliable, cost-effective alternative to the time, money, and animal lives necessary to determine chemical toxicity by traditional methods. Additionally, humans are exposed to tens of thousands of chemicals in their lifetimes, necessitating the determination of chemical toxicity and screening for those posing the greatest risk to human health. This study developed models to predict toxic endpoints for three bioassays specific to several stages of carcinogenesis. The ethoxyresorufin O-deethylase assay (EROD), the Salmonella/microsome assay, and a gap junction intercellular communication (GJIC) assay were chosen for their ability to measure toxic endpoints specific to activation-, induction-, and promotion-related effects of polycyclic aromatic hydrocarbons (PAH). Shape-electronic, spatial, information content, and topological descriptors proved to be important descriptors in predicting the toxicity of PAH in these bioassays. Bioassay-based toxic equivalency factors (TEF(B)) were developed for several PAH using the quantitative structure-toxicity relationships (QSTR) developed. Predicting toxicity for a specific PAH compound, such as a bioassay-based potential potency (PP(B)) or a TEF(B), is possible by combining the predicted behavior from the QSTR models. These toxicity estimates may then be incorporated into a risk assessment for compounds that lack toxicity data. Accurate toxicity predictions are made by examining each type of endpoint important to the process of carcinogenicity, and a clearer understanding between composition and toxicity can be obtained.

Activation of cGAS-dependent antiviral responses by DNA intercalating agents.

Science.gov (United States)

Pépin, Geneviève; Nejad, Charlotte; Thomas, Belinda J; Ferrand, Jonathan; McArthur, Kate; Bardin, Philip G; Williams, Bryan R G; Gantier, Michael P

2017-01-09

Acridine dyes, including proflavine and acriflavine, were commonly used as antiseptics before the advent of penicillins in the mid-1940s. While their mode of action on pathogens was originally attributed to their DNA intercalating activity, work in the early 1970s suggested involvement of the host immune responses, characterized by induction of interferon (IFN)-like activities through an unknown mechanism. We demonstrate here that sub-toxic concentrations of a mixture of acriflavine and proflavine instigate a cyclic-GMP-AMP (cGAMP) synthase (cGAS)-dependent type-I IFN antiviral response. This pertains to the capacity of these compounds to induce low level DNA damage and cytoplasmic DNA leakage, resulting in cGAS-dependent cGAMP-like activity. Critically, acriflavine:proflavine pre-treatment of human primary bronchial epithelial cells significantly reduced rhinovirus infection. Collectively, our findings constitute the first evidence that non-toxic DNA binding agents have the capacity to act as indirect agonists of cGAS, to exert potent antiviral effects in mammalian cells. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Memory and pattern storage in neural networks with activity dependent synapses

Science.gov (United States)

Mejias, J. F.; Torres, J. J.

2009-01-01

We present recently obtained results on the influence of the interplay between several activity dependent synaptic mechanisms, such as short-term depression and facilitation, on the maximum memory storage capacity in an attractor neural network [1]. In contrast with the case of synaptic depression, which drastically reduces the capacity of the network to store and retrieve activity patterns [2], synaptic facilitation is able to enhance the memory capacity in different situations. In particular, we find that a convenient balance between depression and facilitation can enhance the memory capacity, reaching maximal values similar to those obtained with static synapses, that is, without activity-dependent processes. We also argue, employing simple arguments, that this level of balance is compatible with experimental data recorded from some cortical areas, where depression and facilitation may play an important role for both memory-oriented tasks and information processing. We conclude that depressing synapses with a certain level of facilitation allow to recover the good retrieval properties of networks with static synapses while maintaining the nonlinear properties of dynamic synapses, convenient for information processing and coding.

Goal- and retrieval-dependent activity in the striatum during memory recognition.

Science.gov (United States)

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fentanyl activates hypoxia-inducible factor 1 in neuronal SH-SY5Y cells and mice under non-hypoxic conditions in a μ-opioid receptor-dependent manner.

Science.gov (United States)

Daijo, Hiroki; Kai, Shinichi; Tanaka, Tomoharu; Wakamatsu, Takuhiko; Kishimoto, Shun; Suzuki, Kengo; Harada, Hiroshi; Takabuchi, Satoshi; Adachi, Takehiko; Fukuda, Kazuhiko; Hirota, Kiichi

2011-09-30

Hypoxia-inducible factor 1 (HIF-1) is the main transcription factor responsible for hypoxia-induced gene expression. Perioperative drugs including anesthetics have been reported to affect HIF-1 activity. However, the effect of fentanyl on HIF-1 activity is not well documented. In this study, we investigated the effect of fentanyl and other opioids on HIF-1 activity in human SH-SY5Y neuroblastoma cells, hepatoma Hep3B cells, lung adenocarcinoma A549 cells and mice. Cells were exposed to fentanyl, and HIF-1 protein expression was examined by Western blot analysis using anti-HIF-1α and β antibodies. HIF-1-dependent gene expression was investigated by semi-quantitative real-time reverse transcriptase (RT)-PCR (qRT-PCR) and luciferase assay. Furthermore, fentanyl was administered intraperitoneally and HIF-1-dependent gene expression was investigated by qRT-PCR in the brains and kidneys of mice. A 10-μM concentration of fentanyl and other opioids, including 1 μM morphine and 4 μM remifentanil, induced HIF-1α protein expression and HIF-1 target gene expression in an opioid receptor-dependent manner in SH-SY5Y cells with activity peaking at 24h. Fentanyl did not augment HIF-1α expression during hypoxia-induced induction. HIF-1α stabilization assays and experiments with cycloheximide revealed that fentanyl increased translation from HIF-1α mRNA but did not stabilize the HIF-1α protein. Furthermore, fentanyl induced HIF-1 target gene expression in the brains of mice but not in their kidneys in a naloxone-sensitive manner. In this report, we describe for the first time that fentanyl, both in vitro and in vivo, induces HIF-1 activation under non-hypoxic conditions, leading to increases in expression of genes associated with adaptation to hypoxia. Copyright © 2011 Elsevier B.V. All rights reserved.

A quantitative speciation model for the adsorption of organic pollutants on activated carbon.

Science.gov (United States)

Grivé, M; García, D; Domènech, C; Richard, L; Rojo, I; Martínez, X; Rovira, M

2013-01-01

Granular activated carbon (GAC) is commonly used as adsorbent in water treatment plants given its high capacity for retaining organic pollutants in aqueous phase. The current knowledge on GAC behaviour is essentially empirical, and no quantitative description of the chemical relationships between GAC surface groups and pollutants has been proposed. In this paper, we describe a quantitative model for the adsorption of atrazine onto GAC surface. The model is based on results of potentiometric titrations and three types of adsorption experiments which have been carried out in order to determine the nature and distribution of the functional groups on the GAC surface, and evaluate the adsorption characteristics of GAC towards atrazine. Potentiometric titrations have indicated the existence of at least two different families of chemical groups on the GAC surface, including phenolic- and benzoic-type surface groups. Adsorption experiments with atrazine have been satisfactorily modelled with the geochemical code PhreeqC, assuming that atrazine is sorbed onto the GAC surface in equilibrium (log Ks = 5.1 ± 0.5). Independent thermodynamic calculations suggest a possible adsorption of atrazine on a benzoic derivative. The present work opens a new approach for improving the adsorption capabilities of GAC towards organic pollutants by modifying its chemical properties.

Time-dependent restricted-active-space self-consistent-field theory for laser-driven many-electron dynamics

DEFF Research Database (Denmark)

Miyagi, Haruhide; Madsen, Lars Bojer

2013-01-01

We present the time-dependent restricted-active-space self-consistent-field (TD-RASSCF) theory as a framework for the time-dependent many-electron problem. The theory generalizes the multiconfigurational time-dependent Hartree-Fock (MCTDHF) theory by incorporating the restricted-active-space scheme...... well known in time-independent quantum chemistry. Optimization of the orbitals as well as the expansion coefficients at each time step makes it possible to construct the wave function accurately while using only a relatively small number of electronic configurations. In numerical calculations of high...

TNF-α mediates choroidal neovascularization by upregulating VEGF expression in RPE through ROS-dependent β-catenin activation.

Science.gov (United States)

Wang, Haibo; Han, Xiaokun; Wittchen, Erika S; Hartnett, M Elizabeth

2016-01-01

Inflammation, oxidative stress, and angiogenesis have been proposed to interact in age-related macular degeneration. It has been postulated that external stimuli that cause oxidative stress can increase production of vascular endothelial growth factor (VEGF) in retinal pigment epithelial (RPE) cells. In this study, we tested the hypothesis that the inflammatory cytokine, tumor necrosis factor alpha (TNF-α), contributed to choroidal neovascularization (CNV) by upregulating VEGF in RPE through intracellular reactive oxygen species (ROS)-dependent signaling and sought to understand the mechanisms involved. In a murine laser-induced CNV model, 7 days after laser treatment and intravitreal neutralizing mouse TNF-α antibody or isotype immunoglobulin G (IgG) control, the following measurements were made: 1) TNF-α protein and VEGF protein in RPE/choroids with western blot, 2) CNV volume in RPE/choroidal flatmounts, and 3) semiquantification of oxidized phospholipids stained with E06 antibody within CNV with immunohistochemistry (IHC). In cultured human RPE cells treated with TNF-α or PBS control, 1) ROS generation was measured using the 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence assay, and 2) NOX4 protein and VEGF protein or mRNA were measured with western blot or quantitative real-time PCR in cells pretreated with apocynin or nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) inhibitor, VAS 2870, or transfected with p22phox siRNA, and each was compared to its appropriate control. Western blots of phosphorylated p65 (p-p65), total p65 and β-actin, and quantitative real-time PCR of VEGF mRNA were measured in human RPE cells treated with TNF-α and pretreatment with the nuclear factor kappa B inhibitor, Bay 11-7082 or control. Western blots of β-catenin, VEGF, and p22phox and coimmunoprecipitation of β-catenin and T-cell transcriptional factor were performed in human RPE cells treated with TNF-α following pretreatment with �

Quantitatively accurate activity measurements with a dedicated cardiac SPECT camera: Physical phantom experiments

Energy Technology Data Exchange (ETDEWEB)

Pourmoghaddas, Amir, E-mail: apour@ottawaheart.ca; Wells, R. Glenn [Physics Department, Carleton University, Ottawa, Ontario K1S 5B6, Canada and Cardiology, The University of Ottawa Heart Institute, Ottawa, Ontario K1Y4W7 (Canada)

2016-01-15

Purpose: Recently, there has been increased interest in dedicated cardiac single photon emission computed tomography (SPECT) scanners with pinhole collimation and improved detector technology due to their improved count sensitivity and resolution over traditional parallel-hole cameras. With traditional cameras, energy-based approaches are often used in the clinic for scatter compensation because they are fast and easily implemented. Some of the cardiac cameras use cadmium-zinc-telluride (CZT) detectors which can complicate the use of energy-based scatter correction (SC) due to the low-energy tail—an increased number of unscattered photons detected with reduced energy. Modified energy-based scatter correction methods can be implemented, but their level of accuracy is unclear. In this study, the authors validated by physical phantom experiments the quantitative accuracy and reproducibility of easily implemented correction techniques applied to {sup 99m}Tc myocardial imaging with a CZT-detector-based gamma camera with multiple heads, each with a single-pinhole collimator. Methods: Activity in the cardiac compartment of an Anthropomorphic Torso phantom (Data Spectrum Corporation) was measured through 15 {sup 99m}Tc-SPECT acquisitions. The ratio of activity concentrations in organ compartments resembled a clinical {sup 99m}Tc-sestamibi scan and was kept consistent across all experiments (1.2:1 heart to liver and 1.5:1 heart to lung). Two background activity levels were considered: no activity (cold) and an activity concentration 1/10th of the heart (hot). A plastic “lesion” was placed inside of the septal wall of the myocardial insert to simulate the presence of a region without tracer uptake and contrast in this lesion was calculated for all images. The true net activity in each compartment was measured with a dose calibrator (CRC-25R, Capintec, Inc.). A 10 min SPECT image was acquired using a dedicated cardiac camera with CZT detectors (Discovery NM530c, GE

Time-dependent changes in rat lymphocyte activity in response to isolation

International Nuclear Information System (INIS)

Jessop, J.J.; Bayer, B.M.

1986-01-01

The authors have found that isolation of rats, previously adapted to group-housing conditions, resulted in time-dependent changes in mitogenic and cytolytic responses of lymphocytes. A depression (40-60%) of the uptake of 3 H-thymidine by splenic and blood lymphocytes stimulated with either phytohemagglutinin (PHA) or lipopolysaccharide (LPS) was observed during the first 48 hours after transfer of the animals to individual cages. Within 4 days the mitogenic response increased and was comparable to that of animals which had been continuously group-housed. The response continued to increase and by 10 days was enhanced by 2 to 4 fold and remained elevated for at least 8 weeks. Similar changes in activity were observed with both splenic and blood lymphocytes, however, thymic lymphocytes taken from isolated animals demonstrated no change in reactivity to PHA. As with mitogenic responses, the cytolytic activity of splenic lymphocytes was also depressed during the initial days of isolation and as isolation continued, the activity returned to normal and was significantly enhanced (80%) within 5 weeks. These data show that changes in lymphocyte activity are dependent on the duration of exposure to isolated housing conditions and may be a part of the acute, adaptive and chronic phases of the response of rats to the stress of isolation

Quantitative proteomic analysis of post-translational modifications of human histones

DEFF Research Database (Denmark)

Beck, Hans Christian; Nielsen, Eva C; Matthiesen, Rune

2006-01-01

, and H4 in a site-specific and dose-dependent manner. This unbiased analysis revealed that a relative increase in acetylated peptide from the histone variants H2A, H2B, and H4 was accompanied by a relative decrease of dimethylated Lys(57) from histone H2B. The dose-response results obtained...... by quantitative proteomics of histones from HDACi-treated cells were consistent with Western blot analysis of histone acetylation, cytotoxicity, and dose-dependent expression profiles of p21 and cyclin A2. This demonstrates that mass spectrometry-based quantitative proteomic analysis of post-translational...

Dependence of Photocatalytic Activity of TiO2-SiO2 Nanopowders

Directory of Open Access Journals (Sweden)

M. Riazian

2014-10-01

Full Text Available Structural properties and chemical composition change the photocatalytic activity in TiO2-SiO2 nanopowder composite. The SiO2-TiO2 nanostructure is synthesized based on sol–gel method. The nanoparticles are characterized by x-ray fluorescents (XRF, x- ray diffraction (XRD, tunneling electron microscopy (TEM, field emission scanning electron microscopy (FE-SEM, UV-vis. Spectrophotometer and furrier transmission create infrared absorption (FTIR techniques. The rate constant k for the degradation of methylen blue in its aqueous solution under UV irradiation is determined as a measure of photocatalytic activity. Dependence between photocatalytic activity and SiO2 content in the composite is determined. Rate constant k is found dependent on the content of SiO2 in the composite that calcined at 900 oC. The addition of low composition SiO2 to the TiO2 matrix (lower than 45% enhances the photocatalytic activity due to thermal stability and increasing in the surface area. The effects of chemical compositions on the surface topography and the crystallization of phases are studied.

Free radical activity during development of insulin-dependent diabetes mellitus in the rat

Energy Technology Data Exchange (ETDEWEB)

Pitkaenen, O.M.; Akerblom, H.K.; Sariola, H.; Andersson, S.M. (Univ. of Helsinki (Finland)); Martin, J.M. (Hospital for Sick Children, Toronto, Ontario (Canada)); Hallman, M. (Univ. of California, Irvine (United States))

1991-01-01

Free radical-induced lipid peroxidation was quantified by measuring expired pentane from diabetic prone BB Wistar rats of 45-90 d of age. Insulin-dependent diabetes mellitus was manifest at the age of 71 {plus minus} 8 d. Expired pentane increased from 2.1 {plus minus} 0.7 to 5.0 {plus minus}3.0 pmol/100g/min (p <0.01) at manifestation of the disease and remained high throughout the test period. In healthy age-matched control rats it persisted low. In rats made diabetic with streptozotocin, expired pentane remained low. The changes in expired pentane suggest that the development of endogenous insulin-dependent diabetes mellitus in BB rats is associated with increased free radical activity. This is not due to hyperglycemia or ketosis per se, and reflects a fundamental difference in the free radical activity between the spontaneously diabetic BB rats and the disease produced by streptozotocin. Development of spontaneous insulin-dependent diabetes in BB rats is associated with increased free radical activity that persists after the manifestation of the disease.

Bacteria and viruses modulate FcεRI-dependent mast cell activity 

Directory of Open Access Journals (Sweden)

Aleksandra Słodka

2013-03-01

Full Text Available 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. 

Quantitative determination of glycyrrhizinic acid by square-wave

Directory of Open Access Journals (Sweden)

Aneta Dimitrovska

2003-06-01

Full Text Available Novel adsorptive stripping square-wave voltammetric method as well as a new high-pressure liquid chromatographic method for direct determination of glycyrrhizinic acid in dosage pharmaceutical preparation, used against virus infections, have been developed. Glycyrrhizinic acid is an electrochemically active compound, which undergoes irreversible reduction on a mercury electrode surface in an aqueous medium. Its redox properties were studied thoroughly by means of square-wave voltammetry, as one of the most advanced electroanalytical technique. The voltammetric response depends mainly on the pH of the medium, composition of the supporting electrolyte, as well as the parameters of the excitement signal. It was also observed that the voltammetric properties strongly depend on the accumulation time and potential, revealing significant adsorption of glycyrrhizinic acid onto the mercury electrode surface. Upon this feature, an adsorptive stripping voltammetric method for quantitative determination of glycyrrhizinic acid was developed. A simple, sensitive and precise reversed phase HPLC method with photodiode array UV detection has also been developed, mainly for comparison and conformation of the results obtained with the voltammetric method.

Constitutive NADPH-Dependent Electron Transferase Activity of the Nox4 Dehydrogenase Domain?

OpenAIRE

Nisimoto, Yukio; Jackson, Heather M.; Ogawa, Hisamitsu; Kawahara, Tsukasa; Lambeth, J. David

2010-01-01

NADPH oxidase 4 (Nox4) is constitutively active, while Nox2 requires the cytosolic regulatory subunits p47 phox and p67 phox and activated Rac with activation by phorbol 12-myristate 13-acetate (PMA). This study was undertaken to identify the domain on Nox4 that confers constitutive activity. Lysates from Nox4-expressing cells exhibited constitutive NADPH- but not NADH-dependent hydrogen peroxide production with a K m for NADPH of 55 ? 10 ?M. The concentration of Nox4 in cell lysates was esti...

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration.

Directory of Open Access Journals (Sweden)

Donghee Park

Full Text Available Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration.

Science.gov (United States)

Park, Donghee; Song, Gillsoo; Jo, Yongjun; Won, Jongho; Son, Taeyoon; Cha, Ohrum; Kim, Jinho; Jung, Byungjo; Park, Hyunjin; Kim, Chul-Woo; Seo, Jongbum

2016-01-01

Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa) causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with microbubbles depends on the

Quantitative and Label-Free Detection of Protein Kinase A Activity Based on Surface-Enhanced Raman Spectroscopy with Gold Nanostars.

Science.gov (United States)

He, Shuai; Kyaw, Yi Mon Ei; Tan, Eddie Khay Ming; Bekale, Laurent; Kang, Malvin Wei Cherng; Kim, Susana Soo-Yeon; Tan, Ivan; Lam, Kong-Peng; Kah, James Chen Yong

2018-04-26

The activity of extracellular protein kinase A (PKA) is known to be a biomarker for cancer. However, conventional PKA assays based on colorimetric, radioactive, and fluorometric techniques suffer from intensive labeling-related preparations, background interference, photobleaching, and safety concerns. While surface-enhanced Raman spectroscopy (SERS)-based assays have been developed for various enzymes to address these limitations, their use in probing PKA activity is limited due to subtle changes in the Raman spectrum with phosphorylation. Here, we developed a robust colloidal SERS-based scheme for label-free quantitative measurement of PKA activity using gold nanostars (AuNS) as a SERS substrate functionalized with bovine serum albumin (BSA)-kemptide (Kem) bioconjugate (AuNS-BSA-Kem), where BSA conferred colloidal stability and Kem is a high-affinity peptide substrate for PKA. By performing principle component analysis (PCA) on the SERS spectrum, we identified two Raman peaks at 725 and 1395 cm -1 , whose ratiometric intensity change provided a quantitative measure of Kem phosphorylation by PKA in vitro and allowed us to distinguish MDA-MB-231 and MCF-7 breast cancer cells known to overexpress extracellular PKA catalytic subunits from noncancerous human umbilical vein endothelial cells (HUVEC) based on their PKA activity in cell culture supernatant. The outcome demonstrated potential application of AuNS-BSA-Kem as a SERS probe for cancer screening based on PKA activity.

Quantitative structure-activity relationships of selective antagonists of glucagon receptor using QuaSAR descriptors.

Science.gov (United States)

Manoj Kumar, Palanivelu; Karthikeyan, Chandrabose; Hari Narayana Moorthy, Narayana Subbiah; Trivedi, Piyush

2006-11-01

In the present paper, quantitative structure activity relationship (QSAR) approach was applied to understand the affinity and selectivity of a novel series of triaryl imidazole derivatives towards glucagon receptor. Statistically significant and highly predictive QSARs were derived for glucagon receptor inhibition by triaryl imidazoles using QuaSAR descriptors of molecular operating environment (MOE) employing computer-assisted multiple regression procedure. The generated QSAR models revealed that factors related to hydrophobicity, molecular shape and geometry predominantly influences glucagon receptor binding affinity of the triaryl imidazoles indicating the relevance of shape specific steric interactions between the molecule and the receptor. Further, QSAR models formulated for selective inhibition of glucagon receptor over p38 mitogen activated protein (MAP) kinase of the compounds in the series highlights that the same structural features, which influence the glucagon receptor affinity, also contribute to their selective inhibition.

Introduction to the Symposium "Leading Students and Faculty to Quantitative Biology through Active Learning".

Science.gov (United States)

Waldrop, Lindsay D; Miller, Laura A

2015-11-01

The broad aim of this symposium and set of associated papers is to motivate the use of inquiry-based, active-learning teaching techniques in undergraduate quantitative biology courses. Practical information, resources, and ready-to-use classroom exercises relevant to physicists, mathematicians, biologists, and engineers are presented. These resources can be used to address the lack of preparation of college students in STEM fields entering the workforce by providing experience working on interdisciplinary and multidisciplinary problems in mathematical biology in a group setting. Such approaches can also indirectly help attract and retain under-represented students who benefit the most from "non-traditional" learning styles and strategies, including inquiry-based, collaborative, and active learning. © The Author 2015. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

Origins and implications of temperature-dependent activation energy barriers for dislocation nucleation in face-centered cubic metals

International Nuclear Information System (INIS)

Warner, D.H.; Curtin, W.A.

2009-01-01

The linking of atomistic simulations of stress-driven processes to experimentally observed mechanical behavior via the computation of activation energy barriers is a topic of intense current research. Using dislocation nucleation from a crack tip as the reaction process, long-time multiscale molecular dynamics simulations show that the activation barrier can exhibit significant temperature dependence. Using an analytic model for the nucleation process and computing the relevant material properties (elastic constants and stacking fault energies), the temperature dependence is shown to arise primarily from the temperature dependence of the material parameters for both Al and Ni. After thermally activated emission of the first partial dislocation, there is then a competition between two other thermally activated processes: twinning and full dislocation emission. Because the activation barriers depend on temperature, this transition is more complex than usually envisioned. Simulations in Al reveal that a transition from twinning to full dislocation emission back to twinning occurs with increasing temperature, which is counter to traditional metallurgical wisdom. Temperature-dependent activation energies are thus essential to accurate understanding and prediction of those phenomena that control fracture and deformation in metals at realistic loading rates.

Active ion transport in the renal proximal tubule. II. Ionic dependence of the Na pump

OpenAIRE

1984-01-01

The dependence of Na pump activity on intracellular and extracellular Na+ and K+ was investigated using a suspension of rabbit cortical tubules that contained mostly (86%) proximal tubules. The ouabain- sensitive rate of respiration (QO2) was used to measure the Na pump activity of intact tubules, and the Na,K-ATPase hydrolytic activity was measured using lysed proximal tubule membranes. The dependence (K0.5) of the Na pump on intracellular Na+ was affected by the relative intracellular conce...

Phospholipase A2 activity-dependent and -independent fusogenic activity of Naja nigricollis CMS-9 on zwitterionic and anionic phospholipid vesicles.

Science.gov (United States)

Chiou, Yi-Ling; Chen, Ying-Jung; Lin, Shinne-Ren; Chang, Long-Sen

2011-11-01

CMS-9, a phospholipase A(2) (PLA(2)) from Naja nigricollis venom, induced the death of human breast cancer MCF-7 cells accompanied with the formation of cell clumps without clear boundaries between cells. Annexin V-FITC staining indicated that abundant phosphatidylserine appeared on the outer membrane of MCF-7 cell clumps, implying the possibility that CMS-9 may promote membrane fusion via anionic phospholipids. To validate this proposition, fusogenic activity of CMS-9 on vesicles composed of zwitterionic phospholipid alone or a combination of zwitterionic and anionic phospholipids was examined. Although CMS-9-induced fusion of zwitterionic phospholipid vesicles depended on PLA(2) activity, CMS-9-induced fusion of vesicles containing anionic phospholipids could occur without the involvement of PLA(2) activity. Membrane-damaging activity of CMS-9 was associated with its fusogenicity. Moreover, CMS-9 induced differently membrane leakage and membrane fusion of vesicles with different compositions. Membrane fluidity and binding capability with phospholipid vesicles were not related to the fusogenicity of CMS-9. However, membrane-bound conformation and mode of CMS-9 depended on phospholipid compositions. Collectively, our data suggest that PLA(2) activity-dependent and -independent fusogenicity of CMS-9 are closely related to its membrane-bound modes and targeted membrane compositions. Copyright © 2011 Elsevier Ltd. All rights reserved.

Quantitative proteomics reveals the mechanism and consequence of gliotoxin-mediated dysregulation of the methionine cycle in Aspergillus niger

OpenAIRE

Manzanares-Miralles, Lara; Bayram, Ozgur; Sarikaya-Bayram, Ozlem; Smith, Elizabeth B.; Dolan, Stephen K.; Jones, Gary W.; Doyle, Sean

2016-01-01

Gliotoxin (GT) is a redox-active metabolite, produced by Aspergillus fumigatus,which inhibits the growth of other fungi. Here we demonstrate how Aspergillus niger responds to GT exposure. Quantitative proteomics revealed that GT dysregulated the abundance of 378 proteins including those involved in methionine metabolism and induced de novo abundance of two S-adenosylmethionine (SAM)-dependent methyltransferases. Increased abundance of enzymes S-adenosylhomocysteinase (p = 0.0018) ...

Shaping inhibition: activity dependent structural plasticity of GABAergic synapses

Directory of Open Access Journals (Sweden)

Carmen E Flores

2014-10-01

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

Frequency dependence of the active impedance component of silicon thin-film resistors

International Nuclear Information System (INIS)

Belogurov, S.V.; Gostilo, V.V.; Yurov, A.S.

