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Sample records for activation depend quantitatively

  1. The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification

    DEFF Research Database (Denmark)

    Harboe, Morten; Garred, Peter; Karlstrøm, Ellen

    2009-01-01

    was not observed even at high mannan concentrations since addition of the inhibiting anti-MBL mAb 3F8 completely abolished generation of the terminal C5b-9 complex (TCC). However, selective blockade of AP by anti-factor D inhibited more than 80% of TCC release into the fluid phase after LP activation showing...... that AP amplification is quantitatively responsible for the final effect of initial specific LP activation. TCC generation on the solid phase was distinctly but less inhibited by anti-fD. C2 bypass of the LP pathway could be demonstrated, and AP amplification was also essential during C2 bypass in LP...... as shown by complete inhibition of TCC generation in C2-deficient serum by anti-fD and anti-properdin antibodies. In conclusion, the down-stream effect of LP activation depends strongly on AP amplification in normal human serum and in the C2 bypass pathway....

  2. Age-dependent decrease in the activity of succinic dehydrogenase in rat CA1 pyramidal cells: a quantitative cytochemical study.

    Science.gov (United States)

    Bertoni-Freddari, C; Fattoretti, P; Caselli, U; Paoloni, R; Meier-Ruge, W

    1996-09-09

    A computer-assisted morphometric study has been carried out on the ultrastructure of perikaryal CA1 pyramidal cell mitochondria positive to the copper ferricyanide cytochemical reaction for succinic dehydrogenase (SDH) in rats of 3, 12 and 23 months of age. The cytoplasmic volume fraction occupied by the positive mitochondria (Volume density: Vv), the number of organelles/micron 3 of CA1 pyramidal cell cytoplasm (Numerical density: Nv) and the average mitochondrial volume (V) were automatically calculated by means of computer-assisted morphometry. Vv was significantly decreased in 23-month-old animals versus the other age groups. Nv was unchanged between 3 and 12 months of age, but was decreased to a significant extent in old animals. V did not undergo significant changes in the three age groups taken into account. In the old animals the percent of organelles smaller than 0.16 micron 3 is above 20%, while in the young and adult groups the same size of mitochondria accounts for 7 and 3%, respectively. Thus, a reduction in the number of medium sized organelles appears to be responsible for the decrease in Vv due to age. Since SDH activity is known to support maximum rates of respiration, quantitative estimation of the active mitochondria provides information on the metabolic competence of the cells investigated when energy demand is high. In this context, our present findings document that a significant impairment in the efficiency to match actual energy provisions occurs in old CA1 pyramidal cells.

  3. Myofilament length dependent activation

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-05-25

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

  4. 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?"

  5. Quantitative electroencephalography analysis in university students with hazardous alcohol consumption, but not alcohol dependence.

    Science.gov (United States)

    Núñez-Jaramillo, Luis; Vega-Perera, Paulo; Ramírez-Lugo, Leticia; Reyes-López, Julián V; Santiago-Rodríguez, Efraín; Herrera-Morales, Wendy V

    2015-07-08

    Hazardous alcohol consumption is a pattern of consumption that leads to a higher risk of harmful consequences either for the user or for others. This pattern of alcohol consumption has been linked to risky behaviors, accidents, and injuries. Individuals with hazardous alcohol consumption do not necessarily present alcohol dependence; thus, a study of particular neurophysiological correlates of this alcohol consumption pattern needs to be carried out in nondependent individuals. Here, we carried out a quantitative electroencephalography analysis in health sciences university students with hazardous alcohol consumption, but not alcohol dependence (HAC), and control participants without hazardous alcohol consumption or alcohol dependence (NHAC). We analyzed Absolute Power (AP), Relative Power (RP), and Mean Frequency (MF) for beta and theta frequency bands under both eyes closed and eyes open conditions. We found that participants in the HAC group presented higher beta AP at centroparietal region, as well as lower beta MF at frontal and centroparietal regions in the eyes closed condition. Interestingly, participants did not present any change in theta activity (AP, RP, or MF), whereas previous reports indicate an increase in theta AP in alcohol-dependent individuals. Our results partially resemble those found in alcohol-dependent individuals, although are not completely identical, suggesting a possible difference in the underlying neuronal mechanism behind alcohol dependence and hazardous alcohol consumption. Similarities could be explained considering that both hazardous alcohol consumption and alcohol dependence are manifestations of behavioral disinhibition.

  6. 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.

  7. Quantitative diagnosis of small approximal caries lesions utilizing wavelength-dependent fiber-optic transillumination

    NARCIS (Netherlands)

    Vaarkamp, J; TenBosch, JJ; Verdonschot, EH; Tranaeus, S

    The instruments clinically available for the diagnosis of approximal caries lesions are inadequate to detect lesions early and quantitatively. The aim of this study was to investigate whether wavelength-dependent light scattering and absorption of carious tissues may be utilized for the quantitative

  8. 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.

  9. The Arabidopsis thaliana Cyclic-Nucleotide-Dependent Response – a Quantitative Proteomic and Phosphoproteomic Analysis

    KAUST Repository

    Alqurashi, May M.

    2013-11-01

    Protein phosphorylation governs many regulatory pathways and an increasing number of kinases, proteins that transfer phosphate groups, are in turn activated by cyclic nucleotides. One of the cyclic nucleotides, cyclic adenosine monophosphate (cAMP), has been shown to be a second messenger in abiotic and biotic stress responses. However, little is known about the precise role of cAMP in plants and in the down-stream activation of kinases, and hence cAMP-dependent phosphorylation. To increase our understanding of the role of cAMP, proteomic and phosphoproteomic profiles of Arabidopsis thaliana suspension culture cells were analyzed before and after treatment of cells with two different concentrations of 8-Bromo-cAMP (1 µM and 100 nM) and over a time-course of one hour. A comparative quantitative analysis was undertaken using two- dimensional gel electrophoresis and the Delta 2D software (DECODON) followed by protein spot identification by tandem mass spectrometry combined with Mascot and Scaffold. Differentially expressed proteins and regulated phosphoproteins were categorized according to their biological function using bioinformatics tools. The results revealed that the treatment with 1 µM and 100 nM 8-Bromo-cAMP was sufficient to induce specific concentration- and time-dependent changes at the proteome and phosphoproteome levels. In particular, different phosphorylation patterns were observed overtime preferentially affecting proteins in a number of functional categories, notably phosphatases, proteins that remove phosphate groups. This suggests that cAMP both transiently activates and deactivates proteins through specific phosphorylation events and provides new insight into biological mechanisms and functions at the systems level.

  10. Precursor Dependent Structural Properties and Antibacterial Activity ...

    Indian Academy of Sciences (India)

    71

    The antibacterial activity of the synthesized CuO were studied against human pathogens like Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) bacterial strains which are proved to be efficient and precursor dependent. The minimum inhibitory concentration of CuO against E. coli and S. aureus were found to.

  11. 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

  12. 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

  13. Light-dependent electrogenic activity of cyanobacteria.

    Directory of Open Access Journals (Sweden)

    John M Pisciotta

    Full Text Available BACKGROUND: 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]. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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

  14. (Quantitative structure-activity relationships in environmental toxicology)

    Energy Technology Data Exchange (ETDEWEB)

    Turner, J.E.

    1990-10-04

    The traveler attended the Fourth International Workshop on QSAR (Quantitative Structure-Activity Relationships) in Environmental Toxicology. He was an author or co-author on one platform and two poster presentations. The subject of the workshop offers a framework for analyzing and predicting the fate of chemical pollutants in organisms and the environment. QSAR is highly relevant to the ORNL program on the physicochemical characterization of chemical pollutants for health protection.

  15. Dependence of quantitative accuracy of CT perfusion imaging on system parameters

    Science.gov (United States)

    Li, Ke; Chen, Guang-Hong

    2017-03-01

    Deconvolution is a popular method to calculate parametric perfusion parameters from four dimensional CT perfusion (CTP) source images. During the deconvolution process, the four dimensional space is squeezed into three-dimensional space by removing the temporal dimension, and a prior knowledge is often used to suppress noise associated with the process. These additional complexities confound the understanding about deconvolution-based CTP imaging system and how its quantitative accuracy depends on parameters and sub-operations involved in the image formation process. Meanwhile, there has been a strong clinical need in answering this question, as physicians often rely heavily on the quantitative values of perfusion parameters to make diagnostic decisions, particularly during an emergent clinical situation (e.g. diagnosis of acute ischemic stroke). The purpose of this work was to develop a theoretical framework that quantitatively relates the quantification accuracy of parametric perfusion parameters with CTP acquisition and post-processing parameters. This goal was achieved with the help of a cascaded systems analysis for deconvolution-based CTP imaging systems. Based on the cascaded systems analysis, the quantitative relationship between regularization strength, source image noise, arterial input function, and the quantification accuracy of perfusion parameters was established. The theory could potentially be used to guide developments of CTP imaging technology for better quantification accuracy and lower radiation dose.

  16. Quantitative Structure Activity Relationships of Aquatic Narcosis: A Review.

    Science.gov (United States)

    Adhikari, Chandana; Mishra, Bijay Kumar

    2017-07-11

    Prior estimation of toxicity of each and every, existing and yet to be synthesized chemicals is a must to elude their adverse effect on the environment. Experimental determination of such parameters is time consuming, cost effective and above all it demands the sacrifice of many vertebrates. At this end the REACH regulations advocate for the use of non-testing predictive methods such as read-across, weight-of-evidence and QSAR (quantitative structure-activity relationship) techniques. Among these methods, QSAR is found to be the best as it is based on molecular structure only. The descriptors used in deriving the model in QSAR vary according to the nature of the narcotics as well as the species used for. The success of a model in predicting the toxicity of a narcotic purely depends on the type of descriptors selected that explains the structural features closely related to the property under study. In this review we focused on the different types of descriptors and QSAR models used to explain the narcosis phenomenon. Literature was scanned for acute toxicity of chemicals on species like tadpoles, protozoa, planktonic crustaceans, and small fishes like million fish, rainbow fish etc. from different sources. The toxicity and toxicants were classified considering their polarity and specific interactions of the compounds. Due to complex nature of the substrate, the mechanism of action of toxicant is uncertain. However, the overall results obtained from the biological study have been subjected to QSAR studies to obtain various models, which can provide some ideas on the mode of toxicological action. Different types of molecular descriptors derived both experimentally and theoretically have been used in the QSAR studies. Mostly biochemicals have a specific signature on oil/water partition (Ko/w, P), which is the crux in biological activity. Accordingly, the toxicological activities have a good correlations with log P. Addition of some more structural descriptors improves

  17. Quantitative analysis of HGF and EGF-dependent phosphotyrosine signaling networks

    DEFF Research Database (Denmark)

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

    2010-01-01

    We have used stable isotope labeling by amino acids in cell culture (SILAC), in combination with high-resolution mass spectrometry, to identify common and discrete components of the respective receptor tyrosine kinase-dependent phosphotyrosine-associated networks induced by acute stimulation of A......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...

  18. 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.

  19. 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...

  20. 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.

  1. [Multiple dependent variables LS-SVM regression algorithm and its application in NIR spectral quantitative analysis].

    Science.gov (United States)

    An, Xin; Xu, Shuo; Zhang, Lu-Da; Su, Shi-Guang

    2009-01-01

    In the present paper, on the basis of LS-SVM algorithm, we built a multiple dependent variables LS-SVM (MLS-SVM) regression model whose weights can be optimized, and gave the corresponding algorithm. Furthermore, we theoretically explained the relationship between MLS-SVM and LS-SVM. Sixty four broomcorn samples were taken as experimental material, and the sample ratio of modeling set to predicting set was 51 : 13. We first selected randomly and uniformly five weight groups in the interval [0, 1], and then in the way of leave-one-out (LOO) rule determined one appropriate weight group and parameters including penalizing parameters and kernel parameters in the model according to the criterion of the minimum of average relative error. Then a multiple dependent variables quantitative analysis model was built with NIR spectrum and simultaneously analyzed three chemical constituents containing protein, lysine and starch. Finally, the average relative errors between actual values and predicted ones by the model of three components for the predicting set were 1.65%, 6.47% and 1.37%, respectively, and the correlation coefficients were 0.9940, 0.8392 and 0.8825, respectively. For comparison, LS-SVM was also utilized, for which the average relative errors were 1.68%, 6.25% and 1.47%, respectively, and the correlation coefficients were 0.9941, 0.8310 and 0.8800, respectively. It is obvious that MLS-SVM algorithm is comparable to LS-SVM algorithm in modeling analysis performance, and both of them can give satisfying results. The result shows that the model with MLS-SVM algorithm is capable of doing multi-components NIR quantitative analysis synchronously. Thus MLS-SVM algorithm offers a new multiple dependent variables quantitative analysis approach for chemometrics. In addition, the weights have certain effect on the prediction performance of the model with MLS-SVM, which is consistent with our intuition and is validated in this study. Therefore, it is necessary to optimize

  2. Quantitative Assessment of Landscape Load Caused by Mining Activity

    Directory of Open Access Journals (Sweden)

    Csüllög Gábor

    2017-06-01

    Full Text Available In Hungary, not only the aftermath of the extraction in the past nearly 150 years, but also the economic changes taking place in the past two decades have had significant environmental consequences manifested, above all, in the landscape. It is, however, not sufficient to investigate the landscape components separately; it is necessary to explore connections within the landscape. Accordingly, the chief aim of this presentation has been, on the one hand, to work out the method of landscape load index, based on a quantitative database of mining claims and deposits of mining waste, which has revealed their impacts on the landscape as well. On the other hand, we have also aimed at developing the method of the mining load index of certain geographical landscape units. By calculating and analysing the indices, we have intended to build a quantitative database suitable for investigating the impacts of mining activities on the landscape. On the basis of the indices, the impacts and consequences could be ranked, and it was also possible to compare the impacts of different mining claims and waste deposits in three different landscape categories. With the main result of our examination, this will make it possible to investigate concrete problems and landscape conflicts caused by the landscape use of mining or its aftermath in different landscape units with a high load index.

  3. Quantitative structure activity relationship studies of mushroom tyrosinase inhibitors

    Science.gov (United States)

    Xue, Chao-Bin; Luo, Wan-Chun; Ding, Qi; Liu, Shou-Zhu; Gao, Xing-Xiang

    2008-05-01

    Here, we report our results from quantitative structure-activity relationship studies on tyrosinase inhibitors. Interactions between benzoic acid derivatives and tyrosinase active sites were also studied using a molecular docking method. These studies indicated that one possible mechanism for the interaction between benzoic acid derivatives and the tyrosinase active site is the formation of a hydrogen-bond between the hydroxyl (aOH) and carbonyl oxygen atoms of Tyr98, which stabilized the position of Tyr98 and prevented Tyr98 from participating in the interaction between tyrosinase and ORF378. Tyrosinase, also known as phenoloxidase, is a key enzyme in animals, plants and insects that is responsible for catalyzing the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones. In the present study, the bioactivities of 48 derivatives of benzaldehyde, benzoic acid, and cinnamic acid compounds were used to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field (CoMFA) and comparative molecular similarity indices (CoMSIA) analyses. After superimposition using common substructure-based alignments, robust and predictive 3D-QSAR models were obtained from CoMFA ( q 2 = 0.855, r 2 = 0.978) and CoMSIA ( q 2 = 0.841, r 2 = 0.946), with 6 optimum components. Chemical descriptors, including electronic (Hammett σ), hydrophobic (π), and steric (MR) parameters, hydrogen bond acceptor (H-acc), and indicator variable ( I), were used to construct a 2D-QSAR model. The results of this QSAR indicated that π, MR, and H-acc account for 34.9, 31.6, and 26.7% of the calculated biological variance, respectively. The molecular interactions between ligand and target were studied using a flexible docking method (FlexX). The best scored candidates were docked flexibly, and the interaction between the benzoic acid derivatives and the tyrosinase active site was elucidated in detail. We believe

  4. 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...

  5. Activated sludge characterization through microscopy: A review on quantitative image analysis and chemometric techniques

    Energy Technology Data Exchange (ETDEWEB)

    Mesquita, Daniela P. [IBB-Institute for Biotechnology and Bioengineering, Centre of Biological Engineering, Universidade do Minho, Campus de Gualtar, 4710-057 Braga (Portugal); Amaral, A. Luís [IBB-Institute for Biotechnology and Bioengineering, Centre of Biological Engineering, Universidade do Minho, Campus de Gualtar, 4710-057 Braga (Portugal); Instituto Politécnico de Coimbra, ISEC, DEQB, Rua Pedro Nunes, Quinta da Nora, 3030-199 Coimbra (Portugal); Ferreira, Eugénio C., E-mail: ecferreira@deb.uminho.pt [IBB-Institute for Biotechnology and Bioengineering, Centre of Biological Engineering, Universidade do Minho, Campus de Gualtar, 4710-057 Braga (Portugal)

    2013-11-13

    Graphical abstract: -- Highlights: •Quantitative image analysis shows potential to monitor activated sludge systems. •Staining techniques increase the potential for detection of operational problems. •Chemometrics combined with quantitative image analysis is valuable for process monitoring. -- Abstract: In wastewater treatment processes, and particularly in activated sludge systems, efficiency is quite dependent on the operating conditions, and a number of problems may arise due to sludge structure and proliferation of specific microorganisms. In fact, bacterial communities and protozoa identification by microscopy inspection is already routinely employed in a considerable number of cases. Furthermore, quantitative image analysis techniques have been increasingly used throughout the years for the assessment of aggregates and filamentous bacteria properties. These procedures are able to provide an ever growing amount of data for wastewater treatment processes in which chemometric techniques can be a valuable tool. However, the determination of microbial communities’ properties remains a current challenge in spite of the great diversity of microscopy techniques applied. In this review, activated sludge characterization is discussed highlighting the aggregates structure and filamentous bacteria determination by image analysis on bright-field, phase-contrast, and fluorescence microscopy. An in-depth analysis is performed to summarize the many new findings that have been obtained, and future developments for these biological processes are further discussed.

  6. 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.

  7. 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,

  8. A Novel Two-Step Hierarchial Quantitative Structure-Activity ...

    Science.gov (United States)

    Background: Accurate prediction of in vivo toxicity from in vitro testing is a challenging problem. Large public–private consortia have been formed with the goal of improving chemical safety assessment by the means of high-throughput screening. Methods and results: A database containing experimental cytotoxicity values for in vitro half-maximal inhibitory concentration (IC50) and in vivo rodent median lethal dose (LD50) for more than 300 chemicals was compiled by Zentralstelle zur Erfassung und Bewertung von Ersatz- und Ergaenzungsmethoden zum Tierversuch (ZEBET ; National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments) . The application of conventional quantitative structure–activity relationship (QSAR) modeling approaches to predict mouse or rat acute LD50 values from chemical descriptors of ZEBET compounds yielded no statistically significant models. The analysis of these data showed no significant correlation between IC50 and LD50. However, a linear IC50 versus LD50 correlation could be established for a fraction of compounds. To capitalize on this observation, we developed a novel two-step modeling approach as follows. First, all chemicals are partitioned into two groups based on the relationship between IC50 and LD50 values: One group comprises compounds with linear IC50 versus LD50 relationships, and another group comprises the remaining compounds. Second, we built conventional binary classification QSAR models t

  9. Quantitative structure-activity relationship study of amide mosquito repellents.

    Science.gov (United States)

    Wang, P; Xu, X; Liao, S; Song, J; Fan, G; Chen, S; Wang, Z

    2017-04-01

    A quantitative structure-activity relationship (QSAR) study on 43 amide repellents was carried out by the heuristic method in order to reveal the correlations between molecular parameters of these amides and their repellency against Aedes aegypti. Sketches and optimizations of molecular structures were achieved by the Gaussian software package. Generation and screening of molecular parameters were accomplished using CODESSA 2.7.10 software. The leave-one-out method was applied for the model validation. The results showed that a four-descriptor QSAR model with r 2 of 0.897 was obtained. The average r 2 values of the training set and test set of the QSAR model were 0.901 and 0.863, respectively, which suggested that the stability and predictability of the model were confirmed. Analysis of the implications of the descriptors that constitute the QSAR model indicated that all the descriptors were related to the charge distribution over the molecule and affect the dipole moment of the repellents.

  10. Quantum mechanical quantitative structure-activity relationships to avoid mutagenicity.

    Science.gov (United States)

    Holder, Andrew J; Ye, Lin

    2009-01-01

    The purpose of this work is to develop a quantum mechanically based quantitative structure-activity relationship (QMQSAR or QSAR hereafter) adequate to predict and explain Ames TA100-derived mutagenicities for a number of organic molecules. A set of 35 structurally similar molecules with epoxide (oxirane) functionalities and systematic, reliable experimental data were selected to construct a QSAR model. The SAM1 quantum mechanical method was used to perform conformational analysis and properties calculations. This QM information was used to compute a variety of descriptors. From this a two-descriptor regression model was constructed. The two descriptors are ESP-HACA-1/TMSA and HOMO-LUMO energy gap. Statistical results for the model: R(2)=0.857, R(adj)(2)=0.818,R(cv)(2)=0.848,s(2)=0.0618. The variance inflation factor and significance for both descriptors were 1.082 and design of non-mutagenic monomers that may be useful for dental restorative composites. The model also serves as a screening tool for rating the mutagenicity of new candidate materials.

  11. Halden project activities on software dependability

    International Nuclear Information System (INIS)

    Dahll, G.; Sivertsen.

    1994-01-01

    Since 1977, the OECD Halden Reactor Project has been working in the field of software dependability. Special emphasis has been put on the use of software in safety critical systems. All phases in software development, from specification through software development, verification, and validation have been covered and are discussed in this article

  12. Quantitative evaluation of sonophoresis efficiency and its dependence on sonication parameters and particle size.

    Science.gov (United States)

    Lee, Kun Loong; Zhou, Yufeng

    2015-03-01

    Transdermal drug delivery makes a critical contribution to medical practice and some advantages over conventional oral administration and hypodermic injection. Enhancement of percutaneous absorption or penetration of therapeutic agents (ie, drugs and macromolecules) by ultrasound, termed sonophoresis, has been applied and studied for decades. In this study, the penetration percentage through porcine ear skin specimens was determined quantitatively by measuring the fluorescence from nanoparticles of 60, 220, and 840 nm in size in a receptor chamber at different sonication parameters (ie, duty cycle, 20%-100%; acoustic intensity, 0.3-1.0 W/cm(2); duration, 7-30 minutes; and frequency, 1 MHz). In general, the sonophoresis efficiency increased with the acoustic intensity, duty cycle, and sonication duration but decreased with the particle size (mean ± SD, 62.6% ± 5.4% for 60-nm versus 11.9% ± 1.1% for 840-nm polystyrene nanospheres after 30 minutes of sonication at 0.5 W/cm(2) and a 100% duty cycle; P sonophoresis efficiency is dependent on the ultrasound parameters and particle size. Sufficient sonication would lead to satisfactory penetration of even submicrometer objects through the pores. © 2015 by the American Institute of Ultrasound in Medicine.

  13. Magnetic field dependence of vortex activation energy

    Indian Academy of Sciences (India)

    ... the resistance as a function of temperature and magnetic field in clean polycrystalline samples of NbSe2, MgB2 and Bi2Sr2Ca2Cu3O10 (BSCCO) superconductors. Thermally activated flux flow behaviour is seen in all the three systems and clearly identified in bulk MgB2. While the activation energy at low fields for MgB2 ...

  14. Dual gene activation and knockout screen reveals directional dependencies in genetic networks. | Office of Cancer Genomics

    Science.gov (United States)

    Understanding the direction of information flow is essential for characterizing how genetic networks affect phenotypes. However, methods to find genetic interactions largely fail to reveal directional dependencies. We combine two orthogonal Cas9 proteins from Streptococcus pyogenes and Staphylococcus aureus to carry out a dual screen in which one gene is activated while a second gene is deleted in the same cell. We analyze the quantitative effects of activation and knockout to calculate genetic interaction and directionality scores for each gene pair.

  15. 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 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...... 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 genotypes....

  16. 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

  17. THE COMPARATIVE ANALYSIS OF THE ACTIVITY ASSAY METHODS FOR MG2+-DEPENDENT NA+/K+-ACTIVATED ATPASE IN ERYTHROCYTE MEMBRANES

    Directory of Open Access Journals (Sweden)

    Polina Anatolevna Petrova

    2017-12-01

    Full Text Available This review considers the methodological reasons for the wide range of results for the red blood cells Mg2+-dependent Na+/K+-ATPase activity described by different authors. We assert that the differences in the Na+/K+-ATPase activity obtained by the researchers are due to the methodological peculiarities associated with methods of obtaining and measurement of the enzyme activity, such as red blood cells separation and storage (centrifugation, concentration and composition of the lysing solution, time and temperature of hemolysis and freezing, as well as the peculiarities of methods for the quantitative determination of protein and inorganic phosphorus. On the basis of the literature data analysis we recommend that for the most accurate determination of the Na+/K+-ATPase activity it is better to use the chelator in the lysing buffer solution and Fiske-Subbarow and Lowry methods for the determination of inorganic phosphorus and quantitative protein content, respectively.

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

    Science.gov (United States)

    Corwin, Jason A; Copeland, Daniel; Feusier, Julie; Subedy, Anushriya; Eshbaugh, Robert; Palmer, Christine; Maloof, Julin; Kliebenstein, Daniel J

    2016-02-01

    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 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 genotypes.

  19. 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

  20. Apricot DNA as an indicator for persipan: detection and quantitation in marzipan using ligation-dependent probe amplification.

    Science.gov (United States)

    Luber, Florian; Demmel, Anja; Hosken, Anne; Busch, Ulrich; Engel, Karl-Heinz

    2012-06-13

    The confectionery ingredient marzipan is exclusively prepared from almond kernels and sugar. The potential use of apricot kernels, so-called persipan, is an important issue for the quality assessment of marzipan. Therefore, a ligation-dependent probe amplification (LPA) assay was developed that enables a specific and sensitive detection of apricot DNA, as an indicator for the presence of persipan. The limit of detection was determined to be 0.1% persipan in marzipan. The suitability of the method was confirmed by the analysis of 20 commercially available food samples. The integration of a Prunus -specific probe in the LPA assay as a reference allowed for the relative quantitation of persipan in marzipan. The limit of quantitation was determined to be 0.5% persipan in marzipan. The analysis of two self-prepared mixtures of marzipan and persipan demonstrated the applicability of the quantitation method at concentration levels of practical relevance for quality control.

  1. In vivo toxicity of nitroaromatics: A comprehensive quantitative structure-activity relationship study.

    Science.gov (United States)

    Gooch, Aminah; Sizochenko, Natalia; Rasulev, Bakhtiyor; Gorb, Leonid; Leszczynski, Jerzy

    2017-08-01

    The toxicity data of 90 nitroaromatic compounds related to their 50% lethal dose concentration for rats (LD50) were analyzed to develop quantitative structure-activity relationship (QSAR) models. Quantum-chemically calculated descriptors together with molecular descriptors generated by DRAGON, PaDEL, and HiT-QSAR software were utilized to build QSAR models. Quality and validity of the models were determined by internal and external validation techniques. The results show that the toxicity of nitroaromatic compounds depends on various factors, such as the number of nitro-groups, the topological state, and the presence of certain structural fragments. The developed models based on the largest (to date) dataset of nitroaromatics in vivo toxicity showed a good predictive ability. The results provide important input that could be applied in a preliminary assessment of nitroaromatic compounds' toxicity to mammals. Environ Toxicol Chem 2017;36:2227-2233. © 2017 SETAC. © 2017 SETAC.

  2. 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.

  3. 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.

  4. Quantitative in vivo Analyses Reveal Calcium-dependent Phosphorylation Sites and Identifies a Novel Component of the Toxoplasma Invasion Motor Complex

    Science.gov (United States)

    Nebl, Thomas; Prieto, Judith Helena; Kapp, Eugene; Smith, Brian J.; Williams, Melanie J.; Yates, John R.; Cowman, Alan F.; Tonkin, Christopher J.

    2011-01-01

    Apicomplexan parasites depend on the invasion of host cells for survival and proliferation. Calcium-dependent signaling pathways appear to be essential for micronemal release and gliding motility, yet the target of activated kinases remains largely unknown. We have characterized calcium-dependent phosphorylation events during Toxoplasma host cell invasion. Stimulation of live tachyzoites with Ca2+-mobilizing drugs leads to phosphorylation of numerous parasite proteins, as shown by differential 2-DE display of 32[P]-labeled protein extracts. Multi-dimensional Protein Identification Technology (MudPIT) identified ∼546 phosphorylation sites on over 300 Toxoplasma proteins, including 10 sites on the actomyosin invasion motor. Using a Stable Isotope of Amino Acids in Culture (SILAC)-based quantitative LC-MS/MS analyses we monitored changes in the abundance and phosphorylation of the invasion motor complex and defined Ca2+-dependent phosphorylation patterns on three of its components - GAP45, MLC1 and MyoA. Furthermore, calcium-dependent phosphorylation of six residues across GAP45, MLC1 and MyoA is correlated with invasion motor activity. By analyzing proteins that appear to associate more strongly with the invasion motor upon calcium stimulation we have also identified a novel 15-kDa Calmodulin-like protein that likely represents the MyoA Essential Light Chain of the Toxoplasma invasion motor. This suggests that invasion motor activity could be regulated not only by phosphorylation but also by the direct binding of calcium ions to this new component. PMID:21980283

  5. Antitumor activity of 3,4-ethylenedioxythiophene derivatives and quantitative structure-activity relationship analysis

    Science.gov (United States)

    Jukić, Marijana; Rastija, Vesna; Opačak-Bernardi, Teuta; Stolić, Ivana; Krstulović, Luka; Bajić, Miroslav; Glavaš-Obrovac, Ljubica

    2017-04-01

    The aim of this study was to evaluate nine newly synthesized amidine derivatives of 3,4- ethylenedioxythiophene (3,4-EDOT) for their cytotoxic activity against a panel of human cancer cell lines and to perform a quantitative structure-activity relationship (QSAR) analysis for the antitumor activity of a total of 27 3,4-ethylenedioxythiophene derivatives. Induction of apoptosis was investigated on the selected compounds, along with delivery options for the optimization of activity. The best obtained QSAR models include the following group of descriptors: BCUT, WHIM, 2D autocorrelations, 3D-MoRSE, GETAWAY descriptors, 2D frequency fingerprint and information indices. Obtained QSAR models should be relieved in elucidation of important physicochemical and structural requirements for this biological activity. Highly potent molecules have a symmetrical arrangement of substituents along the x axis, high frequency of distance between N and O atoms at topological distance 9, as well as between C and N atoms at topological distance 10, and more C atoms located at topological distances 6 and 3. Based on the conclusion given in the QSAR analysis, a new compound with possible great activity was proposed.

  6. Synthesis, biological activities, and quantitative structure-activity relationship (QSAR) study of novel camptothecin analogues.

    Science.gov (United States)

    Wu, Dan; Zhang, Shao-Yong; Liu, Ying-Qian; Wu, Xiao-Bing; Zhu, Gao-Xiang; Zhang, Yan; Wei, Wei; Liu, Huan-Xiang; Chen, An-Liang

    2015-05-13

    In continuation of our program aimed at the development of natural product-based pesticidal agents, three series of novel camptothecin derivatives were designed, synthesized, and evaluated for their biological activities against T. Cinnabarinus, B. brassicae, and B. xylophilus. All of the derivatives showed good-to-excellent activity against three insect species tested, with LC50 values ranging from 0.00761 to 0.35496 mmol/L. Remarkably, all of the compounds were more potent than CPT against T. Cinnabarinus, and compounds 4d and 4c displayed superior activity (LC50 0.00761 mmol/L and 0.00942 mmol/L, respectively) compared with CPT (LC50 0.19719 mmol/L) against T. Cinnabarinus. Based on the observed bioactivities, preliminary structure-activity relationship (SAR) correlations were also discussed. Furthermore, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) was built. The model gave statistically significant results with the cross-validated q2 values of 0.580 and correlation coefficient r2 of 0.991 and  of 0.993. The QSAR analysis indicated that the size of the substituents play an important in the activity of 7-modified camptothecin derivatives. These findings will pave the way for further design, structural optimization, and development of camptothecin-derived compounds as pesticidal agents.

  7. 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.

  8. 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.

  9. Quantitative structure-activity relationship of antifungal activity of rosin derivatives.

    Science.gov (United States)

    Wang, Hui; Nguyen, Thi Thanh Hien; Li, Shujun; Liang, Tao; Zhang, Yuanyuan; Li, Jian

    2015-01-15

    To develop new rosin-based wood preservatives with good antifungal activity, 24 rosin derivatives were synthesized, bioassay tested with Trametes versicolor and Gloeophyllum trabeum, and subjected to analysis of their quantitative structure-activity relationships (QSAR). A QSAR analysis using Ampac 9.2.1 and Codessa 2.7.16 software built two QSAR models of antifungal ratio for T. versicolor and G. trabeum with values of R(2)=0.9740 and 0.9692, respectively. Based on the models, tri-N-(3-hydroabietoxy-2-hydroxy) propyl-triethyl ammonium chloride was designed and the bioassay test result proved its better inhibitory effect against the two selected fungi as expected. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. ROS-activated ATM-dependent phosphorylation of cytoplasmic substrates identified by large scale phosphoproteomics screen

    DEFF Research Database (Denmark)

    Kozlov, Sergei V; Waardenberg, Ashley J; Engholm-Keller, Kasper

    2016-01-01

    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 A-T (ataxia-telangiectasia) 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......-dependent after H2O2 exposure and another protein (S100A11) demonstrated ATM-dependence for translocation from the cytoplasm to the nucleus. These data provide new insights into the activation of ATM by oxidative stress through identification of novel substrates for ATM in the cytoplasm. 2....

  11. Students (female physical capacity assessment depending on physical activity.

    Directory of Open Access Journals (Sweden)

    Skyriene V.

    2011-06-01

    Full Text Available Assessment of the social sciences university students (female physical capacity assessment depending on the chosen form of physical activity. Revealed that physical activity within the subject "Physical training" allows students (female to achieve a number of indicators average or above average for the citizens of the republic level of physical fitness. In experiment took part 258 students.

  12. 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

  13. 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.)

  14. Demystifying Multitask Deep Neural Networks for Quantitative Structure-Activity Relationships.

    Science.gov (United States)

    Xu, Yuting; Ma, Junshui; Liaw, Andy; Sheridan, Robert P; Svetnik, Vladimir

    2017-10-23

    Deep neural networks (DNNs) are complex computational models that have found great success in many artificial intelligence applications, such as computer vision1,2 and natural language processing.3,4 In the past four years, DNNs have also generated promising results for quantitative structure-activity relationship (QSAR) tasks.5,6 Previous work showed that DNNs can routinely make better predictions than traditional methods, such as random forests, on a diverse collection of QSAR data sets. It was also found that multitask DNN models-those trained on and predicting multiple QSAR properties simultaneously-outperform DNNs trained separately on the individual data sets in many, but not all, tasks. To date there has been no satisfactory explanation of why the QSAR of one task embedded in a multitask DNN can borrow information from other unrelated QSAR tasks. Thus, using multitask DNNs in a way that consistently provides a predictive advantage becomes a challenge. In this work, we explored why multitask DNNs make a difference in predictive performance. Our results show that during prediction a multitask DNN does borrow "signal" from molecules with similar structures in the training sets of the other tasks. However, whether this borrowing leads to better or worse predictive performance depends on whether the activities are correlated. On the basis of this, we have developed a strategy to use multitask DNNs that incorporate prior domain knowledge to select training sets with correlated activities, and we demonstrate its effectiveness on several examples.

  15. 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

    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...

  16. Quantitative comparison of fire danger index performance using fire activity

    CSIR Research Space (South Africa)

    Steenkamp, KC

    2012-07-01

    Full Text Available and in logistic planning of fire fighting resources. In this study historical fire activity from remotely sensed data are compared with various FDIs to identify which index has the strongest statistical relationship with fire occurrences and therefore the highest...

  17. Novel TPP-riboswitch activators bypass metabolic enzyme dependency.

    Science.gov (United States)

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

    2014-01-01

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

  18. 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)

  19. Quantitative assessment of accumulation of radionuclides in fish organism in dependence on water temperature

    International Nuclear Information System (INIS)

    Katkov, A.E.

    1980-01-01

    Eperimentally studied are the changes of levels of several indices of radionuclide metabolism in fishes in dependence on water temperature at its absorption directly from water and at introduction into the digestive tract. Presented are the coefficients of radionuclide storage by the fish tissues in the dependence on temperature (scales and fins, gills, head, intestines, skin, muscles, axial skeleton) and the coefficients of radionuclide retention in the whole fish. It is shown that the connection between the coefficient of radionuclide storage in the fish organism and water temperature is described by the logarithmic dependence. At the systematic entering of radionuclides into the digestive tract the retention coefficient of them in the organism expressed in the form of the ratio of residual quantity in the fish to the quantity in day dose is constant

  20. 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

  1. Quantitative structure-activity relationships of salicylamide neuroleptic agents.

    Science.gov (United States)

    Gupta, S P; Saha, R N; Singh, P

    1990-05-01

    The in vitro antidopamine activity of substituted N-[(1-alkyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides was found to be well correlated with the hydrophobic and electronic nature of substituents at the 3-position, and with the steric nature of groups replacing the hydrogen atom of the salicyl hydroxy group. In contrast, only the hydrophobic and steric characteristics were found to be important in the in vivo activity of these neuroleptics. This difference suggests that different mechanisms are probably involved in their in vitro and in vivo actions, and that the relevant receptors are slightly different in structure. The in vitro results suggest that electron donation by the 3-substituent strengthens the formation of a hydrogen bond between the carbonyl group of the amide moiety and a hydrogen of the receptor.

  2. Quantitative study of temperature-dependent order in thin films of cylindrical morphology block copolymer

    Science.gov (United States)

    Mishra, Vindhya; Kramer, Edward

    2010-03-01

    Disordering and defect generation in block copolymer systems at high temperatures is of significance to get a better understanding of the physics governing these systems, which can also direct efforts to minimize them. We have studied the smectic-nematic-isotropic transition in confined monolayers and bilayers of cylindrical morphology poly (styrene-b-2vinyl pyridine) diblock copolymer. Previous studies of melting phenomena in block copolymer thin films have relied on quantitative AFM studies alone. We have supplemented AFM studies with grazing incidence small angle X-ray diffraction lineshape analysis to quantify the decay of translational and orientational order with increasing temperature. The results have been interpreted in the context of the Toner-Nelson theory of melting for layered systems.

  3. Account of spectral dependence of instrumental factor in quantitative X-ray fluorescence analysis

    International Nuclear Information System (INIS)

    Pershin, N.V.; Mosichev, V.I.

    1990-01-01

    A new method for calibration of X-ray fluorescence spectrometers using scanning spectrometric channel is proposed. The method is based on a separate account of matrix and instrumental effects and needs no calibration standards for the element analysed. For calibration in the whole spectral range of XRS (0.03-1.0 nm) it is sufficient to have from 10 to 15 pure element emitters made of most wide spread elements. The method provides rapid development of quantitative analysis for the elements which are not provided with standard samples and preparation of pure element emitters for which is impossible or problematic. The practical verification of the method was made by analysing a set of 146 standard samples covering a wide group of alloys. The mean relative error of the method was 3-5 % in an analytical range of 0.1-3.0 wt %

  4. Invasive growth of Saccharomyces cerevisiae depends on environmental triggers: a quantitative model.

    Science.gov (United States)

    Zupan, Jure; Raspor, Peter

    2010-04-01

    In this contribution, the influence of various physicochemical factors on Saccharomyces cerevisiae invasive growth is examined quantitatively. Agar-invasion assays are generally applied for in vitro studies on S. cerevisiae invasiveness, the phenomenon observed as a putative virulence trait in this clinically more and more concerning yeast. However, qualitative agar-invasion assays, used until now, strongly limit the feasibility and interpretation of analyses and therefore needed to be improved. Besides, knowledge in this field concerning the physiology of invasive growth, influenced by stress conditions related to the human alimentary tract and food, is poor and should be expanded. For this purpose, a quantitative agar-invasion assay, presented in our previous work, was applied in this contribution to clarify the significance of the stress factors controlling the adhesion and invasion of the yeast in greater detail. Ten virulent and non-virulent S. cerevisiae strains were assayed at various temperatures, pH values, nutrient starvation, modified atmosphere, and different concentrations of NaCl, CaCl2 and preservatives. With the use of specific parameters, like a relative invasion, eight invasive growth models were hypothesized, which enabled intelligible interpretation of the results. A strong preference for invasive growth (meaning high relative invasion) was observed when the strains were grown on nitrogen- and glucose-depleted media. A significant increase in the invasion of the strains was also determined at temperatures typical for human fever (37-39 degrees C). On the other hand, a strong repressive effect on invasion was found in the presence of salts, anoxia and some preservatives. Copyright 2010 John Wiley & Sons, Ltd.

  5. Developments in Quantitative Structure-Activity Relationships (QSAR). A Review

    Science.gov (United States)

    1976-07-01

    AspergiL us niger, phenyl methacrylates upon Ranse-nula awmat~a and RR’NCSS Na+ upon Botrytis cinerea conformed to the general equation 35. The equations...8217 i - •.. i i r ’: I I ----- ’ 1--- 114 isolated enzyme does not ensure high activity in in vivo tests (see page 84). Competing processes such as...log II vs log kw *79 Botrytis cinerea , 41, 64 -lg! slgý,7 Bovine hemoglobin, 36 lg Elv o .,7 Bovine serum albumin, 36 - log iI vs log P, 79 - log JE

  6. Quantitative requirement for ATP for active transport in isolated renal cells

    International Nuclear Information System (INIS)

    Tessitore, N.; Sakhrani, L.M.; Massry, S.G.

    1986-01-01

    We investigated the quantitative relationship between cellular ATP concentration and Na+-K+-ATPase activity as measured by ouabain-sensitive 86Rb influx in rabbit proximal renal cells. Cellular ATP was reduced in a stepwise manner by rotenone (10(-7) to 10(-5) M) and was increased by 10 mM adenosine. During these maneuvers, ouabain-sensitive 86Rb influx was linearly related to cellular ATP and did not saturate up to 9.9 mM ATP. In contrast, Na+-K+-ATPase activity in membranes prepared from these cells saturated at 2.0 mM ATP at various sodium (10-100 mM) and potassium (4-100 mM) concentrations. Sodium-dependent phosphate uptake and alpha-methylglucoside (alpha-MG) uptake were both inhibited to a similar degree when cellular ATP was reduced. We conclude that 1) the ATP requirement for saturation of Na+-K+-ATPase is higher in intact renal cells than in the membranes, and 2) the uptake of phosphate and alpha-MG are similarly influenced by reduction in ATP. This effect of ATP on phosphate and AMG uptake is most likely an indirect one and is secondary to changes in the sodium gradient across the cell

  7. 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...

  8. 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.

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

    International Nuclear Information System (INIS)

    Masadeh, A. S.; Bozin, E. S.; Farrow, C. L.; Paglia, G.; Juhas, P.; Billinge, S. J. L.; Karkamkar, A.; Kanatzidis, M. G.

    2007-01-01

    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 ∼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

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

    Science.gov (United States)

    Masadeh, A. S.; Božin, E. S.; Farrow, C. L.; Paglia, G.; Juhas, P.; Billinge, S. J. L.; Karkamkar, A.; Kanatzidis, M. G.

    2007-09-01

    The size-dependent structure of CdSe nanoparticles, with diameters ranging from 2to4nm , 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 ˜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 2nm diameter particles. This study demonstrates the size-dependent quantitative structural information that can be obtained even from very small nanoparticles using the PDF approach.

  11. 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.

  12. Anharmonic onsets in polypeptides revealed by neutron scattering: experimental evidences and quantitative description of energy resolution dependence.

    Science.gov (United States)

    Schiró, Giorgio

    2013-01-01

    Neutron scattering measurements on protein powders reveal two deviations from harmonic dynamics at low temperature, whose molecular origin, physical nature and biological relevance are still matter of discussion. In this study we present a new experimental and theoretical approach to evidence the resolution dependence of anharmonic onsets: the use of strategically selected homomeric polypeptides allows revealing the exact resolution dependence; a two-site energy landscape model, where resolution effects are explicitly taken into account, is able to interpret quantitatively the experimental data in terms of energy landscape parameters. The energetic description provided by this analysis, together with recent experimental evidences obtained on chemically and structurally different peptide systems, allows us to connect the protein/water energy landscape structure with the two-wells water interaction potential proposed to explain the low-density→high-density liquid-liquid transition observed in supercooled water. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation.

    Directory of Open Access Journals (Sweden)

    Xuan Fu

    2008-04-01

    Full Text Available DNA damage such as double-stranded DNA breaks (DSBs has been reported to stimulate mitochondrial biogenesis. However, the underlying mechanism is poorly understood. The major player in response to DSBs is ATM (ataxia telangiectasia mutated. Upon sensing DSBs, ATM is activated through autophosphorylation and phosphorylates a number of substrates for DNA repair, cell cycle regulation and apoptosis. ATM has been reported to phosphorylate the alpha subunit of AMP-activated protein kinase (AMPK, which senses AMP/ATP ratio in cells, and can be activated by upstream kinases. Here we provide evidence for a novel role of ATM in mitochondrial biogenesis through AMPK activation in response to etoposide-induced DNA damage.Three pairs of human ATM+ and ATM- cells were employed. Cells treated with etoposide exhibited an ATM-dependent increase in mitochondrial mass as measured by 10-N-Nonyl-Acridine Orange and MitoTracker Green FM staining, as well as an increase in mitochondrial DNA content. In addition, the expression of several known mitochondrial biogenesis regulators such as the major mitochondrial transcription factor NRF-1, PGC-1alpha and TFAM was also elevated in response to etoposide treatment as monitored by RT-PCR. Three pieces of evidence suggest that etoposide-induced mitochondrial biogenesis is due to ATM-dependent activation of AMPK. First, etoposide induced ATM-dependent phosphorylation of AMPK alpha subunit at Thr172, indicative of AMPK activation. Second, inhibition of AMPK blocked etoposide-induced mitochondrial biogenesis. Third, activation of AMPK by AICAR (an AMP analogue stimulated mitochondrial biogenesis in an ATM-dependent manner, suggesting that ATM may be an upstream kinase of AMPK in the mitochondrial biogenesis pathway.These results suggest that activation of ATM by etoposide can lead to mitochondrial biogenesis through AMPK activation. We propose that ATM-dependent mitochondrial biogenesis may play a role in DNA damage response

  14. Magnetic field dependence of vortex activation energy: A ...

    Indian Academy of Sciences (India)

    Home; Journals; Pramana – Journal of Physics; Volume 71; Issue 6. Magnetic field dependence of vortex activation energy: A comparison between MgB2, NbSe2 and Bi2Sr2Ca2Cu3O10 superconductors. S D Kaushik V Braccini S Patnaik. Research Articles Volume 71 Issue 6 December 2008 pp 1335-1343 ...

  15. The watercolor effect: quantitative evidence for luminance-dependent mechanisms of long-range color assimilation.

    Science.gov (United States)

    Devinck, Frédéric; Delahunt, Peter B; Hardy, Joseph L; Spillmann, Lothar; Werner, John S

    2005-05-01

    When a dark chromatic contour delineating a figure is flanked on the inside by a brighter chromatic contour, the brighter color will spread into the entire enclosed area. This is known as the watercolor effect (WCE). Here we quantified the effect of color spreading using both color-matching and hue-cancellation tasks. Over a wide range of stimulus chromaticities, there was a reliable shift in color appearance that closely followed the direction of the inducing contour. When the contours were equated in luminance, the WCE was still present, but weak. The magnitude of the color spreading increased with increases in luminance contrast between the two contours. Additionally, as the luminance contrast between the contours increased, the chromaticity of the induced color more closely resembled that of the inside contour. The results support the hypothesis that the WCE is mediated by luminance-dependent mechanisms of long-range color assimilation.

  16. Biological activity, quantitative structure–activity relationship analysis, and molecular docking of xanthone derivatives as anticancer drugs

    Science.gov (United States)

    Miladiyah, Isnatin; Jumina, Jumina; Haryana, Sofia Mubarika; Mustofa, Mustofa

    2018-01-01

    Background Xanthone derivatives have a wide range of pharmacological activities, such as those involving antibacterial, antiviral, antimalarial, anthelmintic, anti-inflammatory, antiprotozoal, and anticancer properties. Among these, we investigated the anticancer properties of xanthone. This research aimed to analyze the biological activity of ten novel xanthone derivatives, to investigate the most contributing-descriptors for their cytotoxic activities, and to examine the possible mechanism of actions of xanthone compound through molecular docking. Materials and methods The cytotoxic tests were carried out on WiDR and Vero cell lines, by a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay method. The structural features required for xanthone’s anticancer activity were conducted by using the semi-empirical Austin Model-1 method, and continued with quantitative structure-activity relationship (QSAR) analysis using BuildQSAR program. The study of the possible mechanism of actions of the selected xanthone compound was done through molecular docking with PLANTS. Results The three novel xanthone derivatives (compounds 5, 7, and 8) exhibited cytotoxic activity with compound 5 showed the highest degree of cytotoxicity at concentration 9.23 µg/mL (37.8 µM). The following best equation model was obtained from the BuildQSAR calculation: log 1/IC50 = −8.124 qC1 −35.088 qC2 −6.008 qC3 + 1.831 u + 0.540 logP −9.115 (n = 10, r = 0.976, s = 0.144, F = 15.920, Q2 = 0.651, SPRESS = 0.390). This equation model generated 15 proposed new xanthone compounds with better-predicted anticancer activities. A molecular docking study of compound 5 showed that xanthone formed binding interactions with some receptors involved in cancer pathology, including telomerase, tumor-promoting inflammation (COX-2), and cyclin-dependent kinase-2 (CDK2) inhibitor. Conclusion The results suggested that compound 5 showed the best cytotoxic activity among the xanthone

  17. 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

  18. Quantitative in vivo analyses reveal calcium-dependent phosphorylation sites and identifies a novel component of the Toxoplasma invasion motor complex.

