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Sample records for modulated transgenomic interactions

  1. Top-down systems biology integration of conditional prebiotic modulated transgenomic interactions in a humanized microbiome mouse model

    PubMed Central

    Martin, Francois-Pierre J; Wang, Yulan; Sprenger, Norbert; Yap, Ivan K S; Rezzi, Serge; Ramadan, Ziad; Peré-Trepat, Emma; Rochat, Florence; Cherbut, Christine; van Bladeren, Peter; Fay, Laurent B; Kochhar, Sunil; Lindon, John C; Holmes, Elaine; Nicholson, Jeremy K

    2008-01-01

    Gut microbiome–host metabolic interactions affect human health and can be modified by probiotic and prebiotic supplementation. Here, we have assessed the effects of consumption of a combination of probiotics (Lactobacillus paracasei or L. rhamnosus) and two galactosyl-oligosaccharide prebiotics on the symbiotic microbiome–mammalian supersystem using integrative metabolic profiling and modeling of multiple compartments in germ-free mice inoculated with a model of human baby microbiota. We have shown specific impacts of two prebiotics on the microbial populations of HBM mice when co-administered with two probiotics. We observed an increase in the populations of Bifidobacterium longum and B. breve, and a reduction in Clostridium perfringens, which were more marked when combining prebiotics with L. rhamnosus. In turn, these microbial effects were associated with modulation of a range of host metabolic pathways observed via changes in lipid profiles, gluconeogenesis, and amino-acid and methylamine metabolism associated to fermentation of carbohydrates by different bacterial strains. These results provide evidence for the potential use of prebiotics for beneficially modifying the gut microbial balance as well as host energy and lipid homeostasis. PMID:18628745

  2. Evolutionary transgenomics: prospects and challenges

    PubMed Central

    Correa, Raul; Baum, David A.

    2015-01-01

    Many advances in our understanding of the genetic basis of species differences have arisen from transformation experiments, which allow us to study the effect of genes from one species (the donor) when placed in the genetic background of another species (the recipient). Such interspecies transformation experiments are usually focused on candidate genes – genes that, based on work in model systems, are suspected to be responsible for certain phenotypic differences between the donor and recipient species. We suggest that the high efficiency of transformation in a few plant species, most notably Arabidopsis thaliana, combined with the small size of typical plant genes and their cis-regulatory regions allow implementation of a screening strategy that does not depend upon a priori candidate gene identification. This approach, transgenomics, entails moving many large genomic inserts of a donor species into the wild type background of a recipient species and then screening for dominant phenotypic effects. As a proof of concept, we recently conducted a transgenomic screen that analyzed more than 1100 random, large genomic inserts of the Alabama gladecress Leavenworthia alabamica for dominant phenotypic effects in the A. thaliana background. This screen identified one insert that shortens fruit and decreases A. thaliana fertility. In this paper we discuss the principles of transgenomic screens and suggest methods to help minimize the frequencies of false positive and false negative results. We argue that, because transgenomics avoids committing in advance to candidate genes it has the potential to help us identify truly novel genes or cryptic functions of known genes. Given the valuable knowledge that is likely to be gained, we believe the time is ripe for the plant evolutionary community to invest in transgenomic screens, at least in the mustard family Brassicaceae where many species are amenable to efficient transformation. PMID:26579137

  3. Water-module interaction studies

    NASA Technical Reports Server (NTRS)

    Mon, G.; Wen, L.; Ross, R., Jr.

    1988-01-01

    Mechanisms by which moisture enters photovoltaic modules and techniques for reducing such interactions are reported. Results from a study of the effectiveness of various module sealants are given. Techniques for measuring the rate and quantity of moisture ingress are discussed. It is shown that scribe lines and porous frit bridging conductors provide preferential paths for moisture ingress and that moisture diffusion by surface/interfacial paths is considerably more rapid than diffusion by bulk paths, which implies that thin-film substrate and supersubstrate modules are much more vulnerable to moist environments than are bulk-encapsulated crystalline-silicon modules. Design approaches that reduce moisture entry are discussed.

  4. Water-module interaction studies

    NASA Astrophysics Data System (ADS)

    Mon, G.; Wen, L.; Ross, R., Jr.

    Mechanisms by which moisture enters photovoltaic modules and techniques for reducing such interactions are reported. Results from a study of the effectiveness of various module sealants are given. Techniques for measuring the rate and quantity of moisture ingress are discussed. It is shown that scribe lines and porous frit bridging conductors provide preferential paths for moisture ingress and that moisture diffusion by surface/interfacial paths is considerably more rapid than diffusion by bulk paths, which implies that thin-film substrate and supersubstrate modules are much more vulnerable to moist environments than are bulk-encapsulated crystalline-silicon modules. Design approaches that reduce moisture entry are discussed.

  5. Modulational interactions in quantum plasmas

    NASA Astrophysics Data System (ADS)

    Sayed, F.; Vladimirov, S. V.; Tyshetskiy, Yu.; Ishihara, O.

    2013-07-01

    A formalism for treating modulational interactions of electrostatic fields in collisionless quantum plasmas is developed, based on the kinetic Wigner-Poisson model of quantum plasma. This formalism can be used in a range of problems of nonlinear interaction between electrostatic fields in a quantum plasma, such as development of turbulence, self-organization, as well as transition from the weak turbulent state to strong turbulence. In particular, using this formalism, we obtain the kinetic quantum Zakharov equations that describe nonlinear coupling of high frequency Langmuir waves to low frequency plasma density variations, for cases of non-degenerate and degenerate plasma electrons.

  6. Modulational interactions in quantum plasmas

    SciTech Connect

    Sayed, F.; Tyshetskiy, Yu.; Vladimirov, S. V.; Ishihara, O.

    2013-07-15

    A formalism for treating modulational interactions of electrostatic fields in collisionless quantum plasmas is developed, based on the kinetic Wigner-Poisson model of quantum plasma. This formalism can be used in a range of problems of nonlinear interaction between electrostatic fields in a quantum plasma, such as development of turbulence, self-organization, as well as transition from the weak turbulent state to strong turbulence. In particular, using this formalism, we obtain the kinetic quantum Zakharov equations that describe nonlinear coupling of high frequency Langmuir waves to low frequency plasma density variations, for cases of non-degenerate and degenerate plasma electrons.

  7. Applying Economics Using Interactive Learning Modules

    ERIC Educational Resources Information Center

    Goma, Ophelia D.

    2010-01-01

    This article describes the use of web-based, interactive learning modules in the principles of economics course. The learning modules introduce students to important, historical economic events while providing real-world application of the economic theory presented in class. Each module is designed to supplement and complement the economic theory…

  8. Solar cell modules for plasma interaction evaluation

    NASA Technical Reports Server (NTRS)

    1981-01-01

    A plasma interaction analysis in support of the solar electric propulsion subsystem examined the effects of a large high voltage solar array interacting with an ion thruster produced plasma. Two solar array test modules consisting of 36 large area wraparound contact solar cells welded to a flexible Kapton integrated circuit substrate were abricated. The modules contained certain features of the effects of insulation, din-holes, and bonding of the cell to the substrate and a ground plane. The possibility of a significant power loss occurring due to the collection of charged particles on the solar array interconnects was the focus of the research.

  9. Functional module identification in protein interaction networks by interaction patterns

    PubMed Central

    Wang, Yijie; Qian, Xiaoning

    2014-01-01

    Motivation: Identifying functional modules in protein–protein interaction (PPI) networks may shed light on cellular functional organization and thereafter underlying cellular mechanisms. Many existing module identification algorithms aim to detect densely connected groups of proteins as potential modules. However, based on this simple topological criterion of ‘higher than expected connectivity’, those algorithms may miss biologically meaningful modules of functional significance, in which proteins have similar interaction patterns to other proteins in networks but may not be densely connected to each other. A few blockmodel module identification algorithms have been proposed to address the problem but the lack of global optimum guarantee and the prohibitive computational complexity have been the bottleneck of their applications in real-world large-scale PPI networks. Results: In this article, we propose a novel optimization formulation LCP2 (low two-hop conductance sets) using the concept of Markov random walk on graphs, which enables simultaneous identification of both dense and sparse modules based on protein interaction patterns in given networks through searching for LCP2 by random walk. A spectral approximate algorithm SLCP2 is derived to identify non-overlapping functional modules. Based on a bottom-up greedy strategy, we further extend LCP2 to a new algorithm (greedy algorithm for LCP2) GLCP2 to identify overlapping functional modules. We compare SLCP2 and GLCP2 with a range of state-of-the-art algorithms on synthetic networks and real-world PPI networks. The performance evaluation based on several criteria with respect to protein complex prediction, high level Gene Ontology term prediction and especially sparse module detection, has demonstrated that our algorithms based on searching for LCP2 outperform all other compared algorithms. Availability and implementation: All data and code are available at http://www.cse.usf.edu/∼xqian/fmi/slcp2hop

  10. Solar Array Module Plasma Interaction Experiment (SAMPIE)

    NASA Technical Reports Server (NTRS)

    Ferguson, Dale C.

    1992-01-01

    The objective of the Solar Array Module Plasma Interaction Experiment (SAMPIE) is to investigate, by means of a shuttle-based flight experiment and relevant ground-based testing, the arcing and current collection behavior of materials and geometries likely to be exposed to the LEO plasma on high-voltage space power systems, in order to minimize adverse environmental interactions. An overview of the SAMPIE program is presented in outline and graphical form.

  11. Magnetic interactions in compositionally modulated nanowire arrays

    NASA Astrophysics Data System (ADS)

    Palmero, Ester M.; Béron, Fanny; Bran, Cristina; del Real, Rafael P.; Vázquez, Manuel

    2016-10-01

    Series of high hexagonally ordered compositionally modulated nanowire arrays, with different Cu layer and FeCoCu segment thicknesses and a constant diameter of 35 nm, were fabricated by electroplating from a single electrolytic bath into anodic aluminum oxide membranes. The objective of the study was to determine the influence of ferromagnetic (FM) segment and non-ferromagnetic (NFM) layer thickness on the magnetic properties, particularly coercivity and magnetic interactions. First-order reversal curve (FORC) measurements and simulations were performed to quantify the effect of the inter-/intra-nanowire magnetostatic interactions on the coercivity and interaction field distributions. The FORC coercivity increases for a thick NFM layer and long FM segments due to decoupling of the the FM segments and the increased shape anisotropy, respectively. On the other hand, the interaction field presents a parallel strong reduction for a thick NFM layer and thin FM segments, which is ascribed to a similar NFM/FM thickness ratio and degree of FM segment decoupling along the nanowire.

  12. A Usability Study of Interactive Web-Based Modules

    ERIC Educational Resources Information Center

    Girard, Tulay; Pinar, Musa

    2011-01-01

    This research advances the understanding of the usability of marketing case study modules in the area of interactive web-based technologies through the assignment of seven interactive case modules in a Principles of Marketing course. The case modules were provided for marketing students by the publisher, McGraw Hill Irwin, of the "Marketing"…

  13. MoNetFamily: a web server to infer homologous modules and module-module interaction networks in vertebrates.

    PubMed

    Lin, Chun-Yu; Lin, Yi-Wei; Yu, Shang-Wen; Lo, Yu-Shu; Yang, Jinn-Moon

    2012-07-01

    A module is a fundamental unit forming with highly connected proteins and performs a certain kind of biological functions. Modules and module-module interaction (MMI) network are essential for understanding cellular processes and functions. The MoNetFamily web server can identify the modules, homologous modules (called module family) and MMI networks across multiple species for the query protein(s). This server first finds module candidates of the query by using BLASTP to search the module template database (1785 experimental and 1252 structural templates). MoNetFamily then infers the homologous modules of the selected module candidate using protein-protein interaction (PPI) families. According to homologous modules and PPIs, we statistically calculated MMIs and MMI networks across multiple species. For each module candidate, MoNetFamily identifies its neighboring modules and their MMIs in module networks of Homo sapiens, Mus musculus and Danio rerio. Finally, MoNetFamily shows the conserved proteins, PPI profiles and functional annotations of the module family. Our results indicate that the server can be useful for MMI network (e.g. 1818 modules and 9678 MMIs in H. sapiens) visualizations and query annotations using module families and neighboring modules. We believe that the server is able to provide valuable insights to determine homologous modules and MMI networks across multiple species for studying module evolution and cellular processes. The MoNetFamily sever is available at http://monetfamily.life.nctu.edu.tw.

  14. Electrooptic interaction in oversized waveguide modulators

    NASA Astrophysics Data System (ADS)

    Scholtz, A. L.

    1983-06-01

    The electrooptic characteristics of oversized waveguide modulators are examined theoretically in terms of the bandwidth and spatial-coherence-conservation properties required for space laser-communication techniques. The differential equations describing the conversion from TE to TM mode, based on the mode-coupling theory, are presented and solved for the general case and for oversized modulators, with allowance for the orientation of the electrooptic tensor relative to the coordinates of the waveguide and for the differences and inhomogeneities of the optical and electrical field distributions. The numerical calculation of equivalent phase retardation is demonstrated using the parameters of a lightpipe CeTe modulator suitable for use with a CO2 laser at 10.6 microns; good agreement with experimental data is found.

  15. Infant Smiling during Social Interaction: Arousal Modulation or Activation Indicator?

    ERIC Educational Resources Information Center

    Ewy, Richard

    In a study of infant smiling, 20 mother-infant dyads were videotaped in normal face-to-face interaction when the infants were 9 and 14 weeks of age. Videotapes were used to determine which of two classes of smiling behavior models, either arousal modulation or activation indicator, was most supported by empirical data. Arousal modulation models…

  16. Cosmic ray modulation and merged interaction regions

    NASA Technical Reports Server (NTRS)

    Burlaga, L. F.; Goldstein, M. L.; Mcdonald, F. B.

    1985-01-01

    Beyond several AU, interactions among shocks and streams give rise to merged interaction regions in which the magnetic field is turbulent. The integral intensity of . 75 MeV/Nuc cosmic rays at Voyager is generally observed to decrease when a merged interaction region moves past the spacecraft and to increase during the passage of a rarefaction region. When the separation between interaction regions is relatively large, the cosmic ray intensity tends to increase on a scale of a few months. This was the case at Voyager 1 from July 1, 1983 to May 1, 1984, when the spacecraft moved from 16.7 to 19.6 AU. Changes in cosmic ray intensity were related to the magnetic field strength in a simple way. It is estimated that the diffusion coefficient in merged interaction regions at this distance is similar to 0.6 x 10 to the 22nd power sq cm/s.

  17. Modulational instability in optical-microwave interaction

    NASA Astrophysics Data System (ADS)

    Bubke, K.; Hutchings, D. C.; Peschel, U.; Lederer, F.

    2002-09-01

    The stability of continuous optical and microwave fields is studied in the presence of dispersion and second order nonlinearity. The cascade combination of optical rectification and the electro-optic effect induces modulational instability (MI) in a wide range of system parameters. It is demonstrated that MI can lead potentially to filamentation of high power optical pulses as well as the generation of terahertz radiation.

  18. Solar Array Module Plasma Interaction Experiment (SAMPIE): Technical requirements document

    NASA Technical Reports Server (NTRS)

    Hillard, G. Barry; Ferguson, Dale C.

    1992-01-01

    The Solar Array Module Plasma Interactions Experiment (SAMPIE) is a NASA shuttle space flight experiment scheduled for launch in early 1994. The SAMPIE experiment will investigate plasma interactions of high voltage space power systems in low earth orbit. Solar cell modules, representing several technologies, will be biased to high voltages to characterize both arcing and plasma current collection. Other solar modules, specially modified in accordance with current theories of arcing and breakdown, will demonstrate the possibility of arc suppression. Finally, several test modules will be included to study the basic nature of these interactions. The science and technology goals for the project are defined in the Technical Requirements Document (TRD) which is presented here.

  19. Module organization and variance in protein-protein interaction networks

    NASA Astrophysics Data System (ADS)

    Lin, Chun-Yu; Lee, Tsai-Ling; Chiu, Yi-Yuan; Lin, Yi-Wei; Lo, Yu-Shu; Lin, Chih-Ta; Yang, Jinn-Moon

    2015-03-01

    A module is a group of closely related proteins that act in concert to perform specific biological functions through protein-protein interactions (PPIs) that occur in time and space. However, the underlying module organization and variance remain unclear. In this study, we collected module templates to infer respective module families, including 58,041 homologous modules in 1,678 species, and PPI families using searches of complete genomic database. We then derived PPI evolution scores and interface evolution scores to describe the module elements, including core and ring components. Functions of core components were highly correlated with those of essential genes. In comparison with ring components, core proteins/PPIs were conserved across multiple species. Subsequently, protein/module variance of PPI networks confirmed that core components form dynamic network hubs and play key roles in various biological functions. Based on the analyses of gene essentiality, module variance, and gene co-expression, we summarize the observations of module organization and variance as follows: 1) a module consists of core and ring components; 2) core components perform major biological functions and collaborate with ring components to execute certain functions in some cases; 3) core components are more conserved and essential during organizational changes in different biological states or conditions.

  20. Interactive online optics modules for the college physics course

    NASA Astrophysics Data System (ADS)

    Hoeling, Barbara M.

    2012-04-01

    A new learning tool for geometrical optics is presented which has been developed for an algebra based introductory college physics course for life science majors. The interactive online learning module contains images, videos of problem solutions, short animated videos, and interactive animations, which allow students to actively explore the physics content beyond the pictures in a textbook. These elements are accompanied by narration and a transcript to guide the students while allowing them to navigate freely between the different parts of the module. The results of student learning, a comparison with a control group, and a survey of student attitudes toward this new instruction method are discussed.

  1. Interactive Learning in a Higher Education Level 1 Mechanics Module.

    ERIC Educational Resources Information Center

    Booth, Kathryn M.; James, Brian W.

    2001-01-01

    Encourages Level 1 students (those taking a subject for the first time at the higher education level) to develop a deeper learning approach. Uses a cooperative learning approach to pose conceptual questions for interactive discussions and changes both teaching method and form of examination paper for a Mechanics module. (Contains 17 references.)…

  2. Developing Interactive Learning Objects for a Computing Mathematics Module

    ERIC Educational Resources Information Center

    Lim, Cher Ping; Lee, Siew Lie; Richards, Cameron

    2006-01-01

    Based on a case study of the online component of a Computing Mathematics module at a local polytechnic in Singapore, this article provides a descriptive account of the development and employment of interactive learning objects to enhance the learning experiences of the students in the course. The experimented learning objects were branded as…

  3. Favouritism in the motor system: social interaction modulates action simulation.

    PubMed

    Kourtis, Dimitrios; Sebanz, Natalie; Knoblich, Günther

    2010-12-23

    The ability to anticipate others' actions is crucial for social interaction. It has been shown that this ability relies on motor areas of the human brain that are not only active during action execution and action observation, but also during anticipation of another person's action. Recording electroencephalograms during a triadic social interaction, we assessed whether activation of motor areas pertaining to the human mirror-neuron system prior to action observation depends on the social relationship between the actor and the observer. Anticipatory motor activation was stronger when participants expected an interaction partner to perform a particular action than when they anticipated that the same action would be performed by a third person they did not interact with. These results demonstrate that social interaction modulates action simulation.