1987-01-01

A high-resistant resistor on the silicon thin-film substrate considerably superior in noise and frequency performance than commercial resistors is described. The frequency dependence of the active impedance component is tested for determining noise and frequency dependences of silicon thin-film resistors. The obtained results permit to calculate the energy equivalent of resistor noise in nuclear radiation detection units at any temperature according to its frequency characteristic at room temperature

Spatial-temporal patterns of retinal waves underlying activity-dependent refinement of retinofugal projections.

Science.gov (United States)

Stafford, Ben K; Sher, Alexander; Litke, Alan M; Feldheim, David A

2009-10-29

During development, retinal axons project coarsely within their visual targets before refining to form organized synaptic connections. Spontaneous retinal activity, in the form of acetylcholine-driven retinal waves, is proposed to be necessary for establishing these projection patterns. In particular, both axonal terminations of retinal ganglion cells (RGCs) and the size of receptive fields of target neurons are larger in mice that lack the beta2 subunit of the nicotinic acetylcholine receptor (beta2KO). Here, using a large-scale, high-density multielectrode array to record activity from hundreds of RGCs simultaneously, we present analysis of early postnatal retinal activity from both wild-type (WT) and beta2KO retinas. We find that beta2KO retinas have correlated patterns of activity, but many aspects of these patterns differ from those of WT retina. Quantitative analysis suggests that wave directionality, coupled with short-range correlated bursting patterns of RGCs, work together to refine retinofugal projections.

Time-dependent restricted-active-space self-consistent-field theory for bosonic many-body systems

International Nuclear Information System (INIS)

Lévêque, Camille; Madsen, Lars Bojer

2017-01-01

We develop an ab initio time-dependent wavefunction based theory for the description of a many-body system of cold interacting bosons. Like the multi-configurational time-dependent Hartree method for bosons (MCTDHB), the theory is based on a configurational interaction Ansatz for the many-body wavefunction with time-dependent self-consistent-field orbitals. The theory generalizes the MCTDHB method by incorporating restrictions on the active space of the orbital excitations. The restrictions are specified based on the physical situation at hand. The equations of motion of this time-dependent restricted-active-space self-consistent-field (TD-RASSCF) theory are derived. The similarity between the formal development of the theory for bosons and fermions is discussed. The restrictions on the active space allow the theory to be evaluated under conditions where other wavefunction based methods due to exponential scaling in the numerical effort cannot, and to clearly identify the excitations that are important for an accurate description, significantly beyond the mean-field approach. For ground state calculations we find it to be important to allow a few particles to have the freedom to move in many orbitals, an insight facilitated by the flexibility of the restricted-active-space Ansatz . Moreover, we find that a high accuracy can be obtained by including only even excitations in the many-body self-consistent-field wavefunction. Time-dependent simulations of harmonically trapped bosons subject to a quenching of their noncontact interaction, show failure of the mean-field Gross-Pitaevskii approach within a fraction of a harmonic oscillation period. The TD-RASSCF theory remains accurate at much reduced computational cost compared to the MCTDHB method. Exploring the effect of changes of the restricted-active-space allows us to identify that even self-consistent-field excitations are mainly responsible for the accuracy of the method. (paper)

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

Science.gov (United States)

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

2016-01-01

Abstract 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

Time-Dependent Changes in T1 during Fracture Healing in Juvenile Rats: A Quantitative MR Approach.

Directory of Open Access Journals (Sweden)

Katharina Baron

Full Text Available Quantitative magnetic resonance imaging (qMRI offers several advantages in imaging and determination of soft tissue alterations when compared to qualitative imaging techniques. Although applications in brain and muscle tissues are well studied, its suitability to quantify relaxation times of intact and injured bone tissue, especially in children, is widely unknown. The objective observation of a fracture including its age determination can become of legal interest in cases of child abuse or maltreatment. Therefore, the aim of this study is the determination of time dependent changes in intact and corresponding injured bones in immature rats via qMRI, to provide the basis for an objective and radiation-free approach for fracture dating. Thirty-five MR scans of 7 Sprague-Dawley rats (male, 4 weeks old, 100 ± 5 g were acquired on a 3T MRI scanner (TimTrio, Siemens AG, Erlangen, Germany after the surgical infliction of an epiphyseal fracture in the tibia. The images were taken at days 1, 3, 7, 14, 28, 42 and 82 post-surgery. A proton density-weighted and a T1-weighted 3D FLASH sequence were acquired to calculate the longitudinal relaxation time T1 of the fractured region and the surrounding tissues. The calculation of T1 in intact and injured bone resulted in a quantitative observation of bone development in intact juvenile tibiae as well as the bone healing process in the injured tibiae. In both areas, T1 decreased over time. To evaluate the differences in T1 behaviour between the intact and injured bone, the relative T1 values (bone-fracture were calculated, showing clear detectable alterations of T1 after fracture occurrence. These results indicate that qMRI has a high potential not only for clinically relevant applications to detect growth defects or developmental alterations in juvenile bones, but also for forensically relevant applications such as the dating of fractures in cases of child abuse or maltreatment.

Task-dependent modulation of oscillatory neural activity during movements

DEFF Research Database (Denmark)

Herz, D. M.; Christensen, M. S.; Reck, C.

2011-01-01

connectivity was strongest between central and cerebellar regions. Our results show that neural coupling within motor networks is modulated in distinct frequency bands depending on the motor task. They provide evidence that dynamic causal modeling in combination with EEG source analysis is a valuable tool......Neural oscillations in different frequency bands have been observed in a range of sensorimotor tasks and have been linked to coupling of spatially distinct neurons. The goal of this study was to detect a general motor network that is activated during phasic and tonic movements and to study the task......-dependent modulation of frequency coupling within this network. To this end we recorded 122-multichannel EEG in 13 healthy subjects while they performed three simple motor tasks. EEG data source modeling using individual MR images was carried out with a multiple source beamformer approach. A bilateral motor network...

The effect of sports activities in children and adolescents on the calcaneus - an investigation with quantitative ultrasound

International Nuclear Information System (INIS)

Mentzel, H.J.; Malich, A.; Boettcher, J.; Vogt, S.; Kaiser, W.A.; Wuensche, K.

2005-01-01

Purpose: To determine whether quantitative ultrasound (QUS) parameters speed of sound (SOS) and broadband ultrasound attenuation (BUA) on the calcaneus are different between athletic children and a reference population. Patients and Methods: From a college of physical education, 177 children and adolescents (121 boys and 56 girls, age range from 11 to 18 years) were included in this study. QUS was performed on the calcaneus using the Sahara trademark device (Hologic, USA). SOS and BUA were estimated. Regional reference values of 3299 children were used to determine significant differences between athletes and reference population. The influence of activity level, age, height, and weight was estimated using correlation analysis. Results: Sportsmen showed significant (p<0.05) higher values of the QUS parameters (SOS 1581.1 m/s; BUA 69.7 dB/MHz) compared to the reference data (SOS 1563.9 m/s; BUA 64.2 dB/MHz). Significant correlation was observed between BUA and the level of activity, age, weight, and height (p<0.01) and between SOS and weight and height (p<0.05). In the group of soccer players and athletes, significant correlation was found between BUA vs. age and BUA vs. weight (p<0.05). Furthermore, significant correlation was observed between BUA vs. age and weight in Judokas and Wrestlers. For the level of activity, a significant correlation to BUA was only found in the group of Judokas and Wrestlers (p<0.01). Conclusion: An increase in quantitative ultrasound parameters on the calcaneus occurs in children and adolescents with increased physical activity. (orig.)

Prostasin-dependent activation of epithelial Na+ channels by low plasmin concentrations

DEFF Research Database (Denmark)

Svenningsen, Per; Uhrenholt, Torben R; Palarasah, Yaseelan

2009-01-01

by which plasmin stimulates ENaC activity. Cy3-labeled plasmin was found to bind to the surface of the mouse cortical collecting duct cell line, M-1. Binding depended on a glycosylphosphatidylinositol (GPI)-anchored protein. Biotin-label transfer showed that plasmin interacted with the GPI-anchored protein...... plasmin-stimulated ENaC current in monolayers of M-1 cells at low plasmin concentration (1-4 microg/ml). At a high plasmin concentration of 30 microg/ml, there was no difference between cell layers treated with or without PI-PLC. Knockdown of prostasin attenuated binding of plasmin to M1 cells and blocked...... labeling of M-1 cells. Pretreatment with plasmin abolished labeling of M-1 cells in a prostasin-dependent way. We conclude that, at low concentrations, plasmin interacts with GPI-anchored prostasin, which leads to cleavage of the gamma-subunit and activation of ENaC, while at higher concentrations, plasmin...

Molecular mechanism of bacterial Hsp90 pH-dependent ATPase activity.

Science.gov (United States)

Jin, Yi; Hoxie, Reyal S; Street, Timothy O

2017-06-01

Hsp90 is a dimeric molecular chaperone that undergoes an essential and highly regulated open-to-closed-to-open conformational cycle upon ATP binding and hydrolysis. Although it has been established that a large energy barrier to closure is responsible for Hsp90's low ATP hydrolysis rate, the specific molecular contacts that create this energy barrier are not known. Here we discover that bacterial Hsp90 (HtpG) has a pH-dependent ATPase activity that is unique among other Hsp90 homologs. The underlying mechanism is a conformation-specific electrostatic interaction between a single histidine, H255, and bound ATP. H255 stabilizes ATP only while HtpG adopts a catalytically inactive open configuration, resulting in a striking anti-correlation between nucleotide binding affinity and chaperone activity over a wide range of pH. Linkage analysis reveals that the H255-ATP salt bridge contributes 1.5 kcal/mol to the energy barrier of closure. This energetic contribution is structurally asymmetric, whereby only one H255-ATP salt-bridge per dimer of HtpG controls ATPase activation. We find that a similar electrostatic mechanism regulates the ATPase of the endoplasmic reticulum Hsp90, and that pH-dependent activity can be engineered into eukaryotic cytosolic Hsp90. These results reveal site-specific energetic information about an evolutionarily conserved conformational landscape that controls Hsp90 ATPase activity. © 2017 The Protein Society.

Oxygen exchange at gas/oxide interfaces: how the apparent activation energy of the surface exchange coefficient depends on the kinetic regime.

Science.gov (United States)

Fielitz, Peter; Borchardt, Günter

2016-08-10

In the dedicated literature the oxygen surface exchange coefficient KO and the equilibrium oxygen exchange rate [Fraktur R] are considered to be directly proportional to each other regardless of the experimental circumstances. Recent experimental observations, however, contradict the consequences of this assumption. Most surprising is the finding that the apparent activation energy of KO depends dramatically on the kinetic regime in which it has been determined, i.e. surface exchange controlled vs. mixed or diffusion controlled. This work demonstrates how the diffusion boundary condition at the gas/solid interface inevitably entails a correlation between the oxygen surface exchange coefficient KO and the oxygen self-diffusion coefficient DO in the bulk ("on top" of the correlation between KO and [Fraktur R] for the pure surface exchange regime). The model can thus quantitatively explain the range of apparent activation energies measured in the different regimes: in the surface exchange regime the apparent activation energy only contains the contribution of the equilibrium exchange rate, whereas in the mixed or in the diffusion controlled regime the contribution of the oxygen self-diffusivity has also to be taken into account, which may yield significantly higher apparent activation energies and simultaneously quantifies the correlation KO ∝ DO(1/2) observed for a large number of oxides in the mixed or diffusion controlled regime, respectively.

Quantitative structure-activity relationship analysis of substituted arylazo pyridone dyes in photocatalytic system: Experimental and theoretical study

Energy Technology Data Exchange (ETDEWEB)

Dostanić, J., E-mail: jasmina@nanosys.ihtm.bg.ac.rs [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, Njegoševa 12, 11000 Belgrade (Serbia); Lončarević, D. [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, Njegoševa 12, 11000 Belgrade (Serbia); Zlatar, M. [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Chemistry, Njegoševa 12, 11000 Belgrade (Serbia); Vlahović, F. [University of Belgrade, Innovation center of the Faculty of Chemistry, 11000 Belgrade (Serbia); Jovanović, D.M. [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, Njegoševa 12, 11000 Belgrade (Serbia)

2016-10-05

Highlights: • Electronic effects of para substituted arylazo pyridone dyes. • Linear relationship between Hammett σ{sub p} constants and dyes photoreactivity. • The photocatalytic reactions facilitated by el.-acceptors and retarded by el.-donors. • Fukui functions to analyze the reactivity on concurrent sites within a molecule. • Hydroxyl radicals sustain attack from two reaction sites, depending on a substituent type. - Abstract: A series of arylazo pyridone dyes was synthesized by changing the type of the substituent group in the diazo moiety, ranging from strong electron-donating to strong electron-withdrawing groups. The structural and electronic properties of the investigated dyes was calculated at the M062X/6-31 + G(d,p) level of theory. The observed good linear correlations between atomic charges and Hammett σ{sub p} constants provided a basis to discuss the transmission of electronic substituent effects through a dye framework. The reactivity of synthesized dyes was tested through their decolorization efficiency in TiO{sub 2} photocatalytic system (Degussa P-25). Quantitative structure-activity relationship analysis revealed a strong correlation between reactivity of investigated dyes and Hammett substituent constants. The reaction was facilitated by electron-withdrawing groups, and retarded by electron-donating ones. Quantum mechanical calculations was used in order to describe the mechanism of the photocatalytic oxidation reactions of investigated dyes and interpret their reactivities within the framework of the Density Functional Theory (DFT). According to DFT based reactivity descriptors, i.e. Fukui functions and local softness, the active site moves from azo nitrogen atom linked to benzene ring to pyridone carbon atom linked to azo bond, going from dyes with electron-donating groups to dyes with electron-withdrawing groups.

Quantitative structure-activity relationship analysis of substituted arylazo pyridone dyes in photocatalytic system: Experimental and theoretical study

International Nuclear Information System (INIS)

Dostanić, J.; Lončarević, D.; Zlatar, M.; Vlahović, F.; Jovanović, D.M.

2016-01-01

Highlights: • Electronic effects of para substituted arylazo pyridone dyes. • Linear relationship between Hammett σ_p constants and dyes photoreactivity. • The photocatalytic reactions facilitated by el.-acceptors and retarded by el.-donors. • Fukui functions to analyze the reactivity on concurrent sites within a molecule. • Hydroxyl radicals sustain attack from two reaction sites, depending on a substituent type. - Abstract: A series of arylazo pyridone dyes was synthesized by changing the type of the substituent group in the diazo moiety, ranging from strong electron-donating to strong electron-withdrawing groups. The structural and electronic properties of the investigated dyes was calculated at the M062X/6-31 + G(d,p) level of theory. The observed good linear correlations between atomic charges and Hammett σ_p constants provided a basis to discuss the transmission of electronic substituent effects through a dye framework. The reactivity of synthesized dyes was tested through their decolorization efficiency in TiO_2 photocatalytic system (Degussa P-25). Quantitative structure-activity relationship analysis revealed a strong correlation between reactivity of investigated dyes and Hammett substituent constants. The reaction was facilitated by electron-withdrawing groups, and retarded by electron-donating ones. Quantum mechanical calculations was used in order to describe the mechanism of the photocatalytic oxidation reactions of investigated dyes and interpret their reactivities within the framework of the Density Functional Theory (DFT). According to DFT based reactivity descriptors, i.e. Fukui functions and local softness, the active site moves from azo nitrogen atom linked to benzene ring to pyridone carbon atom linked to azo bond, going from dyes with electron-donating groups to dyes with electron-withdrawing groups.

Quantitation of Na+, K+-atpase Enzymatic Activity in Tissues of the Mammalian Vestibular System

Science.gov (United States)

Kerr, T. P.

1985-01-01

In order to quantify vestibular Na(+), K(+)-ATPase, a microassay technique was developed which is sufficiently sensitive to measure the enzymatic activity in tissue from a single animal. The assay was used to characterize ATPase in he vestibular apparatus of the Mongolian gerbil. The quantitative procedure employs NPP (5 mM) as synthetic enzyme substrate. The assay relies upon spectrophotometric measurement (410 nm) of nitrophenol (NP) released by enzymatic hydrolysis of the substrate. Product formation in the absence of ouabain reflects both specific (Na(+), K(+)-ATPase) and non-specific (Mg(++)-ATPase) enzymatic activity. By measuring the accumulation of reaction product (NP) at three-minute intervals during the course of incubation, it is found that the overall enzymatic reaction proceeds linearly for at least 45 minutes. It is therefore possible to determine two separate reaction rates from a single set of tissues. Initial results indicate that total activity amounts to 53.3 + or - 11.2 (S.E.M.) nmol/hr/mg dry tissue, of which approximately 20% is ouabain-sensitive.

Participation in environmental enhancement and conservation activities for health and well-being in adults: a review of quantitative and qualitative evidence.

Science.gov (United States)

Husk, Kerryn; Lovell, Rebecca; Cooper, Chris; Stahl-Timmins, Will; Garside, Ruth

2016-05-21

-being. Eligible interventions needed to include each of the following: intended to improve the outdoor natural or built environment at either a local or wider level; took place in urban or rural locations in any country; involved active participation; and were NOT experienced through paid employment.We included quantitative and qualitative research. Includable quantitative study designs were: randomised controlled trials (RCTs), cluster RCTs, quasi-RCTs, cluster quasi-RCTs, controlled before-and-after studies, interrupted-time-series, cohort studies (prospective or retrospective), case-control studies and uncontrolled before-and-after studies (uBA). We included qualitative research if it used recognised qualitative methods of data collection and analysis. One reviewer extracted data, and another reviewer checked the data. Two review authors independently appraised study quality using the Effective Public Health Practice Project tool (for quantitative studies) or Wallace criteria (for qualitative studies). Heterogeneity of outcome measures and poor reporting of intervention specifics prevented meta-analysis so we synthesised the results narratively. We synthesised qualitative research findings using thematic analysis. Database searches identified 21,420 records, with 21,304 excluded at title/abstract. Grey literature searches identified 211 records. We screened 327 full-text articles from which we included 21 studies (reported in 28 publications): two case-studies (which were not included in the synthesis due to inadequate robustness), one case-control, one retrospective cohort, five uBA, three mixed-method (uBA, qualitative), and nine qualitative studies. The 19 studies included in the synthesis detailed the impacts to a total of 3,603 participants: 647 from quantitative intervention studies and 2630 from a retrospective cohort study; and 326 from qualitative studies (one not reporting sample size).Included studies shared the key elements of EECA defined above, but the range of

What environmental factors influence resumption of valued activities post stroke: a systematic review of qualitative and quantitative findings.

Science.gov (United States)

Jellema, Sandra; van Hees, Suzanne; Zajec, Jana; van der Sande, Rob; Nijhuis-van der Sanden, Maria Wg; Steultjens, Esther Mj

2017-07-01

Identify the environmental factors that influence stroke-survivors' reengagement in personally valued activities and determine what specific environmental factors are related to specific valued activity types. PubMed, CINAHL and PsycINFO were searched until June 2016 using multiple search-terms for stroke, activities, disability, and home and community environments. An integrated mixed-method systematic review of qualitative, quantitative and mixed-design studies was conducted. Two researchers independently identified relevant studies, assessed their methodological quality and extracted relevant findings. To validly compare and combine the various findings, all findings were classified and grouped by environmental category and level of evidence. The search yielded 4024 records; 69 studies were included. Most findings came from low-evidence-level studies such as single qualitative studies. All findings were consistent in that the following factors facilitated reengagement post-stroke: personal adapted equipment; accessible environments; transport; services; education and information. Barriers were: others' negative attitudes and behaviour; long distances and inconvenient environmental conditions (such as bad weather). Each type of valued activity, such as mobility or work, had its own pattern of environmental influences, social support was a facilitator to all types of activities. Although in many qualitative studies others' attitudes, behaviour and stroke-related knowledge were seen as important for reengagement, these factors were hardly studied quantitatively. A diversity of environmental factors was related to stroke-survivors' reengagement. Most findings came from low-evidence-level studies so that evidence on causal relationships was scarce. In future, more higher-level-evidence studies, for example on the attitudes of significant others, should be conducted.

Determination of glutamate dehydrogenase activity and its kinetics in mouse tissues using metabolic mapping (quantitative enzyme histochemistry).

Science.gov (United States)

Botman, Dennis; Tigchelaar, Wikky; Van Noorden, Cornelis J F

2014-11-01

Glutamate dehydrogenase (GDH) catalyses the reversible conversion of glutamate into α-ketoglutarate with the concomitant reduction of NAD(P)(+) to NAD(P)H or vice versa. GDH activity is subject to complex allosteric regulation including substrate inhibition. To determine GDH kinetics in situ, we assessed the effects of various glutamate concentrations in combination with either the coenzyme NAD(+) or NADP(+) on GDH activity in mouse liver cryostat sections using metabolic mapping. NAD(+)-dependent GDH V(max) was 2.5-fold higher than NADP(+)-dependent V(max), whereas the K(m) was similar, 1.92 mM versus 1.66 mM, when NAD(+) or NADP(+) was used, respectively. With either coenzyme, V(max) was determined at 10 mM glutamate and substrate inhibition was observed at higher glutamate concentrations with a K(i) of 12.2 and 3.95 for NAD(+) and NADP(+) used as coenzyme, respectively. NAD(+)- and NADP(+)-dependent GDH activities were examined in various mouse tissues. GDH activity was highest in liver and much lower in other tissues. In all tissues, the highest activity was found when NAD(+) was used as a coenzyme. In conclusion, GDH activity in mice is highest in the liver with NAD(+) as a coenzyme and highest GDH activity was determined at a glutamate concentration of 10 mM. © The Author(s) 2014.

Quantitative structure-activity relationship (QSAR) models for polycyclic aromatic hydrocarbons (PAHs) dissipation in rhizosphere based on molecular structure and effect size

International Nuclear Information System (INIS)

Ma Bin; Chen Huaihai; Xu Minmin; Hayat, Tahir; He Yan; Xu Jianming

2010-01-01

Rhizoremediation is a significant form of bioremediation for polycyclic aromatic hydrocarbons (PAHs). This study examined the role of molecular structure in determining the rhizosphere effect on PAHs dissipation. Effect size in meta-analysis was employed as activity dataset for building quantitative structure-activity relationship (QSAR) models and accumulative effect sizes of 16 PAHs were used for validation of these models. Based on the genetic algorithm combined with partial least square regression, models for comprehensive dataset, Poaceae dataset, and Fabaceae dataset were built. The results showed that information indices, calculated as information content of molecules based on the calculation of equivalence classes from the molecular graph, were the most important molecular structural indices for QSAR models of rhizosphere effect on PAHs dissipation. The QSAR model, based on the molecular structure indices and effect size, has potential to be used in studying and predicting the rhizosphere effect of PAHs dissipation. - Effect size based on meta-analysis was used for building PAHs dissipation quantitative structure-activity relationship (QSAR) models.

Quantitative structure-activity relationship (QSAR) models for polycyclic aromatic hydrocarbons (PAHs) dissipation in rhizosphere based on molecular structure and effect size

Energy Technology Data Exchange (ETDEWEB)

Ma Bin; Chen Huaihai; Xu Minmin; Hayat, Tahir [Zhejiang Provincial Key Laboratory of Subtropical Soil and Plant Nutrition, College of Environmental and Natural Resource Sciences, Zhejiang University, Hangzhou 310029 (China); He Yan, E-mail: yhe2006@zju.edu.c [Zhejiang Provincial Key Laboratory of Subtropical Soil and Plant Nutrition, College of Environmental and Natural Resource Sciences, Zhejiang University, Hangzhou 310029 (China); Xu Jianming, E-mail: jmxu@zju.edu.c [Zhejiang Provincial Key Laboratory of Subtropical Soil and Plant Nutrition, College of Environmental and Natural Resource Sciences, Zhejiang University, Hangzhou 310029 (China)

2010-08-15

Rhizoremediation is a significant form of bioremediation for polycyclic aromatic hydrocarbons (PAHs). This study examined the role of molecular structure in determining the rhizosphere effect on PAHs dissipation. Effect size in meta-analysis was employed as activity dataset for building quantitative structure-activity relationship (QSAR) models and accumulative effect sizes of 16 PAHs were used for validation of these models. Based on the genetic algorithm combined with partial least square regression, models for comprehensive dataset, Poaceae dataset, and Fabaceae dataset were built. The results showed that information indices, calculated as information content of molecules based on the calculation of equivalence classes from the molecular graph, were the most important molecular structural indices for QSAR models of rhizosphere effect on PAHs dissipation. The QSAR model, based on the molecular structure indices and effect size, has potential to be used in studying and predicting the rhizosphere effect of PAHs dissipation. - Effect size based on meta-analysis was used for building PAHs dissipation quantitative structure-activity relationship (QSAR) models.

Hypoxia-ischemia or excitotoxin-induced tissue plasminogen activator- dependent gelatinase activation in mice neonate brain microvessels.

Directory of Open Access Journals (Sweden)

Priscilla L Omouendze

Full Text Available Hypoxia-ischemia (HI and excitotoxicity are validated causes of neonatal brain injuries and tissue plasminogen activator (t-PA participates in the processes through proteolytic and receptor-mediated pathways. Brain microvascular endothelial cells from neonates in culture, contain and release more t-PA and gelatinases upon glutamate challenge than adult cells. We have studied t-PA to gelatinase (MMP-2 and MMP-9 activity links in HI and excitotoxicity lesion models in 5 day-old pups in wild type and in t-PA or its inhibitor (PAI-1 genes inactivated mice. Gelatinolytic activities were detected in SDS-PAGE zymograms and by in situ fluorescent DQ-gelatin microscopic zymographies. HI was achieved by unilateral carotid ligature followed by a 40 min hypoxia (8%O₂. Excitotoxic lesions were produced by intra parenchymal cortical (i.c. injections of 10 µg ibotenate (Ibo. Gel zymograms in WT cortex revealed progressive extinction of MMP-2 and MMP-9 activities near day 15 or day 8 respectively. MMP-2 expression was the same in all strains while MMP-9 activity was barely detectable in t-PA⁻/⁻ and enhanced in PAI-1⁻/⁻ mice. HI or Ibo produced activation of MMP-2 activities 6 hours post-insult, in cortices of WT mice but not in t-PA⁻/⁻ mice. In PAI-1⁻/⁻ mice, HI or vehicle i.c. injection increased MMP-2 and MMP-9 activities. In situ zymograms using DQ-gelatin revealed vessel associated gelatinolytic activity in lesioned areas in PAI-1⁻/⁻ and in WT mice. In WT brain slices incubated ex vivo, glutamate (200 µM induced DQ-gelatin activation in vessels. The effect was not detected in t-PA⁻/⁻ mice, but was restored by concomitant exposure to recombinant t-PA (20 µg/mL. In summary, neonatal brain lesion paradigms and ex vivo excitotoxic glutamate evoked t-PA-dependent gelatinases activation in vessels. Both MMP-2 and MMP-9 activities appeared t-PA-dependent. The data suggest that vascular directed protease inhibition may have

Activation of cAMP-dependent signaling induces oxidative modification of the cardiac Na+-K+ pump and inhibits its activity.