    Directory of Open Access Journals (Sweden)

    Thomas Nebl

    2011-09-01

    Full Text Available Apicomplexan parasites depend on the invasion of host cells for survival and proliferation. Calcium-dependent signaling pathways appear to be essential for micronemal release and gliding motility, yet the target of activated kinases remains largely unknown. We have characterized calcium-dependent phosphorylation events during Toxoplasma host cell invasion. Stimulation of live tachyzoites with Ca²⁺-mobilizing drugs leads to phosphorylation of numerous parasite proteins, as shown by differential 2-DE display of ³²[P]-labeled protein extracts. Multi-dimensional Protein Identification Technology (MudPIT identified ∼546 phosphorylation sites on over 300 Toxoplasma proteins, including 10 sites on the actomyosin invasion motor. Using a Stable Isotope of Amino Acids in Culture (SILAC-based quantitative LC-MS/MS analyses we monitored changes in the abundance and phosphorylation of the invasion motor complex and defined Ca²⁺-dependent phosphorylation patterns on three of its components--GAP45, MLC1 and MyoA. Furthermore, calcium-dependent phosphorylation of six residues across GAP45, MLC1 and MyoA is correlated with invasion motor activity. By analyzing proteins that appear to associate more strongly with the invasion motor upon calcium stimulation we have also identified a novel 15-kDa Calmodulin-like protein that likely represents the MyoA Essential Light Chain of the Toxoplasma invasion motor. This suggests that invasion motor activity could be regulated not only by phosphorylation but also by the direct binding of calcium ions to this new component.

  19. Breathing route dependence of upper airway muscle activity during hyperpnea.

    Science.gov (United States)

    Shi, Y X; Seto-Poon, M; Wheatley, J R

    1998-05-01

    Exercise (Ex) and hypercapnia (HC) both lead to increases in ventilation and upper airway muscle (UAM) activity. To determine whether different breathing routes (nasal vs. oral) or stimuli produced differential UAM activation, electromyographic (EMG) activity of the alae nasi (AN) and genioglossus (GG) were measured in seven normal subjects seated on a bicycle ergometer. Subjects performed paired runs during both progressive Ex and HC while breathing through the nose alone (N) or the mouth alone (O). During hyperpnea, AN EMG was greater when the subjects were breathing via N [81 +/- 6% maximum (HC) and 69 +/- 7% maximum (Ex)] than when they were breathing via O [30 +/- 5% maximum (HC) and 27 +/- 5% maximum (Ex); both P route. We conclude that UAM activation was independent of the nature of the stimulus. However, the AN muscle but not the GG muscle demonstrated breathing-route dependence of activity.

  20. Impact of high (131)I-activities on quantitative (124)I-PET

    DEFF Research Database (Denmark)

    Braad, P E N; Hansen, Søren B.; Høilund-Carlsen, P F

    2015-01-01

    relevant [Formula: see text]I/[Formula: see text]I-activities were performed on a clinical PET/CT-system. Noise equivalent count rate (NECR) curves and quantitation accuracy were determined from repeated scans performed over several weeks on a decaying NEMA NU-2 1994 cylinder phantom initially filled...... [Formula: see text]I-activities was good and image quantification unaffected except at very high count rates. Quantitation accuracy and contrast recovery were uninfluenced at [Formula: see text]I-activities below 1000 MBq, whereas image noise was slightly increased. The NECR peaked at 550 MBq of [Formula......: see text]I, where it was 2.8 times lower than without [Formula: see text]I in the phantom. Quantitative peri-therapeutic [Formula: see text]I-PET is feasible....

  1. 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

    the feasibility of using accelerometers to quantitatively and continuously measure physical activity simultaneously from all 4 extremities and the hip in patients with acute ischemic stroke and transient ischemic attack. Our study provides quantitative evidence of physical inactivity in patients with acute......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...... ischemic stroke or transient ischemic attack admitted to our acute stroke unit wore Actical accelerometers attached to both wrists and ankles and the hip for ≤7 days. Patients were included within 72 hours of symptom onset. Accelerometer output was measured in activity counts (AC). Patients were tested...

  2. Prediction of toxicity of phenols and anilines to algae by quantitative structure-activity relationship.

    Science.gov (United States)

    Lu, Guang-Hua; Wang, Chao; Guo, Xiao-Ling

    2008-06-01

    To measure the toxicity of phenol, aniline, and their derivatives to algae and to assess, model, and predict the toxicity using quantitative structure-activity relationship (QSAR) method. Oxygen production was used as the response endpoint for assessing the toxic effects of chemicals on algal photosynthesis. The energy of the lowest unoccupied molecular orbital (E(LUMO)) and the energy of the highest occupied molecular orbital (E(HOMO)) were obtained from the ChemOffice 2004 program using the quantum chemical method MOPAC, and the frontier orbital energy gap (deltaE) was obtained. The compounds exhibited a reasonably wide range of algal toxicity. The most toxic compound was alpha-naphthol, whereas the least toxic one was aniline. A two-descriptor model was derived from the algal toxicity and structural parameters: log1/EC50 = 0.268,logKow - 1.006deltaE + 11.769 (n = 20, r2 = 0.946). This model was stable and satisfactory for predicting toxicity. CONCLUSION Phenol, aniline, and their derivatives are polar narcotics. Their toxicity is greater than estimated by hydrophobicity only, and addition of the frontier orbital energy gap deltaE can significantly improve the prediction of logKow-dependent models.

  3. Synthesis, photodynamic activity, and quantitative structure-activity relationship modelling of a series of BODIPYs.

    Science.gov (United States)

    Caruso, Enrico; Gariboldi, Marzia; Sangion, Alessandro; Gramatica, Paola; Banfi, Stefano

    2017-02-01

    Here we report the synthesis of eleven new BODIPYs (14-24) characterized by the presence of an aromatic ring on the 8 (meso) position and of iodine atoms on the pyrrolic 2,6 positions. These molecules, together with twelve BODIPYs already reported by us (1-12), represent a large panel of BODIPYs showing different atoms or groups as substituent of the aromatic moiety. Two physico-chemical features ( 1 O 2 generation rate and lipophilicity), which can play a fundamental role in the outcome as photosensitizers, have been studied. The in vitro photo-induced cell-killing efficacy of 23 PSs was studied on the SKOV3 cell line treating the cells for 24h in the dark then irradiating for 2h with a green LED device (fluence 25.2J/cm 2 ). The cell-killing efficacy was assessed with the MTT test and compared with that one of meso un-substituted compound (13). In order to understand the possible effect of the substituents, a predictive quantitative structure-activity relationship (QSAR) regression model, based on theoretical holistic molecular descriptors, was developed. The results clearly indicate that the presence of an aromatic ring is fundamental for an excellent photodynamic response, whereas the electronic effects and the position of the substituents on the aromatic ring do not influence the photodynamic efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Antiproliferative Pt(IV) complexes: synthesis, biological activity, and quantitative structure-activity relationship modeling.

    Science.gov (United States)

    Gramatica, Paola; Papa, Ester; Luini, Mara; Monti, Elena; Gariboldi, Marzia B; Ravera, Mauro; Gabano, Elisabetta; Gaviglio, Luca; Osella, Domenico

    2010-09-01

    Several Pt(IV) complexes of the general formula [Pt(L)2(L')2(L'')2] [axial ligands L are Cl-, RCOO-, or OH-; equatorial ligands L' are two am(m)ine or one diamine; and equatorial ligands L'' are Cl- or glycolato] were rationally designed and synthesized in the attempt to develop a predictive quantitative structure-activity relationship (QSAR) model. Numerous theoretical molecular descriptors were used alongside physicochemical data (i.e., reduction peak potential, Ep, and partition coefficient, log Po/w) to obtain a validated QSAR between in vitro cytotoxicity (half maximal inhibitory concentrations, IC50, on A2780 ovarian and HCT116 colon carcinoma cell lines) and some features of Pt(IV) complexes. In the resulting best models, a lipophilic descriptor (log Po/w or the number of secondary sp3 carbon atoms) plus an electronic descriptor (Ep, the number of oxygen atoms, or the topological polar surface area expressed as the N,O polar contribution) is necessary for modeling, supporting the general finding that the biological behavior of Pt(IV) complexes can be rationalized on the basis of their cellular uptake, the Pt(IV)-->Pt(II) reduction, and the structure of the corresponding Pt(II) metabolites. Novel compounds were synthesized on the basis of their predicted cytotoxicity in the preliminary QSAR model, and were experimentally tested. A final QSAR model, based solely on theoretical molecular descriptors to ensure its general applicability, is proposed.

  5. Validation of quantitative structure-activity relationship (QSAR) model for photosensitizer activity prediction.

    Science.gov (United States)

    Frimayanti, Neni; Yam, Mun Li; Lee, Hong Boon; Othman, Rozana; Zain, Sharifuddin M; Rahman, Noorsaadah Abd

    2011-01-01

    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, r(2) value, r(2) (CV) value and r(2) 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 IC(50) values ranging from 0.39 μM to 7.04 μM. Thus the model showed good correlative and predictive ability, with a predictive correlation coefficient (r(2) 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.

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

    Science.gov (United States)

    Frimayanti, Neni; Yam, Mun Li; Lee, Hong Boon; Othman, Rozana; Zain, Sharifuddin M.; Rahman, Noorsaadah Abd.

    2011-01-01

    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. PMID:22272096

  7. 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.

  8. Magnetic field dependence of vortex activation energy: A ...

    Indian Academy of Sciences (India)

    Magnetic field dependence of vortex activation energy: A comparison between MgB2, NbSe2 and Bi2Sr2Ca2Cu3O10 superconductors. S D KAUSHIK1, V BRACCINI2 and S PATNAIK1,∗. 1School of Physical Sciences, Jawaharlal Nehru University, New Delhi 110 067, India. 2CNR-INFM LAMIA, C.so, Perrone 24, 16152, ...

  9. Activity Dependency and Aging in the Regulation of Adult Neurogenesis

    Science.gov (United States)

    Kempermann, Gerd

    2015-01-01

    Age and activity might be considered the two antagonistic key regulators of adult neurogenesis. Adult neurogenesis decreases with age but remains present, albeit at a very low level, even in the oldest individuals. Activity, be it physical or cognitive, increases adult neurogenesis and thereby seems to counteract age effects. It is, thus, proposed that activity-dependent regulation of adult neurogenesis might contribute to some sort of “neural reserve,” the brain’s ability to compensate functional loss associated with aging or neurodegeneration. Activity can have nonspecific and specific effects on adult neurogenesis. Mechanistically, nonspecific stimuli that largely affect precursor cell stages might be related by the local microenvironment, whereas more specific, survival-promoting effects take place at later stages of neuronal development and require the synaptic integration of the new cell and its particular synaptic plasticity. PMID:26525149

  10. 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.

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

    Science.gov (United States)

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

    2010-01-01

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

  12. Active Space Dependence in Multiconfiguration Pair-Density Functional Theory.

    Science.gov (United States)

    Sharma, Prachi; Truhlar, Donald G; Gagliardi, Laura

    2018-02-13

    In multiconfiguration pair-density functional theory (MC-PDFT), multiconfiguration self-consistent-field calculations and on-top density functionals are combined to describe both static and dynamic correlation. Here, we investigate how the MC-PDFT total energy and its components depend on the active space choice in the case of the H 2 and N 2 molecules. The active space dependence of the on-top pair density, the total density, the ratio of on-top pair density to half the square of the electron density, and the satisfaction of the virial theorem are also explored. We find that the density and on-top pair density do not change significantly with changes in the active space. However, the on-top ratio does change significantly with respect to active space change, and this affects the on-top energy. This study provides a foundation for designing on-top density functionals and automatizing the active space choice in MC-PDFT.

  13. Using Active Learning to Teach Concepts and Methods in Quantitative Biology.

    Science.gov (United States)

    Waldrop, Lindsay D; Adolph, Stephen C; Diniz Behn, Cecilia G; Braley, Emily; Drew, Joshua A; Full, Robert J; Gross, Louis J; Jungck, John A; Kohler, Brynja; Prairie, Jennifer C; Shtylla, Blerta; Miller, Laura A

    2015-11-01

    This article provides a summary of the ideas discussed at the 2015 Annual Meeting of the Society for Integrative and Comparative Biology society-wide symposium on Leading Students and Faculty to Quantitative Biology through Active Learning. It also includes a brief review of the recent advancements in incorporating active learning approaches into quantitative biology classrooms. We begin with an overview of recent literature that shows that active learning can improve students' outcomes in Science, Technology, Engineering and Math Education disciplines. We then discuss how this approach can be particularly useful when teaching topics in quantitative biology. Next, we describe some of the recent initiatives to develop hands-on activities in quantitative biology at both the graduate and the undergraduate levels. Throughout the article we provide resources for educators who wish to integrate active learning and technology into their classrooms. © 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.

  14. 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.

  15. A quantitative immunohistochemical study on the time-dependent course of acute inflammatory cellular response to human brain injury.

    Science.gov (United States)

    Hausmann, R; Kaiser, A; Lang, C; Bohnert, M; Betz, P

    1999-01-01

    The time-dependent inflammatory cell reaction in human cortical contusions has been investigated during the first 30 weeks after blunt head injury. Immunohistochemical staining was carried out using CD 15 for granulocytes and LCA, CD 3 and UCHL-1 for mononuclear leucocytes. In order to provide reliable data for a forensic wound age estimation, the intensity of the cellular reaction was evaluated with a quantitative image analysis system. CD 15-labelled granulocytes were detectable earliest 10 min after brain injury, whereas significantly increased numbers of mononuclear leucocytes occurred in cortical contusions after a postinfliction interval of at least 1.1 days (LCA), 2 days (CD 3) or 3.7 days (UCHL-1), respectively.

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

    Science.gov (United States)

    Breaker, Ronald R.; Joyce, Gerald F.

    1995-01-01

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

  17. 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

  18. 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

  19. 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...

  20. 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...

  1. Promises and pitfalls of Quantitative Structure-Activity Relationship approaches for predicting metabolism and toxicity

    NARCIS (Netherlands)

    Zvinavashe, E.; Murk, A.J.; Rietjens, I.M.C.M.

    2008-01-01

    The description of quantitative structure¿activity relationship (QSAR) models has been a topic for scientific research for more than 40 years and a topic within the regulatory framework for more than 20 years. At present, efforts on QSAR development are increasing because of their promise for

  2. Quantitation of the receptor for urokinase plasminogen activator by enzyme-linked immunosorbent assay

    DEFF Research Database (Denmark)

    Rønne, E; Behrendt, N; Ploug, M

    1994-01-01

    Binding of the urokinase plasminogen activator (uPA) to a specific cell surface receptor (uPAR) plays a crucial role in proteolysis during tissue remodelling and cancer invasion. An immunosorbent assay for the quantitation of uPAR has now been developed. This assay is based on two monoclonal anti...

  3. Nicotine activates TRPM5-dependent and independent taste pathways.

    Science.gov (United States)

    Oliveira-Maia, Albino J; Stapleton-Kotloski, Jennifer R; Lyall, Vijay; Phan, Tam-Hao T; Mummalaneni, Shobha; Melone, Pamela; Desimone, John A; Nicolelis, Miguel A L; Simon, Sidney A

    2009-02-03

    The orosensory responses elicited by nicotine are relevant for the development and maintenance of addiction to tobacco products. However, although nicotine is described as bitter tasting, the molecular and neural substrates encoding the taste of nicotine are unclear. Here, rats and mice were used to determine whether nicotine activates peripheral and central taste pathways via TRPM5-dependent mechanisms, which are essential for responses to other bitter tastants such as quinine, and/or via nicotinic acetylcholine receptors (nAChRs). When compared with wild-type mice, Trpm5(-/-) mice had reduced, but not abolished, chorda tympani (CT) responses to nicotine. In both genotypes, lingual application of mecamylamine, a nAChR-antagonist, inhibited CT nerve responses to nicotine and reduced behavioral responses of aversion to this stimulus. In accordance with these findings, rats were shown to discriminate between nicotine and quinine presented at intensity-paired concentrations. Moreover, rat gustatory cortex (GC) neural ensemble activity could also discriminate between these two bitter tastants. Mecamylamine reduced both behavioral and GC neural discrimination between nicotine and quinine. In summary, nicotine elicits taste responses through peripheral TRPM5-dependent pathways, common to other bitter tastants, and nAChR-dependent and TRPM5-independent pathways, thus creating a unique sensory representation that contributes to the sensory experience of tobacco products.

  4. Heparin cofactor II-dependent antithrombin activity of calcium spirulan.

    Science.gov (United States)

    Hayakawa, Y; Hayashi, T; Hayashi, K; Hayashi, T; Ozawa, T; Niiya, K; Sakuragawa, N

    1996-07-01

    Calcium spirulan (Ca-SP), a novel sulfated polysaccharide isolated from the blue-green alga Spirulina platensis, enhanced the antithrombin activity of heparin cofactor II (HC II) more than 10000-fold. The apparent second-order rate constant of thrombin inhibition by HC II was calculated to be 4.2 x 10(4) M-1 min-1 in the absence of Ca-SP, and it increased in the presence of 50 micrograms/ml Ca-SP to 4.5 x 10(8) M-1 min-1. Ca-SP effectively induced the formation of a thrombin-HC II complex in plasma. In the presence of Ca-SP, both the recombinant HC II variants Lys173-->Leu and Arg 189-->His, which are defective in interactions with heparin and dermatan sulfate, respectively, inhibited thrombin in a manner similar to native rHC II. This result indicates that the binding site of HC II for Ca-SP is different from the heparin- or dermatan sulfate-binding site. When we removed the calcium from the Ca-SP, the compound did not exert any antithrombin activity. Furthermore, Na-SP, which was prepared by replacement of the calcium in Ca-SP with sodium, accelerated the antithrombin activity of HC II as Ca-SP did. We therefore suggest that the molecular conformation maintained by Ca or Na is indispensable to the antithrombin activity of Ca-SP. The HC II-dependent antithrombin activity of Ca-SP was almost totally abolished by treatment with chondroitinase AC I, heparinase or heparitinase, but not by treatment with chondroitinase ABC and chondroitinase AC II, suggesting that a heparin- or dermatan sulfate-like structure is not responsible for the activation of HC II by Ca-SP. Ca-SP is therefore thought to be a unique sulfated polysaccharide which shows a strong antithrombin effect in an exclusively HC II-dependent manner.

  5. 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.

  6. Quantitative structure activity relationship of benzoxazinone derivatives as neuropeptide Y Y5 receptor antagonists.

    Science.gov (United States)

    Deswal, S; Roy, N

    2006-04-01

    Quantitative structure activity relationship (QSAR) has been established for 30 benzoxazinone derivatives acting as neuropeptide Y Y5 receptor antagonists. The genetic algorithm and multiple linear regression were used to generate the relationship between biological activity and calculated descriptors. Model with good statistical qualities was developed using four descriptors from topological, thermodynamic, spatial and electrotopological class. The validation of the model was done by cross validation, randomization and external test set prediction.

  7. Quantitative Laser Biospeckle Method for the Evaluation of the Activity of Trypanosoma cruzi Using VDRL Plates and Digital Analysis.

    Science.gov (United States)

    Grassi, Hilda Cristina; García, Lisbette C; Lobo-Sulbarán, María Lorena; Velásquez, Ana; Andrades-Grassi, Francisco A; Cabrera, Humberto; Andrades-Grassi, Jesús E; Andrades, Efrén D J

    2016-12-01

    In this paper we report a quantitative laser Biospeckle method using VDRL plates to monitor the activity of Trypanosoma cruzi and the calibration conditions including three image processing algorithms and three programs (ImageJ and two programs designed in this work). Benznidazole was used as a test drug. Variable volume (constant density) and variable density (constant volume) were used for the quantitative evaluation of parasite activity in calibrated wells of the VDRL plate. The desiccation process within the well was monitored as a function of volume and of the activity of the Biospeckle pattern of the parasites as well as the quantitative effect of the surface parasite quantity (proportion of the object's plane). A statistical analysis was performed with ANOVA, Tukey post hoc and Descriptive Statistics using R and R Commander. Conditions of volume (100μl) and parasite density (2-4x104 parasites/well, in exponential growth phase), assay time (up to 204min), frame number (11 frames), algorithm and program (RCommander/SAGA) for image processing were selected to test the effect of variable concentrations of benznidazole (0.0195 to 20μg/mL / 0.075 to 76.8μM) at various times (1, 61, 128 and 204min) on the activity of the Biospeckle pattern. The flat wells of the VDRL plate were found to be suitable for the quantitative calibration of the activity of Trypanosoma cruzi using the appropriate algorithm and program. Under these conditions, benznidazole produces at 1min an instantaneous effect on the activity of the Biospeckle pattern of T. cruzi, which remains with a similar profile up to 1 hour. A second effect which is dependent on concentrations above 1.25μg/mL and is statistically different from the effect at lower concentrations causes a decrease in the activity of the Biospeckle pattern. This effect is better detected after 1 hour of drug action. This behavior may be explained by an instantaneous effect on a membrane protein of Trypanosoma cruzi that could

  8. 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

  9. 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.

  10. 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.

  11. Quantitative Imaging Test Approval and Biomarker Qualification: Interrelated but Distinct Activities

    Science.gov (United States)

    Bresolin, Linda; Dunnick, N. Reed; Sullivan, Daniel C.

    2011-01-01

    Quantitative imaging biomarkers could speed the development of new treatments for unmet medical needs and improve routine clinical care. However, it is not clear how the various regulatory and nonregulatory (eg, reimbursement) processes (often referred to as pathways) relate, nor is it clear which data need to be collected to support these different pathways most efficiently, given the time- and cost-intensive nature of doing so. The purpose of this article is to describe current thinking regarding these pathways emerging from diverse stakeholders interested and active in the definition, validation, and qualification of quantitative imaging biomarkers and to propose processes to facilitate the development and use of quantitative imaging biomarkers. A flexible framework is described that may be adapted for each imaging application, providing mechanisms that can be used to develop, assess, and evaluate relevant biomarkers. From this framework, processes can be mapped that would be applicable to both imaging product development and to quantitative imaging biomarker development aimed at increasing the effectiveness and availability of quantitative imaging. © RSNA, 2011 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100800/-/DC1 PMID:21325035

  12. Novel peptide-specific quantitative structure-activity relationship (QSAR) analysis applied to collagen IV peptides with antiangiogenic activity.

    Science.gov (United States)

    Rivera, Corban G; Rosca, Elena V; Pandey, Niranjan B; Koskimaki, Jacob E; Bader, Joel S; Popel, Aleksander S

    2011-10-13

    Angiogenesis is the growth of new blood vessels from existing vasculature. Excessive vascularization is associated with a number of diseases including cancer. Antiangiogenic therapies have the potential to stunt cancer progression. Peptides derived from type IV collagen are potent inhibitors of angiogenesis. We wanted to gain a better understanding of collagen IV structure-activity relationships using a ligand-based approach. We developed novel peptide-specific QSAR models to study the activity of the peptides in endothelial cell proliferation, migration, and adhesion inhibition assays. We found that the models produced quantitatively accurate predictions of activity and provided insight into collagen IV derived peptide structure-activity relationships.

  13. 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.

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

    Science.gov (United States)

    Ganguly, Karunesh; Poo, Mu-Ming

    2013-10-30

    Much progress has been made in understanding how behavioral experience and neural activity can modify the structure and function of neural circuits during development and in the adult brain. Studies of physiological and molecular mechanisms underlying activity-dependent plasticity in animal models have suggested potential therapeutic approaches for a wide range of brain disorders in humans. Physiological and electrical stimulations as well as plasticity-modifying molecular agents may facilitate functional recovery by selectively enhancing existing neural circuits or promoting the formation of new functional circuits. Here, we review the advances in basic studies of neural plasticity mechanisms in developing and adult nervous systems and current clinical treatments that harness neural plasticity, and we offer perspectives on future development of plasticity-based therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. A Test of the Active-Day Fraction Method of Sunspot Group Number Calibration: Dependence on the Level of Solar Activity

    Science.gov (United States)

    Willamo, T.; Usoskin, I. G.; Kovaltsov, G. A.

    2018-04-01

    The method of active-day fraction (ADF) was proposed recently to calibrate different solar observers to standard observational conditions. The result of the calibration may depend on the overall level of solar activity during the observational period. This dependency is studied quantitatively using data of the Royal Greenwich Observatory by formally calibrating synthetic pseudo-observers to the full reference dataset. It is shown that the sunspot group number is precisely estimated by the ADF method for periods of moderate activity, may be slightly underestimated by 0.5 - 1.5 groups ({≤} 10%) for strong and very strong activity, and is strongly overestimated by up to 2.5 groups ({≤} 30%) for weak-to-moderate activity. The ADF method becomes inapplicable for the periods of grand minima of activity. In general, the ADF method tends to overestimate the overall level of activity and to reduce the long-term trends.

  16. Ketamine-dependent neuronal activation in healthy volunteers.

    Science.gov (United States)

    Höflich, Anna; Hahn, Andreas; Küblböck, Martin; Kranz, Georg S; Vanicek, Thomas; Ganger, Sebastian; Spies, Marie; Windischberger, Christian; Kasper, Siegfried; Winkler, Dietmar; Lanzenberger, Rupert

    2017-04-01

    Over the last years, a number of studies have been conducted to clarify the neurobiological correlates of ketamine application. However, comprehensive information regarding the influence of ketamine on cortical activity is still lacking. Using resting-state functional MRI and integrating pharmacokinetic information, a double-blind, randomized, placebo-controlled, crossover study was performed to determine the effects of ketamine on neuronal activation. During a 55 min resting-state fMRI scan, esketamine (Ketanest S ® ) was administered intravenously to 35 healthy volunteers. Neural activation as indicated by the BOLD signal using the pharmacokinetic curve of ketamine plasma levels as a regressor was computed. Compared with placebo, ketamine-dependent increases of neural activation were observed in the midcingulate cortex, the dorsal part of the anterior cingulate cortex, the insula bilaterally, and the thalamus (t values ranging between 5.95-9.78, p ketamine condition compared to placebo was found in a cluster within the subgenual/subcallosal part of the anterior cingulate cortex, the orbitofrontal cortex and the gyrus rectus (t = 7.81, p ketamine could be revealed.

  17. Effects of Ayahuasca and its Alkaloids on Drug Dependence: A Systematic Literature Review of Quantitative Studies in Animals and Humans.

    Science.gov (United States)

    Nunes, Amanda A; Dos Santos, Rafael G; Osório, Flávia L; Sanches, Rafael F; Crippa, José Alexandre S; Hallak, Jaime E C

    2016-01-01

    Recently, the anti-addictive potential of ayahuasca, a dimethyltryptamine(DMT)- and β-carboline-rich hallucinogenic beverage traditionally used by indigenous groups of the Northwest Amazon and currently by syncretic churches worldwide, has received increased attention. To better evaluate this topic, we performed a systematic literature review using the PubMed database to find quantitative studies (using statistical analysis) that assessed the effects of ayahuasca or its components in drug-related symptoms or disorders. We found five animal studies (using harmaline, harmine, or ayahuasca) and five observational studies of regular ayahuasca consumers. All animal studies showed improvement of biochemical or behavioral parameters related to drug-induced disorders. Of the five human studies, four reported significant reductions of dependence symptoms or substance use, while one did not report significant results. The mechanisms responsible for the anti-addictive properties of ayahuasca and its alkaloids are not clarified, apparently involving both peripheral MAO-A inhibition by the β-carbolines and central agonism of DMT at 5-HT2A receptors expressed in brain regions related to the regulation of mood and emotions. Although results are promising, controlled studies are needed to replicate these preliminary findings.

  18. Quantitative assessment on soil enzyme activities of heavy metal contaminated soils with various soil properties.

    Science.gov (United States)

    Xian, Yu; Wang, Meie; Chen, Weiping

    2015-11-01

    Soil enzyme activities are greatly influenced by soil properties and could be significant indicators of heavy metal toxicity in soil for bioavailability assessment. Two groups of experiments were conducted to determine the joint effects of heavy metals and soil properties on soil enzyme activities. Results showed that arylsulfatase was the most sensitive soil enzyme and could be used as an indicator to study the enzymatic toxicity of heavy metals under various soil properties. Soil organic matter (SOM) was the dominant factor affecting the activity of arylsulfatase in soil. A quantitative model was derived to predict the changes of arylsulfatase activity with SOM content. When the soil organic matter content was less than the critical point A (1.05% in our study), the arylsulfatase activity dropped rapidly. When the soil organic matter content was greater than the critical point A, the arylsulfatase activity gradually rose to higher levels showing that instead of harm the soil microbial activities were enhanced. The SOM content needs to be over the critical point B (2.42% in our study) to protect its microbial community from harm due to the severe Pb pollution (500mgkg(-1) in our study). The quantitative model revealed the pattern of variation of enzymatic toxicity due to heavy metals under various SOM contents. The applicability of the model under wider soil properties need to be tested. The model however may provide a methodological basis for ecological risk assessment of heavy metals in soil. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Predicting Flash Point of Organosilicon Compounds Using Quantitative Structure Activity Relationship Approach

    OpenAIRE

    Chen-Peng Chen; Chan-Cheng Chen; Hsu-Fang Chen

    2014-01-01

    The flash point (FP) of a compound is the primary property used in the assessment of fire hazards for flammable liquids and is amongst the crucial information that people handling flammable liquids must possess as far as industrial safety is concerned. In this work, the FPs of 236 organosilicon compounds were collected and used to construct a quantitative structure activity relationship (QSAR) model for predicting their FPs. The CODESSA PRO software was adopted to calculate the required molec...

  20. Quantitative structure–activity relationships (QSARs) for the transformation of organic micropollutants during oxidative water treatment

    OpenAIRE

    Lee, Yunho; Von Gunten, Urs

    2012-01-01

    Various oxidants such as chlorine, chlorine dioxide, ferrateVI, ozone, and hydroxyl radicals can be applied for eliminating organic micropollutant by oxidative transformation during water treatment in systems such as drinking water, wastewater, and water reuse. Over the last decades, many second-order rate constants (k) have been determined for the reaction of these oxidants with model compounds and micropollutants. Good correlations (quantitative structure–activity relationships or QSARs) ar...

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

    Science.gov (United States)

    Januszek, Kazimierz; Długa, Joanna; Socha, Jarosław

    2015-01-01

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

  2. Network activity of mirror neurons depends on experience.

    Science.gov (United States)

    Ushakov, Vadim L; Kartashov, Sergey I; Zavyalova, Victoria V; Bezverhiy, Denis D; Posichanyuk, Vladimir I; Terentev, Vasliliy N; Anokhin, Konstantin V

    2013-03-01

    In this work, the investigation of network activity of mirror neurons systems in animal brains depending on experience (existence or absence performance of the shown actions) was carried out. It carried out the research of mirror neurons network in the C57/BL6 line mice in the supervision task of swimming mice-demonstrators in Morris water maze. It showed the presence of mirror neurons systems in the motor cortex M1, M2, cingular cortex, hippocampus in mice groups, having experience of the swimming and without it. The conclusion is drawn about the possibility of the new functional network systems formation by means of mirror neurons systems and the acquisition of new knowledge through supervision by the animals in non-specific tasks.

  3. Design, synthesis and exploring the quantitative structure-activity relationship of some antioxidant flavonoid analogues.

    Science.gov (United States)

    Das, Sreeparna; Mitra, Indrani; Batuta, Shaikh; Niharul Alam, Md; Roy, Kunal; Begum, Naznin Ara

    2014-11-01

    A series of flavonoid analogues were synthesized and screened for the in vitro antioxidant activity through their ability to quench 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical. The activity of these compounds, measured in comparison to the well-known standard antioxidants (29-32), their precursors (38-42) and other bioactive moieties (38-42) resembling partially the flavone skeleton was analyzed further to develop Quantitative Structure-Activity Relationship (QSAR) models using the Genetic Function Approximation (GFA) technique. Based on the essential structural requirements predicted by the QSAR models, some analogues were designed, synthesized and tested for activity. The predicted and experimental activities of these compounds were well correlated. Flavone analogue 20 was found to be the most potent antioxidant. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. 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.

  5. Determinants of activity at human Toll-like receptors 7 and 8: quantitative structure-activity relationship (QSAR) of diverse heterocyclic scaffolds.

    Science.gov (United States)

    Yoo, Euna; Salunke, Deepak B; Sil, Diptesh; Guo, Xiaoqiang; Salyer, Alex C D; Hermanson, Alec R; Kumar, Manoj; Malladi, Subbalakshmi S; Balakrishna, Rajalakshmi; Thompson, Ward H; Tanji, Hiromi; Ohto, Umeharu; Shimizu, Toshiyuki; David, Sunil A

    2014-10-09

    Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-à-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing "heuristics" to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity.

  6. 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.

  7. THE TEMPERATURE DEPENDENCE OF SOLAR ACTIVE REGION OUTFLOWS

    International Nuclear Information System (INIS)

    Warren, Harry P.; Ugarte-Urra, Ignacio; Young, Peter R.; Stenborg, Guillermo

    2011-01-01

    Spectroscopic observations with the EUV Imaging Spectrometer (EIS) on Hinode have revealed large areas of high-speed outflows at the periphery of many solar active regions. These outflows are of interest because they may connect to the heliosphere and contribute to the solar wind. In this paper, we use slit rasters from EIS in combination with narrowband slot imaging to study the temperature dependence and morphology of an outflow region and show that it is more complicated than previously thought. Outflows are observed primarily in emission lines from Fe XI to Fe XV. Observations at lower temperatures (Si VII), in contrast, show bright fan-like structures that are dominated by inflows. These data also indicate that the morphology of the outflows and the fans is different, outflows are observed in regions where there is no emission in Si VII. This suggests that the fans, which are often associated with outflows in studies involving imaging data, are not directly related to the active region outflows.

  8. Transcription-dependent association of HDAC2 with active chromatin.

    Science.gov (United States)

    Jahan, Sanzida; Sun, Jian-Min; He, Shihua; Davie, James R

    2018-02-01

    Histone deacetylase 2 (HDAC2) catalyzes deacetylation of histones at the promoter and coding regions of transcribed genes and regulates chromatin structure and transcription. To explore the role of HDAC2 and phosphorylated HDAC2 in gene regulation, we studied the location along transcribed genes, the mode of recruitment and the associated proteins with HDAC2 and HDAC2S394ph in chicken polychromatic erythrocytes. We show that HDAC2 and HDAC2S394ph are associated with transcriptionally active chromatin and located in the interchromatin channels. HDAC2S394ph was present primarly at the upstream promoter region of the transcribed CA2 and GAS41 genes, while total HDAC2 was also found within the coding region of the CA2 gene. Recruitment of HDAC2 to these genes was partially dependent upon on-going transcription. Unmodified HDAC2 was associated with RNA binding proteins and interacted with RNA bound to the initiating and elongating forms of RNA polymerase II. HDAC2S394ph was not associated with RNA polymerase II. These results highlight the differential properties of unmodified and phosphorylated HDAC2 and the organization of acetylated transcriptionally active chromatin in the chicken polychromatic erythrocyte. © 2017 Wiley Periodicals, Inc.

  9. Motor-Skill Learning Is Dependent on Astrocytic Activity

    Directory of Open Access Journals (Sweden)

    Ragunathan Padmashri

    2015-01-01

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

  10. Motor-Skill Learning Is Dependent on Astrocytic Activity.

    Science.gov (United States)

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

    2015-01-01

    Motor-skill learning induces changes in synaptic structure and function in the primary motor cortex through the involvement of a long-term potentiation- (LTP-) like mechanism. Although there is evidence that calcium-dependent release of gliotransmitters by astrocytes plays an important role in synaptic transmission and plasticity, the role of astrocytes in motor-skill learning is not known. To test the hypothesis that astrocytic activity is necessary for motor-skill learning, we perturbed astrocytic function using pharmacological and genetic approaches. We find that perturbation of astrocytes either by selectively attenuating IP3R2 mediated astrocyte Ca(2+) signaling or using an astrocyte specific metabolic inhibitor fluorocitrate (FC) results in impaired motor-skill learning of a forelimb reaching-task in mice. Moreover, the learning impairment caused by blocking astrocytic activity using FC was rescued by administration of the gliotransmitter D-serine. The learning impairments are likely caused by impaired LTP as FC blocked LTP in slices and prevented motor-skill training-induced increases in synaptic AMPA-type glutamate receptor in vivo. These results support the conclusion that normal astrocytic Ca(2+) signaling during a reaching task is necessary for motor-skill learning.

  11. 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.

  12. Group Active Engagements Using Quantitative Modeling of Physiology Concepts in Large-Enrollment Biology Classes

    Directory of Open Access Journals (Sweden)

    Karen L. Carleton

    2016-12-01

    Full Text Available Organismal Biology is the third introductory biology course taught at the University of Maryland. Students learn about the geometric, physical, chemical, and thermodynamic constraints that are common to all life, and their implications for the evolution of multicellular organisms based on a common genetic “toolbox.”  An additional goal is helping students to improve their scientific logic and comfort with quantitative modeling.  We recently developed group active engagement exercises (GAEs for this Organismal Biology class.  Currently, our class is built around twelve GAE activities implemented in an auditorium lecture hall in a large enrollment class.  The GAEs examine scientific concepts using a variety of models including physical models, qualitative models, and Excel-based quantitative models. Three quantitative GAEs give students an opportunity to build their understanding of key physiological ideas. 1 The Escape from Planet Ranvier exercise reinforces student understanding that membrane permeability means that ions move through open channels in the membrane.  2 The Stressing and Straining exercise requires students to quantify the elastic modulus from data gathered either in class or from scientific literature. 3 In Leveraging Your Options exercise, students learn about lever systems and apply this knowledge to biological systems.

  13. In Vivo Quantitative Measurement of Arthritis Activity Based on Hydrophobically Modified Glycol Chitosan in Inflammatory Arthritis: More Active than Passive Accumulation

    Directory of Open Access Journals (Sweden)

    Kyeong Soon Park

    2012-09-01

    Full Text Available We demonstrated that arthritis could be visualized noninvasively using hydrophobically modified glycol chitosan nanoparticles labeled with Cy5.5 (HGC-Cy5.5 and an optical imaging system. Activated macrophages expressing Mac-1 molecules effectively phagocytosed HGC-Cy5.5, which formed spherical nanoparticles under physiologic conditions. We estimated the applicability of HGC-Cy5.5 to quantitative analysis of arthritis development and progression. Near-infrared fluorescence images, captured after HGC-Cy5.5 injection in mice with collagen-induced arthritis, showed stronger fluorescence intensity in the active arthritis group than in the nonarthritis group. According to the progression of arthritis in both collagen-induced arthritis and collagen antibody-induced arthritis models, total photon counts (TPCs increased in parallel with the clinical arthritis index. Quantitative analysis of fluorescence after treatment with methotrexate showed a significant decrease in TPC in a dose-dependent manner. Histologic evaluation confirmed that the mechanism underlying selective accumulation of HGC-Cy5.5 within synovitis tissues included enhanced phagocytosis of the probe by Mac-1-expressing macrophages as well as enhanced permeability through leaky vessels. These results suggest that optical imaging of arthritis using HGC-Cy5.5 can provide an objective measurement of disease activity and, at the same time, therapeutic responses in rheumatoid arthritis.

  14. The mass dependence of chromospheric activity evolution & implications for gyrochronology

    Science.gov (United States)

    Curtis, Jason

    2018-01-01

    We know chromospheric emission decays over time, and yet this empirical relation is still fundamentally an interpolation over 3.5 Gyr from the Hyades to the Sun despite 45 years of progress. Furthermore, its very existence was called into question by Pace et al. (2004, 2009, 2013), who argued that activity plummets and flatlines around 1-2 Gyr. I will present new Ca II H & K data for NGC 752 (1.5 Gyr) and Ruprecht 147 (3 Gyr), and ISM-corrected data for M67 (4 Gyr, Curtis 2017), and pair this with the Sun's re-calibrated history (Egeland et al. 2017) and data on field stars from the Keck exoplanet program. I calculated ages for the field star sample using the [Y/Mg] "chemical clock," which was discovered from studies of solar twins and is due to galactic chemical enrichment. I find a mass dependence that matches the prediction from the activity-rotation-age relation of Mamajek & Hillenbrand (2008), where F stars rapidly plummet at 1-2 Gyr in line with the observations of F stars in clusters of similar age by Pace et al., whereas activity continuously declines for G and K dwarfs to approximately 5 and 7 Gyr, respectively. I will show that comparing ages estimated from [Y/Mg] to activity--rotation ages reveals known hot Jupiter hosts and other potentially anomalous stars. Combining the empirical relation between activity and Rossby number with estimates of stellar mass from spectroscopy and age from [Y/Mg] yields a gyrochronology relationship for FG and early K dwarfs that is independent of the cluster age scale and appears consistent with models from Mamajek & Hillenbrand (2008) and Barnes (2010). However, I have separately measured rotation periods for mid to late K dwarfs in 3 Gyr Ruprecht 147 with K2 and I find that they are rotating too rapidly relative to these empirical models and the semi-physical model of Matt et al. (2015). Apparently, K dwarfs spin down more slowly than the Skumanich square-root Law. Determining the K dwarf spin-down law is critical for

  15. Quantitative analysis of temperature dependent acoustic trapping characteristics by using concentric annular type dual element ultrasonic transducer.

    Science.gov (United States)

    Chung, In-Young; Lee, Jungwoo

    2015-02-01

    This paper presents the temperature dependence of lateral acoustic trapping capability by probing the speed of sound in individual lipid droplets at a given temperature of water and measuring its corresponding displacement, a value for quantitatively evaluating a spring-like behavior of the acoustic trap with certain strength. A 20/40 MHz dual element LiNbO3 ultrasonic transducer is fabricated to simultaneously perform both transverse trapping and sound speed measurement for each droplet over a discrete temperature range from 20°C to 30°C. Time of flight method is employed for pulse tracking that determines the arrival time of an echo reflected back from either a trapped droplet or a mylar film. The estimated speeds of sound in water and droplets are 1484.8 m/s and 1431.6 m/s at 20°C, while 1506.0 m/s and 1400.6 m/s at 30°C, respectively. As the temperature rises, the sound speed in droplets decreases at an average rate of 3.1 m/s/°C, and the speed in water increases at 2.1 m/s/°C. The average displacement varies from 150.0 μm to 179.0 μm with an increasing rate of 2.9 μm/°C, and its standard deviation is obtained between 1.0 μm and 2.0 μm over the same temperature range. Reduced sound speed as a function of rising temperature results in increased displacement, indicating that the trapping strength is adjustable by regulating ambient temperature in water as well as by changing transducer excitation parameters. Therefore, the results suggest that the temperature dependence of this trapping technique can be exploited for developing a remote manipulation tool of micron-sized particles in a thermally fluctuating environment. It is also shown that any deviated trapping strength caused by thermal disturbance near the trap can be restored to its desired level by compensating either temperature difference or trapping system condition. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. NOVEL DESIGN OF CALANONE DERIVATIVES AS ANTI-LEUKEMIA COMPOUNDS BASED ON QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS

    Directory of Open Access Journals (Sweden)

    Ponco Iswanto

    2011-07-01

    Full Text Available Leukemia drug discovery based on calanone compound was conducted in previous research and produced 6 calanone derivatives. Most of them have lower activities against leukemia cell L1210 than pure calanone. A Quantitative Structure-Activity Relationship (QSAR analysis is conducted in this work to find more active calanone derivatives. Six compounds were used as the material of the research because they already have anti-leukemia activity data expressed in Inhibitory Concentration of Fifty Percent Cell Lethal (IC50, in mg/mL. Calculation of predictors was performed by AM1 semiempirical method. QSAR equation is determined using Principle Component Regression (PCR analysis, with Log IC50 as dependent variable. Independent variables (predictors are atomic net charges, dipole moment (m, and coefficient partition of n-octanol/water (Log P. This work recommends 3 novel designs of calanone derivatives that may have higher activities (in mg/mL than those already available, i.e. gemdiol calanone (57.78, 2,4-dinitrophenylhydrazone calanone (30.94 and 2,4,6-trinitrophenylhydrazone calanone (18.96.

  17. Quantitative proteomic analysis reveals that transmissible gastroenteritis virus activates the JAK-STAT1 signaling pathway.

    Science.gov (United States)

    An, Kang; Fang, Liurong; Luo, Rui; Wang, Dang; Xie, Lilan; Yang, Jing; Chen, Huanchun; Xiao, Shaobo

    2014-12-05

    Transmissible gastroenteritis virus (TGEV), a porcine enteropathogenic coronavirus, causes lethal watery diarrhea and severe dehydration in piglets. In this study, liquid chromatography-tandem mass spectrometry coupled to isobaric tags for relative and absolute quantification labeling was used to quantitatively identify differentially expressed cellular proteins after TGEV infection in PK-15 cells. In total, 162 differentially expressed cellular proteins were identified, including 60 upregulated proteins and 102 downregulated proteins. These differentially expressed proteins were involved in the cell cycle, cellular growth and proliferation, the innate immune response, etc. Interestingly, many upregulated proteins were associated with interferon signaling, especially signal transducer and activator of transcription 1 (STAT1) and interferon-stimulated genes (ISGs). Immunoblotting and real-time quantitative reverse transcription polymerase chain reaction demonstrated that TGEV infection induces STAT1 phosphorylation and nuclear translocation, as well as ISG expression. This study for the first time reveals that TGEV induces interferon signaling from the point of proteomic analysis.

  18. Modeling the nucleophilic reactivity of small organochlorine electrophiles: A mechanistically based quantitative structure-activity relationship

    Energy Technology Data Exchange (ETDEWEB)

    Verhaar, H.J.M.; Seinen, W.; Hermens, J.L.M. [Utrecht Univ. (Netherlands); Rorije, E. [Dutch Inst. of Public Health and Environmental Protection, Bilthoven (Netherlands); Borkent, H. [Univ. of Nijmegen (Netherlands)

    1996-06-01

    Environmental pollutants can be divided into four broad categories, narcosis-type chemicals, less inert (polar narcosis) chemicals, reactive chemicals, and specifically acting chemicals. For narcosis-type, or baseline, chemicals and for less inert chemicals, adequate quantitative structure-activity relationships (QSARs) are available for estimation of toxicity to aquatic species. This is not the case for reactive chemicals and specifically acting chemicals. A possible approach to develop aquatic toxicity QSARs for reactive chemicals based on simple considerations regarding their reactivity is given. It is shown that quantum chemical calculations on reaction transition states can be used to quantitatively predict the reactivity of sets of reactive chemicals. These predictions can then be used to develop aquatic toxicity QSARs.

  19. 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

  20. 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

  1. 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.

  2. Synthesis, evaluation and quantitative structure-activity relationship (QSAR) analysis of Wogonin derivatives as cytotoxic agents.

    Science.gov (United States)

    Bian, Jinlei; Li, Tinghan; Weng, Tianwei; Wang, Jubo; Chen, Yu; Li, Zhiyu

    2017-02-15

    A novel series of 49 wogonin derivatives were synthesized by introducing group at 7-, 8- or B ring of wogonin. The cytotoxic activities against HepG2, A549 and BCG-823 cancer cell lines were also investigated in vitro. Several of them showed obvious cytotoxic activities and compound 3h possessed the highest potency against HepG2, A549, and BCG-823 with IC 50 values of 1.07μM, 1.74μM and 0.98μM, respectively. A quantitative structure-activity relationship (QSAR) study of these synthetic derivatives as well as wogonin indicated that high solubility and low octanol/water partition coefficient are favorable, and excessive electrostatic properties and refractivity are unfavorable for the cytotoxic activities of these wogonin derivatives. These findings and results provide a base for further investigations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Quantitative structure activity relationship (QSAR) studies on nitazoxanide-based analogues against Clostridium difficile In vitro.

    Science.gov (United States)

    Zhang, Han; Liu, Xiwang; Yang, Yajun; Li, Jianyong

    2016-09-01

    Quantitative structure activity relationship (QSAR) has been established between the various physiochemical parameters of a series of nitazoxanide-based analogues and its antibacterial activity against Clostridium difficile. Genetic function approximation (GFA) and comparative molecular field analysis (CoMFA) techniques were used to identify the descriptors that have influence on biological activity. The most influencing molecular descriptors identified in 2D-QSAR include spatial, topological, and electronic descriptors, while electrostatic and stereoscopic fields were the most influencing molecular descriptors identified in 3D-QSAR. Statistical qualities (r2, q2) indicated the significance and predictability of the developed models. The study indicated that antibacterial activity of Clostridium difficile can be improved by increasing molecular connectivity index, local charge surface index, sharp index and decreasing molecular flexibility index.

  4. Biochemical quantitation of the eIF5A hypusination in Arabidopsis thaliana uncovers ABA-dependent regulation

    Science.gov (United States)

    Belda-Palazón, Borja; Nohales, María A.; Rambla, José L.; Aceña, José L.; Delgado, Oscar; Fustero, Santos; Martínez, M. Carmen; Granell, Antonio; Carbonell, Juan; Ferrando, Alejandro

    2014-01-01

    The eukaryotic translation elongation factor eIF5A is the only protein known to contain the unusual amino acid hypusine which is essential for its biological activity. This post-translational modification is achieved by the sequential action of the enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). The crucial molecular function of eIF5A during translation has been recently elucidated in yeast and it is expected to be fully conserved in every eukaryotic cell, however the functional description of this pathway in plants is still sparse. The genetic approaches with transgenic plants for either eIF5A overexpression or antisense have revealed some activities related to the control of cell death processes but the molecular details remain to be characterized. One important aspect of fully understanding this pathway is the biochemical description of the hypusine modification system. Here we have used recombinant eIF5A proteins either modified by hypusination or non-modified to establish a bi-dimensional electrophoresis (2D-E) profile for the three eIF5A protein isoforms and their hypusinated or unmodified proteoforms present in Arabidopsis thaliana. The combined use of the recombinant 2D-E profile together with 2D-E/western blot analysis from whole plant extracts has provided a quantitative approach to measure the hypusination status of eIF5A. We have used this information to demonstrate that treatment with the hormone abscisic acid produces an alteration of the hypusine modification system in Arabidopsis thaliana. Overall this study presents the first biochemical description of the post-translational modification of eIF5A by hypusination which will be functionally relevant for future studies related to the characterization of this pathway in Arabidopsis thaliana. PMID:24904603

  5. An integrated strategy for the quantitative analysis of endogenous proteins: A case of gender-dependent expression of P450 enzymes in rat liver microsome.