  4. Alternative modulation of protein–protein interactions by small molecules

    PubMed Central

    Fischer, Gerhard; Rossmann, Maxim; Hyvönen, Marko

    2015-01-01

    Protein–protein interactions (PPI) have become increasingly popular drug targets, with a number of promising compounds currently in clinical trials. Recent research shows, that PPIs can be modulated in more ways than direct inhibition, where novel non-competitive modes of action promise a solution for the difficult nature of PPI drug discovery. Here, we review recently discovered PPI modulators in light of their mode of action and categorise them as disrupting versus stabilising, orthosteric versus allosteric and by their ability to affect the proteins’ dynamics. We also give recent examples of compounds successful in the clinic, analyse their physicochemical properties and discuss how to overcome the hurdles in discovering alternative modes of modulation. PMID:25935873

  5. Cross interaction of melanocortinergic and dopaminergic systems in neural modulation

    PubMed Central

    He, Zhi-Gang; Liu, Bao-Wen; Xiang, Hong-Bing

    2015-01-01

    Melanocortinergic and dopaminergic systems are widely distributed in the CNS and have been established as a crucial regulatory component in diverse physiological functions. The pharmacology of both melanocortinergic and dopaminergic systems including their individual receptors, signaling mechanisms, agonists and antagonists has been extensively studied. Several lines of evidence showed that there existed a cross interaction between the receptors of melanocortinergic and dopaminergic systems. The data available at present had expanded our understanding of melanocortinergic and dopaminergic system interaction in neural modulation, which will be main discussed in this paper. PMID:26823964

  6. Metal-graphene heterojunction modulation via H2 interaction

    NASA Astrophysics Data System (ADS)

    Cadore, A. R.; Mania, E.; de Morais, E. A.; Watanabe, K.; Taniguchi, T.; Lacerda, R. G.; Campos, L. C.

    2016-07-01

    Combining experiment and theory, we investigate how a naturally created heterojunction (pn junction) at a graphene and metallic contact interface is modulated via interaction with molecular hydrogen (H2). Due to an electrostatic interaction, metallic electrodes induce pn junctions in graphene, leading to an asymmetrical resistance in electronic transport for electrons and holes. We report that the asymmetry in the resistance can be tuned in a reversible manner by exposing graphene devices to H2. The interaction between the H2 and graphene occurs solely at the graphene-contact pn junction and induces a modification on the electrostatic interaction between graphene and metallic contacts. We explain the experimental data with theory providing information concerning the length of the heterojunction and how it changes as a function of H2 adsorption. Our results are valuable for understanding the nature of the metal-graphene interfaces and have potential application for selective sensors of molecular hydrogen.

  7. Apparatus and method for interaction phenomena with world modules in data-flow-based simulation

    DOEpatents

    Xavier, Patrick G.; Gottlieb, Eric J.; McDonald, Michael J.; Oppel, III, Fred J.

    2006-08-01

    A method and apparatus accommodate interaction phenomenon in a data-flow-based simulation of a system of elements, by establishing meta-modules to simulate system elements and by establishing world modules associated with interaction phenomena. World modules are associated with proxy modules from a group of meta-modules associated with one of the interaction phenomenon. The world modules include a communication world, a sensor world, a mobility world, and a contact world. World modules can be further associated with other world modules if necessary. Interaction phenomenon are simulated in corresponding world modules by accessing member functions in the associated group of proxy modules. Proxy modules can be dynamically allocated at a desired point in the simulation to accommodate the addition of elements in the system of elements such as a system of robots, a system of communication terminals, or a system of vehicles, being simulated.

  8. How Auxin and Cytokinin Phytohormones Modulate Root Microbe Interactions.

    PubMed

    Boivin, Stéphane; Fonouni-Farde, Camille; Frugier, Florian

    2016-01-01

    A large range of microorganisms can associate with plants, resulting in neutral, friendly or hostile interactions. The ability of plants to recognize compatible and incompatible microorganisms and to limit or promote their colonization is therefore crucial for their survival. Elaborated communication networks determine the degree of association between the host plant and the invading microorganism. Central to these regulations of plant microbe interactions, phytohormones modulate microorganism plant associations and coordinate cellular and metabolic responses associated to the progression of microorganisms across different plant tissues. We review here hormonal regulations, focusing on auxin and cytokinin phytohormones, involved in the interactions between plant roots and soil microorganisms, including bacterial and fungi associations, either beneficial (symbiotic) or detrimental (pathogenic). The aim is to highlight similarities and differences in cytokinin/auxin functions amongst various compatible versus incompatible associations.

  9. How Auxin and Cytokinin Phytohormones Modulate Root Microbe Interactions

    PubMed Central

    Boivin, Stéphane; Fonouni-Farde, Camille; Frugier, Florian

    2016-01-01

    A large range of microorganisms can associate with plants, resulting in neutral, friendly or hostile interactions. The ability of plants to recognize compatible and incompatible microorganisms and to limit or promote their colonization is therefore crucial for their survival. Elaborated communication networks determine the degree of association between the host plant and the invading microorganism. Central to these regulations of plant microbe interactions, phytohormones modulate microorganism plant associations and coordinate cellular and metabolic responses associated to the progression of microorganisms across different plant tissues. We review here hormonal regulations, focusing on auxin and cytokinin phytohormones, involved in the interactions between plant roots and soil microorganisms, including bacterial and fungi associations, either beneficial (symbiotic) or detrimental (pathogenic). The aim is to highlight similarities and differences in cytokinin/auxin functions amongst various compatible versus incompatible associations. PMID:27588025

  10. How Auxin and Cytokinin Phytohormones Modulate Root Microbe Interactions.

    PubMed

    Boivin, Stéphane; Fonouni-Farde, Camille; Frugier, Florian

    2016-01-01

    A large range of microorganisms can associate with plants, resulting in neutral, friendly or hostile interactions. The ability of plants to recognize compatible and incompatible microorganisms and to limit or promote their colonization is therefore crucial for their survival. Elaborated communication networks determine the degree of association between the host plant and the invading microorganism. Central to these regulations of plant microbe interactions, phytohormones modulate microorganism plant associations and coordinate cellular and metabolic responses associated to the progression of microorganisms across different plant tissues. We review here hormonal regulations, focusing on auxin and cytokinin phytohormones, involved in the interactions between plant roots and soil microorganisms, including bacterial and fungi associations, either beneficial (symbiotic) or detrimental (pathogenic). The aim is to highlight similarities and differences in cytokinin/auxin functions amongst various compatible versus incompatible associations. PMID:27588025

  11. Control/structure interactions of Freedom's solar dynamic modules

    NASA Technical Reports Server (NTRS)

    Quinn, R. D.; Yunis, I.

    1990-01-01

    The purpose of this paper is to address potential control/structures interaction (CSI) problems of large flexible multibody structures in the presence of pointing and tracking requirements. A control approach is introduced for the simultaneous tracking and vibration control of multibody space structures. The application that is discussed is Space Station Freedom configured with solar dynamic (SD) modules. The SD fine-pointing and tracking requirements may necessitate controller frequencies above the structural natural frequencies of Freedom and the SD modules. It is well known that this can give rise to CSI problems if the controller is designed without due consideration given to the structural dynamics of the system. In this paper, possible CSI problems of Freedom's solar dynamic power systems are demonstrated using a simple lumped mass model. A NASTRAN model of Freedom developed at NASA Lewis is used to demonstrate potential CSI problems and the proposed tracking and vibration control approach.

  12. Modulation of hydrophobic interactions by proximally immobilized ions.

    PubMed

    Ma, C Derek; Wang, Chenxuan; Acevedo-Vélez, Claribel; Gellman, Samuel H; Abbott, Nicholas L

    2015-01-15

    The structure of water near non-polar molecular fragments or surfaces mediates the hydrophobic interactions that underlie a broad range of interfacial, colloidal and biophysical phenomena. Substantial progress over the past decade has improved our understanding of hydrophobic interactions in simple model systems, but most biologically and technologically relevant structures contain non-polar domains in close proximity to polar and charged functional groups. Theories and simulations exploring such nanometre-scale chemical heterogeneity find it can have an important effect, but the influence of this heterogeneity on hydrophobic interactions has not been tested experimentally. Here we report chemical force microscopy measurements on alkyl-functionalized surfaces that reveal a dramatic change in the surfaces' hydrophobic interaction strengths on co-immobilization of amine or guanidine groups. Protonation of amine groups doubles the strength of hydrophobic interactions, and guanidinium groups eliminate measurable hydrophobic interactions in all pH ranges investigated. We see these divergent effects of proximally immobilized cations also in single-molecule measurements on conformationally stable β-peptides with non-polar subunits located one nanometre from either amine- or guanidine-bearing subunits. Our results demonstrate the importance of nanometre-scale chemical heterogeneity, with hydrophobicity not an intrinsic property of any given non-polar domain but strongly modulated by functional groups located as far away as one nanometre. The judicious placing of charged groups near hydrophobic domains thus provides a strategy for tuning hydrophobic driving forces to optimize molecular recognition or self-assembly processes.

  13. Modulation of hydrophobic interactions by proximally immobilized ions

    NASA Astrophysics Data System (ADS)

    Ma, C. Derek; Wang, Chenxuan; Acevedo-Vélez, Claribel; Gellman, Samuel H.; Abbott, Nicholas L.

    2015-01-01

    The structure of water near non-polar molecular fragments or surfaces mediates the hydrophobic interactions that underlie a broad range of interfacial, colloidal and biophysical phenomena. Substantial progress over the past decade has improved our understanding of hydrophobic interactions in simple model systems, but most biologically and technologically relevant structures contain non-polar domains in close proximity to polar and charged functional groups. Theories and simulations exploring such nanometre-scale chemical heterogeneity find it can have an important effect, but the influence of this heterogeneity on hydrophobic interactions has not been tested experimentally. Here we report chemical force microscopy measurements on alkyl-functionalized surfaces that reveal a dramatic change in the surfaces' hydrophobic interaction strengths on co-immobilization of amine or guanidine groups. Protonation of amine groups doubles the strength of hydrophobic interactions, and guanidinium groups eliminate measurable hydrophobic interactions in all pH ranges investigated. We see these divergent effects of proximally immobilized cations also in single-molecule measurements on conformationally stable β-peptides with non-polar subunits located one nanometre from either amine- or guanidine-bearing subunits. Our results demonstrate the importance of nanometre-scale chemical heterogeneity, with hydrophobicity not an intrinsic property of any given non-polar domain but strongly modulated by functional groups located as far away as one nanometre. The judicious placing of charged groups near hydrophobic domains thus provides a strategy for tuning hydrophobic driving forces to optimize molecular recognition or self-assembly processes.

  14. Interaction of two modulational instabilities in a semiconductor resonator.

    PubMed

    Kozyreff, G; Chapman, S J; Tlidi, M

    2003-07-01

    The interaction of two neighboring modulational instabilities in a coherently driven semiconductor cavity is investigated. First, an asymptotic reduction of the general equations is performed in the limit of a nearly vertical input-output characteristic. Next, a normal form is derived in the limit where the two instabilities are close to one other. An infinity of branches of periodic solutions are found to emerge from the unstable portion of the homogeneous branch. These branches have a nontrivial envelope in the bifurcation diagram that can either smoothly join the two instability points or form an isolated branch of solutions. PMID:12935188

  15. Membrane cholesterol modulates galanin-GalR2 interaction.

    PubMed

    Pang, L; Graziano, M; Wang, S

    1999-09-14

    The neuropeptide galanin mediates a number of diverse physiological and pathophysiological actions via interaction with membrane-bound receptors. The role that membrane cholesterol plays in modulating the interaction between galanin and one of the three cloned galanin receptor subtypes (GalR2) expressed in Chinese hamster ovary (CHO) cells was examined. Reduction of membrane cholesterol by treatment with methyl-beta-cyclodextrin (CD) or by culturing cells in lipoprotein-deficient serum markedly decreased galanin binding to the receptor. Addition of cholesterol back to CD-treated, cholesterol-depleted membranes restored galanin binding to control levels. Hill analysis suggests that the GalR2 binds multiple molecules of cholesterol (n >/= 3) in a positively cooperative manner. This interaction appears to be cholesterol-specific as only cholesterol and a limited number of cholesterol analogues were able to rescue galanin binding. The inability of some of these analogues to rescue the binding activity also suggests that binding of galanin to GalR2 is independent of membrane fluidity as, like cholesterol, cholesterol analogues generally rigidize membranes. In addition, treatment of the membranes with other modulators of membrane fluidity, e.g. ethanol, did not affect galanin binding to the GalR2. In contrast, treatment of membranes, with filipin, a molecule that clusters cholesterol within the membranes, or with cholesterol oxidase resulted in markedly reduced galanin binding. Incubation of membranes with 100 microM GTP-gamma-S did not alter the IC(50) for CD in the prebinding assay treatment suggesting that the effect of cholesterol was independent of G protein interaction. Preincubation of intact cells with CD also drastically impaired the ability of galanin to activate intracellular inositol phosphate accumulation in GalR2-transfected CHO cells. These data detail a new mechanism for the regulation of galanin receptor signaling which may link altered functions of Gal

  16. Angiotensin-converting enzymes modulate aphid–plant interactions

    PubMed Central

    Wang, Wei; Luo, Lan; Lu, Hong; Chen, Shaoliang; Kang, Le; Cui, Feng

    2015-01-01

    Angiotensin-converting enzymes (ACEs) are key components of the renin–angiotensin system in mammals. However, the function of ACE homologs in insect saliva is unclear. Aphids presumably deliver effector proteins via saliva into plant cells to maintain a compatible insect–plant interaction. In this study, we showed that ACE modulates aphid–plant interactions by affecting feeding behavior and survival of aphids on host plants. Three ACE genes were identified from the pea aphid Acyrthosiphon pisum genome. ACE1 and ACE2 were highly expressed in the salivary glands and are predicted to function as secretory proteins. The ACE2 transcript level decreased in aphids fed on artificial diet compared with aphids fed on Vicia faba. The knockdown of the expression of each ACE by RNAi failed to affect aphid survival. When ACE1 and ACE2 were simultaneously knocked down, aphid feeding was enhanced. Aphids required less time to find the phloem sap and showed longer passive ingestion. However, the simultaneous knockdown of ACE1 and ACE2 resulted in a higher mortality rate than the control group when aphids were fed on plants. These results indicated that ACE1 and ACE2 function together to modulate A. pisum feeding and survival on plants. PMID:25744345

  17. Modulation of Microtubule Interprotofilament Interactions by Modified Taxanes

    PubMed Central

    Matesanz, Ruth; Rodríguez-Salarichs, Javier; Pera, Benet; Canales, Ángeles; Andreu, José Manuel; Jiménez-Barbero, Jesús; Bras, Wim; Nogales, Aurora; Fang, Wei-Shuo; Díaz, José Fernando

    2011-01-01

    Microtubules assembled with paclitaxel and docetaxel differ in their numbers of protofilaments, reflecting modification of the lateral association between αβ-tubulin molecules in the microtubule wall. These modifications of microtubule structure, through a not-yet-characterized mechanism, are most likely related to the changes in tubulin-tubulin interactions responsible for microtubule stabilization by these antitumor compounds. We have used a set of modified taxanes to study the structural mechanism of microtubule stabilization by these ligands. Using small-angle x-ray scattering, we have determined how modifications in the shape and size of the taxane substituents result in changes in the interprotofilament angles and in their number. The observed effects have been explained using NMR-aided docking and molecular dynamic simulations of taxane binding at the microtubule pore and luminal sites. Modeling results indicate that modification of the size of substituents at positions C7 and C10 of the taxane core influence the conformation of three key elements in microtubule lateral interactions (the M-loop, the S3 β-strand, and the H3 helix) that modulate the contacts between adjacent protofilaments. In addition, modifications of the substituents at position C2 slightly rearrange the ligand in the binding site, modifying the interaction of the C7 substituent with the M-loop. PMID:22208196

  18. Effector proteins that modulate plant--insect interactions.

    PubMed

    Hogenhout, Saskia A; Bos, Jorunn I B

    2011-08-01

    Insect herbivores have highly diverse life cycles and feeding behaviors. They establish close interactions with their plant hosts and suppress plant defenses. Chewing herbivores evoke characteristic defense responses distinguishable from general mechanical damage. In addition, piercing-sucking hemipteran insects display typical feeding behavior that suggests active suppression of plant defense responses. Effectors that modulate plant defenses have been identified in the saliva of these insects. Tools for high-throughput effector identification and functional characterization have been developed. In addition, in some insect species it is possible to silence gene expression by RNAi. Together, this technological progress has enabled the identification of insect herbivore effectors and their targets that will lead to the development of novel strategies for pest resistances in plants.

  19. Self, others, objects: how this triadic interaction modulates our behavior.

    PubMed

    Lugli, Luisa; Baroni, Giulia; Gianelli, Claudia; Borghi, Anna M; Nicoletti, Roberto

    2012-11-01

    Two experiments investigated whether the triadic interaction between objects, ourselves and other persons modulates motor system activation during language comprehension. Participants were faced with sentences formed by a descriptive part referring to a positive or negative emotively connoted object and an action part composed of an imperative verb implying a motion toward the self or toward other persons (e.g., "The object is attractive/ugly. Bring it toward you/Give it to another person/Give it to a friend"). Participants judged whether each sentence was sensible or not by moving the mouse toward or away from their body. Findings showed that the simulation of a social context influenced both (1) the motor system and (2) the coding of stimulus valence. Implications of the results for theories of embodied and social cognition are discussed.