Science.gov (United States)

White, Caroline N; Liu, Chia-Chi; Garcia, Alvaro; Hamilton, Elisha J; Chia, Karin K M; Figtree, Gemma A; Rasmussen, Helge H

2010-04-30

Cellular signaling can inhibit the membrane Na(+)-K(+) pump via protein kinase C (PKC)-dependent activation of NADPH oxidase and a downstream oxidative modification, glutathionylation, of the beta(1) subunit of the pump alpha/beta heterodimer. It is firmly established that cAMP-dependent signaling also regulates the pump, and we have now examined the hypothesis that such regulation can be mediated by glutathionylation. Exposure of rabbit cardiac myocytes to the adenylyl cyclase activator forskolin increased the co-immunoprecipitation of NADPH oxidase subunits p47(phox) and p22(phox), required for its activation, and increased superoxide-sensitive fluorescence. Forskolin also increased glutathionylation of the Na(+)-K(+) pump beta(1) subunit and decreased its co-immunoprecipitation with the alpha(1) subunit, findings similar to those already established for PKC-dependent signaling. The decrease in co-immunoprecipitation indicates a decrease in the alpha(1)/beta(1) subunit interaction known to be critical for pump function. In agreement with this, forskolin decreased ouabain-sensitive electrogenic Na(+)-K(+) pump current (arising from the 3:2 Na(+):K(+) exchange ratio) of voltage-clamped, internally perfused myocytes. The decrease was abolished by the inclusion of superoxide dismutase, the inhibitory peptide for the epsilon-isoform of PKC or inhibitory peptide for NADPH oxidase in patch pipette solutions that perfuse the intracellular compartment. Pump inhibition was also abolished by inhibitors of protein kinase A and phospholipase C. We conclude that cAMP- and PKC-dependent inhibition of the cardiac Na(+)-K(+) pump occurs via a shared downstream oxidative signaling pathway involving NADPH oxidase activation and glutathionylation of the pump beta(1) subunit.

Activity-Dependent IGF-1 Exocytosis is Controlled by the Ca2+-Sensor Synaptotagmin-10

Science.gov (United States)

Cao, Peng; Maximov, Anton; Südhof, Thomas C.

2011-01-01

Synaptotagmins Syt1, Syt2, Syt7, and Syt9 act as Ca2+-sensors for synaptic and neuroendocrine exocytosis, but the function of other synaptotagmins remains unknown. Here, we show that olfactory bulb neurons secrete IGF-1 by an activity-dependent pathway of exocytosis, and that Syt10 functions as the Ca2+-sensor that triggers IGF-1 exocytosis in these neurons. Deletion of Syt10 impaired activity-dependent IGF-1 secretion in olfactory bulb neurons, resulting in smaller neurons and an overall decrease in synapse numbers. Exogenous IGF-1 completely reversed the Syt10 knockout phenotype. Syt10 co-localized with IGF-1 in somatodendritic vesicles of olfactory bulb neurons, and Ca2+-binding to Syt10 caused these vesicles to undergo exocytosis, thereby secreting IGF-1. Thus, Syt10 controls a previously unrecognized pathway of Ca2+-dependent exocytosis that is spatially and temporally distinct from Ca2+-dependent synaptic vesicle exocytosis controlled by Syt1 in the same neurons, and two different synaptotagmins regulate distinct Ca2+-dependent membrane fusion reactions during exocytosis in the same neuron. PMID:21496647

Long lasting protein synthesis- and activity-dependent spine shrinkage and elimination after synaptic depression.

Directory of Open Access Journals (Sweden)

Yazmín Ramiro-Cortés

Full Text Available Neuronal circuits modify their response to synaptic inputs in an experience-dependent fashion. Increases in synaptic weights are accompanied by structural modifications, and activity dependent, long lasting growth of dendritic spines requires new protein synthesis. When multiple spines are potentiated within a dendritic domain, they show dynamic structural plasticity changes, indicating that spines can undergo bidirectional physical modifications. However, it is unclear whether protein synthesis dependent synaptic depression leads to long lasting structural changes. Here, we investigate the structural correlates of protein synthesis dependent long-term depression (LTD mediated by metabotropic glutamate receptors (mGluRs through two-photon imaging of dendritic spines on hippocampal pyramidal neurons. We find that induction of mGluR-LTD leads to robust and long lasting spine shrinkage and elimination that lasts for up to 24 hours. These effects depend on signaling through group I mGluRs, require protein synthesis, and activity. These data reveal a mechanism for long lasting remodeling of synaptic inputs, and offer potential insights into mental retardation.

Improvement of quantitation in SPECT: Attenuation and scatter correction using non-uniform attenuation data

International Nuclear Information System (INIS)

Mukai, T.; Torizuka, K.; Douglass, K.H.; Wagner, H.N.

1985-01-01

Quantitative assessment of tracer distribution with single photon emission computed tomography (SPECT) is difficult because of attenuation and scattering of gamma rays within the object. A method considering the source geometry was developed, and effects of attenuation and scatter on SPECT quantitation were studied using phantoms with non-uniform attenuation. The distribution of attenuation coefficients (μ) within the source were obtained by transmission CT. The attenuation correction was performed by an iterative reprojection technique. The scatter correction was done by convolution of the attenuation corrected image and an appropriate filter made by line source studies. The filter characteristics depended on μ and SPEC measurement at each pixel. The SPECT obtained by this method showed the most reasonable results than the images reconstructed by other methods. The scatter correction could compensate completely for a 28% scatter components from a long line source, and a 61% component for thick and extended source. Consideration of source geometries was necessary for effective corrections. The present method is expected to be valuable for the quantitative assessment of regional tracer activity

Glutathionylation regulates cytosolic NADP+-dependent isocitrate dehydrogenase activity.

Science.gov (United States)

Shin, Seoung Woo; Oh, Chang Joo; Kil, In Sup; Park, Jeen-Woo

2009-04-01

Cytosolic NADP+-dependent isocitrate dehydrogenase (IDPc) is susceptible to inactivation by numerous thiol-modifying reagents. This study now reports that Cys269 of IDPc is a target for S-glutathionylation and that this modification is reversed by dithiothreitol as well as enzymatically by cytosolic glutaredoxin in the presence of GSH. Glutathionylated IDPc was significantly less susceptible than native protein to peptide fragmentation by reactive oxygen species and proteolytic digestion. Glutathionylation may play a protective role in the degradation of protein through the structural alterations of IDPc. HEK293 cells treated with diamide displayed decreased IDPc activity and accumulated glutathionylated enzyme. Using immunoprecipitation with an anti-IDPc IgG and immunoblotting with an anti-GSH IgG, we purified and positively identified glutathionylated IDPc from the kidneys of mice subjected to ischemia/reperfusion injury and from the livers of ethanol-administered rats. These results suggest that IDPc activity is modulated through enzymatic glutathionylation and deglutathionylation during oxidative stress.

Visualization of plant viral suppressor silencing activity in intact leaf lamina by quantitative fluorescent imaging

Directory of Open Access Journals (Sweden)

Francis Kevin P

2011-08-01

Full Text Available Abstract Background Transient expression of proteins in plants has become a favoured method over the production of stably transformed plants because, in addition to enabling high protein yields, it is both fast and easy to apply. An enhancement of transient protein expression can be achieved by plant virus-encoded RNA silencing suppressor proteins. Since viral suppressor proteins differ in their efficiency to enhance transient protein expression in plants, we developed a whole-leaf green fluorescent protein (GFP-based imaging assay to quantitatively assess suppressor protein activity. Results In a transient GFP-expression assay using wild-type and GFP-transgenic N. benthamiana, addition of the plant viral suppressors Beet mild yellowing virus (BMYV-IPP P0 or Plum pox virus (PPV HC-Pro was shown to increase fluorescent protein expression 3-4-fold, 7 days post inoculation (dpi when compared to control plants. In contrast, in agroinfiltrated patches without suppressor activity, near complete silencing of the GFP transgene was observed in the transgenic N. benthamiana at 21 dpi. Both co-infiltrated suppressors significantly enhanced GFP expression over time, with HC-Pro co-infiltrations leading to higher short term GFP fluorescence (at 7 dpi and P0 giving higher long term GFP fluorescence (at 21 dpi. Additionally, in contrast to HC-Pro co-infiltrations, an area of complete GFP silencing was observed at the edge of P0 co-infiltrated areas. Conclusions Fluorescence imaging of whole intact leaves proved to be an easy and effective method for spatially and quantitatively observing viral suppressor efficiency in plants. This suppressor assay demonstrates that plant viral suppressors greatly enhanced transient GFP expression, with P0 showing a more prolonged suppressor activity over time than HC-Pro. Both suppressors could prove to be ideal candidates for enhancing target protein expression in plants.

Variability of Pinus halepensis Mill. Essential Oils and Their Antioxidant Activities Depending on the Stage of Growth During Vegetative Cycle.

Science.gov (United States)

Djerrad, Zineb; Djouahri, Abderrahmane; Kadik, Leila

2017-04-01

The impact of growth stages during vegetative cycle (B 0  - B 5 ) on chemical composition and antioxidant activities of Pinus halepensis Mill. needles essential oils was investigated for the first time. GC and GC/MS analyses pointed to a quantitative variability of components; terpene hydrocarbons derivatives, represented by α-pinene (8.5 - 12.9%), myrcene (17.5 - 21.6%), p-cymene (7.9 - 11.9%) and (Z)-β-caryophyllene (17.3 - 21.2%) as major components, decreased from 88.9% at B 0 growth stage to 66.9% at B 5 growth stage, whereas oxygenated derivatives, represented by caryophyllene oxide (5.4 - 12.6%) and terpinen-4-ol (0.4 - 3.3%) as major components, increased from 7% at B 0 growth stage to 28.4% at B 5 growth stage. Furthermore, our findings showed that essential oil of P. halepensis needles collected at B 5 growth stage possess higher antioxidant activities by four different testing systems than those collected at B 0  - B 4 growth stages. This highlighted variability led to conclude that we should select essential oils to be investigated carefully depending on growth stage, in order to have the highest effectiveness of essential oil in terms of biological activities for human health purposes. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

Review of quantitative phase-digital holographic microscopy: promising novel imaging technique to resolve neuronal network activity and identify cellular biomarkers of psychiatric disorders

KAUST Repository

Marquet, Pierre

2014-09-22

Quantitative phase microscopy (QPM) has recently emerged as a new powerful quantitative imaging technique well suited to noninvasively explore a transparent specimen with a nanometric axial sensitivity. In this review, we expose the recent developments of quantitative phase-digital holographic microscopy (QP-DHM). Quantitative phase-digital holographic microscopy (QP-DHM) represents an important and efficient quantitative phase method to explore cell structure and dynamics. In a second part, the most relevant QPM applications in the field of cell biology are summarized. A particular emphasis is placed on the original biological information, which can be derived from the quantitative phase signal. In a third part, recent applications obtained, with QP-DHM in the field of cellular neuroscience, namely the possibility to optically resolve neuronal network activity and spine dynamics, are presented. Furthermore, potential applications of QPM related to psychiatry through the identification of new and original cell biomarkers that, when combined with a range of other biomarkers, could significantly contribute to the determination of high risk developmental trajectories for psychiatric disorders, are discussed.

Field dependence-independence as related to young women's participation in sports activity.

Science.gov (United States)

Lambrecht, Jeanne L; Cuevas, Jacqueline L

2007-06-01

To estimate association between field dependence-independence measured by scores on the Group Embedded Figures Test and young women's participation in sports activity. Participants were 37 undergraduate college women between the ages of 18 and 25 years (M=21). Participants were categorized into two groups, one high in participation in sports activity and one low. A one-tailed independent samples t test yielded no significant difference. Correlations of .36 and .18 were significant but account for little common variance. An ad hoc analysis performed without participants who reported softball activity but who were highly involved in sport activities was significant.

Quantitative transmission electron microscopy and atom probe tomography study of Ag-dependent precipitation of Ω phase in Al-Cu-Mg alloys

Energy Technology Data Exchange (ETDEWEB)

Bai, Song; Ying, Puyou [Key Laboratory of Nonferrous Metal Materials Science and Engineering, Ministry of Education, Central South University, Changsha 410083 (China); School of Material Science and Engineering, Central South University, Changsha 410083 (China); Liu, Zhiyi, E-mail: liuzhiyi@csu.edu.cn [Key Laboratory of Nonferrous Metal Materials Science and Engineering, Ministry of Education, Central South University, Changsha 410083 (China); School of Material Science and Engineering, Central South University, Changsha 410083 (China); Wang, Jian; Li, Junlin [Key Laboratory of Nonferrous Metal Materials Science and Engineering, Ministry of Education, Central South University, Changsha 410083 (China); School of Material Science and Engineering, Central South University, Changsha 410083 (China)

2017-02-27

The close association between the Ω precipitation and various Ag additions is systematically investigated by quantitative transmission electron microscopy and atom probe tomography analysis. Our results suggest that the precipitation of Ω phase is strongly dependent on Ag variations. Increasing the bulk Ag content favors a denser Ω precipitation and hence leads to a greater age-hardening response of Al-Cu-Mg-Ag alloy. This phenomenon, as proposed by proximity histograms, is directly related to the greater abundance of Ag solutes within Ω precursors. This feature lowers its nucleation barrier and increases the nucleation rate of Ω phase, finally contributes to the enhanced Ω precipitation. Also, it is noted that increasing Ag remarkably restricts the precipitation of θ' phase.

Bone mineral density changes during pregnancy in actively exercising women as measured by quantitative ultrasound.

Science.gov (United States)

To, William W K; Wong, Margaret W N

2012-08-01

To evaluate whether bone mineral density (BMD) changes in women engaged in active exercises during pregnancy would be different from non-exercising women. Consecutive patients with singleton pregnancies who were engaged in active exercise training during pregnancy were prospectively recruited over a period of 6 months. Quantitative USG measurements of the os calcis BMD were performed at 14-20 weeks and at 36-38 weeks. These patients were compared to a control cohort of non-exercising low-risk women. A total of 24 physically active women undergoing active physical training of over 10 h per week at 20 weeks gestation and beyond (mean 13.1 h, SD 3.3) were compared to 94 non-exercising low-risk women. A marginal fall in BMD of 0.015 g/cm(2) (SD 0.034) was demonstrable from early to late gestation in the exercising women, which was significantly lower than that of non-exercising women (0.041 g/cm(2); SD 0.042; p = 0.005). Logistic regression models confirmed that active exercises in pregnancy were significantly associated with the absence of or less BMD loss in pregnancy. In women actively engaged in physical training during pregnancy, the physiological fall in BMD during pregnancy was apparently less compared to those who did not regularly exercise.

Health Impacts of Increased Physical Activity from Changes in Transportation Infrastructure: Quantitative Estimates for Three Communities

Science.gov (United States)

2015-01-01

Recently, two quantitative tools have emerged for predicting the health impacts of projects that change population physical activity: the Health Economic Assessment Tool (HEAT) and Dynamic Modeling for Health Impact Assessment (DYNAMO-HIA). HEAT has been used to support health impact assessments of transportation infrastructure projects, but DYNAMO-HIA has not been previously employed for this purpose nor have the two tools been compared. To demonstrate the use of DYNAMO-HIA for supporting health impact assessments of transportation infrastructure projects, we employed the model in three communities (urban, suburban, and rural) in North Carolina. We also compared DYNAMO-HIA and HEAT predictions in the urban community. Using DYNAMO-HIA, we estimated benefit-cost ratios of 20.2 (95% C.I.: 8.7–30.6), 0.6 (0.3–0.9), and 4.7 (2.1–7.1) for the urban, suburban, and rural projects, respectively. For a 40-year time period, the HEAT predictions of deaths avoided by the urban infrastructure project were three times as high as DYNAMO-HIA's predictions due to HEAT's inability to account for changing population health characteristics over time. Quantitative health impact assessment coupled with economic valuation is a powerful tool for integrating health considerations into transportation decision-making. However, to avoid overestimating benefits, such quantitative HIAs should use dynamic, rather than static, approaches. PMID:26504832

Length and activation dependent variations in muscle shear wave speed

International Nuclear Information System (INIS)

Chernak, L A; DeWall, R J; Lee, K S; Thelen, D G

2013-01-01

Muscle stiffness is known to vary as a result of a variety of disease states, yet current clinical methods for quantifying muscle stiffness have limitations including cost and availability. We investigated the capability of shear wave elastography (SWE) to measure variations in gastrocnemius shear wave speed induced via active contraction and passive stretch. Ten healthy young adults were tested. Shear wave speeds were measured using a SWE transducer positioned over the medial gastrocnemius at ankle angles ranging from maximum dorsiflexion to maximum plantarflexion. Shear wave speeds were also measured during voluntary plantarflexor contractions at a fixed ankle angle. Average shear wave speed increased significantly from 2.6 to 5.6 m s –1 with passive dorsiflexion and the knee in an extended posture, but did not vary with dorsiflexion when the gastrocnemius was shortened in a flexed knee posture. During active contractions, shear wave speed monotonically varied with the net ankle moment generated, reaching 8.3 m s –1 in the maximally contracted condition. There was a linear correlation between shear wave speed and net ankle moment in both the active and passive conditions; however, the slope of this linear relationship was significantly steeper for the data collected during passive loading conditions. The results show that SWE is a promising approach for quantitatively assessing changes in mechanical muscle loading. However, the differential effect of active and passive loading on shear wave speed makes it important to carefully consider the relevant loading conditions in which to use SWE to characterize in vivo muscle properties. (paper)

Activation of peroxisome proliferator-activated receptor-γ (PPARγ) induces cell death through MAPK-dependent mechanism in osteoblastic cells

International Nuclear Information System (INIS)

Kim, Sung Hun; Yoo, Chong Il; Kim, Hui Taek; Park, Ji Yeon; Kwon, Chae Hwa; Keun Kim, Yong

2006-01-01

The present study was undertaken to determine the role of the mitogen-activated protein kinase (MAPK) subfamilies in cell death induced by PPARγ agonists in osteoblastic cells. Ciglitazone and troglitazone, PPARγ agonists, resulted in a concentration- and time-dependent cell death, which was largely attributed to apoptosis. But a PPARα agonist ciprofibrate did not affect the cell death. Ciglitazone caused reactive oxygen species (ROS) generation and ciglitazone-induced cell death was prevented by antioxidants, suggesting an important role of ROS generation in the ciglitazone-induced cell death. ROS generation and cell death induced by ciglitazone were inhibited by the PPARγ antagonist GW9662. Ciglitazone treatment caused activation of extracellular signal-regulated kinase (ERK) and p38. Activation of ERK was dependent on epidermal growth factor receptor (EGFR) and that of p38 was independent. Ciglitazone-induced cell death was significantly prevented by PD98059, an inhibitor of ERK upstream kinase MEK1/2, and SB203580, a p38 inhibitor. Ciglitazone treatment increased Bax expression and caused a loss of mitochondrial membrane potential, and its effect was prevented by N-acetylcysteine, PD98059, and SB203580. Ciglitazone induced caspase activation, which was prevented by PD98059 and SB203580. The general caspase inhibitor z-DEVD-FMK and the specific inhibitor of caspases-3 DEVD-CHO exerted the protective effect against the ciglitazone-induced cell death. The EGFR inhibitors AG1478 and suramin protected against the ciglitazone-induced cell death. Taken together, these findings suggest that the MAPK signaling pathways play an active role in mediating the ciglitazone-induced cell death of osteoblasts and function upstream of a mitochondria-dependent mechanism. These data may provide a novel insight into potential therapeutic strategies for treatment of osteoporosis

Aldose Reductase Inhibitor Protects against Hyperglycemic Stress by Activating Nrf2-Dependent Antioxidant Proteins.

Science.gov (United States)

Shukla, Kirtikar; Pal, Pabitra Bikash; Sonowal, Himangshu; Srivastava, Satish K; Ramana, Kota V

2017-01-01

We have shown earlier that pretreatment of cultured cells with aldose reductase (AR) inhibitors prevents hyperglycemia-induced mitogenic and proinflammatory responses. However, the effects of AR inhibitors on Nrf2-mediated anti-inflammatory responses have not been elucidated yet. We have investigated how AR inhibitor fidarestat protects high glucose- (HG-) induced cell viability changes by increasing the expression of Nrf2 and its dependent phase II antioxidant enzymes. Fidarestat pretreatment prevents HG (25 mM)-induced Thp1 monocyte viability. Further, treatment of Thp1 monocytes with fidarestat caused a time-dependent increase in the expression as well as the DNA-binding activity of Nrf2. In addition, fidarestat augmented the HG-induced Nrf2 expression and activity and also upregulated the expression of Nrf2-dependent proteins such as hemeoxygenase-1 (HO1) and NQO1 in Thp1 cells. Similarly, treatment with AR inhibitor also induced the expression of Nrf2 and HO1 in STZ-induced diabetic mice heart and kidney tissues. Further, AR inhibition increased the HG-induced expression of antioxidant enzymes such as SOD and catalase and activation of AMPK- α 1 in Thp1 cells. Our results thus suggest that pretreatment with AR inhibitor prepares the monocytes against hyperglycemic stress by overexpressing the Nrf2-dependent antioxidative proteins.

Fingerprint analysis, multi-component quantitation, and antioxidant activity for the quality evaluation of Salvia miltiorrhiza var. alba by high-performance liquid chromatography and chemometrics.

Science.gov (United States)

Zhang, Danlu; Duan, Xiaoju; Deng, Shuhong; Nie, Lei; Zang, Hengchang

2015-10-01

Salvia miltiorrhiza Bge. var. alba C.Y. Wu and H.W. Li has wide prospects in clinical practice. A useful comprehensive method was developed for the quality evaluation of S. miltiorrhiza var. alba by three quantitative parameters: high-performance liquid chromatography fingerprint, ten-component contents, and antioxidant activity. The established method was validated for linearity, precision, repeatability, stability, and recovery. Principal components analysis and hierarchical clustering analysis were both used to evaluate the quality of the samples from different origins. The results showed that there were category discrepancies in quality of S. miltiorrhiza var. alba samples according to the three quantitative parameters. Multivariate linear regression was adopted to explore the relationship between components and antioxidant activity. Three constituents, namely, danshensu, rosmarinic acid, and salvianolic acid B, significantly correlated with antioxidant activity, and were successfully elucidated by the optimized multivariate linear regression model. The combined use of high-performance liquid chromatography fingerprint analysis, simultaneous multicomponent quantitative analysis, and antioxidant activity for the quality evaluation of S. miltiorrhiza var. alba is a reliable, comprehensive, and promising approach, which might provide a valuable reference for other herbal products in general to improve their quality control. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Development of the Quantitative Reasoning Items on the National Survey of Student Engagement

Directory of Open Access Journals (Sweden)

Amber D. Dumford

2015-01-01

Full Text Available As society’s needs for quantitative skills become more prevalent, college graduates require quantitative skills regardless of their career choices. Therefore, it is important that institutions assess students’ engagement in quantitative activities during college. This study chronicles the process taken by the National Survey of Student Engagement (NSSE to develop items that measure students’ participation in quantitative reasoning (QR activities. On the whole, findings across the quantitative and qualitative analyses suggest good overall properties for the developed QR items. The items show great promise to explore and evaluate the frequency with which college students participate in QR-related activities. Each year, hundreds of institutions across the United States and Canada participate in NSSE, and, with the addition of these new items on the core survey, every participating institution will have information on this topic. Our hope is that these items will spur conversations on campuses about students’ use of quantitative reasoning activities.

Heme Oxygenase-1 Inhibits HLA Class I Antibody-Dependent Endothelial Cell Activation.

Directory of Open Access Journals (Sweden)

Eva Zilian

Full Text Available Antibody-mediated rejection (AMR is a key limiting factor for long-term graft survival in solid organ transplantation. Human leukocyte antigen (HLA class I (HLA I antibodies (Abs play a major role in the pathogenesis of AMR via their interactions with HLA molecules on vascular endothelial cells (ECs. The antioxidant enzyme heme oxygenase (HO-1 has anti-inflammatory functions in the endothelium. As complement-independent effects of HLA I Abs can activate ECs, it was the goal of the current study to investigate the role of HO-1 on activation of human ECs by HLA I Abs. In cell cultures of various primary human macro- and microvascular ECs treatment with monoclonal pan- and allele-specific HLA I Abs up-regulated the expression of inducible proinflammatory adhesion molecules and chemokines (vascular cell adhesion molecule-1 [VCAM-1], intercellular cell adhesion molecule-1 [ICAM-1], interleukin-8 [IL-8] and monocyte chemotactic protein 1 [MCP-1]. Pharmacological induction of HO-1 with cobalt-protoporphyrin IX reduced, whereas inhibition of HO-1 with either zinc-protoporphyrin IX or siRNA-mediated knockdown increased HLA I Ab-dependent up-regulation of VCAM-1. Treatment with two carbon monoxide (CO-releasing molecules, which liberate the gaseous HO product CO, blocked HLA I Ab-dependent EC activation. Finally, in an in vitro adhesion assay exposure of ECs to HLA I Abs led to increased monocyte binding, which was counteracted by up-regulation of HO-1. In conclusion, HLA I Ab-dependent EC activation is modulated by endothelial HO-1 and targeted induction of this enzyme may be a novel therapeutic approach for the treatment of AMR in solid organ transplantation.

Allometric trajectories and "stress": a quantitative approach

Directory of Open Access Journals (Sweden)

Tommaso Anfodillo

2016-11-01

Full Text Available The term stress is an important but vague term in plant biology. We show situations in which thinking in terms of stress is profitably replaced by quantifying distance from functionally optimal scaling relationships between plant parts. These relationships include, for example, the often-cited one between leaf area and sapwood area, which presumably reflects mutual dependence between source and sink tissues and which scales positively within individuals and across species. These relationships seem to be so basic to plant functioning that they are favored by selection across nearly all plant lineages. Within a species or population, individuals that are far from the common scaling patterns are thus expected to perform negatively. For instance, too little leaf area (e.g. due to herbivory or disease per unit of active stem mass would be expected to incur to low carbon income per respiratory cost and thus lead to lower growth. We present a framework that allows quantitative study of phenomena traditionally assigned to stress, without need for recourse to this term. Our approach contrasts with traditional approaches for studying stress, e.g. revealing that small stressed plants likely are in fact well suited to local conditions. We thus offer a quantitative perspective to the study of phenomena often referred to under such terms as stress, plasticity, adaptation, and acclimation.

Allometric Trajectories and "Stress": A Quantitative Approach.