    Science.gov (United States)

    Shao, Yuhao; Yin, Xiaoxi; Kang, Dian; Shen, Boyu; Zhu, Zhangpei; Li, Xinuo; Li, Haofeng; Xie, Lin; Wang, Guangji; Liang, Yan

    2017-08-01

    Liquid chromatography mass spectrometry based methods provide powerful tools for protein analysis. Cytochromes P450 (CYPs), the most important drug metabolic enzymes, always exhibit sex-dependent expression patterns and metabolic activities. To date, analysis of CYPs based on mass spectrometry is still facing critical technical challenges due to the complexity and diversity of CYP isoforms besides lack of corresponding standards. The aim of present work consisted in developing a label-free qualitative and quantitative strategy for endogenous proteins, and then applying to the gender-difference study for CYPs in rat liver microsomes (RLMs). Initially, trypsin digested RLM specimens were analyzed by the nanoLC-LTQ-Orbitrap MS/MS. Skyline, an open source and freely available software for targeted proteomics research, was then used to screen the main CYP isoforms in RLMs under a series of criteria automatically, and a total of 40 and 39 CYP isoforms were identified in male and female RLMs, respectively. More importantly, a robust quantitative method in a tandem mass spectrometry-multiple reaction mode (MS/MS-MRM) was built and optimized under the help of Skyline, and successfully applied into the CYP gender difference study in RLMs. In this process, a simple and accurate approach named 'Standard Curve Slope" (SCS) was established based on the difference of standard curve slopes of CYPs between female and male RLMs in order to assess the gender difference of CYPs in RLMs. This presently developed methodology and approach could be widely used in the protein regulation study during drug pharmacological mechanism research. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Stage-dependent ethoxyresorufin-O-deethylase (EROD) in vivo activity in medaka (Oryzias latipes) embryos.

    Science.gov (United States)

    González-Doncel, Miguel; Carbonell, Gregoria; San Segundo, Laura; Sastre, Salvador; Beltrán, Eulalia M; Fernández-Torija, Carlos

    2015-09-01

    Using medaka (Oryzias latipes) embryos, this study aimed to quantitatively characterize the stage-dependent in vivo ethoxyresorufin-O-deethylase (EROD) as indicator of cytochrome P4501A (CYP1A) activity. Embryos were challenged for 24-h to an agonist (β-naphthoflavone [BNF], 2.5, 5, 10, and 20 μg L(-1)) or to its combination (2.5 μg L(-1)) with an antagonist (α-naphthoflavone [ANF], 25, 50, 100, and 200 μg L(-1)), initiated at four different developmental time points (1, 3, 6, and 9 d post-fertilization [dpf]). Respective induction and competitive inhibition were evaluated over fluorescent images of whole embryo (nonorgan-specific [NOS] EROD activity) and gallbladder (organ-specific [OS] EROD activity). Both flavonoids showed signs of stability in solution. Generally speaking, the mean fluorescence intensity (MFI) values for NOS EROD increased with BNF concentration and exposure challenge. BNF co-exposure with ⩾50 μg ANF L(-1) during the 1-2 and 3-4 dpf challenges lowered NOS EROD to undetectably induced levels. Significant increments in MFIs for OS-EROD were seen from exposures to ⩾2.5 μg BNF L(-1), peaking during the 6-7 dpf challenge regardless of BNF concentration. The simultaneous BNF/ANF incubation showed competitive inhibition for OS EROD activity, although levels were generally detectably induced during all challenges and at all ANF concentrations. The morphometric in vivo gallbladder analysis indicated significant dilation in the 10 dpf-old embryos co-exposed to BNF and 200 μg ANF L(-1). This quantitative approach can be used successfully at 4 dpf at the NOS-EROD or OS-EROD levels, although the NOS-EROD response was sensitive enough to induction or inhibition, even at 2 dpf. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. 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...

  8. Hepatitis C virus translation preferentially depends on active RNA replication.

    Directory of Open Access Journals (Sweden)

    Helene Minyi Liu

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

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

    Science.gov (United States)

    Mansfield, Theodore J; MacDonald Gibson, Jacqueline

    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.

  10. Role of ongoing, intrinsic activity of neuronal populations for quantitative neuroimaging of functional magnetic resonance imaging-based networks.

    Science.gov (United States)

    Hyder, Fahmeed; Herman, Peter; Sanganahalli, Basavaraju G; Coman, Daniel; Blumenfeld, Hal; Rothman, Douglas L

    2011-01-01

    A primary objective in neuroscience is to determine how neuronal populations process information within networks. In humans and animal models, functional magnetic resonance imaging (fMRI) is gaining increasing popularity for network mapping. Although neuroimaging with fMRI-conducted with or without tasks-is actively discovering new brain networks, current fMRI data analysis schemes disregard the importance of the total neuronal activity in a region. In task fMRI experiments, the baseline is differenced away to disclose areas of small evoked changes in the blood oxygenation level-dependent (BOLD) signal. In resting-state fMRI experiments, the spotlight is on regions revealed by correlations of tiny fluctuations in the baseline (or spontaneous) BOLD signal. Interpretation of fMRI-based networks is obscured further, because the BOLD signal indirectly reflects neuronal activity, and difference/correlation maps are thresholded. Since the small changes of BOLD signal typically observed in cognitive fMRI experiments represent a minimal fraction of the total energy/activity in a given area, the relevance of fMRI-based networks is uncertain, because the majority of neuronal energy/activity is ignored. Thus, another alternative for quantitative neuroimaging of fMRI-based networks is a perspective in which the activity of a neuronal population is accounted for by the demanded oxidative energy (CMR(O2)). In this article, we argue that network mapping can be improved by including neuronal energy/activity of both the information about baseline and small differences/fluctuations of BOLD signal. Thus, total energy/activity information can be obtained through use of calibrated fMRI to quantify differences of ΔCMR(O2) and through resting-state positron emission tomography/magnetic resonance spectroscopy measurements for average CMR(O2).

  11. Role of Ongoing, Intrinsic Activity of Neuronal Populations for Quantitative Neuroimaging of Functional Magnetic Resonance Imaging–Based Networks

    Science.gov (United States)

    Herman, Peter; Sanganahalli, Basavaraju G.; Coman, Daniel; Blumenfeld, Hal; Rothman, Douglas L.

    2011-01-01

    Abstract A primary objective in neuroscience is to determine how neuronal populations process information within networks. In humans and animal models, functional magnetic resonance imaging (fMRI) is gaining increasing popularity for network mapping. Although neuroimaging with fMRI—conducted with or without tasks—is actively discovering new brain networks, current fMRI data analysis schemes disregard the importance of the total neuronal activity in a region. In task fMRI experiments, the baseline is differenced away to disclose areas of small evoked changes in the blood oxygenation level-dependent (BOLD) signal. In resting-state fMRI experiments, the spotlight is on regions revealed by correlations of tiny fluctuations in the baseline (or spontaneous) BOLD signal. Interpretation of fMRI-based networks is obscured further, because the BOLD signal indirectly reflects neuronal activity, and difference/correlation maps are thresholded. Since the small changes of BOLD signal typically observed in cognitive fMRI experiments represent a minimal fraction of the total energy/activity in a given area, the relevance of fMRI-based networks is uncertain, because the majority of neuronal energy/activity is ignored. Thus, another alternative for quantitative neuroimaging of fMRI-based networks is a perspective in which the activity of a neuronal population is accounted for by the demanded oxidative energy (CMRO2). In this article, we argue that network mapping can be improved by including neuronal energy/activity of both the information about baseline and small differences/fluctuations of BOLD signal. Thus, total energy/activity information can be obtained through use of calibrated fMRI to quantify differences of ΔCMRO2 and through resting-state positron emission tomography/magnetic resonance spectroscopy measurements for average CMRO2. PMID:22433047

  12. 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.

  13. Interpretation of Quantitative Structure-Activity Relationship Models: Past, Present, and Future.

    Science.gov (United States)

    Polishchuk, Pavel

    2017-11-27

    This paper is an overview of the most significant and impactful interpretation approaches of quantitative structure-activity relationship (QSAR) models, their development, and application. The evolution of the interpretation paradigm from "model → descriptors → (structure)" to "model → structure" is indicated. The latter makes all models interpretable regardless of machine learning methods or descriptors used for modeling. This opens wide prospects for application of corresponding interpretation approaches to retrieve structure-property relationships captured by any models. Issues of separate approaches are discussed as well as general issues and prospects of QSAR model interpretation.

  14. Curating and Preparing High-Throughput Screening Data for Quantitative Structure-Activity Relationship Modeling.

    Science.gov (United States)

    Kim, Marlene T; Wang, Wenyi; Sedykh, Alexander; Zhu, Hao

    2016-01-01

    Publicly available bioassay data often contains errors. Curating massive bioassay data, especially high-throughput screening (HTS) data, for Quantitative Structure-Activity Relationship (QSAR) modeling requires the assistance of automated data curation tools. Using automated data curation tools are beneficial to users, especially ones without prior computer skills, because many platforms have been developed and optimized based on standardized requirements. As a result, the users do not need to extensively configure the curation tool prior to the application procedure. In this chapter, a freely available automatic tool to curate and prepare HTS data for QSAR modeling purposes will be described.

  15. Daphnia and fish toxicity of (benzo)triazoles: validated QSAR models, and interspecies quantitative activity-activity modelling.

    Science.gov (United States)

    Cassani, Stefano; Kovarich, Simona; Papa, Ester; Roy, Partha Pratim; van der Wal, Leon; Gramatica, Paola

    2013-08-15

    Due to their chemical properties synthetic triazoles and benzo-triazoles ((B)TAZs) are mainly distributed to the water compartments in the environment, and because of their wide use the potential effects on aquatic organisms are cause of concern. Non testing approaches like those based on quantitative structure-activity relationships (QSARs) are valuable tools to maximize the information contained in existing experimental data and predict missing information while minimizing animal testing. In the present study, externally validated QSAR models for the prediction of acute (B)TAZs toxicity in Daphnia magna and Oncorhynchus mykiss have been developed according to the principles for the validation of QSARs and their acceptability for regulatory purposes, proposed by the Organization for Economic Co-operation and Development (OECD). These models are based on theoretical molecular descriptors, and are statistically robust, externally predictive and characterized by a verifiable structural applicability domain. They have been applied to predict acute toxicity for over 300 (B)TAZs without experimental data, many of which are in the pre-registration list of the REACH regulation. Additionally, a model based on quantitative activity-activity relationships (QAAR) has been developed, which allows for interspecies extrapolation from daphnids to fish. The importance of QSAR/QAAR, especially when dealing with specific chemical classes like (B)TAZs, for screening and prioritization of pollutants under REACH, has been highlighted. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Quantitative MR imaging of intra-orbital structures: Tissue-specific measurements and age dependency compared to extra-orbital structures using multispectral quantitative MR imaging.

    Science.gov (United States)

    Watanabe, Memi; Buch, Karen; Fujita, Akifumi; Jara, Hernán; Qureshi, Muhammad Mustafa; Sakai, Osamu

    2017-08-01

    The orbit can be affected by unique pathologic conditions and often requires MRI evaluation. The purpose of this study was to investigate the age-related changes in multiple intra-orbital structures using quantitative MRI (qMRI). Thirty-eight subjects (20 males, 18 females; ages 0.5-87 years) underwent MRI with a mixed turbo spin echo sequence. T1 and T2 measurements were obtained within ROI in 6 intra-orbital structures (medial and lateral rectus muscles, medial and lateral retrobulbar fat, lacrimal gland, and optic nerve), and compared with those of corresponding extra-orbital structures (masseter muscle, subcutaneous cheek fat, buccal fat, parotid gland, and frontal white matter). Statistical analyses were performed using Pearson's correlation coefficients. T1 and T2 values of the extra-ocular muscles increased with age, with higher T1 and T2 values compared to the masseter muscles. Retrobulbar fat showed significant age-associated increases in T1 values in the lateral side and in T2 values in both sides. T1 and T2 values in the lacrimal gland increased with age, while the parotid gland showed an age-associated increase in T2 values and decrease in T1 values. Optic nerves demonstrated age-related changes, similar to that of frontal white matter; rapid decreases with age in T1 and T2 times in early stages of life, and slight increases in T1 and T2 times later in life. Intra-orbital structures demonstrated specific qMRI measurements and aging patterns, which were different from extra-orbital structures. Location-specific age-related changes of intra-orbital structures should be considered in the qMRI assessment of the orbital pathology.

  17. Quantitative comparison of HTLV-1 and HIV-1 cell-to-cell infection with new replication dependent vectors.

    Directory of Open Access Journals (Sweden)

    Dmitriy Mazurov

    2010-02-01

    Full Text Available We have developed an efficient method to quantify cell-to-cell infection with single-cycle, replication dependent reporter vectors. This system was used to examine the mechanisms of infection with HTLV-1 and HIV-1 vectors in lymphocyte cell lines. Effector cells transfected with reporter vector, packaging vector, and Env expression plasmid produced virus-like particles that transduced reporter gene activity into cocultured target cells with zero background. Reporter gene expression was detected exclusively in target cells and required an Env-expression plasmid and a viral packaging vector, which provided essential structural and enzymatic proteins for virus replication. Cell-cell fusion did not contribute to infection, as reporter protein was rarely detected in syncytia. Coculture of transfected Jurkat T cells and target Raji/CD4 B cells enhanced HIV-1 infection two fold and HTLV-1 infection ten thousand fold in comparison with cell-free infection of Raji/CD4 cells. Agents that interfere with actin and tubulin polymerization strongly inhibited HTLV-1 and modestly decreased HIV-1 cell-to-cell infection, an indication that cytoskeletal remodeling was more important for HTLV-1 transmission. Time course studies showed that HTLV-1 transmission occurred very rapidly after cell mixing, whereas slower kinetics of HIV-1 coculture infection implies a different mechanism of infectious transmission. HTLV-1 Tax was demonstrated to play an important role in altering cell-cell interactions that enhance virus infection and replication. Interestingly, superantigen-induced synapses between Jurkat cells and Raji/CD4 cells did not enhance infection for either HTLV-1 or HIV-1. In general, the dependence on cell-to-cell infection was determined by the virus, the effector and target cell types, and by the nature of the cell-cell interaction.

  18. QUANTITATIVE ELECTRONIC STRUCTURE - ACTIVITY RELATIONSHIPS ANALYSIS ANTIMUTAGENIC BENZALACETONE DERIVATIVES BY PRINCIPAL COMPONENT REGRESSION APPROACH

    Directory of Open Access Journals (Sweden)

    Yuliana Yuliana

    2010-06-01

    Full Text Available Quantitative Electronic Structure Activity Relationship (QSAR analysis of a series of benzalacetones has been investigated based on semi empirical PM3 calculation data using Principal Components Regression (PCR. Investigation has been done based on antimutagen activity from benzalacetone compounds (presented by log 1/IC50 and was studied as linear correlation with latent variables (Tx resulted from transformation of atomic net charges using Principal Component Analysis (PCA. QSAR equation was determinated based on distribution of selected components and then was analysed with PCR. The result was described by the following QSAR equation : log 1/IC50 = 6.555 + (2.177.T1 + (2.284.T2 + (1.933.T3 The equation was significant on the 95% level with statistical parameters : n = 28 r = 0.766  SE  = 0.245  Fcalculation/Ftable = 3.780 and gave the PRESS result 0.002. It means that there were only a relatively few deviations between the experimental and theoretical data of antimutagenic activity.          New types of benzalacetone derivative compounds were designed  and their theoretical activity were predicted based on the best QSAR equation. It was found that compounds number 29, 30, 31, 32, 33, 35, 36, 37, 38, 40, 41, 42, 44, 47, 48, 49 and 50  have  a relatively high antimutagenic activity.   Keywords: QSAR; antimutagenic activity; benzalaceton; atomic net charge

  19. 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.)

  20. Polar bear hepatic cytochrome P450: Immunochemical quantitation, EROD/PROD activity and organochlorines

    Energy Technology Data Exchange (ETDEWEB)

    Letcher, R.J.; Norstrom, R.J. [Carleton Univ., Ottawa, Ontario (Canada). Centre for Analytical and Environmental Chemistry]|[Environment Canada, Ottawa, Ontario (Canada). Canadian Wildlife Service

    1994-12-31

    Polar bears (Ursus maritimus) are an ubiquitous mammal atop the arctic marine food chain and bioaccumulate lipophilic environmental contaminants. Antibodies prepared against purified rat liver cytochrome P450-1 Al, -1 A2, -2Bl and -3Al enzymes have been found to cross-react with structurally-related orthologues present in the hepatic microsomes of wild polar bears, immunochemically determined levels of P450-1 A and -2B proteins in polar bear liver relative to liver of untreated rats suggested enzyme induction, probably as a result of exposure to xenobiotic contaminants. Optical density quantitation of the most immunochemically responsive isozymes P450-I Al, -IA2 and -2Bi to polygonal rabbit anti-rat P450-IA/IA2 sera and -2BI antibodies in hepatic microsomes of 13 adult male polar bars from the Resolute Bay area of the Canadian Arctic is presented. Correlations with EROD and PROD catalytic activities and levels of organochlorines, such as polychlorinated biphenyls (PCBs), 1,1-dichloro-2,2-bis(4-chlorophenyl)ethene (p,p-DDE) and their methyl sulfone (MeSO2-) metabolites are made to determine if compound-specific enzyme induction linkages exist. Inter-species immunochemical quantitation of isozymic P450 cytochromes can serve as an indicator of exposure to biologically active contaminant.

  1. 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.

  2. Development and Validation of Quantitative Structure-Activity Relationship Models for Compounds Acting on Serotoninergic Receptors

    Directory of Open Access Journals (Sweden)

    Grażyna Żydek

    2012-01-01

    Full Text Available A quantitative structure-activity relationship (QSAR study has been made on 20 compounds with serotonin (5-HT receptor affinity. Thin-layer chromatographic (TLC data and physicochemical parameters were applied in this study. RP2 TLC 60F254 plates (silanized impregnated with solutions of propionic acid, ethylbenzene, 4-ethylphenol, and propionamide (used as analogues of the key receptor amino acids and their mixtures (denoted as S1–S7 biochromatographic models were used in two developing phases as a model of drug-5-HT receptor interaction. The semiempirical method AM1 (HyperChem v. 7.0 program and ACD/Labs v. 8.0 program were employed to calculate a set of physicochemical parameters for the investigated compounds. Correlation and multiple linear regression analysis were used to search for the best QSAR equations. The correlations obtained for the compounds studied represent their interactions with the proposed biochromatographic models. The good multivariate relationships (R2=0.78–0.84 obtained by means of regression analysis can be used for predicting the quantitative effect of biological activity of different compounds with 5-HT receptor affinity. “Leave-one-out” (LOO and “leave-N-out” (LNO cross-validation methods were used to judge the predictive power of final regression equations.

  3. 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

  4. 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.

  5. 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.

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

    DEFF Research Database (Denmark)

    Kelstrup, Jesper Dahl

    2017-01-01

    research on think and the study of policy advice by arguing for a focus on the dissemination of policy advice by asking how the dissemination activities of think tanks vary across different policy advisory systems and what this implies for the study of policy advice. This question is explored...... 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...... controlled for the number of full-time staff. The study indicates that factors beyond the policy process such as developments of funding and media environments should be analysed further as they are likely to be important for how and where think tank disseminate their policy advice....

  7. 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.

  8. QUANTITATIVE ELECTRONIC STRUCTURE - ACTIVITY RELATIONSHIP OF ANTIMALARIAL COMPOUND OF ARTEMISININ DERIVATIVES USING PRINCIPAL COMPONENT REGRESSION APPROACH

    Directory of Open Access Journals (Sweden)

    Paul Robert Martin Werfette

    2010-06-01

    Full Text Available Analysis of quantitative structure - activity relationship (QSAR for a series of antimalarial compound artemisinin derivatives has been done using principal component regression. The descriptors for QSAR study were representation of electronic structure i.e. atomic net charges of the artemisinin skeleton calculated by AM1 semi-empirical method. The antimalarial activity of the compound was expressed in log 1/IC50 which is an experimental data. The main purpose of the principal component analysis approach is to transform a large data set of atomic net charges to simplify into a data set which known as latent variables. The best QSAR equation to analyze of log 1/IC50 can be obtained from the regression method as a linear function of several latent variables i.e. x1, x2, x3, x4 and x5. The best QSAR model is expressed in the following equation,  (;;   Keywords: QSAR, antimalarial, artemisinin, principal component regression

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

    Science.gov (United States)

    Zhantayev, Zhumabek; Khachikyan, Galina; Breusov, Nikolay

    2014-05-01

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

  10. 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

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

    Science.gov (United States)

    Shimono, Masaki; Higaki, Takumi; Kaku, Hanae; Shibuya, Naoto; Hasezawa, Seiichiro

    2016-01-01

    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 immune signaling in

  12. Synthesis and quantitative structure activity relationship (QSAR) of arylidene (benzimidazol-1-yl)acetohydrazones as potential antibacterial agents.

    Science.gov (United States)

    El-Kilany, Yeldez; Nahas, Nariman M; Al-Ghamdi, Mariam A; Badawy, Mohamed E I; El Ashry, El Sayed H

    2015-01-01

    Ethyl (benzimidazol-1-yl)acetate was subjected to hydrazinolysis with hydrazine hydrate to give (benzimidazol-1-yl)acetohydrazide. The latter was reacted with various aromatic aldehydes to give the respective arylidene (1H-benzimidazol-1-yl)acetohydrazones. Solutions of the prepared hydrazones were found to contain two geometric isomers. Similarly (2-methyl-benzimidazol-1-yl)acetohydrazide was reacted with various aldehydes to give the corresponding hydrazones. The antibacterial activity was evaluated in vitro by minimum inhibitory concentration (MIC) against Agrobacterium tumefaciens (A. tumefaciens), Erwinia carotovora (E. carotovora), Corynebacterium fascians (C. fascians) and Pseudomonas solanacearum (P. solanacearum). MIC result demonstrated that salicylaldehyde(1H-benzimidazol-1-yl)acetohydrazone (4) was the most active compound (MIC = 20, 35, 25 and 30 mg/L against A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively). Quantitative structure activity relationship (QSAR) investigation using Hansch analysis was applied to find out the correlation between antibacterial activity and physicochemical properties. Various physicochemical descriptors and experimentally determined MIC values for different microorganisms were used as independent and dependent variables, respectively. pMICs of the compounds exhibited good correlation (r = 0.983, 0.914, 0.960 and 0.958 for A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively) with the prediction made by the model. QSAR study revealed that the hydrophobic parameter (ClogP), the aqueous solubility (LogS), calculated molar refractivity, topological polar surface area and hydrogen bond acceptor were found to have overall significant correlation with antibacterial activity. The statistical results of training set, correlation coefficient (r and r (2)), the ratio between regression and residual variances (f, Fisher's statistic), the standard error of estimates and

  13. Pilot clinical study to assess caries lesion activity using quantitative light-induced fluorescence during dehydration

    Science.gov (United States)

    Ando, Masatoshi; Ferreira-Zandoná, Andrea G.; Eckert, George J.; Zero, Domenick T.; Stookey, George K.

    2017-03-01

    This study aimed to evaluate the ability of quantitative light-induced fluorescence (QLF) to assess caries lesion activity using visual examination (VE) as the gold standard. Twenty-four visible white spot lesions on buccal surfaces were examined from 23 children, ages 9 to 14 years. At baseline, the surface was hydrated with water, and thereafter, it was dehydrated with continuous compressed air during image acquisition. QLF images were acquired at 0 (baseline), 5, and 15 s. QLF variables [QLFV: fluorescence loss (ΔF), lesion size (S), ΔQ: ΔF×S] was recorded. Changes-in-QLFV per second (ΔQLFV) were determined: ΔQLFV=(QLFVN-QLF/N), where N indicates dehydration time. One experienced dentist conducted VE independently using a dental unit's light, compressed air, and explorer. QLFV and ΔQLFV of the active group (n=11) were compared with those of the inactive group (n=13) using two-sample t-tests. As the surface was dehydrated, S and ΔQ values of the active group increased, whereas QLFV of the inactive group showed only a small change. ΔQLFV of the active group were larger than those of the inactive group; however, the difference did not reach statistical significance (p>0.11). Within the limitations of this study, QLF data indicated increments for lesions designated as active and minimal change for lesions defined as inactive.

  14. Quantitative assessment of TRPM5-dependent oral aversiveness of pharmaceuticals using a mouse brief-access taste aversion assay.

    Science.gov (United States)

    Devantier, Heather R; Long, Daniel J; Brennan, Francis X; Carlucci, Stacy A; Hendrix, Cynthia; Bryant, Robert W; Salemme, F Raymond; Palmer, R Kyle

    2008-10-01

    Many orally administered pharmaceuticals are regarded by humans as aversive, most often described as 'bitter'. Taste aversiveness often leads to patient noncompliance and reduced treatment effectiveness. 'Bitter' taste is mediated by T2R G-protein coupled receptors through a peripheral signaling pathway critically dependent upon function of the TRPM5 ion channel. The brief-access taste aversion (BATA) assay operationally defines aversive taste as suppression of the rate at which a rodent licks from sipper tubes that deliver tastant solutions or suspensions. We have used a mouse BATA assay for rapid quantification of oral aversiveness from a set of 20 active pharmaceutical ingredients (APIs). Robust lick-rate dose-response functions were obtained from both C57BL/6J wild type (WT) and C57BL/6J/TRPM5-/- (TRPM5 knockout) mouse strains, generating reliable determinations of potency and relative maximal oral aversiveness for each API. A subset of APIs was also evaluated in a human bitterness assessment test; effective concentrations for half-maximum responses (EC50s) from both the human test and WT mouse BATA were equivalent. Relative to WT potencies, EC50s from TRPM5 knockout mice were right-shifted more than 10-fold for most APIs. However, APIs were identified for which EC50s were essentially identical in both mouse strains, indicating a TRPM5-independent alternative aversive pathway. Our results suggest the BATA assay will facilitate formulation strategies and taste assessment of late development-phase APIs.

  15. Health game interventions to enhance physical activity self-efficacy of children: a quantitative systematic review.

    Science.gov (United States)

    Pakarinen, Anni; Parisod, Heidi; Smed, Jouni; Salanterä, Sanna

    2017-04-01

    To describe and explore health game interventions that enhance the physical activity self-efficacy of children and to evaluate the effectiveness of these interventions. Physical inactivity among children has increased globally. Self-efficacy is one of the key determinants of physical activity engagement in children. There is a need to explore new and innovative interventions to enhance physical activity self-efficacy that are also acceptable for today's children. Quantitative systematic review. MEDLINE (Ovid), CINAHL, PsychInfo, EMBASE and the Cochrane Library between 1996-2016. A review was conducted in accordance with the Cochrane Collaboration guidelines. A systematic search was done in June 2016 by two independent reviewers according to the eligibility criteria as follows: controlled trial, comparison of digital game intervention with no game intervention control condition, participants younger than 18 years of age and reported statistical analyses of a physical activity self-efficacy outcome measure. Altogether, five studies met the eligibility criteria. Four game interventions, employing three active games and one educational game, had positive effects on children's physical activity self-efficacy. An intervention, employing a game-themed mobile application, showed no intervention effects. The variation between intervention characteristics was significant and the quality of the studies was found to be at a medium level. Although health game interventions seemingly enhance the physical activity self-efficacy of children and have potential as a means of increasing physical activity, more rigorous research is needed to clarify how effective such interventions are in the longer run to contribute to the development of game-based interventions. © 2016 John Wiley & Sons Ltd.

  16. Quantitative Structure-Activity Relationship of Insecticidal Activity of Benzyl Ether Diamidine Derivatives

    Science.gov (United States)

    Zhai, Mengting; Chen, Yan; Li, Jing; Zhou, Jun

    2017-12-01

    The molecular electrongativity distance vector (MEDV-13) was used to describe the molecular structure of benzyl ether diamidine derivatives in this paper, Based on MEDV-13, The three-parameter (M 3, M 15, M 47) QSAR model of insecticidal activity (pIC 50) for 60 benzyl ether diamidine derivatives was constructed by leaps-and-bounds regression (LBR) . The traditional correlation coefficient (R) and the cross-validation correlation coefficient (R CV ) were 0.975 and 0.971, respectively. The robustness of the regression model was validated by Jackknife method, the correlation coefficient R were between 0.971 and 0.983. Meanwhile, the independent variables in the model were tested to be no autocorrelation. The regression results indicate that the model has good robust and predictive capabilities. The research would provide theoretical guidance for the development of new generation of anti African trypanosomiasis drugs with efficiency and low toxicity.

  17. Concentration dependence of alpha-synuclein fibril length assessed by quantitative atomic force microscopy and statistical-mechanical theory

    NARCIS (Netherlands)

    van Raaij, Martijn E; van Gestel, Jeroen; Segers-Nolten, Ine M J; de Leeuw, Simon W; Subramaniam, Vinod

    2008-01-01

    The initial concentration of monomeric amyloidogenic proteins is a crucial factor in the in vitro formation of amyloid fibrils. We use quantitative atomic force microscopy to study the effect of the initial concentration of human alpha-synuclein on the mean length of mature alpha-synuclein fibrils,

  18. 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.

  19. Diurnal and water salinity-dependent metabolic activity of juvenile ...

    African Journals Online (AJOL)

    In order to contribute to ecophysiogical data on this species, oxygen consumption by white steenbras was determined to quantify metabolic activity. White steenbras were most active during daylight hours when oxygen consumption was 28% higher than during the scotophase. Standard, routine and active metabolic rate ...

  20. Fuzzy tricentric pharmacophore fingerprints. 2. Application of topological fuzzy pharmacophore triplets in quantitative structure-activity relationships.

    Science.gov (United States)

    Bonachéra, Fanny; Horvath, Dragos

    2008-02-01

    Topological fuzzy pharmacophore triplets (2D-FPT), using the number of interposed bonds to measure separation between the atoms representing pharmacophore types, were employed to establish and validate quantitative structure-activity relationships (QSAR). Thirteen data sets for which state-of-the-art QSAR models were reported in literature were revisited in order to benchmark 2D-FPT biological activity-explaining propensities. Linear and nonlinear QSAR models were constructed for each compound series (following the original author's splitting into training/validation subsets) with three different 2D-FPT versions, using the genetic algorithm-driven Stochastic QSAR sampler (SQS) to pick relevant triplets and fit their coefficients. 2D-FPT QSARs are computationally cheap, interpretable, and perform well in benchmarking. In a majority of cases (10/13), default 2D-FPT models validated better than or as well as the best among those reported, including 3D overlay-dependent approaches. Most of the analogues series, either unaffected by protonation equilibria or unambiguously adopting expected protonation states, were equally well described by rule- or pKa-based pharmacophore flagging. Thermolysin inhibitors represent a notable exception: pKa-based flagging boosts model quality, although--surprisingly--not due to proteolytic equilibrium effects. The optimal degree of 2D-FPT fuzziness is compound set dependent. This work further confirmed the higher robustness of nonlinear over linear SQS models. In spite of the wealth of studied sets, benchmarking is nevertheless flawed by low intraset diversity: a whole series of thereby caused artifacts were evidenced, implicitly raising questions about the way QSAR studies are conducted nowadays. An in-depth investigation of thrombin inhibition models revealed that some of the selected triplets make sense (one of these stands for a topological pharmacophore covering the P1 and P2 binding pockets). Nevertheless, equations were either

  1. 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.

  2. 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

  3. Quantitative structure-activity relationship models of chemical transformations from matched pairs analyses.

    Science.gov (United States)

    Beck, Jeremy M; Springer, Clayton

    2014-04-28

    The concepts of activity cliffs and matched molecular pairs (MMP) are recent paradigms for analysis of data sets to identify structural changes that may be used to modify the potency of lead molecules in drug discovery projects. Analysis of MMPs was recently demonstrated as a feasible technique for quantitative structure-activity relationship (QSAR) modeling of prospective compounds. Although within a small data set, the lack of matched pairs, and the lack of knowledge about specific chemical transformations limit prospective applications. Here we present an alternative technique that determines pairwise descriptors for each matched pair and then uses a QSAR model to estimate the activity change associated with a chemical transformation. The descriptors effectively group similar transformations and incorporate information about the transformation and its local environment. Use of a transformation QSAR model allows one to estimate the activity change for novel transformations and therefore returns predictions for a larger fraction of test set compounds. Application of the proposed methodology to four public data sets results in increased model performance over a benchmark random forest and direct application of chemical transformations using QSAR-by-matched molecular pairs analysis (QSAR-by-MMPA).

  4. Technology Efficacy in Active Prosthetic Knees for Transfemoral Amputees: A Quantitative Evaluation

    Science.gov (United States)

    El-Sayed, Amr M.; Abu Osman, Noor Azuan

    2014-01-01

    Several studies have presented technological ensembles of active knee systems for transfemoral prosthesis. Other studies have examined the amputees' gait performance while wearing a specific active prosthesis. This paper combined both insights, that is, a technical examination of the components used, with an evaluation of how these improved the gait of respective users. This study aims to offer a quantitative understanding of the potential enhancement derived from strategic integration of core elements in developing an effective device. The study systematically discussed the current technology in active transfemoral prosthesis with respect to its functional walking performance amongst above-knee amputee users, to evaluate the system's efficacy in producing close-to-normal user performance. The performances of its actuator, sensory system, and control technique that are incorporated in each reported system were evaluated separately and numerical comparisons were conducted based on the percentage of amputees' gait deviation from normal gait profile points. The results identified particular components that contributed closest to normal gait parameters. However, the conclusion is limitedly extendable due to the small number of studies. Thus, more clinical validation of the active prosthetic knee technology is needed to better understand the extent of contribution of each component to the most functional development. PMID:25110727

  5. 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)

  6. 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...

  7. Quantitative structure-activity relationship and molecular docking studies on designing inhibitors of the perforin.

    Science.gov (United States)

    Song, Fucheng; Cui, Lianhua; Piao, Jinmei; Liang, Hui; Si, Hongzong; Duan, Yunbo; Zhai, Honglin

    2017-10-01

    Quantitative structure-activity relationship (QSAR) studies were performed on a series of 5-arylidene-2thioxoimidazolidin-4-ones derivatives as the inhibitors of perforin and to gain insights about the structural determinants for designing new drug molecules. The heuristic method could explore the descriptors responsible for bioactivity and gain a best linear model with R 2 .82. Gene expression programming method generated a novel nonlinear function model with R 2 .92 for training set and R 2 .85 for test set. The predicted IC 50 by QSAR, molecular docking analysis, and property explorer applet show that 42a acts as a well-pleasing potent inhibitor for perforin. This study may lay a reliable theoretical foundation for the development of designing perforin inhibitor structures. © 2017 John Wiley & Sons A/S.

  8. Study of Dependencies in Executions of E-Contract Activities

    Science.gov (United States)

    Vidyasankar, K.; Krishna, P. Radha; Karlapalem, Kamalakar

    An e-contract is a contract modeled, specified, executed, controlled and monitored by a software system. A contract is a legal agreement involving parties, activities, clauses and payments. The goals of an e-contract include precise specification of the activities of the contract, mapping them into deployable workflows, and providing transactional support in their execution. Activities in a contract are generally complex and interdependent. They may be executed by different parties autonomously and in a loosely coupled fashion. They differ from database transactions in many ways: (i) Different successful executions are possible for an activity; (ii) Unsuccessful executions may be compensated or re-executed to get different results; (iii) Whether an execution is successful or not may not be known until after several subsequent activities are executed, and so it may be compensated and/or re-executed at different times relative to the execution of other activities; (iv) Compensation or re-execution of an activity may require compensation or re-execution of several other activities; etc. In this paper, we study the interdependencies between the executions of e-contract activities. This study will be helpful in monitoring behavioral conditions stated in an e-contracts during its execution.

  9. Novel autism subtype-dependent genetic variants are revealed by quantitative trait and subphenotype association analyses of published GWAS data.

    Directory of Open Access Journals (Sweden)

    Valerie W Hu

    Full Text Available The heterogeneity of symptoms associated with autism spectrum disorders (ASDs has presented a significant challenge to genetic analyses. Even when associations with genetic variants have been identified, it has been difficult to associate them with a specific trait or characteristic of autism. Here, we report that quantitative trait analyses of ASD symptoms combined with case-control association analyses using distinct ASD subphenotypes identified on the basis of symptomatic profiles result in the identification of highly significant associations with 18 novel single nucleotide polymorphisms (SNPs. The symptom categories included deficits in language usage, non-verbal communication, social development, and play skills, as well as insistence on sameness or ritualistic behaviors. Ten of the trait-associated SNPs, or quantitative trait loci (QTL, were associated with more than one subtype, providing partial replication of the identified QTL. Notably, none of the novel SNPs is located within an exonic region, suggesting that these hereditary components of ASDs are more likely related to gene regulatory processes (or gene expression than to structural or functional changes in gene products. Seven of the QTL reside within intergenic chromosomal regions associated with rare copy number variants that have been previously reported in autistic samples. Pathway analyses of the genes associated with the QTL identified in this study implicate neurological functions and disorders associated with autism pathophysiology. This study underscores the advantage of incorporating both quantitative traits as well as subphenotypes into large-scale genome-wide analyses of complex disorders.

  10. QSAR DataBank repository: open and linked qualitative and quantitative structure-activity relationship models.

    Science.gov (United States)

    Ruusmann, V; Sild, S; Maran, U

    2015-01-01

    Structure-activity relationship models have been used to gain insight into chemical and physical processes in biomedicine, toxicology, biotechnology, etc. for almost a century. They have been recognized as valuable tools in decision support workflows for qualitative and quantitative predictions. The main obstacle preventing broader adoption of quantitative structure-activity relationships [(Q)SARs] is that published models are still relatively difficult to discover, retrieve and redeploy in a modern computer-oriented environment. This publication describes a digital repository that makes in silico (Q)SAR-type descriptive and predictive models archivable, citable and usable in a novel way for most common research and applied science purposes. The QSAR DataBank (QsarDB) repository aims to make the processes and outcomes of in silico modelling work transparent, reproducible and accessible. Briefly, the models are represented in the QsarDB data format and stored in a content-aware repository (a.k.a. smart repository). Content awareness has two dimensions. First, models are organized into collections and then into collection hierarchies based on their metadata. Second, the repository is not only an environment for browsing and downloading models (the QDB archive) but also offers integrated services, such as model analysis and visualization and prediction making. The QsarDB repository unlocks the potential of descriptive and predictive in silico (Q)SAR-type models by allowing new and different types of collaboration between model developers and model users. The key enabling factor is the representation of (Q)SAR models in the QsarDB data format, which makes it easy to preserve and share all relevant data, information and knowledge. Model developers can become more productive by effectively reusing prior art. Model users can make more confident decisions by relying on supporting information that is larger and more diverse than before. Furthermore, the smart repository

  11. 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.

  12. 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

  13. Muscle activity pattern dependent pain development and alleviation

    DEFF Research Database (Denmark)

    Sjøgaard, Gisela; Søgaard, Karen

    2014-01-01

    Muscle activity is for decades considered to provide health benefits irrespectively of the muscle activity pattern performed and whether it is during e.g. sports, transportation, or occupational work tasks. Accordingly, the international recommendations for public health-promoting physical activi...

  14. An active form of calcium and calmodulin dependant protein kinase ...

    African Journals Online (AJOL)

    The removal of the auto-inhibitory domain that negatively regulates the kinase activity in M. truncatula results in a constitutively-active form, inducing symbiotic responses in the absence of bacterial signals. In this study, we verified the functionality of a DMI3 variant and its ability to induce spontaneous nodules in M.

  15. 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.

  16. Advances in the molecular modeling and quantitative structure-activity relationship-based design for antihistamines.

    Science.gov (United States)

    Galvez, Jorge; Galvez-Llompart, Maria; Zanni, Riccardo; Garcia-Domenech, Ramon

    2013-03-01

    Nowadays the use of antihistamines (AH) is increasing steadily. These drugs are able to act on a variety of pathological conditions of the organism. A number of computer-aided (in silico) approaches have been developed to discover and develop novel AH drugs. Among these methods stand the ones based on drug-receptor docking, thermodynamics, as well as the quantitative structure-activity relationships (QSAR). This review collates the most recent advances in the use of computer approaches for the search and characterization of novel AH drugs. Within the QSAR methods, particular attention will be paid to those based on molecular topology (MT) because of their demonstrated efficacy in discovering new drugs. Collateral topics will also be dealt with including: docking studies, thermodynamic aspects, molecular modeling and so on. These issues will be treated to the extent that they have interest as complementary to QSAR-MT. Given the importance of the use of AHs, the search for new drugs in this field has become imperative today. In this regard, the use of QSAR methods based on MT, namely QSAR-MT, has proven to be a powerful tool when the goal is discovering new hit or lead structures. It has been shown that antihistaminic activity is complex and different for the four known types of receptors (H1 to H4) and that electronic, steric and physicochemical issues determine drug activity. These factors, along with the purely structural ones, can be deduced from topological and topochemical information.

  17. Detecting the quantitative hydrological response to changes in climate and human activities.

    Science.gov (United States)

    Wu, Jingwen; Miao, Chiyuan; Zhang, Xiaoming; Yang, Tiantian; Duan, Qingyun

    2017-05-15

    Understanding the relative contributions of climate change and human activities to changes in runoff is important for sustainable management of regional water resources. In this study, we systematically review ten commonly used quantitative methods drawn from three main categories-empirical statistics, elasticity-based methods, and hydrological modeling. We explain the calculation processes for the different methods and summarize their applications and characteristics. Then, using the Yanhe River basin as a case study, we employ all ten methods to separate out the effects of climate change and human activities on changes in runoff. The results show that climate change played a dominant role in the decline in runoff in the Yanhe River basin. Climate change was estimated to account for 46.1%-60.8% (mean 54.1%) of the total decrease in runoff, whereas human activities accounted for 39.1%-53.9% (mean 45.9%). Elasticity-based methods and hydrological modeling produced similar estimates, but the estimates made using empirical statistics were different. Empirical statistics were not a suitable method for the Yanhe River basin. We also discuss the factors that influence the different methods and the applicable conditions for each methodological category. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. 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.

  19. Activity-dependent changes in intrinsic excitability of human spinal motoneurones produced by natural activity.

    Science.gov (United States)

    Rossi, Alessandro; Rossi, Simone; Ginanneschi, Federica

    2012-11-01

    The current study was designed to evaluate activity-dependent changes intrinsic to the spinal motoneurones (MNs) associated with sustained contractions. The excitability of spinal MNs (reflected by the antidromically evoked F-wave) innervating the abductor digiti minimi muscle (ADM) was measured in 12 healthy subjects following maximum voluntary contractions (MVCs) of ADM lasting 5 s, 15 s, 30 s, and 60 s. Upon cessation of the contractions, F-waves showed a depression, which increased in depth and duration with increasing duration of contraction. Following a 5-s contraction, there was a 20% decrease, which waned in 2 min, whereas a 60-s contraction produced a 40% decrease and waned in over 15 min. The changes in excitability of peripheral motor axons produced by the MVCs were measured by recording an ADM compound muscle action potential (CMAP) of ~50% of maximum to a constant ulnar nerve electrical stimulation. On cessation of the contractions, there was a prominent decrease in size of the CMAP: following a 5-s MVC, it produced a 10% decrease in the size of the test CMAP, which recovered in 2 min, whereas following a 60-s MVC, it produced a 30% decrease, which recovered in over 15 min. Statistical analysis (correntropy) showed a high-order mutual dependence between F-wave and CMAP, and both were significantly dependent on MVC duration. Because of the parallel excitability changes in peripheral axons and spinal MNs, our interpretation is that intrinsic excitability of the axon initial segment (i.e., where the action potential is generated) and peripheral axon segments changed in a similar, activity-dependent manner.

  20. 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.

  1. Comparison of trunk electromyographic muscle activity depends on sitting postures.

    Science.gov (United States)

    Lee, DongGeon; Yu, SeoJeong; Song, SunHae; Lee, Se-Han; An, SeungHeon; Cho, Hwi-Young; Cho, Ki-Hun; Lee, GyuChang

    2017-01-01

    Different postural positions can be characterized by the activation and relative contributions of different postural muscles, and may variously contribute to the recovery from or worsening of chronic lower back pain. The present study aimed to investigates trunk muscle activities in four types of seated postures: cross-legged, long, side, and W-shaped. Eight healthy adults participated in the study. Trunk muscle activities of the external oblique (EO), rectus abdominis (RA), latissimus dorsi (LD), and erector spinae (ES) muscles in each of the sitting postures including cross-legged, long, side, and W-shaped were collected utilizing surface electromyography (sEMG). The mean sEMG signals in each of the sitting postures were used for statistical comparisons. There were no significant differences in electromyographic muscle activity of EO, RA, LD, and ES in the four postures (p > 0.05). However, in the W-shape sitting posture, the left LD showed the greatest electromyographic muscle activity, followed by the right LD and left EO, respectively. The right and left LD in the long sitting posture and left ES in the side sitting posture showed greater electromyographic muscle activity than that of other muscles. Based on the results, trunk muscle activity did not significantly differ between the four types of sitting postures. However, our study is limited by its experimental method and sample size. Thus, in the Future, further study will be needed.

  2. 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 ...

  3. Structural alerts for predicting clastogenic activity of pro-oxidant flavonoid compounds: quantitative structure-activity relationship study.

    Science.gov (United States)

    Yordi, Estela Guardado; Pérez, Enrique Molina; Matos, Maria Joao; Villares, Eugenio Uriarte

    2012-02-01

    Flavonoids have been reported to exert multiple biological effects that include acting as pro-oxidants at very high doses. The authors determined a structural alert to identify the clastogenic activity of a series of flavonoids with pro-oxidant activity. The methodology was based on a quantitative structure-activity relationship (QSAR) study. Specifically, the authors developed a virtual screening method for a clastogenic model using the topological substructural molecular design (TOPS-MODE) approach. It represents a useful platform for the automatic generation of structural alerts, based on the calculation of spectral moments of molecular bond matrices appropriately weighted, taking into account the hydrophobic, electronic, and steric molecular features. Therefore, it was possible to establish the structural criteria for maximal clastogenicity of pro-oxidant flavonoids: the presence of a 3-hydroxyl group and a 4-carbonyl group in ring C, the maximal number of hydroxyl groups in ring B, the presence of methoxyl and phenyl groups, the absence of a 2,3-double bond in ring C, and the presence of 5,7 hydroxyl groups in ring A. The presented clastogenic model may be useful for screening new pro-oxidant compounds. This alert could help in the design of new and efficient flavonoids, which could be used as bioactive compounds in nutraceuticals and functional food.

  4. 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

  5. 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

  6. On-Beads Digestion in Conjunction with Data-Dependent Mass Spectrometry: A Shortcut to Quantitative and Dynamic Interaction Proteomics

    Directory of Open Access Journals (Sweden)

    Benedetta Turriziani

    2014-04-01

    Full Text Available With the advent of the “-omics” era, biological research has shifted from functionally analyzing single proteins to understanding how entire protein networks connect and adapt to environmental cues. Frequently, pathological processes are initiated by a malfunctioning protein network rather than a single protein. It is therefore crucial to investigate the regulation of proteins in the context of a pathway first and signaling network second. In this study, we demonstrate that a quantitative interaction proteomic approach, combining immunoprecipitation, in-solution digestion and label-free quantification mass spectrometry, provides data of high accuracy and depth. This protocol is applicable, both to tagged, exogenous and untagged, endogenous proteins. Furthermore, it is fast, reliable and, due to a label-free quantitation approach, allows the comparison of multiple conditions. We further show that we are able to generate data in a medium throughput fashion and that we can quantify dynamic interaction changes in signaling pathways in response to mitogenic stimuli, making our approach a suitable method to generate data for system biology approaches.

  7. A Caco-2 cell-based quantitative antioxidant activity assay for antioxidants.

    Science.gov (United States)

    Wan, Hongxia; Liu, Dong; Yu, Xiangying; Sun, Haiyan; Li, Yan

    2015-05-15

    A Caco-2 cell-based antioxidant activity (CAA) assay for quantitative evaluation of antioxidants was developed by optimizing seeding density and culture time of Caco-2 cells, incubation time and concentration of fluorescent probe (2',7'-dichlorofluorescin diacetate, DCFH-DA), incubation way and incubation time of antioxidants (pure phytochemicals) and DCFH-DA with cells, and detection time of fluorescence. Results showed that the CAA assay was of good reproducibility and could be used to evaluate the antioxidant activity of antioxidants at the following conditions: seeding density of 5 × 10(4)/well, cell culture time of 24h, co-incubation of 60 μM DCFH-DA and pure phytochemicals with Caco-2 cells for 20 min and fluorescence recorded for 90 min. Additionally, a significant correlation was observed between CAA values and rat plasma ORAC values following the intake of antioxidants for selected pure phytochemicals (R(2) = 0.815, p < 0.01), demonstrating the good biological relevance of CAA assay. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Prediction of environmental toxicity and fate using quantitative structure-activity relationships (QSARs

    Directory of Open Access Journals (Sweden)

    Dearden John C.

    2002-01-01

    Full Text Available Little or nothing is known about the toxicity of most of the >100,000 chemicals released into the environment. The cost of obtaining such information experimentally would be enormous in terms of money, time and animals. Companies and regulatory agencies are therefore turning to the prediction of environmental toxicity and fate through the use of quantitative structure-activity relationships (QSARs. This paper examines the use of QSARs in this context. Generally, QSARs are mechanism-specific, so that the first step is to classify a toxicant into one of four broad classes of toxicity: non-polar narcosis, polar narcosis, unselective reactivity and specific action (e.g. anticholinesterase activity. An appropriate QSAR can then be selected in order to predict the toxicity of a given chemical. There are also some expert systems available for toxicity prediction. QSAR predictions of bioconcentration, soil sorption and biodegradability can also be made; again, expert systems are available for such prediction. QSAR and expert system prediction of physico-chemical properties such as partition coefficient, aqueous solubility, melting and boiling point, vapour pressure and Henry's law constant can readily be made.