  20. Designing high-quality interactive multimedia learning modules.

    PubMed

    Huang, Camillan

    2005-01-01

    Modern research has broadened scientific knowledge and revealed the interdisciplinary nature of the sciences. For today's students, this advance translates to learning a more diverse range of concepts, usually in less time, and without supporting resources. Students can benefit from technology-enhanced learning supplements that unify concepts and are delivered on-demand over the Internet. Such supplements, like imaging informatics databases, serve as innovative references for biomedical information, but could improve their interaction interfaces to support learning. With information from these digital datasets, multimedia learning tools can be designed to transform learning into an active process where students can visualize relationships over time, interact with dynamic content, and immediately test their knowledge. This approach bridges knowledge gaps, fosters conceptual understanding, and builds problem-solving and critical thinking skills-all essential components to informatics training for science and medicine. Additional benefits include cost-free access and ease of dissemination over the Internet or CD-ROM. However, current methods for the design of multimedia learning modules are not standardized and lack strong instructional design. Pressure from administrators at the top and students from the bottom are pushing faculty to use modern technology to address the learning needs and expectations of contemporary students. Yet, faculty lack adequate support and training to adopt this new approach. So how can faculty learn to create educational multimedia materials for their students? This paper provides guidelines on best practices in educational multimedia design, derived from the Virtual Labs Project at Stanford University. The development of a multimedia module consists of five phases: (1) understand the learning problem and the users needs; (2) design the content to harness the enabling technologies; (3) build multimedia materials with web style standards and

  1. Designing high-quality interactive multimedia learning modules.

    PubMed

    Huang, Camillan

    2005-01-01

    Modern research has broadened scientific knowledge and revealed the interdisciplinary nature of the sciences. For today's students, this advance translates to learning a more diverse range of concepts, usually in less time, and without supporting resources. Students can benefit from technology-enhanced learning supplements that unify concepts and are delivered on-demand over the Internet. Such supplements, like imaging informatics databases, serve as innovative references for biomedical information, but could improve their interaction interfaces to support learning. With information from these digital datasets, multimedia learning tools can be designed to transform learning into an active process where students can visualize relationships over time, interact with dynamic content, and immediately test their knowledge. This approach bridges knowledge gaps, fosters conceptual understanding, and builds problem-solving and critical thinking skills-all essential components to informatics training for science and medicine. Additional benefits include cost-free access and ease of dissemination over the Internet or CD-ROM. However, current methods for the design of multimedia learning modules are not standardized and lack strong instructional design. Pressure from administrators at the top and students from the bottom are pushing faculty to use modern technology to address the learning needs and expectations of contemporary students. Yet, faculty lack adequate support and training to adopt this new approach. So how can faculty learn to create educational multimedia materials for their students? This paper provides guidelines on best practices in educational multimedia design, derived from the Virtual Labs Project at Stanford University. The development of a multimedia module consists of five phases: (1) understand the learning problem and the users needs; (2) design the content to harness the enabling technologies; (3) build multimedia materials with web style standards and

  2. BioSIGHT: Interactive Visualization Modules for Science Education

    NASA Technical Reports Server (NTRS)

    Wong, Wee Ling

    1998-01-01

    Redefining science education to harness emerging integrated media technologies with innovative pedagogical goals represents a unique challenge. The Integrated Media Systems Center (IMSC) is the only engineering research center in the area of multimedia and creative technologies sponsored by the National Science Foundation. The research program at IMSC is focused on developing advanced technologies that address human-computer interfaces, database management, and high-speed network capabilities. The BioSIGHT project at is a demonstration technology project in the area of education that seeks to address how such emerging multimedia technologies can make an impact on science education. The scope of this project will help solidify NASA's commitment for the development of innovative educational resources that promotes science literacy for our students and the general population as well. These issues must be addressed as NASA marches toward the goal of enabling human space exploration that requires an understanding of life sciences in space. The IMSC BioSIGHT lab was established with the purpose of developing a novel methodology that will map a high school biology curriculum into a series of interactive visualization modules that can be easily incorporated into a space biology curriculum. Fundamental concepts in general biology must be mastered in order to allow a better understanding and application for space biology. Interactive visualization is a powerful component that can capture the students' imagination, facilitate their assimilation of complex ideas, and help them develop integrated views of biology. These modules will augment the role of the teacher and will establish the value of student-centered interactivity, both in an individual setting as well as in a collaborative learning environment. Students will be able to interact with the content material, explore new challenges, and perform virtual laboratory simulations. The BioSIGHT effort is truly cross

  3. BioSIGHT: Interactive Visualization Modules for Science Education

    NASA Technical Reports Server (NTRS)

    Wong, Wee Ling

    1998-01-01

    Redefining science education to harness emerging integrated media technologies with innovative pedagogical goals represents a unique challenge. The Integrated Media Systems Center (IMSC) is the only engineering research center in the area of multimedia and creative technologies sponsored by the National Science Foundation. The research program at IMSC is focused on developing advanced technologies that address human-computer interfaces, database management, and high- speed network capabilities. The BioSIGHT project at IMSC is a demonstration technology project in the area of education that seeks to address how such emerging multimedia technologies can make an impact on science education. The scope of this project will help solidify NASA's commitment for the development of innovative educational resources that promotes science literacy for our students and the general population as well. These issues must be addressed as NASA marches towards the goal of enabling human space exploration that requires an understanding of life sciences in space. The IMSC BioSIGHT lab was established with the purpose of developing a novel methodology that will map a high school biology curriculum into a series of interactive visualization modules that can be easily incorporated into a space biology curriculum. Fundamental concepts in general biology must be mastered in order to allow a better understanding and application for space biology. Interactive visualization is a powerful component that can capture the students' imagination, facilitate their assimilation of complex ideas, and help them develop integrated views of biology. These modules will augment the role of the teacher and will establish the value of student-centered interactivity, both in an individual setting as well as in a collaborative learning environment. Students will be able to interact with the content material, explore new challenges, and perform virtual laboratory simulations. The BioSIGHT effort is truly cross

  4. Capacitance-modulated transistor detects odorant binding protein chiral interactions

    PubMed Central

    Mulla, Mohammad Yusuf; Tuccori, Elena; Magliulo, Maria; Lattanzi, Gianluca; Palazzo, Gerardo; Persaud, Krishna; Torsi, Luisa

    2015-01-01

    Peripheral events in olfaction involve odorant binding proteins (OBPs) whose role in the recognition of different volatile chemicals is yet unclear. Here we report on the sensitive and quantitative measurement of the weak interactions associated with neutral enantiomers differentially binding to OBPs immobilized through a self-assembled monolayer to the gate of an organic bio-electronic transistor. The transduction is remarkably sensitive as the transistor output current is governed by the small capacitance of the protein layer undergoing minute changes as the ligand–protein complex is formed. Accurate determination of the free-energy balances and of the capacitance changes associated with the binding process allows derivation of the free-energy components as well as of the occurrence of conformational events associated with OBP ligand binding. Capacitance-modulated transistors open a new pathway for the study of ultra-weak molecular interactions in surface-bound protein–ligand complexes through an approach that combines bio-chemical and electronic thermodynamic parameters. PMID:25591754

  5. Capacitance-modulated transistor detects odorant binding protein chiral interactions.

    PubMed

    Mulla, Mohammad Yusuf; Tuccori, Elena; Magliulo, Maria; Lattanzi, Gianluca; Palazzo, Gerardo; Persaud, Krishna; Torsi, Luisa

    2015-01-01

    Peripheral events in olfaction involve odorant binding proteins (OBPs) whose role in the recognition of different volatile chemicals is yet unclear. Here we report on the sensitive and quantitative measurement of the weak interactions associated with neutral enantiomers differentially binding to OBPs immobilized through a self-assembled monolayer to the gate of an organic bio-electronic transistor. The transduction is remarkably sensitive as the transistor output current is governed by the small capacitance of the protein layer undergoing minute changes as the ligand-protein complex is formed. Accurate determination of the free-energy balances and of the capacitance changes associated with the binding process allows derivation of the free-energy components as well as of the occurrence of conformational events associated with OBP ligand binding. Capacitance-modulated transistors open a new pathway for the study of ultra-weak molecular interactions in surface-bound protein-ligand complexes through an approach that combines bio-chemical and electronic thermodynamic parameters. PMID:25591754

  6. Capacitance-modulated transistor detects odorant binding protein chiral interactions

    NASA Astrophysics Data System (ADS)

    Mulla, Mohammad Yusuf; Tuccori, Elena; Magliulo, Maria; Lattanzi, Gianluca; Palazzo, Gerardo; Persaud, Krishna; Torsi, Luisa

    2015-01-01

    Peripheral events in olfaction involve odorant binding proteins (OBPs) whose role in the recognition of different volatile chemicals is yet unclear. Here we report on the sensitive and quantitative measurement of the weak interactions associated with neutral enantiomers differentially binding to OBPs immobilized through a self-assembled monolayer to the gate of an organic bio-electronic transistor. The transduction is remarkably sensitive as the transistor output current is governed by the small capacitance of the protein layer undergoing minute changes as the ligand-protein complex is formed. Accurate determination of the free-energy balances and of the capacitance changes associated with the binding process allows derivation of the free-energy components as well as of the occurrence of conformational events associated with OBP ligand binding. Capacitance-modulated transistors open a new pathway for the study of ultra-weak molecular interactions in surface-bound protein-ligand complexes through an approach that combines bio-chemical and electronic thermodynamic parameters.

  7. Telescience operations with the solar array module plasma interaction experiment

    NASA Technical Reports Server (NTRS)

    Wald, Lawrence W.; Bibyk, Irene K.

    1995-01-01

    The Solar Array Module Plasma Interactions Experiment (SAMPIE) is a flight experiment that flew on the Space Shuttle Columbia (STS-62) in March 1994, as part of the OAST-2 mission. The overall objective of SAMPIE was to determine the adverse environmental interactions within the space plasma of low earth orbit (LEO) on modern solar cells and space power system materials which are artificially biased to high positive and negative direct current (DC) voltages. The two environmental interactions of interest included high voltage arcing from the samples to the space plasma and parasitic current losses. High voltage arcing can cause physical damage to power system materials and shorten expected hardware life. parasitic current losses can reduce power system efficiency because electric currents generated in a power system drain into the surrounding plasma via parasitic resistance. The flight electronics included two programmable high voltage DC power supplies to bias the experiment samples, instruments to measure the surrounding plasma environment in the STS cargo bay, and the on-board data acquisition system (DAS). The DAS provided in-flight experiment control, data storage, and communications through the Goddard Space Flight Center (GSFC) Hitchhiker flight avionics to the GSFC Payload Operations Control Center (POCC). The DAS and the SAMPIE POCC computer systems were designed for telescience operations; this paper will focus on the experiences of the SAMPIE team regarding telescience development and operations from the GSFC POCC during STS-62. The SAMPIE conceptual development, hardware design, and system verification testing were accomplished at the NASA Lewis Research Center (LeRC). SAMPIE was developed under the In-Space Technology Experiment Program (IN-STEP), which sponsors NASA, industry, and university flight experiments designed to enable and enhance space flight technology. The IN-STEP Program is sponsored by the Office of Space Access and Technology (OSAT).

  8. An Interactive Videodisc Module for Forage Quality and Testing Instruction.

    ERIC Educational Resources Information Center

    Hannaway, D. B.; And Others

    1988-01-01

    Announces the development of a videodisc module which provides access to the U.S. Department of Agriculture information network. Relates sources of information, module description, recommendations for use, and software specifications. Describes the equipment needed. (RT)

  9. Perilipin polymorphism interacts with dietary carbohydrates to modulate anthropometric traits in Hispanics of Caribbean origin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Perilipin (PLIN) is the major protein surrounding lipid droplets in adipocytes and regulates adipocyte metabolism by modulating the interaction between lipases and triacylglycerol stores. Associations between PLIN gene polymorphisms and obesity risk have been described, but interactions with die...

  10. Modulation and interactions of charged biomimetic membranes with bivalent ions

    NASA Astrophysics Data System (ADS)

    Kazadi Badiambile, Adolphe

    biomolecules in a dynamic environment and the lack of appropriate physical and biochemical tools. In contrast, biomimetic membrane models that rely on the amphiphilic properties of phospholipids are powerful tools that enable the study of these molecules in vitro. By having control over the different experimental parameters such as temperature and pH, reliable and repeatable experimental conditions can be created. One of the key questions I investigated in this thesis is related to the clustering mechanism of PtdIns(4, 5)P2 into pools or aggregates that enable independent cellular control of this species by geometric separation. The lateral aggregation of PtdIns(4, 5)P2 and its underlying physical causes is still a matter of debate. In the first part of this thesis I introduce the general information on lipid membranes with a special focus on the PtdIns family and their associated signaling events. In addition, I explain the Langmuir-Blodgett film balance (LB) system as tool to study lipid membranes and lipid interactions. In the second chapter, I describe my work on the lateral compressibility of PtdIns(4, 5)P2, PtdIns and DOPG monolayers and its modulation by bivalent ions using Langmuir monolayers. In addition, a theoretical framework of compressibility that depends on a surface potential induced by a planar layer of charged molecules and ions in the bulk was provided. In the third part, I present my work on the excess Gibbs free energy of the lipid systems PtdIns(4, 5)P2 --POPC, PtdIns(4, 5)P2, and POPC as they are modulated by bivalent ions. In the fourth part, I report on my foray in engineering a light-based system that relies on different dye properties to simulate calcium induced calcium release (CICR) that occurs in many cell types. In the final chapter, I provide a general conclusion and present directions for future research that would build on my findings.

  11. Cross-Modulated Amplitudes and Frequencies Characterize Interacting Components in Complex Systems

    NASA Astrophysics Data System (ADS)

    Gans, Fabian; Schumann, Aicko Y.; Kantelhardt, Jan W.; Penzel, Thomas; Fietze, Ingo

    2009-03-01

    The dynamics of complex systems is characterized by oscillatory components on many time scales. To study the interactions between these components we analyze the cross modulation of their instantaneous amplitudes and frequencies, separating synchronous and antisynchronous modulation. We apply our novel technique to brain-wave oscillations in the human electroencephalogram and show that interactions between the α wave and the δ or β wave oscillators as well as spatial interactions can be quantified and related with physiological conditions (e.g., sleep stages). Our approach overcomes the limitation to oscillations with similar frequencies and enables us to quantify directly nonlinear effects such as positive or negative frequency modulation.

  12. Interaction of modulated gravity water waves of finite depth

    NASA Astrophysics Data System (ADS)

    Giannoulis, Ioannis

    2016-10-01

    We consider the capillary-gravity water wave problem of finite depth with a flat bottom of one or two horizontal dimensions. We derive the modulation equations of leading and next-to-leading order in the hyperbolic scaling for three weakly amplitude-modulated plane wave solutions of the linearized problem in the absence of quadratic and cubic resonances. We justify the derived system of macroscopic equations in the case of gravity waves using the stability of the finite depth water wave problem on the time scale O (1 / ɛ).

  13. A response to "Responding to challenging interactions with families: A training module for inpatient oncology nurses".

    PubMed

    Heyn, Lena

    2016-09-01

    Comments on the original article by Zaider and colleagues (see record ) about the training module they developed for inpatient oncology nurses. The training module, called "Responding to Challenging Interactions with Families" (RCIF), used a collaborative, strength-based, and family centered framework. The goal was to help nurses respond to stressful family situations. (PsycINFO Database Record PMID:27632544

  14. A Matlab/Simulink-Based Interactive Module for Servo Systems Learning

    ERIC Educational Resources Information Center

    Aliane, N.

    2010-01-01

    This paper presents an interactive module for learning both the fundamental and practical issues of servo systems. This module, developed using Simulink in conjunction with the Matlab graphical user interface (Matlab-GUI) tool, is used to supplement conventional lectures in control engineering and robotics subjects. First, the paper introduces the…

  15. Development and Evaluation of an Interactive Internet-Based Pharmacokinetic Teaching Module.

    ERIC Educational Resources Information Center

    Hedaya, Mohsen A.

    1998-01-01

    Describes an Internet-based, interactive, learner-centered, asynchronous instructional module for pharmacokinetics that requires minimal computer knowledge to operate. Main components are concept presentation, a simulation exercise, and self-assessment questions. The module has been found effective in teaching the steady state concept at the…

  16. Rationale, Development, and Validation of a Series of Self-Instructional Modules in Interaction Analysis.

    ERIC Educational Resources Information Center

    Suiter, Phil Edward; Queen, Bernard

    This study was designed to develop a series of instructional modules to teach inservice teachers the Flanders System of Interaction Analysis. Instructional modules were constructed based on research information, and then modified from feedback from experts and random trials. Two field-test groups were used to provide data for validation testing,…

  17. Bridging the gap between modules in isolation and as part of networks: A systems framework for elucidating interaction and regulation of signalling modules

    NASA Astrophysics Data System (ADS)

    Menon, Govind; Krishnan, J.

    2016-07-01

    While signalling and biochemical modules have been the focus of numerous studies, they are typically studied in isolation, with no examination of the effects of the ambient network. In this paper we formulate and develop a systems framework, rooted in dynamical systems, to understand such effects, by studying the interaction of signalling modules. The modules we consider are (i) basic covalent modification, (ii) monostable switches, (iii) bistable switches, (iv) adaptive modules, and (v) oscillatory modules. We systematically examine the interaction of these modules by analyzing (a) sequential interaction without shared components, (b) sequential interaction with shared components, and (c) oblique interactions. Our studies reveal that the behaviour of a module in isolation may be substantially different from that in a network, and explicitly demonstrate how the behaviour of a given module, the characteristics of the ambient network, and the possibility of shared components can result in new effects. Our global approach illuminates different aspects of the structure and functioning of modules, revealing the importance of dynamical characteristics as well as biochemical features; this provides a methodological platform for investigating the complexity of natural modules shaped by evolution, elucidating the effects of ambient networks on a module in multiple cellular contexts, and highlighting the capabilities and constraints for engineering robust synthetic modules. Overall, such a systems framework provides a platform for bridging the gap between non-linear information processing modules, in isolation and as parts of networks, and a basis for understanding new aspects of natural and engineered cellular networks.

  18. Bridging the gap between modules in isolation and as part of networks: A systems framework for elucidating interaction and regulation of signalling modules.

    PubMed

    Menon, Govind; Krishnan, J

    2016-07-21

    While signalling and biochemical modules have been the focus of numerous studies, they are typically studied in isolation, with no examination of the effects of the ambient network. In this paper we formulate and develop a systems framework, rooted in dynamical systems, to understand such effects, by studying the interaction of signalling modules. The modules we consider are (i) basic covalent modification, (ii) monostable switches, (iii) bistable switches, (iv) adaptive modules, and (v) oscillatory modules. We systematically examine the interaction of these modules by analyzing (a) sequential interaction without shared components, (b) sequential interaction with shared components, and (c) oblique interactions. Our studies reveal that the behaviour of a module in isolation may be substantially different from that in a network, and explicitly demonstrate how the behaviour of a given module, the characteristics of the ambient network, and the possibility of shared components can result in new effects. Our global approach illuminates different aspects of the structure and functioning of modules, revealing the importance of dynamical characteristics as well as biochemical features; this provides a methodological platform for investigating the complexity of natural modules shaped by evolution, elucidating the effects of ambient networks on a module in multiple cellular contexts, and highlighting the capabilities and constraints for engineering robust synthetic modules. Overall, such a systems framework provides a platform for bridging the gap between non-linear information processing modules, in isolation and as parts of networks, and a basis for understanding new aspects of natural and engineered cellular networks.

  19. Bridging the gap between modules in isolation and as part of networks: A systems framework for elucidating interaction and regulation of signalling modules.