Science.gov (United States)

Anfodillo, Tommaso; Petit, Giai; Sterck, Frank; Lechthaler, Silvia; Olson, Mark E

2016-01-01

The term "stress" is an important but vague term in plant biology. We show situations in which thinking in terms of "stress" is profitably replaced by quantifying distance from functionally optimal scaling relationships between plant parts. These relationships include, for example, the often-cited one between leaf area and sapwood area, which presumably reflects mutual dependence between sources and sink tissues and which scales positively within individuals and across species. These relationships seem to be so basic to plant functioning that they are favored by selection across nearly all plant lineages. Within a species or population, individuals that are far from the common scaling patterns are thus expected to perform negatively. For instance, "too little" leaf area (e.g., due to herbivory or disease) per unit of active stem mass would be expected to incur to low carbon income per respiratory cost and thus lead to lower growth. We present a framework that allows quantitative study of phenomena traditionally assigned to "stress," without need for recourse to this term. Our approach contrasts with traditional approaches for studying "stress," e.g., revealing that small "stressed" plants likely are in fact well suited to local conditions. We thus offer a quantitative perspective to the study of phenomena often referred to under such terms as "stress," plasticity, adaptation, and acclimation.

Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain.

Science.gov (United States)

Bonanni, Laura; Chachar, Mushtaque; Jover-Mengual, Teresa; Li, Hongmei; Jones, Adrienne; Yokota, Hidenori; Ofengeim, Dimitry; Flannery, Richard J; Miyawaki, Takahiro; Cho, Chang-Hoon; Polster, Brian M; Pypaert, Marc; Hardwick, J Marie; Sensi, Stefano L; Zukin, R Suzanne; Jonas, Elizabeth A

2006-06-21

Transient global ischemia is a neuronal insult that induces delayed cell death. A hallmark event in the early post-ischemic period is enhanced permeability of mitochondrial membranes. The precise mechanisms by which mitochondrial function is disrupted are, as yet, unclear. Here we show that global ischemia promotes alterations in mitochondrial membrane contact points, a rise in intramitochondrial Zn2+, and activation of large, multi-conductance channels in mitochondrial outer membranes by 1 h after insult. Mitochondrial channel activity was associated with enhanced protease activity and proteolytic cleavage of BCL-xL to generate its pro-death counterpart, deltaN-BCL-xL. The findings implicate deltaN-BCL-xL in large, multi-conductance channel activity. Consistent with this, large channel activity was mimicked by introduction of recombinant deltaN-BCL-xL to control mitochondria and blocked by introduction of a functional BCL-xL antibody to post-ischemic mitochondria via the patch pipette. Channel activity was also inhibited by nicotinamide adenine dinucleotide, indicative of a role for the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane. In vivo administration of the membrane-impermeant Zn2+ chelator CaEDTA before ischemia or in vitro application of the membrane-permeant Zn2+ chelator tetrakis-(2-pyridylmethyl) ethylenediamine attenuated channel activity, suggesting a requirement for Zn2+. These findings reveal a novel mechanism by which ischemic insults disrupt the functional integrity of the outer mitochondrial membrane and implicate deltaN-BCL-xL and VDAC in the large, Zn2+-dependent mitochondrial channels observed in post-ischemic hippocampal mitochondria.

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

Science.gov (United States)

Biagini, Giuseppe; D'Antuono, Margherita; Inaba, Yuji; Kano, Toshiyuki; Ragsdale, David; Avoli, Massimo

2015-04-01

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

Comparative pharmacodynamic analysis of imidazoline compounds using rat model of ocular mydriasis with a test of quantitative structure-activity relationships.

Science.gov (United States)

Raczak-Gutknecht, Joanna; Nasal, Antoni; Frąckowiak, Teresa; Kornicka, Anita; Sączewski, Franciszek; Wawrzyniak, Renata; Kubik, Łukasz; Kaliszan, Roman

2017-09-10

Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain. It was proved that the central nervous system (CNS)-localized I1-imidazoline receptors are not engaged in those effects. It appeared interesting to analyze the CNS-mediated pharmacodynamics of imidazole(in)e agents in terms of their chromatographic and calculation chemistry-derived parameters. In the present study a systematic determination and comparative pharmacometric analysis of mydriatic effects in rats were performed on a series of 20 imidazol(in)e agents, composed of the well-known drugs and of the substances used in experimental pharmacology. The eye pupil dilatory activities of the compounds were assessed in anesthetized Wistar rats according to the established Koss method. Among twenty imidazol(in)e derivatives studied, 18 produced diverse dose-dependent mydriatic effects. In the quantitative structure-activity relationships (QSAR) analysis, the pharmacological data (half maximum mydriatic effect - ED 50 in μmol/kg) were considered along with the structural parameters of the agents from molecular modeling. The theoretically calculated lipophilicity parameters, CLOGP, of imidazol(in)es, as well as their lipophilicity parameters from HPLC, logk w , were also considered. The attempts to derive statistically significant QSAR equations for a full series of the agents under study were unsuccessful. However, for a subgroup of eight apparently structurally related imidazol(in)es a significant relationship between log(1/ED 50 ) and logk w values was

Sex-dependent differences in voluntary physical activity.

Science.gov (United States)

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. © 2016 Wiley Periodicals, Inc.

Quantitative detection and biological propagation of scrapie seeding activity in vitro facilitate use of prions as model pathogens for disinfection.

Directory of Open Access Journals (Sweden)

Sandra Pritzkow

Full Text Available Prions are pathogens with an unusually high tolerance to inactivation and constitute a complex challenge to the re-processing of surgical instruments. On the other hand, however, they provide an informative paradigm which has been exploited successfully for the development of novel broad-range disinfectants simultaneously active also against bacteria, viruses and fungi. Here we report on the development of a methodological platform that further facilitates the use of scrapie prions as model pathogens for disinfection. We used specifically adapted serial protein misfolding cyclic amplification (PMCA for the quantitative detection, on steel wires providing model carriers for decontamination, of 263K scrapie seeding activity converting normal protease-sensitive into abnormal protease-resistant prion protein. Reference steel wires carrying defined amounts of scrapie infectivity were used for assay calibration, while scrapie-contaminated test steel wires were subjected to fifteen different procedures for disinfection that yielded scrapie titre reductions of ≤10(1- to ≥10(5.5-fold. As confirmed by titration in hamsters the residual scrapie infectivity on test wires could be reliably deduced for all examined disinfection procedures, from our quantitative seeding activity assay. Furthermore, we found that scrapie seeding activity present in 263K hamster brain homogenate or multiplied by PMCA of scrapie-contaminated steel wires both triggered accumulation of protease-resistant prion protein and was further propagated in a novel cell assay for 263K scrapie prions, i.e., cerebral glial cell cultures from hamsters. The findings from our PMCA- and glial cell culture assays revealed scrapie seeding activity as a biochemically and biologically replicative principle in vitro, with the former being quantitatively linked to prion infectivity detected on steel wires in vivo. When combined, our in vitro assays provide an alternative to titrations of biological

Quantitative Adverse Outcome Pathways and Their ...

Science.gov (United States)

A quantitative adverse outcome pathway (qAOP) consists of one or more biologically based, computational models describing key event relationships linking a molecular initiating event (MIE) to an adverse outcome. A qAOP provides quantitative, dose–response, and time-course predictions that can support regulatory decision-making. Herein we describe several facets of qAOPs, including (a) motivation for development, (b) technical considerations, (c) evaluation of confidence, and (d) potential applications. The qAOP used as an illustrative example for these points describes the linkage between inhibition of cytochrome P450 19A aromatase (the MIE) and population-level decreases in the fathead minnow (FHM; Pimephales promelas). The qAOP consists of three linked computational models for the following: (a) the hypothalamic-pitutitary-gonadal axis in female FHMs, where aromatase inhibition decreases the conversion of testosterone to 17β-estradiol (E2), thereby reducing E2-dependent vitellogenin (VTG; egg yolk protein precursor) synthesis, (b) VTG-dependent egg development and spawning (fecundity), and (c) fecundity-dependent population trajectory. While development of the example qAOP was based on experiments with FHMs exposed to the aromatase inhibitor fadrozole, we also show how a toxic equivalence (TEQ) calculation allows use of the qAOP to predict effects of another, untested aromatase inhibitor, iprodione. While qAOP development can be resource-intensive, the quan

Aberrant regional brain activities in alcohol dependence: a functional magnetic resonance imaging study

Directory of Open Access Journals (Sweden)

Tu XZ

2018-03-01

Full Text Available Xianzhu Tu,1 Juanjuan Wang,2 Xuming Liu,3 Jiyong Zheng4 1Department of Psychiatry, Seventh People’s Hospital of Wenzhou City, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Neurology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Radiology, The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Department of Medical Imaging, The Affiliated Huai’an No 1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China Objective: Whether moderate alcohol consumption has health benefits remains controversial, but the harmful effects of excessive alcohol consumption on behavior and brain function are well recognized. The aim of this study was to investigate alcohol-induced regional brain activities and their relationships with behavioral factors. Subjects and methods: A total of 29 alcohol-dependent subjects (9 females and 20 males and 29 status-matched healthy controls (11 females and 18 males were recruited. Severity of alcohol dependence questionnaire (SADQ and alcohol use disorders identification test (AUDIT were used to evaluate the severity of alcohol craving. Regional homogeneity (ReHo analysis was used to explore the alcohol-induced regional brain changes. Receiver operating characteristic (ROC curve was used to investigate the ability of regional brain activities to distinguish alcohol-dependent subjects from healthy controls. Pearson correlations were used to investigate the relationships between alcohol-induced ReHo differences and behavioral factors. Results: Alcohol-dependent subjects related to healthy controls showed higher ReHo areas in the right superior frontal gyrus (SFG, bilateral medial frontal gyrus (MFG, left precentral gyrus (PG, bilateral middle temporal gyrus (MTG, and right inferior temporal gyrus (ITG and lower ReHo areas in

New Modified UPLC/Tandem Mass Spectrometry Method for Determination of Risperidone and Its Active Metabolite 9-Hydroxyrisperidone in Plasma: Application to Dose-Dependent Pharmacokinetic Study in Sprague-Dawley Rats

Directory of Open Access Journals (Sweden)

Essam Ezzeldin

2017-01-01

Full Text Available Sensitive and specific liquid-chromatography tandem mass spectrometry (UPLC-MS/MS assay has been developed and validated for simultaneous quantification of risperidone (RIS and its active metabolite 9-hydroxyrisperidone (9-OH-RIS in rat plasma using olanzapine (OLA as internal standard (IS. Pharmacokinetics of risperidone and its active metabolite 9-hydroxyrisperidone was compared across different doses (0.3, 1.0, and 6.0 mg/kg. Serial blood sample was collected over a time of 48 hours and analyzed for risperidone and its active metabolite 9-hydroxyrisperidone. The pharmacokinetics parameters including Cmax, tmax, and AUC were determined for risperidone and its active ingredient. The method was linear in the concentration range of 0.2–500 ng/mL for risperidone and 9-OH-risperidone, with coefficients of determination greater than 0.998 and lower limit of quantitation of 0.2 ng/mL. Blood levels of risperidone and its active metabolite were roughly dose-proportional. The method developed herein is simple and rapid and was successfully applied for dose-dependent pharmacokinetic study.

Quantitation of microbicidal activity of mononuclear phagocytes: an in vitro technique.

Directory of Open Access Journals (Sweden)

Rege N

1993-01-01

Full Text Available An in vitro assay technique was set up to determine the phagocytic and microbicidal activity of a monocyte-macrophage cell line using Candida species as test organisms. The norms were determined for the activity of peritoneal macrophages of rats (24.69 +/- 2.6% phagocytosis and 35.4 +/- 5.22% ICK and human (27.89 +/- 3.63% phagocytosis and 50.91 +/- 6.3% ICK. The assay technique was used to test the degree of activation of macrophages induced by metronidazole, Tinospora cordifolia and Asparaqus racemousus and to compare their effects with a standard immunomodulator muramyl-dipeptide. All the three test agents increased the phagocytic and killing capacity of macrophages in a dose dependent manner upto a certain dose, beyond which either these activities were found to have plateaued or decreased. The optimal doses for MDP, Metronidazole, Asparagus racemosus and Tinospora cordifolia were found to be 100 micrograms, 300 mg/kg, 200 mg/kg and 100 mg/kg respectively. Patients with cirrhosis were screened for defects in monocyte function. The depressed monocyte function (20.58 +/- 5% phago and 41.24 +/- 12.19% ICK; P < 0.05 was observed indicating a compromised host defense. The utility of this candidicidal assay in experimental and clinical studies is discussed.

A CT-based method for fully quantitative TI SPECT

International Nuclear Information System (INIS)

Willowson, Kathy; Bailey, Dale; Baldock, Clive

2009-01-01

Full text: Objectives: To develop and validate a method for quantitative 2 0 l TI SPECT data based on corrections derived from X-ray CT data, and to apply the method in the clinic for quantitative determination of recurrence of brain tumours. Method: A previously developed method for achieving quantitative SPECT with 9 9 m Tc based on corrections derived from xray CT data was extended to apply to 2 0 l Tl. Experimental validation was performed on a cylindrical phantom by comparing known injected activity and measured concentration to quantitative calculations. Further evaluation was performed on a RSI Striatal Brain Phantom containing three 'lesions' with activity to background ratios of 1: 1, 1.5: I and 2: I. The method was subsequently applied to a series of scans from patients with suspected recurrence of brain tumours (principally glioma) to determine an SUV-like measure (Standardised Uptake Value). Results: The total activity and concentration in the phantom were calculated to within 3% and I % of the true values, respectively. The calculated values for the concentration of activity in the background and corresponding lesions of the brain phantom (in increasing ratios) were found to be within 2%,10%,1% and 2%, respectively, of the true concentrations. Patient studies showed that an initial SUV greater than 1.5 corresponded to a 56% mortality rate in the first 12 months, as opposed to a 14% mortality rate for those with a SUV less than 1.5. Conclusion: The quantitative technique produces accurate results for the radionuclide 2 0 l Tl. Initial investigation in clinical brain SPECT suggests correlation between quantitative uptake and survival.

Antiretroviral treatment is associated with increased attentional load-dependent brain activation in HIV patients.

Science.gov (United States)

Chang, L; Yakupov, R; Nakama, H; Stokes, B; Ernst, T

2008-06-01

The purpose of this paper was to determine whether antiretroviral medications, especially the nucleoside analogue reverse transcriptase inhibitors, lead to altered brain activation due to their potential neurotoxic effects in patients with human immunodeficiency virus (HIV) infection. Forty-two right-handed men were enrolled in three groups: seronegative controls (SN, n = 18), HIV subjects treated with antiretroviral medications (HIV+ARV, n = 12), or not treated with antiretroviral medications (HIV+NARV, n = 12). Each subject performed a set of visual attention tasks with increasing difficulty or load (tracking two, three or four balls) during functional magnetic resonance imaging. HIV subjects, both groups combined, showed greater load-dependent increases in brain activation in the right frontal regions compared to SN (p-corrected = 0.006). HIV+ARV additionally showed greater load-dependent increases in activation compared to SN in bilateral superior frontal regions (p-corrected = 0.032) and a lower percent accuracy on the performance of the most difficult task (tracking four balls). Region of interest analyses further demonstrated that SN showed load-dependent decreases (with repeated trials despite increasing difficulty), while HIV subjects showed load-dependent increases in activation with the more difficult tasks, especially those on ARVs. These findings suggest that chronic ARV treatments may lead to greater requirement of the attentional network reserve and hence less efficient usage of the network and less practice effects in these HIV patients. As the brain has a limited reserve capacity, exhausting the reserve capacity in HIV+ARV would lead to declined performance with more difficult tasks that require more attention.

Quantitative structure–activity relationship model for amino acids as corrosion inhibitors based on the support vector machine and molecular design

International Nuclear Information System (INIS)

Zhao, Hongxia; Zhang, Xiuhui; Ji, Lin; Hu, Haixiang; Li, Qianshu

2014-01-01

Highlights: • Nonlinear quantitative structure–activity relationship (QSAR) model was built by the support vector machine. • Descriptors for QSAR model were selected by principal component analysis. • Binding energy was taken as one of the descriptors for QSAR model. • Acidic solution and protonation of the inhibitor were considered. - Abstract: The inhibition performance of nineteen amino acids was studied by theoretical methods. The affection of acidic solution and protonation of inhibitor were considered in molecular dynamics simulation and the results indicated that the protonated amino-group was not adsorbed on Fe (1 1 0) surface. Additionally, a nonlinear quantitative structure–activity relationship (QSAR) model was built by the support vector machine. The correlation coefficient was 0.97 and the root mean square error, the differences between predicted and experimental inhibition efficiencies (%), was 1.48. Furthermore, five new amino acids were theoretically designed and their inhibition efficiencies were predicted by the built QSAR model

Quantitative Verification and Synthesis of Attack-Defence Scenarios

DEFF Research Database (Denmark)

Aslanyan, Zaruhi; Nielson, Flemming; Parker, David

2016-01-01

analysis of quantitative properties of complex attack-defence scenarios, using an extension of attack-defence trees which models temporal ordering of actions and allows explicit dependencies in the strategies adopted by attackers and defenders. We adopt a game-theoretic approach, translating attack...... which guarantee or optimise some quantitative property, such as the probability of a successful attack, the expected cost incurred, or some multi-objective trade-off between the two. We implement our approach, building upon the PRISM-games model checker, and apply it to a case study of an RFID goods...

From retinal waves to activity-dependent retinogeniculate map development.

Science.gov (United States)

Markowitz, Jeffrey; Cao, Yongqiang; Grossberg, Stephen

2012-01-01

A neural model is described of how spontaneous retinal waves are formed in infant mammals, and how these waves organize activity-dependent development of a topographic map in the lateral geniculate nucleus, with connections from each eye segregated into separate anatomical layers. The model simulates the spontaneous behavior of starburst amacrine cells and retinal ganglion cells during the production of retinal waves during the first few weeks of mammalian postnatal development. It proposes how excitatory and inhibitory mechanisms within individual cells, such as Ca(2+)-activated K(+) channels, and cAMP currents and signaling cascades, can modulate the spatiotemporal dynamics of waves, notably by controlling the after-hyperpolarization currents of starburst amacrine cells. Given the critical role of the geniculate map in the development of visual cortex, these results provide a foundation for analyzing the temporal dynamics whereby the visual cortex itself develops.

Impaired Na⁺-dependent regulation of acetylcholine-activated inward-rectifier K⁺ current modulates action potential rate dependence in patients with chronic atrial fibrillation.

Science.gov (United States)

Voigt, Niels; Heijman, Jordi; Trausch, Anne; Mintert-Jancke, Elisa; Pott, Lutz; Ravens, Ursula; Dobrev, Dobromir

2013-08-01

Shortened action-potential duration (APD) and blunted APD rate adaptation are hallmarks of chronic atrial fibrillation (cAF). Basal and muscarinic (M)-receptor-activated inward-rectifier K(+) currents (IK1 and IK,ACh, respectively) contribute to regulation of human atrial APD and are subject to cAF-dependent remodeling. Intracellular Na(+) ([Na(+)]i) enhances IK,ACh in experimental models but the effect of [Na(+)]i-dependent regulation of inward-rectifier K(+) currents on APD in human atrial myocytes is currently unknown. Here, we report a [Na(+)]i-dependent inhibition of outward IK1 in atrial myocytes from sinus rhythm (SR) or cAF patients. In contrast, IK,ACh activated by carbachol, a non-selective M-receptor agonist, increased with elevation of [Na(+)]i in SR. This [Na(+)]i-dependent IK,ACh regulation was absent in cAF. Including [Na(+)]i dependence of IK1 and IK,ACh in a recent computational model of the human atrial myocyte revealed that [Na(+)]i accumulation at fast rates inhibits IK1 and blunts physiological APD rate dependence in both groups. [Na(+)]i-dependent IK,ACh augmentation at fast rates increased APD rate dependence in SR, but not in cAF. These results identify impaired Na(+)-sensitivity of IK,ACh as one potential mechanism contributing to the blunted APD rate dependence in patients with cAF. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes". Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Quantitative detection of powdered activated carbon in wastewater treatment plant effluent by thermogravimetric analysis (TGA).

Science.gov (United States)

Krahnstöver, Therese; Plattner, Julia; Wintgens, Thomas

2016-09-15

For the elimination of potentially harmful micropollutants, powdered activated carbon (PAC) adsorption is applied in many wastewater treatment plants (WWTP). This holds the risk of PAC leakage into the WWTP effluent and desorption of contaminants into natural water bodies. In order to assess a potential PAC leakage, PAC concentrations below several mg/L have to be detected in the WWTP effluent. None of the methods that are used for water analysis today are able to differentiate between activated carbon and solid background matrix. Thus, a selective, quantitative and easily applicable method is still needed for the detection of PAC residues in wastewater. In the present study, a method was developed to quantitatively measure the PAC content in wastewater by using filtration and thermogravimetric analysis (TGA), which is a well-established technique for the distinction between different solid materials. For the sample filtration, quartz filters with a temperature stability up to 950 °C were used. This allowed for sensitive and well reproducible measurements, as the TGA was not affected by the presence of the filter. The sample's mass fractions were calculated by integrating the mass decrease rate obtained by TGA in specific, clearly identifiable peak areas. A two-step TGA heating method consisting of N2 and O2 atmospheres led to a good differentiation between PAC and biological background matrix, thanks to the reduction of peak overlapping. A linear correlation was found between a sample's PAC content and the corresponding peak areas under N2 and O2, the sample volume and the solid mass separated by filtration. Based on these findings, various wastewater samples from different WWTPs were then analyzed by TGA with regard to their PAC content. It was found that, compared to alternative techniques such as measurement of turbidity or total suspended solids, the newly developed TGA method allows for a quantitative and selective detection of PAC concentrations down to 0

Applying quantitative structure–activity relationship approaches to nanotoxicology: Current status and future potential

International Nuclear Information System (INIS)

Winkler, David A.; Mombelli, Enrico; Pietroiusti, Antonio; Tran, Lang; Worth, Andrew; Fadeel, Bengt; McCall, Maxine J.

2013-01-01

The potential (eco)toxicological hazard posed by engineered nanoparticles is a major scientific and societal concern since several industrial sectors (e.g. electronics, biomedicine, and cosmetics) are exploiting the innovative properties of nanostructures resulting in their large-scale production. Many consumer products contain nanomaterials and, given their complex life-cycle, it is essential to anticipate their (eco)toxicological properties in a fast and inexpensive way in order to mitigate adverse effects on human health and the environment. In this context, the application of the structure–toxicity paradigm to nanomaterials represents a promising approach. Indeed, according to this paradigm, it is possible to predict toxicological effects induced by chemicals on the basis of their structural similarity with chemicals for which toxicological endpoints have been previously measured. These structure–toxicity relationships can be quantitative or qualitative in nature and they can predict toxicological effects directly from the physicochemical properties of the entities (e.g. nanoparticles) of interest. Therefore, this approach can aid in prioritizing resources in toxicological investigations while reducing the ethical and monetary costs that are related to animal testing. The purpose of this review is to provide a summary of recent key advances in the field of QSAR modelling of nanomaterial toxicity, to identify the major gaps in research required to accelerate the use of quantitative structure–activity relationship (QSAR) methods, and to provide a roadmap for future research needed to achieve QSAR models useful for regulatory purposes

Aldose Reductase Inhibitor Protects against Hyperglycemic Stress by Activating Nrf2-Dependent Antioxidant Proteins

Directory of Open Access Journals (Sweden)

Kirtikar Shukla

2017-01-01

Full Text Available We have shown earlier that pretreatment of cultured cells with aldose reductase (AR inhibitors prevents hyperglycemia-induced mitogenic and proinflammatory responses. However, the effects of AR inhibitors on Nrf2-mediated anti-inflammatory responses have not been elucidated yet. We have investigated how AR inhibitor fidarestat protects high glucose- (HG- induced cell viability changes by increasing the expression of Nrf2 and its dependent phase II antioxidant enzymes. Fidarestat pretreatment prevents HG (25 mM-induced Thp1 monocyte viability. Further, treatment of Thp1 monocytes with fidarestat caused a time-dependent increase in the expression as well as the DNA-binding activity of Nrf2. In addition, fidarestat augmented the HG-induced Nrf2 expression and activity and also upregulated the expression of Nrf2-dependent proteins such as hemeoxygenase-1 (HO1 and NQO1 in Thp1 cells. Similarly, treatment with AR inhibitor also induced the expression of Nrf2 and HO1 in STZ-induced diabetic mice heart and kidney tissues. Further, AR inhibition increased the HG-induced expression of antioxidant enzymes such as SOD and catalase and activation of AMPK-α1 in Thp1 cells. Our results thus suggest that pretreatment with AR inhibitor prepares the monocytes against hyperglycemic stress by overexpressing the Nrf2-dependent antioxidative proteins.

Strong renormalization scheme dependence in τ-lepton decay: Fact or fiction?

International Nuclear Information System (INIS)

Chyla, J.

1995-01-01

The question of the renormalization scheme dependence of the τ semileptonic decay rate is examined in response to a recent criticism. Particular attention is payed to a distinction between a consistent quantitative description of this dependence and the actual selection of a subset of ''acceptable'' renormalization schemes. It is pointed out that this criticism is valid only within a particular definition of the ''strength'' of the renormalization scheme dependence and should not discourage further attempts to use the semileptonic τ decay rate for quantitative tests of perturbative QCD

GABAergic activities control spike timing- and frequency-dependent long-term depression at hippocampal excitatory synapses

Directory of Open Access Journals (Sweden)

Makoto Nishiyama

2010-06-01

Full Text Available GABAergic interneuronal network activities in the hippocampus control a variety of neural functions, including learning and memory, by regulating θ and γ oscillations. How these GABAergic activities at pre- and post-synaptic sites of hippocampal CA1 pyramidal cells differentially contribute to synaptic function and plasticity during their repetitive pre- and post-synaptic spiking at θ and γ oscillations is largely unknown. We show here that activities mediated by postsynaptic GABAARs and presynaptic GABABRs determine, respectively, the spike timing- and frequency-dependence of activity-induced synaptic modifications at Schaffer collateral-CA1 excitatory synapses. We demonstrate that both feedforward and feedback GABAAR-mediated inhibition in the postsynaptic cell controls the spike timing-dependent long-term depression of excitatory inputs (“e-LTD” at the θ frequency. We also show that feedback postsynaptic inhibition specifically causes e-LTD of inputs that induce small postsynaptic currents (<70 pA with LTP timing, thus enforcing the requirement of cooperativity for induction of long-term potentiation at excitatory inputs (“e-LTP”. Furthermore, under spike-timing protocols that induce e-LTP and e-LTD at excitatory synapses, we observed parallel induction of LTP and LTD at inhibitory inputs (“i-LTP” and “i-LTD” to the same postsynaptic cells. Finally, we show that presynaptic GABABR-mediated inhibition plays a major role in the induction of frequency-dependent e-LTD at α and β frequencies. These observations demonstrate the critical influence of GABAergic interneuronal network activities in regulating the spike timing and frequency dependences of long-term synaptic modifications in the hippocampus.