  9. Development and validation of a quantitative structure-activity relationship for chronic narcosis to fish.

    Science.gov (United States)

    Claeys, Lieve; Iaccino, Federica; Janssen, Colin R; Van Sprang, Patrick; Verdonck, Frederik

    2013-10-01

    Vertebrate testing under the European Union's regulation on Registration, Evaluation, Authorisation and Restriction of Chemical substances (REACH) is discouraged, and the use of alternative nontesting approaches such as quantitative structure-activity relationships (QSARs) is encouraged. However, robust QSARs predicting chronic ecotoxicity of organic compounds to fish are not available. The Ecological Structure Activity Relationships (ECOSAR) Class Program is a computerized predictive system that estimates the acute and chronic toxicity of organic compounds for several chemical classes based on their log octanol-water partition coefficient (K(OW)). For those chemical classes for which chronic training data sets are lacking, acute to chronic ratios are used to predict chronic toxicity to aquatic organisms. Although ECOSAR reaches a high score against the Organisation for Economic Co-operation and Development (OECD) principles for QSAR validation, the chronic QSARs in ECOSAR are not fully compliant with OECD criteria in the framework of REACH or CLP (classification, labeling, and packaging) regulation. The objective of the present study was to develop a chronic ecotoxicity QSAR for fish for compounds acting via nonpolar and polar narcosis. These QSARs were built using a database of quality screened toxicity values, considering only chronic exposure durations and relevant end points. After statistical multivariate diagnostic analysis, literature-based, mechanistically relevant descriptors were selected to develop a multivariate regression model. Finally, these QSARs were tested for their acceptance for regulatory purposes and were found to be compliant with the OECD principles for the validation of a QSAR. © 2013 SETAC.

  10. 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.

  11. Calcaneal Quantitative Ultrasound Indicates Reduced Bone Status Among Physically Active Adult Forager-Horticulturalists.

    Science.gov (United States)

    Stieglitz, Jonathan; Madimenos, Felicia; Kaplan, Hillard; Gurven, Michael

    2016-03-01

    Sedentary lifestyle contributes to osteoporosis and fragility fracture risks among modern humans, but whether such risks are prevalent in physically active preindustrial societies with lower life expectancies is unclear. Osteoporosis should be readily observable in preindustrial societies if it was regularly experienced over human history. In this study of 142 older adult Tsimane forager-horticulturalists (mean age ± SD, 62.1 ± 8.6 years; range, 50 to 85 years; 51% female) we used calcaneal quantitative ultrasonography (qUS) to assess bone status, document prevalence of adults with reduced bone status, and identify factors (demographic, anthropometric, immunological, kinesthetic) associated with reduced bone status. Men (23%) are as likely as women (25%) to have reduced bone status, although age-related decline in qUS parameters is attenuated for men. Adiposity and fat-free mass positively co-vary with qUS parameters for women but not men. Leukocyte count is inversely associated with qUS parameters controlling for potential confounders; leukocyte count is positively correlated within adults over time, and adults with persistently low counts have higher adjusted qUS parameters (6% to 8%) than adults with a high count. Reduced bone status characteristic of osteoporosis is common among active Tsimane with minimal exposure to osteoporosis risk factors found in industrialized societies, but with energetic constraints and high pathogen burden. © 2015 American Society for Bone and Mineral Research.

  12. Three-dimensional quantitative structure-activity relationships of mazindol analogues at the dopamine transporter.

    Science.gov (United States)

    Kulkarni, Santosh S; Newman, Amy Hauck; Houlihan, William J

    2002-09-12

    A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a series of mazindol analogues using the comparative molecular field analysis (CoMFA) method with their corresponding binding affinities for the displacement of [(3)H]WIN 35 428 from rat caudate putamen tissue. The cross-validated CoMFA models were derived from a training set of 50 compounds, and the predictive ability of the resulting CoMFA models was evaluated against a test set of 21 compounds. A set of alignment rules was derived to superimpose these compounds onto a template structure, mazindol (1). These CoMFA models yielded significant cross-validated r(2)(cv) values. Inclusion of additional descriptors did not improve the significance of the CoMFA models; thus, steric and electrostatic fields are the relevant descriptors for these compounds. The best QSAR model was selected on the basis of the predictive ability of the activity on the external test set of compounds. The analysis of coefficient contour maps provided further insight into the binding interactions of mazindol analogues with the DAT. The aromatic rings C and D are involved in hydrophobic interactions in which ring D may bind in a large hydrophobic groove. The relative orientation of these two rings is also important for high binding affinity to the DAT.

  13. Sarcomere length-dependence of activity-dependent twitch potentiation in mouse skeletal muscle

    Directory of Open Access Journals (Sweden)

    MacIntosh Brian R

    2002-12-01

    Full Text Available Abstract Background It has been reported that potentiation of a skeletal muscle twitch response is proportional to muscle length with a negative slope during staircase, and a positive slope during posttetanic potentiation. This study was done to directly compare staircase and posttetanic responses with measurement of sarcomere length to compare their length-dependence. Methods Mouse extensor digitorum longus (EDL muscles were dissected to small bundles of fibers, which permit measurement of sarcomere length (SL, by laser diffraction. In vitro fixed-end contractions of EDL fiber bundles were elicited at 22°C and 35°C at sarcomere lengths ranging from 2.35 μm to 3.85 μm. Twitch contractions were assessed before and after 1.5 s of 75 Hz stimulation at 22°C or during 10 s of 10 Hz stimulation at 22°C or 35°C. Results Staircase potentiation was greater at 35°C than 22°C, and the relative magnitude of the twitch contraction (Pt*/Pt was proportional to sarcomere length with a negative slope, over the range 2.3 μm – 3.7 μm. Linear regression yielded the following: Pt*/Pt = -0.59·SL+3.27 (r2 = 0.74; Pt*/Pt = -0.39·SL+2.34 (r2 = 0.48; and Pt*/Pt = -0.50·SL+2.45 (r2 = 0.80 for staircase at 35°C, and 22°C and posttetanic response respectively. Posttetanic depression rather than potentiation was present at long SL. This indicates that there may be two processes operating in these muscles to modulate the force: one that enhances and a second that depresses the force. Either or both of these processes may have a length-dependence of its mechanism. Conclusion There is no evidence that posttetanic potentiation is fundamentally different from staircase in these muscles.

  14. 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...

  15. Task-dependent modulation of oscillatory neural activity during movements

    DEFF Research Database (Denmark)

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

    2011-01-01

    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 ta...

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

    African Journals Online (AJOL)

    The comparison of estimated frictional coefficient from numerical output is in agreement with vis-à-vis corresponding similar computed from the virtual braking system model in the Simulink. The results indicated that highest frictional coefficient of 0.7 was obtained on the piston side of the rotor disc and active friction radius is ...

  17. Activity Dependent Degeneration Explains Hub Vulnerability in Alzheimer's Disease

    NARCIS (Netherlands)

    de Haan, W.; Mott, K.; van Straaten, E.C.W.; Scheltens, P.; Stam, C.J.

    2012-01-01

    Brain connectivity studies have revealed that highly connected 'hub' regions are particularly vulnerable to Alzheimer pathology: they show marked amyloid-β deposition at an early stage. Recently, excessive local neuronal activity has been shown to increase amyloid deposition. In this study we use a

  18. Applying quantitative structure-activity relationship (QSAR) methodology for modeling postmortem redistribution of benzodiazepines and tricyclic antidepressants.

    Science.gov (United States)

    Giaginis, Constantinos; Tsantili-Kakoulidou, Anna; Theocharis, Stamatios

    2014-06-01

    Postmortem redistribution (PMR) constitutes a multifaceted process, which complicates the interpretation of drug concentrations by forensic toxicologists. The present study aimed to apply quantitative structure-activity relationship (QSAR) analysis for modeling PMR data of structurally related drugs, 10 benzodiazepines and 10 tricyclic antidepressants. For benzodiazepines, an adequate QSAR model was obtained (R(2) = 0.98, Q(2) = 0.88, RMSEE = 0.12), in which energy, ionization and molecular size exerted significant impact. For tricyclic antidepressants, an adequate QSAR model with slightly inferior statistics (R(2) = 0.95, Q(2) = 0.87, RMSEE = 0.29) was established after exclusion of maprotiline, in which energy parameters, basicity character and lipophilicity exerted significant contribution. Thus, QSAR analysis could be used as a complementary tool to provide an informative illustration of the contributing molecular, physicochemical and structural properties in PMR process. However, the complexity, non-static and time-dependent nature of PMR endpoints raises serious concerns whether QSAR methodology could predict the degree of redistribution, highlighting the need for animal-derived PMR data.

  19. Quantitative simulation of intracellular signaling cascades in a Virtual Liver: estimating dose dependent changes in hepatocellular proliferation and apoptosis

    Science.gov (United States)

    The US EPA Virtual Liver (v-Liver™) is developing an approach to predict dose-dependent hepatotoxicity as an in vivo tissue level response using in vitro data. The v-Liver accomplishes this using an in silico agent-based systems model that dynamically integrates environmental exp...

  20. Localized heuristic inverse quantitative structure activity relationship with bulk descriptors using numerical gradients.

    Science.gov (United States)

    Stålring, Jonna; Almeida, Pedro R; Carlsson, Lars; Helgee Ahlberg, Ernst; Hasselgren, Catrin; Boyer, Scott

    2013-08-26

    State-of-the-art quantitative structure-activity relationship (QSAR) models are often based on nonlinear machine learning algorithms, which are difficult to interpret. From a pharmaceutical perspective, QSARs are used to enhance the chemical design process. Ultimately, they should not only provide a prediction but also contribute to a mechanistic understanding and guide modifications to the chemical structure, promoting compounds with desirable biological activity profiles. Global ranking of descriptor importance and inverse QSAR have been used for these purposes. This paper introduces localized heuristic inverse QSAR, which provides an assessment of the relative ability of the descriptors to influence the biological response in an area localized around the predicted compound. The method is based on numerical gradients with parameters optimized using data sets sampled from analytical functions. The heuristic character of the method reduces the computational requirements and makes it applicable not only to fragment based methods but also to QSARs based on bulk descriptors. The application of the method is illustrated on congeneric QSAR data sets, and it is shown that the predicted influential descriptors can be used to guide structural modifications that affect the biological response in the desired direction. The method is implemented into the AZOrange Open Source QSAR package. The current implementation of localized heuristic inverse QSAR is a step toward a generally applicable method for elucidating the structure activity relationship specifically for a congeneric region of chemical space when using QSARs based on bulk properties. Consequently, this method could contribute to accelerating the chemical design process in pharmaceutical projects, as well as provide information that could enhance the mechanistic understanding for individual scaffolds.

  1. Dose-Dependent Activation of Putative Oncogene SBSN by BORIS

    OpenAIRE

    Gaykalova, Daria; Vatapalli, Rajita; Glazer, Chad A.; Bhan, Sheetal; Shao, Chunbo; Sidransky, David; Ha, Patrick K.; Califano, Joseph A.

    2012-01-01

    Testis-specific transcription factor BORIS (Brother of the Regulator of Imprinted Sites), a paralog and proposed functional antagonist of the widely expressed CTCF, is abnormally expressed in multiple tumor types and has been implicated in the epigenetic activation of cancer-testis antigens (CTAs). We have reported previously that suprabasin (SBSN), whose expression is restricted to the epidermis, is epigenetically derepressed in lung cancer. In this work, we establish that SBSN is a novel no...

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

    Science.gov (United States)

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

    2013-03-01

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

  3. Dose-dependent activation of putative oncogene SBSN by BORIS.

    Science.gov (United States)

    Gaykalova, Daria; Vatapalli, Rajita; Glazer, Chad A; Bhan, Sheetal; Shao, Chunbo; Sidransky, David; Ha, Patrick K; Califano, Joseph A

    2012-01-01

    Testis-specific transcription factor BORIS (Brother of the Regulator of Imprinted Sites), a paralog and proposed functional antagonist of the widely expressed CTCF, is abnormally expressed in multiple tumor types and has been implicated in the epigenetic activation of cancer-testis antigens (CTAs). We have reported previously that suprabasin (SBSN), whose expression is restricted to the epidermis, is epigenetically derepressed in lung cancer. In this work, we establish that SBSN is a novel non-CTA target of BORIS epigenetic regulation. With the use of a doxycycline-inducible BORIS expressing vector, we demonstrate that relative BORIS dosage is critical for SBSN activation. At lower concentrations, BORIS induces demethylation of the SBSN CpG island and disruption and activation of chromatin around the SBSN transcription start site (TSS), resulting in a 35-fold increase in SBSN expression in the H358 human lung cancer cell line. Interestingly, increasing BORIS concentrations leads to a subsequent reduction in SBSN expression via chromatin repression. In a similar manner, increase in BORIS concentrations leads to eventual decrease of cell growth and colony formation. This is the first report demonstrating that different amount of BORIS defines its varied effects on the expression of a target gene via chromatin structure reorganization.

  4. Dose-dependent activation of putative oncogene SBSN by BORIS.

    Directory of Open Access Journals (Sweden)

    Daria Gaykalova

    Full Text Available Testis-specific transcription factor BORIS (Brother of the Regulator of Imprinted Sites, a paralog and proposed functional antagonist of the widely expressed CTCF, is abnormally expressed in multiple tumor types and has been implicated in the epigenetic activation of cancer-testis antigens (CTAs. We have reported previously that suprabasin (SBSN, whose expression is restricted to the epidermis, is epigenetically derepressed in lung cancer. In this work, we establish that SBSN is a novel non-CTA target of BORIS epigenetic regulation. With the use of a doxycycline-inducible BORIS expressing vector, we demonstrate that relative BORIS dosage is critical for SBSN activation. At lower concentrations, BORIS induces demethylation of the SBSN CpG island and disruption and activation of chromatin around the SBSN transcription start site (TSS, resulting in a 35-fold increase in SBSN expression in the H358 human lung cancer cell line. Interestingly, increasing BORIS concentrations leads to a subsequent reduction in SBSN expression via chromatin repression. In a similar manner, increase in BORIS concentrations leads to eventual decrease of cell growth and colony formation. This is the first report demonstrating that different amount of BORIS defines its varied effects on the expression of a target gene via chromatin structure reorganization.

  5. CDK activity provides temporal and quantitative cues for organizing genome duplication.

    Directory of Open Access Journals (Sweden)

    Anthony Perrot

    2018-02-01

    Full Text Available In eukaryotes, the spatial and temporal organization of genome duplication gives rise to distinctive profiles of replication origin usage along the chromosomes. While it has become increasingly clear that these programs are important for cellular physiology, the mechanisms by which they are determined and modulated remain elusive. Replication initiation requires the function of cyclin-dependent kinases (CDKs, which associate with various cyclin partners to drive cell proliferation. Surprisingly, although we possess detailed knowledge of the CDK regulators and targets that are crucial for origin activation, little is known about whether CDKs play a critical role in establishing the genome-wide pattern of origin selection. We have addressed this question in the fission yeast, taking advantage of a simplified cell cycle network in which cell proliferation is driven by a single cyclin-CDK module. This system allows us to precisely control CDK activity in vivo using chemical genetics. First, in contrast to previous reports, our results clearly show that distinct cyclin-CDK pairs are not essential for regulating specific subsets of origins and for establishing a normal replication program. Importantly, we then demonstrate that the timing at which CDK activity reaches the S phase threshold is critical for the organization of replication in distinct efficiency domains, while the level of CDK activity at the onset of S phase is a dose-dependent modulator of overall origin efficiencies. Our study therefore implicates these different aspects of CDK regulation as versatile mechanisms for shaping the architecture of DNA replication across the genome.

  6. 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...

  7. 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.

  8. LCK dependent Fyn activation requires C-terminus dependent targeting of kinase active LCK to lipid rafts

    Czech Academy of Sciences Publication Activity Database

    Filipp, Dominik; Moemeni, B.; Ferzoco, A.; Kirishanthy, K.; Zhang, J.; Ballek, Ondřej; Davidson, D.; Veillette, A.; Julius, M.

    2008-01-01

    Roč. 283, č. 39 (2008), s. 26409-26422 ISSN 0021-9258 Institutional research plan: CEZ:AV0Z50520514 Keywords : T cell activation * Lck * Fyn Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.520, year: 2008

  9. Quantitative comparison of the convulsive activity of combinations of twelve fluoroquinolones with five nonsteroidal antiinflammatory agents.

    Science.gov (United States)

    Kim, Jahye; Ohtani, Hisakazu; Tsujimoto, Masayuki; Sawada, Yasufumi

    2009-01-01

    Concomitant administration of certain fluoroquinolone antimicrobials and nonsteroidal antiinflammatory agents (NSAIDs) induces serious convulsion in humans. There are differences in convulsive activity among fluoroquinolones and in the potentiation of fluoroquinolone-induced convulsion among NSAIDs, but a comprehensive, quantitative comparison has not been carried out. This study evaluates the inhibitory effects of twelve fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pazufloxacin, prulifloxacin, sparfloxacin, and tosufloxacin) alone or in the presence of an NSAID (4-biphenylacetic acid, diclofenac sodium, loxoprofen, lornoxicam or zaltoprofen) on the GABA(A) receptor binding of [(3)H]muscimol in an in vitro study using mice synaptic plasma membrane. The rank order of inhibitory effects of the fluoroquinolones was prulifloxacin asymptotically equal to norfloxacin > ciprofloxacin > or = enoxacin > gatifloxacin > or = ofloxacin asymptotically equal to tosufloxacin asymptotically equal to lomefloxacin > levofloxacin > or = sparfloxacin > or = pazufloxacin asymptotically equal to fleroxacin. 4-Biphenylacetic acid most potently enhanced the inhibitory effects of the fluoroquinolones, while zaltoprofen, loxoprofen, lornoxicam and diclofenac had essentially no effect. The clinical risk of convulsion for each combination was estimated using a pharmacodynamic model based on receptor occupancy using the in vitro data set obtained and pharmacokinetic parameters in humans collected from the literature. The combinations of 4-biphenylacetic acid with prulifloxacin and enoxacin were concluded to be the most hazardous.

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

    Science.gov (United States)

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

    2017-07-01

    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 diverse polymers which are capable to estimate green algae growth inhibition (EC50). The model (N = 43, R 2  = 0.73, RMSE = 0.28) is a regression-based decision tree using one structural descriptor for each of three polymer classes separated based on charge. The QSAR is applicable to linear homo polymers as well as copolymers and does not require information on the size of the polymer particle or underlying core material. Highly branched polymers, non-nitrogen cationic polymers and polymeric surfactants are not included in the model and thus cannot be evaluated. The model works best for cationic and non-ionic polymers for which cellular adsorption, disruption of the cell wall and photosynthesis inhibition were the mechanisms of action. For anionic polymers, specific properties of the polymer and test characteristics need to be known for detailed assessment. The data and QSAR results for anionic polymers, when combined with molecular dynamics simulations indicated that nutrient depletion is likely the dominant mode of toxicity. Nutrient depletion in turn, is determined by the non-linear interplay between polymer charge density and backbone flexibility. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Quantitative Structure--Activity Relationship (QSAR) for the Oxidation of Trace Organic Contaminants by Sulfate Radical.

    Science.gov (United States)

    Xiao, Ruiyang; Ye, Tiantian; Wei, Zongsu; Luo, Shuang; Yang, Zhihui; Spinney, Richard

    2015-11-17

    The sulfate radical anion (SO4•–) based oxidation of trace organic contaminants (TrOCs) has recently received great attention due to its high reactivity and low selectivity. In this study, a meta-analysis was conducted to better understand the role of functional groups on the reactivity between SO4•– and TrOCs. The results indicate that compounds in which electron transfer and addition channels dominate tend to exhibit a faster second-order rate constants (kSO4•–) than that of H–atom abstraction, corroborating the SO4•– reactivity and mechanisms observed in the individual studies. Then, a quantitative structure activity relationship (QSAR) model was developed using a sequential approach with constitutional, geometrical, electrostatic, and quantum chemical descriptors. Two descriptors, ELUMO and EHOMO energy gap (ELUMO–EHOMO) and the ratio of oxygen atoms to carbon atoms (#O:C), were found to mechanistically and statistically affect kSO4•– to a great extent with the standardized QSAR model: ln kSO4•– = 26.8–3.97 × #O:C – 0.746 × (ELUMO–EHOMO). In addition, the correlation analysis indicates that there is no dominant reaction channel for SO4•– reactions with various structurally diverse compounds. Our QSAR model provides a robust predictive tool for estimating emerging micropollutants removal using SO4•– during wastewater treatment processes.

  12. Quantitative structure-activity relationship: promising advances in drug discovery platforms.

    Science.gov (United States)

    Wang, Tao; Wu, Mian-Bin; Lin, Jian-Ping; Yang, Li-Rong

    2015-12-01

    Quantitative structure-activity relationship (QSAR) modeling is one of the most popular computer-aided tools employed in medicinal chemistry for drug discovery and lead optimization. It is especially powerful in the absence of 3D structures of specific drug targets. QSAR methods have been shown to draw public attention since they were first introduced. In this review, the authors provide a brief discussion of the basic principles of QSAR, model development and model validation. They also highlight the current applications of QSAR in different fields, particularly in virtual screening, rational drug design and multi-target QSAR. Finally, in view of recent controversies, the authors detail the challenges faced by QSAR modeling and the relevant solutions. The aim of this review is to show how QSAR modeling can be applied in novel drug discovery, design and lead optimization. QSAR should intentionally be used as a powerful tool for fragment-based drug design platforms in the field of drug discovery and design. Although there have been an increasing number of experimentally determined protein structures in recent years, a great number of protein structures cannot be easily obtained (i.e., membrane transport proteins and G-protein coupled receptors). Fragment-based drug discovery, such as QSAR, could be applied further and have a significant role in dealing with these problems. Moreover, along with the development of computer software and hardware, it is believed that QSAR will be increasingly important.

  13. Advances in quantitative structure-activity relationship models of anti-Alzheimer's agents.

    Science.gov (United States)

    Ambure, Pravin; Roy, Kunal

    2014-06-01

    Alzheimer's disease (AD) is one of the lethal diseases, mainly affecting older people. The unclear root cause and involvement of various enzymes in the pathological conditions confirm the complexity of the disease. Quantitative structure-activity relationship (QSAR) techniques are of great significance in the design of drugs against AD. In the present review, the authors provide a basic background about AD and QSAR techniques. Furthermore, they review the various QSAR studies reported against various targets of AD. The information provided for each QSAR study includes chemical scaffold and target enzyme under study, applied QSAR technique and outcomes of the respective study. In silico techniques like QSAR hold great potential in designing leads against a complex disease like AD. In combination with other in silico techniques, QSAR can provide more useful and rational insight to facilitate the discovery of novel compounds. Only few QSAR studies on imaging agents have been reported; hence, more QSAR studies are recommended to explore the biomarker or imaging agents for improving diagnosis. Again, for proper symptomatic treatment, multi-target drugs acting on more than one target are required. Hence, more multi-target QSAR studies are recommended in future to achieve this goal.

  14. Quantitative Structure-activity Relationship (QSAR) Models for Docking Score Correction.

    Science.gov (United States)

    Fukunishi, Yoshifumi; Yamasaki, Satoshi; Yasumatsu, Isao; Takeuchi, Koh; Kurosawa, Takashi; Nakamura, Haruki

    2017-01-01

    In order to improve docking score correction, we developed several structure-based quantitative structure activity relationship (QSAR) models by protein-drug docking simulations and applied these models to public affinity data. The prediction models used descriptor-based regression, and the compound descriptor was a set of docking scores against multiple (∼600) proteins including nontargets. The binding free energy that corresponded to the docking score was approximated by a weighted average of docking scores for multiple proteins, and we tried linear, weighted linear and polynomial regression models considering the compound similarities. In addition, we tried a combination of these regression models for individual data sets such as IC 50 , K i , and %inhibition values. The cross-validation results showed that the weighted linear model was more accurate than the simple linear regression model. Thus, the QSAR approaches based on the affinity data of public databases should improve docking scores. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  15. Quantitative structure-activity relationships for aqueous metal-siderophore complexes.

    Science.gov (United States)

    Duckworth, Owen W; Bargar, John R; Sposito, Garrison

    2009-01-15

    Siderophores, biogenic chelating agents that facilitate the solubilization and uptake of ferric iron, form stable complexes with a wide range of nutrient and contaminant metals and thus may profoundly affect their fate, transport, and biogeochemical cycling. To understand more comprehensively the factors that control the stability and reactivity, as well as the potential for microbial uptake, of metal-siderophore complexes, we probed the structures of complexes formed between the trihydroxamate siderophore desferrioxamine B (DFOB) and Cu(II), Ga(III), Mn(II), Ni(II), and Zn(II) in solution by using extended X-ray absorption fine structure (EXAFS) spectroscopy. We find that all metals studied are dominantly in octahedral coordination, with significant Jahn-Teller distortion of the Cu(II)HDFOB(0) complex. Additionally, log-transformed complex stability constants correlate not only with the charge-normalized interatomic distances within the complex, affirming and expanding existing predictive relationships, but also with the Debye-Waller parameter of the first coordination shell. The derived structure-activity relationships not only quantitatively relate the measured physical architecture of aqueous complexes to their observed stability but also allow for the prediction of siderophore-metal stability constants.

  16. Quantitative structure-activity relationships of nitroaromatics toxicity to the algae (Scenedesmus obliguus).

    Science.gov (United States)

    Yan, Xiu-Fen; Xiao, He-Ming; Gong, Xue-Dong; Ju, Xue-Hai

    2005-04-01

    The DFT-B3LYP method, with the basis set 6-311G( * *), was employed to calculate the molecular geometries and electronic structures of 25 nitroaromatics. The acute toxicity (-lgEC(50)) of these compounds to the algae (Scenedesmus obliguus) along with hydrophobicity described by logK(OW), and two quantum chemical parameters-energy of the lowest unoccupied molecular orbital, E(LUMO), and the charge of the nitro group, [ForQ(NO2), were used to establish the quantitative structure-activity relationships (QSARs). For 18 mononitro derivatives, the hydrophobicity parameter logK(OW) could interpret the toxic mechanism successfully. Dinitro aromatic compounds were susceptible to be reduced to aniline for their electrophilic nature. Their toxicity was controlled mainly by electronic factors instead of hydrophobicity. The electronic parameters, E(LUMO) and Q(NO2), were used to yield the following model: -lg EC(50) = 3.746 - 25.053 E(LUMO) + 6.481 Q(NO2) (n=22, R=0.926, SE=0.206, F=56.854, Ptoxic values using the above equation are in good agreement with the experimental values.

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

    Directory of Open Access Journals (Sweden)

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

    2012-10-01

    Full Text Available 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 of unknown pesticides in the milk of cattle using their known physicochemical properties such as molecular weight (MW, melting point (MP, and log octanol to water partition coefficient (Ko/w as well as the milk characteristics such as pH, % fat, and specific gravity (SG in this species. The analysis revealed good correlation coefficients (R2 = 0.91 for cattle QSAR model. The coefficient for Ko/w for the studied pesticides was higher in cattle milk. Risk analysis was conducted based upon the determined pesticide residues and their provisional tolerable daily intakes. The daily intake levels of pesticide residues including cyhalothrin, chlorpyrifos and cypermethrin in present study were 3, 11, 2.5 times higher, respectively in cattle milk. This intake of pesticide contaminated milk might pose health hazards to humans in this locality.

  18. Quantitative structure-activity relationships and ecological risk assessment: an overview of predictive aquatic toxicology research.

    Science.gov (United States)

    Bradbury, S P

    1995-09-01

    In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible tools for predicting the toxicity of chemicals when little or no empirical data are available. A fundamental understanding of toxicological principles has been considered an important component to the acceptance and application of QSAR approaches as biologically relevant in ecological risk assessments. As a consequence, there has been an evolution of QSAR development and application from that of a chemical-class perspective to one that is more consistent with assumptions regarding modes of toxic action. In this review, techniques to assess modes of toxic action from chemical structure are discussed, with consideration that toxicodynamic knowledge bases must be clearly defined with regard to exposure regimes, biological models/endpoints and compounds that adequately span the diversity of chemicals anticipated for future applications. With such knowledge bases, classification systems, including rule-based expert systems, have been established for use in predictive aquatic toxicology applications. The establishment of QSAR techniques that are based on an understanding of toxic mechanisms is needed to provide a link to physiologically based toxicokinetic and toxicodynamic models, which can provide the means to extrapolate adverse effects across species and exposure regimes.

  19. Utilization of quantitative structure-activity relationships (QSARs) in risk assessment: Alkylphenols

    Energy Technology Data Exchange (ETDEWEB)

    Beck, B.D.; Toole, A.P.; Callahan, B.G.; Siddhanti, S.K. (Gradient Corporation, Cambridge, MA (United States))

    1991-12-01

    Alkylphenols are a class of environmentally pervasive compounds, found both in natural (e.g., crude oils) and in anthropogenic (e.g., wood tar, coal gasification waste) materials. Despite the frequent environmental occurrence of these chemicals, there is a limited toxicity database on alkylphenols. The authors have therefore developed a 'toxicity equivalence approach' for alkylphenols which is based on their ability to inhibit, in a specific manner, the enzyme cyclooxygenase. Enzyme-inhibiting ability for individual alkylphenols can be estimated based on the quantitative structure-activity relationship developed by Dewhirst (1980) and is a function of the free hydroxyl group, electron-donating ring substituents, and hydrophobic aromatic ring substituents. The authors evaluated the toxicological significance of cyclooxygenase inhibition by comparison of the inhibitory capacity of alkylphenols with the inhibitory capacity of acetylsalicylic acid, or aspirin, a compound whose low-level effects are due to cyclooxygenase inhibition. Since nearly complete absorption for alkylphenols and aspirin is predicted, based on estimates of hydrophobicity and fraction of charged molecules at gastrointestinal pHs, risks from alkylphenols can be expressed directly in terms of 'milligram aspirin equivalence,' without correction for absorption differences. They recommend this method for assessing risks of mixtures of alkylphenols, especially for those compounds with no chronic toxicity data.38 references.

  20. A Ligand-Based Approach To Identify Quantitative Structure–Activity Relationships for the Androgen Receptor

    Science.gov (United States)

    Bohl, Casey E.; Chang, Cheng; Mohler, Michael L.; Chen, Jiyun; Miller, Duane D.; Swaan, Peter W.; Dalton, James T.

    2007-01-01

    We examined the three-dimensional quantitative structure–activity relationship (QSAR) of a group of endogenous and synthetic compounds for the androgen receptor (AR) using comparative molecular field analysis (CoMFA). The goal of these studies was to identify structural features necessary for high binding affinity and optimization of selective androgen receptor modulators (SARMs). A homology model of the AR was used as a scaffold to align six lead compounds that served as templates for alignment of the remaining 116 structures prior to CoMFA modeling. The conventional r2 and cross-validated q2 relating observed and predicted relative binding affinity (RBA) were 0.949 and 0.593, respectively. Comparison of predicted and observed RBA for a test set of 10 compounds resulted in an r2 of 0.954, demonstrating the excellent predictive ability of the model. These integrated homology modeling and CoMFA studies identified critical amino acids for SARM interactions and provided QSAR data as the basis for mechanistic studies of AR structure, function, and design of optimized SARMs. PMID:15239655

  1. Predicting Flash Point of Organosilicon Compounds Using Quantitative Structure Activity Relationship Approach

    Directory of Open Access Journals (Sweden)

    Chen-Peng Chen

    2014-01-01

    Full Text Available The flash point (FP of a compound is the primary property used in the assessment of fire hazards for flammable liquids and is amongst the crucial information that people handling flammable liquids must possess as far as industrial safety is concerned. In this work, the FPs of 236 organosilicon compounds were collected and used to construct a quantitative structure activity relationship (QSAR model for predicting their FPs. The CODESSA PRO software was adopted to calculate the required molecular descriptors, and 350 molecular descriptors were developed for each compound. A modified stepwise regression algorithm was applied to choose descriptors that were highly correlated with the FP of organosilicon compounds. The proposed model was a linear regression model consisting of six descriptors. This 6-descriptor model gave an R2 value of 0.9174, QLOO2 value of 0.9106, and Q2 value of 0.8989. The average fitting error and the average predictive error were found to be of 10.34 K and 11.22 K, respectively, and the average fitting error in percentage and the average predictive error in percentage were found to be of 3.30 and 3.60%, respectively. Compared with the known reproducibility of FP measurement using standard test method, these predicted results were of a satisfactory precision.

  2. Time-dependent relative activities in the radioactive families

    International Nuclear Information System (INIS)

    Wiernik, M.

    1976-01-01

    The relative activities of the members of the principal radioactive families, with respect to the initial activities of chosen parents were calculated for a wide range of time intervals. Tables ard graphs that are useful for radiochemistry, source standardization and chronology are presented.Three series of graphs and tables are included; series A corresponds to the family 4n, series B corresponds to the family 4n+ x, series C corresponds to the family 4n+2. A foustry, source standardization and chronology are presented. rth series 4n+1 ( 241 Pu/ 209 Bi) was not included, because it does not exist in nature and, thus, is of little interest. Each series begins with a table identified by a plain letter (A,B,C) where all the nuclides considered for the calculations and their half-lives are listed. Branching was neglected. All the series begin with isotopes of plutonium in order to show some examples of no-equilibrium, and five of the longest lived members of each family were chosen as the parents of the sub-families. The graphs show that, besides their obvious use in radiochemical separations and standardizations, each family beginning with a naturally occuring nuclide has a particular time span (before secular equilibrium occurs) that can be used for chronology. Thus, if the proper radionuclides are present, we can use the wide range families in geological and archeological research and the short range ones in other kinds of jobs, like checking the authenticity of art masterpieces and other forensic problems. (T.G.)

  3. 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

  4. Quantitative structure activity relationship for the computational prediction of nitrocompounds carcinogenicity.

    Science.gov (United States)

    Morales, Aliuska Helguera; Pérez, Miguel Angel Cabrera; Combes, Robert D; González, Maykel Pérez

    2006-03-01

    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.

  5. New insights into the mechanisms of acetic acid resistance in Acetobacter pasteurianus using iTRAQ-dependent quantitative proteomic analysis.

    Science.gov (United States)

    Xia, Kai; Zang, Ning; Zhang, Junmei; Zhang, Hong; Li, Yudong; Liu, Ye; Feng, Wei; Liang, Xinle

    2016-12-05

    Acetobacter pasteurianus is the main starter in rice vinegar manufacturing due to its remarkable abilities to resist and produce acetic acid. Although several mechanisms of acetic acid resistance have been proposed and only a few effector proteins have been identified, a comprehensive depiction of the biological processes involved in acetic acid resistance is needed. In this study, iTRAQ-based quantitative proteomic analysis was adopted to investigate the whole proteome of different acidic titers (3.6, 7.1 and 9.3%, w/v) of Acetobacter pasteurianus Ab3 during the vinegar fermentation process. Consequently, 1386 proteins, including 318 differentially expressed proteins (pacetic acid stress, where >150 proteins were differentially expressed. Specifically, proteins involved in amino acid metabolic processes and fatty acid biosynthesis were differentially expressed, which may contribute to the acetic acid resistance of Acetobacter. Transcription factors, two component systems and toxin-antitoxin systems were implicated in the modulatory network at multiple levels. In addition, the identification of proteins involved in redox homeostasis, protein metabolism, and the cell envelope suggested that the whole cellular system is mobilized in response to acid stress. These findings provide a differential proteomic profile of acetic acid resistance in Acetobacter pasteurianus and have potential application to highly acidic rice vinegar manufacturing. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Quantitative analysis with advanced compensated polarized light microscopy on wavelength dependence of linear birefringence of single crystals causing arthritis

    Science.gov (United States)

    Takanabe, Akifumi; Tanaka, Masahito; Taniguchi, Atsuo; Yamanaka, Hisashi; Asahi, Toru

    2014-07-01

    To improve our ability to identify single crystals causing arthritis, we have developed a practical measurement system of polarized light microscopy called advanced compensated polarized light microscopy (A-CPLM). The A-CPLM system is constructed by employing a conventional phase retardation plate, an optical fibre and a charge-coupled device spectrometer in a polarized light microscope. We applied the A-CPLM system to measure linear birefringence (LB) in the visible region, which is an optical anisotropic property, for tiny single crystals causing arthritis, i.e. monosodium urate monohydrate (MSUM) and calcium pyrophosphate dihydrate (CPPD). The A-CPLM system performance was evaluated by comparing the obtained experimental data using the A-CPLM system with (i) literature data for a standard sample, MgF2, and (ii) experimental data obtained using an established optical method, high-accuracy universal polarimeter, for the MSUM. The A-CPLM system was found to be applicable for measuring the LB spectra of the single crystals of MSUM and CPPD, which cause arthritis, in the visible regions. We quantitatively reveal the large difference in LB between MSUM and CPPD crystals. These results demonstrate the usefulness of the A-CPLM system for distinguishing the crystals causing arthritis.

  7. The contact-system dependent plasminogen activator from human plasma: Identification and characterization

    NARCIS (Netherlands)

    Binnema, D.J.; Dooijewaard, G.; Iersel, J.J.L. van; Turion, P.N.C.; Kluft, C.

    1990-01-01

    Apart from tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), a third PA appears to occur in human plasma. Its activity is initiated when appropriate triggers of the contact system are added, and the activation depends on the presence of factor XII and

  8. Quantitative time-course metabolomics in human red blood cells reveal the temperature dependence of human metabolic networks.

    Science.gov (United States)

    Yurkovich, James T; Zielinski, Daniel C; Yang, Laurence; Paglia, Giuseppe; Rolfsson, Ottar; Sigurjónsson, Ólafur E; Broddrick, Jared T; Bordbar, Aarash; Wichuk, Kristine; Brynjólfsson, Sigurður; Palsson, Sirus; Gudmundsson, Sveinn; Palsson, Bernhard O

    2017-12-01

    The temperature dependence of biological processes has been studied at the levels of individual biochemical reactions and organism physiology ( e.g. basal metabolic rates) but has not been examined at the metabolic network level. Here, we used a systems biology approach to characterize the temperature dependence of the human red blood cell (RBC) metabolic network between 4 and 37 °C through absolutely quantified exo- and endometabolomics data. We used an Arrhenius-type model ( Q 10 ) to describe how the rate of a biochemical process changes with every 10 °C change in temperature. Multivariate statistical analysis of the metabolomics data revealed that the same metabolic network-level trends previously reported for RBCs at 4 °C were conserved but accelerated with increasing temperature. We calculated a median Q 10 coefficient of 2.89 ± 1.03, within the expected range of 2-3 for biological processes, for 48 individual metabolite concentrations. We then integrated these metabolomics measurements into a cell-scale metabolic model to study pathway usage, calculating a median Q 10 coefficient of 2.73 ± 0.75 for 35 reaction fluxes. The relative fluxes through glycolysis and nucleotide metabolism pathways were consistent across the studied temperature range despite the non-uniform distributions of Q 10 coefficients of individual metabolites and reaction fluxes. Together, these results indicate that the rate of change of network-level responses to temperature differences in RBC metabolism is consistent between 4 and 37 °C. More broadly, we provide a baseline characterization of a biochemical network given no transcriptional or translational regulation that can be used to explore the temperature dependence of metabolism. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. A quantitative description of the voltage-dependent capacitance in frog skeletal muscle in terms of equilibrium statistical mechanics.

    Science.gov (United States)

    Duane, S; Huang, C L

    1982-04-22

    We present an analysis of experimental steady-state properties of charge movements in voltage-clamped frog skeletal muscle; by adopting an approach based on equilibrium statistical mechanics, detailed assumptions about the dynamics of the charge movement were avoided. Different components of the charge movements, as characterized by their sensitivities to local anaesthetics, were taken to correspond to different types of independent subsystem (integral membrane proteins). Quantitative agreement with the data for the q beta and q gamma components was obtained for the simplest subsystems, having two energy levels; however, q alpha required three (or more) energy levels. Each of the subsystems can be interpreted as having a charged group, minimum valency z, able to occupy two or more positions within the membrane. The tetracaine-sensitive q gamma charge can be described in terms of an ensemble of subsystems having z = 4.5, each occupying one of two levels whose free energies at zero applied voltage differ by 1.7 x 10(-1) eV. Likewise, the lidocaine-sensitive q beta has z = 1.0, free energy difference 1.9 x 10(-2) eV. However, the simplest model for the lidocaine-resistant q alpha involves a charge of valency 1.7 moving between three levels having relative free energies at zero applied voltage -9.7 x 10(-2), 0, and 2.1 x 10(-2) eV respectively, where the intermediate level 'sees' about 50% of the applied voltage.

  10. 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.

  11. 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...

  12. 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

  13. 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

  14. Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors

    Science.gov (United States)

    Oprea, Tudor I.; García, Angel E.

    1996-06-01

    Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/Ki), with an explained variance r2 of 0.885, and a cross-validated q2 of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q2 for one component was 0.62 and 0.61, respectively, while r2 was 0.674. We demonstrate that the predictive r2 based on the mean activity (Ym) of the training set is misleading, while the test set Ym-based predictive r2 index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substitutents, and a smaller one at the C6-beta region.

  15. Quantitative DNA methylation analyses reveal stage dependent DNA methylation and association to clinico-pathological factors in breast tumors

    International Nuclear Information System (INIS)

    Klajic, Jovana; Tost, Jörg; Kristensen, Vessela N; Fleischer, Thomas; Dejeux, Emelyne; Edvardsen, Hege; Warnberg, Fredrik; Bukholm, Ida; Lønning, Per Eystein; Solvang, Hiroko; Børresen-Dale, Anne-Lise

    2013-01-01

    Aberrant DNA methylation of regulatory genes has frequently been found in human breast cancers and correlated to clinical outcome. In the present study we investigate stage specific changes in the DNA methylation patterns in order to identify valuable markers to understand how these changes affect breast cancer progression. Quantitative DNA methylation analyses of 12 candidate genes ABCB1, BRCCA1, CDKN2A, ESR1, GSTP1, IGF2, MGMT, HMLH1, PPP2R2B, PTEN, RASSF1A and FOXC1 was performed by pyrosequencing a series of 238 breast cancer tissue samples from DCIS to invasive tumors stage I to IV. Significant differences in methylation levels between the DCIS and invasive stage II tumors were observed for six genes RASSF1A, CDKN2A, MGMT, ABCB1, GSTP1 and FOXC1. RASSF1A, ABCB1 and GSTP1 showed significantly higher methylation levels in late stage compared to the early stage breast carcinoma. Z-score analysis revealed significantly lower methylation levels in DCIS and stage I tumors compared with stage II, III and IV tumors. Methylation levels of PTEN, PPP2R2B, FOXC1, ABCB1 and BRCA1 were lower in tumors harboring TP53 mutations then in tumors with wild type TP53. Z-score analysis showed that TP53 mutated tumors had significantly lower overall methylation levels compared to tumors with wild type TP53. Methylation levels of RASSF1A, PPP2R2B, GSTP1 and FOXC1 were higher in ER positive vs. ER negative tumors and methylation levels of PTEN and CDKN2A were higher in HER2 positive vs. HER2 negative tumors. Z-score analysis also showed that HER2 positive tumors had significantly higher z-scores of methylation compared to the HER2 negative tumors. Univariate survival analysis identifies methylation status of PPP2R2B as significant predictor of overall survival and breast cancer specific survival. In the present study we report that the level of aberrant DNA methylation is higher in late stage compared with early stage of invasive breast cancers and DCIS for genes mentioned above

  16. 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...

  17. Design, synthesis, antiviral bioactivity and three-dimensional quantitative structure-activity relationship study of novel ferulic acid ester derivatives containing quinazoline moiety.

    Science.gov (United States)

    Wu, Zengxue; Zhang, Jian; Chen, Jixiang; Pan, Jianke; Zhao, Lei; Liu, Dengyue; Zhang, Awei; Chen, Jin; Hu, Deyu; Song, Baoan

    2017-10-01

    Ferulic acid and quinazoline derivatives possess good antiviral activities. In order to develop novel compounds with high antiviral activities, a series of ferulic acid ester derivatives containing quinazoline were synthesized and evaluated for their antiviral activities. Bioassays indicated that some of the compounds exhibited good antiviral activities in vivo against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). One of the compounds demonstrated significant curative and protective activities against TMV and CMV, with EC 50 values of 162.14, 114.61 and 255.49, 138.81 mg L -1 , respectively, better than those of ningnanmycin (324.51, 168.84 and 373.88, 272.70 mg L -1 ). The values of q 2 and r 2 for comparative molecular field analysis and comparative molecular similarity index analysis in the TMV (0.508, 0.663 and 0.992, 0.930) and CMV (0.530, 0.626 and 0.997, 0.981) models presented good predictive abilities. Some of the title compounds demonstrated good antiviral activities. Three-dimensional quantitative structure-activity relationship models revealed that the antiviral activities depend on steric and electrostatic properties. These results could provide significant structural insights for the design of highly active ferulic acid derivatives. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  18. Toxicity of ionic liquids: Database and prediction via quantitative structure–activity relationship method

    International Nuclear Information System (INIS)

    Zhao, Yongsheng; Zhao, Jihong; Huang, Ying; Zhou, Qing; Zhang, Xiangping; Zhang, Suojiang

    2014-01-01

    Highlights: • A comprehensive database on toxicity of ionic liquids (ILs) was established. • Relationship between structure and toxicity of IL has been analyzed qualitatively. • Two new QSAR models were developed for predicting toxicity of ILs to IPC-81. • Accuracy of proposed nonlinear SVM model is much higher than the linear MLR model. • The established models can be explored in designing novel green agents. - Abstract: A comprehensive database on toxicity of ionic liquids (ILs) is established. The database includes over 4000 pieces of data. Based on the database, the relationship between IL's structure and its toxicity has been analyzed qualitatively. Furthermore, Quantitative Structure–Activity relationships (QSAR) model is conducted to predict the toxicities (EC 50 values) of various ILs toward the Leukemia rat cell line IPC-81. Four parameters selected by the heuristic method (HM) are used to perform the studies of multiple linear regression (MLR) and support vector machine (SVM). The squared correlation coefficient (R 2 ) and the root mean square error (RMSE) of training sets by two QSAR models are 0.918 and 0.959, 0.258 and 0.179, respectively. The prediction R 2 and RMSE of QSAR test sets by MLR model are 0.892 and 0.329, by SVM model are 0.958 and 0.234, respectively. The nonlinear model developed by SVM algorithm is much outperformed MLR, which indicates that SVM model is more reliable in the prediction of toxicity of ILs. This study shows that increasing the relative number of O atoms of molecules leads to decrease in the toxicity of ILs

  19. Quantitative structure-activity relationships (QSARs) for the transformation of organic micropollutants during oxidative water treatment.

    Science.gov (United States)

    Lee, Yunho; von Gunten, Urs

    2012-12-01

    Various oxidants such as chlorine, chlorine dioxide, ferrate(VI), ozone, and hydroxyl radicals can be applied for eliminating organic micropollutant by oxidative transformation during water treatment in systems such as drinking water, wastewater, and water reuse. Over the last decades, many second-order rate constants (k) have been determined for the reaction of these oxidants with model compounds and micropollutants. Good correlations (quantitative structure-activity relationships or QSARs) are often found between the k-values for an oxidation reaction of closely related compounds (i.e. having a common organic functional group) and substituent descriptor variables such as Hammett or Taft sigma constants. In this study, we developed QSARs for the oxidation of organic and some inorganic compounds and organic micropollutants transformation during oxidative water treatment. A number of 18 QSARs were developed based on overall 412 k-values for the reaction of chlorine, chlorine dioxide, ferrate, and ozone with organic compounds containing electron-rich moieties such as phenols, anilines, olefins, and amines. On average, 303 out of 412 (74%) k-values were predicted by these QSARs within a factor of 1/3-3 compared to the measured values. For HO(·) reactions, some principles and estimation methods of k-values (e.g. the Group Contribution Method) are discussed. The developed QSARs and the Group Contribution Method could be used to predict the k-values for various emerging organic micropollutants. As a demonstration, 39 out of 45 (87%) predicted k-values were found within a factor 1/3-3 compared to the measured values for the selected emerging micropollutants. Finally, it is discussed how the uncertainty in the predicted k-values using the QSARs affects the accuracy of prediction for micropollutant elimination during oxidative water treatment. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Membrane-interaction quantitative structure--activity relationship (MI-QSAR) analyses of skin penetration enhancers.

    Science.gov (United States)

    Zheng, Tao; Hopfinger, A J; Esposito, Emilio X; Liu, Jianzhong; Tseng, Yufeng J

    2008-06-01

    Membrane-interaction quantitative structure-activity relationship (MI-QSAR) models for two skin penetration enhancer data sets of 61 and 42 compounds were constructed and compared to QSAR models constructed for the same two data sets using only classic intramolecular QSAR descriptors. These two data sets involve skin penetration enhancement of hydrocortisone and hydrocortisone acetate, and the enhancers are generally similar in structure to lipids and surfactants. A new MI-QSAR descriptor, the difference in the integrated cylindrical distribution functions over the phospholipid monolayer model, in and out of the presence of the skin penetration enhancer, DeltaSigma h(r), was developed. This descriptor is dominant in the optimized MI-QSAR models of both training sets studied and greatly reduces the size and complexity of the MI-QSAR models as compared to those QSAR models developed using the classic intramolecular descriptors. The MI-QSAR models indicate that good penetration enhancers make bigger "holes" in the monolayer and are less aqueous-soluble, so as to preferentially enter the monolayer, than are poor penetration enhancers. The skin penetration enhancer thus alters the structure and organization of the monolayer. This space and time alteration in the structure and dynamics of the membrane monolayer is captured by DeltaSigma h(r) and is simplistically referred to as "holes" in the monolayer. The MI-QSAR models explain 70-80% of the variance in skin penetration enhancement across each of the two training sets and are stable predictive models using accepted diagnostic measures of robustness and predictivity.

  1. Quantitative structure-activity analysis of the algae toxicity of nitroaromatic compounds.

    Science.gov (United States)

    Schmitt, H; Altenburger, R; Jastorff, B; Schüürmann, G

    2000-06-01

    Proliferation toxicity toward the algae Scenedesmus vacuolatus in a 24 h one-generation reproduction assay was determined for nitrobenzene and 18 derivatives, including two phenols. The resultant EC(50) values covering more than 4 orders of magnitude were subjected to a quantitative structure-activity analysis (QSAR) using hydrophobicity in terms of the octanol/water partition coefficient in logarithmic form, log K(ow), and 16 quantum chemical descriptors of molecular reactivity that were calculated with the AM1 scheme. For 13 mononitro derivatives and the highly hydrophobic trifluralin, a narcotic-type mode of action can explain most of the toxicity variation. Correction of log K(ow) for ionization for the phenols and quantification of the molecular susceptibility for one-electron reduction as apparently rate-determining biotransformation step by the energy of the lowest unoccupied molecular orbital, E(LUMO), yields a highly significant QSAR for all 19 compounds (r(adj)(2) = 0.90), which can be further improved when adding the maximum net atomic charge at the nitro nitrogen, q(nitro)(-)(N), as the third descriptor (r(adj)(2) = 0.93). Comparison of the energy of the singly occupied molecular orbital, E(SOMO), of the radical anions as initial metabolites with the E(SOMO) of known redox cyclers suggests that dinitrobenzenes and TFM as well as multiply chlorinated nitrobenzenes may also exert oxidative stress. This is based on an E(SOMO) window of -0.30 to 0. 55 eV as a tentative criterion for molecular structures to have the potential for redox cycling, derived from a set of eight known redox cyclers. The discussion includes a detailed analysis of apparently relevant metabolic pathways and associated modes of toxic action of nitroaromatics.