    PubMed

    Menon, Govind; Krishnan, J

    2016-07-21

    While signalling and biochemical modules have been the focus of numerous studies, they are typically studied in isolation, with no examination of the effects of the ambient network. In this paper we formulate and develop a systems framework, rooted in dynamical systems, to understand such effects, by studying the interaction of signalling modules. The modules we consider are (i) basic covalent modification, (ii) monostable switches, (iii) bistable switches, (iv) adaptive modules, and (v) oscillatory modules. We systematically examine the interaction of these modules by analyzing (a) sequential interaction without shared components, (b) sequential interaction with shared components, and (c) oblique interactions. Our studies reveal that the behaviour of a module in isolation may be substantially different from that in a network, and explicitly demonstrate how the behaviour of a given module, the characteristics of the ambient network, and the possibility of shared components can result in new effects. Our global approach illuminates different aspects of the structure and functioning of modules, revealing the importance of dynamical characteristics as well as biochemical features; this provides a methodological platform for investigating the complexity of natural modules shaped by evolution, elucidating the effects of ambient networks on a module in multiple cellular contexts, and highlighting the capabilities and constraints for engineering robust synthetic modules. Overall, such a systems framework provides a platform for bridging the gap between non-linear information processing modules, in isolation and as parts of networks, and a basis for understanding new aspects of natural and engineered cellular networks. PMID:27448907

  20. Developing an On-Line Interactive Health Psychology Module

    ERIC Educational Resources Information Center

    Upton, Dominic; Cooper, Carol

    2006-01-01

    On-line teaching material in health psychology was developed which ensured a range of students could access appropriate material for their course and level of study. This material has been developed around the concept of smaller "content chunks" which can be combined into whole units of learning (topics), and ultimately, a module. On the basis of…

  1. Interactions between amplitude modulation and frequency modulation processing: Effects of age and hearing loss.

    PubMed

    Paraouty, Nihaad; Ewert, Stephan D; Wallaert, Nicolas; Lorenzi, Christian

    2016-07-01

    Frequency modulation (FM) and amplitude modulation (AM) detection thresholds were measured for a 500-Hz carrier frequency and a 5-Hz modulation rate. For AM detection, FM at the same rate as the AM was superimposed with varying FM depth. For FM detection, AM at the same rate was superimposed with varying AM depth. The target stimuli always contained both amplitude and frequency modulations, while the standard stimuli only contained the interfering modulation. Young and older normal-hearing listeners, as well as older listeners with mild-to-moderate sensorineural hearing loss were tested. For all groups, AM and FM detection thresholds were degraded in the presence of the interfering modulation. AM detection with and without interfering FM was hardly affected by either age or hearing loss. While aging had an overall detrimental effect on FM detection with and without interfering AM, there was a trend that hearing loss further impaired FM detection in the presence of AM. Several models using optimal combination of temporal-envelope cues at the outputs of off-frequency filters were tested. The interfering effects could only be predicted for hearing-impaired listeners. This indirectly supports the idea that, in addition to envelope cues resulting from FM-to-AM conversion, normal-hearing listeners use temporal fine-structure cues for FM detection.

  2. Topological interactive analysis of power system and its communication module: A complex network approach

    NASA Astrophysics Data System (ADS)

    Hu, Jianqiang; Yu, Jie; Cao, Jinde; Ni, Ming; Yu, Wenjie

    2014-12-01

    Power system and its communication system, which can be called a cyber-physical system, are interconnected and interdependent on each other. This paper considers the interaction problem between power system and its communication module from the perspective of the topological structure. Firstly, some structural properties and centrality measures of complex networks are briefly reviewed. Furthermore, novel interactive measures are proposed to describe the interactive system in terms of topologies. Finally, based on these metrics, the statistical properties and the interactive relationships of the main power system and its communication module (abstracted as two complex heterogeneous networks) of one province in China are investigated.

  3. Chaotic saddles in nonlinear modulational interactions in a plasma

    SciTech Connect

    Miranda, Rodrigo A.; Rempel, Erico L.; Chian, Abraham C.-L.

    2012-11-15

    A nonlinear model of modulational processes in the subsonic regime involving a linearly unstable wave and two linearly damped waves with different damping rates in a plasma is studied numerically. We compute the maximum Lyapunov exponent as a function of the damping rates in a two-parameter space, and identify shrimp-shaped self-similar structures in the parameter space. By varying the damping rate of the low-frequency wave, we construct bifurcation diagrams and focus on a saddle-node bifurcation and an interior crisis associated with a periodic window. We detect chaotic saddles and their stable and unstable manifolds, and demonstrate how the connection between two chaotic saddles via coupling unstable periodic orbits can result in a crisis-induced intermittency. The relevance of this work for the understanding of modulational processes observed in plasmas and fluids is discussed.

  4. DHCVIM: A direct heating containment vessel interactions module

    SciTech Connect

    Ginsberg, T.; Tutu, N.K.

    1987-01-01

    Models for prediction of direct containment heating phenomena as implemented in the DHCVIM computer module are described. The models were designed to treat thermal, chemical and hydrodynamic processes in the three regions of the Sandia National Laboratory Surtsey DCH test facility: the melt generator, cavity and vessel. The fundamental balance equations, along with constitutive relations are described. A combination of Eulerian treatment for the gas phase and Lagrangian treatment for the droplet phase is used in the modeling. Comparisons of calculations and DCH-1 test results are presented. Reasonable agreement is demonstrated for the vessel pressure rise, melt generator pressure decay and particle size distribution.

  5. Virtual Reality Simulations and Animations in a Web-Based Interactive Manufacturing Engineering Module

    ERIC Educational Resources Information Center

    Ong, S. K.; Mannan, M. A.

    2004-01-01

    This paper presents a web-based interactive teaching package that provides a comprehensive and conducive yet dynamic and interactive environment for a module on automated machine tools in the Manufacturing Division at the National University of Singapore. The use of Internet technologies in this teaching tool makes it possible to conjure…

  6. Interharmonic modulation products as a means to quantify nonlinear D-region interactions

    NASA Astrophysics Data System (ADS)

    Moore, Robert

    Experimental observations performed during dual beam ionospheric HF heating experiments at the High frequency Active Auroral Research Program (HAARP) HF transmitter in Gakona, Alaska are used to quantify the relative importance of specific nonlinear interactions that occur within the D region ionosphere. During these experiments, HAARP broadcast two amplitude modulated HF beams whose center frequencies were separated by less than 20 kHz. One beam was sinusoidally modulated at 500 Hz while the second beam was sinusoidally modulated using a 1-7 kHz linear frequency-time chirp. ELF/VLF observations performed at two different locations (3 and 98 km from HAARP) provide clear evidence of strong interactions between all field components of the two HF beams in the form of low and high order interharmonic modulation products. From a theoretical standpoint, the observed interharmonic modulation products could be produced by several different nonlinearities. The two primary nonlinearities take the form of wave-medium interactions (i.e., cross modulation), wherein the ionospheric conductivity modulation produced by one signal crosses onto the other signal via collision frequency modification, and wave-wave interactions, wherein the conduction current associated with one wave mixes with the electric field of the other wave to produce electron temperature oscillations. We are able to separate and quantify these two different nonlinearities, and we conclude that the wave-wave interactions dominate the wave-medium interactions by a factor of two. These results are of great importance for the modeling of transioinospheric radio wave propagation, in that both the wave-wave and the wave-medium interactions could be responsible for a significant amount of anomalous absorption.

  7. Perceived live interaction modulates the developing social brain.

    PubMed

    Rice, Katherine; Moraczewski, Dustin; Redcay, Elizabeth

    2016-09-01

    Although children's social development is embedded in social interaction, most developmental neuroscience studies have examined responses to non-interactive social stimuli (e.g. photographs of faces). The neural mechanisms of real-world social behavior are of special interest during middle childhood (roughly ages 7-13), a time of increased social complexity and competence coinciding with structural and functional social brain development. Evidence from adult neuroscience studies suggests that social interaction may alter neural processing, but no neuroimaging studies in children have directly examined the effects of live social-interactive context on social cognition. In the current study of middle childhood, we compare the processing of two types of speech: speech that children believed was presented over a real-time audio-feed by a social partner and speech that they believed was recorded. Although in reality all speech was prerecorded, perceived live speech resulted in significantly greater neural activation in regions associated with social cognitive processing. These findings underscore the importance of using ecologically-valid and interactive methods to understand the developing social brain.

  8. Perceived live interaction modulates the developing social brain.

    PubMed

    Rice, Katherine; Moraczewski, Dustin; Redcay, Elizabeth

    2016-09-01

    Although children's social development is embedded in social interaction, most developmental neuroscience studies have examined responses to non-interactive social stimuli (e.g. photographs of faces). The neural mechanisms of real-world social behavior are of special interest during middle childhood (roughly ages 7-13), a time of increased social complexity and competence coinciding with structural and functional social brain development. Evidence from adult neuroscience studies suggests that social interaction may alter neural processing, but no neuroimaging studies in children have directly examined the effects of live social-interactive context on social cognition. In the current study of middle childhood, we compare the processing of two types of speech: speech that children believed was presented over a real-time audio-feed by a social partner and speech that they believed was recorded. Although in reality all speech was prerecorded, perceived live speech resulted in significantly greater neural activation in regions associated with social cognitive processing. These findings underscore the importance of using ecologically-valid and interactive methods to understand the developing social brain. PMID:27272314

  9. Self Assembly Modulated by Interactions of Two Heterogeneously Charged Surfaces

    NASA Astrophysics Data System (ADS)

    Brewster, R.; Pincus, P. A.; Safran, S. A.

    2008-09-01

    Recent experiments have measured attractive interactions between two surfaces that each bear two molecular species with opposite charge. Such surfaces form charged domains of finite size. We present a theoretical model that predicts the dependence of the domain size, phase behavior and the interlayer forces as a function of spacing and salt concentration for two such interacting surfaces. A strong correlation between two length scales, the screening length and the surface separation, at the spinodal is shown. Remarkably, the first-order phase transition to infinite sized domains depends logarithmically on the ratio of the domain size to the molecular size. Finally, we fit the predicted pressure with experiments.

  10. Interaction between heterogeneously charged surfaces: Surface patches and charge modulation

    NASA Astrophysics Data System (ADS)

    Ben-Yaakov, Dan; Andelman, David; Diamant, Haim

    2013-02-01

    When solid surfaces are immersed in aqueous solutions, some of their charges can dissociate and leave behind charged patches on the surface. Although the charges are distributed heterogeneously on the surface, most of the theoretical models treat them as homogeneous. For overall non-neutral surfaces, the assumption of surface charge homogeneity is rather reasonable since the leading terms of two such interacting surfaces depend on the nonzero average charge. However, for overall neutral surfaces the nature of the surface charge distribution is crucial in determining the intersurface interaction. In the present work we study the interaction between two charged surfaces across an aqueous solution for several charge distributions. The analysis is preformed within the framework of the linearized Poisson-Boltzmann theory. For periodic charge distributions the interaction is found to be repulsive at small separations, unless the two surface distributions are completely out-of-phase with respect to each other. For quenched random charge distributions we find that due to the presence of the ionic solution in between the surfaces, the intersurface repulsion dominates over the attraction in the linear regime of the Poisson-Boltzmann theory. The effect of quenched charge heterogeneity is found to be particularly substantial in the case of large charged domains.

  11. Modulating intramolecular P···N pnictogen interactions.

    PubMed

    Sánchez-Sanz, Goar; Trujillo, Cristina; Alkorta, Ibon; Elguero, José

    2016-04-01

    A computational study of the intramolecular pnictogen bond in 8-phosphinonaphthalen-1-amine derivatives (1-NX2, 8-PX2 with X = H, F, Cl, Br, CH3, CN and NC), proton sponge analogues, has been carried out to determine their structural and geometric parameters, interaction energies and electronic properties such as the electron density of the intramolecular interaction. Our results show that substitution of H atoms in the PH2 group by electron withdrawing groups on the Lewis acid moiety strengthens the P···N pnictogen bond, evidenced by the increasing electron density values at the bond critical point and by shorter distances. However, substitutions on the Lewis base moiety (NX2) show weaker P···N interactions than when the substitution is done on the Lewis acid counterpart (PX2). Nevertheless, in all cases, pnictogen bonds are enhanced upon substitution with respect to the parent 1-NH2, 8-PH2 system. Second-order orbital interaction energies, electron density maps, electron delocalization functions and charge transfer corroborate the evolution of the P···N strength upon substitution. PMID:26972057

  12. Deciphering peculiar protein-protein interacting modules in Deinococcus radiodurans

    PubMed Central

    Mezhoud, Karim; Sghaier, Haïtham; Barkallah, Insaf

    2009-01-01

    Interactomes of proteins under positive selection from ionizing-radiation-resistant bacteria (IRRB) might be a part of the answer to the question as to how IRRB, particularly Deinococcus radiodurans R1 (Deira), resist ionizing radiation. Here, using the Database of Interacting Proteins (DIP) and the Protein Structural Interactome (PSI)-base server for PSI map, we have predicted novel interactions of orthologs of the 58 proteins under positive selection in Deira and other IRRB, but which are absent in IRSB. Among these, 18 domains and their interactomes have been identified in DNA checkpoint and repair; kinases pathways; energy and nucleotide metabolisms were the important biological processes that were found to be involved. This finding provides new clues to the cellular pathways that can to be important for ionizing-radiation resistance in Deira. PMID:19356244

  13. Multi-Omics Studies towards Novel Modulators of Influenza A Virus–Host Interaction

    PubMed Central

    Söderholm, Sandra; Fu, Yu; Gaelings, Lana; Belanov, Sergey; Yetukuri, Laxman; Berlinkov, Mikhail; Cheltsov, Anton V.; Anders, Simon; Aittokallio, Tero; Nyman, Tuula A.; Matikainen, Sampsa; Kainov, Denis E.

    2016-01-01

    Human influenza A viruses (IAVs) cause global pandemics and epidemics. These viruses evolve rapidly, making current treatment options ineffective. To identify novel modulators of IAV–host interactions, we re-analyzed our recent transcriptomics, metabolomics, proteomics, phosphoproteomics, and genomics/virtual ligand screening data. We identified 713 potential modulators targeting 199 cellular and two viral proteins. Anti-influenza activity for 48 of them has been reported previously, whereas the antiviral efficacy of the 665 remains unknown. Studying anti-influenza efficacy and immuno/neuro-modulating properties of these compounds and their combinations as well as potential viral and host resistance to them may lead to the discovery of novel modulators of IAV–host interactions, which might be more effective than the currently available anti-influenza therapeutics. PMID:27690086

  14. Development of an interactive module to enhance and understand cavity navigation.

    PubMed

    Navarro Newball, Andrés A; Roviello, Franco; Prattichizzo, Domenico; Herrera, Francisco J; Marin, Cesar A

    2007-01-01

    The Interactive Module for Cavity Navigation (IMCA) was created in order to enhance the Web Environment for Surgical Skills Training in Otolaryngology (WESST--OT); later, it was found that it could be used as an independent module which allowed the practice of path navigation in any medical cavity, and its potential use with patients was evidenced. This paper describes the making of IMCA and the potential use of genetic algorithms in path generation.

  15. Matrix interactions modulate neurotrophin-mediated neurite outgrowth and pathfinding.

    PubMed

    Madl, Christopher M; Heilshorn, Sarah C

    2015-04-01

    Both matrix biochemistry and neurotrophic factors are known to modulate neurite outgrowth and pathfinding; however, the interplay between these two factors is less studied. While previous work has shown that the biochemical identity of the matrix can alter the outgrowth of neurites in response to neurotrophins, the importance of the concentration of cell-adhesive ligands is unknown. Using engineered elastin-like protein matrices, we recently demonstrated a synergistic effect between matrix-bound cell-adhesive ligand density and soluble nerve growth factor treatment on neurite outgrowth from dorsal root ganglia. This synergism was mediated by Schwann cell-neurite contact through L1CAM. Cell-adhesive ligand density was also shown to alter the pathfinding behavior of dorsal root ganglion neurites in response to a gradient of nerve growth factor. While more cell-adhesive matrices promoted neurite outgrowth, less cell-adhesive matrices promoted more faithful neurite pathfinding. These studies emphasize the importance of considering both matrix biochemistry and neurotrophic factors when designing biomaterials for peripheral nerve regeneration. PMID:26170800

  16. Matrix interactions modulate neurotrophin-mediated neurite outgrowth and pathfinding

    PubMed Central

    Madl, Christopher M.; Heilshorn, Sarah C.

    2015-01-01

    Both matrix biochemistry and neurotrophic factors are known to modulate neurite outgrowth and pathfinding; however, the interplay between these two factors is less studied. While previous work has shown that the biochemical identity of the matrix can alter the outgrowth of neurites in response to neurotrophins, the importance of the concentration of cell-adhesive ligands is unknown. Using engineered elastin-like protein matrices, we recently demonstrated a synergistic effect between matrix-bound cell-adhesive ligand density and soluble nerve growth factor treatment on neurite outgrowth from dorsal root ganglia. This synergism was mediated by Schwann cell-neurite contact through L1CAM. Cell-adhesive ligand density was also shown to alter the pathfinding behavior of dorsal root ganglion neurites in response to a gradient of nerve growth factor. While more cell-adhesive matrices promoted neurite outgrowth, less cell-adhesive matrices promoted more faithful neurite pathfinding. These studies emphasize the importance of considering both matrix biochemistry and neurotrophic factors when designing biomaterials for peripheral nerve regeneration. PMID:26170800

  17. Neural interactions in unilateral colliculus and between bilateral colliculi modulate auditory signal processing.

    PubMed

    Mei, Hui-Xian; Cheng, Liang; Chen, Qi-Cai

    2013-01-01

    In the auditory pathway, the inferior colliculus (IC) is a major center for temporal and spectral integration of auditory information. There are widespread neural interactions in unilateral (one) IC and between bilateral (two) ICs that could modulate auditory signal processing such as the amplitude and frequency selectivity of IC neurons. These neural interactions are either inhibitory or excitatory, and are mostly mediated by γ-aminobutyric acid (GABA) and glutamate, respectively. However, the majority of interactions are inhibitory while excitatory interactions are in the minority. Such unbalanced properties between excitatory and inhibitory projections have an important role in the formation of unilateral auditory dominance and sound location, and the neural interaction in one IC and between two ICs provide an adjustable and plastic modulation pattern for auditory signal processing.

  18. Neural interactions in unilateral colliculus and between bilateral colliculi modulate auditory signal processing

    PubMed Central

    Mei, Hui-Xian; Cheng, Liang; Chen, Qi-Cai

    2013-01-01

    In the auditory pathway, the inferior colliculus (IC) is a major center for temporal and spectral integration of auditory information. There are widespread neural interactions in unilateral (one) IC and between bilateral (two) ICs that could modulate auditory signal processing such as the amplitude and frequency selectivity of IC neurons. These neural interactions are either inhibitory or excitatory, and are mostly mediated by γ-aminobutyric acid (GABA) and glutamate, respectively. However, the majority of interactions are inhibitory while excitatory interactions are in the minority. Such unbalanced properties between excitatory and inhibitory projections have an important role in the formation of unilateral auditory dominance and sound location, and the neural interaction in one IC and between two ICs provide an adjustable and plastic modulation pattern for auditory signal processing. PMID:23626523

  19. Visual anticipatory information modulates multisensory interactions of artificial audiovisual stimuli.

    PubMed

    Vroomen, Jean; Stekelenburg, Jeroen J

    2010-07-01

    The neural activity of speech sound processing (the N1 component of the auditory ERP) can be suppressed if a speech sound is accompanied by concordant lip movements. Here we demonstrate that this audiovisual interaction is neither speech specific nor linked to humanlike actions but can be observed with artificial stimuli if their timing is made predictable. In Experiment 1, a pure tone synchronized with a deformation of a rectangle induced a smaller auditory N1 than auditory-only presentations if the temporal occurrence of this audiovisual event was made predictable by two moving disks that touched the rectangle. Local autoregressive average source estimation indicated that this audiovisual interaction may be related to integrative processing in auditory areas. When the moving disks did not precede the audiovisual stimulus--making the onset unpredictable--there was no N1 reduction. In Experiment 2, the predictability of the leading visual signal was manipulated by introducing a temporal asynchrony between the audiovisual event and the collision of moving disks. Audiovisual events occurred either at the moment, before (too "early"), or after (too "late") the disks collided on the rectangle. When asynchronies varied from trial to trial--rendering the moving disks unreliable temporal predictors of the audiovisual event--the N1 reduction was abolished. These results demonstrate that the N1 suppression is induced by visual information that both precedes and reliably predicts audiovisual onset, without a necessary link to human action-related neural mechanisms.