Enhancing NPP Safety Through an Effective Dependability Management

Energy Technology Data Exchange (ETDEWEB)

Vieru, G., E-mail: g_vieru@yahoo.com [AREN, Bucharest (Romania)

2014-10-15

Taking into account the importance of the continuous improvement of the performance and reliability of a NPP and practical measures to strengthen nuclear safety and security, it is to be noted that a good management for a nuclear power reactor involves a ''good dependability management'' of the activities, such as: Reliability, Availability, Maintainability (RAM) and maintenance support. In order to evaluate certain safety assessment criteria intended to be applied at the level of the nuclear reactor unit management, equipment dependability indicators and their impact over the availability and reactor safety have to be evaluated. Reactor equipment dependability indicators provide a quantitative indication of equipment RAM performances (Reliability, Availability and Maintenance). One of the important benefits of maintenance and failure data gathering is that it can be used as a support of probabilistic safety assessment (PSA). Also, a good dependability management implementation may be used to complement reactor level unit performance indicators in the field of safe operation, maintenance and improving operating parameters, as well as for Strengthening Safety and Improving Reliability of a NPP. This paper underlines the importance of nuclear safety and security as prerequisites for nuclear power. In addition, it demonstrates how different technical aspects, through implementation of a good dependability management, contribute to a strengthened safety and an improvement of availability of the NPP through dependability indicators determination and evaluation. (author)

Structures of apicomplexan calcium-dependent protein kinases reveal mechanism of activation by calcium

Energy Technology Data Exchange (ETDEWEB)

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 (Toronto); (WU-MED)

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.

Dependability Evaluation of Advanced Diverse Protection System

International Nuclear Information System (INIS)

Oh, Yang Gyun; Lee, Yoon Hee; Sohn, Se Do; Baek, Seung Min; Lee, Sang Jeong

2014-01-01

For the mitigation of anticipated transients without scram (ATWS) as well as common cause failure (CCF) within the plant protection system (PPS) and the emergency safety feature . component control system (ESF-CCS), the diverse protection system (DPS) has been designed by KEPCO Engineering and Construction Company. Recently KEPCO E and C has developed the advanced diverse protection system (ADPS), which has four redundant channels, in an attempt to enhance a fault-tolerant capability of the system. For the evaluation of overall system improvement effects of the ADPS compared with the DPS, the dependability evaluation results are described herein. For all dependability attributes, this paper suggests a practical dependability evaluation method which uses quantitative dependability scores and indices. An overall dependability evaluation index (DEI) for the ADPS is evaluated with the average value of reliability/ security/maintainability/safety indices (i.e., RID, SID, MID, and SID') for dependability. The evaluation results show that the DEI value of ADPS can be improved by approximately 23% compared with that of the DPS, thanks to its fault-tolerant system architecture, software design changes, and external interface design features. Several suggestions have been made, in this paper, of an overall quantitative dependability evaluation method for the nuclear instrumentation and control (I and C) systems including the DPS and ADPS, and the usefulness of dependability evaluation on nuclear I and C systems has been confirmed

Application of the quantitative autoradiography for determination of specific activity of labelled non-metallic inclusions

International Nuclear Information System (INIS)

Kowalczyk, J.T.; Wilczynski, A.W.

1983-01-01

The knowledge of specific activity of labelled non-metallic inclusions, i.e. the knowledge of the content of the radiotracer in a single inclusion, allows to obtain new information about the mechanism and the kinetics of steel deoxidation. In order to determine this specific activity quantitative autoradiography was used. Fo; this purpose, various standards of aluminium oxides with different amounts of cerium oxide Ce 2 O 3 and an aluminium-cerium alloy were prepared. The standards and the alloy were activated with thermal neutrons. Then several autoradiographs were made for these standards (ORWO AF-3 films were used). The autoradiographs served as the basis for evaluation of the standardization curves: optical density versus dimension of particles for a constant cerium concentration; optical density versus concentration of cerium for a constant dimension of particle. The samples of liquid steel were deoxidated with Al-Ce alloy. After labelled non-metallic inclusions had been isolated, the autoradiographs were made under the same conditions as for the standards. The standardization curves were used to determine the cerium content in the single inclusions. (author)

Bilateral versus ipsilesional cortico-subcortical activity patterns in stroke show hemispheric dependence.

Science.gov (United States)

Vidal, Ana C; Banca, Paula; Pascoal, Augusto G; Cordeiro, Gustavo; Sargento-Freitas, João; Gouveia, Ana; Castelo-Branco, Miguel

2018-01-01

Background Understanding of interhemispheric interactions in stroke patients during motor control is an important clinical neuroscience quest that may provide important clues for neurorehabilitation. In stroke patients bilateral overactivation in both hemispheres has been interpreted as a poor prognostic indicator of functional recovery. In contrast, ipsilesional patterns have been linked with better motor outcomes. Aim We investigated the pathophysiology of hemispheric interactions during limb movement without and with contralateral restraint, to mimic the effects of constraint-induced movement therapy. We used neuroimaging to probe brain activity with such a movement-dependent interhemispheric modulation paradigm. Methods We used a functional magnetic resonance imaging block design during which the plegic/paretic upper limb was recruited/mobilized to perform unilateral arm elevation, as a function of presence versus absence of contralateral limb restriction (n = 20, with balanced left/right lesion sites). Results Analysis of 10 right hemispheric stroke participants yielded bilateral sensorimotor cortex activation in all movement phases in contrast with the unilateral dominance seen in the 10 left hemispheric stroke participants. Superimposition of contralateral restriction led to a prominent shift from activation to deactivation response patterns, in particular in cortical and basal ganglia motor areas in right hemispheric stroke. Left hemispheric stroke was, in general, characterized by reduced activation patterns, even in the absence of restriction, which induced additional cortical silencing. Conclusion The observed hemispheric-dependent activation/deactivation shifts is novel and these pathophysiological observations suggest short-term neuroplasticity that may be useful for hemisphere-tailored neurorehabilitation.

Physical activity level is impaired and diet dependent in preterm newborn pigs

DEFF Research Database (Denmark)

Cao, Muqing; Andersen, Anders Daniel; Van Ginneken, Chris

2015-01-01

and neonatal physical activity. METHODS: In experiment 1, preterm and term pigs were fed parenteral nutrition (PN) or PN plus bovine colostrum (BC, 16-64 ml/kg/d enterally) for 5 d. In experiment 2, preterm pigs were fed PN+BC or PN+formula for 5 d. In experiment 3, preterm pigs were fed BC, formula, or human...... feeding increased HCA, intestinal weights, and necrotizing enteritis resistance, relative to formula (experiment 3). CONCLUSION: Preterm pigs show decreased physical activity, and the first enteral feeds diet dependently stimulate both gut growth and physical activity. The effects may arise from...

Exercise dependence score in patients with longstanding eating disorders and controls: the importance of affect regulation and physical activity intensity.

Science.gov (United States)

Bratland-Sanda, Solfrid; Martinsen, Egil W; Rosenvinge, Jan H; Rø, Oyvind; Hoffart, Asle; Sundgot-Borgen, Jorunn

2011-01-01

To examine associations among exercise dependence score, amount of physical activity and eating disorder (ED) symptoms in patients with longstanding ED and non-clinical controls. Adult female inpatients (n = 59) and 53 age-matched controls participated in this cross sectional study. Assessments included the eating disorders examination, eating disorders inventory, exercise dependence scale, reasons for exercise inventory, and MTI Actigraph accelerometer. Positive associations were found among vigorous, not moderate, physical activity, exercise dependence score and ED symptoms in patients. In the controls, ED symptoms were negatively associated with vigorous physical activity and not correlated with exercise dependence score. Exercise for negative affect regulation, not weight/appearance, and amount of vigorous physical activity were explanatory variables for exercise dependence score in both groups. The positive associations among exercise dependence score, vigorous physical activity and ED symptoms need proper attention in the treatment of longstanding ED. Copyright © 2011 John Wiley & Sons, Ltd and Eating Disorders Association.

Arbitrage Activities between Offshore and Domestic Yen Money Markets since the End of the Quantitative Easing Policy

OpenAIRE

Teppei Nagano; Eiko Ooka; Naohiko Baba

2007-01-01

Transactions in the yen money markets have become active since the end of the quantitative easing policy (QEP) in March 2006. In particular, transactions by foreign financial institutions have been increasing in the offshore markets including the FX swap and euroyen deposit markets, as well as the domestic money markets. This Review surveys the spreads and hence the arbitrage relationship between those offshore markets and the domestic money markets. In the short-term money markets, the sprea...

The 3D protein of duck hepatitis A virus type 1 binds to a viral genomic 3' UTR and shows RNA-dependent RNA polymerase activity.

Science.gov (United States)

Zhang, Yu; Cao, Qianda; Wang, Mingshu; Jia, Renyong; Chen, Shun; Zhu, Dekang; Liu, Mafeng; Sun, Kunfeng; Yang, Qiao; Wu, Ying; Zhao, Xinxin; Chen, Xiaoyue; Cheng, Anchun

2017-12-01

To explore the RNA-dependent RNA polymerase (RdRP) function of the 3D protein of duck hepatitis A virus type 1 (DHAV-1), the gene was cloned into the pET-32a(+) vector for prokaryotic expression. The 3' untranslated region (3' UTR) of DHAV-1 together with a T7 promoter was cloned into the pMD19-T vector for in vitro transcription of 3' UTR RNA, which was further used as a template in RNA-dependent RNA polymerization. In this study, three methods were applied to analyze the RdRP function of the 3D protein: (1) ammonium molybdate spectrophotometry to detect pyrophosphate produced during polymerization; (2) quantitative reverse transcription PCR (RT-qPCR) to investigate the changes in RNA quantity during polymerization; and (3) electrophoresis mobility shift assay to examine the interaction between the 3D protein and 3' UTR. The results showed the 3D protein was successfully expressed in bacteria culture supernatant in a soluble form, which could be purified by affinity chromatography. In 3D enzymatic activity assays, pyrophosphate and RNA were produced, the amounts of which increased based on approximative kinetics, and binding of the 3D protein to the 3' UTR was observed. These results indicate that prokaryotically expressed soluble DHAV-13D protein can bind to a viral genomic 3' UTR and exhibit RdRP activity.

Comparison of 3D quantitative structure-activity relationship methods: Analysis of the in vitro antimalarial activity of 154 artemisinin analogues by hypothetical active-site lattice and comparative molecular field analysis

Science.gov (United States)

Woolfrey, John R.; Avery, Mitchell A.; Doweyko, Arthur M.

1998-03-01

Two three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL), were compared with respect to the analysis of a training set of 154 artemisinin analogues. Five models were created, including a complete HASL and two trimmed versions, as well as two CoMFA models (leave-one-out standard CoMFA and the guided-region selection protocol). Similar r2 and q2 values were obtained by each method, although some striking differences existed between CoMFA contour maps and the HASL output. Each of the four predictive models exhibited a similar ability to predict the activity of a test set of 23 artemisinin analogues, although some differences were noted as to which compounds were described well by either model.

A Novel Time-Dependent CENP-E Inhibitor with Potent Antitumor Activity.

Directory of Open Access Journals (Sweden)

Akihiro Ohashi

Full Text Available Centromere-associated protein E (CENP-E regulates both chromosome congression and the spindle assembly checkpoint (SAC during mitosis. The loss of CENP-E function causes chromosome misalignment, leading to SAC activation and apoptosis during prolonged mitotic arrest. Here, we describe the biological and antiproliferative activities of a novel small-molecule inhibitor of CENP-E, Compound-A (Cmpd-A. Cmpd-A inhibits the ATPase activity of the CENP-E motor domain, acting as a time-dependent inhibitor with an ATP-competitive-like behavior. Cmpd-A causes chromosome misalignment on the metaphase plate, leading to prolonged mitotic arrest. Treatment with Cmpd-A induces antiproliferation in multiple cancer cell lines. Furthermore, Cmpd-A exhibits antitumor activity in a nude mouse xenograft model, and this antitumor activity is accompanied by the elevation of phosphohistone H3 levels in tumors. These findings demonstrate the potency of the CENP-E inhibitor Cmpd-A and its potential as an anticancer therapeutic agent.

Focus Groups in Elderly Ophthalmologic Patients: Setting the Stage for Quantitative Preference Elicitation.

Science.gov (United States)

Danner, Marion; Vennedey, Vera; Hiligsmann, Mickaël; Fauser, Sascha; Stock, Stephanie

2016-02-01

Patients suffering from age-related macular degeneration (AMD) are rarely actively involved in decision-making, despite facing preference-sensitive treatment decisions. This paper presents a qualitative study to prepare quantitative preference elicitation in AMD patients. The aims of this study were (1) to gain familiarity with and learn about the special requirements of the AMD patient population for quantitative data collection; and (2) to select/refine patient-relevant treatment attributes and levels, and gain insights into preference structures. Semi-structured focus group interviews were performed. An interview guide including preselected categories in the form of seven potentially patient-relevant treatment attributes was followed. To identify the most patient-relevant treatment attributes, a ranking exercise was performed. Deductive content analyses were done by two independent reviewers for each attribute to derive subcategories (potential levels of attributes) and depict preference trends. The focus group interviews included 21 patients. The interviews revealed that quantitative preference surveys in this population will have to be interviewer assisted to make the survey feasible for patients. The five most patient-relevant attributes were the effect on visual function [ranking score (RS): 139], injection frequency (RS: 101), approval status (RS: 83), side effects (RS: 79), and monitoring frequency (RS: 76). Attribute and level refinement was based on patients' statements. Preference trends and dependencies between attributes informed the quantitative instrument design. This study suggests that qualitative research is a very helpful step to prepare the design and administration of quantitative preference elicitation instruments. It especially facilitated familiarization with the target population and its preferences, and it supported attribute/level refinement.

Support vector regression-guided unravelling: antioxidant capacity and quantitative structure-activity relationship predict reduction and promotion effects of flavonoids on acrylamide formation

Science.gov (United States)

Huang, Mengmeng; Wei, Yan; Wang, Jun; Zhang, Yu

2016-09-01

We used the support vector regression (SVR) approach to predict and unravel reduction/promotion effect of characteristic flavonoids on the acrylamide formation under a low-moisture Maillard reaction system. Results demonstrated the reduction/promotion effects by flavonoids at addition levels of 1-10000 μmol/L. The maximal inhibition rates (51.7%, 68.8% and 26.1%) and promote rates (57.7%, 178.8% and 27.5%) caused by flavones, flavonols and isoflavones were observed at addition levels of 100 μmol/L and 10000 μmol/L, respectively. The reduction/promotion effects were closely related to the change of trolox equivalent antioxidant capacity (ΔTEAC) and well predicted by triple ΔTEAC measurements via SVR models (R: 0.633-0.900). Flavonols exhibit stronger effects on the acrylamide formation than flavones and isoflavones as well as their O-glycosides derivatives, which may be attributed to the number and position of phenolic and 3-enolic hydroxyls. The reduction/promotion effects were well predicted by using optimized quantitative structure-activity relationship (QSAR) descriptors and SVR models (R: 0.926-0.994). Compared to artificial neural network and multi-linear regression models, SVR models exhibited better fitting performance for both TEAC-dependent and QSAR descriptor-dependent predicting work. These observations demonstrated that the SVR models are competent for predicting our understanding on the future use of natural antioxidants for decreasing the acrylamide formation.

Definition of regional dependence of activity antioxidative enzymes means of the dispersive analysis

Directory of Open Access Journals (Sweden)

Anatoly T. Bykov

2011-05-01

Full Text Available In article application of the dispersive analysis for an estimation of dependence of activity antioxidative enzymes from region of constant residing, age, sex and the disease diagnosis is considered.

A quantitative phase field model for hydride precipitation in zirconium alloys: Part I. Development of quantitative free energy functional

International Nuclear Information System (INIS)

Shi, San-Qiang; Xiao, Zhihua

2015-01-01

A temperature dependent, quantitative free energy functional was developed for the modeling of hydride precipitation in zirconium alloys within a phase field scheme. The model takes into account crystallographic variants of hydrides, interfacial energy between hydride and matrix, interfacial energy between hydrides, elastoplastic hydride precipitation and interaction with externally applied stress. The model is fully quantitative in real time and real length scale, and simulation results were compared with limited experimental data available in the literature with a reasonable agreement. The work calls for experimental and/or theoretical investigations of some of the key material properties that are not yet available in the literature

From retinal waves to activity-dependent retinogeniculate map development.

Directory of Open Access Journals (Sweden)

Jeffrey Markowitz

Full Text Available A neural model is described of how spontaneous retinal waves are formed in infant mammals, and how these waves organize activity-dependent development of a topographic map in the lateral geniculate nucleus, with connections from each eye segregated into separate anatomical layers. The model simulates the spontaneous behavior of starburst amacrine cells and retinal ganglion cells during the production of retinal waves during the first few weeks of mammalian postnatal development. It proposes how excitatory and inhibitory mechanisms within individual cells, such as Ca(2+-activated K(+ channels, and cAMP currents and signaling cascades, can modulate the spatiotemporal dynamics of waves, notably by controlling the after-hyperpolarization currents of starburst amacrine cells. Given the critical role of the geniculate map in the development of visual cortex, these results provide a foundation for analyzing the temporal dynamics whereby the visual cortex itself develops.

Rosmarinic acid counteracts activation of hepatic stellate cells via inhibiting the ROS-dependent MMP-2 activity: Involvement of Nrf2 antioxidant system

Energy Technology Data Exchange (ETDEWEB)

Lu, Changfang; Zou, Yu; Liu, Yuzhang; Niu, Yingcai, E-mail: nyc1968@126.com

2017-03-01

Recently, oxidative stress is involved in hepatofibrogenesis. Matrix metalloproteinase-2 (MMP-2) is required for activation of hepatic stellate cells (HSCs) in response to reactive oxygen species (ROS). This study was designed to explore the hypothesis that the inhibitory effect of rosmarinic acid (RA) on HSCs activation might mainly result from its antioxidant capability by increasing the synthesis of glutathione (GSH) involved in nuclear factor kappa B (NF-κB)-dependent inhibition of MMP-2 activity. Here, we demonstrate that RA reverses activated HSCs to quiescent cells. Concomitantly, RA inhibits MMP-2 activity. RNA interference-imposed knockdown of NF-κB abolished down-regulation of MMP-2 by RA. RA-mediated inactivation of NF-κB could be blocked by the diphenyleneiodonium chloride (DPI; a ROS inhibitor). Conversely, transfection of dominant-negative (DN) mutant of extracellular signal-regulated kinases 2 (ERK2), c-Jun N-terminal kinase 1 (JNK1), or p38α kinase had no such effect. Simultaneously, RA suppresses ROS generation and lipid peroxidation (LPO) whereas increases cellular GSH in HSC-T6 cells. Furthermore, RA significantly increased antioxidant response element (ARE)-mediated luciferase activity, nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and catalytic subunits from glutamate cysteine ligase (GCLc) expression, but not modulatory subunits from GCL (GCLm). RA-mediated up-regulation of GClc is inhibited by the shRNA-induced Nrf2 knockdown. The knocking down of Nrf2 or buthionine sulfoximine (a GCL inhibitor) abolished RA-mediated inhibition of ROS. Collectively, these results provide novel insights into the mechanisms of RA as an antifibrogenic candidate in the prevention and treatment of liver fibrosis. - Highlights: • RA reverses activated HSCs to quiescent cells. • RA suppresses MMP-2 activity through a NF-κB-dependent pathway. • Inhibition of oxidative stress by RA is dependent on nuclear translocation of Nrf2

Rosmarinic acid counteracts activation of hepatic stellate cells via inhibiting the ROS-dependent MMP-2 activity: Involvement of Nrf2 antioxidant system

International Nuclear Information System (INIS)

Lu, Changfang; Zou, Yu; Liu, Yuzhang; Niu, Yingcai

2017-01-01

Recently, oxidative stress is involved in hepatofibrogenesis. Matrix metalloproteinase-2 (MMP-2) is required for activation of hepatic stellate cells (HSCs) in response to reactive oxygen species (ROS). This study was designed to explore the hypothesis that the inhibitory effect of rosmarinic acid (RA) on HSCs activation might mainly result from its antioxidant capability by increasing the synthesis of glutathione (GSH) involved in nuclear factor kappa B (NF-κB)-dependent inhibition of MMP-2 activity. Here, we demonstrate that RA reverses activated HSCs to quiescent cells. Concomitantly, RA inhibits MMP-2 activity. RNA interference-imposed knockdown of NF-κB abolished down-regulation of MMP-2 by RA. RA-mediated inactivation of NF-κB could be blocked by the diphenyleneiodonium chloride (DPI; a ROS inhibitor). Conversely, transfection of dominant-negative (DN) mutant of extracellular signal-regulated kinases 2 (ERK2), c-Jun N-terminal kinase 1 (JNK1), or p38α kinase had no such effect. Simultaneously, RA suppresses ROS generation and lipid peroxidation (LPO) whereas increases cellular GSH in HSC-T6 cells. Furthermore, RA significantly increased antioxidant response element (ARE)-mediated luciferase activity, nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and catalytic subunits from glutamate cysteine ligase (GCLc) expression, but not modulatory subunits from GCL (GCLm). RA-mediated up-regulation of GClc is inhibited by the shRNA-induced Nrf2 knockdown. The knocking down of Nrf2 or buthionine sulfoximine (a GCL inhibitor) abolished RA-mediated inhibition of ROS. Collectively, these results provide novel insights into the mechanisms of RA as an antifibrogenic candidate in the prevention and treatment of liver fibrosis. - Highlights: • RA reverses activated HSCs to quiescent cells. • RA suppresses MMP-2 activity through a NF-κB-dependent pathway. • Inhibition of oxidative stress by RA is dependent on nuclear translocation of Nrf2

Investigation of Antileishmanial Activities of Acridines Derivatives against Promastigotes and Amastigotes Form of Parasites Using Quantitative Structure Activity Relationship Analysis

Directory of Open Access Journals (Sweden)

Samir Chtita

2016-01-01

Full Text Available In a search of newer and potent antileishmanial (against promastigotes and amastigotes form of parasites drug, a series of 60 variously substituted acridines derivatives were subjected to a quantitative structure activity relationship (QSAR analysis for studying, interpreting, and predicting activities and designing new compounds by using multiple linear regression and artificial neural network (ANN methods. The used descriptors were computed with Gaussian 03, ACD/ChemSketch, Marvin Sketch, and ChemOffice programs. The QSAR models developed were validated according to the principles set up by the Organisation for Economic Co-operation and Development (OECD. The principal component analysis (PCA has been used to select descriptors that show a high correlation with activities. The univariate partitioning (UP method was used to divide the dataset into training and test sets. The multiple linear regression (MLR method showed a correlation coefficient of 0.850 and 0.814 for antileishmanial activities against promastigotes and amastigotes forms of parasites, respectively. Internal and external validations were used to determine the statistical quality of QSAR of the two MLR models. The artificial neural network (ANN method, considering the relevant descriptors obtained from the MLR, showed a correlation coefficient of 0.933 and 0.918 with 7-3-1 and 6-3-1 ANN models architecture for antileishmanial activities against promastigotes and amastigotes forms of parasites, respectively. The applicability domain of MLR models was investigated using simple and leverage approaches to detect outliers and outsides compounds. The effects of different descriptors in the activities were described and used to study and design new compounds with higher activities compared to the existing ones.

Light wavelength dependency of mating activity in the drosophila melanogaster species subgroup

International Nuclear Information System (INIS)

Sakai, Takaomi; Tomaru, Masatoshi; Oguma, Yuzuru; Isono, Kunio; Fukatami, Akishi

2002-01-01

The action spectra of mating activity among the six species of the Drosophila melanogaster species subgroup were compared to understand how light wavelength affects mating activity. The species fell into three groups with respect to the action spectrum of mating activity. We chose one representative species from each of the three types for detailed study: D. melanogaster, D. sechellia and D. yakuba. The mating activities were investigated under three different light intensities of three monochromatic lights stimulus. Each species showed a unique spectral and intensity response. To know the evolutionary meaning of the light wavelength dependency of mating activity, we superimposed the type of action spectrum of mating activity in these six species on a cladogram. Mating inhibition under UV was conserved in evolution among these species. Furthermore we clarified that D. melanogaster showed low mating activity under UV because males courted less under UV. (author)

Activity-dependent astrocyte swelling is mediated by pH-regulating mechanisms.

Science.gov (United States)

Larsen, Brian Roland; MacAulay, Nanna

2017-10-01

During neuronal activity in the mammalian brain, the K + released into the synaptic space is initially buffered by the astrocytic compartment. In parallel, the extracellular space (ECS) shrinks, presumably due to astrocytic cell swelling. With the Na + /K + /2Cl - cotransporter and the Kir4.1/AQP4 complex not required for the astrocytic cell swelling in the hippocampus, the molecular mechanisms underlying the activity-dependent ECS shrinkage have remained unresolved. To identify these molecular mechanisms, we employed ion-sensitive microelectrodes to measure changes in ECS, [K + ] o and [H + ] o /pH o during electrical stimulation of rat hippocampal slices. Transporters and receptors responding directly to the K + and glutamate released into the extracellular space (the K + /Cl - cotransporter, KCC, glutamate transporters and G protein-coupled receptors) did not modulate the extracellular space dynamics. The HCO3--transporting mechanism, which in astrocytes mainly constitutes the electrogenic Na + / HCO3- cotransporter 1 (NBCe1), is activated by the K + -mediated depolarization of the astrocytic membrane. Inhibition of this transporter reduced the ECS shrinkage by ∼25% without affecting the K + transients, pointing to NBCe1 as a key contributor to the stimulus-induced astrocytic cell swelling. Inhibition of the monocarboxylate cotransporters (MCT), like-wise, reduced the ECS shrinkage by ∼25% without compromising the K + transients. Isosmotic reduction of extracellular Cl - revealed a requirement for this ion in parts of the ECS shrinkage. Taken together, the stimulus-evoked astrocytic cell swelling does not appear to occur as a direct effect of the K + clearance, as earlier proposed, but partly via the pH-regulating transport mechanisms activated by the K + -induced astrocytic depolarization and the activity-dependent metabolism. © 2017 Wiley Periodicals, Inc.

Novel time-dependent vascular actions of Δ9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

International Nuclear Information System (INIS)

O'Sullivan, Saoirse E.; Tarling, Elizabeth J.; Bennett, Andrew J.; Kendall, David A.; Randall, Michael D.

2005-01-01

Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, Δ 9 -tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPARγ). In vitro, THC (10 μM) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPARγ agonist rosiglitazone and was inhibited by the PPARγ antagonist GW9662 (1 μM), but not the cannabinoid CB 1 receptor antagonist AM251 (1 μM). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPARγ, transiently expressed in combination with retinoid X receptor α and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 μM). In vitro incubation with THC (1 or 10 μM, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPARγ ligands. The present results provide strong evidence that THC is a PPARγ ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors

Velocity & displacement-dependent damper: A novel passive shock absorber inspired by the semi-active control

Science.gov (United States)

Nie, Shida; Zhuang, Ye; Wang, Yong; Guo, Konghui

2018-01-01

The performance of velocity & displacement-dependent damper (VDD), inspired by the semi-active control, is analyzed. The main differences among passive, displacement-dependent and semi-active dampers are compared on their damping properties. Valve assemblies of VDD are modelled to get an insight into its working principle. The mechanical structure composed by four valve assemblies helps to enable VDD to approach the performance by those semi-active control dampers. The valve structure parameters are determined by the suggested two-step process. Hydraulic model of the damper is built with AMEsim. Simulation result of F-V curves, which is similar to those of semi-active control damper, demonstrates that VDD could achieve the similar performance of semi-active control damper. The performance of a quarter vehicle model employing VDD is analyzed and compared with semi-active suspension. Simulation results show that VDD could perform as good as a semi-active control damper. In addition, no add-on hardware or energy consumption is needed for VDD to achieve the remarkable performance.