  2. Quantitative Structure Activity Relationship and Risk Analysis of Some Pesticides in the Goat milk

    Directory of Open Access Journals (Sweden)

    Faqir Muhammad

    2013-01-01

    Full Text Available The detection and quantification of different pesticides in the goat milk samples collected from different localities of Faisalabad, Pakistan was performed by HPLC using solid phase microextraction. The analysis showed that about 50% milk samples were contaminated with pesticides. The mean+/-SEM levels (ppm of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.34+/-0.007, 0.063+/-0.002, 0.034+/-0.002 and 0.092+/-0.002, respectively; whereas, methyl parathion was not detected in any of the analyzed samples. Quantitative structure activity relationship (QSAR models were suggested to predict the residues of unknown pesticides in the goat milk using their known physicochemical characteristics including molecular weight (MW, melting point (MP, and log octanol to water partition coefficient (Ko/w in relation to the characteristics such as pH, % fat, specific gravity and refractive index of goat milk. The analysis revealed good correlation coefficient (R2 = 0.985 for goat QSAR model. The coefficients for Ko/w and refractive index for the studied pesticides were higher in goat milk. This suggests that these are better determinants for pesticide residue prediction in the milk of these animals. Based upon the determined pesticide residues and their provisional tolerable daily intakes, risk analysis was also conducted which showed that daily intake levels of pesticide residues including cyhalothrin, chlorpyrifos and cypermethrin in present study are 2.68, 5.19 and 2.71 times higher, respectively in the goat milk. This intake of pesticide contaminated milk might pose health hazards to humans in this locality.

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

    Science.gov (United States)

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

    2014-01-01

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

  4. 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.

  5. Newly developed quantitative transactivation system shows difference in activation by Vitis CBF transcription factors on DRE/CRT elements.

    Science.gov (United States)

    Nassuth, Annette; Siddiqua, Mahbuba; Xiao, Huogen; Moody, Michelle A; Carlow, Chevonne E

    2014-01-01

    Agroinfiltration-based transactivation systems can determine if a protein functions as a transcription factor, and via which promoter element. However, this activation is not always a yes or no proposition. Normalization for variation in plasmid delivery into plant cells, sample collection and protein extraction is desired to allow for a quantitative comparison between transcription factors or promoter elements. We developed new effector and reporter plasmids which carry additional reporter genes, as well as a procedure to assay all three reporter enzymes from a single extract. The applicability of these plasmids was demonstrated with the analysis of CBF transcription factors and their target promoter sequence, DRE/CRT. Changes in the core DRE/CRT sequence abolished activation by Vitis CBF1 or Vitis CBF4, whereas changes in the surrounding sequence lowered activation by Vitis CBF1 but much less so for Vitis CBF4. The system also detected a reduction in activation due to one amino acid change in Vitis CBF1. The newly developed effector and reporter plasmids improve the ability to quantitatively compare the activation on two different promoter elements by the same transcription factor, or between two different transcription factors on the same promoter element. The quantitative difference in activation by VrCBF1 and VrCBF4 on various DRE/CRT elements support the hypothesis that these transcription factors have unique roles in the cold acclimation process.

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

    Science.gov (United States)

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

    2008-10-01

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

  7. 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.

  8. The evaluation of gallbladder function by quantitative radionuclide cholescintigraphy in patients with noninsulin-dependent diabetes mellitus

    International Nuclear Information System (INIS)

    Kao, C.H.; Tsou, C.T.; Wang, S.J.; Yeh, S.H.

    1993-01-01

    Twenty-nine patients (24 males, 5 females; aged 62.8 ± 10.1 years) with noninsulin-dependent diabetes mellitus (NIDDM) without gallstones and impaired liver function were included in our study. The patients were categorized by blood sugar control and disease duration. Twelve normal controls (10 males, 2 females; aged 62.8 ± 12.4 years) were also studied for comparison. The gallbladder filling fraction (FF) and ejection fraction (EF) were calculated. The results showed no significant difference between (1) NIDDM and normal controls in FF (69.1 ± 29.4 versus 67.5 ± 24.0%) and EF (45.0 ± 23.5 versus 54.8 ± 10.0%) by a t-test, (2) good and poor blood sugar control in FF (64.9 ± 30.9 versus 73.7 ± 26.4%) and EF (42.0 ± 25.4 versus 54.8 ± 10.0%) by a Mann-Whitney U test, (3) long and short disease durations in FF (70.9 ± 29.7 versus 67.9 ± 28.7%) and EF (37.9 ± 20.7 versus 50.0 ± 24.1%) by a Mann-Whitney U test. In conclusion, the results challenge some previous reports and warrant further research. (author)

  9. The evaluation of gallbladder function by quantitative radionuclide cholescintigraphy in patients with noninsulin-dependent diabetes mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Kao, C.H.; Tsou, C.T.; Wang, S.J.; Yeh, S.H. (Taichung Veterans General Hospital (Taiwan))

    1993-10-01

    Twenty-nine patients (24 males, 5 females; aged 62.8 [+-] 10.1 years) with noninsulin-dependent diabetes mellitus (NIDDM) without gallstones and impaired liver function were included in our study. The patients were categorized by blood sugar control and disease duration. Twelve normal controls (10 males, 2 females; aged 62.8 [+-] 12.4 years) were also studied for comparison. The gallbladder filling fraction (FF) and ejection fraction (EF) were calculated. The results showed no significant difference between (1) NIDDM and normal controls in FF (69.1 [+-] 29.4 versus 67.5 [+-] 24.0%) and EF (45.0 [+-] 23.5 versus 54.8 [+-] 10.0%) by a t-test, (2) good and poor blood sugar control in FF (64.9 [+-] 30.9 versus 73.7 [+-] 26.4%) and EF (42.0 [+-] 25.4 versus 54.8 [+-] 10.0%) by a Mann-Whitney U test, (3) long and short disease durations in FF (70.9 [+-] 29.7 versus 67.9 [+-] 28.7%) and EF (37.9 [+-] 20.7 versus 50.0 [+-] 24.1%) by a Mann-Whitney U test. In conclusion, the results challenge some previous reports and warrant further research. (author).

  10. Assessment of active and inactive sacroiliitis in patients with ankylosing spondylitis using quantitative dynamic contrast-enhanced MRI.

    Science.gov (United States)

    Zhang, Mengchao; Zhou, Le; Huang, Ning; Zeng, Hong; Liu, Songyan; Liu, Lin

    2017-07-01

    To investigate the feasibility of using quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to differentiate the active and inactive stage of sacroiliitis and the correlation between quantitative parameters and disease activity as measured by clinical scores. Forty-two patients with ankylosing spondylitis underwent DCE-MRI on a 3.0T MRI unit. According to the results of the blood sedimentation rate (ESR), C-reactive protein (CRP), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the patients were grouped into inactive and active groups. Pharmacokinetic models were used to generate the semiquantitative and quantitative hemodynamic parameters of DCE-MRI. The between-group differences were analyzed using the Wilcoxon rank sum test, and the correlations between the pharmacokinetic parameters and BASDAI score were analyzed using Spearman's correlation coefficient. The efficacies of different parameters in differentiating the active and inactive phase of sacroiliitis were evaluated and compared using receiver operator characteristics (ROC) curve analysis. K trans , K ep , V e , time to peak (TTP), max concentration (MAX Conc), and area under the curve (AUC) of the active group were significantly higher than those of the inactive stage group (P 0.05), except between AUC and MAX Conc (P = 0.0012). Quantitative DCE-MRI parameters can differentiate between active and inactive ankylosing spondylitis. Among those, K trans had the highest correlation coefficient with the BASDAI score. 2 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:71-78. © 2016 International Society for Magnetic Resonance in Medicine.

  11. 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.

  12. 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.

  13. Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors.

    Directory of Open Access Journals (Sweden)

    Oliver N F King

    2010-11-01

    Full Text Available Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N(ε-Methylation of lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. N(ε-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors.High-throughput screening of a ∼236,000-member collection of diverse molecules arrayed as dilution series was used to identify inhibitors of the JMJD2 (KDM4 family of 2-oxoglutarate-dependent histone demethylases. Initial screening hits were prioritized by a combination of cheminformatics, counterscreening using a coupled assay enzyme, and orthogonal confirmatory detection of inhibition by mass spectrometric assays. Follow-up studies were carried out on one of the series identified, 8-hydroxyquinolines, which were shown by crystallographic analyses to inhibit by binding to the active site Fe(II and to modulate demethylation at the H3K9 locus in a cell-based assay.These studies demonstrate that diverse compound screening can yield novel inhibitors of 2OG dependent histone demethylases and provide starting points for the development of potent and selective agents to interrogate epigenetic regulation.

  14. Improvement of multivariate image analysis applied to quantitative structure-activity relationship (QSAR) analysis by using wavelet-principal component analysis ranking variable selection and least-squares support vector machine regression: QSAR study of checkpoint kinase WEE1 inhibitors.

    Science.gov (United States)

    Cormanich, Rodrigo A; Goodarzi, Mohammad; Freitas, Matheus P

    2009-02-01

    Inhibition of tyrosine kinase enzyme WEE1 is an important step for the treatment of cancer. The bioactivities of a series of WEE1 inhibitors have been previously modeled through comparative molecular field analyses (CoMFA and CoMSIA), but a two-dimensional image-based quantitative structure-activity relationship approach has shown to be highly predictive for other compound classes. This method, called multivariate image analysis applied to quantitative structure-activity relationship, was applied here to derive quantitative structure-activity relationship models. Whilst the well-known bilinear and multilinear partial least squares regressions (PLS and N-PLS, respectively) correlated multivariate image analysis descriptors with the corresponding dependent variables only reasonably well, the use of wavelet and principal component ranking as variable selection methods, together with least-squares support vector machine, improved significantly the prediction statistics. These recently implemented mathematical tools, particularly novel in quantitative structure-activity relationship studies, represent an important advance for the development of more predictive quantitative structure-activity relationship models and, consequently, new drugs.

  15. Cdk5 targets active Src for ubiquitin-dependent degradation by phosphorylating Src(S75)

    Science.gov (United States)

    Pan, Q.; Qiao, F.; Gao, C.; Norman, B.; Optican, L.

    2011-01-01

    The non-receptor tyrosine kinase Src is a critical regulator of cytoskeletal contraction, cell adhesion, and migration. In normal cells, Src activity is stringently controlled by Csk-dependent phosphorylation of Src(Y530), and by Cullin-5-dependent ubiquitinylation, which affects active Src(pY419) exclusively, leading to its degradation by the proteosome. Previous work has shown that Src activity is also limited by Cdk5, a proline-directed kinase, which has been shown to phosphorylate Src(S75). Here we show that this phosphorylation promotes the ubiquitin-dependent degradation of Src, thus restricting the availability of active Src. We demonstrate that Src(S75) phosphorylation occurs in vivo in epithelial cells, and like ubiquitinylation, is associated only with active Src. Preventing Cdk5-dependent phosphorylation of Src(S75), by site-specific mutation of S75 or by Cdk5 inhibition or suppression, increases Src(Y419) phosphorylation and kinase activity, resulting in Src-dependent cytoskeletal changes. In transfected cells, ubiquitinylation of Src(S75A) is about 35% that of wild-type Src-V5, and its half-life is approximately 2.5-fold greater. Cdk5 suppression leads to a comparable decrease in the ubiquitinylation of endogenous Src and a similar increase in Src stability. Together, these findings demonstrate that Cdk5-dependent phosphorylation of Src(S75) is a physiologically significant mechanism of regulating intracellular Src activity. PMID:21442427

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. Effects of Drawing on Alpha Activity: A Quantitative EEG Study with Implications for Art Therapy

    Science.gov (United States)

    Belkofer, Christopher M.; Van Hecke, Amy Vaughan; Konopka, Lukasz M.

    2014-01-01

    Little empirical evidence exists as to how materials used in art therapy affect the brain and its neurobiological functioning. This pre/post within-groups study utilized the quantitative electroencephalogram (qEEG) to measure residual effects in the brain after 20 minutes of drawing. EEG recordings were conducted before and after participants (N =…

  2. Quantitative structure-activity relationship (QSAR) analysis to predict drug-drug interactions of ABC transporter ABCG2.

    Science.gov (United States)

    Ishikawa, T; Hirano, H; Saito, H; Sano, K; Ikegami, Y; Yamaotsu, N; Hirono, S

    2012-06-01

    Quantitative structure-activity relationship (QSAR) analysis is a practical approach by which chemical structure is quantitatively correlated with biological activity or chemical reactivity. Human ABC transporter ABCG2 exhibits broad substrate specificity toward structurally diverse compounds. To gain insight into the relationship between the molecular structures of compounds and the interaction with ABCG2, we have developed an algorithm that analyzes QSAR to evaluate ABCG2-drug interactions. In addition, to support QSAR analysis, we developed a high-speed screening method for analyzing the drug-drug interactions of ABCG2. Based on both experimental results and computational QSAR analysis data, we propose a hypothetical mechanism underlying ABC-mediated drug transport and its interaction with drugs.

  3. Definition of a Bidirectional Activity-Dependent Pathway Involving BDNF and Narp

    Directory of Open Access Journals (Sweden)

    Abigail Mariga

    2015-12-01

    Full Text Available One of the cardinal features of neural development and adult plasticity is the contribution of activity-dependent signaling pathways. However, the interrelationships between different activity-dependent genes are not well understood. The immediate early gene neuronal-activity-regulated pentraxin (NPTX2 or Narp encodes a protein that has been associated with excitatory synaptogenesis, AMPA receptor aggregation, and the onset of critical periods. Here, we show that Narp is a direct transcriptional target of brain-derived neurotrophic factor (BDNF, another highly regulated activity-dependent gene involved in synaptic plasticity. Unexpectedly, Narp is bidirectionally regulated by BDNF. Acute BDNF withdrawal results in downregulation of Narp, whereas transcription of Narp is greatly enhanced by BDNF. Furthermore, our results show that BDNF directly regulates Narp to mediate glutamatergic transmission and mossy fiber plasticity. Hence, Narp serves as a significant epistatic target of BDNF to regulate synaptic plasticity during periods of dynamic activity.

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

    OpenAIRE

    Chen G.; Vijver M.G.; Xiao Y.; Peijnenburg W.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 preliminary attempts of correlating ENMs’ characteristics to the biological effects elicited by ENMs highlighted the potential applicability of (Q)SARs in the nanotoxicity field. This review discusse...

  5. 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...... levels of uPAR across different human cancer xenograft models in mice and to illustrate the clinical potential of uPAR PET in future settings for individualized therapy....

  6. Does the benefit on survival from leisure time physical activity depend on physical activity at work?

    DEFF Research Database (Denmark)

    Holtermann, Andreas; Marott, Jacob Louis; Gyntelberg, Finn

    2013-01-01

    To investigate if persons with high physical activity at work have the same benefits from leisure time physical activity as persons with sedentary work.......To investigate if persons with high physical activity at work have the same benefits from leisure time physical activity as persons with sedentary work....

  7. 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.

  8. 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.)

  9. Activation autoradiography: imaging and quantitative determination of endogenous and exogenous oxygen in the rat brain

    International Nuclear Information System (INIS)

    Kawashima, K.; Iwata, R.; Kogure, K.; Ohtomo, H.; Orihara, H.; Ido, T.

    1987-01-01

    Endogenous and exogenous oxygen in the rat brain were quantitatively determined using an autoradiographic technique. The oxygen images of frozen and dried rat brain sections were obtained as 18 F images by using the 16 O ( 3 He,p) 18 F reaction for endogenous 16 O images and the 18 O(p,n) 18 F reaction for endogenous and exogenous 18 O images. These autoradiograms demonstrated the different distribution of oxygen between gray and white matter. These images also allowed differentiation of the individual structures of hippocampal formation, owing to the differing water content of the various structures. Local oxygen contents were quantitatively determined from autoradiograms of brain sections and standard sections with known oxygen contents. The estimated values were 75.6 +/- 4.6 wt% in gray matter and 72.2 +/- 4.0 wt% in white matter. The systematic error in the present method was estimated to be 4.9%

  10. Quantitative structure-activity relationship (QSAR) study of a series of benzimidazole derivatives as inhibitors of Saccharomyces cerevisiae.

    Science.gov (United States)

    Podunavac-Kuzmanović, Sonja O; Cvetković, Dragoljub D; Jevrić, Lidija R; Uzelac, Natasa J

    2013-01-01

    A quantitative structure activity relationship (QSAR) has been carried out on a series of benzimidazole derivatives to identify the structural requirements for their inhibitory activity against yeast Saccharomyces cerevisiae. A multiple linear regression (MLR) procedure was used to model the relationships between various physicochemical, steric, electronic, and structural molecular descriptors and antifungal activity of benzimidazole derivatives. The QSAR expressions were generated using a training set of 16 compounds and the predictive ability of the resulting models was evaluated against a test set of 8 compounds. The best QSAR models were further validated by leave one out technique as well as by the calculation of statistical parameters for the established theoretical models. Therefore, satisfactory relationships between antifungal activity and molecular descriptors were found. QSAR analysis reveals that lipophilicity descriptor (logP), dipole moment (DM) and surface area grid (SAG) govern the inhibitory activity of compounds studied against Saccharomyces cerevisiae.

  11. User activity dependent paging scheme in a multi-cell campus ...

    African Journals Online (AJOL)

    Nigerian Journal of Technological Development ... WLAN, which will take advantage of the unique campus setting and activities We, therefore, · propose a User-Activity Dependent Paging Scheme (UADPS) in a Multi-Cell Campus WLAN Environment a paging algorithm that considers mobile devices in a multi cell WLAN.

  12. T-dependent B-cell activation is signalled by an early increase in potassium influx

    DEFF Research Database (Denmark)

    Owens, T; Kaplan, J G

    1982-01-01

    (previously demonstrated when B and T lymphocytes were separately stimulated) also occurs when B cells are stimulated through cooperation with mitogen-activated T cells, and is also detectable early in culture. T-dependent activation of B cells is therefore detectable considerably earlier than by conventional...

  13. Cdk5 targets active Src for ubiquitin-dependent degradation by phosphorylating Src(S75)

    OpenAIRE

    Pan, Q.; Qiao, F.; Gao, C.; Norman, B.; Optican, L.; Zelenka, Peggy S.

    2011-01-01

    The non-receptor tyrosine kinase Src is a critical regulator of cytoskeletal contraction, cell adhesion, and migration. In normal cells, Src activity is stringently controlled by Csk-dependent phosphorylation of Src(Y530), and by Cullin-5-dependent ubiquitinylation, which affects active Src(pY419) exclusively, leading to its degradation by the proteosome. Previous work has shown that Src activity is also limited by Cdk5, a proline-directed kinase, which has been shown to phosphorylate Src(S75...

  14. Activity-dependent brain-derived neurotrophic factor expression regulates cortistatin-interneurons and sleep behavior

    Directory of Open Access Journals (Sweden)

    Martinowich Keri

    2011-03-01

    Full Text Available Abstract Background Sleep homeostasis is characterized by a positive correlation between sleep length and intensity with the duration of the prior waking period. A causal role for brain-derived neurotrophic factor (BDNF in sleep homeostasis has been suggested, but the underlying mechanisms remain unclear. Cortistatin, a neuropeptide expressed primarily in a subset of cortical GABAergic interneurons, is another molecule implicated in sleep homeostasis. Results We confirmed that sleep deprivation leads to an increase in cortical cortistatin mRNA expression. Disruption of activity-dependent BDNF expression in a genetically modified mouse line impairs both baseline levels of cortistatin mRNA as well as its levels following sleep deprivation. Disruption of activity-dependent BDNF also leads to a decrease in sleep time during the active (dark phase. Conclusion Our studies suggest that regulation of cortistatin-expressing interneurons by activity-dependent BDNF expression may contribute to regulation of sleep behavior.

  15. 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

  16. 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.

  17. The calcium-dependent protein kinase 3 of toxoplasma influences basal calcium levels and functions beyond egress as revealed by quantitative phosphoproteome analysis.

    Directory of Open Access Journals (Sweden)

    Moritz Treeck

    2014-06-01

    Full Text Available Calcium-dependent protein kinases (CDPKs are conserved in plants and apicomplexan parasites. In Toxoplasma gondii, TgCDPK3 regulates parasite egress from the host cell in the presence of a calcium-ionophore. The targets and the pathways that the kinase controls, however, are not known. To identify pathways regulated by TgCDPK3, we measured relative phosphorylation site usage in wild type and TgCDPK3 mutant and knock-out parasites by quantitative mass-spectrometry using stable isotope-labeling with amino acids in cell culture (SILAC. This revealed known and novel phosphorylation events on proteins predicted to play a role in host-cell egress, but also a novel function of TgCDPK3 as an upstream regulator of other calcium-dependent signaling pathways, as we also identified proteins that are differentially phosphorylated prior to egress, including proteins important for ion-homeostasis and metabolism. This observation is supported by the observation that basal calcium levels are increased in parasites where TgCDPK3 has been inactivated. Most of the differential phosphorylation observed in CDPK3 mutants is rescued by complementation of the mutants with a wild type copy of TgCDPK3. Lastly, the TgCDPK3 mutants showed hyperphosphorylation of two targets of a related calcium-dependent kinase (TgCDPK1, as well as TgCDPK1 itself, indicating that this latter kinase appears to play a role downstream of TgCDPK3 function. Overexpression of TgCDPK1 partially rescues the egress phenotype of the TgCDPK3 mutants, reinforcing this conclusion. These results show that TgCDPK3 plays a pivotal role in regulating tachyzoite functions including, but not limited to, egress.

  18. The Calcium-Dependent Protein Kinase 3 of Toxoplasma Influences Basal Calcium Levels and Functions beyond Egress as Revealed by Quantitative Phosphoproteome Analysis

    Science.gov (United States)

    Treeck, Moritz; Sanders, John L.; Gaji, Rajshekhar Y.; LaFavers, Kacie A.; Child, Matthew A.; Arrizabalaga, Gustavo; Elias, Joshua E.; Boothroyd, John C.

    2014-01-01

    Calcium-dependent protein kinases (CDPKs) are conserved in plants and apicomplexan parasites. In Toxoplasma gondii, TgCDPK3 regulates parasite egress from the host cell in the presence of a calcium-ionophore. The targets and the pathways that the kinase controls, however, are not known. To identify pathways regulated by TgCDPK3, we measured relative phosphorylation site usage in wild type and TgCDPK3 mutant and knock-out parasites by quantitative mass-spectrometry using stable isotope-labeling with amino acids in cell culture (SILAC). This revealed known and novel phosphorylation events on proteins predicted to play a role in host-cell egress, but also a novel function of TgCDPK3 as an upstream regulator of other calcium-dependent signaling pathways, as we also identified proteins that are differentially phosphorylated prior to egress, including proteins important for ion-homeostasis and metabolism. This observation is supported by the observation that basal calcium levels are increased in parasites where TgCDPK3 has been inactivated. Most of the differential phosphorylation observed in CDPK3 mutants is rescued by complementation of the mutants with a wild type copy of TgCDPK3. Lastly, the TgCDPK3 mutants showed hyperphosphorylation of two targets of a related calcium-dependent kinase (TgCDPK1), as well as TgCDPK1 itself, indicating that this latter kinase appears to play a role downstream of TgCDPK3 function. Overexpression of TgCDPK1 partially rescues the egress phenotype of the TgCDPK3 mutants, reinforcing this conclusion. These results show that TgCDPK3 plays a pivotal role in regulating tachyzoite functions including, but not limited to, egress. PMID:24945436

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

    Directory of Open Access Journals (Sweden)

    Jong-Seok Moon

    2015-07-01

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

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

    Science.gov (United States)

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

    2015-07-07

    The mammalian target of rapamycin complex 1 (mTORC1) regulates activation of immune cells and cellular energy metabolism. Although glycolysis has been linked to immune functions, the mechanisms by which glycolysis regulates NLRP3 inflammasome activation remain unclear. Here, we demonstrate that mTORC1-induced glycolysis provides an essential mechanism for NLRP3 inflammasome activation. Moreover, we demonstrate that hexokinase 1 (HK1)-dependent glycolysis, under the regulation of mTORC1, represents a critical metabolic pathway for NLRP3 inflammasome activation. Downregulation of glycolysis by inhibition of Raptor/mTORC1 or HK1 suppressed both pro-IL-1β maturation and caspase-1 activation in macrophages in response to LPS and ATP. These results suggest that upregulation of HK1-dependent glycolysis by mTORC1 regulates NLRP3 inflammasome activation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2014-01-01

    Methamphetamine (MA) dependence is associated with cognitive deficits. Methylphenidate (MPH) has been shown to improve inhibitory control in healthy and cocaine-dependent subjects. This study aimed to understand the neurophysiological effects before and after acute MPH administration in active MA-dependent and control subjects. Fifteen MA-dependent and 18 control subjects aged 18–46 years were scanned using functional magnetic resonance imaging before and after either a single oral dose of MPH (18 mg) or placebo while performing a color-word Stroop task. Baseline accuracy was lower (p = 0.026) and response time (RT) was longer (p cognitive control. Increased activation of the dorsolateral prefrontal cortex (DLPFC) and parietal cortex during the incongruent and Stroop effect conditions, respectively was observed in MA-dependent compared to control subjects (p Stroop effect were observed in MA-dependent subjects (p Stroop effect conditions (p Stroop conflict resolution, and a decreased need for recruitment of neural resources in parietal and occipital regions compared to the other groups, while maintaining a comparable level of task performance to that achieved pre-drug administration. Due to the small sample size, the results from this study are preliminary; however, they inform us about the effects of MPH on the neural correlates of cognitive control in active MA-dependent subjects. PMID:24639656

  2. Sequential reinstatement of neocortical activity during slow oscillations depends on cells’ global activity

    NARCIS (Netherlands)

    Peyrache, A.; Benchenane, K.; Khamassi, M.; Wiener, S.I.; Battaglia, F.P.

    2010-01-01

    During Slow Wave Sleep (SWS), cortical activity is dominated by endogenous processes modulated by slow oscillations (0.1-1 Hz): cell ensembles fluctuate between states of sustained activity (UP states) and silent epochs (DOWN states). We investigate here the temporal structure of ensemble activity

  3. IKK/NF-κB-dependent satellite glia activation induces spinal cord microglia activation and neuropathic pain after nerve injury.

    Science.gov (United States)

    Lim, Hyoungsub; Lee, Hyunkyoung; Noh, Kyungchul; Lee, Sung Joong

    2017-09-01

    Increasing evidence indicates that both microglia and satellite glial cell (SGC) activation play causal roles in neuropathic pain development after peripheral nerve injury; however, the activation mechanisms and their contribution to neuropathic pain remain elusive. To address this issue, we generated Ikkβ conditional knockout mice (Cnp-Cre/Ikkβ; cIkkβ) in which IKK/NF-κB-dependent proinflammatory SGC activation was abrogated. In these mice, nerve injury-induced spinal cord microglia activation and pain hypersensitivity were significantly attenuated compared to those in control mice. In addition, nerve injury-induced proinflammatory gene expression and macrophage infiltration into the dorsal root ganglion (DRG) were severely compromised. However, macrophages recruited into the DRG had minimal effects on spinal cord microglia activation, suggesting a causal effect for SGC activation on spinal cord microglia activation. In an effort to elucidate the molecular mechanisms, we measured Csf1 expression in the DRG, which is implicated in spinal cord microglia activation after nerve injury. In cIkkβ mice, nerve injury-induced Csf1 upregulation was ameliorated indicating that IKK/NF-κΒ-dependent SGC activation induced Csf1 expression in sensory neurons. Taken together, our data suggest that nerve injury-induced SGC activation triggers Csf1 induction in sensory neurons, spinal cord microglia activation, and subsequent central pain sensitization.

  4. 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

  5. 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.

  6. Dose-dependent induction of astrocyte activation and reactive astrogliosis in mouse brain following maternal exposure to carbon black nanoparticle.

    Science.gov (United States)

    Onoda, Atsuto; Takeda, Ken; Umezawa, Masakazu

    2017-02-02

    Recent studies indicate that maternal exposure to ambient ultrafine particles and nanoparticles has adverse effects of on the central nervous system. Quantitative dose-response data is required to better understand the developmental neurotoxicity of nanoparticles. The present study investigated dose-dependent effects of maternal exposure to carbon black nanoparticle (CB-NP) on astrocyte in the brains of mouse offspring. A CB-NP suspension (2.9, 15, or 73 μg/kg) was intranasally administered to pregnant ICR mice on gestational days 5 and 9. Cerebral cortex samples were collected from 6-week-old offspring and examined by Western blotting, immunostaining, microarray analysis, and quantitative reverse transcriptase-polymerase chain reaction. Placentae were collected from pregnant dams on gestational day 13 and examined by microarray analysis. Maternal exposure to CB-NP induced a dose-dependent increase in glial fibrillary acidic protein (GFAP) expression in the cerebral cortex; this increase was particularly observed in astrocytic end-feet attached to denatured perivascular macrophages. Moreover, maternal CB-NP exposure dose-dependently increased aquaporin-4 expression in the brain parenchyma region around blood vessels. The changes in the expression profiles of GFAP and Aqp4 in offspring after maternal CB-NP exposure were similar to those observed in mice of a more advanced age. The expression levels of mRNAs associated with angiogenesis, cell migration, proliferation, chemotaxis, and growth factor production were also altered in the cerebral cortex of offspring after maternal CB-NP exposure. Differentially expressed genes in placental tissues after CB-NP exposure did not populate any specific gene ontology category. Maternal CB-NP exposure induced long-term activation of astrocytes resulting in reactive astrogliosis in the brains of young mice. Our observations suggest a potentially increased risk of the onset of age-related neurodegenerative diseases by maternal

  7. Semisynthesis and quantitative structure-activity relationship (QSAR) study of some cholesterol-based hydrazone derivatives as insecticidal agents.

    Science.gov (United States)

    Yang, Chun; Shao, Yonghua; Zhi, Xiaoyan; Huan, Qu; Yu, Xiang; Yao, Xiaojun; Xu, Hui

    2013-09-01

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, four series of novel cholesterol-based hydrazone derivatives were synthesized, and their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. All the derivatives showed the better insecticidal activity than their precursor cholesterol. Quantitative structure-activity relationship (QSAR) model demonstrated that six descriptors such as RDF085v, Mor06u, Mor11u, Dv, HATS0v and H-046, are likely to influence the insecticidal activity of these compounds. Among them, two important ones are the Mor06u and RDF085v. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. 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

  9. 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.

  10. Development in the central nervous system: studies of activity-dependent plasticity and synapse refinement

    OpenAIRE

    Gaudias, Julien

    2015-01-01

    The central nervous system (CNS) is a highly specified structure, involved in a large range of function, from sensory processing to motor behavior to cognition. The CNS development is genetically programmed but also heavily dependent on environmental cues. The CNS is a highly plastic structure, most prominently at the synaptic level. Plasticity is a physiological process allowing a rapid change of synaptic strength depending on experience, use and surrounding neuronal activity. It...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-10-08

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

  12. Integration of conventional quantitative and phospho-proteomics reveals new elements in activated Jurkat T-cell receptor pathway maintenance.

    Science.gov (United States)

    Jouy, Florent; Müller, Stephan A; Wagner, Juliane; Otto, Wolfgang; von Bergen, Martin; Tomm, Janina M

    2015-01-01

    Recent years have seen a constant development of tools for the global assessment of phosphoproteins. Here, we outline a concept for integrating approaches for quantitative proteomics and phosphoproteomics. The strategy was applied to the analysis of changes in signalling and protein synthesis occurring after activation of the T-cell receptor (TCR) pathway in a T-cell line (Jurkat cells). For this purpose, peptides were obtained from four biological replicates of activated and control Jurkat T-cells and phosphopeptides enriched via a TiO2-based chromatographic step. Both phosphopeptide-enriched and flow-through fractions were analyzed by LC-MS. We observed 1314 phosphopeptides in the enriched fraction whereas 19 were detected in the flow-through, enabling the quantification of 414 and eight phosphoproteins in the respective fractions. Pathway analysis revealed the differential regulation of many metabolic pathways. Among the quantified proteins, 11 kinases with known TCR-related function were detected. A kinase-substrate database search for the phosphosites identified also confirmed the activity of a further ten kinases. In total, these two approaches provided evidence of 19 unique TCR-related kinases. The combination of phosphoproteomics and conventional quantitative shotgun analysis leads to a more comprehensive assessment of the signalling networks needed for the maintenance of the activated status of Jurkat T-cells. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. 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.

  14. 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.

  15. The effects of methylphenidate on cognitive control in active methamphetamine dependence using functional magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Reem Kais Jan

    2014-03-01

    Full Text Available Methamphetamine (MA dependence is associated with cognitive deficits. Methylphenidate (MPH has been shown to improve inhibitory control in healthy and cocaine-dependent subjects. This study aimed to understand the neurophysiological effects before and after acute MPH administration in active MA-dependent and control subjects. Fifteen MA-dependent and 18 control subjects aged 18-46 years were scanned using functional magnetic resonance imaging before and after either a single oral dose of MPH (18mg or placebo while performing a colour-word Stroop task.Baseline accuracy was lower (p=0.026 and response time (RT was longer (pPost- compared to pre-MPH treatment, increased RT and DLPFC activation for the Stroop effect were observed in MA-dependent subjects (pDue to the small sample size, the results from this study are preliminary; however, they inform us about the effects of MPH on the neural correlates of cognitive control in active MA-dependent subjects

  16. Comparison between 5,10,15,20-tetraaryl- and 5,15-diarylporphyrins as photosensitizers: synthesis, photodynamic activity, and quantitative structure-activity relationship modeling.

    Science.gov (United States)

    Banfi, Stefano; Caruso, Enrico; Buccafurni, Loredana; Murano, Roberto; Monti, Elena; Gariboldi, Marzia; Papa, Ester; Gramatica, Paola

    2006-06-01

    The synthesis of a panel of seven nonsymmetric 5,10,15,20-tetraarylporphyrins, 13 symmetric and nonsymmetric 5,15-diarylporphyrins, and one 5,15-diarylchlorin is described. In vitro photodynamic activities on HCT116 human colon adenocarcinoma cells were evaluated by standard cytotoxicity assays. A predictive quantitative structure-activity relationship (QSAR) regression model, based on theoretical holistic molecular descriptors, of a series of 34 tetrapyrrolic photosensitizers (PSs), including the 24 compounds synthesized in this work, was developed to describe the relationship between structural features and photodynamic activity. The present study demonstrates that structural features significantly influence the photodynamic activity of tetrapyrrolic derivatives: diaryl compounds were more active with respect to the tetraarylporphyrins, and among the diaryl derivatives, hydroxy-substituted compounds were more effective than the corresponding methoxy-substituted ones. Furthermore, three monoarylporphyrins, isolated as byproducts during diarylporphyrin synthesis, were considered for both photodynamic and QSAR studies; surprisingly they were found to be particularly active photosensitizers.

  17. Quantitative physical activity assessment of children and adolescents in a rural population from Eastern Nepal.

    Science.gov (United States)

    Williams, Kimberly D; Subedi, Janardan; Jha, Bharat; Blangero, John; Williams-Blangero, Sarah; Towne, Bradford

    2016-01-01

    We report cross-sectional, objectively measured physical activity data for 399 children and adolescents aged 6 to 18 years. We evaluated physical activity of children and adolescents, considered time spent in each activity intensity category, and explored the impact of growth disruption (stunting and wasting) on physical activity patterns. Participants wore an Actical (Mini-Mitter, Bend, OR) omnidirectional accelerometer for one week as part of their annual visit to the Jiri Growth Study. The percentage of time spent in standard activity intensities were computed using standard metabolic equivalents (METS) cutpoints and compared by chronological age, sex, and school versus non-school days. Primary findings include (1) children are more active on non-school days and adolescents are more active during the school week; (2) Jirel children do not exhibit the reduction in physical activity that most Western populations experience during the transition from childhood to adolescence; and (3) Jirel children and adolescents routinely meet the suggested one hour/day MVPA threshold; (4) Stunting is prevalent and factors leading to this growth disruption may contribute to the amount of time in sedentary or light physical activity. We report child and adolescent physical activity patterns from the Jirel population of eastern Nepal. In this rural context, children and adolescents are more active than populations reported from Western contexts. This key finding has important biomedical implications for the maintenance of healthy body composition, skeletal health, and other health traits. © 2015 Wiley Periodicals, Inc.

  18. Heterogeneity of hydrolytic enzyme activities under drought: imaging and quantitative analysis

    Science.gov (United States)

    Sanaullah, Muhammad; Razavi, Bahar S.; Kuzyakov, Yakov

    2015-04-01

    The zymography-based "snap-shoot" of enzyme activities in the rhizosphere is challenging to detect the in situ microbial response to global climate change. We developed in situ soil zymography and used it for identification and localization of hotspots of β-glucosidase activity in the rhizosphere of maize under drought stress (30% of field capacity). The zymographic signals were especially high at root tips and were much stronger for activity of β-glucosidase under drought as compared with optimal moisture (70% of field capacity). This distribution of enzyme activity was confirmed by fluorogenically labelled substrates applied directly to the root exudates. The activity of β-glucosidase in root exudates (produced by root and microorganism associated on the root surface), sampled within 1 hour after zymography was significantly higher by drought stressed plants as compared with optimal moisture. In contrast, the β-glucosidase activity in destructively sampled rhizosphere soil was lower under drought stress compared with optimal moisture. Furthermore, drought stress did not affected β-glucosidase activity in bulk soil, away from rhizosphere. Consequently, we conclude that higher release of mucilage by roots und drought stimulated β-glucosidase activity in the rhizosphere. Thus, the zymography revealed plant-mediated mechanisms accelerating β-glucosidase activity under drought at the root-soil interface. So, coupling of zymography and enzyme assays in the rhizosphere and non-rhizosphere soil enables precise mapping the changes in two-dimensional distribution of enzyme activities due to climate change within dynamic soil interfaces.

  19. Quantitative relationship between trimethylamine-oxide aldolase activity and formaldehyde accumulation in white muscle from gadiform fish during frozen storage

    DEFF Research Database (Denmark)

    Nielsen, Michael Krogsgaard; Jørgensen, Bo

    2004-01-01

    species that were analyzed. Enzyme activities in the major white muscle of gadiform fish showed large variations between species as well as between individuals. A frozen storage experiment showed a similarly large variation in the rate of formaldehyde accumulation, which could be accounted...... for by the endogenous white muscle in situ TMAOase activity. This TMAOase activity also correlated with the rate of insolubilization of otherwise high ionic strength soluble protein. A simple model describing the accumulation of free formaldehyde during frozen storage of gadiform fish is proposed. The model is based...... on a storage time-dependent decay of substrate-saturated white muscle TMAOase activity....

  20. 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.

  1. Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner.

    Directory of Open Access Journals (Sweden)

    Seiko Oda

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

  2. Voltage-dependent activation in purified reconstituted sodium channels from rabbit T-tubular membranes

    Energy Technology Data Exchange (ETDEWEB)

    Furman, R.E.; Tanaka, J.C.; Mueller, P.; Barchi, R.L.

    1986-01-01

    The authors have examined the voltage-dependent gating of batrachotoxin-modified sodium channels purified from rabbit T-tubular membranes in two ways. First, purified channels were reconstituted into planar bilayers and single-channel properties were measured. Batrachotoxin-activated channels showed steep voltage-dependent activation with half-maximal opening probabilities at potentials between -95 and -116 mV. The single-channel conductance averaged 20 pS and was independent of membrane potential. A second approach was used to establish that this voltage dependence was a characteristic of the entire population of purified channels and not just those few channels observed in planar bilayers. Channels reconstituted into egg phosphophatidyl-choline vesicles were functionally oriented by inclusion of internal saxitoxin; vesicle membrane potentials were then generated by K/sup +/ gradients in the presence of valinomycin. All of the specific /sup 22/Na/sup +/ influx activated by batrachotoxin and blocked by saxitoxin was found to be voltage sensitive, activating between predicted membrane potentials of -100 and -50 mV. The single-channel properties of the purified T-tubular sodium channel correspond closely to those seen with native sodium channels from rat sarcolemma. The voltage-dependent activation of the bactrachotoxin-modified reconstituted channel is the same as that seen with native channels in situ or in bilayers after exposure this toxin.

  3. Chromatin-dependent cooperativity between constitutive and inducible activation domains in CREB.

    Science.gov (United States)

    Asahara, H; Santoso, B; Guzman, E; Du, K; Cole, P A; Davidson, I; Montminy, M

    2001-12-01

    The cyclic AMP (cAMP)-responsive factor CREB induces target gene expression via constitutive (Q2) and inducible (KID, for kinase-inducible domain) activation domains that function synergistically in response to cellular signals. KID stimulates transcription via a phospho (Ser133)-dependent interaction with the coactivator paralogs CREB binding protein and p300, whereas Q2 recruits the TFIID complex via a direct association with hTAF(II)130. Here we investigate the mechanism underlying cooperativity between the Q2 domain and KID in CREB by in vitro transcription assay with naked DNA and chromatin templates containing the cAMP-responsive somatostatin promoter. The Q2 domain was highly active on a naked DNA template, and Ser133 phosphorylation had no additional effect on transcriptional initiation in crude extracts. Q2 activity was repressed on a chromatin template, however, and this repression was relieved by the phospho (Ser133) KID-dependent recruitment of p300 histone acetyltransferase activity to the promoter. In chromatin immunoprecipitation assays of NIH 3T3 cells, cAMP-dependent recruitment of p300 to the somatostatin promoter stimulated acetylation of histone H4. Correspondingly, overexpression of hTAFII130 potentiated CREB activity in cells exposed to cAMP, but had no effect on reporter gene expression in unstimulated cells. We propose that cooperativity between the KID and Q2 domains proceeds via a chromatin-dependent mechanism in which recruitment of p300 facilitates subsequent interaction of CREB with TFIID.

  4. Correlation between a deep clearing test and quantitative methods for lipolytic activity of filamentous fungi

    OpenAIRE

    Santos, Isabel M.; Lima, Nelson

    2003-01-01

    The deep clearing test (DC) is a simple method for measuring the relative lipolytic activity of fungi. The depth of the clear zone below the fungal colony provides a visual measure of the lipolytic activity on a continuous cumulative basis. The depth of clearing was determined for four commercial enzyme concentrations and compared by correlation analysis with results obtained by a titrimetric method and a colorimetric method for measuring lipolytic activity. Good correlation...

  5. 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%

  6. A quantitative structure-activity relationship (QSAR) study of some diaryl urea derivatives of B-RAF inhibitors.

    Science.gov (United States)

    Sadeghian-Rizi, Sedighe; Sakhteman, Amirhossein; Hassanzadeh, Farshid

    2016-12-01

    In the current study, both ligand-based molecular docking and receptor-based quantitative structure activity relationships (QSAR) modeling were performed on 35 diaryl urea derivative inhibitors of V600E B-RAF. In this QSAR study, a linear (multiple linear regressions) and a nonlinear (partial least squares least squares support vector machine (PLS-LS-SVM)) were used and compared. The predictive quality of the QSAR models was tested for an external set of 31 compounds, randomly chosen out of 35 compounds. The results revealed the more predictive ability of PLS-LS-SVM in analysis of compounds with urea structure. The selected descriptors indicated that size, degree of branching, aromaticity, and polarizability affected the inhibition activity of these inhibitors. Furthermore, molecular docking was carried out to study the binding mode of the compounds. Docking analysis indicated some essential H-bonding and orientations of the molecules in the active site.

  7. Computational modeling in nanomedicine: prediction of multiple antibacterial profiles of nanoparticles using a quantitative structure-activity relationship perturbation model.

    Science.gov (United States)

    Speck-Planche, Alejandro; Kleandrova, Valeria V; Luan, Feng; Cordeiro, Maria Natália D S

    2015-01-01

    We introduce the first quantitative structure-activity relationship (QSAR) perturbation model for probing multiple antibacterial profiles of nanoparticles (NPs) under diverse experimental conditions. The dataset is based on 300 nanoparticles containing dissimilar chemical compositions, sizes, shapes and surface coatings. In general terms, the NPs were tested against different bacteria, by considering several measures of antibacterial activity and diverse assay times. The QSAR perturbation model was created from 69,231 nanoparticle-nanoparticle (NP-NP) pairs, which were randomly generated using a recently reported perturbation theory approach. The model displayed an accuracy rate of approximately 98% for classifying NPs as active or inactive, and a new copper-silver nanoalloy was correctly predicted by this model with consensus accuracy of 77.73%. Our QSAR perturbation model can be used as an efficacious tool for the virtual screening of antibacterial nanomaterials.

  8. Quantitative measurement of membrane Na+-K+ ATPase activity using thallium-201: comparison with rubidium-86

    International Nuclear Information System (INIS)

    Lee, Jae Tae; Shon, Sang Kyun; Lee, Kyu Bo; Lee, In Kyu

    1998-01-01

    Na + -K + ATPase activity has been estimated by the degree of inhibition of cation transport by cardiac glycosides (ouabain) using Rb-86 as a substrate. The biological characteristics of Tl-201 is known to be similar to those of potassium as a transport substrate in the presence of glucose, insulin or phobol myristate acetate (PMA). The purpose of this study was to measure ouabain sensitive Na + -K + ATPase activity using Tl-201 and compare with that using Rb-86. Smooth muscle cells isolated from rat aorta or human placental umbilical artery were cultured, and used to measure cellular Na + -K + ATPase activity. Na + -K + ATPase activity was measured as a percentage decrease in cellular uptake of Tl-201 or Rb-86 by ouabain under the presence of glucose, insulin or PMA in media. Na + -K + ATPase activity measured with Tl-201, as a transport substrate, was not different from those measured with Rb-86 in rat or human smooth muscle cell preparation. Incubation with high concentration glucose resulted in about 30% decrease in enzyme activity. In contrast, insulin or PMA resulted in 50-70% or 28% increase from baseline activity, respectively. These results suggests that Tl-201 could replace Rb-86 in measurement of ouabain sensitive Na + -K + ATPase activity in vitro. High level of glucose concentration decreased cellular Na + -K + ATPase activity, but insulin or PMA increased it

  9. Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity

    Directory of Open Access Journals (Sweden)

    Moens Ugo

    2007-11-01

    Full Text Available Abstract Background The mitogen-activated protein kinases, MAPKs for short, constitute cascades of signalling pathways involved in the regulation of several cellular processes that include cell proliferation, differentiation and motility. They also intervene in neurological processes like fear conditioning and memory. Since little remains known about the MAPK-Activated Protein Kinase, MAPKAPK5, we constructed the first MAPKAPK knockin mouse model, using a constitutive active variant of MAPKAPK5 and analyzed the resulting mice for changes in anxiety-related behaviour. Methods We performed primary SHIRPA observations during background breeding into the C57BL/6 background and assessed the behaviour of the background-bred animals on the elevated plus maze and in the light-dark test. Our results were analyzed using Chi-square tests and homo- and heteroscedatic T-tests. Results Female transgenic mice displayed increased amounts of head dips and open arm time on the maze, compared to littermate controls. In addition, they also explored further into the open arm on the elevated plus maze and were less active in the closed arm compared to littermate controls. Male transgenic mice displayed no differences in anxiety, but their locomotor activity increased compared to non-transgenic littermates. Conclusion Our results revealed anxiety-related traits and locomotor differences between transgenic mice expressing constitutive active MAPKAPK5 and control littermates.

  10. 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)

  11. Prediction of the relationship between the structural features of andrographolide derivatives and α-glucosidase inhibitory activity: a quantitative structure-activity relationship (QSAR) study.

    Science.gov (United States)

    Moorthy, N S Hari Narayana; Ramos, Maria J; Fernandes, Pedro A

    2011-02-01

    In order to predict the structural features responsible for α-glucosidase inhibitory activity, a quantitative structure-activity relationship (QSAR) analysis was performed on a series of andrographolide derivatives. To determine the quantitative relationship for the statistically significant models in terms of r (>0.8), F (99%) and Q(2) (>0.71) values were selected. The promising results we obtained could be used to predict the structural requirements for the inhibition of α-glucosidase activity. The models developed included: subdivided surface area, adjacency, surface volume and shape, molecular orbital package (MOPAC) and partial charge descriptors and showed a high correlation with the inhibitory activity. The descriptors used revealed that a van der Waals (vdW) surface with significant polar volume is favourable to the activity. The positive effect of the shape descriptors; PM3-LUMO and vsurf_wp7 and the negative effect of GCUT_PEOE_2 indicated that the active site may contain some nucleophilic positions that could interact with the ligand and the hydrogen acceptor and/or donor groups for hydrogen bonding with inhibitors.

  12. Quantitative structure-activity relationship analysis to elucidate the clearance mechanisms of Tc-99m labeled quinolone antibiotics

    International Nuclear Information System (INIS)

    Salahinejad, M.; Mirshojaei, S.F.

    2016-01-01

    This study aims to establish molecular modeling methods for predicting the liver and kidney uptakes of Tc-99m labeled quinolone antibiotics. Some three-dimensional quantitative-activity relationships (3D-QSAR) models were developed using comparative molecular field analysis and grid-independent descriptors procedures. As a first report on 3D-QSAR modeling, the predicted liver and kidney uptakes for quinolone antibiotics were in good agreement with the experimental values. The obtained results confirm the importance of hydrophobic interactions, size and steric hindrance of antibiotic molecules in their liver uptakes, while the electrostatic interactions and hydrogen bonding ability have impressive effects on their kidney uptakes. (author)

  13. Public open space characteristics influencing adolescents' use and physical activity: A systematic literature review of qualitative and quantitative studies.