  20. T Cell Motility as Modulator of Interactions with Dendritic Cells

    PubMed Central

    Stein, Jens V.

    2015-01-01

    It is well established that the balance of costimulatory and inhibitory signals during interactions with dendritic cells (DCs) determines T cell transition from a naïve to an activated or tolerant/anergic status. Although many of these molecular interactions are well reproduced in reductionist in vitro assays, the highly dynamic motility of naïve T cells in lymphoid tissue acts as an additional lever to fine-tune their activation threshold. T cell detachment from DCs providing suboptimal stimulation allows them to search for DCs with higher levels of stimulatory signals, while storing a transient memory of short encounters. In turn, adhesion of weakly reactive T cells to DCs presenting peptides presented on major histocompatibility complex with low affinity is prevented by lipid mediators. Finally, controlled recruitment of CD8+ T cells to cognate DC–CD4+ T cell clusters shapes memory T cell formation and the quality of the immune response. Dynamic physiological lymphocyte motility therefore constitutes a mechanism to mitigate low avidity T cell activation and to improve the search for “optimal” DCs, while contributing to peripheral tolerance induction in the absence of inflammation. PMID:26579132

  1. Foveal visual acuity is worse and shows stronger contour interaction effects for contrast-modulated than luminance-modulated Cs.

    PubMed

    Hairol, Mohd Izzuddin; Formankiewicz, Monika A; Waugh, Sarah J

    2013-05-01

    Contrast-modulated (CM) stimuli are processed by spatial mechanisms that operate at larger spatial scales than those processing luminance-modulated (LM) stimuli and may be more prone to deficits in developing, amblyopic, and aging visual systems. Understanding neural mechanisms of contour interaction or crowding will help in detecting disorders of spatial vision. In this study, contour interaction effects on visual acuity for LM and CM C and bar stimuli are assessed in normal foveal vision. In Experiment 1, visual acuity is measured for all-LM and all-CM stimuli, at ~3.5× above their respective modulation thresholds. In Experiment 2, visual acuity is measured for Cs and bars of different type (LM C with CM bars and vice versa). Visual acuity is degraded for CM compared with LM Cs (0.46 ± 0.04 logMAR vs. 0.18 ± 0.04 logMAR). With nearby bars, CM acuity is degraded further (0.23 ± 0.01 logMAR or ~2 lines on an acuity chart), significantly more than LM acuity (0.11 ± 0.01 logMAR, ~1 line). Contour interaction for CM stimuli extends over greater distances (arcmin) than it does for LM stimuli, but extents are similar with respect to acuities (~3.5× the C gap width). Contour interaction is evident when the Cs and bars are defined differently: it is stronger when an LM C is flanked by CM bars (0.17 ± 0.03 logMAR) than when a CM C is flanked by LM bars (0.08 ± 0.02 logMAR). Our results suggest that contour interaction for foveally viewed acuity stimuli involves feature integration, such that the outputs of receptive fields representing Cs and bars are combined. Contour interaction operates at LM and CM representational stages, it can occur across stage, and it is enhanced at the CM stage. Greater contour interaction for CM Cs and bars could hold value for visual acuity testing and earlier diagnosis of conditions for which crowding is important, such as in amblyopia.

  2. Engineering interactions and anyon statistics by multicolor lattice-depth modulations

    NASA Astrophysics Data System (ADS)

    Cardarelli, Lorenzo; Greschner, Sebastian; Santos, Luis

    2016-08-01

    We show that a multicolor modulation of the depth of an optical lattice allows for a flexible independent control of correlated hopping, occupation-dependent gauge fields, effective on-site interactions without Feshbach resonances, and nearest-neighbor interactions. As a result, the lattice-depth modulation opens the possibility of engineering with minimal experimental complexity a broad class of lattice models in current experiments with ultracold atoms, including Hubbard models with correlated hopping, peculiar extended models, and two-component anyon-Hubbard models.

  3. A room temperature LSO/PIN photodiode PET detector module that measures depth of interaction

    SciTech Connect

    Moses, W.W.; Derenzo, S.E.; Melcher, C.L.; Manente, R.A.

    1994-11-01

    We present measurements of a 4 element PET detector module that uses a 2{times}2 array of 3 mm square PIN photodiodes to both measure the depth of interaction (DOI) and identify the crystal of interaction. Each photodiode is coupled to one end of a 3{times}3{times}25 mm LSO crystal, with the opposite ends of all 4 crystals attached to a single PMT that provides a timing signal and initial energy discrimination. Each LSO crystal is coated with a {open_quotes}lossy{close_quotes} reflector, so the ratio of light detected in the photodiode and PMT depends on the position of interaction in the crystal, and is used to determine this position on an event by event basis. This module is operated at +25{degrees}C with a photodiode amplifier peaking time of 2 {mu}s. When excited by a collimated beam of 511 keV photons at the photodiode end of the module (i.e. closest to the patient), the DOI resolution is 4 mm fwhm and the crystal of interaction is identified correctly 95% of the time. When excited at the opposite end of the module, the DOI resolution is 13 mm fwhm and the crystal of interaction is identified correctly 73% of the time. The channel to channel variations in performance are minimal.

  4. Surface charge interactions of the FMN module govern catalysis by nitric-oxide synthase.

    PubMed

    Panda, Koustubh; Haque, Mohammad Mahfuzul; Garcin-Hosfield, Elsa D; Durra, Deborah; Getzoff, Elizabeth D; Stuehr, Dennis J

    2006-12-01

    The FMN module of nitric-oxide synthase (NOS) plays a pivotal role by transferring NADPH-derived electrons to the enzyme heme for use in oxygen activation. The process may involve a swinging mechanism in which the same face of the FMN module accepts and provides electrons during catalysis. Crystal structure shows that this face of the FMN module is electronegative, whereas the complementary interacting surface is electropositive, implying that charge interactions enable function. We used site-directed mutagenesis to investigate the roles of six electronegative surface residues of the FMN module in electron transfer and catalysis in neuronal NOS. Results are interpreted in light of crystal structures of NOS and related flavoproteins. Neutralizing or reversing the negative charge of each residue altered the NO synthesis, NADPH oxidase, and cytochrome c reductase activities of neuronal NOS and also altered heme reduction. The largest effects occurred at the NOS-specific charged residue Glu(762). Together, the results suggest that electrostatic interactions of the FMN module help to regulate electron transfer and to minimize flavin autoxidation and the generation of reactive oxygen species during NOS catalysis. PMID:17001078

  5. Interaction of frequency-modulated light beams in multistage parametric amplifiers at the maximum gain bandwidth

    SciTech Connect

    Vlasov, Sergei N; Koposova, E V; Freidman, Gennadii I

    2009-05-31

    Conditions of the applicability of equations in the quasi-static approximation for studying the parametric interaction of frequency-modulated light beams in multistage amplifiers are considered. This approximation is used to simulate numerically processes in a multistage DKDP crystal amplifier with the output power exceeding 10 PW and suppressed luminescence. (lasers and amplifiers)

  6. Apollo program soil mechanics experiment. [interaction of the lunar module with the lunar surface

    NASA Technical Reports Server (NTRS)

    Scott, R. F.

    1975-01-01

    The soil mechanics investigation was conducted to obtain information relating to the landing interaction of the lunar module (LM) with the lunar surface, and lunar soil erosion caused by the spacecraft engine exhaust. Results obtained by study of LM landing performance on each Apollo mission are summarized.

  7. The Goals and Development of an Interactive Web Module for a Teacher Education Course.

    ERIC Educational Resources Information Center

    Schnorr, Donna; Bracken, Nicole; Hazari, Sunil

    The World Wide Web has become a promising medium for delivery of instruction. This paper describes a case study in which the Internet was used to supplement teacher education course instruction via an Interactive Web module. The goals of using such a medium for facilitating teaching and enhancing learning are described as they relate to learning…

  8. Exploring Space Science Concepts using Interactive Animations and Learning Modules (Invited)

    NASA Astrophysics Data System (ADS)

    Hallau, K.

    2009-12-01

    Many concepts in the planetary sciences can be difficult to teach using traditional or laboratory methods, but interactive media may provide unique opportunities to explore these. Such “interactives” can engage the user by allowing them to manipulate variables, view multiple trials in succession, and explore sophisticated conceptual information within a dynamic graphical interface. In formal educational settings, interactives accompanied by student data sheets can be used to foster and evaluate learning. At Montana State University’s Extended University we have developed interactive animations using Flash® to explore concepts such as gravity assist maneuvers and spin-orbit resonance as part of the education and public outreach efforts for NASA’s MESSENGER and New Horizons missions (to Mercury and Pluto, respectively). Some of theses interactives are paired with standards-based hands-on classroom activities. Here we will demonstrate several interactives and accompanying learning modules.

  9. Rational optimization of the DSL ligase ribozyme with GNRA/receptor interacting modules.

    PubMed

    Ishikawa, Junya; Matsumura, Shigeyoshi; Jaeger, Luc; Inoue, Tan; Furuta, Hiroyuki; Ikawa, Yoshiya

    2009-10-15

    The DSL ribozyme is a class of artificial ligase ribozymes with a highly modular architecture, which catalyzes template-directed RNA ligation on a helical substrate module that can be either covalently connected (cis-DSL) or physically separated (trans-DSL) from the catalytic module. Substrate recognition by the catalytic module is promoted by one or two sets of GNRA/receptor interactions acting as clamps in the cis or trans configurations, respectively. In this study, we have rationally designed and analyzed the catalytic and self-assembly properties of several trans-DSL ribozymes with different sets of natural and artificial GNRA-receptor clamps. Two variants newly designed in this study showed significantly enhanced catalytic properties with respect of the original trans-DSL construct. While this work allows dissection of the turnover and catalytic properties of the trans-DSL ribozyme, it also emphasizes the remarkable modularity of RNA tertiary structure for nano-construction of complex functions.

  10. Immunobiotic lactobacilli reduce viral-associated pulmonary damage through the modulation of inflammation-coagulation interactions.

    PubMed

    Zelaya, Hortensia; Tsukida, Kohichiro; Chiba, Eriko; Marranzino, Gabriela; Alvarez, Susana; Kitazawa, Haruki; Agüero, Graciela; Villena, Julio

    2014-03-01

    The exacerbated disease due to immune- and coagulative-mediated pulmonary injury during acute respiratory viruses infection results in severe morbidity and mortality. Identifying novel approaches to modulate virus-induced inflammation-coagulation interactions could be important alternatives for treating acute respiratory viruses infections. In this study we investigated the effect of the probiotic strain Lactobacillus rhamnosus CRL1505 on lung TLR3-mediated inflammation, and its ability to modulate inflammation-coagulation interaction during respiratory viral infection. Our findings reveal for the first time that a probiotic bacterium is able to influence lung immune-coagulative reaction triggered by TLR3 activation, by modulating the production of proinflammatory and anti-inflammatory cytokines as well as expression of tissue factor and thrombomodulin in the lung. We also demonstrated that the preventive treatment with the probiotic bacteria beneficially modulates the fine tune balance between clearing respiratory viruses (respiratory syncytial virus and influenza virus) and controlling immune-coagulative responses in the lung, allowing normal lung function to be maintained in the face of a viral attack. Our data also pinpoint a crucial role for IL-10 in the immune protection induced by L. rhamnosus CRL1505 during respiratory viral infections. These observations might be helpful to propose new preventive or therapeutic approaches to better control virus-inflammatory lung damage using probiotic functional foods.

  11. Bilateral Collicular Interaction: Modulation of Auditory Signal Processing in Amplitude Domain

    PubMed Central

    Fu, Zi-Ying; Wang, Xin; Jen, Philip H.-S.; Chen, Qi-Cai

    2012-01-01

    In the ascending auditory pathway, the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from many lower auditory nuclei, intrinsic projections within the IC, contralateral IC through the commissure of the IC and from the auditory cortex. All these connections make the IC a major center for subcortical temporal and spectral integration of auditory information. In this study, we examine bilateral collicular interaction in modulating amplitude-domain signal processing using electrophysiological recording, acoustic and focal electrical stimulation. Focal electrical stimulation of one (ipsilateral) IC produces widespread inhibition (61.6%) and focused facilitation (9.1%) of responses of neurons in the other (contralateral) IC, while 29.3% of the neurons were not affected. Bilateral collicular interaction produces a decrease in the response magnitude and an increase in the response latency of inhibited IC neurons but produces opposite effects on the response of facilitated IC neurons. These two groups of neurons are not separately located and are tonotopically organized within the IC. The modulation effect is most effective at low sound level and is dependent upon the interval between the acoustic and electric stimuli. The focal electrical stimulation of the ipsilateral IC compresses or expands the rate-level functions of contralateral IC neurons. The focal electrical stimulation also produces a shift in the minimum threshold and dynamic range of contralateral IC neurons for as long as 150 minutes. The degree of bilateral collicular interaction is dependent upon the difference in the best frequency between the electrically stimulated IC neurons and modulated IC neurons. These data suggest that bilateral collicular interaction mainly changes the ratio between excitation and inhibition during signal processing so as to sharpen the amplitude sensitivity of IC neurons. Bilateral interaction may be also involved in acoustic

  12. Interaction between ketopantolactone and chirally modified Pt investigated by attenuated total reflection IR concentration modulation spectroscopy.

    PubMed

    Bonalumi, Norberto; Bürgi, Thomas; Baiker, Alfons

    2003-11-01

    The combination of ATR-IR and modulation spectroscopy allowed for the study of the interaction of ketopantolactone with Pt/Al2O3 films chirally modified by cinchonidine under hydrogenation conditions. The spectra reveal a significant influence of ketopantolactone on the adsorption of the modifier and indicate a N-H-O hydrogen bond between modifier and reactant. The latter was corroborated by a comparative study with N-methyl cinchonidine chloride modified Pt/Al2O3.

  13. Transitive closure and metric inequality of weighted graphs:detecting protein interaction modules using cliques

    SciTech Connect

    Ding, Chris; He, Xiaofeng; Xiong, Hui; Peng, Hanchuan; Holbrook,Stephen R.

    2006-06-02

    We study transitivity properties of edge weights in complex networks. We show that enforcing transitivity leads to a transitivity inequality which is equivalent to ultra-metric inequality. This can be used to define transitive closure on weighted undirected graphs, which can be computed using a modified Floyd-Warshall algorithm. We outline several applications and present results of detecting protein functional modules in a protein interaction network.

  14. How biologically relevant are interaction-based modules in protein networks?

    PubMed Central

    Poyatos, Juan F; Hurst, Laurence D

    2004-01-01

    By applying a graph-based algorithm to yeast protein-interaction networks we have extracted modular structures and show that they can be validated using information from the phylogenetic conservation of the network components. We show that the module cores, the parts with the highest intramodular connectivity, are biologically relevant components of the networks. These constituents correlate only weakly with other levels of organization. We also discuss how such structures could be used for finding targets for antimicrobial drugs. PMID:15535869

  15. Fast Quantum Nondemolition Readout by Parametric Modulation of Longitudinal Qubit-Oscillator Interaction.

    PubMed

    Didier, Nicolas; Bourassa, Jérôme; Blais, Alexandre

    2015-11-13

    We show how to realize fast and high-fidelity quantum nondemolition qubit readout using longitudinal qubit-oscillator interaction. This is accomplished by modulating the longitudinal coupling at the cavity frequency. The qubit-oscillator interaction then acts as a qubit-state dependent drive on the cavity, a situation that is fundamentally different from the standard dispersive case. Single-mode squeezing can be exploited to exponentially increase the signal-to-noise ratio of this readout protocol. We present an implementation of this longitudinal parametric readout in circuit quantum electrodynamics and a possible multiqubit architecture. PMID:26613438

  16. Fast Quantum Nondemolition Readout by Parametric Modulation of Longitudinal Qubit-Oscillator Interaction.

    PubMed

    Didier, Nicolas; Bourassa, Jérôme; Blais, Alexandre

    2015-11-13

    We show how to realize fast and high-fidelity quantum nondemolition qubit readout using longitudinal qubit-oscillator interaction. This is accomplished by modulating the longitudinal coupling at the cavity frequency. The qubit-oscillator interaction then acts as a qubit-state dependent drive on the cavity, a situation that is fundamentally different from the standard dispersive case. Single-mode squeezing can be exploited to exponentially increase the signal-to-noise ratio of this readout protocol. We present an implementation of this longitudinal parametric readout in circuit quantum electrodynamics and a possible multiqubit architecture.

  17. Few-boson tunneling in a double well with spatially modulated interaction

    SciTech Connect

    Chatterjee, Budhaditya; Brouzos, Ioannis; Schmelcher, Peter; Zoellner, Sascha

    2010-10-15

    We study few-boson tunneling in a one-dimensional double well with a spatially modulated interaction. The dynamics changes from Rabi oscillations in the noninteracting case to a highly suppressed tunneling for intermediate coupling strengths followed by a reappearance near the fermionization limit. With extreme interaction inhomogeneity in the regime of strong correlations, we observe tunneling between the higher bands. The dynamics is explained on the basis of the few-body spectrum and stationary eigenstates. For a higher number of particles N{>=}3, it is shown that the inhomogeneity of the interaction can be tuned to generate tunneling resonances. Finally, a tilted double well and its interplay with the interaction asymmetry are discussed.

  18. PIPE: a protein–protein interaction passage extraction module for BioCreative challenge

    PubMed Central

    Chu, Chun-Han; Su, Yu-Chen; Chen, Chien Chin; Hsu, Wen-Lian

    2016-01-01

    Identifying the interactions between proteins mentioned in biomedical literatures is one of the frequently discussed topics of text mining in the life science field. In this article, we propose PIPE, an interaction pattern generation module used in the Collaborative Biocurator Assistant Task at BioCreative V (http://www.biocreative.org/) to capture frequent protein-protein interaction (PPI) patterns within text. We also present an interaction pattern tree (IPT) kernel method that integrates the PPI patterns with convolution tree kernel (CTK) to extract PPIs. Methods were evaluated on LLL, IEPA, HPRD50, AIMed and BioInfer corpora using cross-validation, cross-learning and cross-corpus evaluation. Empirical evaluations demonstrate that our method is effective and outperforms several well-known PPI extraction methods. Database URL: PMID:27524807

  19. PIPE: a protein-protein interaction passage extraction module for BioCreative challenge.

    PubMed

    Chang, Yung-Chun; Chu, Chun-Han; Su, Yu-Chen; Chen, Chien Chin; Hsu, Wen-Lian

    2016-01-01

    Identifying the interactions between proteins mentioned in biomedical literatures is one of the frequently discussed topics of text mining in the life science field. In this article, we propose PIPE, an interaction pattern generation module used in the Collaborative Biocurator Assistant Task at BioCreative V (http://www.biocreative.org/) to capture frequent protein-protein interaction (PPI) patterns within text. We also present an interaction pattern tree (IPT) kernel method that integrates the PPI patterns with convolution tree kernel (CTK) to extract PPIs. Methods were evaluated on LLL, IEPA, HPRD50, AIMed and BioInfer corpora using cross-validation, cross-learning and cross-corpus evaluation. Empirical evaluations demonstrate that our method is effective and outperforms several well-known PPI extraction methods. DATABASE URL. PMID:27524807

  20. Transcriptional modulation of enterotoxigenic Escherichia coli virulence genes in response to epithelial cell interactions.