Structure modification and functionality of whey proteins: quantitative structure-activity relationship approach.

Science.gov (United States)

Nakai, S; Li-Chan, E

1985-10-01

According to the original idea of quantitative structure-activity relationship, electric, hydrophobic, and structural parameters should be taken into consideration for elucidating functionality. Changes in these parameters are reflected in the property of protein solubility upon modification of whey proteins by heating. Although solubility is itself a functional property, it has been utilized to explain other functionalities of proteins. However, better correlations were obtained when hydrophobic parameters of the proteins were used in conjunction with solubility. Various treatments reported in the literature were applied to whey protein concentrate in an attempt to obtain whipping and gelling properties similar to those of egg white. Mapping simplex optimization was used to search for the best results. Improvement in whipping properties by pepsin hydrolysis may have been due to higher protein solubility, and good gelling properties resulting from polyphosphate treatment may have been due to an increase in exposable hydrophobicity. However, the results of angel food cake making were still unsatisfactory.

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

Science.gov (United States)

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

Fragile X Mental Retardation Protein Regulates Activity-Dependent Membrane Trafficking and Trans-Synaptic Signaling Mediating Synaptic Remodeling

Science.gov (United States)

Sears, James C.; Broadie, Kendal

2018-01-01

Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. The disease arises through loss of fragile X mental retardation protein (FMRP), which normally exhibits peak expression levels in early-use critical periods, and is required for activity-dependent synaptic remodeling during this transient developmental window. FMRP canonically binds mRNA to repress protein translation, with targets that regulate cytoskeleton dynamics, membrane trafficking, and trans-synaptic signaling. We focus here on recent advances emerging in these three areas from the Drosophila disease model. In the well-characterized central brain mushroom body (MB) olfactory learning/memory circuit, FMRP is required for activity-dependent synaptic remodeling of projection neurons innervating the MB calyx, with function tightly restricted to an early-use critical period. FMRP loss is phenocopied by conditional removal of FMRP only during this critical period, and rescued by FMRP conditional expression only during this critical period. Consistent with FXS hyperexcitation, FMRP loss defects are phenocopied by heightened sensory experience and targeted optogenetic hyperexcitation during this critical period. FMRP binds mRNA encoding Drosophila ESCRTIII core component Shrub (human CHMP4 homolog) to restrict Shrub translation in an activity-dependent mechanism only during this same critical period. Shrub mediates endosomal membrane trafficking, and perturbing Shrub expression is known to interfere with neuronal process pruning. Consistently, FMRP loss and Shrub overexpression targeted to projection neurons similarly causes endosomal membrane trafficking defects within synaptic boutons, and genetic reduction of Shrub strikingly rescues Drosophila FXS model defects. In parallel work on the well-characterized giant fiber (GF) circuit, FMRP limits iontophoretic dye loading into central interneurons, demonstrating an FMRP role controlling core neuronal properties through the

Quantitative study of undersampled recoverability for sparse images in computed tomography

DEFF Research Database (Denmark)

Jørgensen, Jakob Heide; Sidky, Emil Y.; Hansen, Per Christian

2012-01-01

on artificial random sampling patterns. We establish quantitatively an average-case relation between image sparsity and sufficient number of measurements for recovery, and we show that the transition from non-recovery to recovery is sharp within well-defined classes of simple and semi-realistic test images....... The specific behavior depends on the type of image, but the same quantitative relation holds independently of image size....

Quantitative whole body scintigraphy - a simplified approach

International Nuclear Information System (INIS)

Marienhagen, J.; Maenner, P.; Bock, E.; Schoenberger, J.; Eilles, C.

1996-01-01

In this paper we present investigations on a simplified method of quantitative whole body scintigraphy by using a dual head LFOV-gamma camera and a calibration algorithm without the need of additional attenuation or scatter correction. Validation of this approach to the anthropomorphic phantom as well as in patient studies showed a high accuracy concerning quantification of whole body activity (102.8% and 97.72%, resp.), by contrast organ activities were recovered with an error range up to 12%. The described method can be easily performed using commercially available software packages and is recommendable especially for quantitative whole body scintigraphy in a clinical setting. (orig.) [de

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

Science.gov (United States)

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.

Radiological interpretation 2020: Toward quantitative image assessment

International Nuclear Information System (INIS)

Boone, John M.

2007-01-01

The interpretation of medical images by radiologists is primarily and fundamentally a subjective activity, but there are a number of clinical applications such as tumor imaging where quantitative imaging (QI) metrics (such as tumor growth rate) would be valuable to the patient’s care. It is predicted that the subjective interpretive environment of the past will, over the next decade, evolve toward the increased use of quantitative metrics for evaluating patient health from images. The increasing sophistication and resolution of modern tomographic scanners promote the development of meaningful quantitative end points, determined from images which are in turn produced using well-controlled imaging protocols. For the QI environment to expand, medical physicists, physicians, other researchers and equipment vendors need to work collaboratively to develop the quantitative protocols for imaging, scanner calibrations, and robust analytical software that will lead to the routine inclusion of quantitative parameters in the diagnosis and therapeutic assessment of human health. Most importantly, quantitative metrics need to be developed which have genuine impact on patient diagnosis and welfare, and only then will QI techniques become integrated into the clinical environment.

Growth activity in human septal cartilage: age-dependent incorporation of labeled sulfate in different anatomic locations

International Nuclear Information System (INIS)

Vetter, U.; Pirsig, W.; Heinze, E.

1983-01-01

Growth activity in different areas of human septal cartilage was measured by the in vitro incorporation of 35 S-labeled NaSO 4 into chondroitin sulfate. Septal cartilage without perichondrium was obtained during rhinoplasty from 36 patients aged 6 to 35 years. It could be shown that the anterior free end of the septum displays high growth activity in all age groups. The supra-premaxillary area displayed its highest growth activity during prepuberty, showing thereafter a continuous decline during puberty and adulthood. A similar age-dependent pattern in growth activity was found in the caudal prolongation of the septal cartilage. No age-dependent variations could be detected in the posterior area of the septal cartilage

NAD(P-DEPENDENT DEHYDROGENASE ACTIVITY IN PERIPHERAL BLOOD LYMPHOCYTES OF INFANTS WITH ENLARGEMENT OF PHARYNGEAL TONSILS

Directory of Open Access Journals (Sweden)

L. M. Kurtasova

2014-01-01

Full Text Available We have observed and examined 57 children 1 to 3 years old diagnosed with enlargement of pharyngeal tonsils. A control group was presented by 35 healthy children. Bioluminescence technique was applied for studying NAD(P-dependent dehydrogenase activity in peripheral blood lymphocytes. Activation of aerobic respiration and increasing activity of pentose phosphate cycle-dependent plastic processes were registered in blood lymphocytes of children with hypertrophic pharyngeal tonsils; along with decreased function of malate-aspartate shunt in energy metabolism of the cells, diminished anaerobic reaction of NADHdependent LDH, lower interaction between Krebs cycle and reactions of amino acid metabolism, and reduced activity of glutathione reductase.

FAK/src-family dependent activation of the Ste20-like kinase SLK is required for microtubule-dependent focal adhesion turnover and cell migration.

Directory of Open Access Journals (Sweden)

Simona Wagner

2008-04-01

Full Text Available Cell migration involves a multitude of signals that converge on cytoskeletal reorganization, essential for development, immune responses and tissue repair. Using knockdown and dominant negative approaches, we show that the microtubule-associated Ste20-like kinase SLK is required for focal adhesion turnover and cell migration downstream of the FAK/c-src complex. Our results show that SLK co-localizes with paxillin, Rac1 and the microtubules at the leading edge of migrating cells and is activated by scratch wounding. SLK activation is dependent on FAK/c-src/MAPK signaling, whereas SLK recruitment to the leading edge is src-dependent but FAK independent. Our results show that SLK represents a novel focal adhesion disassembly signal.

Activity-dependent trafficking of lysosomes in dendrites and dendritic spines.

Science.gov (United States)

Goo, Marisa S; Sancho, Laura; Slepak, Natalia; Boassa, Daniela; Deerinck, Thomas J; Ellisman, Mark H; Bloodgood, Brenda L; Patrick, Gentry N

2017-08-07

In neurons, lysosomes, which degrade membrane and cytoplasmic components, are thought to primarily reside in somatic and axonal compartments, but there is little understanding of their distribution and function in dendrites. Here, we used conventional and two-photon imaging and electron microscopy to show that lysosomes traffic bidirectionally in dendrites and are present in dendritic spines. We find that lysosome inhibition alters their mobility and also decreases dendritic spine number. Furthermore, perturbing microtubule and actin cytoskeletal dynamics has an inverse relationship on the distribution and motility of lysosomes in dendrites. We also find trafficking of lysosomes is correlated with synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. Strikingly, lysosomes traffic to dendritic spines in an activity-dependent manner and can be recruited to individual spines in response to local activation. These data indicate the position of lysosomes is regulated by synaptic activity and thus plays an instructive role in the turnover of synaptic membrane proteins. © 2017 Goo et al.

Comparative study on economic security of enterprises depending on implemented business activities quantity

OpenAIRE

Shkarina Tatyana; Chudnova Olga; Mokhova Olga

2017-01-01

The results of a comparative study on economic security of enterprises depending on the quantity of business activities are published in the article. The sampling for analysis was conducted based on statistic data of Primorsky Region of the Russian Federation. The control points are the years of the most thorough data collection on the business activities of one-field and diversified enterprises: 2005, 2009, 2013, 2015.

Synaptic Mechanisms of Activity-Dependent Remodeling in Visual Cortex during Monocular Deprivation

Directory of Open Access Journals (Sweden)

Cynthia D. Rittenhouse

2009-01-01

Full Text Available It has long been appreciated that in the visual cortex, particularly within a postnatal critical period for experience-dependent plasticity, the closure of one eye results in a shift in the responsiveness of cortical cells toward the experienced eye. While the functional aspects of this ocular dominance shift have been studied for many decades, their cortical substrates and synaptic mechanisms remain elusive. Nonetheless, it is becoming increasingly clear that ocular dominance plasticity is a complex phenomenon that appears to have an early and a late component. Early during monocular deprivation, deprived eye cortical synapses depress, while later during the deprivation open eye synapses potentiate. Here we review current literature on the cortical mechanisms of activity-dependent plasticity in the visual system during the critical period. These studies shed light on the role of activity in shaping neuronal structure and function in general and can lead to insights regarding how learning is acquired and maintained at the neuronal level during normal and pathological brain development.

Automatic reference selection for quantitative EEG interpretation: identification of diffuse/localised activity and the active earlobe reference, iterative detection of the distribution of EEG rhythms.

Science.gov (United States)

Wang, Bei; Wang, Xingyu; Ikeda, Akio; Nagamine, Takashi; Shibasaki, Hiroshi; Nakamura, Masatoshi

2014-01-01

EEG (Electroencephalograph) interpretation is important for the diagnosis of neurological disorders. The proper adjustment of the montage can highlight the EEG rhythm of interest and avoid false interpretation. The aim of this study was to develop an automatic reference selection method to identify a suitable reference. The results may contribute to the accurate inspection of the distribution of EEG rhythms for quantitative EEG interpretation. The method includes two pre-judgements and one iterative detection module. The diffuse case is initially identified by pre-judgement 1 when intermittent rhythmic waveforms occur over large areas along the scalp. The earlobe reference or averaged reference is adopted for the diffuse case due to the effect of the earlobe reference depending on pre-judgement 2. An iterative detection algorithm is developed for the localised case when the signal is distributed in a small area of the brain. The suitable averaged reference is finally determined based on the detected focal and distributed electrodes. The presented technique was applied to the pathological EEG recordings of nine patients. One example of the diffuse case is introduced by illustrating the results of the pre-judgements. The diffusely intermittent rhythmic slow wave is identified. The effect of active earlobe reference is analysed. Two examples of the localised case are presented, indicating the results of the iterative detection module. The focal and distributed electrodes are detected automatically during the repeating algorithm. The identification of diffuse and localised activity was satisfactory compared with the visual inspection. The EEG rhythm of interest can be highlighted using a suitable selected reference. The implementation of an automatic reference selection method is helpful to detect the distribution of an EEG rhythm, which can improve the accuracy of EEG interpretation during both visual inspection and automatic interpretation. Copyright © 2013 IPEM

4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells

International Nuclear Information System (INIS)

Fu, Meili; Wan, Fuqiang; Li, Zhengling; Zhang, Fenghua

2016-01-01

The aim of the present study is to investigate the potential anti-hepatocellular carcinoma (HCC) cell activity by 4SC-202, a novel class I HDAC inhibitor (HDACi). The associated signaling mechanisms were also analyzed. We showed that 4SC-202 treatment induced potent cytotoxic and proliferation–inhibitory activities against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, adding 4SC-202 in HCC cells activated mitochondrial apoptosis pathway, which was evidenced by mitochondrial permeability transition pore (mPTP) opening, cytochrome C cytosol release and caspase-3/-9 activation. Inhibition of this apoptosis pathway, by caspase-3/-9 inhibitors, mPTP blockers, or by shRNA-mediated knockdown of cyclophilin-D (Cyp-D, a key component of mPTP), significantly attenuated 4SC-202-induced HCC cell death and apoptosis. Reversely, over-expression of Cyp-D enhanced 4SC-202's sensitivity in HCC cells. Further studies showed that 4SC-202 induced apoptosis signal-regulating kinase 1 (ASK1) activation, causing it translocation to mitochondria and physical association with Cyp-D. This mitochondrial ASK1-Cyp-D complexation appeared required for mediating 4SC-202-induced apoptosis activation. ASK1 stable knockdown by targeted-shRNAs largely inhibited 4SC-202-induced mPTP opening, cytochrome C release, and following HCC cell apoptotic death. Together, we suggest that 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to potently inhibit human HCC cells. - Highlights: • 4SC-202 exerts potent anti-proliferative and cytotoxic activity against established/primary HCC cells. • SC-202-induced anti-HCC cell activity relies on caspase-dependent apoptosis activation. • 4SC-202 activates Cyp-D-dependent mitochondrial apoptosis pathway in HCC cells. • 4SC-202 activates ASK1 in HCC cells, causing it translocation to mitochondria. • Mitochondrial ASK1-Cyp-D complexation mediates 4SC-202's activity in HCC cells.

4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells

Energy Technology Data Exchange (ETDEWEB)

Fu, Meili, E-mail: fumeilidrlinyi@tom.com [Department of Infectious Disease, Linyi People' s Hospital, Linyi 276000 (China); Wan, Fuqiang [Department of Head and Neck Surgery, Linyi Tumor Hospital, Linyi 276000 (China); Li, Zhengling [Department of Nursing, Tengzhou Central People' s Hospital, Tengzhou 277500 (China); Zhang, Fenghua [Department of Operating Room, Linyi People' s Hospital, Linyi 276000 (China)

2016-03-04

The aim of the present study is to investigate the potential anti-hepatocellular carcinoma (HCC) cell activity by 4SC-202, a novel class I HDAC inhibitor (HDACi). The associated signaling mechanisms were also analyzed. We showed that 4SC-202 treatment induced potent cytotoxic and proliferation–inhibitory activities against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, adding 4SC-202 in HCC cells activated mitochondrial apoptosis pathway, which was evidenced by mitochondrial permeability transition pore (mPTP) opening, cytochrome C cytosol release and caspase-3/-9 activation. Inhibition of this apoptosis pathway, by caspase-3/-9 inhibitors, mPTP blockers, or by shRNA-mediated knockdown of cyclophilin-D (Cyp-D, a key component of mPTP), significantly attenuated 4SC-202-induced HCC cell death and apoptosis. Reversely, over-expression of Cyp-D enhanced 4SC-202's sensitivity in HCC cells. Further studies showed that 4SC-202 induced apoptosis signal-regulating kinase 1 (ASK1) activation, causing it translocation to mitochondria and physical association with Cyp-D. This mitochondrial ASK1-Cyp-D complexation appeared required for mediating 4SC-202-induced apoptosis activation. ASK1 stable knockdown by targeted-shRNAs largely inhibited 4SC-202-induced mPTP opening, cytochrome C release, and following HCC cell apoptotic death. Together, we suggest that 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to potently inhibit human HCC cells. - Highlights: • 4SC-202 exerts potent anti-proliferative and cytotoxic activity against established/primary HCC cells. • SC-202-induced anti-HCC cell activity relies on caspase-dependent apoptosis activation. • 4SC-202 activates Cyp-D-dependent mitochondrial apoptosis pathway in HCC cells. • 4SC-202 activates ASK1 in HCC cells, causing it translocation to mitochondria. • Mitochondrial ASK1-Cyp-D complexation mediates 4SC-202's activity in HCC cells.

Which learning activities enhance physiotherapy practice? A systematic review protocol of quantitative and qualitative studies.

Science.gov (United States)

Leahy, Edmund; Chipchase, Lucy; Blackstock, Felicity

2017-04-17

Learning activities are fundamental for the development of expertise in physiotherapy practice. Continuing professional development (CPD) encompasses formal and informal learning activities undertaken by physiotherapists. Identifying the most efficient and effective learning activities is essential to enable the profession to assimilate research findings and improve clinical skills to ensure the most efficacious care for clients. To date, systematic reviews on the effectiveness of CPD provide limited guidance on the most efficacious models of professional development for physiotherapists. The aim of this systematic review is to evaluate which learning activities enhance physiotherapy practice. A search of Ovid MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO (Psychological Abstracts), PEDro, Cochrane Library, AMED and Educational Resources and Information Center (ERIC) will be completed. Citation searching and reference list searching will be undertaken to locate additional studies. Quantitative and qualitative studies will be included if they examine the impact of learning activities on clinician's behaviour, attitude, knowledge, beliefs, skills, self-efficacy, work satisfaction and patient outcomes. Risk of bias will be assessed by two independent researchers. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) and Confidence in the Evidence from Reviews of Qualitative research (CERQual) will be used to synthesise results where a meta-analysis is possible. Where a meta-analysis is not possible, a narrative synthesis will be conducted. PROSPERO CRD42016050157.

Quantitative analysis of geomorphic processes using satellite image data at different scales

Science.gov (United States)

Williams, R. S., Jr.

1985-01-01

When aerial and satellite photographs and images are used in the quantitative analysis of geomorphic processes, either through direct observation of active processes or by analysis of landforms resulting from inferred active or dormant processes, a number of limitations in the use of such data must be considered. Active geomorphic processes work at different scales and rates. Therefore, the capability of imaging an active or dormant process depends primarily on the scale of the process and the spatial-resolution characteristic of the imaging system. Scale is an important factor in recording continuous and discontinuous active geomorphic processes, because what is not recorded will not be considered or even suspected in the analysis of orbital images. If the geomorphic process of landform change caused by the process is less than 200 m in x to y dimension, then it will not be recorded. Although the scale factor is critical, in the recording of discontinuous active geomorphic processes, the repeat interval of orbital-image acquisition of a planetary surface also is a consideration in order to capture a recurring short-lived geomorphic process or to record changes caused by either a continuous or a discontinuous geomorphic process.

TALE activators regulate gene expression in a position- and strand-dependent manner in mammalian cells.

Science.gov (United States)

Uhde-Stone, Claudia; Cheung, Edna; Lu, Biao

2014-01-24

Transcription activator-like effectors (TALEs) are a class of transcription factors that are readily programmable to regulate gene expression. Despite their growing popularity, little is known about binding site parameters that influence TALE-mediated gene activation in mammalian cells. We demonstrate that TALE activators modulate gene expression in mammalian cells in a position- and strand-dependent manner. To study the effects of binding site location, we engineered TALEs customized to recognize specific DNA sequences located in either the promoter or the transcribed region of reporter genes. We found that TALE activators robustly activated reporter genes when their binding sites were located within the promoter region. In contrast, TALE activators inhibited the expression of reporter genes when their binding sites were located on the sense strand of the transcribed region. Notably, this repression was independent of the effector domain utilized, suggesting a simple blockage mechanism. We conclude that TALE activators in mammalian cells regulate genes in a position- and strand-dependent manner that is substantially different from gene activation by native TALEs in plants. These findings have implications for optimizing the design of custom TALEs for genetic manipulation in mammalian cells. Copyright © 2013 Elsevier Inc. All rights reserved.

Quantitative analysis of boron by neutron radiography

International Nuclear Information System (INIS)

Bayuelken, A.; Boeck, H.; Schachner, H.; Buchberger, T.

1990-01-01

The quantitative determination of boron in ores is a long process with chemical analysis techniques. As nuclear techniques like X-ray fluorescence and activation analysis are not applicable for boron, only the neutron radiography technique, using the high neutron absorption cross section of this element, can be applied for quantitative determinations. This paper describes preliminary tests and calibration experiments carried out at a 250 kW TRIGA reactor. (orig.) [de

Shape-dependent guidance of active Janus particles by chemically patterned surfaces

Science.gov (United States)

Uspal, W. E.; Popescu, M. N.; Tasinkevych, M.; Dietrich, S.

2018-01-01

Self-phoretic chemically active Janus particles move by inducing—via non-equilibrium chemical reactions occurring on their surfaces—changes in the chemical composition of the solution in which they are immersed. This process leads to gradients in chemical composition along the surface of the particle, as well as along any nearby boundaries, including solid walls. Chemical gradients along a wall can give rise to chemi-osmosis, i.e., the gradients drive surface flows which, in turn, drive flow in the volume of the solution. This bulk flow couples back to the particle, and thus contributes to its self-motility. Since chemi-osmosis strongly depends on the molecular interactions between the diffusing molecular species and the wall, the response flow induced and experienced by a particle encodes information about any chemical patterning of the wall. Here, we extend previous studies on self-phoresis of a sphere near a chemically patterned wall to the case of particles with rod-like, elongated shape. We focus our analysis on the new phenomenology potentially emerging from the coupling—which is inoperative for a spherical shape—of the elongated particle to the strain rate tensor of the chemi-osmotic flow. Via detailed numerical calculations, we show that the dynamics of a rod-like particle exhibits a novel ‘edge-following’ steady state: the particle translates along the edge of a chemical step at a steady distance from the step and with a steady orientation. Moreover, within a certain range of system parameters, the edge-following state co-exists with a ‘docking’ state (the particle stops at the step, oriented perpendicular to the step edge), i.e., a bistable dynamics occurs. These findings are rationalized as a consequence of the competition between the fluid vorticity and the rate of strain by using analytical theory based on the point-particle approximation which captures quasi-quantitatively the dynamics of the system.

Quantitative X-ray microanalysis of biological specimens

International Nuclear Information System (INIS)

Roomans, G.M.

1988-01-01

Qualitative X-ray microanalysis of biological specimens requires an approach that is somewhat different from that used in the materials sciences. The first step is deconvolution and background subtraction on the obtained spectrum. The further treatment depends on the type of specimen: thin, thick, or semithick. For thin sections, the continuum method of quantitation is most often used, but it should be combined with an accurate correction for extraneous background. However, alternative methods to determine local mass should also be considered. In the analysis of biological bulk specimens, the ZAF-correction method appears to be less useful, primarily because of the uneven surface of biological specimens. The peak-to-local background model may be a more adequate method for thick specimens that are not mounted on a thick substrate. Quantitative X-ray microanalysis of biological specimens generally requires the use of standards that preferably should resemble the specimen in chemical and physical properties. Special problems in biological microanalysis include low count rates, specimen instability and mass loss, extraneous contributions to the spectrum, and preparative artifacts affecting quantitation. A relatively recent development in X-ray microanalysis of biological specimens is the quantitative determination of local water content

Macrophages migrate in an activation-dependent manner to chemokines involved in neuroinflammation

NARCIS (Netherlands)

Vogel, D.Y.S.; Heijnen, D.A.M.; Breur, M.; de Vries, H.E.; Tool, A.T.; Amor, S.; Dijkstra, C.D.

2014-01-01

Background: In neuroinflammatory diseases, macrophages can play a dual role in the process of tissue damage, depending on their activation status (M1 / M2). M1 macrophages are considered to exert damaging effects to neurons, whereas M2 macrophages are reported to aid regeneration and repair of

Quantitative structure activity relationship for the computational prediction of nitrocompounds carcinogenicity

International Nuclear Information System (INIS)

Morales, Aliuska Helguera; Perez, Miguel Angel Cabrera; Combes, Robert D.; Gonzalez, Maykel Perez

2006-01-01

Several nitrocompounds have been screened for carcinogenicity in rodents, but this is a lengthy and expensive process, taking two years and typically costing 2.5 million dollars, and uses large numbers of animals. There is, therefore, much impetus to develop suitable alternative methods. One possible way of predicting carcinogenicity is to use quantitative structure-activity relationships (QSARs). QSARs have been widely utilized for toxicity testing, thereby contributing to a reduction in the need for experimental animals. This paper describes the results of applying a TOPological substructural molecular design (TOPS-MODE) approach for predicting the rodent carcinogenicity of nitrocompounds. The model described 79.10% of the experimental variance, with a standard deviation of 0.424. The predictive power of the model was validated by leave-one-out validation, with a determination coefficient of 0.666. In addition, this approach enabled the contribution of different fragments to carcinogenic potency to be assessed, thereby making the relationships between structure and carcinogenicity to be transparent. It was found that the carcinogenic activity of the chemicals analysed was increased by the presence of a primary amine group bonded to the aromatic ring, a manner that was proportional to the ring aromaticity. The nitro group bonded to an aromatic carbon atom is a more important determinant of carcinogenicity than the nitro group bonded to an aliphatic carbon. Finally, the TOPS-MODE approach was compared with four other predictive models, but none of these could explain more than 66% of the variance in the carcinogenic potency with the same number of variables

Wise, a context-dependent activator and inhibitor of Wnt signalling.

Science.gov (United States)

Itasaki, Nobue; Jones, C Michael; Mercurio, Sara; Rowe, Alison; Domingos, Pedro M; Smith, James C; Krumlauf, Robb

2003-09-01

We have isolated a novel secreted molecule, Wise, by a functional screen for activities that alter the anteroposterior character of neuralised Xenopus animal caps. Wise encodes a secreted protein capable of inducing posterior neural markers at a distance. Phenotypes arising from ectopic expression or depletion of Wise resemble those obtained when Wnt signalling is altered. In animal cap assays, posterior neural markers can be induced by Wnt family members, and induction of these markers by Wise requires components of the canonical Wnt pathway. This indicates that in this context Wise activates the Wnt signalling cascade by mimicking some of the effects of Wnt ligands. Activation of the pathway was further confirmed by nuclear accumulation of beta-catenin driven by Wise. By contrast, in an assay for secondary axis induction, extracellularly Wise antagonises the axis-inducing ability of Wnt8. Thus, Wise can activate or inhibit Wnt signalling in a context-dependent manner. The Wise protein physically interacts with the Wnt co-receptor, lipoprotein receptor-related protein 6 (LRP6), and is able to compete with Wnt8 for binding to LRP6. These activities of Wise provide a new mechanism for integrating inputs through the Wnt coreceptor complex to modulate the balance of Wnt signalling.