    Science.gov (United States)

    Van Hecke, Linde; Ghekiere, Ariane; Veitch, Jenny; Van Dyck, Delfien; Van Cauwenberg, Jelle; Clarys, Peter; Deforche, Benedicte

    2018-04-06

    The objective of this systematic review was to provide insight into the specific characteristics of public open spaces (POS) associated with adolescents' POS visitation and physical activity (PA). Qualitative research suggests many characteristics to be associated with POS visitation and PA. Quantitative evidence confirmed a positive association between presence of trails, playgrounds and specific types of sports fields (e.g. basketball) with POS visitation and PA, whereas safety and aesthetics seemed subordinate. Suggestions for future research, as well as some methodological recommendations are provided. Copyright © 2018 Elsevier Ltd. All rights reserved.

  14. Quantitative structure-activity relationship modeling of polycyclic aromatic hydrocarbon mutagenicity by classification methods based on holistic theoretical molecular descriptors.

    Science.gov (United States)

    Gramatica, Paola; Papa, Ester; Marrocchi, Assunta; Minuti, Lucio; Taticchi, Aldo

    2007-03-01

    Various polycyclic aromatic hydrocarbons (PAHs), ubiquitous environmental pollutants, are recognized mutagens and carcinogens. A homogeneous set of mutagenicity data (TA98 and TA100,+S9) for 32 benzocyclopentaphenanthrenes/chrysenes was modeled by the quantitative structure-activity relationship classification methods k-nearest neighbor and classification and regression tree, using theoretical holistic molecular descriptors. Genetic algorithm provided the selection of the best subset of variables for modeling mutagenicity. The models were validated by leave-one-out and leave-50%-out approaches and have good performance, with sensitivity and specificity ranges of 90-100%. Mutagenicity assessment for these PAHs requires only a few theoretical descriptors of their molecular structure.

  15. A quantitative method for the specific assessment of caspase-6 activity in cell culture

    DEFF Research Database (Denmark)

    Ehrnhoefer, Dagmar E; Skotte, Niels H; Savill, Jane

    2011-01-01

    Aberrant activation of caspase-6 has recently emerged as a major contributor to the pathogeneses of neurodegenerative disorders such as Alzheimer's and Huntington disease. Commercially available assays to measure caspase-6 activity commonly use the VEID peptide as a substrate. However these methods...

  16. 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...... directly activates ENaC. Key words: Serine proteases, Sodium retention, Kidney, M-1 cells....

  17. The Evaluation of Bioelectrical Activity of Pelvic Floor Muscles Depending on Probe Location: A Pilot Study

    OpenAIRE

    Halski, Tomasz; Ptaszkowski, Kuba; Słupska, Lucyna; Dymarek, Robert

    2013-01-01

    Objectives. The main objective was to determine how the depth of probe placement affects functional and resting bioelectrical activity of the PFM and whether the recorded signal might be dependent on the direction in which the probe is rotated. Participants. The study comprised of healthy, nulliparous women between the ages of 21 and 25. Outcome Measures. Bioelectric activity of the PFM was recorded from four locations of the vagina by surface EMG and vaginal probe. Results. There were no sta...

  18. 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.

  19. Antileishmanial chalcones: statistical design, synthesis, and three-dimensional quantitative structure-activity relationship analysis

    DEFF Research Database (Denmark)

    Nielsen, S F; Christensen, S B; Cruciani, G

    1998-01-01

    A large number of substituted chalcones have been synthesized and tested for antileishmanial and lymphocyte-suppressing activities. A subset of the chalcones was designed by using statistical methods. 3D-QSAR analyses using 67 (antileishmanial activity) and 63 (lymphocyte-suppressing activity...... of high quality (lymphocyte-suppressing model, R2 = 0. 90, Q2 = 0.80; antileishmanial model, R2 = 0.73, Q2 = 0.63). The coefficient plots indicate that steric interactions between the chalcones and the target are of major importance for the potencies of the compounds. A comparison of the coefficient plots...... for the antileishmanial effect and the lymphocyte-suppressing activity discloses significant differences which should make it possible to design chalcones having a high antileishmanial activity without suppressing the proliferation of lymphocytes....

  20. Quantitative analysis of silicates by instrumental epithermal neutron activation using (n,p) reactions

    International Nuclear Information System (INIS)

    Gladney, E.S.; Perrin, D.R.

    1979-01-01

    Instrumental epithermal neutron activation (IENA) involves the use of a neutron filter to screen out the thermal portion of the reactor neutron energy spectrum. Both Cd and B are efficient neutron filters. The principal advantage of epithermal over conventional thermal neutron activation for elemental analysis of geological materials is that the most common rock forming elements, which activate strongly with thermal neutrons (Na, Al, P, K, Fe, and Sc), have their activities suppressed, relative to elements which have cross-sectional resonances in the epithermal energy region. One-gram samples of various silicate standard reference materials were encapsulated in polyethylene vials and irradiated in the Los Alamos Omega West Reactor epithermal facility. Only six elements (F, Si, Na, Fe, Ni, and Ti) were successfully determined in geological matrices via (n,p) reactions. The single standard deviations among the measurements were less than 10% in all cases. The production ratio of (n,p) to (n,γ) and (n,p) to (n,α) interfering reactions are included for silicate materials having Mason's average crustal abundance of elements. Epithermal activation via (n,p) reactions provides an alternative method for the determination of Fe, Al, Na, Ni, and F. The preferred techniques are probably thermal neutron activation for the first three elements, atomic absorption for Ni, and ion selective electrode for F.Titanium and Si can be measured much more sensitively using the (n,p) reaction than by thermal neutron activation. 4 tables

  1. Salinomycin activates AMP-activated protein kinase-dependent autophagy in cultured osteoblastoma cells: a negative regulator against cell apoptosis.

    Directory of Open Access Journals (Sweden)

    Lun-qing Zhu

    Full Text Available The malignant osteoblastoma has poor prognosis, thus the search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects both in vivo and in vitro, however, its role in osteoblastoma is still not clear.Salinomycin induced both apoptosis and autophagy in cultured U2OS and MG-63 osteoblastoma cells. Inhibition of autophagy by 3-methyladenine (3-MA, or by RNA interference (RNAi of light chain 3B (LC3B, enhanced salinomycin-induced cytotoxicity and apoptosis. Salinomycin induced a profound AMP-activated protein kinase (AMPK activation, which was required for autophagy induction. AMPK inhibition by compound C, or by AMPKα RNAi prevented salinomycin-induced autophagy activation, while facilitating cancer cell death and apoptosis. On the other hand, the AMPK agonist AICAR promoted autophagy activation in U2OS cells. Salinomycin-induced AMPK activation was dependent on reactive oxygen species (ROS production in osteoblastoma cells. Antioxidant n-acetyl cysteine (NAC significantly inhibited salinomycin-induced AMPK activation and autophagy induction.Salinomycin activates AMPK-dependent autophagy in osteoblastoma cells, which serves as a negative regulator against cell apoptosis. AMPK-autophagy inhibition might be a novel strategy to sensitize salinomycin's effect in cancer cells.

  2. Salinomycin activates AMP-activated protein kinase-dependent autophagy in cultured osteoblastoma cells: a negative regulator against cell apoptosis.

    Science.gov (United States)

    Zhu, Lun-qing; Zhen, Yun-fang; Zhang, Ya; Guo, Zhi-xiong; Dai, Jin; Wang, Xiao-dong

    2013-01-01

    The malignant osteoblastoma has poor prognosis, thus the search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects both in vivo and in vitro, however, its role in osteoblastoma is still not clear. Salinomycin induced both apoptosis and autophagy in cultured U2OS and MG-63 osteoblastoma cells. Inhibition of autophagy by 3-methyladenine (3-MA), or by RNA interference (RNAi) of light chain 3B (LC3B), enhanced salinomycin-induced cytotoxicity and apoptosis. Salinomycin induced a profound AMP-activated protein kinase (AMPK) activation, which was required for autophagy induction. AMPK inhibition by compound C, or by AMPKα RNAi prevented salinomycin-induced autophagy activation, while facilitating cancer cell death and apoptosis. On the other hand, the AMPK agonist AICAR promoted autophagy activation in U2OS cells. Salinomycin-induced AMPK activation was dependent on reactive oxygen species (ROS) production in osteoblastoma cells. Antioxidant n-acetyl cysteine (NAC) significantly inhibited salinomycin-induced AMPK activation and autophagy induction. Salinomycin activates AMPK-dependent autophagy in osteoblastoma cells, which serves as a negative regulator against cell apoptosis. AMPK-autophagy inhibition might be a novel strategy to sensitize salinomycin's effect in cancer cells.

  3. Salinomycin Activates AMP-Activated Protein Kinase-Dependent Autophagy in Cultured Osteoblastoma Cells: A Negative Regulator against Cell Apoptosis

    Science.gov (United States)

    Zhang, Ya; Guo, Zhi-xiong; Dai, Jin; Wang, Xiao-dong

    2013-01-01

    Background The malignant osteoblastoma has poor prognosis, thus the search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects both in vivo and in vitro, however, its role in osteoblastoma is still not clear. Key Findings Salinomycin induced both apoptosis and autophagy in cultured U2OS and MG-63 osteoblastoma cells. Inhibition of autophagy by 3-methyladenine (3-MA), or by RNA interference (RNAi) of light chain 3B (LC3B), enhanced salinomycin-induced cytotoxicity and apoptosis. Salinomycin induced a profound AMP-activated protein kinase (AMPK) activation, which was required for autophagy induction. AMPK inhibition by compound C, or by AMPKα RNAi prevented salinomycin-induced autophagy activation, while facilitating cancer cell death and apoptosis. On the other hand, the AMPK agonist AICAR promoted autophagy activation in U2OS cells. Salinomycin-induced AMPK activation was dependent on reactive oxygen species (ROS) production in osteoblastoma cells. Antioxidant n-acetyl cysteine (NAC) significantly inhibited salinomycin-induced AMPK activation and autophagy induction. Conclusions Salinomycin activates AMPK-dependent autophagy in osteoblastoma cells, which serves as a negative regulator against cell apoptosis. AMPK-autophagy inhibition might be a novel strategy to sensitize salinomycin’s effect in cancer cells. PMID:24358342

  4. Anxiolytic activity of tenoten and diazepam depends on conditions in Vogel conflict test.

    Science.gov (United States)

    Kheyfets, I A; Voronina, T A; Dugina, J L; Molodavkin, G M; Sergeeva, S A

    2011-07-01

    We compared two modifications of Vogel conflict test and assessed anxyolitic activity of two drugs: diazepam (benzodiazepine anxiolitic) and tenoten (ultra-low doses of antibodies to S-100 protein) in both modifications of the test. It was found that the intensity of anxiolitic effect of the drugs depends on the conditions of Vogel test.

  5. 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

  6. Diverse phosphoregulatory mechanisms controlling cyclin-dependent kinase-activating kinases in Arabidopsis

    Czech Academy of Sciences Publication Activity Database

    Shimotohno, A.; Ohno, R.; Bišová, Kateřina; Sakaguchi, N.; Huang, J.; Koncz, C.; Uchimiya, H.; Umeda, M.

    2006-01-01

    Roč. 47, - (2006), s. 701-710 ISSN 0960-7412 Institutional research plan: CEZ:AV0Z50200510 Keywords : cyclin -dependent kinase * cdk-activating kinase * cyclin Subject RIV: EE - Microbiology, Virology Impact factor: 6.565, year: 2006

  7. Reduced activity-dependent protein levels in a mouse model of the fragile X premutation

    NARCIS (Netherlands)

    R.E. von Leden (Ramona); L.C. Curley (Lindsey); G.D. Greenberg (Gian); M.R. Hunsaker (Michael); R. Willemsen (Rob); R.F. Berman (Robert)

    2014-01-01

    textabstractEnvironmental enrichment results in increased levels of Fmrp in brain and increased dendritic complexity. The present experiment evaluated activity-dependent increases in Fmrp levels in the motor cortex in response to training on a skilled forelimb reaching task in the CGG KI mouse model

  8. Dual core quantum dots for highly quantitative ratiometric detection of trypsin activity in cystic fibrosis patients

    Science.gov (United States)

    Castelló Serrano, Iván; Stoica, Georgiana; Matas Adams, Alba; Palomares, Emilio

    2014-10-01

    We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of trypsin in humans. Current detection methods for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a highly sensitive, fast (minutes), and single-step approach nanosensor for the screening and diagnosis of cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range relevant for clinical applications (25-350 μg L-1). Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human genotypes, i.e. CF homozygotic, CF heterozygotic, and unaffected, respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescent biomarkers for recessive genetic diseases like human cystic fibrosis. In a screening program in which the goal is to detect disease and also the carrier status, early diagnosis could be of great help.We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of trypsin in humans. Current detection methods for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a highly sensitive, fast (minutes), and single-step approach nanosensor for the screening and diagnosis of cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range relevant for clinical applications (25-350 μg L-1). Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human genotypes, i.e. CF homozygotic, CF heterozygotic, and unaffected, respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescent biomarkers for

  9. Ligand-Dependent Degradation of SRC-1 Is Pivotal for Progesterone Receptor Transcriptional Activity

    Science.gov (United States)

    Amazit, Larbi; Roseau, Audrey; Khan, Junaid A.; Chauchereau, Anne; Tyagi, Rakesh K.; Loosfelt, Hugues; Leclerc, Philippe; Lombès, Marc

    2011-01-01

    The progesterone receptor (PR), a ligand-activated transcription factor, recruits the primary coactivator steroid receptor coactivator-1 (SRC-1) gene promoters. It is known that PR transcriptional activity is paradoxically coupled to its ligand-dependent down-regulation. However, despite its importance in PR function, the regulation of SRC-1 expression level during hormonal exposure is poorly understood. Here we report that SRC-1 expression level (but not other p160 family members) is down-regulated by the agonist ligand R5020 in a PR-dependent manner. In contrast, the antagonist RU486 fails to induce down-regulation of the coactivator and impairs PR agonist-dependent degradation of SRC-1. We show that SRC-1 proteolysis is a proteasome- and ubiquitin-mediated process that, predominantly but not exclusively, occurs in the cytoplasmic compartment in which SRC-1 colocalizes with proteasome antigens as demonstrated by confocal imaging. Moreover, SRC-1 was stabilized in the presence of leptomycin B or several proteasomal inhibitors. Two degradation motifs, amino-acids 2–16 corresponding to a PEST motif and amino acids 41–136 located in the basic helix loop helix domain of the coactivator, were identified and shown to control the stability as well as the hormone-dependent down-regulation of the coactivator. SRC-1 degradation is of physiological importance because the two nondegradable mutants that still interacted with PR as demonstrated by coimmunoprecipitation failed to stimulate transcription of exogenous and endogenous target genes, suggesting that concomitant PR/SRC-1 ligand-dependent degradation is a necessary step for PR transactivation activity. Collectively our findings are consistent with the emerging role of proteasome-mediated proteolysis in the gene-regulating process and indicate that the ligand-dependent down-regulation of SRC-1 is critical for PR transcriptional activity. PMID:21273440

  10. Fatigue resistance of rat extraocular muscles does not depend on creatine kinase activity

    Directory of Open Access Journals (Sweden)

    Hayeß Katrin

    2005-08-01

    Full Text Available Abstract Background Creatine kinase (CK links phosphocreatine, an energy storage system, to cellular ATPases. CK activity serves as a temporal and spatial buffer for ATP content, particularly in fast-twitch skeletal muscles. The extraocular muscles are notoriously fast and active, suggesting the need for efficient ATP buffering. This study tested the hypotheses that (1 CK isoform expression and activity in rat extraocular muscles would be higher, and (2 the resistance of these muscles to fatigue would depend on CK activity. Results We found that mRNA and protein levels for cytosolic and mitochondrial CK isoforms were lower in the extraocular muscles than in extensor digitorum longus (EDL. Total CK activity was correspondingly decreased in the extraocular muscles. Moreover, cytoskeletal components of the sarcomeric M line, where a fraction of CK activity is found, were downregulated in the extraocular muscles as was shown by immunocytochemistry and western blotting. CK inhibition significantly accelerated the development of fatigue in EDL muscle bundles, but had no major effect on the extraocular muscles. Searching for alternative ATP buffers that could compensate for the relative lack of CK in extraocular muscles, we determined that mRNAs for two adenylate kinase (AK isoforms were expressed at higher levels in these muscles. Total AK activity was similar in EDL and extraocular muscles. Conclusion These data indicate that the characteristic fatigue resistance of the extraocular muscles does not depend on CK activity.

  11. Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain

    DEFF Research Database (Denmark)

    Thomsen, Morten S; Hay-Schmidt, Anders; Hansen, Henrik H

    2010-01-01

    alpha(7) nicotinic acetylcholine receptor (nAChR) agonists are candidates for the treatment of cognitive deficits in schizophrenia. Selective alpha(7) nAChR agonists, such as SSR180711, activate neurons in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (ACCshell) in rats, regions......, as measured by c-Fos immunoreactivity, a marker of neuronal activation. Selective depletion of these cholinergic neurons abolishes the SSR180711-induced activation of the mPFC but not the ACCshell, demonstrating their critical importance for alpha(7) nAChR-dependent activation of the mPFC. Contrarily......, selective depletion of dopaminergic neurons in the ventral tegmental area abolishes the SSR180711-induced activation of the ACCshell but not the mPFC or HDB. These results demonstrate 2 distinct neural pathways activated by SSR180711. The BF and mPFC are important for attentional function and may subserve...

  12. French practices concerning quantitative evaluation of potential atmospheric pollution connected to nuclear activities

    International Nuclear Information System (INIS)

    Doury, A.

    1980-10-01

    Since 1945, French nuclear development has been accompanied, in the field of prevention and control of atmospheric pollution, by special efforts which were significantly stepped up after the accident that occurred at Reactor no.1, Windscale, Great Britain, in October 1957. With a view to quantitative evaluation of concentrations and doses, a first stage has been undertaken which consisted in rapidly setting up practical abacuses without mathematical support directly deduced from full-scale tests by means of tracers on various French sites. Then, from approximately 1970 onwards, partly in answer to new necessities and new problems related to the radiological security of the Pacific atomic tests, one has been striving-through necessary reliance on data obtained from different occasional or concerted 'traced' tests, both French and foreign, to develop a scale reduction having general, yet sufficiently simple characteristics to allow for practicality and efficiency, while being capable of processing as many concrete problems as possible, in particular by overstepping the rather restrictive operating limitations of previous abacuses. The two procedures, the first of which is still being used in an old version, by the nuclear sector of Electricite de France, while the second one begins to be applied by the Technical Support of the Public Authority, are presented and discussed. They are then compared, both as regards their respective performance and complementarity, and from the viewpoint of numerical results, especially in the light of corresponding results obtained with foreign methods [fr

  13. Quantitative study on Vancomycin release from cement in 3 different formulations: preliminary results and antimicrobial activity.

    Science.gov (United States)

    Fenga, D; Currò, M; Rosi, M; Ortolà, D J; Cantivalli, A; Ientile, R; Rosa, M A

    2016-01-01

    The purpose of this study is to investigate the best preparation method of the cement powder mixture, solvent and antibiotic in order to obtain the greatest amount of antibiotic in the joint for the longest time as possible. At time T0 the three samples, packed in a sterile environment in different formulations, were placed in sterile tubes, adding to each one 5 ml of saline phosphate buffer solution (PBS) and put in a stove at 37°C for 24 h. A sample of PBS without cement (T control) was also created. Qualitative and quantitative assessment of the incubated liquid with cement was performed along with biochemical analysis with High Performance Liquid Chromatography (HPLC). The analysis of the raw data demonstrated that at T1 there was a prevalence of antibiotic release from sample , compared to sample 2 and 3. This difference was maintained until the T20; from T21 the antibiotic release gradually leveled in 3 samples. The elution of the antibiotic remained detectable up to T60. Our work shows that the sample preparation is decisive on the quantity of released antibiotic. These results are confirmed by microbiological tests. It is useful to know the actual kinetics of antibiotics in articulation. Further studies are necessary to determine the effectiveness of antibiotic against micro-organisms and how long it acts.

  14. Calmodulin dependent protein kinase II activation by exercise regulates saturated & unsaturated fatty acids and improves some metabolic syndrome markers.

    Science.gov (United States)

    Mukwevho, Emmanuel; Joseph, Jitcy S

    2014-08-28

    Activation of Calmodulin dependent protein kinase (CaMK)-II by exercise has a plethora of benefits in health. Fatty acids play a pivotal role in the pathogenesis of metabolic syndrome (MetS). Prevention of MetS and treatment of its main characteristics are very significant to fight against type 2 diabetes. CaMKII activation in the regulation of saturated and unsaturated fatty acids in relation to type 2 diabetes and MetS has not been studied, which became the focus of this present study. Using Gas chromatography-Mass spectrometry, we investigated saturated fatty acids and unsaturated fatty acids. Quantitative real time PCR was also used to assess the gene expression. Results indicate that both palmitoleic acid and oleic acid which are monounsaturated fatty acids were increased in response to CaMKII activation. On the other hand, myristic acid and palmitic acid which are saturated fatty acids known to increase the risk factors of MetS and type 2 diabetes were decreased by exercise induction of CaMKII. Conversely, lauric acid also a saturated fatty acid was increased in response to CaMKII activation by exercise. This fatty acid is known to have beneficial effects in alleviating symptoms of both type 2 diabetes and MetS. According to our knowledge, this is the first study to show that CaMKII activation by exercise regulates fatty acids essential in type 2 diabetes and MetS. CaMKII can be an avenue of designing novel therapeutic drugs in the management and treatment of type 2 diabetes and MetS. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. 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.

  16. Disposable lateral flow-through strip for smartphone-camera to quantitatively detect alkaline phosphatase activity in milk.

    Science.gov (United States)

    Yu, Ling; Shi, ZhuanZhuan; Fang, Can; Zhang, YuanYuan; Liu, YingShuai; Li, ChangMing

    2015-07-15

    A disposable lateral flow-through strip was developed for smartphone to fast one-step quantitatively detect alkaline phosphatase (ALP) activity in raw milk. The strip comprises two functional components, a conjugation pad loaded with phosphotyrosine-coated gold nanoparticles (AuNPs@Cys-Try-p) and a testing line coated with anti-phosphotryosine antibody (anti-Tyr-p mAb). The dephosphorylation activity of ALP at the testing zone can be quantitatively assayed by monitoring the accumulated AuNPs-induced color changes by smartphone camera, thus providing a highly convenient portable detection method. A trace amount of ALP as low as 0.1UL(-1) with a linear dynamic range of 0.1-150UL(-1) (R(2)=0.999) in pasteurized milk and raw milk can be one-step detected by the developed flow-through strip within 10min, demonstrating the potential of smartphone-based portable sensing device for pathogen detection. This bio-hazards free lateral flow-through testing strip can be also used to fabricate rapid, sensitive and inexpensive enzyme or immunosensors for broad portable clinic diagnosis and food contamination analysis, particularly in point-of-care and daily food quality inspection. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. 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.

  18. 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...

  19. Ligand structure-dependent activation of estrogen receptor alpha/Sp by estrogens and xenoestrogens.

    Science.gov (United States)

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

    2008-05-01

    This study investigated the effects of E2, diethylstilbestrol (DES), antiestrogens, the phytoestrogen resveratrol, and the xenoestrogens octylphenol (OP), nonylphenol (NP), endosulfan, kepone, 2,3,4,5-tetrachlorobiphenyl-4-ol (HO-PCB-Cl(4)), bisphenol-A (BPA), and 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) on induction of luciferase activity in breast cancer cells transfected with a construct (pSp1(3)) containing three tandem GC-rich Sp binding sites linked to luciferase and wild-type or variant ERalpha. The results showed that induction of luciferase activity was highly structure-dependent in both MCF-7 and MDA-MB-231 cells. Moreover, RNA interference assays using small inhibitory RNAs for Sp1, Sp3 and Sp4 also demonstrated structure-dependent differences in activation of ERalpha/Sp1, ERalpha/Sp3 and ERalpha/Sp4. These results demonstrate for the first time that various structural classes of ER ligands differentially activate wild-type and variant ERalpha/Sp-dependent transactivation, selectively use different Sp proteins, and exhibit selective ER modulator (SERM)-like activity.

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

    Science.gov (United States)

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

    2008-01-01

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

  1. Flow-induced elongation of von Willebrand factor precedes tension-dependent activation.

    Science.gov (United States)

    Fu, Hongxia; Jiang, Yan; Yang, Darren; Scheiflinger, Friedrich; Wong, Wesley P; Springer, Timothy A

    2017-08-23

    Von Willebrand factor, an ultralarge concatemeric blood protein, must bind to platelet GPIbα during bleeding to mediate hemostasis, but not in the normal circulation to avoid thrombosis. Von Willebrand factor is proposed to be mechanically activated by flow, but the mechanism remains unclear. Using microfluidics with single-molecule imaging, we simultaneously monitored reversible Von Willebrand factor extension and binding to GPIbα under flow. We show that Von Willebrand factor is activated through a two-step conformational transition: first, elongation from compact to linear form, and subsequently, a tension-dependent local transition to a state with high affinity for GPIbα. High-affinity sites develop only in upstream regions of VWF where tension exceeds ~21 pN and depend upon electrostatic interactions. Re-compaction of Von Willebrand factor is accelerated by intramolecular interactions and increases GPIbα dissociation rate. This mechanism enables VWF to be locally activated by hydrodynamic force in hemorrhage and rapidly deactivated downstream, providing a paradigm for hierarchical mechano-regulation of receptor-ligand binding.Von Willebrand factor (VWF) is a blood protein involved in clotting and is proposed to be activated by flow, but the mechanism is unknown. Here the authors show that VWF is first converted from a compact to linear form by flow, and is subsequently activated to bind GPIbα in a tension-dependent manner.

  2. Hydrophilic Phage-Mimicking Membrane Active Antimicrobials Reveal Nanostructure-Dependent Activity and Selectivity.

    Science.gov (United States)

    Jiang, Yunjiang; Zheng, Wan; Kuang, Liangju; Ma, Hairong; Liang, Hongjun

    2017-09-08

    The prevalent wisdom on developing membrane active antimicrobials (MAAs) is to seek a delicate, yet unquantified, cationic-hydrophobic balance. Inspired by phages that use nanostructured protein devices to invade bacteria efficiently and selectively, we study here the antibiotic role of nanostructures by designing spherical and rod-like polymer molecular brushes (PMBs) that mimic the two basic structural motifs of bacteriophages. Three model PMBs with different well-defined geometries consisting of multiple, identical copies of densely packed poly(4-vinyl-N-methylpyridine iodide) branches are synthesized by controlled/"living" polymerization, reminiscent of the viral structural motifs comprised of multiple copies of protein subunits. We show that, while the individual linear-chain polymer branch that makes up the PMBs is hydrophilic and a weak antimicrobial, amphiphilicity is not a required antibiotic trait once nanostructures come into play. The nanostructured PMBs induce an unusual topological transition of bacterial but not mammalian membranes to form pores. The sizes and shapes of the nanostructures further help define the antibiotic activity and selectivity of the PMBs against different families of bacteria. This study highlights the importance of nanostructures in the design of MAAs with high activity, low toxicity, and target specificity.

  3. Use of Quantitative Structure-Activity Relationship (QSAR) and ADMET prediction studies as screening methods for design of benzyl urea derivatives for anti-cancer activity.

    Science.gov (United States)

    Lokwani, Deepak; Bhandari, Shashikant; Pujari, Radha; Shastri, Padma; Shelke, Ganesh; Pawar, Vidya

    2011-06-01

    2D and 3D quantitative structure-activity relationship studies have been carried out for establishing a correlation between the structural properties of benzyl urea derivatives and their anti-tumour activities. From this correlation, the new chemical entities were designed, and their activity and absorption, distribution, metabolism, excretion, and toxicity properties were also predicted. Finally, the most promising compounds from these screening were synthesized and biologically evaluated for their anti-cancer properties. Compound 1-(2, 4-dimethylphenyl)-3, 3-dimethyl-1-(2-nitrobenzyl) urea (7d) showed significant anti-proliferative activity (at 100 µg/mL) in human cancer cell lines-T-cell leukemia (Jurkat J6), myelogenous leukemia (K562), and breast cancer (MCF-7) compared to reference standard 5-flurouracil.

  4. Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner

    Science.gov (United States)

    Schafer, Dorothy P; Lehrman, Emily K; Kautzman, Amanda G; Koyama, Ryuta; Mardinly, Alan R; Yamasaki, Ryo; Ransohoff, Richard M; Greenberg, Michael E; Barres, Ben A; Stevens, Beth

    2012-01-01

    SUMMARY Microglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses. PMID:22632727

  5. 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.

  6. 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.

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

    Directory of Open Access Journals (Sweden)

    Saad Hannan

    2016-08-01

    Full Text Available 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 Ca2+-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.

  8. Lactate racemase is a nickel-dependent enzyme activated by a widespread maturation system

    Science.gov (United States)

    Desguin, Benoît; Goffin, Philippe; Viaene, Eric; Kleerebezem, Michiel; Martin-Diaconescu, Vlad; Maroney, Michael J; Declercq, Jean-Paul; Soumillion, Patrice; Hols, Pascal

    2014-01-01

    Racemases catalyze the inversion of stereochemistry in biological molecules, giving the organism the ability to use both isomers. Among them, lactate racemase remains unexplored due to its intrinsic instability and lack of molecular characterization. Here we determine the genetic basis of lactate racemization in Lactobacillus plantarum. We show that, unexpectedly, the racemase is a nickel-dependent enzyme with a novel α/β fold. In addition, we decipher the process leading to an active enzyme, which involves the activation of the apo-enzyme by a single nickel-containing maturation protein that requires preactivation by two other accessory proteins. Genomic investigations reveal the wide distribution of the lactate racemase system among prokaryotes, showing the high significance of both lactate enantiomers in carbon metabolism. The even broader distribution of the nickel-based maturation system suggests a function beyond activation of the lactate racemase and possibly linked with other undiscovered nickel-dependent enzymes. PMID:24710389

  9. Quantitative Analysis of Major Constituents in Green Tea with Different Plucking Periods and Their Antioxidant Activity

    Directory of Open Access Journals (Sweden)

    Lan-Sook Lee

    2014-07-01

    Full Text Available The objective of this study was to determine the relationship between the plucking periods and the major constituents and the antioxidant activity in green tea. Green tea was prepared from leaves plucked from the end of April 2013 to the end of May 2013 at intervals of one week or longer. The contents of theanine, theobromine, caffeine, catechin (C, and gallocatechin gallate (GCg were significantly decreased, whereas those of epicatechin (EC, epigallocatechin gallate (EGCg and epigallocatechin (EGC were significantly increased along with the period of tea leaf plucking. In addition, antioxidant activity of green tea and standard catechins was investigated using ABTS, FRAP and DPPH assays. The highest antioxidant activity was observed in relatively the oldest leaf, regardless of the assay methods used. Additionally, the order of antioxidant activity of standard catechins was as follows: EGCg ³ GCg ³ ECg > EGC ³ GC ³ EC ³ C. Moreover, the cis-catechins contents were the key factor affecting the antioxidant activity of green tea in all assays employed (ABTS, r = 0.731, p < 0.01; FRAP, r = 0.886, p < 0.01; DPPH, r = 0.778, p < 0.01.

  10. Sporadic Creutzfeldt-Jakob disease: the extent of microglia activation is dependent on the biochemical type of PrPSc.

    Science.gov (United States)

    Puoti, Gianfranco; Giaccone, Giorgio; Mangieri, Michela; Limido, Lucia; Fociani, Paolo; Zerbi, Pietro; Suardi, Silvia; Rossi, Giacomina; Iussich, Selina; Capobianco, Raffaella; Di Fede, Giuseppe; Marcon, Gabriella; Cotrufo, Roberto; Filippini, Graziella; Bugiani, Orso; Tagliavini, Fabrizio

    2005-10-01

    In prion-related encephalopathies, microglial activation occurs early and is dependent on accumulation of disease-specific forms of the prion protein (PrPSc) and may play a role in nerve cell death. Previously, we found that different types of PrPSc (i.e. type 1 and type 2) coexisted in approximately 25% of patients with sporadic Creutzfeldt-Jakob disease (CJD); and a close relationship was detected between PrPSc type, the pattern of PrP immunoreactivity, and extent of spongiform degeneration. To investigate whether microglial reaction is related to the biochemical type and deposition pattern of PrPSc, we carried out a neuropathologic and biochemical study on 26 patients with sporadic CJD, including all possible genotypes at codon 129 of the prion protein gene. By quantitative analysis, we demonstrated that strong microglial activation was associated with type 1 PrPSc and diffuse PrP immunoreactivity, whereas type 2 PrPSc and focal PrP deposits were accompanied by mild microglia reaction. These findings support the view that the phenotypic heterogeneity of sporadic CJD is largely determined by the physicochemical properties of distinct PrPSc conformers.

  11. Identifying different types of bulking in an activated sludge system through quantitative image analysis.

    Science.gov (United States)

    Mesquita, D P; Amaral, A L; Ferreira, E C

    2011-10-01

    The present study proposes an image analysis methodology for the identification of different types of disturbances in wastewater treatment activated sludge systems. Up to date, most reported image analysis methodologies have been used in activated sludge processes with the aim of filamentous bulking detection, however, other disturbances could be foreseen in wastewater treatment plants. Such disturbances can lead to fluctuations in the biomass contents, affecting the mixed liquor suspended solids (MLSS), and in the sludge settling ability, affecting the sludge volume index (SVI). Therefore, this work focuses on predicting the MLSS and SVI parameters for different types of disturbances affecting an activated sludge system. Four experiments were conducted simulating filamentous bulking, zoogleal or viscous bulking, pinpoint floc formation, and normal operating conditions. Alongside the MLSS and SVI determination, the aggregated and filamentous biomass contents and morphology were studied as well as the biomass Gram and viability status, by means of image analysis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. 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.

  13. Task-dependent activations of human auditory cortex during pitch discrimination and pitch memory tasks.

    Science.gov (United States)

    Rinne, Teemu; Koistinen, Sonja; Salonen, Oili; Alho, Kimmo

    2009-10-21

    The functional organization of auditory cortex (AC) is still poorly understood. Previous studies suggest segregation of auditory processing streams for spatial and nonspatial information located in the posterior and anterior AC, respectively (Rauschecker and Tian, 2000; Arnott et al., 2004; Lomber and Malhotra, 2008). Furthermore, previous studies have shown that active listening tasks strongly modulate AC activations (Petkov et al., 2004; Fritz et al., 2005; Polley et al., 2006). However, the task dependence of AC activations has not been systematically investigated. In the present study, we applied high-resolution functional magnetic resonance imaging of the AC and adjacent areas to compare activations during pitch discrimination and n-back pitch memory tasks that were varied parametrically in difficulty. We found that anterior AC activations were increased during discrimination but not during memory tasks, while activations in the inferior parietal lobule posterior to the AC were enhanced during memory tasks but not during discrimination. We also found that wide areas of the anterior AC and anterior insula were strongly deactivated during the pitch memory tasks. While these results are consistent with the proposition that the anterior and posterior AC belong to functionally separate auditory processing streams, our results show that this division is present also between tasks using spatially invariant sounds. Together, our results indicate that activations of human AC are strongly dependent on the characteristics of the behavioral task.

  14. 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.)

  15. Heat production and quantitative oxidation of nutrients by physical activity in humans

    DEFF Research Database (Denmark)

    Thorbek, G; Chwalibog, André; Jakobsen, K

    1994-01-01

    The effect of physical activity on heat production and oxidation of nutrients was measured by means of indirect calorimetry. The experiment included 6 male and 4 female healthy subjects who, during a 24-hour stay in the respiration chambers, performed, in the morning and afternoon, 15 min cycling...... of 66.2 kJ by cycling caused on average a heat increment of 309 kJ, yielding the mean energetic efficiency for the performed work of 0.22. The activity caused an increment of 11.5 g oxidized carbohydrate and 2.6 g oxidized fat....

  16. Quantitative kinetic and structural analysis of geopolymers. Part 2. Thermodynamics of sodium silicate activation of metakaolin

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Zuhua, E-mail: zuhua.zhang2@usq.edu.au [Faculty of Engineering and Surveying, University of Southern Queensland, Toowoomba, QLD 4350 (Australia); Provis, John L. [Department of Materials Science and Engineering, The University of Sheffield, Mappin St, Sheffield S1 3JD (United Kingdom); Wang, Hao; Bullen, Frank [Faculty of Engineering and Surveying, University of Southern Queensland, Toowoomba, QLD 4350 (Australia); Reid, Andrew [Halok Pty Ltd. West End, QLD 4101 (Australia)

    2013-08-10

    Highlights: • ICC is confirmed again to be useful in studying the thermodynamics of geopolymerization. • Na-silicate activation of metakaolin at 25 °C processes an extent of ∼0.20, far from the final structure. • Na/Al has a more pronounced influence on the reaction extent of metakaolin than do temperature and Si/Al ratio. • ICC is expected to be a powerful technique in quantifying the reactivity of various aluminosilicate precursors. - Abstract: The paper describes the outcomes of a study using isothermal conduction calorimetry (ICC) to characterize the geopolymerization kinetics of metakaolin activated with sodium silicate. Two exothermic peaks are observed in the calorimetric curves for all systems reacting within the temperature range 20–40 °C. The peaks are assigned to the dissolution of metakaolin, and the formation of geopolymeric gels with disordered structure, respectively. Compared with the use of NaOH solution to activate metakaolin, the presence of soluble silicate in the activator hinders the reorganization of the local structure of geopolymeric gels and also suppresses the formation of zeolites or zeolite precursors. The ICC data are used via a thermochemical model to quantify the reaction kinetics of geopolymerization, by assuming that the geopolymeric gels have an analcime-like local structure and taking into account the speciation of the silicate monomers and dimers in the activator. Decreasing the modulus from 1.6 to 1.0 increases the fractional reaction extent from 0.12 to 0.26 after 72 h at 25 °C. When the modulus is 1.2, increasing the reaction temperature from 20 °C to 35 °C results in an improved reaction extent from 0.24 to 0.35. The rapid polymerization that occurs at 40 °C appears to hinder the further reaction of MK and consequently results in a lower reaction extent than at 35 °C. Combined with the findings from previous analysis of systems where NaOH was used to activate MK, the concentration of available Na

  17. Acaricidal and quantitative structure activity relationship of monoterpenes against the two-spotted spider mite, Tetranychus urticae.

    Science.gov (United States)

    Badawy, Mohamed E I; El-Arami, Sailan A A; Abdelgaleil, Samir A M

    2010-11-01

    The acaricidal activity of 12 monoterpenes against the two-spotted spider mite, Tetranychus urticae Koch, was examined using fumigation and direct contact application methods. Cuminaldehyde and (-)-linalool showed the highest fumigant toxicity with LC(50) = 0.31 and 0.56 mg/l, respectively. The other monoterpenes exhibited a strong fumigant toxicity, the LC(50) values ranging from 1.28 to 8.09 mg/l, except camphene, which was the least effective (LC(50) = 61.45 mg/l). Based on contact activity, the results were rather different: menthol displayed the highest acaricidal activity (LC(50) = 128.53 mg/l) followed by thymol (172.0 mg/l), geraniol (219.69 mg/l) and (-)-limonene (255.44 mg/l); 1-8-cineole, cuminaldehyde and (-)-linalool showed moderate toxicity. At 125 mg/l, (-)-Limonene and (-)-carvone caused the highest egg mortality among the tested compounds (70.6 and 66.9% mortality, respectively). In addition, the effect of molecular descriptors was also analyzed using the quantitative structure activity relationship (QSAR) procedure. The QSAR model showed excellent agreement between the estimated and experimentally measured toxicity parameter (LC(50)) for the tested monoterpenes and the fumigant activity increased significantly with the vapor pressure. Comparing the results of the fumigant and contact toxicity assays of monoterpenes against T. urticae with the results of acetylcholinesterase (AChE) inhibitory effect revealed that some of the tested compounds showed a strong acaricidal activity and a potent AChE inhibitory activity, such as cuminaldehyde, (-)-linalool, (-)-limonene and menthol. However, other compounds such as (-)-carvone revealed a strong fumigant activity but a weak AChE inhibitory activity.

  18. Activity-dependent myelination of parvalbumin interneurons mediated by axonal morphological plasticity.

    Science.gov (United States)

    Stedehouder, J; Brizee, D; Shpak, G; Kushner, S A

    2018-03-05

    Axonal myelination of neocortical pyramidal neurons is dynamically modulated by neuronal activity. Recent studies have shown that a substantial proportion of neocortical myelin content is contributed by fast-spiking, parvalbumin (PV)-positive interneurons. However, it remains unknown whether the myelination of PV + interneurons is also modulated by intrinsic activity. Here, we utilized cell-type specific Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in adult male and female mice to activate a sparse population of medial prefrontal cortex PV + interneurons. Using single-cell axonal reconstructions, we find that DREADD-stimulated PV + interneurons exhibit a nearly two-fold increase in total length of myelination, predominantly mediated by a parallel increase of axonal arborization and number of internodes. In contrast, the distribution of axonal inter-branch segment distance and myelin internode length were not significantly altered. Topographical analysis revealed that myelination of DREADD-stimulated cells extended to higher axonal branch orders, while retaining a similar inter-branch distance threshold for myelination. Together, our results demonstrate that chemogenetically-induced neuronal activity increases the myelination of neocortical PV + interneurons mediated at least in part by an elaboration of their axonal morphology. SIGNIFICANCE STATEMENT Myelination is the wrapping of an axon in order to optimize conduction velocity in an energy-efficient manner. Previous studies have shown that myelination of neocortical pyramidal neurons is experience and activity-dependent. We now show that activity-dependent myelin plasticity in the adult neocortex extends to parvalbumin-expressing fast-spiking interneurons. Specifically, chemogenetic stimulation of parvalbumin interneurons in the medial prefrontal cortex significantly enhanced axonal myelination, which was paralleled by an increase in axonal arborization. This suggests that activity-dependent

  19. 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.

  20. 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.

  1. 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.

  2. Striatal Volume Increases in Active Methamphetamine-Dependent Individuals and Correlation with Cognitive Performance

    Directory of Open Access Journals (Sweden)

    Rob R. Kydd

    2012-10-01

    Full Text Available The effect of methamphetamine (MA dependence on the structure of the human brain has not been extensively studied, especially in active users. Previous studies reported cortical deficits and striatal gains in grey matter (GM volume of abstinent MA abusers compared with control participants. This study aimed to investigate structural GM changes in the brains of 17 active MA-dependent participants compared with 20 control participants aged 18–46 years using voxel-based morphometry and region of interest volumetric analysis of structural magnetic resonance imaging data, and whether these changes might be associated with cognitive performance. Significant volume increases were observed in the right and left putamen and left nucleus accumbens of MA-dependent compared to control participants. The volumetric gain in the right putamen remained significant after Bonferroni correction, and was inversely correlated with the number of errors (standardised z-scores on the Go/No-go task. MA-dependent participants exhibited cortical GM deficits in the left superior frontal and precentral gyri in comparison to control participants, although these findings did not survive correction for multiple comparisons. In conclusion, consistent with findings from previous studies of abstinent users, active chronic MA-dependent participants showed significant striatal enlargement which was associated with improved performance on the Go/No-go, a cognitive task of response inhibition and impulsivity. Striatal enlargement may reflect the involvement of neurotrophic effects, inflammation or microgliosis. However, since it was associated with improved cognitive function, it is likely to reflect a compensatory response to MA-induced neurotoxicity in the striatum, in order to maintain cognitive function. Follow-up studies are recommended to ascertain whether this effect continues to be present following abstinence. Several factors may have contributed to the lack of more

  3. Quantitative structure-activity relationships (QSAR) of 4-amino-2,6-diarylpyrimidine-5-carbonitriles with anti-inflammatory activity

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Joao Bosco P. da; Ramos, Mozart N.; Barros Neto, Benicio de [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Quimica Fundamental]. E-mail: mramos@ufpe.br; Melo, Sebastiao Jose de [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Antibioticos]. E-mail: melosebastiao@yahoo.com.br; Falcao, Emerson Peter da Silva [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Centro Academico de Vitoria de Santo Antao; Catanho, Maria Teresa J. de Almeida [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Biofisica e Radiobiologia

    2008-07-01

    The experimental anti-inflammatory activities of eight 4-amino-2,6-diarylpyrimidine-5- carbonitriles were subjected to a QSAR analysis based on results from B3LYP/6-31G(d,p) and AM1 electronic structure calculations. Principal component analyses and regressions based on these data indicate that potentially more active compounds should have low dipole moment and partition coefficient values and also be affected by the values of the charges of the carbon atoms through which the two aromatic rings are bonded to the pyrimidinic ring. Two new molecules were predicted to be at least as active as those with the highest activities used in the model building stage. One of them, having a methoxy group attached to one of the aromatic rings, was predicted to have an anti-inflammatory activity value of 52.3%. This molecule was synthesized and its experimental activity was found to be 52.8%, in agreement with the AM1 theoretical prediction. This value is 5% higher than the largest value used for modeling. (author)

  4. Quantitative structure-activity relationships (QSAR) of 4-amino-2,6-diarylpyrimidine-5-carbonitriles with anti-inflammatory activity

    International Nuclear Information System (INIS)

    Silva, Joao Bosco P. da; Ramos, Mozart N.; Barros Neto, Benicio de; Melo, Sebastiao Jose de; Falcao, Emerson Peter da Silva; Catanho, Maria Teresa J. de Almeida

    2008-01-01

    The experimental anti-inflammatory activities of eight 4-amino-2,6-diarylpyrimidine-5- carbonitriles were subjected to a QSAR analysis based on results from B3LYP/6-31G(d,p) and AM1 electronic structure calculations. Principal component analyses and regressions based on these data indicate that potentially more active compounds should have low dipole moment and partition coefficient values and also be affected by the values of the charges of the carbon atoms through which the two aromatic rings are bonded to the pyrimidinic ring. Two new molecules were predicted to be at least as active as those with the highest activities used in the model building stage. One of them, having a methoxy group attached to one of the aromatic rings, was predicted to have an anti-inflammatory activity value of 52.3%. This molecule was synthesized and its experimental activity was found to be 52.8%, in agreement with the AM1 theoretical prediction. This value is 5% higher than the largest value used for modeling. (author)

  5. Complementary three-dimensional quantitative structure-activity relationship modeling of binding affinity and functional potency

    DEFF Research Database (Denmark)

    Tosco, Paolo; Ahring, Philip K; Dyhring, Tino

    2009-01-01

    Complementary 3D-QSAR modeling of binding affinity and functional potency is proposed as a tool to pinpoint the molecular features of the ligands, and the corresponding amino acids in the receptor, responsible for high affinity binding vs those driving agonist behavior and receptor activation...

  6. Quantitation of the degree of osteoporosis by measure of total-body calcium employing neutron activation

    International Nuclear Information System (INIS)

    Cohn, S.H.; Zanzi, I.; Vaswani, A.; Wallach, S.; Aloia, J.; Ellis, K.J.

    1975-01-01

    Two techniques for measuring the amount of Ca in the total skeleton were employed: total-body neutron activation analysis (TBNAA) and the determination of the mineral content of a bone of the appendicular skeleton (absorptiometric measurement of the radius, BMC). (U.S.)

  7. A Combined Quantitative Structure-Activity Relationship Research of Quinolinone Derivatives as Androgen Receptor Antagonists.

    Science.gov (United States)

    Wang, Yuwei; Bai, Fang; Cao, Hong; Li, Jiazhong; Liu, Huanxiang; Gramatica, Paola

    2015-01-01

    Antiandrogens bicalutamide, flutamide and enzalutamide etc. have been used in clinical trials to treat prostate cancer by binding to and antagonizing androgen receptor (AR). Although initially effective, the drug resistance problem will emerge eventually, which results in a high medical need for novel AR antagonist exploitation. Here in this work, to facilitate the rational design of novel AR antagonists, we studied the structure-activity relationships of a series of 2-quinolinone derivatives and investigated the structural requirements for their antiandrogenic activities. Different modeling methods, including 2D MLR, 3D CoMFA and CoMSIA, were implemented to evolve QSAR models. All these models, thoroughly validated, demonstrated satisfactory results especially for the good predictive abilities. The contour maps from 3D CoMFA and CoMSIA models provide visualized explanation of key structural characteristics relevant to the antiandrogenic activities, which is summarized to a position-specific conclusion at the end. The obtained results from this research are practically useful for rational design and screening of promising chemicals with high antiandrogenic activities.

  8. Children's Physical Activity Levels during Primary School Break Times: A Quantitative and Qualitative Research Design

    Science.gov (United States)

    Powell, Emma; Woodfield, Lorayne A.; Nevill, Alan A. M.

    2016-01-01

    The overall aim of this study was to assess the diversity of primary school children's physical activity (PA) during outdoor recess. The study was grounded in a mixed method approach, assisting in the identification of multifaceted predictors of children's PA, including insights to social behaviours during break time. Data were obtained from…

  9. 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.

  10. Antinociceptive Activity of Stephanolepis hispidus Skin Aqueous Extract Depends Partly on Opioid System Activation

    Directory of Open Access Journals (Sweden)

    Hugo Castro-Faria-Neto

    2013-04-01

    Full Text Available Stephanolepis hispidus is one of the most common filefish species in Brazil. Its skin is traditionally used as a complementary treatment for inflammatory disorders. However, there are very few studies on chemical and pharmacological properties using the skin of this fish. This study was undertaken in order to investigate the effect of aqueous crude extract of S. hispidus skin (SAE in different nociception models. Here, we report that intraperitoneal administration of SAE inhibited the abdominal constrictions induced by acetic acid in mice. In addition to the effect seen in the abdominal constriction model, SAE was also able to inhibit the hyperalgesia induced by carrageenan and prostaglandin E2 (PGE2 in mice. This potent antinociceptive effect was observed in the hot plate model too, but not in tail-flick test. Naloxone, an opioid receptor antagonist, was able to block the antinociceptive effect of SAE in the abdominal constriction and hot plate models. In addition, SAE did not present cytotoxic or genotoxic effect in human peripheral blood cells. Our results suggest that aqueous crude extract from S. hispidus skin has antinociceptive activity in close relationship with the partial activation of opioid receptors in the nervous system. Moreover, aqueous crude extract from S. hispidus skin does not present toxicity and is therefore endowed with the potential for pharmacological control of pain.