    PubMed

    Kansal, Rita; Rasko, David A; Sahl, Jason W; Munson, George P; Roy, Koushik; Luo, Qingwei; Sheikh, Alaullah; Kuhne, Kurt J; Fleckenstein, James M

    2013-01-01

    Enterotoxigenic Escherichia coli (ETEC) strains are a leading cause of morbidity and mortality due to diarrheal illness in developing countries. There is currently no effective vaccine against these important pathogens. Because genes modulated by pathogen-host interactions potentially encode putative vaccine targets, we investigated changes in gene expression and surface morphology of ETEC upon interaction with intestinal epithelial cells in vitro. Pan-genome microarrays, quantitative reverse transcriptase PCR (qRT-PCR), and transcriptional reporter fusions of selected promoters were used to study changes in ETEC transcriptomes. Flow cytometry, immunofluorescence microscopy, and scanning electron microscopy were used to investigate alterations in surface antigen expression and morphology following pathogen-host interactions. Following host cell contact, genes for motility, adhesion, toxin production, immunodominant peptides, and key regulatory molecules, including cyclic AMP (cAMP) receptor protein (CRP) and c-di-GMP, were substantially modulated. These changes were accompanied by visible changes in both ETEC architecture and the expression of surface antigens, including a novel highly conserved adhesin molecule, EaeH. The studies reported here suggest that pathogen-host interactions are finely orchestrated by ETEC and are characterized by coordinated responses involving the sequential deployment of multiple virulence molecules. Elucidation of the molecular details of these interactions could highlight novel strategies for development of vaccines for these important pathogens. PMID:23115039

  1. Divergent modulation of Src-family kinase regulatory interactions with ATP-competitive inhibitors.

    PubMed

    Leonard, Stephen E; Register, A C; Krishnamurty, Ratika; Brighty, Gabriel J; Maly, Dustin J

    2014-08-15

    Multidomain protein kinases, central controllers of signal transduction, use regulatory domains to modulate catalytic activity in a complex cellular environment. Additionally, these domains regulate noncatalytic functions, including cellular localization and protein-protein interactions. Src-family kinases (SFKs) are promising therapeutic targets for a number of diseases and are an excellent model for studying the regulation of multidomain kinases. Here, we demonstrate that the regulatory domains of the SFKs Src and Hck are divergently affected by ligands that stabilize two distinct inactive ATP-binding site conformations. Conformation-selective, ATP-competitive inhibitors differentially modulate the ability of the SH3 and SH2 domains of Src and Hck to engage in intermolecular interactions and the ability of the kinase-inhibitor complex to undergo post-translational modification by effector enzymes. This surprising divergence in regulatory domain behavior by two classes of inhibitors that each stabilize inactive ATP-binding site conformations is found to occur through perturbation or stabilization of the αC helix. These studies provide insight into how conformation-selective, ATP-competitive inhibitors can be designed to modulate domain interactions and post-translational modifications distal to the ATP-binding site of kinases.

  2. TNF Superfamily Protein–Protein Interactions: Feasibility of Small-Molecule Modulation

    PubMed Central

    Song, Yun; Buchwald, Peter

    2015-01-01

    The tumor necrosis factor (TNF) superfamily (TNFSF) contains about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Almost all of these cell surface protein-protein interactions (PPIs) represent high-value therapeutic targets for inflammatory or immune modulation in autoimmune diseases, transplant recipients, or cancers, and there are several biologics including antibodies and fusion proteins targeting them that are in various phases of clinical development. Small-molecule inhibitors or activators could represent possible alternatives if the difficulties related to the targeting of protein-protein interactions by small molecules can be addressed. Compounds proving the feasibility of such approaches have been identified through different drug discovery approaches for a number of these TNFSFR-TNFSF type PPIs including CD40-CD40L, BAFFR-BAFF, TRAIL-DR5, and OX40-OX40L. Corresponding structural, signaling, and medicinal chemistry aspects are briefly reviewed here. While none of these small-molecule modulators identified so far seems promising enough to be pursued for clinical development, they provide proof-of-principle evidence that these interactions are susceptible to small-molecule modulation and can serve as starting points toward the identification of more potent and selective candidates. PMID:25706111

  3. Ingroup favoritism or the black sheep effect: Perceived intentions modulate subjective responses to aggressive interactions.

    PubMed

    Wang, Lei; Zheng, Jiehui; Meng, Liang; Lu, Qiang; Ma, Qingguo

    2016-07-01

    Social categorization plays an important role in provoking the victim's responses to aggressive interactions. Pioneering studies suggested that uncertainty in the perpetrator's hostile intention influences whether ingroup favoritism or the black sheep effect (ingroup strictness) will be manifested to a greater extent. However, when the hostile intention is ambiguous, subjective perception of the perpetrator's intention may still be quite different due to the inherent information gap between participants, and this discrepancy in perceived intentions may further modulate subjective responses to social aggression. In the present study, subjects played as responders of the Ultimatum Game, and received varied offers proposed by either ingroup or outgroup members. Electrophysiological results showed that, when proposers were perceived to be intentional, unfair offers from ingroups elicited significantly larger Feedback-related Negativity (FRN) than those from outgroups, potentially providing neural evidence for the black sheep effect. The opposite FRN pattern was observed when proposers were perceived to be unintentional, which might suggest ingroup favoritism. Interestingly, despite contrary neural patterns, perceived intentions did not modulate behavioral response to aggressive interactions. Thus, converging results suggested that, when the perpetrator's hostile intention remained ambiguous, perceived intentions modulated the victim's electrophysiological response while not the rational behavioral response to aggressive interactions. PMID:26851770

  4. Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution

    PubMed Central

    Merkulova, Maria; Hurtado-Lorenzo, Andrés; Hosokawa, Hiroyuki; Zhuang, Zhenjie; Brown, Dennis; Ausiello, Dennis A.

    2011-01-01

    Previously, we demonstrated that the vacuolar-type H+-ATPase (V-ATPase) a2-subunit functions as an endosomal pH sensor that interacts with the ADP-ribosylation factor (Arf) guanine nucleotide exchange factor, ARNO. In the present study, we showed that ARNO directly interacts not only with the a2-subunit but with all a-isoforms (a1–a4) of the V-ATPase, indicating a widespread regulatory interaction between V-ATPase and Arf GTPases. We then extended our search for other ARNO effectors that may modulate V-ATPase-dependent vesicular trafficking events and actin cytoskeleton remodeling. Pull-down experiments using cytosol of mouse proximal tubule cells (MTCs) showed that ARNO interacts with aldolase, but not with other enzymes of the glycolytic pathway. Direct interaction of aldolase with the pleckstrin homology domain of ARNO was revealed by pull-down assays using recombinant proteins, and surface plasmon resonance revealed their high avidity interaction with a dissociation constant: KD = 2.84 × 10−10 M. MTC cell fractionation revealed that aldolase is also associated with membranes of early endosomes. Functionally, aldolase knockdown in HeLa cells produced striking morphological changes accompanied by long filamentous cell protrusions and acidic vesicle redistribution. However, the 50% knockdown we achieved did not modulate the acidification capacity of endosomal/lysosomal compartments. Finally, a combination of small interfering RNA knockdown and overexpression revealed that the expression of aldolase is inversely correlated with gelsolin levels in HeLa cells. In summary, we have shown that aldolase forms a complex with ARNO/Arf6 and the V-ATPase and that it may contribute to remodeling of the actin cytoskeleton and/or the trafficking and redistribution of V-ATPase-dependent acidic compartments via a combination of protein-protein interaction and gene expression mechanisms. PMID:21307348

  5. Molecular tweezers modulate 14-3-3 protein-protein interactions.

    PubMed

    Bier, David; Rose, Rolf; Bravo-Rodriguez, Kenny; Bartel, Maria; Ramirez-Anguita, Juan Manuel; Dutt, Som; Wilch, Constanze; Klärner, Frank-Gerrit; Sanchez-Garcia, Elsa; Schrader, Thomas; Ottmann, Christian

    2013-03-01

    Supramolecular chemistry has recently emerged as a promising way to modulate protein functions, but devising molecules that will interact with a protein in the desired manner is difficult as many competing interactions exist in a biological environment (with solvents, salts or different sites for the target biomolecule). We now show that lysine-specific molecular tweezers bind to a 14-3-3 adapter protein and modulate its interaction with partner proteins. The tweezers inhibit binding between the 14-3-3 protein and two partner proteins--a phosphorylated (C-Raf) protein and an unphosphorylated one (ExoS)--in a concentration-dependent manner. Protein crystallography shows that this effect arises from the binding of the tweezers to a single surface-exposed lysine (Lys214) of the 14-3-3 protein in the proximity of its central channel, which normally binds the partner proteins. A combination of structural analysis and computer simulations provides rules for the tweezers' binding preferences, thus allowing us to predict their influence on this type of protein-protein interactions. PMID:23422566

  6. Sensitivity to abscisic acid modulates positive interactions between Arabidopsis thaliana individuals.

    PubMed

    Zhang, Hao; Shen, Zhuxia; Wang, Genxuan; Dai, Xinfeng; Huang, Qiaoqiao; Zheng, Kefeng

    2010-03-01

    The ability of abscisic acid (ABA) to modulate positive interactions between Arabidopsis thaliana individuals under salinity stress was investigated using abi1-1 (insensitive to ABA), era1-2 (hypersensitive to ABA) mutant and wild type plants. The results showed that sensitivity to ABA affects relative interaction intensity (RII) between Arabidopsis thaliana individuals. The neighbor removal experiments also confirmed the role of phenotypic responses in linking plant-plant interactions and sensitivity to ABA. For abi1-1 mutants, the absolute value differences between neighbor removal and control of stem length, root length, leaf area, leaf thickness, flower density, above biomass/belowground biomass (A/U), photosynthetic rate, stomatal conductance, leaf water content and water-use efficiency were smaller than those of the wild type, while for era1-2 mutants, these absolute value differences were larger than those of the wild type. Thus, it is suggested that positive interactions between Arabidopsis thaliana individuals are at least partly modulated by different sensitivity to ABA through different physiological and phenotypic plasticity. PMID:20377695

  7. Bilateral collicular interaction: modulation of auditory signal processing in frequency domain.

    PubMed

    Cheng, L; Mei, H-X; Tang, J; Fu, Z-Y; Jen, P H-S; Chen, Q-C

    2013-04-01

    In the ascending auditory pathway, the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from a variety of lower auditory nuclei, intrinsic projections within the IC, contralateral IC through the commissure of the IC and the auditory cortex. All these connections make the IC a major center for subcortical temporal and spectral integration of auditory information. In this study, we examine bilateral collicular interaction in the modulation of frequency-domain signal processing of mice using electrophysiological recording and focal electrical stimulation. Focal electrical stimulation of neurons in one IC produces widespread inhibition and focused facilitation of responses of neurons in the other IC. This bilateral collicular interaction decreases the response magnitude and lengthens the response latency of inhibited IC neurons but produces an opposite effect on the response of facilitated IC neurons. In the frequency domain, the focal electrical stimulation of one IC sharpens or expands the frequency tuning curves (FTCs) of neurons in the other IC to improve frequency sensitivity and the frequency response range. The focal electrical stimulation also produces a shift in the best frequency (BF) of modulated IC (ICMdu) neurons toward that of electrically stimulated IC (ICES) neurons. The degree of bilateral collicular interaction is dependent upon the difference in the BF between the ICES neurons and ICMdu neurons. These data suggest that bilateral collicular interaction is a part of dynamic acoustic signal processing that adjusts and improves signal processing as well as reorganizes collicular representation of signal parameters according to the acoustic experience.

  8. Biotic Interactions in Microbial Communities as Modulators of Biogeochemical Processes: Methanotrophy as a Model System

    PubMed Central

    Ho, Adrian; Angel, Roey; Veraart, Annelies J.; Daebeler, Anne; Jia, Zhongjun; Kim, Sang Yoon; Kerckhof, Frederiek-Maarten; Boon, Nico; Bodelier, Paul L. E.

    2016-01-01

    Microbial interaction is an integral component of microbial ecology studies, yet the role, extent, and relevance of microbial interaction in community functioning remains unclear, particularly in the context of global biogeochemical cycles. While many studies have shed light on the physico-chemical cues affecting specific processes, (micro)biotic controls and interactions potentially steering microbial communities leading to altered functioning are less known. Yet, recent accumulating evidence suggests that the concerted actions of a community can be significantly different from the combined effects of individual microorganisms, giving rise to emergent properties. Here, we exemplify the importance of microbial interaction for ecosystem processes by analysis of a reasonably well-understood microbial guild, namely, aerobic methane-oxidizing bacteria (MOB). We reviewed the literature which provided compelling evidence for the relevance of microbial interaction in modulating methane oxidation. Support for microbial associations within methane-fed communities is sought by a re-analysis of literature data derived from stable isotope probing studies of various complex environmental settings. Putative positive interactions between active MOB and other microbes were assessed by a correlation network-based analysis with datasets covering diverse environments where closely interacting members of a consortium can potentially alter the methane oxidation activity. Although, methanotrophy is used as a model system, the fundamentals of our postulations may be applicable to other microbial guilds mediating other biogeochemical processes.

  9. Biotic Interactions in Microbial Communities as Modulators of Biogeochemical Processes: Methanotrophy as a Model System

    PubMed Central

    Ho, Adrian; Angel, Roey; Veraart, Annelies J.; Daebeler, Anne; Jia, Zhongjun; Kim, Sang Yoon; Kerckhof, Frederiek-Maarten; Boon, Nico; Bodelier, Paul L. E.

    2016-01-01

    Microbial interaction is an integral component of microbial ecology studies, yet the role, extent, and relevance of microbial interaction in community functioning remains unclear, particularly in the context of global biogeochemical cycles. While many studies have shed light on the physico-chemical cues affecting specific processes, (micro)biotic controls and interactions potentially steering microbial communities leading to altered functioning are less known. Yet, recent accumulating evidence suggests that the concerted actions of a community can be significantly different from the combined effects of individual microorganisms, giving rise to emergent properties. Here, we exemplify the importance of microbial interaction for ecosystem processes by analysis of a reasonably well-understood microbial guild, namely, aerobic methane-oxidizing bacteria (MOB). We reviewed the literature which provided compelling evidence for the relevance of microbial interaction in modulating methane oxidation. Support for microbial associations within methane-fed communities is sought by a re-analysis of literature data derived from stable isotope probing studies of various complex environmental settings. Putative positive interactions between active MOB and other microbes were assessed by a correlation network-based analysis with datasets covering diverse environments where closely interacting members of a consortium can potentially alter the methane oxidation activity. Although, methanotrophy is used as a model system, the fundamentals of our postulations may be applicable to other microbial guilds mediating other biogeochemical processes. PMID:27602021

  10. Biotic Interactions in Microbial Communities as Modulators of Biogeochemical Processes: Methanotrophy as a Model System.

    PubMed

    Ho, Adrian; Angel, Roey; Veraart, Annelies J; Daebeler, Anne; Jia, Zhongjun; Kim, Sang Yoon; Kerckhof, Frederiek-Maarten; Boon, Nico; Bodelier, Paul L E

    2016-01-01

    Microbial interaction is an integral component of microbial ecology studies, yet the role, extent, and relevance of microbial interaction in community functioning remains unclear, particularly in the context of global biogeochemical cycles. While many studies have shed light on the physico-chemical cues affecting specific processes, (micro)biotic controls and interactions potentially steering microbial communities leading to altered functioning are less known. Yet, recent accumulating evidence suggests that the concerted actions of a community can be significantly different from the combined effects of individual microorganisms, giving rise to emergent properties. Here, we exemplify the importance of microbial interaction for ecosystem processes by analysis of a reasonably well-understood microbial guild, namely, aerobic methane-oxidizing bacteria (MOB). We reviewed the literature which provided compelling evidence for the relevance of microbial interaction in modulating methane oxidation. Support for microbial associations within methane-fed communities is sought by a re-analysis of literature data derived from stable isotope probing studies of various complex environmental settings. Putative positive interactions between active MOB and other microbes were assessed by a correlation network-based analysis with datasets covering diverse environments where closely interacting members of a consortium can potentially alter the methane oxidation activity. Although, methanotrophy is used as a model system, the fundamentals of our postulations may be applicable to other microbial guilds mediating other biogeochemical processes. PMID:27602021

  11. Controlling Non-Covalent Interactions to Modulate the Dispersion of Fullerenes in Polymer Nanocomposites

    SciTech Connect

    Sumpter, Bobby G

    2011-01-01

    Polymer nanocomposites (PNCs) are materials based on a class of filled plastics that contain relatively small amounts of nanoparticles, which can impart improved structural, mechanical, and thermal properties relative to the neat polymer. However, the homogeneous dispersion of the nanoparticles into a polymer matrix is critical and an impeding factor for the controlled enhancement of PNC properties. In this work, we provide new insight into the importance of polymer chain connectivity and nanoparticle shape and curvature on the formation of noncovalent electron donor-acceptor (EDA) interactions between polymers and nanoparticles. This is accomplished by experimentally monitoring the dispersion of nanoparticles in copolymers containing varying amounts of functional moieties that can form noncovalent interactions with carbon nanoparticles with corroboration through density functional calculations. The results show that the presence of a minority of interacting functional groups within a polymer chain leads to an optimum interaction between the polymer and fullerene. Density functional theory calculations that identify the binding energy and geometry of the interaction between the functional monomers and fullerenes correspond very well with the experimental results. Moreover, comparison of these results to similar studies with single-walled carbon nanotubes (SWNT) indicate a distinct difference in the ability of EDA interactions to improve the dispersion of fullerenes relative to their impact on SWNT. Thus, the polymer chain connectivity, the polymer chain conformation, and size and shape of the nanoparticle modulate the formation of intermolecular interactions and directly impact the dispersion of the resultant nanocomposite.

  12. Biotic Interactions in Microbial Communities as Modulators of Biogeochemical Processes: Methanotrophy as a Model System.

    PubMed

    Ho, Adrian; Angel, Roey; Veraart, Annelies J; Daebeler, Anne; Jia, Zhongjun; Kim, Sang Yoon; Kerckhof, Frederiek-Maarten; Boon, Nico; Bodelier, Paul L E

    2016-01-01

    Microbial interaction is an integral component of microbial ecology studies, yet the role, extent, and relevance of microbial interaction in community functioning remains unclear, particularly in the context of global biogeochemical cycles. While many studies have shed light on the physico-chemical cues affecting specific processes, (micro)biotic controls and interactions potentially steering microbial communities leading to altered functioning are less known. Yet, recent accumulating evidence suggests that the concerted actions of a community can be significantly different from the combined effects of individual microorganisms, giving rise to emergent properties. Here, we exemplify the importance of microbial interaction for ecosystem processes by analysis of a reasonably well-understood microbial guild, namely, aerobic methane-oxidizing bacteria (MOB). We reviewed the literature which provided compelling evidence for the relevance of microbial interaction in modulating methane oxidation. Support for microbial associations within methane-fed communities is sought by a re-analysis of literature data derived from stable isotope probing studies of various complex environmental settings. Putative positive interactions between active MOB and other microbes were assessed by a correlation network-based analysis with datasets covering diverse environments where closely interacting members of a consortium can potentially alter the methane oxidation activity. Although, methanotrophy is used as a model system, the fundamentals of our postulations may be applicable to other microbial guilds mediating other biogeochemical processes.