GPC and quantitative phase imaging

DEFF Research Database (Denmark)

Palima, Darwin; Banas, Andrew Rafael; Villangca, Mark Jayson

2016-01-01

shaper followed by the potential of GPC for biomedical and multispectral applications where we experimentally demonstrate the active light shaping of a supercontinuum laser over most of the visible wavelength range. Finally, we discuss how GPC can be advantageously applied for Quantitative Phase Imaging...

Shape-dependent bactericidal activity of copper oxide nanoparticle mediated by DNA and membrane damage

International Nuclear Information System (INIS)

Laha, Dipranjan; Pramanik, Arindam; Laskar, Aparna; Jana, Madhurya; Pramanik, Panchanan; Karmakar, Parimal

2014-01-01

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

Shape-dependent bactericidal activity of copper oxide nanoparticle mediated by DNA and membrane damage

Energy Technology Data Exchange (ETDEWEB)

Laha, Dipranjan; Pramanik, Arindam [Department of Life Science and Biotechnology, Jadavpur University, 188, Raja S C Mallick Road, Kolkata 700032 (India); Laskar, Aparna [CSIR-Indian Institute of Chemical Biology, Kolkata 700032 (India); Jana, Madhurya [Department of Life Science and Biotechnology, Jadavpur University, 188, Raja S C Mallick Road, Kolkata 700032 (India); Pramanik, Panchanan [Department of Chemistry, Indian Institute of Technology, Kharagpur 721302 (India); Karmakar, Parimal, E-mail: pkarmakar_28@yahoo.co.in [Department of Life Science and Biotechnology, Jadavpur University, 188, Raja S C Mallick Road, Kolkata 700032 (India)

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.

JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells.

LENUS (Irish Health Repository)

Donnellan, Fergal

2010-01-01

Neuroimmune agonists induce epithelial Cl(-) secretion through elevations in intracellular Ca2+ or cAMP. Previously, we demonstrated that epidermal growth factor receptor (EGFR) transactivation and subsequent ERK MAPK activation limits secretory responses to Ca2+-dependent, but not cAMP-dependent, agonists. Although JNK MAPKs are also expressed in epithelial cells, their role in regulating transport function is unknown. Here, we investigated the potential role for JNK in regulating Cl(-) secretion in T(84) colonic epithelial cells. Western blot analysis revealed that a prototypical Ca2+-dependent secretagogue, carbachol (CCh; 100 microM), induced phosphorylation of both the 46-kDa and 54-kDa isoforms of JNK. This effect was mimicked by thapsigargin (TG), which specifically elevates intracellular Ca2+, but not by forskolin (FSK; 10 microM), which elevates cAMP. CCh-induced JNK phosphorylation was attenuated by the EGFR inhibitor, tyrphostin-AG1478 (1 microM). Pretreatment of voltage-clamped T(84) cells with SP600125 (2 microM), a specific JNK inhibitor, potentiated secretory responses to both CCh and TG but not to FSK. The effects of SP600125 on CCh-induced secretion were not additive with those of the ERK inhibitor, PD98059. Finally, in apically permeabilized T(84) cell monolayers, SP600125 potentiated CCh-induced K+ conductances but not Na+\\/K+ATPase activity. These data demonstrate a novel role for JNK MAPK in regulating Ca2+ but not cAMP-dependent epithelial Cl(-) secretion. JNK activation is mediated by EGFR transactivation and exerts its antisecretory effects through inhibition of basolateral K+ channels. These data further our understanding of mechanisms regulating epithelial secretion and underscore the potential for exploitation of MAPK-dependent signaling in treatment of intestinal transport disorders.

Odor-active constituents in fresh pineapple (Ananas comosus [L.] Merr.) by quantitative and sensory evaluation.

Science.gov (United States)

Tokitomo, Yukiko; Steinhaus, Martin; Büttner, Andrea; Schieberle, Peter

2005-07-01

By application of aroma extract dilution analysis (AEDA) to an aroma distillate prepared from fresh pineapple using solvent-assisted flavor evaporation (SAFE), 29 odor-active compounds were detected in the flavor dilution (FD) factor range of 2 to 4,096. Quantitative measurements performed by stable isotope dilution assays (SIDA) and a calculation of odor activity values (OAVs) of 12 selected odorants revealed the following compounds as key odorants in fresh pineapple flavor: 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDF; sweet, pineapple-like, caramel-like), ethyl 2-methylpropanoate (fruity), ethyl 2-methylbutanoate (fruity) followed by methyl 2-methylbutanoate (fruity, apple-like) and 1-(E,Z)-3,5-undecatriene (fresh, pineapple-like). A mixture of these 12 odorants in concentrations equal to those in the fresh pineapple resulted in an odor profile similar to that of the fresh juice. Furthermore, the results of omission tests using the model mixture showed that HDF and ethyl 2-methylbutanoate are character impact odorants in fresh pineapple.

Semi-quantitative evaluation of gallium-67 scintigraphy in lupus nephritis

International Nuclear Information System (INIS)

Lin Wanyu; Hsieh Jihfang; Tsai Shihchuan; Lan Joungliang; Cheng Kaiyuan; Wang Shyhjen

2000-01-01

Within nuclear medicine there is a trend towards quantitative analysis. Gallium renal scan has been reported to be useful in monitoring the disease activity of lupus nephritis. However, only visual interpretation using a four-grade scale has been performed in previous studies, and this method is not sensitive enough for follow-up. In this study, we developed a semi-quantitative method for gallium renal scintigraphy to find a potential parameter for the evaluation of lupus nephritis. Forty-eight patients with lupus nephritis underwent renal biopsy to determine World Health Organization classification, activity index (AI) and chronicity index (CI). A delayed 48-h gallium scan was also performed and interpreted by visual and semi-quantitative methods. For semi-quantitative analysis of the gallium uptake in both kidneys, regions of interest (ROIs) were drawn over both kidneys, the right forearm and the adjacent spine. The uptake ratios between these ROIs were calculated and expressed as the ''kidney/spine ratio (K/S ratio)'' or the ''kidney/arm ratio (K/A ratio)''. Spearman's rank correlation test and Mann-Whitney U test were used for statistical analysis. Our data showed a good correlation between the semi-quantitative gallium scan and the results of visual interpretation. K/S ratios showed a better correlation with AI than did K/A ratios. Furthermore, the left K/S ratio displayed a better correlation with AI than did the right K/S ratio. In contrast, CI did not correlate well with the results of semi-quantitative gallium scan. In conclusion, semi-quantitative gallium renal scan is easy to perform and shows a good correlation with the results of visual interpretation and renal biopsy. The left K/S ratio from semi-quantitative renal gallium scintigraphy displays the best correlation with AI and is a useful parameter in evaluating the disease activity in lupus nephritis. (orig.)

Temporal phases of activity-dependent plasticity and memory are mediated by compartmentalized routing of MAPK signaling in aplysia sensory neurons.

Science.gov (United States)

Shobe, Justin L; Zhao, Yali; Stough, Shara; Ye, Xiaojing; Hsuan, Vickie; Martin, Kelsey C; Carew, Thomas J

2009-01-15

An activity-dependent form of intermediate memory (AD-ITM) for sensitization is induced in Aplysia by a single tail shock that gives rise to plastic changes (AD-ITF) in tail sensory neurons (SNs) via the interaction of action potential firing in the SN coupled with the release of serotonin in the CNS. Activity-dependent long-term facilitation (AD-LTF, lasting >24hr) requires protein synthesis dependent persistent mitogen-activated protein kinase (MAPK) activation and translocation to the SN nucleus. We now show that the induction of the earlier temporal phase (AD-ITM and AD-ITF), which is translation and transcription independent, requires the activation of a compartmentally distinct novel signaling cascade that links second messengers, MAPK and PKC into a unified pathway within tail SNs. Since both AD-ITM and AD-LTM require MAPK activity, these collective findings suggest that presynaptic SNs route the flow of molecular information to distinct subcellular compartments during the induction of activity-dependent long-lasting memories.

Regulation of KV channel voltage-dependent activation by transmembrane β subunits

Directory of Open Access Journals (Sweden)

Xiaohui eSun

2012-04-01

Full Text Available Voltage-activated K+ (KV channels are important for shaping action potentials and maintaining resting membrane potential in excitable cells. KV channels contain a central pore-gate domain (PGD surrounded by four voltage-sensing domains (VSD. The VSDs will change conformation in response to alterations of the membrane potential thereby inducing the opening of the PGD. Many KV channels are heteromeric protein complexes containing auxiliary β subunits. These β subunits modulate channel expression and activity to increase functional diversity and render tissue specific phenotypes. This review focuses on the KV β subunits that contain transmembrane (TM segments including the KCNE family and the β subunits of large conductance, Ca2+- and voltage-activated K+ (BK channels. These TM β subunits affect the voltage-dependent activation of KV α subunits. Experimental and computational studies have described the structural location of these β subunits in the channel complexes and the biophysical effects on VSD activation, PGD opening and VSD-PGD coupling. These results reveal some common characteristics and mechanistic insights into KV channel modulation by TM β subunits.

Relationship Between Functional Mobility and Balance and Dependency in Activity of Daily Living in Elderly After “Hip Arthroplasty”

Directory of Open Access Journals (Sweden)

Gholam Hassan Mirzaie

2013-01-01

Full Text Available Objectives: The purpose of this study was to investigate correlation between functional mobility with balance and dependency in activity of daily living in elderly after “hip arthroplasty” (HA and its comparison with healthy subjects. Methods & Materials: The current cross-sectional study was done on 15 patients with age mean and standard deviation (72±9.6 with hip osteoarthritis 6 months after “hip arthroplasty” (HA and 15 healthy subjects with age mean and standard deviation (72.7±1.4 as control group. Patient group was assigned with non- probability convenient sampling and control group selected with matched assignment. Functional mobility measured with Timed Up & Go Test (TUG, functional balance with Functional Reach (FR and Berg Balance Scale (BBS and dependency in activity of daily living measured with Modified Barthel Index (MBI. Pearsons correlation coefficient used for stastistical analysis. Results: Results of this study indicated significantly and stronge correlation between functional mobility and balance and dependency in activity of daily living in patient group (r>0.50. Also medium correlation existed between functional mobility and balance with dependency in activity of daily living in control group (r>0.30. Conclusion: Functional mobility and balance and dependency in activity of daily living in the elderly who had HA showed significant positive correlation. In addition correlation between functional mobility and balance and dependency in activity of daily living in patient group is better and higher than healthy group.

Obscure phenomena in statistical analysis of quantitative structure-activity relationships. Part 1: Multicollinearity of physicochemical descriptors.

Science.gov (United States)

Mager, P P; Rothe, H

1990-10-01

Multicollinearity of physicochemical descriptors leads to serious consequences in quantitative structure-activity relationship (QSAR) analysis, such as incorrect estimators and test statistics of regression coefficients of the ordinary least-squares (OLS) model applied usually to QSARs. Beside the diagnosis of the known simple collinearity, principal component regression analysis (PCRA) also allows the diagnosis of various types of multicollinearity. Only if the absolute values of PCRA estimators are order statistics that decrease monotonically, the effects of multicollinearity can be circumvented. Otherwise, obscure phenomena may be observed, such as good data recognition but low predictive model power of a QSAR model.

Vogel-Fulcher dependence of relaxation rates in a nematic monomer and elastomer

Science.gov (United States)

Shenoy, D.; Filippov, S.; Aliev, F.; Keller, P.; Thomsen, D.; Ratna, B.

2000-12-01

Dielectric relaxation spectroscopy is used to study the relaxation processes in a nematic monomer and the corresponding cross-linked polymer nematic liquid crystal (elastomer). In the frequency window 10 mHz to 2 GHz the monomer liquid crystal shows a single relaxation whereas the polymer exhibits three relaxation processes, two of which are quantitatively analyzed. The temperature dependence of relaxation times in both the monomer and polymer follows a Vogel-Fulcher behavior. The relaxation processes are identified with specific molecular motions and activation energies are calculated in a linear approximation for comparison with literature data.

[The quantitative testing of V617F mutation in gen JAK2 using pyrosequencing technique].

Science.gov (United States)

Dunaeva, E A; Mironov, K O; Dribnokhodova, T E; Subbotina, E E; Bashmakova; Ol'hovskiĭ, I A; Shipulin, G A

2014-11-01

The somatic mutation V617F in gen JAK2 is a frequent cause of chronic myeloprolific diseases not conditioned by BCR/ABL mutation. The quantitative testing of relative percentage of mutant allele can be used in establishing severity of disease and its prognosis and in prescription of remedy inhibiting activity of JAK2. To quantitatively test mutation the pyrosequencing technique was applied. The developed technique permits detecting and quantitatively, testing percentage of mutation fraction since 7%. The "gray zone" is presented by samples with percentage of mutant allele from 4% to 7%. The dependence of expected percentage of mutant fraction in analyzed sample from observed value of signal is described by equation of line with regression coefficients y = - 0.97, x = -1.32 and at that measurement uncertainty consists ± 0.7. The developed technique is approved officially on clinical material from 192 patients with main forms of myeloprolific diseases not conditioned by BCR/ABL mutation. It was detected 64 samples with mautant fraction percentage from 13% to 91%. The developed technique permits implementing monitoring of therapy of myeloprolific diseases and facilitates to optimize tactics of treatment.

Activation of Cyclin-Dependent Kinase 5 Is a Consequence of Cell Death

Directory of Open Access Journals (Sweden)

Yixia Ye

2009-01-01

Full Text Available Cyclin-dependent kinase 5 (Cdk5 is similar to other Cdks but is activated during cell differentiation and cell death rather than cell division. Since activation of Cdk5 has been reported in many situations leading to cell death, we attempted to determine if it was required for any form of cell death. We found that Cdk5 is activated during apoptotic deaths and that the activation can be detected even when the cells continue to secondary necrosis. This activation can occur in the absence of Bim, calpain, or neutral cathepsins. The kinase is typically activated by p25, derived from p35 by calpain-mediated cleavage, but inhibition of calpain does not affect cell death or the activation of Cdk5. Likewise, RNAi-forced suppression of the synthesis of Cdk5 does not affect the incidence or kinetics of cell death. We conclude that Cdk5 is activated as a consequence of metabolic changes that are common to many forms of cell death. Thus its activation suggests processes during cell death that will be interesting or important to understand, but activation of Cdk5 is not necessary for cells to die.

Abscisic acid affects transcription of chloroplast genes via protein phosphatase 2C-dependent activation of nuclear genes: repression by guanosine-3'-5'-bisdiphosphate and activation by sigma factor 5.

Science.gov (United States)

Yamburenko, Maria V; Zubo, Yan O; Börner, Thomas

2015-06-01

Abscisic acid (ABA) represses the transcriptional activity of chloroplast genes (determined by run-on assays), with the exception of psbD and a few other genes in wild-type Arabidopsis seedlings and mature rosette leaves. Abscisic acid does not influence chloroplast transcription in the mutant lines abi1-1 and abi2-1 with constitutive protein phosphatase 2C (PP2C) activity, suggesting that ABA affects chloroplast gene activity by binding to the pyrabactin resistance (PYR)/PYR1-like or regulatory component of ABA receptor protein family (PYR/PYL/RCAR) and signaling via PP2Cs and sucrose non-fermenting protein-related kinases 2 (SnRK2s). Further we show by quantitative PCR that ABA enhances the transcript levels of RSH2, RSH3, PTF1 and SIG5. RelA/SpoT homolog 2 (RSH2) and RSH3 are known to synthesize guanosine-3'-5'-bisdiphosphate (ppGpp), an inhibitor of the plastid-gene-encoded chloroplast RNA polymerase. We propose, therefore, that ABA leads to an inhibition of chloroplast gene expression via stimulation of ppGpp synthesis. On the other hand, sigma factor 5 (SIG5) and plastid transcription factor 1 (PTF1) are known to be necessary for the transcription of psbD from a specific light- and stress-induced promoter (the blue light responsive promoter, BLRP). We demonstrate that ABA activates the psbD gene by stimulation of transcription initiation at BLRP. Taken together, our data suggest that ABA affects the transcription of chloroplast genes by a PP2C-dependent activation of nuclear genes encoding proteins involved in chloroplast transcription. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

Temperature dependence of the activity of polyphenol peroxidases and polyphenol oxidases in modern and buried soils

Science.gov (United States)

Yakushev, A. V.; Kuznetsova, I. N.; Blagodatskaya, E. V.; Blagodatsky, S. A.

2014-05-01

Under conditions of the global climate warming, the changes in the reserves of soil humus depend on the temperature sensitivities of polyphenol peroxidases (PPPOs) and polyphenol oxidases (PPOs). They play an important role in lignin decomposition, mineralization, and humus formation. The temperature dependence of the potential enzyme activity in modern and buried soils has been studied during incubation at 10 or 20°C. The experimental results indicate that it depends on the availability of the substrate and the presence of oxygen. The activity of PPOs during incubation in the absence of oxygen for two months decreases by 2-2.5 times, which is balanced by an increase in the activity of PPPOs by 2-3 times. The increase in the incubation temperature to 20°C and the addition of glucose accelerates this transition due to the more abrupt decrease in the activity of PPOs. The preincubation of the soil with glucose doubles the activity of PPPOs but has no significant effect on the activity of PPOs. The different effects of temperature on two groups of the studied oxidases and the possibility of substituting enzymes by those of another type under changing aeration conditions should be taken into consideration in predicting the effect of the climate warming on the mineralization of the soil organic matter. The absence of statistically significant differences in the enzymatic activity between the buried and modern soil horizons indicates the retention by the buried soil of some of its properties (soil memory) and the rapid restoration of high enzymatic activity during the preincubation.

A new trend to determine biochemical parameters by quantitative FRET assays.

Science.gov (United States)

Liao, Jia-yu; Song, Yang; Liu, Yan

2015-12-01

Förster resonance energy transfer (FRET) has been widely used in biological and biomedical research because it can determine molecule or particle interactions within a range of 1-10 nm. The sensitivity and efficiency of FRET strongly depend on the distance between the FRET donor and acceptor. Historically, FRET assays have been used to quantitatively deduce molecular distances. However, another major potential application of the FRET assay has not been fully exploited, that is, the use of FRET signals to quantitatively describe molecular interactive events. In this review, we discuss the use of quantitative FRET assays for the determination of biochemical parameters, such as the protein interaction dissociation constant (K(d)), enzymatic velocity (k(cat)) and K(m). We also describe fluorescent microscopy-based quantitative FRET assays for protein interaction affinity determination in cells as well as fluorimeter-based quantitative FRET assays for protein interaction and enzymatic parameter determination in solution.

Early survival factor deprivation in the olfactory epithelium enhances activity-dependent survival

Directory of Open Access Journals (Sweden)

Adrien eFrançois

2013-12-01

Full Text Available The neuronal olfactory epithelium undergoes permanent renewal because of environmental aggression. This renewal is partly regulated by factors modulating the level of neuronal apoptosis. Among them, we had previously characterized endothelin as neuroprotective. In this study, we explored the effect of cell survival factor deprivation in the olfactory epithelium by intranasal delivery of endothelin receptors antagonists to rat pups. This treatment induced an overall increase of apoptosis in the olfactory epithelium. The responses to odorants recorded by electroolfactogram were decreased in treated animal, a result consistent with a loss of olfactory sensory neurons (OSNs. However, the treated animal performed better in an olfactory orientation test based on maternal odor compared to non-treated littermates. This improved performance could be due to activity-dependent neuronal survival of OSNs in the context of increased apoptosis level. In order to demonstrate it, we odorized pups with octanal, a known ligand for the rI7 olfactory receptor (Olr226. We quantified the number of OSN expressing rI7 by RT-qPCR and whole mount in situ hybridization. While this number was reduced by the survival factor removal treatment, this reduction was abolished by the presence of its ligand. This improved survival was optimal for low concentration of odorant and was specific for rI7-expressing OSNs. Meanwhile, the number of rI7-expressing OSNs was not affected by the odorization in non-treated littermates; showing that the activity-dependant survival of OSNs did not affect the OSN population during the 10 days of odorization in control conditions. Overall, our study shows that when apoptosis is promoted in the olfactory mucosa, the activity-dependent neuronal plasticity allows faster tuning of the olfactory sensory neuron population towards detection of environmental odorants.

The development of quantitative determination method of organic acids in complex poly herbal extraction

Directory of Open Access Journals (Sweden)

I. L. Dyachok

2016-08-01

Full Text Available Aim. The development of sensible, economical and expressive method of quantitative determination of organic acids in complex poly herbal extraction counted on izovaleric acid with the use of digital technologies. Materials and methods. Model complex poly herbal extraction of sedative action was chosen as a research object. Extraction is composed of these medical plants: Valeriana officinalis L., Crataégus, Melissa officinalis L., Hypericum, Mentha piperita L., Húmulus lúpulus, Viburnum. Based on chemical composition of plant components, we consider that main pharmacologically active compounds, which can be found in complex poly herbal extraction are: polyphenolic substances (flavonoids, which are contained in Crataégus, Viburnum, Hypericum, Mentha piperita L., Húmulus lúpulus; also organic acids, including izovaleric acid, which are contained in Valeriana officinalis L., Mentha piperita L., Melissa officinalis L., Viburnum; the aminoacid are contained in Valeriana officinalis L. For the determination of organic acids content in low concentration we applied instrumental method of analysis, namely conductometry titration which consisted in the dependences of water solution conductivity of complex poly herbal extraction on composition of organic acids. Result. The got analytical dependences, which describes tangent lines to the conductometry curve before and after the point of equivalence, allow to determine the volume of solution expended on titration and carry out procedure of quantitative determination of organic acids in the digital mode. Conclusion. The proposed method enables to determine the point of equivalence and carry out quantitative determination of organic acids counted on izovaleric acid with the use of digital technologies, that allows to computerize the method on the whole.

Calcium/calmodulin-dependent protein kinase II activity regulates the proliferative potential of growth plate chondrocytes.

Science.gov (United States)

Li, Yuwei; Ahrens, Molly J; Wu, Amy; Liu, Jennifer; Dudley, Andrew T

2011-01-01

For tissues that develop throughout embryogenesis and into postnatal life, the generation of differentiated cells to promote tissue growth is at odds with the requirement to maintain the stem cell/progenitor cell population to preserve future growth potential. In the growth plate cartilage, this balance is achieved in part by establishing a proliferative phase that amplifies the number of progenitor cells prior to terminal differentiation into hypertrophic chondrocytes. Here, we show that endogenous calcium/calmodulin-dependent protein kinase II (CamkII, also known as Camk2) activity is upregulated prior to hypertrophy and that loss of CamkII function substantially blocks the transition from proliferation to hypertrophy. Wnt signaling and Pthrp-induced phosphatase activity negatively regulate CamkII activity. Release of this repression results in activation of multiple effector pathways, including Runx2- and β-catenin-dependent pathways. We present an integrated model for the regulation of proliferation potential by CamkII activity that has important implications for studies of growth control and adult progenitor/stem cell populations.

Investigations on abundance and activity of microbial sponge symbionts using quantitative real - time PCR

DEFF Research Database (Denmark)

Kumala, Lars; Hentschel, Ute; Bayer, Kristina

Marine sponges are hosts to dense and diverse microbial consortia that are likely to play a key role in the metabolic processes of the host sponge due to their enormous abundance. Common symbioses between nitrogen transforming microorganisms and sponges indicate complex nitrogen cycling within...... the host. Of particular interest is determining the community structure and function of microbial symbionts in order to gain deeper insight into host-symbiont interactions. We investigated the abundance and activity of microbial symbionts in two Mediterranean sponge species using quantitative real-time PCR....... An absolute quantification of functional genes and transcripts in archaeal and bacterial symbionts was conducted to determine their involvement in nitrification and denitrification, comparing the low microbial abundance (LMA) sponge Dysidea avara with the high microbial abundance (HMA) representative Aplysina...

Quantitative risk assessment system (QRAS)

Science.gov (United States)

Weinstock, Robert M (Inventor); Smidts, Carol S (Inventor); Mosleh, Ali (Inventor); Chang, Yung-Hsien (Inventor); Swaminathan, Sankaran (Inventor); Groen, Francisco J (Inventor); Tan, Zhibin (Inventor)

2001-01-01

A quantitative risk assessment system (QRAS) builds a risk model of a system for which risk of failure is being assessed, then analyzes the risk of the system corresponding to the risk model. The QRAS performs sensitivity analysis of the risk model by altering fundamental components and quantifications built into the risk model, then re-analyzes the risk of the system using the modifications. More particularly, the risk model is built by building a hierarchy, creating a mission timeline, quantifying failure modes, and building/editing event sequence diagrams. Multiplicities, dependencies, and redundancies of the system are included in the risk model. For analysis runs, a fixed baseline is first constructed and stored. This baseline contains the lowest level scenarios, preserved in event tree structure. The analysis runs, at any level of the hierarchy and below, access this baseline for risk quantitative computation as well as ranking of particular risks. A standalone Tool Box capability exists, allowing the user to store application programs within QRAS.

Expression of MMPs is dependent on the activity of mitogen-activated protein kinase in chondrosarcoma.

Science.gov (United States)

Yao, Min; Wang, Xiaomei; Zhao, Yufeng; Wang, Xiaomeng; Gao, Feng

2017-02-01

Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) serve an important role in chondrosarcoma. The present study investigated whether the expression of MMPs was dependent on the activity of mitogen-activated protein kinase (MAPK) in chondrosarcoma. Surgical pathological specimens were collected to detect MMP-1, MMP-13, TIMP-1, type II collagen and phosphorylated MAPK levels in normal cartilage, enchondroma and chondrosarcoma tissues. The expression of MMP‑1, MMP‑13, TIMP‑1 and type II collagen was investigated utilizing MAPK inhibitors in chondrosarcoma cells. It was noted that the expression levels of MMP‑1, MMP‑13 and TIMP‑1 were increased in chondrosarcoma with the activity of MAPK. After chondrosarcoma cells were pretreated with MAPK inhibitors, the levels of MMP‑1, MMP‑13 and TIMP‑1 were inhibited. Furthermore, MMP‑1 and MMP‑13 are essential in regulating the degradation of type II collagen and decomposing cartilage matrix major. The high expression levels of MMP‑1 and MMP‑13 in chondrosarcoma expedite the invasion by chondrosarcoma cells and their expression can be depressed by MAPK inhibitors.

Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

Energy Technology Data Exchange (ETDEWEB)

O' Sullivan, Saoirse E [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Tarling, Elizabeth J [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Bennett, Andrew J [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Kendall, David A [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Randall, Michael D [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom)

2005-11-25

Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, {delta}{sup 9}-tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPAR{gamma}). In vitro, THC (10 {mu}M) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPAR{gamma} agonist rosiglitazone and was inhibited by the PPAR{gamma} antagonist GW9662 (1 {mu}M), but not the cannabinoid CB{sub 1} receptor antagonist AM251 (1 {mu}M). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPAR{gamma}, transiently expressed in combination with retinoid X receptor {alpha} and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 {mu}M). In vitro incubation with THC (1 or 10 {mu}M, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPAR{gamma} ligands. The present results provide strong evidence that THC is a PPAR{gamma} ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors.

DEVELOPMENT OF TECHNIQUES FOR QUANTITATIVE ANALYSIS OF LIME FLOWERS

Directory of Open Access Journals (Sweden)

Demyanenko DV

2016-03-01

extractives taken with methylene chloride was achieved if assay weight is not less than 7 g: relative error was less than 2 %. Study of extraction kinetics showed that after 4 hours lipophilic substances soluble in methylene chloride were taken almost completely. Analyzing 6 batches of lime flowers from different Ukrainian regions, it was found that yield of total extractives taken with methylene chloride did fall within insignificant limits – 1,86-2,26 %, that testifies onto rather stable accumulation of these biologically active substances in lime flowers even despite different climatic conditions. Essential oil content varied in rather wide limits – 0,34-0,55 ml/kg of herbal drug and considerably depended on harvest place: in the batches from Northwest of Ukraine this value was less than in the Eastern ones. Year of harvesting had less influence on quantity of essential oil in lime flowers. The relative error of the quantitative determinations was within 4–8 %. Total flavonoid content in the analyzed batches of lime flowers was considerably variable (from 0,30 to 0,52 % and depended mainly on place of harvesting, and this crude herbal drug from the north-west of Ukraine (Rivno region showed the highest results among the analyzed samples. Besides, if consider the lower limit regulated by the monograph of Belarusian Pharmacopoeia, p. 370, then only one batch conformed to the norm (not less than 0,5 %. Therefore it’s recommended to fix the lower limit 0,3 % for content of total flavonoids in the corresponding monograph draft or analytical normative documentation. The relative error of the quantitative determinations of flavonoids was within 1,5–3,1 %. Conclusion. Six batches of lime flowers harvested in various regions of Ukraine in 2008 and 2009 yrs. were investigated. Based on the results obtained it is offered to regulate the following quantity parameters in the amended monograph draft for lime flower: total extractives taken with methylene chloride – not less

Time-dependent restricted-active-space self-consistent eld theory: Formulation and application to laser-driven many-electron dynamics

DEFF Research Database (Denmark)

Miyagi, Haruhide; Madsen, Lars Bojer

We have developed a new theoretical framework for time-dependent many-electron problems named time-dependent restricted-active-space self-consistent field (TD-RASSCF) theory. The theory generalizes the multicongurational time-dependent Hartree-Fock (MCTDHF) theory by truncating the expansion...

Alzheimer disease: Quantitative analysis of I-123-iodoamphetamine SPECT brain imaging

International Nuclear Information System (INIS)

Hellman, R.S.; Tikofsky, R.S.; Collier, B.D.; Hoffmann, R.G.; Palmer, D.W.; Glatt, S.L.; Antuono, P.G.; Isitman, A.T.; Papke, R.A.

1989-01-01

To enable a more quantitative diagnosis of senile dementia of the Alzheimer type (SDAT), the authors developed and tested a semiautomated method to define regions of interest (ROIs) to be used in quantitating results from single photon emission computed tomography (SPECT) of regional cerebral blood flow performed with N-isopropyl iodine-123-iodoamphetamine. SPECT/IMP imaging was performed in ten patients with probable SDAT and seven healthy subjects. Multiple ROIs were manually and semiautomatically generated, and uptake was quantitated for each ROI. Mean cortical activity was estimated as the average of the mean activity in 24 semiautomatically generated ROIs; mean cerebellar activity was determined from the mean activity in separate ROIs. A ratio of parietal to cerebellar activity less than 0.60 and a ratio of parietal to mean cortical activity less than 0.90 allowed correct categorization of nine of ten and eight of ten patients, respectively, with SDAT and all control subjects. The degree of diminished mental status observed in patients with SDAT correlated with both global and regional changes in IMP uptake

Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate.

Science.gov (United States)

Gao, Haixia; Boillat, Aurélien; Huang, Dongyang; Liang, Ce; Peers, Chris; Gamper, Nikita

2017-08-01

M-type (Kv7, KCNQ) potassium channels are proteins that control the excitability of neurons and muscle cells. Many physiological and pathological mechanisms of excitation operate via the suppression of M channel activity or expression. Conversely, pharmacological augmentation of M channel activity is a recognized strategy for the treatment of hyperexcitability disorders such as pain and epilepsy. However, physiological mechanisms resulting in M channel potentiation are rare. Here we report that intracellular free zinc directly and reversibly augments the activity of recombinant and native M channels. This effect is mechanistically distinct from the known redox-dependent KCNQ channel potentiation. Interestingly, the effect of zinc cannot be attributed to a single histidine- or cysteine-containing zinc-binding site within KCNQ channels. Instead, zinc dramatically reduces KCNQ channel dependence on its obligatory physiological activator, phosphatidylinositol 4,5-bisphosphate (PIP 2 ). We hypothesize that zinc facilitates interactions of the lipid-facing interface of a KCNQ protein with the inner leaflet of the plasma membrane in a way similar to that promoted by PIP 2 Because zinc is increasingly recognized as a ubiquitous intracellular second messenger, this discovery might represent a hitherto unknown native pathway of M channel modulation and provide a fresh strategy for the design of M channel activators for therapeutic purposes.

Comparison of quantitative EEG characteristics of quiet and active sleep in newborns.

Science.gov (United States)

Paul, Karel; Krajca, Vladimír; Roth, Zdenek; Melichar, Jan; Petránek, Svojmil

2003-11-01

The aim of the present study was to verify whether the proposed method of computer-supported EEG analysis is able to differentiate the EEG activity in quiet sleep (QS) from that in active sleep (AS) in newborns. A quantitative description of the neonatal EEG may contribute to a more exact evaluation of the functional state of the brain, as well as to a refinement of diagnostics of brain dysfunction manifesting itself frequently as 'dysrhythmia' or 'dysmaturity'. Twenty-one healthy newborns (10 full-term and 11 pre-term) were examined polygraphically (EEG-eight channels, respiration, ECG, EOG and EMG) in the course of sleep. From each EEG record, two 5-min samples (one from QS and one from AS) were subject to an off-line computerized analysis. The obtained data were averaged with respect to the sleep state and to the conceptional age. The number of variables was reduced by means of factor analysis. All factors identified by factor analysis were highly significantly influenced by sleep states in both developmental periods. Likewise, a comparison of the measured variables between QS and AS revealed many statistically significant differences. The variables describing (a) the number and length of quasi-stationary segments, (b) voltage and (c) power in delta and theta bands contributed to the greatest degree to the differentiation of EEGs between both sleep states. The presented method of the computerized EEG analysis which has good discriminative potential is adequately sensitive and describes the neonatal EEG with convenient accuracy.

Quantitative enzyme activity determination with zeptomole sensitivity by microfluidic gradient-gel zymography.

Science.gov (United States)

Hughes, Alex J; Herr, Amy E

2010-05-01

We describe a sensitive zymography technique that utilizes an automated microfluidic platform to report enzyme molecular weight, amount, and activity (including k(cat) and K(m)) from dilute protein mixtures. Calf intestinal alkaline phosphatase (CIP) is examined in detail as a model enzyme system, and the method is also demonstrated for horseradish peroxidase (HRP). The 40 min assay has a detection limit of 5 zmol ( approximately 3 000 molecules) of CIP. Two-step pore-limit electrophoresis with enzyme assay (PLENZ) is conducted in a single, straight microchannel housing a polyacrylamide (PA) pore-size gradient gel. In the first step, pore limit electrophoresis (PLE) sizes and pseudoimmobilizes resolved proteins. In the second step, electrophoresis transports both charged and neutral substrates into the PLE channel to the entrapped proteins. Arrival of substrate at the resolved enzyme band generates fluorescent product that reveals enzyme molecular weight against a fluorescent protein ladder. Additionally, the PLENZ zymography assay reports the kinetic properties of CIP in a fully quantitative manner. In contrast to covalent enzyme immobilization, physical pseudoimmobilization of CIP in the PA gel does not significantly reduce its maximum substrate turnover rate. However, an 11-fold increase in the Michaelis constant (over the free solution value) is observed, consistent with diffusional limitations on substrate access to the enzyme active site. PLENZ offers a robust platform for rapid and multiplexed functional analysis of heterogeneous protein samples in drug discovery, clinical diagnostics, and biocatalyst engineering.

Novel Uses of In Vitro Data to Develop Quantitative Biological Activity Relationship Models for in Vivo Carcinogenicity Prediction.

Science.gov (United States)

Pradeep, Prachi; Povinelli, Richard J; Merrill, Stephen J; Bozdag, Serdar; Sem, Daniel S

2015-04-01

The availability of large in vitro datasets enables better insight into the mode of action of chemicals and better identification of potential mechanism(s) of toxicity. Several studies have shown that not all in vitro assays can contribute as equal predictors of in vivo carcinogenicity for development of hybrid Quantitative Structure Activity Relationship (QSAR) models. We propose two novel approaches for the use of mechanistically relevant in vitro assay data in the identification of relevant biological descriptors and development of Quantitative Biological Activity Relationship (QBAR) models for carcinogenicity prediction. We demonstrate that in vitro assay data can be used to develop QBAR models for in vivo carcinogenicity prediction via two case studies corroborated with firm scientific rationale. The case studies demonstrate the similarities between QBAR and QSAR modeling in: (i) the selection of relevant descriptors to be used in the machine learning algorithm, and (ii) the development of a computational model that maps chemical or biological descriptors to a toxic endpoint. The results of both the case studies show: (i) improved accuracy and sensitivity which is especially desirable under regulatory requirements, and (ii) overall adherence with the OECD/REACH guidelines. Such mechanism based models can be used along with QSAR models for prediction of mechanistically complex toxic endpoints. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quantitative evaluation of indium-111 (In-111) octreotide pituitary activity: Comparison in patient with and without pituitary tumors

Energy Technology Data Exchange (ETDEWEB)

Gupta, P.; Waxman, A.; Nguyen, K. [Cedars-Sinai Medical Center, Los Angeles, CA (United States)] [and others

1995-05-01

Indium 111 Octreotide is known to detect pituitary tumors. Variable low level pituitary activity has been reported in pts. with no demonstrable pituitary tumors. To our knowledge, there have been no studies which quantitatively categorize pituitary activity with respect to distinguishing normal subject from pts. with pituitary tumors. 13 pts. with proven, treated acromegaly were included, as well as 15 pts. with no history of pituitary disorder. Both groups underwent SPECT In-111 scintigraphy 24 hours post-injection Average count per pixel ratios were obtained for the pituitary/calvarium (P/C) and pituitary/brain (P/B) regions. 10 pts. with acromegaly underwent growth hormone (GH) measurements 2 hours post-glucose load. Statistical correlation between growth hormone levels using P/C and P/B ratios were obtained. P/C ratios, as well as P/B ratios demonstrated high correlation with serum GH levels correlation coefficient(r)= .717 for P/C p<0.05, and correlation coefficient(r) = 0.828 for P/B ratios p<0.005. P/C ratios and P/B ratios for controls correlated closely with the upper level of normal predicted by P/C or P/B ratios as a function of serum growth hormone found in patients with acromegaly. Somatostatin receptor SPECT scintigraphy of the pituitary and appropriate quantitation can predict patients with growth hormone secreting tumors.

NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation

International Nuclear Information System (INIS)

Chen, Zhi-Dong; Xu, Liang; Tang, Kan-Kai; Gong, Fang-Xiao; Liu, Jing-Quan; Ni, Yin; Jiang, Ling-Zhi; Hong, Jun; Han, Fang; Li, Qian; Yang, Xiang-Hong; Sun, Ren-Hua; Mo, Shi-Jing

2016-01-01

Apoptosis of neural cells is one of the main pathological features in hypoxic/ischemic brain injury. Nuclear factor-κB (NF-κB) might be a potential therapeutic target for hypoxic/ischemic brain injury since NF-κB has been found to be inactivated after hypoxia exposure, yet the underlying molecular mechanisms of NF-κB inactivation are largely unknown. Here we report that epidermal growth factor receptor (EGFR) activation prevents neuron-like PC12 cells apoptosis in response to hypoxia via restoring NF-κB-dependent transcriptional upregulation of cyclin D1. Functionally, EGFR activation by EGF stimulation mitigates hypoxia-induced PC12 cells apoptosis in both dose- and time-dependent manner. Of note, EGFR activation elevates IKKβ phosphorylation, increases IκBα ubiquitination, promotes P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as upregulates cyclin D1 expression. EGFR activation also abrogates the decrease of IKKβ phosphorylation, reduction of IκBα ubiquitination, blockade of P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as downregulation of cyclin D1 expression induced by hypoxia. Furthermore, NF-κB-dependent upregulation of cyclin D1 is instrumental for the EGFR-mediated cytoprotection against hypoxic apoptosis. In addition, the dephosphorylation of EGFR induced by either EGF siRNA transfection or anti-HB-EGF neutralization antibody treatment enhances hypoxic cytotoxicity, which are attenuated by EGF administration. Our results highlight the essential role of NF-κB-dependent transcriptional upregulation of cyclin D1 in EGFR-mediated cytoprotective effects under hypoxic preconditioning and support further investigation of EGF in clinical trials of patients with hypoxic/ischemic brain injury. - Highlights: • EGFR activation significantly decreases hypoxia-induced PC12 cells injury. • EGFR activation abrogates the transcriptional repression of cyclin D1 induced by hypoxia in a NF-κB-dependent

NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation

Energy Technology Data Exchange (ETDEWEB)

Chen, Zhi-Dong [Department of Critical Care Medicine, The First Affiliated Hospital of Huzhou Normal College, Huzhou 313000, Zhejiang (China); Xu, Liang [Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang (China); Tang, Kan-Kai [Department of Critical Care Medicine, The First Affiliated Hospital of Huzhou Normal College, Huzhou 313000, Zhejiang (China); Gong, Fang-Xiao; Liu, Jing-Quan; Ni, Yin; Jiang, Ling-Zhi; Hong, Jun; Han, Fang; Li, Qian; Yang, Xiang-Hong [Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang (China); Sun, Ren-Hua, E-mail: jqin168@hotmail.com [Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang (China); Mo, Shi-Jing, E-mail: msj860307@163.com [Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang (China)

2016-09-10

Apoptosis of neural cells is one of the main pathological features in hypoxic/ischemic brain injury. Nuclear factor-κB (NF-κB) might be a potential therapeutic target for hypoxic/ischemic brain injury since NF-κB has been found to be inactivated after hypoxia exposure, yet the underlying molecular mechanisms of NF-κB inactivation are largely unknown. Here we report that epidermal growth factor receptor (EGFR) activation prevents neuron-like PC12 cells apoptosis in response to hypoxia via restoring NF-κB-dependent transcriptional upregulation of cyclin D1. Functionally, EGFR activation by EGF stimulation mitigates hypoxia-induced PC12 cells apoptosis in both dose- and time-dependent manner. Of note, EGFR activation elevates IKKβ phosphorylation, increases IκBα ubiquitination, promotes P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as upregulates cyclin D1 expression. EGFR activation also abrogates the decrease of IKKβ phosphorylation, reduction of IκBα ubiquitination, blockade of P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as downregulation of cyclin D1 expression induced by hypoxia. Furthermore, NF-κB-dependent upregulation of cyclin D1 is instrumental for the EGFR-mediated cytoprotection against hypoxic apoptosis. In addition, the dephosphorylation of EGFR induced by either EGF siRNA transfection or anti-HB-EGF neutralization antibody treatment enhances hypoxic cytotoxicity, which are attenuated by EGF administration. Our results highlight the essential role of NF-κB-dependent transcriptional upregulation of cyclin D1 in EGFR-mediated cytoprotective effects under hypoxic preconditioning and support further investigation of EGF in clinical trials of patients with hypoxic/ischemic brain injury. - Highlights: • EGFR activation significantly decreases hypoxia-induced PC12 cells injury. • EGFR activation abrogates the transcriptional repression of cyclin D1 induced by hypoxia in a NF-κB-dependent

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

Science.gov (United States)

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...

Observation of diameter dependent carrier distribution in nanowire-based transistors

Energy Technology Data Exchange (ETDEWEB)

Schulze, A; Hantschel, T; Eyben, P; Verhulst, A S; Rooyackers, R; Vandooren, A; Mody, J; Nazir, A; Leonelli, D; Vandervorst, W, E-mail: Andreas.Schulze@imec.be [IMEC, Kapeldreef 75, 3001 Leuven (Belgium)

2011-05-06

The successful implementation of nanowire (NW) based field-effect transistors (FET) critically depends on quantitative information about the carrier distribution inside such devices. Therefore, we have developed a method based on high-vacuum scanning spreading resistance microscopy (HV-SSRM) which allows two-dimensional (2D) quantitative carrier profiling of fully integrated silicon NW-based tunnel-FETs (TFETs) with 2 nm spatial resolution. The key elements of our characterization procedure are optimized NW cleaving and polishing steps, the use of in-house fabricated ultra-sharp diamond tips, measurements in high vacuum and a dedicated quantification procedure accounting for the Schottky-like tip-sample contact affected by surface states. In the case of the implanted TFET source regions we find a strong NW diameter dependence of conformality, junction abruptness and gate overlap, quantitatively in agreement with process simulations. In contrast, the arsenic doped drain regions reveal an unexpected NW diameter dependent dopant deactivation. The observed lower drain doping for smaller diameters is reflected in the device characteristics by lower TFET off-currents, as measured experimentally and confirmed by device simulations.

Transportation forecasting : analysis and quantitative methods

Science.gov (United States)

1983-01-01

This Record contains the following papers: Development of Survey Instruments Suitable for Determining Non-Home Activity Patterns; Sequential, History-Dependent Approach to Trip-Chaining Behavior; Identifying Time and History Dependencies of Activity ...

NOX4-dependent Hydrogen peroxide promotes shear stress-induced SHP2 sulfenylation and eNOS activation.

Science.gov (United States)

Sánchez-Gómez, Francisco J; Calvo, Enrique; Bretón-Romero, Rosa; Fierro-Fernández, Marta; Anilkumar, Narayana; Shah, Ajay M; Schröder, Katrin; Brandes, Ralf P; Vázquez, Jesús; Lamas, Santiago

2015-12-01

Laminar shear stress (LSS) triggers signals that ultimately result in atheroprotection and vasodilatation. Early responses are related to the activation of specific signaling cascades. We investigated the participation of redox-mediated modifications and in particular the role of hydrogen peroxide (H2O2) in the sulfenylation of redox-sensitive phosphatases. Exposure of vascular endothelial cells to short periods of LSS (12 dyn/cm(2)) resulted in the generation of superoxide radical anion as detected by the formation of 2-hydroxyethidium by HPLC and its subsequent conversion to H2O2, which was corroborated by the increase in the fluorescence of the specific peroxide sensor HyPer. By using biotinylated dimedone we detected increased total protein sulfenylation in the bovine proteome, which was dependent on NADPH oxidase 4 (NOX4)-mediated generation of peroxide. Mass spectrometry analysis allowed us to identify the phosphatase SHP2 as a protein susceptible to sulfenylation under LSS. Given the dependence of FAK activity on SHP2 function, we explored the role of FAK under LSS conditions. FAK activation and subsequent endothelial NO synthase (eNOS) phosphorylation were promoted by LSS and both processes were dependent on NOX4, as demonstrated in lung endothelial cells isolated from NOX4-null mice. These results support the idea that LSS elicits redox-sensitive signal transduction responses involving NOX4-dependent generation of hydrogen peroxide, SHP2 sulfenylation, and ulterior FAK-mediated eNOS activation. Copyright © 2015 Elsevier Inc. All rights reserved.

Quantitative sputter profiling at surfaces and interfaces

International Nuclear Information System (INIS)

Kirschner, J.; Etzkorn, H.W.

1981-01-01

The key problem in quantitative sputter profiling, that of a sliding depth scale has been solved by combined Auger/X-ray microanalysis. By means of this technique and for the model system Ge/Si (amorphous) the following questions are treated quantitatively: shape of the sputter profiles when sputtering through an interface and origin of their asymmetry; precise location of the interface plane on the depth profile; broadening effects due to limited depth of information and their correction; origin and amount of bombardment induced broadening for different primary ions and energies; depth dependence of the broadening, and basic limits to depth resolution. Comparisons are made to recent theoretical calculations based on recoil mixing in the collision cascade and very good agreement is found

Cell number and transfection volume dependent peptide nucleic acid antisense activity by cationic delivery methods

DEFF Research Database (Denmark)

Llovera Nadal, Laia; Berthold, Peter; Nielsen, Peter E

2012-01-01

have now quantitatively compared the cellular activity (in the pLuc705 HeLa cell splice correction system) of PNA antisense oligomers using lipoplex delivery of cholesterol- and bisphosphonate-PNA conjugates, polyplex delivery via a PNA-polyethyleneimine conjugate and CPP delivery via a PNA......Efficient intracellular delivery is essential for high activity of nucleic acids based therapeutics, including antisense agents. Several strategies have been developed and practically all rely on auxiliary transfection reagents such as cationic lipids, cationic polymers and cell penetrating...... peptides as complexing agents and carriers of the nucleic acids. However, uptake mechanisms remain rather poorly understood, and protocols always require optimization of transfection parameters. Considering that cationic transfection complexes bind to and thus may up-concentrate on the cell surface, we...

Mechanism of interleukin-13 production by granulocyte-macrophage colony-stimulating factor-dependent macrophages via protease-activated receptor-2.

Science.gov (United States)

Yamaguchi, Rui; Yamamoto, Takatoshi; Sakamoto, Arisa; Ishimaru, Yasuji; Narahara, Shinji; Sugiuchi, Hiroyuki; Hirose, Eiji; Yamaguchi, Yasuo

2015-06-01

Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes classically activated M1 macrophages. GM-CSF upregulates protease-activated receptor-2 (PAR-2) protein expression and activation of PAR-2 by human neutrophil elastase (HNE) regulates cytokine production. This study investigated the mechanism of PAR-2-mediated interleukin (IL)-13 production by GM-CSF-dependent macrophages stimulated with HNE. Adherent macrophages were obtained from primary cultures of human mononuclear cells. After stimulation with HNE to activate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, IL-13 mRNA and protein levels were assessed by the reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. PAR-2 protein was detected in GM-CSF-dependent macrophages by Western blotting. Unexpectedly, PD98059 (an ERK1 inhibitor) increased IL-13 production, even at higher concentrations. Interestingly, U0126 (an ERK1/2 inhibitor) reduced IL-13 production in a concentration-dependent manner. Neither SB203580 (a p38alpha/p38beta inhibitor) nor BIRB796 (a p38gamma/p38delta inhibitor) affected IL-13 production, while TMB-8 (a calcium chelator) diminished IL-13 production. Stimulation with HNE promoted the production of IL-13 (a Th2 cytokine) by GM-CSF-dependent M1 macrophages. PAR-2-mediated IL-13 production may be dependent on the Ca(2+)/ERK2 signaling pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

Determination of the spectral dependence of reduced scattering and quantitative second-harmonic generation imaging for detection of fibrillary changes in ovarian cancer

Science.gov (United States)

Campbell, Kirby R.; Tilbury, Karissa B.; Campagnola, Paul J.

2015-03-01

Here, we examine ovarian cancer extracellular matrix (ECM) modification by measuring the wavelength dependence of optical scattering measurements and quantitative second-harmonic generation (SHG) imaging metrics in the range of 800-1100 nm in order to determine fibrillary changes in ex vivo normal ovary, type I, and type II ovarian cancer. Mass fractals of the collagen fiber structure is analyzed based on a power law correlation function using spectral dependence measurements of the reduced scattering coefficient μs' where the mass fractal dimension is related to the power. Values of μs' are measured using independent methods of determining the values of μs and g by on-axis attenuation measurements using the Beer-Lambert Law and by fitting the angular distribution of scattering to the Henyey-Greenstein phase function, respectively. Quantitativespectral SHG imaging on the same tissues determines FSHG/BSHG creation ratios related to size and harmonophore distributions. Both techniques probe fibril packing order, but the optical scattering probes structures of sizes from about 50-2000 nm where SHG imaging - although only able to resolve individual fibers - builds contrast from the assembly of fibrils. Our findings suggest that type I ovarian tumor structure has the most ordered collagen fibers followed by normal ovary then type II tumors showing the least order.

The formation of insoluble Tc depends on bacterial activity

International Nuclear Information System (INIS)

Ishii, Nobuyoshi; Uchida, Shigeo; Koiso, Hiroyuki

2005-01-01

The formation of insoluble Tc (>0.2 μm in size) in ponding water of paddy soil was investigated. The ponding water prepared by flooding with deionized water was collected at a one-week intervals during the 120 days of the experimental period. The collected sample was incubated with 3 kBq mL -1 TcO 4 - at 25degC for 14 days. The mean value of relative amounts of insolubilized Tc was less than 0.6% of total Tc. This result suggested that flooding with deionized water was not effective for the formation of insoluble Tc. When the ponding water sample was incubated with TcO 4 - under anaerobic conditions, Tc was scarcely insolubilized. On the other hand, a significant fraction of the Tc was insolubilized in the ponding water sample supplemented with nutrients that promote bacterial activity. Also, the amount of insoluble Tc increased with time. From these results, it was concluded that the formation of insoluble Tc in the ponding water depends on enhanced bacterial activity rather than just anaerobic conditions. (author)

Activity of Mn-Oxidizing Peroxidases of Ganoderma lucidum Depending on Cultivation Conditions

Directory of Open Access Journals (Sweden)

Jasmina Ćilerdžić

2015-11-01

Full Text Available Trunks and stumps of various deciduous species act as natural habitats for Ganoderma lucidum. The chemical composition of their cell wall affects the development of fungal ligninolytic enzyme system as well as its ability to degrade lignin from the plant cell wall. Additionally, numerous compounds structurally similar to lignin can be degraded by the G. lucidum enzyme system which could take important roles in various biotechnological processes. The laccases, which are the dominant enzymes synthesized by G. lucidum, have been studied more extensively than the Mn-oxidizing peroxidases. Therefore, this study aimed to create the dynamics profile of Mn-oxidizing peroxidases activities in four G. lucidum strains, classifying and determining their properties depending on the cultivation type and plant residue as a carbon source in the medium, as well as to establish whether intraspecific variety exists. The findings suggest that submerged cultivation appeared to be a more appropriate cultivation type for enzyme activities compared with solid-state cultivation, and oak sawdust was a better carbon source than wheat straw. Under the optimum conditions, on day 14, G. lucidum BEOFB 431 was characterized by the highest levels of both Mn-dependent and Mn-independent peroxidase activities (4795.5 and 5170.5 U/L, respectively. Strain, cultivation type, and carbon source were factors that affected the profiles of Mn-oxidizing peroxidases isoenzymes.