  11. Quantitative Analyses of Force-Induced Amyloid Formation in Candida albicans Als5p: Activation by Standard Laboratory Procedures.

    Directory of Open Access Journals (Sweden)

    Cho X J Chan

    Full Text Available Candida albicans adhesins have amyloid-forming sequences. In Als5p, these amyloid sequences cluster cell surface adhesins to create high avidity surface adhesion nanodomains. Such nanodomains form after force is applied to the cell surface by atomic force microscopy or laminar flow. Here we report centrifuging and resuspending S. cerevisiae cells expressing Als5p led to 1.7-fold increase in initial rate of adhesion to ligand coated beads. Furthermore, mechanical stress from vortex-mixing of Als5p cells or C. albicans cells also induced additional formation of amyloid nanodomains and consequent activation of adhesion. Vortex-mixing for 60 seconds increased the initial rate of adhesion 1.6-fold. The effects of vortex-mixing were replicated in heat-killed cells as well. Activation was accompanied by increases in thioflavin T cell surface fluorescence measured by flow cytometry or by confocal microscopy. There was no adhesion activation in cells expressing amyloid-impaired Als5pV326N or in cells incubated with inhibitory concentrations of anti-amyloid dyes. Together these results demonstrated the activation of cell surface amyloid nanodomains in yeast expressing Als adhesins, and further delineate the forces that can activate adhesion in vivo. Consequently there is quantitative support for the hypothesis that amyloid forming adhesins act as both force sensors and effectors.

  12. Nursing students' attendance at learning activities in relation to attainment and passing courses: A prospective quantitative study.

    Science.gov (United States)

    Rejnö, Åsa; Nordin, Per; Forsgren, Susanne; Sundell, Yvonne; Rudolfsson, Gudrun

    2017-03-01

    Students' motivation and ways of engaging in their schoolwork are important for their performance, including passing exams. Attendance at learning activities has also been argued to be of major importance, although no causal relationship with passing exams has been established in nursing education. The aim of this study was to describe the impact of attendance at nonmandatory learning activities on attainment, in terms of passing or failing of exams, in nursing education courses including both mandatory and non-mandatory activities. A prospective quantitative design. The nursing education programme at a Swedish university. Nursing students (n=361) from two courses and four classes within the nursing programme. Attendance was registered at every non-mandatory teaching activity by asking the students to note their attendance on a list. Data such as sex, age, and whether the students had passed the exam were also collected for each course and each semester separately. Increased participation was associated with an increasing proportion of students passing the exam. The chance of passing the exam increased by 13% for every additional learning occasion attended. Logistic regression showed an OR of 5.4 for an attendance of 100%. An increase in attendance gave a higher proportion of exam passes. Encouraging students to attend non-mandatory learning activities could be of value, and potentially contribute to an increased graduation rate for nursing students. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Quantitative structure-activity relationship of substituted imidazothiadiazoles for their binding against the ecdysone receptor of Sf-9 cells.

    Science.gov (United States)

    Yokoi, Taiyo; Nakagawa, Yoshiaki; Miyagawa, Hisashi

    2017-12-01

    Imidazothiadiazoles (ITDs) are a class of potent nonsteroidal ecdysone agonists with larvicidal activity. Previously, we performed the Hansch-Fujita type of quantitative structure-activity relationship (QSAR) analysis for ITD analogs (Yokoi et al., Pestic. Biochem. Physiol.2015, 120, 40-50). The activity was reasonably explained by hydrophobicity and electronegativity of substituents on the imidazothiadiazole ring system. However, the limited data points (n = 8) hampered the examination of other physicochemical parameters. In the present study, we expanded the library of ITD congeners and evaluated their receptor-binding affinity using intact Sf-9 cells. The QSAR analysis for the expanded set revealed the significance of the third physicochemical parameter, the negative steric effect for long substituents. We also evaluated the larvicidal activity of the synthesized compounds against Spodoptera litura; however, it was not correlated to the binding affinity. The results obtained here suggests that the pharmacokinetic properties must be improved to enhance the larvicidal activity of ITDs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Size-dependent regulation of synchronized activity in living neuronal networks.

    Science.gov (United States)

    Yamamoto, Hideaki; Kubota, Shigeru; Chida, Yudai; Morita, Mayu; Moriya, Satoshi; Akima, Hisanao; Sato, Shigeo; Hirano-Iwata, Ayumi; Tanii, Takashi; Niwano, Michio

    2016-07-01

    We study the effect of network size on synchronized activity in living neuronal networks. Dissociated cortical neurons form synaptic connections in culture and generate synchronized spontaneous activity within 10 days in vitro. Using micropatterned surfaces to extrinsically control the size of neuronal networks, we show that synchronized activity can emerge in a network as small as 12 cells. Furthermore, a detailed comparison of small (∼20 cells), medium (∼100 cells), and large (∼400 cells) networks reveal that synchronized activity becomes destabilized in the small networks. A computational modeling of neural activity is then employed to explore the underlying mechanism responsible for the size effect. We find that the generation and maintenance of the synchronized activity can be minimally described by: (1) the stochastic firing of each neuron in the network, (2) enhancement in the network activity in a positive feedback loop of excitatory synapses, and (3) Ca-dependent suppression of bursting activity. The model further shows that the decrease in total synaptic input to a neuron that drives the positive feedback amplification of correlated activity is a key factor underlying the destabilization of synchrony in smaller networks. Spontaneous neural activity plays a critical role in cortical information processing, and our work constructively clarifies an aspect of the structural basis behind this.

  15. Laboratory assessment of Activated Protein C Resistance/Factor V-Leiden and performance characteristics of a new quantitative assay.

    Science.gov (United States)

    Amiral, Jean; Vissac, Anne Marie; Seghatchian, Jerard

    2017-12-01

    Activated Protein C Resistance is mainly associated to a factor V mutation (RQ506), which induces a deficient inactivation of activated factor V by activated protein C, and is associated to an increased risk of venous and arterial thrombosis in affected individuals, caused by the prolonged activated factor V survival. Its prevalence is mainly in Caucasians (about 5%), and this mutation is absent in Africans and Asians. Presence of Factor V-Leiden is usually evidenced with clotting methods, using a two-step APTT assay performed without or with APC: prolongation of blood coagulation time is decreased if this factor is present. The R506Q Factor V-Leiden mutation is now usually characterized using molecular biology, and this technique tends to become the first intention assay for characterization of patients. Both techniques are qualitative, and allow classifying tested individuals as heterozygotes or homozygotes for the mutation, when present. A new quantitative assay for Factor V-Leiden, using a one-step clotting method, has been developed, and designed with highly purified human coagulation proteins. Clotting is triggered with human Factor Xa, in presence of calcium and phospholipids (mixture which favours APC action over clotting process). Diluted tested plasma, is supplemented with a clotting mixture containing human fibrinogen, prothrombin, and protein S at a constant concentration. APC is added, and clotting is initiated with calcium. Calibration is performed with a pool of plasmas from patients carrying the R506Q Factor V mutation, and its mixtures with normal plasma. Homozygous patients have clotting times of about 70sec. Factor V-Leiden concentration is usually >75% in homozygous patients, 30-60% in heterozygous patients and below 5% in normal. The assay is insensitive to clotting factor deficiencies (II, VII, VIII: C, IX, X), dicoumarol or heparin therapies, and has no interference with lupus anticoagulant (LA). This new assay for Factor V-Leiden can be

  16. 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.

  17. 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.

  18. Pentobarbital dose-dependently increases respiratory genioglossus muscle activity while impairing diaphragmatic function in anesthetized rats.

    Science.gov (United States)

    Eikermann, Matthias; Fassbender, Philipp; Zaremba, Sebastian; Jordan, Amy S; Rosow, Carl; Malhotra, Atul; Chamberlin, Nancy L

    2009-06-01

    Anesthetics depress both ventilatory and upper airway dilator muscle activity and thus put the upper airway at risk for collapse. However, these effects are agent-dependent and may involve upper airway and diaphragm muscles to varying degrees. The authors assessed the effects of pentobarbital on upper airway dilator and respiratory pump muscle function in rats and compared these results with the effects of normal sleep. Tracheostomized rats were given increasing doses of pentobarbital to produce deep sedation then light and deep anesthesia, and negative pressure airway stimuli were applied (n = 11). To compare the effects of pentobarbital with those of natural sleep, the authors chronically instrumented rats (n = 10) with genioglossus and neck electromyogram and electroencephalogram electrodes and compared genioglossus activity during wakefulness, sleep (rapid eye movement and non-rapid eye movement), and pentobarbital anesthesia. Pentobarbital caused a dose-dependent decrease in ventilation and in phasic diaphragmatic electromyogram by 11 +/- 0.1%, but it increased phasic genioglossus electromyogram by 23 +/- 0.2%. Natural non-rapid eye movement sleep and pentobarbital anesthesia (10 mg/kg intraperitoneally) decreased respiratory genioglossus electromyogram by 61 +/- 29% and 45 +/- 35%, respectively, and natural rapid eye movement sleep caused the greatest decrease in phasic genioglossus electromyogram (95 +/- 0.3%). Pentobarbital in rats impairs respiratory genioglossus activity compared to the awake state, but the decrease is no greater than seen during natural sleep. During anesthesia, in the absence of pharyngeal airflow, phasic genioglossus activity is increased in a dose-dependent fashion.

  19. Stimulation of microbial extracellular enzyme activities by elevated CO2 depends on soil aggregate size

    Science.gov (United States)

    Dorodnikov, M.; Blagodatskaya, E.; Blagodatsky, S.; Marhan, S.; Fangmeier, A.; Kuzyakov, Y.

    2009-04-01

    Increased belowground carbon (C) transfer by plant roots at elevated CO2 may change properties of the microbial community in the rhizosphere. Previous investigations that focused on total soil organic C or total microbial C showed contrasting results: small increase, small decrease or no changes. We evaluated the effect of 5 years of elevated CO2(550 ppm) on four extracellular enzymes: ß-glucosidase, chitinase, phosphatase, and sulfatase. We expected microorganisms to be differently localized in aggregates of various sizes and, therefore analyzed microbial biomass (Cmic by SIR) and enzyme activities in three aggregate-size classes: large macro- (>2 mm), small macro- (0.25-2 mm), and microaggregates (production, we activated microorganisms by substrate (glucose and nutrients) amendment. Although Ctotal and Cmic as well as the activities of ß-glucosidase, phosphatase, and sulfatase were unaffected in bulk soil and in aggregate-size classes by elevated CO2, significant changes were observed in potential enzyme production after substrate amendment. After adding glucose, enzyme activities under elevated CO2 were 1.2-1.9-fold higher than under ambient CO2. This indicates the increased activity of microorganisms, which leads to accelerated C turnover in soil under elevated CO2. Significantly higher chitinase activity in bulk soil and in large macroaggregates under elevated CO2 revealed an increased contribution of fungi to turnover processes. At the same time, less chitinase activity in microaggregates underlined microaggregate stability and the difficulties for fungal hyphae penetrating them. We conclude that quantitative and qualitative changes of C input by plants into the soil at elevated CO2 affect microbial community functioning, but not its total content. Future studies should therefore focus more on the changes of functions and activities, but less on the pools.

  20. Heat production and quantitative oxidation of nutrients by physical activity in humans

    DEFF Research Database (Denmark)

    Thorbek, G; Chwalibog, André; Jakobsen, K

    1994-01-01

    The effect of physical activity on heat production and oxidation of nutrients was measured by means of indirect calorimetry. The experiment included 6 male and 4 female healthy subjects who, during a 24-hour stay in the respiration chambers, performed, in the morning and afternoon, 15 min cycling...... with the total work of 6,750 kg m. Experiments were repeated twice (3- to 4-week interval) showing no differences between the gas exchange in the morning and afternoon and between first and second experiment. The gas exchange during cycling was about 4 times higher than during basal periods. The identical work...... of 66.2 kJ by cycling caused on average a heat increment of 309 kJ, yielding the mean energetic efficiency for the performed work of 0.22. The activity caused an increment of 11.5 g oxidized carbohydrate and 2.6 g oxidized fat....

  1. QUANTITATIVE STUDY ON THE INVOLVEMENT OF BRICOLAGE COMPANIES IN SOCIAL RESPONSIBILITY ACTIVITIES

    Directory of Open Access Journals (Sweden)

    Mihai-Cosmin FANARU

    2016-07-01

    Full Text Available The main purpose of this paper is to analyze the influence of social responsibility actions of the main bricolage companies doing business in Romania on their value, and mutually the impact these activities have on various social sectors. CSR (Corporate Social Responsibility is a concept related to the contribution that companies need to have to the development of modern society. Over time, this contribution has been theorized by many different schools of thought. "Responsible" initiatives of companies have been named by a variety of terms: corporate citizenship, corporate philanthropy, corporate societal marketing, community affairs, community development etc. Consequently, currently, to demonstrate that it is "socially responsible", a company must understand the principles of CSR that are internationally promoted and regularly report about the integration of these principles in its activities.

  2. The Fidelity Index provides a systematic quantitation of star activity of DNA restriction endonucleases.

    Science.gov (United States)

    Wei, Hua; Therrien, Caitlin; Blanchard, Aine; Guan, Shengxi; Zhu, Zhenyu

    2008-05-01

    Restriction endonucleases are the basic tools of molecular biology. Many restriction endonucleases show relaxed sequence recognition, called star activity, as an inherent property under various digestion conditions including the optimal ones. To quantify this property we propose the concept of the Fidelity Index (FI), which is defined as the ratio of the maximum enzyme amount showing no star activity to the minimum amount needed for complete digestion at the cognate recognition site for any particular restriction endonuclease. Fidelity indices for a large number of restriction endonucleases are reported here. The effects of reaction vessel, reaction volume, incubation mode, substrate differences, reaction time, reaction temperature and additional glycerol, DMSO, ethanol and Mn(2+) on the FI are also investigated. The FI provides a practical guideline for the use of restriction endonucleases and defines a fundamental property by which restriction endonucleases can be characterized.

  3. BAFF promotes autoantibody production via TACI-dependent activation of transitional B cells

    Science.gov (United States)

    Jacobs, Holly M.; Thouvenel, Christopher D.; Leach, Sarah; Arkatkar, Tanvi; Metzler, Genita; Scharping, Nicole E.; Kolhatkar, Nikita S.; Rawlings, David J.; Jackson, Shaun W.

    2016-01-01

    Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear antibodies. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, but the B cell developmental subsets undergoing TACI-dependent activation in settings of excess BAFF remains unclear. We now report that, whereas surface TACI expression is usually limited to mature B cells, excess BAFF promotes the expansion of TACI-expressing transitional B cells. TACIhi transitional cells from BAFF-Tg mice are characterized by an activated, cycling phenotype; and the TACIhi cell subset is specifically enriched for autoreactivity, expresses activation-induced cytidine deaminase (AID) and T-bet and exhibits evidence of somatic hypermutation. Consistent with a potential contribution to BAFF-mediated humoral autoimmunity, TACIhi transitional B cells from BAFF-Tg mice spontaneously produce class-switched autoantibodies ex vivo. These combined findings highlight a novel mechanism whereby BAFF promotes humoral autoimmunity via direct, TACI-dependent activation of transitional B cells. PMID:27022196

  4. Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells.

    Science.gov (United States)

    Jacobs, Holly M; Thouvenel, Christopher D; Leach, Sarah; Arkatkar, Tanvi; Metzler, Genita; Scharping, Nicole E; Kolhatkar, Nikita S; Rawlings, David J; Jackson, Shaun W

    2016-05-01

    Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear Abs. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, but the B cell developmental subsets undergoing TACI-dependent activation in settings of excess BAFF remain unclear. We report that, although surface TACI expression is usually limited to mature B cells, excess BAFF promotes the expansion of TACI-expressing transitional B cells. TACI(+) transitional cells from BAFF-transgenic mice are characterized by an activated, cycling phenotype, and the TACI(+) cell subset is specifically enriched for autoreactivity, expresses activation-induced cytidine deaminase and T-bet, and exhibits evidence of somatic hypermutation. Consistent with a potential contribution to BAFF-mediated humoral autoimmunity, TACI(+) transitional B cells from BAFF-transgenic mice spontaneously produce class-switched autoantibodies ex vivo. These combined findings highlight a novel mechanism through which BAFF promotes humoral autoimmunity via direct, TACI-dependent activation of transitional B cells. Copyright © 2016 by The American Association of Immunologists, Inc.

  5. Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex.

    Science.gov (United States)

    Canettieri, Gianluca; Morantte, Ianessa; Guzmán, Ernesto; Asahara, Hiroshi; Herzig, Stephan; Anderson, Scott D; Yates, John R; Montminy, Marc

    2003-03-01

    The second messenger cAMP stimulates transcription with burst-attenuation kinetics that mirror the PKA-dependent phosphorylation and subsequent protein phosphatase 1 (PP1)-mediated dephosphorylation of the cAMP responsive element binding protein (CREB) at Ser133. Phosphorylation of Ser133 promotes recruitment of the co-activator histone acetylase (HAT) paralogs CBP and P300, which in turn stimulate acetylation of promoter-bound histones during the burst phase. Remarkably, histone deacetylase (HDAC) inhibitors seem to potentiate CREB activity by prolonging Ser133 phosphorylation in response to cAMP stimulus, suggesting a potential role for HDAC complexes in silencing CREB activity. Here we show that HDAC1 associates with and blocks Ser133 phosphorylation of CREB during pre-stimulus and attenuation phases of the cAMP response. HDAC1 promotes Ser133 dephosphorylation via a stable interaction with PP1, which we detected in co-immunoprecipitation and co-purification studies. These results illustrate a novel mechanism by which signaling and chromatin-modifying activities act coordinately to repress the activity of a phosphorylation-dependent activator.

  6. Quantitative evaluation of blood elements by neutron activation analysis in mice immunized with Bothrops snake venoms

    International Nuclear Information System (INIS)

    Zamboni, C.B.; Metairon, S.; Suzuki, M.F.; Furtado, M.F.; Sant'Anna, O.A.; Tambourgi, D.V.

    2009-01-01

    Mice genetically selected for high antibody responsiveness (HIII) were immunized against different Bothrops species snake venoms from distinct region of Brazil. The Neutron Activation Analysis technique was used to evaluate the whole blood concentrations of elements of clinical relevance [Ca, Cl, K, Mg and Na] in order to establish a potential correlation between antibody response and blood constituents after Bothrops venom administration for clinical screening of envenomed patients. (author)

  7. Flavonoids as Vasorelaxant Agents: Synthesis, Biological Evaluation and Quantitative Structure Activities Relationship (QSAR Studies

    Directory of Open Access Journals (Sweden)

    Yongzhou Hu

    2011-09-01

    Full Text Available A series of 2-(2-diethylamino-ethoxychalcone and 6-prenyl(or its isomers-flavanones 10a,b and 11a–g were synthesized and evaluated for their vasorelaxant activities against rat aorta rings pretreated with 1 μM phenylephrine (PE. Several compounds showed potent vasorelaxant activities. Compound 10a (EC50 = 7.6 μM, Emax = 93.1%, the most potent one, would be a promising structural template for development of novel and more efficient vasodilators. Further, 2D-QSAR analysis of compounds 10a,b and 11c-e as well as thirty previously synthesized flavonoids 1-3 and 12-38 using Enhanced Replacement Method-Multiple Linear Regression (ERM-MLR was further performed based on an optimal set of molecular descriptors (H5m, SIC2, DISPe, Mor03u and L3m, leading to a reliable model with good predictive ability (Rtrain2 = 0.839, Qloo2 = 0.733 and Rtest2 = 0.804. The results provide good insights into the structure- activity relationships of the target compounds.

  8. 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.

  9. Quantitation of DNA methyltransferase activity via chronocoulometry in combination with rolling chain amplification.

    Science.gov (United States)

    Ji, Jingjing; Liu, Yuanjian; Wei, Wei; Zhang, Yuanjian; Liu, Songqin

    2016-11-15

    In this paper, a rolling chain amplification (RCA) strategy was proposed for chronocoulometric detection of DNA methyltransferase (MTase) activity. Briefly, after the double DNA helix structure was assembled on the surface of gold electrode, it was first methylated by M. SssI MTase and then RCA was realized in the presence of E. coli and phi29 DNA polymerase. Successively, numerous hexaammineruthenium (III) chloride ([Ru(NH3)6)(3+), RuHex) were adsorbed on replicons by electrostatic interaction and generated a large electrochemical readout, the signal was "on". On the contrary, in the absence of M. SssI MTase, the methylated CpG site in the unmethylated double DNA helix structure could be specifically recognized and cleaved by HpaII, resulting in a disconnection of RCA from the electrode. This led seldom RuHex to be absorbed onto the surface of electrode, the signal was "off". Based on the proposed strategy, the activity of M. SssI MTase was assayed in the range of 0.5-60U/mL with a detection limit of 0.09U/mL (S/N=3). In addition, the inhibition of procaine and epicatechin on M. SssI MTase activity was evaluated. When the proposed method was applied in complex matrix such as human serum samples, acceptable accuracy, precision and high sensitivity were achieved. Therefore, the proposed method was a potential useful mean for clinical diagnosis and drug development. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Quantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer.

    LENUS (Irish Health Repository)

    Gulmann, Christian

    2009-08-01

    Mitogen-activated protein kinases (MAPK) are considered to play significant roles in colonic carcinogenesis and kinase inhibitor therapy has been proposed as a potential tool in the treatment of this disease. Reverse-phase microarray assays using phospho-specific antibodies can directly measure levels of phosphorylated protein isoforms. In the current study, samples from 35 cases of untreated colorectal cancer colectomies were laser capture-microdissected to isolate epithelium and stroma from cancer as well as normal (i.e. uninvolved) mucosa. Lysates generated from these four tissue types were spotted onto reverse-phase protein microarrays and probed with a panel of antibodies to ERK, p-ERK, p38, p-p38, p-JNK, MEK and p-MEK. Whereas total protein levels were unchanged, or slightly elevated (p38, p = 0.0025) in cancers, activated isoforms, including p-ERK, p-p38 and p-JNK, were decreased two- to four-fold in cancers compared with uninvolved mucosa (p < 0.0023 in all cases except for p-JNK in epithelium, where decrement was non-significant). This was backed up by western blotting. Dukes\\' stage B and C cancers displayed lower p-ERK and p-p38 expression than Dukes\\' stage A cancers, although this was not statistically significant. It is concluded that MAPK activity may be down-regulated in colorectal cancer and that further exploration of inhibitory therapy in this system should be carefully evaluated if this finding is confirmed in larger series.

  11. Designing quantitative structure activity relationships to predict specific toxic endpoints for polybrominated diphenyl ethers in mammalian cells.

    Science.gov (United States)

    Rawat, S; Bruce, E D

    2014-01-01

    Polybrominated diphenyl ethers (PBDEs) are known as effective flame retardants and have vast industrial application in products like plastics, building materials and textiles. They are found to be structurally similar to thyroid hormones that are responsible for regulating metabolism in the body. Structural similarity with the hormones poses a threat to human health because, once in the system, PBDEs have the potential to affect thyroid hormone transport and metabolism. This study was aimed at designing quantitative structure-activity relationship (QSAR) models for predicting toxic endpoints, namely cell viability and apoptosis, elicited by PBDEs in mammalian cells. Cell viability was evaluated quantitatively using a general cytotoxicity bioassay using Janus Green dye and apoptosis was evaluated using a caspase assay. This study has thus modelled the overall cytotoxic influence of PBDEs at an early and a late endpoint by the Genetic Function Approximation method. This research was a twofold process including running in vitro bioassays to collect data on the toxic endpoints and modeling the evaluated endpoints using QSARs. Cell viability and apoptosis responses for Hep G2 cells exposed to PBDEs were successfully modelled with an r(2) of 0.97 and 0.94, respectively.

  12. Factors influencing physical activity and rehabilitation in survivors of critical illness: a systematic review of quantitative and qualitative studies.

    Science.gov (United States)

    Parry, Selina M; Knight, Laura D; Connolly, Bronwen; Baldwin, Claire; Puthucheary, Zudin; Morris, Peter; Mortimore, Jessica; Hart, Nicholas; Denehy, Linda; Granger, Catherine L

    2017-04-01

    To identify, evaluate and synthesise studies examining the barriers and enablers for survivors of critical illness to participate in physical activity in the ICU and post-ICU settings from the perspective of patients, caregivers and healthcare providers. Systematic review of articles using five electronic databases: MEDLINE, CINAHL, EMBASE, Cochrane Library, Scopus. Quantitative and qualitative studies that were published in English in a peer-reviewed journal and assessed barriers or enablers for survivors of critical illness to perform physical activity were included. Prospero ID: CRD42016035454. Eighty-nine papers were included. Five major themes and 28 sub-themes were identified, encompassing: (1) patient physical and psychological capability to perform physical activity, including delirium, sedation, illness severity, comorbidities, weakness, anxiety, confidence and motivation; (2) safety influences, including physiological stability and concern for lines, e.g. risk of dislodgement; (3) culture and team influences, including leadership, interprofessional communication, administrative buy-in, clinician expertise and knowledge; (4) motivation and beliefs regarding the benefits/risks; and (5) environmental influences, including funding, access to rehabilitation programs, staffing and equipment. The main barriers identified were patient physical and psychological capability to perform physical activity, safety concerns, lack of leadership and ICU culture of mobility, lack of interprofessional communication, expertise and knowledge, and lack of staffing/equipment and funding to provide rehabilitation programs. Barriers and enablers are multidimensional and span diverse factors. The majority of these barriers are modifiable and can be targeted in future clinical practice.

  13. Synthesis, Cytotoxic Activity on Leukemia Cell Lines and Quantitative Structure-Activity Relationships (QSAR) Studies of Morita-Baylis-Hillman Adducts.

    Science.gov (United States)

    Lima-, Claudio G; Faheina-Martins, Gláucia V; Bomfim, Caio C B; Dantas, Bruna B; Silva, Everton P; Araújo, Demetrius A M de; Filho, Edilson B A; Vasconcellos, Mário L A A

    2016-01-01

    The Morita-Baylis-Hillman reaction is an organocatalyzed chemical transformation that allows access to small poly-functionalized molecules and has considerable synthetic potential and promising biological profiles. The Morita-Baylis-Hillman adducts (MBHA) are a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs, e.g. as anti-Leishmania chagasi and Leishmania amazonensis, anti- Trypanosoma cruzi, anti-Plasmodium falciparum and Plasmodium berghei, lethal against Biomphalaria glabrata, antibacterial, antifungal, herbicide and others. The goal of this work is to describe the primary cytotoxic activities against strains of human leukemia HL-60 cell line for thirty-four Morita-Baylis- Hillman adducts (MBHA), followed by a Quantitative Structure-Activity Relationships study (QSAR). The conventional or microwave-assisted syntheses of MBHA, derived from substituted aromatics or Isatin, were performed in good to excellent yields (70-100%) in short reaction times, using protocols recently developed by us. Isatin derivatives, MBHA 31 and 32, were the most active in this congener series of compounds, with IC50 values of 10.8 μM and 7.8 μM, respectively. The primary cytotoxic activities against chronic leukemia cells (K562) were also evaluated to these two most active compounds (MBHA 31 and 32), presenting IC50 values of 53 μM and 43 μM respectively. QSAR study was performed considering 3D, 2D and constitutional molecular descriptors. These were selected from Ordered Predictor Selection algorithm and submitted to Partial Least Squares Modeling. We present an interesting investigation about cytotoxic activities on human leukemia cell line (HL-60) for 34 synthetic MBHA. In a good way we discovered that the most cytotoxic compounds (31-32, 10.8 μM and 7.8 μM respectively) were also prepared quantitatively (100% yields) in a short reaction time using microwave irradiation. We demonstrate that 31 and 32 induced

  14. Activity Dependent Synaptic Plasticity Mimicked on Indium-Tin-Oxide Electric-Double-Layer Transistor.

    Science.gov (United States)

    Wen, Juan; Zhu, Li Qiang; Fu, Yang Ming; Xiao, Hui; Guo, Li Qiang; Wan, Qing

    2017-10-25

    Ion coupling has provided an additional method to modulate electric properties for solid-state materials. Here, phosphorosilicate glass (PSG)-based electrolyte gated protonic/electronic coupled indium-tin-oxide electric-double-layer (EDL) transistors are fabricated. The oxide transistor exhibits good electrical performances due to an extremely strong proton gating behavior for the electrolyte. With interfacial electrochemical doping, channel conductances of the oxide EDL transistor can be regulated to different levels, corresponding to different initial synaptic weights. Thus, activity dependent synaptic responses such as excitatory postsynaptic current, paired-pulse facilitation, and high-pass filtering are discussed in detail. The proposed proton conductor gated oxide EDL synaptic transistors with activity dependent synaptic plasticities may act as fundamental building blocks for neuromorphic system applications.

  15. Hepatoprotection of sesquiterpenoids: a quantitative structure-activity relationship (QSAR) approach.

    Science.gov (United States)

    Vinholes, Juliana; Rudnitskaya, Alisa; Gonçalves, Pedro; Martel, Fátima; Coimbra, Manuel A; Rocha, Sílvia M

    2014-03-01

    The relative hepatoprotection effect of fifteen sesquiterpenoids, commonly found in plants and plant-derived foods and beverages was assessed. Endogenous lipid peroxidation (assay A) and induced lipid peroxidation (assay B) were evaluated in liver homogenates from Wistar rats by the thiobarbituric acid reactive species test. Sesquiterpenoids with different chemical structures were tested: trans,trans-farnesol, cis-nerolidol, (-)-α-bisabolol, trans-β-farnesene, germacrene D, α-humulene, β-caryophyllene, isocaryophyllene, (+)-valencene, guaiazulene, (-)-α-cedrene, (+)-aromadendrene, (-)-α-neoclovene, (-)-α-copaene, and (+)-cyclosativene. Ascorbic acid was used as a positive antioxidant control. With the exception of α-humulene, all the sesquiterpenoids under study (1mM) were effective in reducing the malonaldehyde levels in both endogenous and induced lipid peroxidation up to 35% and 70%, respectively. The 3D-QSAR models developed, relating the hepatoprotection activity with molecular properties, showed good fit (Radj(2) 0.819 and 0.972 for the assays A and B, respectively) with good prediction power (Q(2)>0.950 and SDEP<2%, for both models A and B). A network of effects associated with structural and chemical features of sesquiterpenoids such as shape, branching, symmetry, and presence of electronegative fragments, can modulate the hepatoprotective activity observed for these compounds. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. An Activity-Dependent Assay for Ricin and Related RNA N-Glycosidases Based on Electrochemiluminescence

    Science.gov (United States)

    2006-01-01

    independently confirm positive results obtained from an ECL immunoassay. The assay format depicted in Fig. 1 involves the RNA N- glyco - sidase-dependent...proportional to the product concentration (data not shown). Since N-glycosidase activity produces an abasic site with an aldehyde group and does not cleave the...protein synthesis , Biofactors 3 (1992) 173–184. [2] J.M. Lord, L.M. Roberts, J.D. Robertus, Ricin: structure, mode of action, and some current

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

    Science.gov (United States)

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

    2014-04-01

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

  18. Molecular Mechanism of Distinct Salt-Dependent Enzyme Activity of Two Halophilic Nucleoside Diphosphate Kinases

    OpenAIRE

    Yamamura, Akihiro; Ichimura, Takefumi; Kamekura, Masahiro; Mizuki, Toru; Usami, Ron; Makino, Tsukasa; Ohtsuka, Jun; Miyazono, Ken-ichi; Okai, Masahiko; Nagata, Koji; Tanokura, Masaru

    2009-01-01

    Nucleoside diphosphate kinases from haloarchaea Haloarcula quadrata (NDK-q) and H. sinaiiensis (NDK-s) are identical except for one out of 154 residues, i.e., Arg31 in NDK-q and Cys31 in NDK-s. However, the salt-dependent activity profiles of NDK-q and NDK-s are quite different: the optimal NaCl concentrations of NDK-q and NDK-s are 1 M and 2 M, respectively. We analyzed the relationships of the secondary, tertiary, and quaternary structures and NDK activity of these NDKs at various salt conc...

  19. Characterization of the double stranded RNA dependent RNase activity associated with recombinant reverse transcriptases.

    OpenAIRE

    Ben-Artzi, H; Zeelon, E; Le-Grice, S F; Gorecki, M; Panet, A

    1992-01-01

    An in situ gel assay was applied to the study of double stranded RNA dependent RNase activity associated with reverse transcriptase (RT) of HIV-1 and murine leukemia virus. Polyacrylamide gels containing [32P] RNA/RNA substrate were used for electrophoresis of proteins under denaturing conditions. The proteins were renatured and in situ enzymatic degradation of 32P-RNA/RNA was followed. E. coli RNaseIII, but not E. coli RNaseH, was active in this in situ gel assay, indicating specificity of t...

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

    Science.gov (United States)

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

    2016-01-01

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

  1. An Evolutionarily Conserved Mechanism for Activity-dependent Visual Circuit Development

    Directory of Open Access Journals (Sweden)

    Kara Geo Pratt

    2016-10-01

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

  2. Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development.

    Science.gov (United States)

    Mill, Pleasantine; Mo, Rong; Fu, Hong; Grachtchouk, Marina; Kim, Peter C W; Dlugosz, Andrzej A; Hui, Chi-chung

    2003-01-15

    Sonic hedgehog (Shh) signaling plays a critical role in hair follicle development and skin cancer, but how it controls these processes remains unclear. Of the three Gli transcription factors involved in transducing Shh signals in vertebrates, we demonstrate here that Gli2 is the key mediator of Shh responses in skin. Similar to Shh(-/-) mice, Gli2(-/-) mutants exhibit an arrest in hair follicle development with reduced cell proliferation and Shh-responsive gene expression, but grossly normal epidermal differentiation. By transgenic rescue experiments, we show that epidermal Gli2 function alone is sufficient to restore hair follicle development in Gli2(-/-) skin. Furthermore, only a constitutively active form of Gli2, but not wild-type Gli2, can activate Shh-responsive gene expression and promote cell proliferation in Shh(-/-) skin. These observations indicate that Shh-dependent Gli2 activator function in the epidermis is essential for hair follicle development. Our data also reveal that Gli2 mediates the mitogenic effects of Shh by transcriptional activation of cyclin D1 and cyclin D2 in the developing hair follicles. Together, our results suggest that Shh-dependent Gli2 activation plays a critical role in epithelial homeostasis by promoting proliferation through the transcriptional control of cell cycle regulators.

  3. 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.

  4. 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.

  5. 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

  6. Cortactin Is a Regulator of Activity-Dependent Synaptic Plasticity Controlled by Wingless.

    Science.gov (United States)

    Alicea, Daniel; Perez, Marizabeth; Maldonado, Carolina; Dominicci-Cotto, Carihann; Marie, Bruno

    2017-02-22

    Major signaling molecules initially characterized as key early developmental regulators are also essential for the plasticity of the nervous system. Previously, the Wingless (Wg)/Wnt pathway was shown to underlie the structural and electrophysiological changes during activity-dependent synaptic plasticity at the Drosophila neuromuscular junction. A challenge remains to understand how this signal mediates the cellular changes underlying this plasticity. Here, we focus on the actin regulator Cortactin, a major organizer of protrusion, membrane mobility, and invasiveness, and define its new role in synaptic plasticity. We show that Cortactin is present presynaptically and postsynaptically at the Drosophila NMJ and that it is a presynaptic regulator of rapid activity-dependent modifications in synaptic structure. Furthermore, animals lacking presynaptic Cortactin show a decrease in spontaneous release frequency, and presynaptic Cortactin is necessary for the rapid potentiation of spontaneous release frequency that takes place during activity-dependent plasticity. Most interestingly, Cortactin levels increase at stimulated synaptic terminals and this increase requires neuronal activity, de novo transcription and depends on Wg/Wnt expression. Because it is not simply the presence of Cortactin in the presynaptic terminal but its increase that is necessary for the full range of activity-dependent plasticity, we conclude that it probably plays a direct and important role in the regulation of this process. SIGNIFICANCE STATEMENT In the nervous system, changes in activity that lead to modifications in synaptic structure and function are referred to as synaptic plasticity and are thought to be the basis of learning and memory. The secreted Wingless/Wnt molecule is a potent regulator of synaptic plasticity in both vertebrates and invertebrates. Understanding the molecular mechanisms that underlie these plastic changes is a major gap in our knowledge. Here, we identify a

  7. Prediction of the Formulation Dependence of the Glass Transition Temperature for Amine-Epoxy Copolymers Using a Quantitative Structure-Property Relationship Based on the AM1 Method

    National Research Council Canada - National Science Library

    Morrill, Jason

    2004-01-01

    A designer Quantitative Structure-Property Relationsbip (QSPR) based upon molecular properties calculated using the AM1 semi-empirical quantum mechanical metbod was developed to predict the glass transition temperature (Tg...

  8. Quantitative temperature-depending mapping of mechanical properties of bitumen at the nanoscale using the AFM operated with PeakForce TappingTM mode

    NARCIS (Netherlands)

    Fischer, H.R.; Stadler, H.; Erina, N.

    2013-01-01

    The mechanical properties of bitumen, such as elasticity/Young's modulus, stickiness/adhesion, hardness and energy loss, and sample deformation were acquired quantitatively and simultaneously with the topology at the microscale, discriminating clearly two separate phases within the bitumen.

  9. In-silico Comparative Study and Quantitative Structure-activity Relationship Analysis of Some Structural and Physiochemical Descriptors of Elvitegravir Analogs.

    Science.gov (United States)

    Satpathy, R; Ghosh, S

    2011-07-01

    Elvitegravir is a new-generation drug which acts as an integrase inhibitor of the HIV virus. The potential inhibition has been tested from the clinical trial data. Here the work basically deals with the quantitative structure-activity relationship (QSAR) analysis by considering some of the physiochemical descriptors like molecular weight, logP, molar volume, and structural descriptors like Winers index, and molecular topological index of the drug analogs. The descriptors were calculated from the E-Dragon server and the multiple linear regression equation models were built by using Minitab tools. The different combinations of structural and physiochemical descriptors were considered for model derivation. The best three models were chosen by observing high R-Sq value, high F-value and low residual errors. The P values (regression) for the three models indicates the significance of the considered descriptors.The overall results obtained with these model suggest that for this perticular drug the activity is dependent on physiochemical descriptors.

  10. 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.

  11. The chromatin Remodeler CHD8 is required for activation of progesterone receptor-dependent enhancers.

    Directory of Open Access Journals (Sweden)

    María Ceballos-Chávez

    2015-04-01

    Full Text Available While the importance of gene enhancers in transcriptional regulation is well established, the mechanisms and the protein factors that determine enhancers activity have only recently begun to be unravelled. Recent studies have shown that progesterone receptor (PR binds regions that display typical features of gene enhancers. Here, we show by ChIP-seq experiments that the chromatin remodeler CHD8 mostly binds promoters under proliferation conditions. However, upon progestin stimulation, CHD8 re-localizes to PR enhancers also enriched in p300 and H3K4me1. Consistently, CHD8 depletion severely impairs progestin-dependent gene regulation. CHD8 binding is PR-dependent but independent of the pioneering factor FOXA1. The SWI/SNF chromatin-remodelling complex is required for PR-dependent gene activation. Interestingly, we show that CHD8 interacts with the SWI/SNF complex and that depletion of BRG1 and BRM, the ATPases of SWI/SNF complex, impairs CHD8 recruitment. We also show that CHD8 is not required for H3K27 acetylation, but contributes to increase accessibility of the enhancer to DNaseI. Furthermore, CHD8 was required for RNAPII recruiting to the enhancers and for transcription of enhancer-derived RNAs (eRNAs. Taken together our data demonstrate that CHD8 is involved in late stages of PR enhancers activation.

  12. Titin isoform variance and length dependence of activation in skinned bovine cardiac muscle.

    Science.gov (United States)

    Fukuda, Norio; Wu, Yiming; Farman, Gerrie; Irving, Thomas C; Granzier, Henk

    2003-11-15

    We have explored the role of the giant elastic protein titin in the Frank-Starling mechanism of the heart by measuring the sarcomere length (SL) dependence of activation in skinned cardiac muscles with different titin-based passive stiffness characteristics. We studied muscle from the bovine left ventricle (BLV), which expresses a high level of a stiff titin isoform, and muscle from the bovine left atrium (BLA), which expresses more compliant titin isoforms. Passive tension was also varied in each muscle type by manipulating the pre-history of stretch prior to activation. We found that the SL-dependent increases in Ca2+ sensitivity and maximal Ca2+-activated tension were markedly more pronounced when titin-based passive tension was high. Small-angle X-ray diffraction experiments revealed that the SL dependence of reduction of interfilament lattice spacing is greater in BLV than in BLA and that the lattice spacing is coupled with titin-based passive tension. These results support the notion that titin-based passive tension promotes actomyosin interaction by reducing the lattice spacing. This work indicates that titin may be a factor involved in the Frank-Starling mechanism of the heart by promoting actomyosin interaction in response to stretch.

  13. 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

  14. TGF-β suppresses β-catenin-dependent tolerogenic activation program in dendritic cells.

    Directory of Open Access Journals (Sweden)

    Bryan Vander Lugt

    Full Text Available The mechanisms that underlie the critical dendritic cell (DC function in maintainance of peripheral immune tolerance are incompletely understood, although the β-catenin signaling pathway is critical for this role. The molecular details by which β-catenin signaling is regulated in DCs are unknown. Mechanical disruption of murine bone marrow-derived DC (BMDC clusters activates DCs while maintaining their tolerogenic potential and this activation is associated with β-catenin signaling, providing a useful model with which to explore tolerance-associated β-catenin signaling in DCs. In this report, we demonstrate novel molecular features of the signaling events that control DC activation in response to mechanical stimulation. Non-canonical β-catenin signaling is an essential component of this tolerogenic activation and is modulated by adhesion molecules, including integrins. This unique β-catenin-dependent signaling pathway is constitutively active at low levels, suggesting that mechanical stimulation is not necessarily required for induction of this unique activation program. We additionally find that the immunomodulatory cytokine TGF-β antagonizes β-catenin in DCs, thereby selectively suppressing signaling associated with tolerogenic DC activation while having no impact on LPS-induced, β-catenin-independent immunogenic activation. These findings provide new molecular insight into the regulation of a critical signaling pathway for DC function in peripheral immune tolerance.

  15. The Evaluation of Bioelectrical Activity of Pelvic Floor Muscles Depending on Probe Location: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Tomasz Halski

    2013-01-01

    Full Text Available Objectives. The main objective was to determine how the depth of probe placement affects functional and resting bioelectrical activity of the PFM and whether the recorded signal might be dependent on the direction in which the probe is rotated. Participants. The study comprised of healthy, nulliparous women between the ages of 21 and 25. Outcome Measures. Bioelectric activity of the PFM was recorded from four locations of the vagina by surface EMG and vaginal probe. Results. There were no statistically significant differences between the results during functional sEMG activity. During resting sEMG activity, the highest bioelectrical activity of the PFM was observed in the L1 and the lowest in the L4 and a statistically significant difference between the highest and the lowest results of resting sEMG activity was observed (P=0.0043. Conclusion. Different electrodes placement during functional contraction of PFM does not affect the obtained results in sEMG evaluation. In order to diagnose the highest resting activity of PFM the recording plates should be placed toward the anterior vaginal wall and distally from the introitus. However, all of the PFM have similar bioelectrical activity and it seems that these muscles could be treated as a single muscle.

  16. Quantitative structure-activity relationships for predicting potential ecological hazard of organic chemicals for use in regulatory risk assessments.

    Science.gov (United States)

    Comber, Mike H I; Walker, John D; Watts, Chris; Hermens, Joop

    2003-08-01

    The use of quantitative structure-activity relationships (QSARs) for deriving the predicted no-effect concentration of discrete organic chemicals for the purposes of conducting a regulatory risk assessment in Europe and the United States is described. In the United States, under the Toxic Substances Control Act (TSCA), the TSCA Interagency Testing Committee and the U.S. Environmental Protection Agency (U.S. EPA) use SARs to estimate the hazards of existing and new chemicals. Within the Existing Substances Regulation in Europe, QSARs may be used for data evaluation, test strategy indications, and the identification and filling of data gaps. To illustrate where and when QSARs may be useful and when their use is more problematic, an example, methyl tertiary-butyl ether (MTBE), is given and the predicted and experimental data are compared. Improvements needed for new QSARs and tools for developing and using QSARs are discussed.

  17. Active auxin uptake by zucchini membrane vesicles: quantitation using ESR volume and delta pH determinations

    International Nuclear Information System (INIS)

    Lomax, T.L.; Mehlhorn, R.J.; Briggs, W.R.

    1985-01-01

    Closed and pH-tight membrane vesicles prepared from hypocotyls of 5-day-old dark-grown seedlings of Cucurbita pepo accumulate the plant growth hormone indole-3-acetic acid along an imposed proton gradient (pH low outside, high inside). The use of electron paramagnetic spin probes permitted quantitation both of apparent vesicle volume and magnitude of the pH gradient. Under the experimental conditions used, hormone accumulation was at minimum 20-fold, a value 4 times larger than what one would predict if accumulation reflected only diffusional equilibrium at the measured pH gradient. It is concluded that hormone uptake is an active process, with each protonated molecule of hormone accompanied by an additional proton. Experiments with ionophores confirm that it is the pH gradient itself which drives the uptake

  18. Quantitative structure-activity relationship (QSAR) study of toxicity of quaternary ammonium compounds on Chlorella pyrenoidosa and Scenedesmus quadricauda.

    Science.gov (United States)

    Jing, Guohua; Zhou, Zuoming; Zhuo, Jing

    2012-01-01

    The acute toxicity of 13 quaternary ammonium compounds (QACs) to Chlorella pyrenoidosa and Scenedesmus quadricauda was investigated in the present study. Significant inhibition on algae biomass was observed and 96 h EC(50)-value of 13 QACs was tested. Sixteen physicochemical and quantum chemical parameters of the QACs were calculated using the semi-empirical MOPAC AMI method. The multiple linear regression (MLR) was employed to derive the quantitative structure-activity relationship (QSAR) models, by which the calculated parameters were correlated to the toxicity of QACs on the two green algaes. Results showed that the alkyl chain lengths (CL) and total connectivity (T(Con)) were the main descriptors in governing the log (1/EC(50)) values of the QACs in the two QSAR models. The two models had high predictive ability and stability, and two parameters were proved to have the general applicability in QSAR study of QACs congeners. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. Assessment of cardiac sympathetic nerve activity in children with chronic heart failure using quantitative iodine-123 metaiodobenzylguanidine imaging

    International Nuclear Information System (INIS)

    Karasawa, Kensuke; Ayusawa, Mamoru; Noto, Nobutaka; Sumitomo, Naokata; Okada, Tomoo; Harada, Kensuke

    2000-01-01

    Cardiac sympathetic nerve activity in children with chronic heart failure was examined by quantitative iodine-123 metaiodobenzylguanidine (MIBG) myocardial imaging in 33 patients aged 7.5±6.1 years (range 0-18 years), including 8 with cardiomyopathy, 15 with congenital heart disease, 3 with anthracycrine cardiotoxicity, 3 with myocarditis, 3 with primary pulmonary hypertension and 1 with Pompe's disease. Anterior planar images were obtained 15 min and 3 hr after the injection of iodine-123 MIBG. The cardiac iodine-123 MIBG uptake was assessed as the heart to upper mediastinum uptake activity ratio of the delayed image (H/M) and the cardiac percentage washout rate (%WR). The severity of chronic heart failure was class I (no medication) in 8 patients, class II (no symptom with medication) in 9, class III (symptom even with medication) in 10 and class IV (late cardiac death) in 6. H/M was 2.33±0.22 in chronic heart failure class I, 2.50±0.34 in class II, 1.95±0.61 in class III, and 1.39±0.29 in class IV (p<0.05). %WR was 24.8±12.8% in chronic heart failure class I, 23.3±10.2% in class II, 49.2±24.5% in class III, and 66.3±26.5% in class IV (p<0.05). The low H/M and high %WR were proportionate to the severity of chronic heart failure. Cardiac iodine-123 MIBG showed cardiac adrenergic neuronal dysfunction in children with severe chronic heart failure. Quantitative iodine-123 MIBG myocardial imaging is clinically useful as a predictor of therapeutic outcome and mortality in children with chronic heart failure. (author)

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

    Directory of Open Access Journals (Sweden)

    D. Anghileri

    2011-06-01

    Full Text Available 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 approach are that: (i the impact quantification is based on a set of performance indicators defined together with the stakeholders, thus explicitly taking into account the water-users preferences; (ii the management policies are obtained by optimal control techniques, linking stakeholder expectations and decision-making; (iii the multi-objective nature of the management problem is fully preserved by simulating a set of Pareto-optimal management policies, which allows for evaluating not only variations in the indicator values but also tradeoffs among conflicting objectives. The framework is demonstrated by application to a real world case study, Lake Como basin (Italy. We show that the most conflicting water-related activities within the basin (i.e. hydropower production and agriculture are likely to be negatively impacted by climate change. We discuss the robustness of the estimated impacts to the climate natural variability and the approximations in modeling the physical system and the socio-economic system, and perform an uncertainty analysis of several sources of uncertainty. We demonstrate that the contribution of natural climate uncertainty is rather remarkable and that, among different modelling uncertainty sources, the one from climate modeling is very significant.

  1. 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.