  13. Online interactive teaching modules enhance quantitative proficiency of introductory biology students.

    PubMed

    Thompson, Katerina V; Nelson, Kären C; Marbach-Ad, Gili; Keller, Michael; Fagan, William F

    2010-01-01

    There is widespread agreement within the scientific and education communities that undergraduate biology curricula fall short in providing students with the quantitative and interdisciplinary problem-solving skills they need to obtain a deep understanding of biological phenomena and be prepared fully to contribute to future scientific inquiry. MathBench Biology Modules were designed to address these needs through a series of interactive, Web-based modules that can be used to supplement existing course content across the biological sciences curriculum. The effect of the modules was assessed in an introductory biology course at the University of Maryland. Over the course of the semester, students showed significant increases in quantitative skills that were independent of previous math course work. Students also showed increased comfort with solving quantitative problems, whether or not they ultimately arrived at the correct answer. A survey of spring 2009 graduates indicated that those who had experienced MathBench in their course work had a greater appreciation for the role of mathematics in modern biology than those who had not used MathBench. MathBench modules allow students from diverse educational backgrounds to hone their quantitative skills, preparing them for more complex mathematical approaches in upper-division courses. PMID:20810959

  14. Numerical study of particle-vortex interaction and turbulence modulation in swirling jets.

    PubMed

    Gui, Nan; Fan, Jianren; Chen, Song

    2010-11-01

    This study carried out a direct numerical simulation of gas-solid swirling jet flow, focusing on the particle-vortex interaction and mechanisms of turbulence modulation. Two cases of flows with either a constant particle flow rate or a constant particle mass loading are simulated. The typical instantaneous particle-vortex interactions are illustrated and analyzed, as well as the spectrum representations and the projections of them. The results show that the small particles (St<1) and light-mass loadings augment the vortices of the large-scale range in the power spectrum representation by shifting the peaks of wave numbers from small to large values as they pass through the large vortices and break them into smaller scales. The large particles and heavy-mass loadings suppress greatly the large scales of vortices, transferring the turbulent kinetic energy from large to relatively smaller scales of vortices, resulting in turbulence augmentation in the large wave numbers and turbulence attenuation in the range of small wave numbers. Moreover, by comparison between the two cases, it is found that the turbulence modulation is more highly sensitive to the effect of mass loadings rather than the dynamical response property of particles. The well-known knowledge on modulation of turbulence is true under the condition of the same mass loading. However, the situation becomes very complicated when the mass loading changes. Finally, these conclusions are verified by the analysis of energy spectrum and dissipation.

  15. MicroRNAs Modulate Interactions between Stress and Risk for Cocaine Addiction.

    PubMed

    Doura, Menahem B; Unterwald, Ellen M

    2016-01-01

    Exposure to stress increases vulnerability to drug abuse, as well as relapse liability in addicted individuals. Chronic drug use alters stress response in a manner that increases drug seeking behaviors and relapse. Drug exposure and withdrawal have been shown to alter stress responses, and corticosteroid mediators of stress have been shown to impact addiction-related brain function and drug-seeking behavior. Despite the documented interplay between stress and substance abuse, the mechanisms by which stress exposure and drug seeking interact remain largely unknown. Recent studies indicate that microRNAs (miRNA) play a significant role in stress modulation as well as addiction-related processes including neurogenesis, synapse development, plasticity, drug acquisition, withdrawal and relapse. MiRNAs are short non-coding RNAs that function as bidirectional epigenetic modulators of gene expression through imperfect sequence targeted degradation and/or translational repression of mRNAs. They serve as dynamic regulators of CNS physiology and pathophysiology, and facilitate rapid and long-lasting changes to complex systems and behaviors. MiRNAs function in glucocorticoid signaling and the mesolimbic dopamine reward system, as well as mood disorders related to drug withdrawal. The literature suggests miRNAs play a pivotal role in the interaction between exposures to stress, addiction-related processes, and negative affective states resulting from extended drug withdrawal. This manuscript reviews recent evidence for the role of miRNAs in the modulation of stress and cocaine responses, and discusses potential mediation of the interaction of these systems by miRNAs. Uncovering the mechanism behind the association of stress and drug taking has the potential to impact the treatment of drug abuse and prevention of relapse. Further comprehension of these complex interactions may provide promising new targets for the treatment of drug addiction. PMID:27303265

  16. MicroRNAs Modulate Interactions between Stress and Risk for Cocaine Addiction

    PubMed Central

    Doura, Menahem B.; Unterwald, Ellen M.

    2016-01-01

    Exposure to stress increases vulnerability to drug abuse, as well as relapse liability in addicted individuals. Chronic drug use alters stress response in a manner that increases drug seeking behaviors and relapse. Drug exposure and withdrawal have been shown to alter stress responses, and corticosteroid mediators of stress have been shown to impact addiction-related brain function and drug-seeking behavior. Despite the documented interplay between stress and substance abuse, the mechanisms by which stress exposure and drug seeking interact remain largely unknown. Recent studies indicate that microRNAs (miRNA) play a significant role in stress modulation as well as addiction-related processes including neurogenesis, synapse development, plasticity, drug acquisition, withdrawal and relapse. MiRNAs are short non-coding RNAs that function as bidirectional epigenetic modulators of gene expression through imperfect sequence targeted degradation and/or translational repression of mRNAs. They serve as dynamic regulators of CNS physiology and pathophysiology, and facilitate rapid and long-lasting changes to complex systems and behaviors. MiRNAs function in glucocorticoid signaling and the mesolimbic dopamine reward system, as well as mood disorders related to drug withdrawal. The literature suggests miRNAs play a pivotal role in the interaction between exposures to stress, addiction-related processes, and negative affective states resulting from extended drug withdrawal. This manuscript reviews recent evidence for the role of miRNAs in the modulation of stress and cocaine responses, and discusses potential mediation of the interaction of these systems by miRNAs. Uncovering the mechanism behind the association of stress and drug taking has the potential to impact the treatment of drug abuse and prevention of relapse. Further comprehension of these complex interactions may provide promising new targets for the treatment of drug addiction. PMID:27303265

  17. Design of Protein-Peptide Interaction Modules for Assembling Supramolecular Structures in Vivo and in Vitro.

    PubMed

    Speltz, Elizabeth B; Nathan, Aparna; Regan, Lynne

    2015-09-18

    Synthetic biology and protein origami both require protein building blocks that behave in a reliable, predictable fashion. In particular, we require protein interaction modules with known specificity and affinity. Here, we describe three designed TRAP (Tetratricopeptide Repeat Affinity Protein)-peptide interaction pairs that are functional in vivo. We show that each TRAP binds to its cognate peptide and exhibits low cross-reactivity with the peptides bound by the other TRAPs. In addition, we demonstrate that the TRAP-peptide interactions are functional in many cellular contexts. In extensions of these designs, we show that the binding affinity of a TRAP-peptide pair can be systematically varied. The TRAP-peptide pairs we present thus represent a powerful set of new building blocks that are suitable for a variety of applications.

  18. Ionic interactions. Subnanoscale hydrophobic modulation of salt bridges in aqueous media.

    PubMed

    Chen, Shuo; Itoh, Yoshimitsu; Masuda, Takuya; Shimizu, Seishi; Zhao, Jun; Ma, Jing; Nakamura, Shugo; Okuro, Kou; Noguchi, Hidenori; Uosaki, Kohei; Aida, Takuzo

    2015-05-01

    Polar interactions such as electrostatic forces and hydrogen bonds play an essential role in biological molecular recognition. On a protein surface, polar interactions occur mostly in a hydrophobic environment because nonpolar amino acid residues cover ~75% of the protein surface. We report that ionic interactions on a hydrophobic surface are modulated by their subnanoscale distance to the surface. We developed a series of ionic head groups-appended self-assembled monolayers with C2, C6, C8, and C12 space-filling alkyl chains, which capture a dendritic guest via the formation of multiple salt bridges. The guest release upon protonolysis is progressively suppressed when its distance from the background hydrophobe changes from 1.2 (C2) to 0.2 (C12) nanometers, with an increase in salt bridge strength of ~3.9 kilocalories per mole.

  19. Mothers' multimodal information processing is modulated by multimodal interactions with their infants

    PubMed Central

    Tanaka, Yukari; Fukushima, Hirokata; Okanoya, Kazuo; Myowa-Yamakoshi, Masako

    2014-01-01

    Social learning in infancy is known to be facilitated by multimodal (e.g., visual, tactile, and verbal) cues provided by caregivers. In parallel with infants' development, recent research has revealed that maternal neural activity is altered through interaction with infants, for instance, to be sensitive to infant-directed speech (IDS). The present study investigated the effect of mother- infant multimodal interaction on maternal neural activity. Event-related potentials (ERPs) of mothers were compared to non-mothers during perception of tactile-related words primed by tactile cues. Only mothers showed ERP modulation when tactile cues were incongruent with the subsequent words, and only when the words were delivered with IDS prosody. Furthermore, the frequency of mothers' use of those words was correlated with the magnitude of ERP differentiation between congruent and incongruent stimuli presentations. These results suggest that mother-infant daily interactions enhance multimodal integration of the maternal brain in parenting contexts. PMID:25322936

  20. Ionic interactions. Subnanoscale hydrophobic modulation of salt bridges in aqueous media.

    PubMed

    Chen, Shuo; Itoh, Yoshimitsu; Masuda, Takuya; Shimizu, Seishi; Zhao, Jun; Ma, Jing; Nakamura, Shugo; Okuro, Kou; Noguchi, Hidenori; Uosaki, Kohei; Aida, Takuzo

    2015-05-01

    Polar interactions such as electrostatic forces and hydrogen bonds play an essential role in biological molecular recognition. On a protein surface, polar interactions occur mostly in a hydrophobic environment because nonpolar amino acid residues cover ~75% of the protein surface. We report that ionic interactions on a hydrophobic surface are modulated by their subnanoscale distance to the surface. We developed a series of ionic head groups-appended self-assembled monolayers with C2, C6, C8, and C12 space-filling alkyl chains, which capture a dendritic guest via the formation of multiple salt bridges. The guest release upon protonolysis is progressively suppressed when its distance from the background hydrophobe changes from 1.2 (C2) to 0.2 (C12) nanometers, with an increase in salt bridge strength of ~3.9 kilocalories per mole. PMID:25931555

  1. Structural And Mechanistic Analysis of Protein Interactions in Module 3 of the 6-Deoxyerythronolide B Synthase

    SciTech Connect

    Tang, Y.; Chen, A.Y.; Kim, C.-Y.; Cane, D.E.; Khosla, C.

    2009-06-04

    We report the 2.6 A X-ray crystal structure of a 190 kDa homodimeric fragment from module 3 of the 6-deoxyerthronolide B synthase covalently bound to the inhibitor cerulenin. The structure shows two well-organized interdomain linker regions in addition to the full-length ketosynthase (KS) and acyltransferase (AT) domains. Analysis of the substrate-binding site of the KS domain suggests that a loop region at the homodimer interface influences KS substrate specificity. We also describe a model for the interaction of the catalytic domains with the acyl carrier protein (ACP) domain. The ACP is proposed to dock within a deep cleft between the KS and AT domains, with interactions that span both the KS homodimer and AT domain. In conjunction with other recent data, our results provide atomic resolution pictures of several catalytically relevant protein interactions in this remarkable family of modular megasynthases.

  2. Spatial attention modulates center-surround interactions in macaque visual area V4

    PubMed Central

    Sundberg, Kristy A.; Mitchell, Jude F.; Reynolds, John H.

    2010-01-01

    Summary In natural viewing a visual stimulus that is the target of attention is generally surrounded by many irrelevant distracters. Stimuli falling in the receptive field surround can influence the neuronal response evoked by a stimulus appearing within the classical receptive field. Such modulation by task-irrelevant distracters may degrade the target-related neuronal signal. We therefore examined whether directing attention to a target stimulus can reduce the influence of task-irrelevant distracters on neuronal response. We find that in area V4 attention to a stimulus within a neuron’s receptive field filters out a large fraction of the suppression induced by distracters appearing in the surround. When attention is instead directed to the surround stimulus suppression is increased, thereby filtering out part of the neuronal response to the irrelevant distracter positioned within the receptive field. These findings demonstrate that attention modulates the neural mechanisms that give rise to center-surround interactions. PMID:19324003

  3. Modulated charge patterns and noise effect in a twisted DNA model with solvent interaction

    NASA Astrophysics Data System (ADS)

    Tabi, C. B.; Dang Koko, A.; Oumarou Doko, R.; Ekobena Fouda, H. P.; Kofané, T. C.

    2016-01-01

    We modify the Peyrard-Bishop-Holstein model and bring out the influence of the torsion and solvent interactions on charge transport in DNA. Through the linear stability analysis, we detect regions of instability and we compare the results with those of the standard Peyrard-Bishop-Holstein model. There are two regimes where modulated charge patterns can occur: the undertwisted and the overtwisted conformations. Numerical simulations are used to confirm our analytical predictions. Charge patterns are obtained and propagate more easily in an overwinded helix than in an underwinded one. The effects of dissipation and thermal fluctuations are also studied, which confirm the robustness of the obtained modulated patterns. On the one hand, we argue that in the absence of twisting, temperature can lead to the breaking of the hydrogen bonds between bases and prevent charges from propagating. On the other hand, when the molecule is overtwisted, the solvent and the temperature will rather enhance charge spreading patterns with random features.

  4. Interaction of dengue virus nonstructural protein 5 with Daxx modulates RANTES production

    SciTech Connect

    Khunchai, Sasiprapa; Junking, Mutita; Suttitheptumrong, Aroonroong; Yasamut, Umpa; Sawasdee, Nunghathai; Netsawang, Janjuree; Morchang, Atthapan; Chaowalit, Prapaipit; Noisakran, Sansanee; Yenchitsomanus, Pa-thai; and others

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer For the first time how DENV NS5 increases RANTES production. Black-Right-Pointing-Pointer DENV NS5 physically interacts with human Daxx. Black-Right-Pointing-Pointer Nuclear localization of NS5 is required for Daxx interaction and RANTES production. -- Abstract: Dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), caused by dengue virus (DENV) infection, are important public health problems in the tropical and subtropical regions. Abnormal hemostasis and plasma leakage are the main patho-physiological changes in DHF/DSS. A remarkably increased production of cytokines, the so called 'cytokine storm', is observed in the patients with DHF/DSS. A complex interaction between DENV proteins and the host immune response contributes to cytokine production. However, the molecular mechanism(s) by which DENV nonstructural protein 5 (NS5) mediates these responses has not been fully elucidated. In the present study, yeast two-hybrid assay was performed to identify host proteins interacting with DENV NS5 and a death-domain-associate protein (Daxx) was identified. The in vivo relevance of this interaction was suggested by co-immunoprecipitation and nuclear co-localization of these two proteins in HEK293 cells expressing DENV NS5. HEK293 cells expressing DENV NS5-K/A, which were mutated at the nuclear localization sequences (NLS), were created to assess its functional roles in nuclear translocation, Daxx interaction, and cytokine production. In the absence of NLS, DENV NS5 could neither translocate into the nucleus nor interact with Daxx to increase the DHF-associated cytokine, RANTES (CCL5) production. This work demonstrates the interaction between DENV NS5 and Daxx and the role of the interaction on the modulation of RANTES production.

  5. Community Structure Detection for Overlapping Modules through Mathematical Programming in Protein Interaction Networks

    PubMed Central

    Bennett, Laura; Kittas, Aristotelis; Liu, Songsong; Papageorgiou, Lazaros G.; Tsoka, Sophia

    2014-01-01

    Community structure detection has proven to be important in revealing the underlying properties of complex networks. The standard problem, where a partition of disjoint communities is sought, has been continually adapted to offer more realistic models of interactions in these systems. Here, a two-step procedure is outlined for exploring the concept of overlapping communities. First, a hard partition is detected by employing existing methodologies. We then propose a novel mixed integer non linear programming (MINLP) model, known as OverMod, which transforms disjoint communities to overlapping. The procedure is evaluated through its application to protein-protein interaction (PPI) networks of the rat, E. coli, yeast and human organisms. Connector nodes of hard partitions exhibit topological and functional properties indicative of their suitability as candidates for multiple module membership. OverMod identifies two types of connector nodes, inter and intra-connector, each with their own particular characteristics pertaining to their topological and functional role in the organisation of the network. Inter-connector proteins are shown to be highly conserved proteins participating in pathways that control essential cellular processes, such as proliferation, differentiation and apoptosis and their differences with intra-connectors is highlighted. Many of these proteins are shown to possess multiple roles of distinct nature through their participation in different network modules, setting them apart from proteins that are simply ‘hubs’, i.e. proteins with many interaction partners but with a more specific biochemical role. PMID:25412367

  6. An Internet-based interactive module for air emissions from fossil fuel based power generation

    SciTech Connect

    Karman, D.; O`Leary, K.; O`Reilly, S. |

    1997-12-31

    The proliferation of the Internet, Web pages and associated software tools available for developing multimedia material provides significant opportunities in training, education and information transfer. This paper will describe the development, testing and evaluation of an interactive teaching module aimed at college and university students that have previous education in thermodynamics and basic chemistry. The module is currently in development at the Department of Civil and Environmental Engineering at Carleton University with support from Environment Canada. Preliminary testing of this module is expected to begin late January. The module contains options to look at CO, CO{sub 2}, SO{sub 2} and NO{sub x} emissions associated with electric power generation in thermal stations that use coal, natural gas, crude and distillate oil. Factors governing the thermal efficiency of typical boiler systems and the thermodynamic limitations for converting heat into work are discussed. Supporting background information such as emission trends and emission factors used in calculations are also included as part of this module. A simple Rankine cycle without reheat or regeneration is considered to compare the emissions per unit energy delivered from each of the fuels considered. For natural gas and distillate oil, combined cycle operation is considered with a gas turbine-heat recovery steam generator combination replacing the boiler in the simple Rankine cycle. For all fuels, the cogeneration option is investigated by expanding the steam to an intermediate pressure in the turbine and utilizing the remaining heat by condensing the steam in a heat recovery application. Emission factors and basic information on CO, SO{sub 2} and NO{sub x} control technologies are utilized to calculate and report the emissions per unit energy delivered under the various scenarios investigated.