  2. Activation of neural stem cells from quiescence drives reactive hippocampal neurogenesis after alcohol dependence.

    Science.gov (United States)

    Hayes, Dayna M; Nickell, Chelsea G; Chen, Kevin Y; McClain, Justin A; Heath, Megan M; Deeny, M Ayumi; Nixon, Kimberly

    2018-05-01

    Neural stem cell-driven adult neurogenesis contributes to the integrity of the hippocampus. Excessive alcohol consumption in alcoholism results in hippocampal degeneration that may recover with abstinence. Reactive, increased adult neurogenesis during abstinence following alcohol dependence may contribute to recovery, but the mechanism driving reactive neurogenesis is not known. Therefore, adult, male rats were exposed to alcohol for four days and various markers were used to examine cell cycle dynamics, the percentage and number of neural progenitor cell subtypes, and the percentage of quiescent versus activated progenitors. Using a screen for cell cycle perturbation, we showed that the cell cycle is not likely altered at 7 days in abstinence. As the vast majority of Bromodeoxyuridine-positive (+) cells were co-labeled with progenitor cell marker, Sox2, we then developed a quadruple fluorescent labeling scheme to examine Type-1, -2a, -2b and -3 progenitor cells simultaneously. Prior alcohol dependence indiscriminately increased all subtypes at 7 days, the peak of the reactive proliferation. An evaluation of the time course of reactive cell proliferation revealed that cells begin proliferating at 5 days post alcohol, where only actively dividing Type 2 progenitors were increased by alcohol. Furthermore, prior alcohol increased the percentage of actively dividing Sox2+ progenitors, which supported that reactive neurogenesis is likely due to the activation of progenitors out of quiescence. These observations were associated with granule cell number returning to normal at 28 days. Therefore, activating stem and progenitor cells out of quiescence may be the mechanism underlying hippocampal recovery in abstinence following alcohol dependence. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. 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.

  4. VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

    International Nuclear Information System (INIS)

    Garcia-Roman, Jonathan; Ibarra-Sanchez, Alfredo; Lamas, Monica; Gonzalez Espinosa, Claudia

    2010-01-01

    Research highlights: → Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. → CoCl 2 -induced VEGF secretion in mast cells occurs by a Ca 2+ -insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. → Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits FcεRI-dependent anaphylactic degranulation in mast cells. → Src family kinase Fyn activation after free radical production is necessary for hypoxia-induced VEGF secretion in mast cells. -- Abstract: Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl 2 ) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl 2 promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl 2 -induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle-associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl 2 -induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl 2 in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N-acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals-dependent Fyn kinase activation.

  5. VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

    Energy Technology Data Exchange (ETDEWEB)

    Garcia-Roman, Jonathan; Ibarra-Sanchez, Alfredo; Lamas, Monica [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del IPN (Cinvestav, IPN) (Mexico); Gonzalez Espinosa, Claudia, E-mail: cgonzal@cinvestav.mx [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del IPN (Cinvestav, IPN) (Mexico)

    2010-10-15

    Research highlights: {yields} Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. {yields} CoCl{sub 2}-induced VEGF secretion in mast cells occurs by a Ca{sup 2+}-insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. {yields} Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits Fc{epsilon}RI-dependent anaphylactic degranulation in mast cells. {yields} Src family kinase Fyn activation after free radical production is necessary for hypoxia-induced VEGF secretion in mast cells. -- Abstract: Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl{sub 2}) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl{sub 2} promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl{sub 2}-induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle-associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl{sub 2}-induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl{sub 2} in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N-acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals-dependent

  6. Application of Scharer's quantitative method for the determination of residual alkaline phosphatase activity in standard Minas

    Directory of Open Access Journals (Sweden)

    C.F. Soares

    2013-08-01

    Full Text Available Milk pasteurization is a critical issue in the dairy industry, and failures in this process can affect final product safety. Scharer's enzymatic method is still traditionally used to verify pasteurization efficiency compliance, and it is based on screening for residual alkaline phosphatase in milk. Although several methods are used to quantify enzymatic activity to assess milk pasteurization efficiency, there is a small amount of published data regarding the use of these methods to quantify alkaline phosphatase in cheese. In this study, the Scharer's modified method was used to determine the levels of residual alkaline phosphatase in standard minas cheese, before and after 20 days of ripening. The cheeses were made using raw or pasteurized milk with the addition of different concentrations of raw milk (0; 0.05%; 0.10%; 0.20%; and 0.50%. In the fresh cheese samples, the method showed a sensitivity of only 0.50% with the addition of raw milk to the pasteurized milk used to make cheese. In addition, levels of up 0.20% of raw milk in pasteurized milk, the concentrations of phenol was inferior to 1μg phenol/g of dairy product which is the preconized indicator value for adequate pasteurization.

  7. Cannabinoid receptor 1 binding activity and quantitative analysis of Cannabis sativa L. smoke and vapor.

    Science.gov (United States)

    Fischedick, Justin; Van Der Kooy, Frank; Verpoorte, Robert

    2010-02-01

    Cannabis sativa L. (cannabis) extracts, vapor produced by the Volcano vaporizer and smoke made from burning cannabis joints were analyzed by GC-flame ionization detecter (FID), GC-MS and HPLC. Three different medicinal cannabis varieties were investigated Bedrocan, Bedrobinol and Bediol. Cannabinoids plus other components such as terpenoids and pyrolytic by-products were identified and quantified in all samples. Cannabis vapor and smoke was tested for cannabinoid receptor 1 (CB1) binding activity and compared to pure Delta(9)-tetrahydrocannabinol (Delta(9)-THC). The top five major compounds in Bedrocan extracts were Delta(9)-THC, cannabigerol (CBG), terpinolene, myrcene, and cis-ocimene in Bedrobinol Delta(9)-THC, myrcene, CBG, cannabichromene (CBC), and camphene in Bediol cannabidiol (CBD), Delta(9)-THC, myrcene, CBC, and CBG. The major components in Bedrocan vapor (>1.0 mg/g) were Delta(9)-THC, terpinolene, myrcene, CBG, cis-ocimene and CBD in Bedrobinol Delta(9)-THC, myrcene and CBD in Bediol CBD, Delta(9)-THC, myrcene, CBC and terpinolene. The major components in Bedrocan smoke (>1.0 mg/g) were Delta(9)-THC, cannabinol (CBN), terpinolene, CBG, myrcene and cis-ocimene in Bedrobinol Delta(9)-THC, CBN and myrcene in Bediol CBD, Delta(9)-THC, CBN, myrcene, CBC and terpinolene. There was no statistically significant difference between CB1 binding of pure Delta(9)-THC compared to cannabis smoke and vapor at an equivalent concentration of Delta(9)-THC.

  8. Predicting Nano-Bio Interactions by Integrating Nanoparticle Libraries and Quantitative Nanostructure Activity Relationship Modeling.

    Science.gov (United States)

    Wang, Wenyi; Sedykh, Alexander; Sun, Hainan; Zhao, Linlin; Russo, Daniel P; Zhou, Hongyu; Yan, Bing; Zhu, Hao

    2017-12-26

    The discovery of biocompatible or bioactive nanoparticles for medicinal applications is an expensive and time-consuming process that may be significantly facilitated by incorporating more rational approaches combining both experimental and computational methods. However, it is currently hindered by two limitations: (1) the lack of high-quality comprehensive data for computational modeling and (2) the lack of an effective modeling method for the complex nanomaterial structures. In this study, we tackled both issues by first synthesizing a large library of nanoparticles and obtained comprehensive data on their characterizations and bioactivities. Meanwhile, we virtually simulated each individual nanoparticle in this library by calculating their nanostructural characteristics and built models that correlate their nanostructure diversity to the corresponding biological activities. The resulting models were then used to predict and design nanoparticles with desired bioactivities. The experimental testing results of the designed nanoparticles were consistent with the model predictions. These findings demonstrate that rational design approaches combining high-quality nanoparticle libraries, big experimental data sets, and intelligent computational models can significantly reduce the efforts and costs of nanomaterial discovery.

  9. Sleep slow-wave activity reveals developmental changes in experience-dependent plasticity.

    Science.gov (United States)

    Wilhelm, Ines; Kurth, Salomé; Ringli, Maya; Mouthon, Anne-Laure; Buchmann, Andreas; Geiger, Anja; Jenni, Oskar G; Huber, Reto

    2014-09-10

    Experience-dependent plasticity, the ability of the brain to constantly adapt to an ever-changing environment, has been suggested to be highest during childhood and to decline thereafter. However, empirical evidence for this is rather scarce. Slow-wave activity (SWA; EEG activity of 1-4.5 Hz) during deep sleep can be used as a marker of experience-dependent plasticity. For example, performing a visuomotor adaptation task in adults increased SWA during subsequent sleep over a locally restricted region of the right parietal cortex, which is known to be involved in visuomotor adaptation. Here, we investigated whether local experience-dependent changes in SWA vary as a function of brain maturation. Three age groups (children, adolescents, and adults) participated in a high-density EEG study with two conditions (baseline and adaptation) of a visuomotor learning task. Compared with the baseline condition, sleep SWA was increased after visuomotor adaptation in a cluster of eight electrodes over the right parietal cortex. The local boost in SWA was highest in children. Baseline SWA in the parietal cluster and right parietal gray matter volume, which both indicate region-specific maturation, were significantly correlated with the local increase in SWA. Our findings indicate that processes of brain maturation favor experience-dependent plasticity and determine how sensitive a specific brain region is for learning experiences. Moreover, our data confirm that SWA is a highly sensitive tool to map maturational differences in experience-dependent plasticity. Copyright © 2014 the authors 0270-6474/14/3412568-08$15.00/0.

  10. 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.

  11. Rapid and quantitative determination of 10 major active components in Lonicera japonica Thunb. by ultrahigh pressure extraction-HPLC/DAD

    Science.gov (United States)

    Fan, Li; Lin, Changhu; Duan, Wenjuan; Wang, Xiao; Liu, Jianhua; Liu, Feng

    2015-01-01

    An ultrahigh pressure extraction (UPE)-high performance liquid chromatography (HPLC)/diode array detector (DAD) method was established to evaluate the quality of Lonicera japonica Thunb. Ten active components, including neochlorogenic acid, chlorogenic acid, 4-dicaffeoylquinic acid, caffeic acid, rutin, luteoloside, isochlorogenic acid B, isochlorogenic acid A, isochlorogenic acid C, and quercetin, were qualitatively evaluated and quantitatively determined. Scanning electron microscope images elucidated the bud surface microstructure and extraction mechanism. The optimal extraction conditions of the UPE were 60% methanol solution, 400 MPa of extraction pressure, 3 min of extraction time, and 1:30 (g/mL) solid:liquid ratio. Under the optimized conditions, the total extraction yield of 10 active components was 57.62 mg/g. All the components showed good linearity (r2 ≥ 0.9994) and recoveries. This method was successfully applied to quantify 10 components in 22 batches of L. japonica samples from different areas. Compared with heat reflux extraction and ultrasonic-assisted extraction, UPE can be considered as an alternative extraction technique for fast extraction of active ingredient from L. japonica.

  12. Quantitative Determination of Alkaloids in Lotus Flower (Flower Buds of Nelumbo nucifera and Their Melanogenesis Inhibitory Activity

    Directory of Open Access Journals (Sweden)

    Toshio Morikawa

    2016-07-01

    Full Text Available A quantitative analytical method for five aporphine alkaloids, nuciferine (1, nornuciferine (2, N-methylasimilobine (3, asimilobine (4, and pronuciferine (5, and five benzylisoquinoline alkaloids, armepavine (6, norarmepavine (7, N-methylcoclaurine (8, coclaurine (9, and norjuziphine (10, identified as the constituents responsible for the melanogenesis inhibitory activity of the extracts of lotus flowers (the flower buds of Nelumbo nucifera, has been developed using liquid chromatography-mass spectrometry. The optimum conditions for separation and detection of these 10 alkaloids were achieved on a πNAP column, a reversed-phase column with naphthylethyl group-bonded silica packing material, with CH3CN–0.2% aqueous acetic acid as the mobile phase and using mass spectrometry equipped with a positive-mode electrospray ionization source. According to the protocol established, distributions of these 10 alkaloids in the petal, receptacle, and stamen parts, which were separated from the whole flower, were examined. As expected, excellent correlations were observed between the total alkaloid content and melanogenesis inhibitory activity. Among the active alkaloids, nornuciferine (2 was found to give a carbamate salt (2′′ via formation of an unstable carbamic acid (2′ by absorption of carbon dioxide from the air.

  13. Quantitative structure-activity relationship study on BTK inhibitors by modified multivariate adaptive regression spline and CoMSIA methods.

    Science.gov (United States)

    Xu, A; Zhang, Y; Ran, T; Liu, H; Lu, S; Xu, J; Xiong, X; Jiang, Y; Lu, T; Chen, Y

    2015-01-01

    Bruton's tyrosine kinase (BTK) plays a crucial role in B-cell activation and development, and has emerged as a new molecular target for the treatment of autoimmune diseases and B-cell malignancies. In this study, two- and three-dimensional quantitative structure-activity relationship (2D and 3D-QSAR) analyses were performed on a series of pyridine and pyrimidine-based BTK inhibitors by means of genetic algorithm optimized multivariate adaptive regression spline (GA-MARS) and comparative molecular similarity index analysis (CoMSIA) methods. Here, we propose a modified MARS algorithm to develop 2D-QSAR models. The top ranked models showed satisfactory statistical results (2D-QSAR: Q(2) = 0.884, r(2) = 0.929, r(2)pred = 0.878; 3D-QSAR: q(2) = 0.616, r(2) = 0.987, r(2)pred = 0.905). Key descriptors selected by 2D-QSAR were in good agreement with the conclusions of 3D-QSAR, and the 3D-CoMSIA contour maps facilitated interpretation of the structure-activity relationship. A new molecular database was generated by molecular fragment replacement (MFR) and further evaluated with GA-MARS and CoMSIA prediction. Twenty-five pyridine and pyrimidine derivatives as novel potential BTK inhibitors were finally selected for further study. These results also demonstrated that our method can be a very efficient tool for the discovery of novel potent BTK inhibitors.

  14. Quantitative MR characterization of disease activity in the knee in children with juvenile idiopathic arthritis: a longitudinal pilot study

    International Nuclear Information System (INIS)

    Workie, Dagnachew W.; Graham, T.B.; Laor, Tal; Racadio, Judy M.; Rajagopal, Akila; O'Brien, Kendall J.; Bommer, Wendy A.; Shire, Norah J.; Dardzinski, Bernard J.

    2007-01-01

    The development of a quantifiable and noninvasive method of monitoring disease activity and response to therapy is vital for arthritis management. The purpose of this study was to investigate the utility of quantitative dynamic contrast-enhanced MRI (DCE-MRI) based on pharmacokinetic (PK) modeling to evaluate disease activity in the knee and correlate the results with the clinical assessment in children with juvenile idiopathic arthritis (JIA). A group of 17 children with JIA underwent longitudinal clinical and laboratory assessment and DCE-MRI of the knee at enrollment, 3 months, and 12 months. A PK model was employed using MRI signal enhancement data to give three parameters, K trans ' (min -1 ), k ep (min -1 ), and V p ' and to calculate synovial volume. The PK parameters, synovial volumes, and clinical and laboratory assessments in most children were significantly decreased (P < 0.05) at 12 months when compared to the enrollment values. There was excellent correlation between the PK and synovial volume and the clinical and laboratory assessments. Differences in MR and clinical parameter values in individual subjects illustrate persistent synovitis when in clinical remission. A decrease in PK parameter values obtained from DCE-MRI in children with JIA likely reflects diminution of disease activity. This technique may be used as an objective follow-up measure of therapeutic efficacy in patients with JIA. MR imaging can detect persistent synovitis in patients considered to be in clinical remission. (orig.)

  15. Actin-dependent activation of serum response factor in T cells by the viral oncoprotein tip

    Directory of Open Access Journals (Sweden)

    Katsch Kristin

    2012-03-01

    Full Text Available Abstract Serum response factor (SRF acts as a multifunctional transcription factor regulated by mutually exclusive interactions with ternary complex factors (TCFs or myocardin-related transcription factors (MRTFs. Binding of Rho- and actin-regulated MRTF:SRF complexes to target gene promoters requires an SRF-binding site only, whereas MAPK-regulated TCF:SRF complexes in addition rely on flanking sequences present in the serum response element (SRE. Here, we report on the activation of an SRE luciferase reporter by Tip, the viral oncoprotein essentially contributing to human T-cell transformation by Herpesvirus saimiri. SRE activation in Tip-expressing Jurkat T cells could not be attributed to triggering of the MAPK pathway. Therefore, we further analyzed the contribution of MRTF complexes. Indeed, Tip also activated a reporter construct responsive to MRTF:SRF. Activation of this reporter was abrogated by overexpression of a dominant negative mutant of the MRTF-family member MAL. Moreover, enrichment of monomeric actin suppressed the Tip-induced reporter activity. Further upstream, the Rho-family GTPase Rac, was found to be required for MRTF:SRF reporter activation by Tip. Initiation of this pathway was strictly dependent on Tip's ability to interact with Lck and on the activity of this Src-family kinase. Independent of Tip, T-cell stimulation orchestrates Src-family kinase, MAPK and actin pathways to induce SRF. These findings establish actin-regulated transcription in human T cells and suggest its role in viral oncogenesis.

  16. GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

    Science.gov (United States)

    Shigeto, Makoto; Ramracheya, Reshma; Tarasov, Andrei I; Cha, Chae Young; Chibalina, Margarita V; Hastoy, Benoit; Philippaert, Koenraad; Reinbothe, Thomas; Rorsman, Nils; Salehi, Albert; Sones, William R; Vergari, Elisa; Weston, Cathryn; Gorelik, Julia; Katsura, Masashi; Nikolaev, Viacheslav O; Vennekens, Rudi; Zaccolo, Manuela; Galione, Antony; Johnson, Paul R V; Kaku, Kohei; Ladds, Graham; Rorsman, Patrik

    2015-12-01

    Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.

  17. HIV-1 infection of macrophages is dependent on evasion of innate immune cellular activation.

    Science.gov (United States)

    Tsang, Jhen; Chain, Benjamin M; Miller, Robert F; Webb, Benjamin L J; Barclay, Wendy; Towers, Greg J; Katz, David R; Noursadeghi, Mahdad

    2009-11-13

    The cellular innate immune response to HIV-1 is poorly characterized. In view of HIV-1 tropism for macrophages, which can be activated via pattern recognition receptors to trigger antimicrobial defences, we investigated innate immune responses to HIV-1 by monocyte-derived macrophages. In a model of productive HIV-1 infection, cellular innate immune responses to HIV-1 were investigated, at the level of transcription factor activation, specific gene expression and genome-wide transcriptional profiling. In addition, the viral determinants of macrophage responses and the physiological effect of innate immune cellular activation on HIV-1 replication were assessed. Productive HIV-1 infection did not activate nuclear factor-kappaB and interferon regulatory factor 3 transcription factors or interferon gene expression (IFN) and caused remarkably small changes to the host-cell transcriptome, with no evidence of inflammatory or IFN signatures. Evasion of IFN induction was not dependent on HIV-1 envelope-mediated cellular entry, inhibition by accessory proteins or reverse transcription of ssRNA that may reduce innate immune cellular activation by viral RNA. Furthermore, IFNbeta priming did not sensitize responses to HIV-1. Importantly, exogenous IFNbeta or stimulation with the RNA analogue poly I:C to simulate innate immune activation invoked HIV-1 restriction. We conclude that macrophages lack functional pattern recognition receptors for this virus and that HIV-1 tropism for macrophages helps to establish a foothold in the host without triggering innate immune cellular activation, which would otherwise block viral infection effectively.

  18. Activation of ZmMKK10, a maize mitogen-activated protein kinase kinase, induces ethylene-dependent cell death.

    Science.gov (United States)

    Chang, Ying; Yang, Hailian; Ren, Dongtao; Li, Yuan

    2017-11-01

    Mitogen-activated protein kinase (MAPK) cascades play important roles in regulating plant growth, development and stress responses. Here, we report that ZmMKK10, a maize MAP kinase kinase, positively regulates cell death. Sequence comparison to Arabidopsis MKKs has led to ZmMKK10 being classified as a group D MKK. Kinase activity analysis of recombinant ZmMKK10 showed that the Mg 2+ ion was required for its kinase activity. Transient expression of ZmMKK10 WT or ZmMKK10 DD (the active form of ZmMKK10) in maize mesophyll protoplast significantly increased the cell death rate. Inducible expression of ZmMKK10 WT or ZmMKK10 DD in Arabidopsis transgenic plants caused rapid HR-like cell death, whereas induction of ZmMKK10 KR (the inactive form of ZmMKK10) expression in transgenic plants did not yield the same phenotype. Genetic and pharmacological analysis revealed that ZmMKK10-induced cell death in transgenic plants requires the activation of Arabidopsis MPK3 and MPK6 and that it partially depended on ethylene biosynthesis. ZmMPK3 and ZmMPK7, the orthologues of Arabidopsis MPK3 and MPK6, interacted with ZmMKK10 in yeast and ZmMKK10 phosphorylated them both in vitro. Our results demonstrate that ZmMKK10 induces cell death in an ethylene-dependent manner. Furthermore, ZmMPK3 and ZmMPK7 may be the downstream MAPKs in this process. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Catalase and NO CATALASE ACTIVITY1 promote autophagy-dependent cell death in Arabidopsis

    DEFF Research Database (Denmark)

    Hackenberg, Thomas; Juul, Trine; Auzina, Aija

    2013-01-01

    Programmed cell death often depends on generation of reactive oxygen species, which can be detoxified by antioxidative enzymes, including catalases. We previously isolated catalase-deficient mutants (cat2) in a screen for resistance to hydroxyurea-induced cell death. Here, we identify...... an Arabidopsis thaliana hydroxyurea-resistant autophagy mutant, atg2, which also shows reduced sensitivity to cell death triggered by the bacterial effector avrRpm1. To test if catalase deficiency likewise affected both hydroxyurea and avrRpm1 sensitivity, we selected mutants with extremely low catalase...... activities and showed that they carried mutations in a gene that we named NO CATALASE ACTIVITY1 (NCA1). nca1 mutants showed severely reduced activities of all three catalase isoforms in Arabidopsis, and loss of NCA1 function led to strong suppression of RPM1-triggered cell death. Basal and starvation...

  20. C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system

    DEFF Research Database (Denmark)

    Elenius Madsen, Daniel; Sidelmann, Johannes Jakobsen; Biltoft, Daniel

    2015-01-01

    attacks. HAE is caused by mutations in the C1-inh encoding gene, and we recently demonstrated that some mutations give rise to the presence of polymerized C1-inh in the plasma of HAE patients. METHODS: C1-inh polymers corresponding to the size of polymers observed in vivo were produced using heat...... denaturation and gel filtration. The ability of these polymers to facilitate FXII activation was assessed in vitro in an FXII activation bandshift assay. After spiking of plasma with C1-inh polymers, kallikrein generation was analyzed in a global kallikrein generation method. Prekallikrein consumption...... in the entire Danish HAE cohort was analyzed using an ELISA method. RESULTS: C1-inh polymers mediated FXII activation, and a dose dependent kallikrein generation in plasma spiked with C1-inh polymers. An increased (pre)kallikrein consumption was observed in plasma samples from HAE patients presenting with C1...

  1. 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.

  2. Modulation of LTP/LTD balance in STDP by an activity-dependent feedback mechanism.

    Science.gov (United States)

    Kubota, Shigeru; Rubin, Jonathan; Kitajima, Tatsuo

    2009-01-01

    Spike-timing-dependent plasticity (STDP) has been suggested to play a role in the development of functional neuronal connections. However, for STDP to contribute to the synaptic organization, its learning curve should satisfy a requirement that the magnitude of long-term potentiation (LTP) is approximately the same as that of long-term depression (LTD). Without such balance between LTP and LTD, all the synapses are potentiated toward the upper limit or depressed toward the lower limit. Therefore, in this study, we explore the mechanisms by which the LTP/LTD balance in STDP can be modulated adequately. We examine a plasticity model that incorporates an activity-dependent feedback (ADFB) mechanism, wherein LTP induction is suppressed by higher postsynaptic activity. In this model, strengthening an ADFB function gradually decreases the temporal average of the ratio of the magnitude of LTP to that of LTD, whereas enhancing background inhibition augments this ratio. Additionally, correlated inputs can be strengthened or weakened depending on whether the correlation time is shorter or longer than a threshold value, respectively, suggesting that STDP may lead to either Hebbian or anti-Hebbian plasticity outcomes. At an intermediate range of correlation times, the reversal between the two distinct plasticity regimes can occur by changing the level of ADFB modulation and inhibition, providing a physiological mechanism for neurons to select from functionally different forms of learning rules.

  3. eRNAs are required for p53-dependent enhancer activity and gene transcription.

    Science.gov (United States)

    Melo, Carlos A; Drost, Jarno; Wijchers, Patrick J; van de Werken, Harmen; de Wit, Elzo; Oude Vrielink, Joachim A F; Elkon, Ran; Melo, Sónia A; Léveillé, Nicolas; Kalluri, Raghu; de Laat, Wouter; Agami, Reuven

    2013-02-07

    Binding within or nearby target genes involved in cell proliferation and survival enables the p53 tumor suppressor gene to regulate their transcription and cell-cycle progression. Using genome-wide chromatin-binding profiles, we describe binding of p53 also to regions located distantly from any known p53 target gene. Interestingly, many of these regions possess conserved p53-binding sites and all known hallmarks of enhancer regions. We demonstrate that these p53-bound enhancer regions (p53BERs) indeed contain enhancer activity and interact intrachromosomally with multiple neighboring genes to convey long-distance p53-dependent transcription regulation. Furthermore, p53BERs produce, in a p53-dependent manner, enhancer RNAs (eRNAs) that are required for efficient transcriptional enhancement of interacting target genes and induction of a p53-dependent cell-cycle arrest. Thus, our results ascribe transcription enhancement activity to p53 with the capacity to regulate multiple genes from a single genomic binding site. Moreover, eRNA production from p53BERs is required for efficient p53 transcription enhancement. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Glutamine Hydrolysis by Imidazole Glycerol Phosphate Synthase Displays Temperature Dependent Allosteric Activation

    Directory of Open Access Journals (Sweden)

    George P. Lisi

    2018-02-01

    Full Text Available The enzyme imidazole glycerol phosphate synthase (IGPS is a model for studies of long-range allosteric regulation in enzymes. Binding of the allosteric effector ligand N'-[5'-phosphoribulosylformimino]-5-aminoimidazole-4-carboxamide-ribonucleotide (PRFAR stimulates millisecond (ms timescale motions in IGPS that enhance its catalytic function. We studied the effect of temperature on these critical conformational motions and the catalytic mechanism of IGPS from the hyperthermophile Thermatoga maritima in an effort to understand temperature-dependent allostery. Enzyme kinetic and NMR dynamics measurements show that apo and PRFAR-activated IGPS respond differently to changes in temperature. Multiple-quantum Carr-Purcell-Meiboom-Gill (CPMG relaxation dispersion experiments performed at 303, 323, and 343 K (30, 50, and 70°C reveal that millisecond flexibility is enhanced to a higher degree in apo IGPS than in the PRFAR-bound enzyme as the sample temperature is raised. We find that the flexibility of the apo enzyme is nearly identical to that of its PRFAR activated state at 343 K, whereas conformational motions are considerably different between these two forms of the enzyme at room temperature. Arrhenius analyses of these flexible sites show a varied range of activation energies that loosely correlate to allosteric communities identified by computational methods and reflect local changes in dynamics that may facilitate conformational sampling of the active conformation. In addition, kinetic assays indicate that allosteric activation by PRFAR decreases to 65-fold at 343 K, compared to 4,200-fold at 303 K, which mirrors the decreased effect of PRFAR on ms motions relative to the unactivated enzyme. These studies indicate that at the growth temperature of T. maritima, PFRAR is a weaker allosteric activator than it is at room temperature and illustrate that the allosteric mechanism of IGPS is temperature dependent.

  5. Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation.

    Science.gov (United States)

    Lin, C S; Boltz, R C; Blake, J T; Nguyen, M; Talento, A; Fischer, P A; Springer, M S; Sigal, N H; Slaughter, R S; Garcia, M L

    1993-03-01

    The role that potassium channels play in human T lymphocyte activation has been investigated by using specific potassium channel probes. Charybdotoxin (ChTX), a blocker of small conductance Ca(2+)-activated potassium channels (PK,Ca) and voltage-gated potassium channels (PK,V) that are present in human T cells, inhibits the activation of these cells. ChTX blocks T cell activation induced by signals (e.g., anti-CD2, anti-CD3, ionomycin) that elicit a rise in intracellular calcium ([Ca2+]i) by preventing the elevation of [Ca2+]i in a dose-dependent manner. However, ChTX has no effect on the activation pathways (e.g., anti-CD28, interleukin 2 [IL-2]) that are independent of a rise in [Ca2+]i. In the former case, both proliferative response and lymphokine production (IL-2 and interferon gamma) are inhibited by ChTX. The inhibitory effect of ChTX can be demonstrated when added simultaneously, or up to 4 h after the addition of the stimulants. Since ChTX inhibits both PK,Ca and PK,V, we investigated which channel is responsible for these immunosuppressive effects with the use of two other peptides, noxiustoxin (NxTX) and margatoxin (MgTX), which are specific for PK,V. These studies demonstrate that, similar to ChTX, both NxTX and MgTX inhibit lymphokine production and the rise in [Ca2+]i. Taken together, these data provide evidence that blockade of PK,V affects the Ca(2+)-dependent pathways involved in T lymphocyte proliferation and lymphokine production by diminishing the rise in [Ca2+]i that occurs upon T cell activation.

  6. Investigating mutation-specific biological activities of small molecules using quantitative structure-activity relationship for epidermal growth factor receptor in cancer.

    Science.gov (United States)

    Anoosha, P; Sakthivel, R; Gromiha, M Michael

    2017-12-01

    Epidermal Growth Factor Receptor (EGFR) is a potential drug target in cancer therapy. Missense mutations play major roles in influencing the protein function, leading to abnormal cell proliferation and tumorigenesis. A number of EGFR inhibitor molecules targeting ATP binding domain were developed for the past two decades. Unfortunately, they become inactive due to resistance caused by new mutations in patients, and previous studies have also reported noticeable differences in inhibitor binding to distinct known driver mutants as well. Hence, there is a high demand for identification of EGFR mutation-specific inhibitors. In our present study, we derived a set of anti-cancer compounds with biological activities against eight typical EGFR known driver mutations and developed quantitative structure-activity relationship (QSAR) models for each separately. The compounds are grouped based on their functional scaffolds, which enhanced the correlation between compound features and respective biological activities. The models for different mutants performed well with a correlation coefficient, (r) in the range of 0.72-0.91 on jack-knife test. Further, we analyzed the selected features in different models and observed that hydrogen bond and aromaticity-related features play important roles in predicting the biological activity of a compound. This analysis is complimented with docking studies, which showed the binding patterns and interactions of ligands with EGFR mutants that could influence their activities. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Cellular Quantitative Structure–Activity Relationship (Cell-QSAR): Conceptual Dissection of Receptor Binding and Intracellular Disposition in Antifilarial Activities of Selwood Antimycins

    Science.gov (United States)

    2012-01-01

    We present the cellular quantitative structure–activity relationship (cell-QSAR) concept that adapts ligand-based and receptor-based 3D-QSAR methods for use with cell-level activities. The unknown intracellular drug disposition is accounted for by the disposition function (DF), a model-based, nonlinear function of a drug’s lipophilicity, acidity, and other properties. We conceptually combined the DF with our multispecies, multimode version of the frequently used ligand-based comparative molecular field analysis (CoMFA) method, forming a single correlation function for fitting the cell-level activities. The resulting cell-QSAR model was applied to the Selwood data on filaricidal activities of antimycin analogues. Their molecules are flexible, ionize under physiologic conditions, form different intramolecular H-bonds for neutral and ionized species, and cross several membranes to reach unknown receptors. The calibrated cell-QSAR model is significantly more predictive than other models lacking the disposition part and provides valuable structure optimization clues by factorizing the cell-level activity of each compound into the contributions of the receptor binding and disposition. PMID:22468611

  8. Cellular quantitative structure-activity relationship (Cell-QSAR): conceptual dissection of receptor binding and intracellular disposition in antifilarial activities of Selwood antimycins.

    Science.gov (United States)

    Natesan, Senthil; Wang, Tiansheng; Lukacova, Viera; Bartus, Vladimir; Khandelwal, Akash; Subramaniam, Rajesh; Balaz, Stefan

    2012-04-26

    We present the cellular quantitative structure-activity relationship (cell-QSAR) concept that adapts ligand-based and receptor-based 3D-QSAR methods for use with cell-level activities. The unknown intracellular drug disposition is accounted for by the disposition function (DF), a model-based, nonlinear function of a drug's lipophilicity, acidity, and other properties. We conceptually combined the DF with our multispecies, multimode version of the frequently used ligand-based comparative molecular field analysis (CoMFA) method, forming a single correlation function for fitting the cell-level activities. The resulting cell-QSAR model was applied to the Selwood data on filaricidal activities of antimycin analogues. Their molecules are flexible, ionize under physiologic conditions, form different intramolecular H-bonds for neutral and ionized species, and cross several membranes to reach unknown receptors. The calibrated cell-QSAR model is significantly more predictive than other models lacking the disposition part and provides valuable structure optimization clues by factorizing the cell-level activity of each compound into the contributions of the receptor binding and disposition.

  9. pH-dependent activation of Streptomyces hygroscopicus transglutaminase mediated by intein.

    Science.gov (United States)

    Du, Kun; Liu, Zhongmei; Cui, Wenjing; Zhou, Li; Liu, Yi; Du, Guocheng; Chen, Jian; Zhou, Zhemin

    2014-01-01

    Microbial transglutaminase (MTG) from Streptomyces is naturally secreted as a zymogen (pro-MTG), which is then activated by the removal of its N-terminal proregion by additional proteases. Inteins are protein-intervening sequences that catalyze protein splicing without cofactors. In this study, a pH-dependent Synechocystis sp. strain PCC6803 DnaB mini-intein (SDB) was introduced into pro-MTG to simplify its activation process by controlling pH. The recombinant protein (pro-SDB-MTG) was obtained, and the activation process was determined to take 24 h at pH 7 in vitro. To investigate the effect of the first residue in MTG on the activity and the cleavage time, two variants, pro-SDB-MTG(D1S) and pro-SDB-MTG(ΔD1), were expressed, and the activation time was found to be 6 h and 30 h, respectively. The enzymatic property and secondary structure of the recombinant MTG and two variants were similar to those of the wild type, indicating that the insertion of mini-intein did not affect the function of MTG. This insignificant effect was further illustrated by molecular dynamics simulations. This study revealed a controllable and effective strategy to regulate the activation process of pro-MTG mediated by a mini-intein, and it may have great potential for industrial MTG production.

  10. Dicer-2-Dependent Activation of Culex Vago Occurs via the TRAF-Rel2 Signaling Pathway

    Science.gov (United States)

    Paradkar, Prasad N.; Duchemin, Jean-Bernard; Voysey, Rhonda; Walker, Peter J.

    2014-01-01

    Despite their importance as vectors of human and livestock diseases, relatively little is known about innate antiviral immune pathways in mosquitoes and other insects. Previous work has shown that Culex Vago (CxVago), which is induced and secreted from West Nile virus (WNV)-infected mosquito cells, acts as a functional homolog of interferon, by activating Jak-STAT pathway and limiting virus replication in neighbouring cells. Here we describe the Dicer-2-dependent pathway leading to WNV-induced CxVago activation. Using a luciferase reporter assay, we show that a NF-κB-like binding site in CxVago promoter region is conserved in mosquito species and is responsible for induction of CxVago expression following WNV infection. Using dsRNA-based gene knockdown, we show that the NF-κB ortholog, Rel2, plays significant role in the signaling pathway that activates CxVago in mosquito cells in vitro and in vivo. Using similar approaches, we also show that TRAF, but not TRAF-3, is involved in activation of Rel2 after viral infection. Overall the study shows that a conserved signaling pathway, which is similar to mammalian interferon activation pathway, is responsible for the induction and antiviral activity of CxVago. PMID:24762775

  11. Dicer-2-dependent activation of Culex Vago occurs via the TRAF-Rel2 signaling pathway.

    Directory of Open Access Journals (Sweden)

    Prasad N Paradkar

    2014-04-01

    Full Text Available Despite their importance as vectors of human and livestock diseases, relatively little is known about innate antiviral immune pathways in mosquitoes and other insects. Previous work has shown that Culex Vago (CxVago, which is induced and secreted from West Nile virus (WNV-infected mosquito cells, acts as a functional homolog of interferon, by activating Jak-STAT pathway and limiting virus replication in neighbouring cells. Here we describe the Dicer-2-dependent pathway leading to WNV-induced CxVago activation. Using a luciferase reporter assay, we show that a NF-κB-like binding site in CxVago promoter region is conserved in mosquito species and is responsible for induction of CxVago expression following WNV infection. Using dsRNA-based gene knockdown, we show that the NF-κB ortholog, Rel2, plays significant role in the signaling pathway that activates CxVago in mosquito cells in vitro and in vivo. Using similar approaches, we also show that TRAF, but not TRAF-3, is involved in activation of Rel2 after viral infection. Overall the study shows that a conserved signaling pathway, which is similar to mammalian interferon activation pathway, is responsible for the induction and antiviral activity of CxVago.

  12. Alternative pathways of thromboplastin-dependent activation of human factor X in plasma

    International Nuclear Information System (INIS)

    Marlar, R.A.; Griffin, J.H.

    1981-01-01

    To determine the interrelationships of the major coagulation pathways, the activation of 3H-labeled factor X in normal and various deficient human plasmas was evaluated when clotting was triggered by dilute rabbit or human thromboplastin. Various dilutions of thromboplastin and calcium were added to plasma samples containing 3H-factor X, and the time course of factor X activation was determined. At a 1/250 dilution of rabbit brain thromboplastin, the rate of factor X activation in plasmas deficient in factor VIII or factor IX was 10% of the activation rate of normal plasma or of factor XI deficient plasma. Reconstitution of the deficient plasmas with factors VIII or IX, respectively, reconstituted normal factor X activation. Similar results were obtained when various dilutions of human thromboplastin replaced the rabbit thromboplastin. From these plasma experiments, it is inferred that the dilute thromboplastin-dependent activation of factor X requires factors VII, IX, and VIII. An alternative extrinsic pathway that involves factors IX and VIII may be the physiologic extrinsic pathway and hence help to explain the consistent clinical observations of bleeding diatheses in patients deficient in factors IX or VIII

  13. Structural basis of divergent cyclin-dependent kinase activation by Spy1/RINGO proteins

    Energy Technology Data Exchange (ETDEWEB)

    McGrath, Denise A.; Fifield, Bre-Anne; Marceau, Aimee H.; Tripathi, Sarvind; Porter, Lisa A.; Rubin, Seth M. (UCSC); (Windsor)

    2017-06-30

    Cyclin-dependent kinases (Cdks) are principal drivers of cell division and are an important therapeutic target to inhibit aberrant proliferation. Cdk enzymatic activity is tightly controlled through cyclin interactions, posttranslational modifications, and binding of inhibitors such as the p27 tumor suppressor protein. Spy1/RINGO (Spy1) proteins bind and activate Cdk but are resistant to canonical regulatory mechanisms that establish cell-cycle checkpoints. Cancer cells exploit Spy1 to stimulate proliferation through inappropriate activation of Cdks, yet the mechanism is unknown. We have determined crystal structures of the Cdk2-Spy1 and p27-Cdk2-Spy1 complexes that reveal how Spy1 activates Cdk. We find that Spy1 confers structural changes to Cdk2 that obviate the requirement of Cdk activation loop phosphorylation. Spy1 lacks the cyclin-binding site that mediates p27 and substrate affinity, explaining why Cdk-Spy1 is poorly inhibited by p27 and lacks specificity for substrates with cyclin-docking sites. We identify mutations in Spy1 that ablate its ability to activate Cdk2 and to proliferate cells. Our structural description of Spy1 provides important mechanistic insights that may be utilized for targeting upregulated Spy1 in cancer.

  14. Brain activations during bimodal dual tasks depend on the nature and combination of component tasks

    Science.gov (United States)

    Salo, Emma; Rinne, Teemu; Salonen, Oili; Alho, Kimmo

    2015-01-01

    We used functional magnetic resonance imaging to investigate brain activations during nine different dual tasks in which the participants were required to simultaneously attend to concurrent streams of spoken syllables and written letters. They performed a phonological, spatial or “simple” (speaker-gender or font-shade) discrimination task within each modality. We expected to find activations associated specifically with dual tasking especially in the frontal and parietal cortices. However, no brain areas showed systematic dual task enhancements common for all dual tasks. Further analysis revealed that dual tasks including component tasks that were according to Baddeley's model “modality atypical,” that is, the auditory spatial task or the visual phonological task, were not associated with enhanced frontal activity. In contrast, for other dual tasks, activity specifically associated with dual tasking was found in the left or bilateral frontal cortices. Enhanced activation in parietal areas, however, appeared not to be specifically associated with dual tasking per se, but rather with intermodal attention switching. We also expected effects of dual tasking in left frontal supramodal phonological processing areas when both component tasks required phonological processing and in right parietal supramodal spatial processing areas when both tasks required spatial processing. However, no such effects were found during these dual tasks compared with their component tasks performed separately. Taken together, the current results indicate that activations during dual tasks depend in a complex manner on specific demands of component tasks. PMID:25767443

  15. Brain activations during bimodal dual tasks depend on the nature and combination of component tasks

    Directory of Open Access Journals (Sweden)

    Emma eSalo

    2015-02-01

    Full Text Available We used functional magnetic resonance imaging to investigate brain activations during nine different dual tasks in which the participants were required to simultaneously attend to concurrent streams of spoken syllables and written letters. They performed a phonological, spatial or simple (speaker-gender or font-shade discrimination task within each modality. We expected to find activations associated specifically with dual tasking especially in the frontal and parietal cortices. However, no brain areas showed systematic dual task enhancements common for all dual tasks. Further analysis revealed that dual tasks including component tasks that were according to Baddeley’s model modality atypical, that is, the auditory spatial task or the visual phonological task, were not associated with enhanced frontal activity. In contrast, for other dual tasks, activity specifically associated with dual tasking was found in the left or bilateral frontal cortices. Enhanced activation in parietal areas, however, appeared not to be specifically associated with dual tasking per se, but rather with intermodal attention switching. We also expected effects of dual tasking in left frontal supramodal phonological processing areas when both component tasks required phonological processing and in right parietal supramodal spatial processing areas when both tasks required spatial processing. However, no such effects were found during these dual tasks compared with their component tasks performed separately. Taken together, the current results indicate that activations during dual tasks depend in a complex manner on specific demands of component tasks.

  16. Brain activations during bimodal dual tasks depend on the nature and combination of component tasks.

    Science.gov (United States)

    Salo, Emma; Rinne, Teemu; Salonen, Oili; Alho, Kimmo

    2015-01-01

    We used functional magnetic resonance imaging to investigate brain activations during nine different dual tasks in which the participants were required to simultaneously attend to concurrent streams of spoken syllables and written letters. They performed a phonological, spatial or "simple" (speaker-gender or font-shade) discrimination task within each modality. We expected to find activations associated specifically with dual tasking especially in the frontal and parietal cortices. However, no brain areas showed systematic dual task enhancements common for all dual tasks. Further analysis revealed that dual tasks including component tasks that were according to Baddeley's model "modality atypical," that is, the auditory spatial task or the visual phonological task, were not associated with enhanced frontal activity. In contrast, for other dual tasks, activity specifically associated with dual tasking was found in the left or bilateral frontal cortices. Enhanced activation in parietal areas, however, appeared not to be specifically associated with dual tasking per se, but rather with intermodal attention switching. We also expected effects of dual tasking in left frontal supramodal phonological processing areas when both component tasks required phonological processing and in right parietal supramodal spatial processing areas when both tasks required spatial processing. However, no such effects were found during these dual tasks compared with their component tasks performed separately. Taken together, the current results indicate that activations during dual tasks depend in a complex manner on specific demands of component tasks.

  17. Time-Dependent Antimicrobial Activity of Filtering Nonwovens with Gemini Surfactant-Based Biocides.

    Science.gov (United States)

    Majchrzycka, Katarzyna; Okrasa, Małgorzata; Szulc, Justyna; Brycki, Bogumił; Gutarowska, Beata

    2017-09-27

    Previous studies on nonwovens used for respiratory protective devices (RPDs) were related to equipment intended for short-term use. There is only limited research on the development of biocidal nonwoven fabrics for reusable RPDs that could be used safely in an industrial work environment where there is a risk of microbial growth. Moreover, a new group of biocides with high antimicrobial activity-gemini surfactants, has never been explored for textile's application in previous studies. The aim of this study was to develop high-efficiency melt-blown nonwovens containing gemini surfactants with time-dependent biocidal activity, and to validate their antimicrobial properties under conditions simulating their use at a plant biomass-processing unit. A set of porous biocidal structures (SPBS) was prepared and applied to the melt-blown polypropylene (PP) nonwovens. The biocidal properties of the structures were triggered by humidity and had different activation rates. Scanning electron microscopy was used to undertake structural studies of the modified PP/SPBS nonwovens. In addition, simulation of plant biomass dust deposition on the nonwovens was performed. The biocidal activity of PP/SPBS nonwovens was evaluated following incubation with Escherichia coli and Aspergillus niger from the American Type Culture Collection, and with Pseudomonas fluorescens and Penicillium chrysogenum isolated from the biomass. PP/SPBS nonwovens exhibited antimicrobial activity to varying levels. Higher antimicrobial activity was noted for bacteria (R = 87.85-97.46%) and lower for moulds (R = 80.11-94.53%).

  18. Characteristics of seasonal variation and solar activity dependence of the geomagnetic solar quiet daily variation

    Science.gov (United States)

    Shinbori, A.; Koyama, Y.; Nose, M.; Hori, T.

    2017-12-01

    Characteristics of seasonal variation and solar activity dependence of the X- and Y-components of the geomagnetic solar quiet (Sq) daily variation at Memanbetsu in mid-latitudes and Guam near the equator have been investigated using long-term geomagnetic field data with 1-h time resolution from 1957 to 2016. In this analysis, we defined the quiet day when the maximum value of the Kp index is less than 3 for that day. In this analysis, we used the monthly average of the adjusted daily F10.7 corresponding to geomagnetically quiet days. For identification of the monthly mean Sq variation in the X and Y components (Sq-X and Sq-Y), we first determined the baseline of the X and Y components from the average value from 22 to 2 h (LT: local time) for each quiet day. Next, we calculated a deviation from the baseline of the X- and Y-components of the geomagnetic field for each quiet day, and computed the monthly mean value of the deviation for each local time. As a result, Sq-X and Sq-Y shows a clear seasonal variation and solar activity dependence. The amplitude of seasonal variation increases significantly during high solar activities, and is proportional to the solar F10.7 index. The pattern of the seasonal variation is quite different between Sq-X and Sq-Y. The result of the correlation analysis between the solar F10.7 index and Sq-X and Sq-Y shows almost the linear relationship, but the slope and intercept of the linear fitted line varies as function of local time and month. This implies that the sensitivity of Sq-X and Sq-Y to the solar activity is different for different local times and seasons. The local time dependence of the offset value of Sq-Y at Guam and its seasonal variation suggest a magnetic field produced by inter-hemispheric field-aligned currents (FACs). From the sign of the offset value of Sq-Y, it is infer that the inter-hemispheric FACs flow from the summer to winter hemispheres in the dawn and dusk sectors and from the winter to summer hemispheres in

  19. Does breast MRI background parenchymal enhancement indicate metabolic activity? Qualitative and 3D quantitative computer imaging analysis.

    Science.gov (United States)

    Mema, Eralda; Mango, Victoria L; Guo, Xiaotao; Karcich, Jenika; Yeh, Randy; Wynn, Ralph T; Zhao, Binsheng; Ha, Richard S

    2018-03-01

    To investigate whether the degree of breast magnetic resonance imaging (MRI) background parenchymal enhancement (BPE) is associated with the amount of breast metabolic activity measured by breast parenchymal uptake (BPU) of 18F-FDG on positron emission tomography / computed tomography (PET/CT). An Institutional Review Board (IRB)-approved retrospective study was performed. Of 327 patients who underwent preoperative breast MRI from 1/1/12 to 12/31/15, 73 patients had 18F-FDG PET/CT evaluation performed within 1 week of breast MRI and no suspicious findings in the contralateral breast. MRI was performed on a 1.5T or 3.0T system. The imaging sequence included a triplane localizing sequence followed by sagittal fat-suppressed T 2 -weighted sequence, and a bilateral sagittal T 1 -weighted fat-suppressed fast spoiled gradient-echo sequence, which was performed before and three times after a rapid bolus injection (gadobenate dimeglumine, Multihance; Bracco Imaging; 0.1 mmol/kg) delivered through an IV catheter. The unaffected contralateral breast in these 73 patients underwent BPE and BPU assessments. For PET/CT BPU calculation, a 3D region of interest (ROI) was drawn around the glandular breast tissue and the maximum standardized uptake value (SUV max ) was determined. Qualitative MRI BPE assessments were performed on a 4-point scale, in accordance with BI-RADS categories. Additional 3D quantitative MRI BPE analysis was performed using a previously published in-house technique. Spearman's correlation test and linear regression analysis was performed (SPSS, v. 24). The median time interval between breast MRI and 18F-FDG PET/CT evaluation was 3 days (range, 0-6 days). BPU SUV max mean value was 1.6 (SD, 0.53). Minimum and maximum BPU SUV max values were 0.71 and 4.0. The BPU SUV max values significantly correlated with both the qualitative and quantitative measurements of BPE, respectively (r(71) = 0.59, P Qualitatively assessed high BPE group (BI-RADS 3/4) had

  20. Dendrimer-induced leukocyte procoagulant activity depends on particle size and surface charge.

    Science.gov (United States)

    Dobrovolskaia, Marina A; Patri, Anil K; Potter, Timothy M; Rodriguez, Jamie C; Hall, Jennifer B; McNeil, Scott E

    2012-02-01

    Thrombogenicity associated with the induction of leukocyte procoagulant activity (PCA) is a common complication in sepsis and cancer. Since nanoparticles are increasingly used for drug delivery, their interaction with coagulation systems is an important part of the safety assessment. The purpose of this study was to investigate the effects of nanoparticle physicochemical properties on leukocyte PCA, and to get insight into the mechanism of PCA induction. A total of 12 formulations of polyamidoamine (PAMAM) dendrimers, varying in size and surface charge, were studied in vitro using recalcification time assay. Irrespective of their size, anionic and neutral dendrimers did not induce leukocyte PCA in vitro. Cationic particles induced PCA in a size- and charge-dependent manner. The mechanism of PCA induction was similar to that of doxorubicin. Cationic dendrimers were also found to exacerbate endotoxin-induced PCA. PAMAM dendrimer-induced leukocyte PCA depends on particle size, charge and density of surface groups.