  7. Photocontrolled Exposure of Pro‐apoptotic Peptide Sequences in LOV Proteins Modulates Bcl‐2 Family Interactions

    PubMed Central

    Mart, Robert J.; Meah, Dilruba

    2015-01-01

    Abstract LOV domains act as biomolecular sensors for light, oxygen or the environment's redox potential. Conformational changes upon the formation of a covalent cysteinyl flavin adduct are propagated through hydrogen‐bonding networks in the core of designed hybrid phototropin LOV2 domains that incorporate the Bcl homology region 3 (BH3) of the key pro‐apoptotic protein BH3‐interacting‐domain death agonist (BID). The resulting change in conformation of a flanking amphiphilic α‐helix creates a light‐dependent optogenetic tool for the modulation of interactions with the anti‐apoptotic B‐cell leukaemia‐2 (Bcl‐2) family member Bcl‐xL. PMID:26493687

  8. Small-molecule modulators of c-Myc/Max and Max/Max interactions.

    PubMed

    Berg, Thorsten

    2011-01-01

    The transcription factor c-Myc is overexpressed in many tumors in human beings and has been identified as a highly promising target for cancer therapy. Most biological functions of c-Myc require heterodimerization with its activation partner Max. Inhibition of the protein-protein interactions between c-Myc and Max by small molecules has been shown to be a feasible and powerful approach toward the inhibition of c-Myc functions. More recently, stabilization of Max homodimers to reduce the amount of Max available for activating c-Myc has also been demonstrated to counteract Myc activity. This review summarizes our current knowledge on small organic molecules that inhibit c-Myc by modulating protein-protein interactions relevant for the biological function of this important oncoprotein.

  9. IGF2BP3 Modulates the Interaction of Invasion-Associated Transcripts with RISC.

    PubMed

    Ennajdaoui, Hanane; Howard, Jonathan M; Sterne-Weiler, Timothy; Jahanbani, Fereshteh; Coyne, Doyle J; Uren, Philip J; Dargyte, Marija; Katzman, Sol; Draper, Jolene M; Wallace, Andrew; Cazarez, Oscar; Burns, Suzanne C; Qiao, Mei; Hinck, Lindsay; Smith, Andrew D; Toloue, Masoud M; Blencowe, Benjamin J; Penalva, Luiz O F; Sanford, Jeremy R

    2016-05-31

    Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) expression correlates with malignancy, but its role(s) in pathogenesis remains enigmatic. We interrogated the IGF2BP3-RNA interaction network in pancreatic ductal adenocarcinoma (PDAC) cells. Using a combination of genome-wide approaches, we have identified 164 direct mRNA targets of IGF2BP3. These transcripts encode proteins enriched for functions such as cell migration, proliferation, and adhesion. Loss of IGF2BP3 reduced PDAC cell invasiveness and remodeled focal adhesion junctions. Individual nucleotide resolution crosslinking immunoprecipitation (iCLIP) revealed significant overlap of IGF2BP3 and microRNA (miRNA) binding sites. IGF2BP3 promotes association of the RNA-induced silencing complex (RISC) with specific transcripts. Our results show that IGF2BP3 influences a malignancy-associated RNA regulon by modulating miRNA-mRNA interactions. PMID:27210763

  10. Mesenchymal stem cell interactions with 3D ECM modules fabricated via multiphoton excited photochemistry.

    PubMed

    Su, Ping-Jung; Tran, Quyen A; Fong, Jimmy J; Eliceiri, Kevin W; Ogle, Brenda M; Campagnola, Paul J

    2012-09-10

    To understand complex micro/nanoscale ECM stem cell interactions, reproducible in vitro models are needed that can strictly recapitulate the relative content and spatial arrangement of native tissue. Additionally, whole ECM proteins are required to most accurately reflect native binding dynamics. To address this need, we use multiphoton excited photochemistry to create 3D whole protein constructs or "modules" to study how the ECM governs stem cell migration. The constructs were created from mixtures of BSA/laminin (LN) and BSA alone, whose comparison afforded studying how the migration dynamics are governed from the combination of morphological and ECM cues. We found that mesenchymal stem cells interacted for significantly longer durations with the BSA/LN constructs than pure BSA, pointing to the importance of binding cues of the LN. Critical to this work was the development of an automated system with feedback based on fluorescence imaging to provide quality control when synthesizing multiple identical constructs.

  11. Interactions between Starch, Lipids, and Proteins in Foods: Microstructure Control for Glycemic Response Modulation.

    PubMed

    Parada, Javier; Santos, Jose L

    2016-10-25

    In real food, starch is usually forming part of a matrix with lipids and proteins. However, research on this ternary system and interactions between such food components has been scarce so far. The control of food microstructure is crucial to determine the product properties, including sensorial and nutritionals ones. This paper reviews the microstructural principles of interactions between starch, lipids, and proteins in foods as well as their effect on postprandial glycemic response, considering human intrinsic differences on postprandial glycemic responses. Several lines of research support the hypothesis that foods without rapidly digestible starch will not mandatorily generate the lowest postprandial glycemic response, highlighting that the full understanding of food microstructure, which modulates starch digestion, plays a key role on food design from a nutritional viewpoint.

  12. IGF2BP3 modulates the interaction of invasion-associated transcripts with RISC

    PubMed Central

    Ennajdaoui, Hanane; Howard, Jonathan M.; Sterne-Weiler, Timothy; Jahanbani, Fereshteh; Coyne, Doyle J.; Uren, Philip J.; Dargyte, Marija; Katzman, Sol; Draper, Jolene M.; Wallace, Andrew; Cazarez, Oscar; Burns, Suzanne C.; Qiao, Mei; Hinck, Lindsay; Smith, Andrew D.; Toloue, Masoud M.; Blencowe, Benjamin J.; Penalva, Luiz O.F.; Sanford, Jeremy R.

    2016-01-01

    Summary Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) expression correlates with malignancy. But its role(s) in pathogenesis remain enigmatic. Here, we interrogated the IGF2BP3-RNA interaction network in pancreatic ductal adenocarcinoma (PDAC) cells. Using a combination of genome-wide approaches we identify 164 direct mRNA targets of IGF2BP3. These transcripts encode proteins enriched for functions such as cell migration, proliferation and adhesion. Loss of IGF2BP3 reduced PDAC cell invasiveness and remodeled focal adhesion junctions. Individual-nucleotide resolution crosslinking immunoprecipitation (iCLIP) revealed significant overlap of IGF2BP3 and miRNA binding sites. IGF2BP3 promotes association of the RNA induced silencing complex (RISC) with specific transcripts. Our results show that IGF2BP3 influences a malignancy-associated RNA regulon by modulating miRNA-mRNA interactions. PMID:27210763

  13. Magnetic properties of cylindrical diameter modulated Ni80Fe20 nanowires: interaction and coercive fields

    NASA Astrophysics Data System (ADS)

    Salem, Mohamed Shaker; Sergelius, Philip; Corona, Rosa M.; Escrig, Juan; Görlitz, Detlef; Nielsch, Kornelius

    2013-04-01

    Magnetic properties of cylindrical Ni80Fe20 nanowires with modulated diameters are investigated theoretically as a function of their geometrical parameters and compared with those produced inside the pores of anodic alumina membranes by pulsed electrodeposition. We observe that the Ni80Fe20 nanowires with modulated diameters reverse their magnetization via the nucleation and propagation of a vortex domain wall. The system begins generating vortex domains in the nanowire ends and in the transition region between the two segments to minimize magnetostatic energy generated by surfaces perpendicular to the initial magnetization of the sample. Besides, we observed an increase of the coercivity for the sample with equal volumes in relation to the sample with equal lengths. Finally, the interaction field is stronger in the case of constant volume segments. These structures could be used to control the motions of magnetic domain walls. In this way, these nanowires with modulated diameters can be an alternative to store information or even perform logic functions.

  14. Prediction of the anti-inflammatory mechanisms of curcumin by module-based protein interaction network analysis.

    PubMed

    Gan, Yanxiong; Zheng, Shichao; Baak, Jan P A; Zhao, Silei; Zheng, Yongfeng; Luo, Nini; Liao, Wan; Fu, Chaomei

    2015-11-01

    Curcumin, the medically active component from Curcuma longa (Turmeric), is widely used to treat inflammatory diseases. Protein interaction network (PIN) analysis was used to predict its mechanisms of molecular action. Targets of curcumin were obtained based on ChEMBL and STITCH databases. Protein-protein interactions (PPIs) were extracted from the String database. The PIN of curcumin was constructed by Cytoscape and the function modules identified by gene ontology (GO) enrichment analysis based on molecular complex detection (MCODE). A PIN of curcumin with 482 nodes and 1688 interactions was constructed, which has scale-free, small world and modular properties. Based on analysis of these function modules, the mechanism of curcumin is proposed. Two modules were found to be intimately associated with inflammation. With function modules analysis, the anti-inflammatory effects of curcumin were related to SMAD, ERG and mediation by the TLR family. TLR9 may be a potential target of curcumin to treat inflammation. PMID:26713275

  15. Prediction of the anti-inflammatory mechanisms of curcumin by module-based protein interaction network analysis

    PubMed Central

    Gan, Yanxiong; Zheng, Shichao; Baak, Jan P.A.; Zhao, Silei; Zheng, Yongfeng; Luo, Nini; Liao, Wan; Fu, Chaomei

    2015-01-01

    Curcumin, the medically active component from Curcuma longa (Turmeric), is widely used to treat inflammatory diseases. Protein interaction network (PIN) analysis was used to predict its mechanisms of molecular action. Targets of curcumin were obtained based on ChEMBL and STITCH databases. Protein–protein interactions (PPIs) were extracted from the String database. The PIN of curcumin was constructed by Cytoscape and the function modules identified by gene ontology (GO) enrichment analysis based on molecular complex detection (MCODE). A PIN of curcumin with 482 nodes and 1688 interactions was constructed, which has scale-free, small world and modular properties. Based on analysis of these function modules, the mechanism of curcumin is proposed. Two modules were found to be intimately associated with inflammation. With function modules analysis, the anti-inflammatory effects of curcumin were related to SMAD, ERG and mediation by the TLR family. TLR9 may be a potential target of curcumin to treat inflammation. PMID:26713275

  16. Determining protein function and interaction from genome analysis

    DOEpatents

    Eisenberg, David; Marcotte, Edward M.; Thompson, Michael J.; Pellegrini, Matteo; Yeates, Todd O.

    2004-08-03

    A computational method system, and computer program are provided for inferring functional links from genome sequences. One method is based on the observation that some pairs of proteins A' and B' have homologs in another organism fused into a single protein chain AB. A trans-genome comparison of sequences can reveal these AB sequences, which are Rosetta Stone sequences because they decipher an interaction between A' and B. Another method compares the genomic sequence of two or more organisms to create a phylogenetic profile for each protein indicating its presence or absence across all the genomes. The profile provides information regarding functional links between different families of proteins. In yet another method a combination of the above two methods is used to predict functional links.

  17. Inositol hexakisphosphate kinase-1 interacts with perilipin1 to modulate lipolysis.

    PubMed

    Ghoshal, Sarbani; Tyagi, Richa; Zhu, Qingzhang; Chakraborty, Anutosh

    2016-09-01

    Lipolysis leads to the breakdown of stored triglycerides (TAG) to release free fatty acids (FFA) and glycerol which is utilized by energy expenditure pathways to generate energy. Therefore, a decrease in lipolysis augments fat accumulation in adipocytes which promotes weight gain. Conversely, if lipolysis is not complemented by energy expenditure, it leads to FFA induced insulin resistance and type-2 diabetes. Thus, lipolysis is under stringent physiological regulation, although the precise mechanism of the regulation is not known. Deletion of inositol hexakisphosphate kinase-1 (IP6K1), the major inositol pyrophosphate biosynthetic enzyme, protects mice from high fat diet (HFD) induced obesity and insulin resistance. IP6K1-KO mice are lean due to enhanced energy expenditure. Therefore, IP6K1 is a target in obesity and type-2 diabetes. However, the mechanism/s by which IP6K1 regulates adipose tissue lipid metabolism is yet to be understood. Here, we demonstrate that IP6K1-KO mice display enhanced basal lipolysis. IP6K1 modulates lipolysis via its interaction with the lipolytic regulator protein perilipin1 (PLIN1). Furthermore, phosphorylation of IP6K1 at a PKC/PKA motif modulates its interaction with PLIN1 and lipolysis. Thus, IP6K1 is a novel regulator of PLIN1 mediated lipolysis. PMID:27373682

  18. Systematic identification of transcriptional regulatory modules from protein–protein interaction networks

    PubMed Central

    Diez, Diego; Hutchins, Andrew Paul; Miranda-Saavedra, Diego

    2014-01-01

    Transcription factors (TFs) combine with co-factors to form transcriptional regulatory modules (TRMs) that regulate gene expression programs with spatiotemporal specificity. Here we present a novel and generic method (rTRM) for the reconstruction of TRMs that integrates genomic information from TF binding, cell type-specific gene expression and protein–protein interactions. rTRM was applied to reconstruct the TRMs specific for embryonic stem cells (ESC) and hematopoietic stem cells (HSC), neural progenitor cells, trophoblast stem cells and distinct types of terminally differentiated CD4+ T cells. The ESC and HSC TRM predictions were highly precise, yielding 77 and 96 proteins, of which ∼75% have been independently shown to be involved in the regulation of these cell types. Furthermore, rTRM successfully identified a large number of bridging proteins with known roles in ESCs and HSCs, which could not have been identified using genomic approaches alone, as they lack the ability to bind specific DNA sequences. This highlights the advantage of rTRM over other methods that ignore PPI information, as proteins need to interact with other proteins to form complexes and perform specific functions. The prediction and experimental validation of the co-factors that endow master regulatory TFs with the capacity to select specific genomic sites, modulate the local epigenetic profile and integrate multiple signals will provide important mechanistic insights not only into how such TFs operate, but also into abnormal transcriptional states leading to disease. PMID:24137002

  19. Interactions of allosteric modulators of AMPA/kainate receptors on spreading depression in the chicken retina.

    PubMed

    Kertész, Szabolcs; Kapus, Gábor; Lévay, György

    2004-10-29

    The functional role of AMPA and kainate receptors in spreading depression (SD) was investigated in the isolated chicken retina. Competitive (NBQX) and non-competitive (GYKI 52466, GYKI 53405 and GYKI 53655) antagonists of the AMPA receptor inhibited AMPA-induced SD in a concentration-dependent manner. Concentrations of drugs caused 50% inhibition (IC(50) values) are 0.2, 16.6, 7.0 and 1.4 microM, respectively. AMPA receptor positive modulator cyclothiazide was more effective in the potentiation of SD evoked by AMPA than by kainate. Slight potentiation of either AMPA- or kainate-induced SD was observed only at high concentration (1 mg/ml) by the kainate receptor modulator concanavalin A. Compounds that positively modulate AMPA receptor function (cyclothiazide, IDRA-21, S 18986, 1-BCP and aniracetam) caused a concentration-dependent potentiation in SD. Concentrations of drugs that caused 50% potentiation (estimated EC(50) values) are 9, 135, 142, 450 and 1383 microM, respectively. Interaction between cyclothiazide, aniracetam or S 18986 administered with each other, or with GYKI 52466, respectively, was also investigated. When cyclothiazide and S 18986 were co-applied, their effects seemed to be additive. However, lack of additivity was obtained when S 18986 was added together with aniracetam. Positive modulators applied at equiactive concentrations reduced the inhibitory action of GYKI 52466 and differently shifted its concentration-response curve. In this respect, S 18986 was the most effective (IC(50) of GYKI 52466 changed from 16.6 to 51.9 microM). Our findings indicate the contribution of AMPA rather than kainate receptors in the mediation of retinal spreading depression. Our data further support the idea that multiple positive modulatory sites are present on the AMPA receptor complex in addition to a negative modulatory site.

  20. Modulation of frontostriatal interaction aligns with reduced primary reward processing under serotonergic drugs.

    PubMed

    Abler, Birgit; Grön, Georg; Hartmann, Antonie; Metzger, Coraline; Walter, Martin

    2012-01-25

    Recently, functional interactions between anteroventral prefrontal cortex and nucleus accumbens (NAcc) have been shown to relate to behavior counteracting reward-desiring (Diekhof and Gruber, 2010). Downregulation of the reward system by serotonin has also been suggested as the mode of action accounting for unsatisfactory effects of serotonin reuptake inhibitors (SSRIs) such as insufficient alleviation or even increase of anhedonia, and loss of interest. However, understanding of the in vivo mechanisms of SSRI-related alteration of the human reward system is still incomplete. Using functional magnetic resonance imaging (fMRI) within a double-blind cross-over within-subjects study design and administering the SSRI paroxetine, the dopamine/norepinephrine reuptake inhibitor bupropione, and placebo for 7 d each, we investigated a group of 18 healthy male subjects. Under paroxetine, subjects showed significantly decreased activation of the bilateral NAcc during processing of primary rewards (erotic videos), but not under bupropion. Similar to the previous study, analysis of psychophysiological interactions revealed that this downregulation relied on negative interactions between left and right NAcc fMRI signals and the bilateral anteroventral prefrontal cortex that now were significantly enhanced under paroxetine and reduced under bupropion. Individual drug-dependent modulations of interacting brain regions were significantly associated with individual expressions of impulsivity as a personality trait. Our results corroborate and extend previous insights on interregional crosstalk from secondary to primary rewards and demonstrate parallels between active inhibitory control of and serotonergic effects on the dopaminergic reward system's activity. PMID:22279217

  1. Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction

    PubMed Central

    Antonelli, Roberta; Pizzarelli, Rocco; Pedroni, Andrea; Fritschy, Jean-Marc; Del Sal, Giannino; Cherubini, Enrico; Zacchi, Paola

    2014-01-01

    The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis–trans isomerase Pin1. This signalling cascade negatively regulates NL2’s ability to interact with gephyrin at GABAergic post-synaptic sites. As a consequence, enhanced accumulation of NL2, gephyrin and GABAA receptors was detected at GABAergic synapses in the hippocampus of Pin1-knockout mice (Pin1−/−) associated with an increase in amplitude of spontaneous GABAA-mediated post-synaptic currents. Our results suggest that Pin1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NL2/gephyrin interaction. PMID:25297980

  2. Behavior modulation of rats to a robotic rat in multi-rat interaction.

    PubMed

    Shi, Qing; Ishii, Hiroyuki; Tanaka, Katsuaki; Sugahara, Yusuke; Takanishi, Atsuo; Okabayashi, Satoshi; Huang, Qiang; Fukuda, Toshio

    2015-10-01

    In this paper, we study the behavioral response of rats to a robotic rat during multi-rat interaction. Experiments are conducted in an open-field where a robotic rat called WR-5 is put together with three laboratory rats. WR-5 is following one rat (target), while avoiding the other two rats (outside observers) during interaction. The behavioral characteristics of each target rat is evaluated by scoring its locomotor activity and frequencies of performing rearing, body grooming and mounting actions. Additionally, the frequency of being mounted by other rats is also measured. Experimental results show that the target becomes more active after interaction. The rat species, with more active behavioral characteristics, is more susceptible to being adjusted by the robot. The increased time spent by the outside observers in the vicinity of the robot indicates that a biomimetic robot has the promise for modulating rat behavior even without direct interaction. Thus, this study provide a novel approach to shaping the sociality of animals living in groups. PMID:26414400

  3. Behavior modulation of rats to a robotic rat in multi-rat interaction.

    PubMed

    Shi, Qing; Ishii, Hiroyuki; Tanaka, Katsuaki; Sugahara, Yusuke; Takanishi, Atsuo; Okabayashi, Satoshi; Huang, Qiang; Fukuda, Toshio

    2015-10-01

    In this paper, we study the behavioral response of rats to a robotic rat during multi-rat interaction. Experiments are conducted in an open-field where a robotic rat called WR-5 is put together with three laboratory rats. WR-5 is following one rat (target), while avoiding the other two rats (outside observers) during interaction. The behavioral characteristics of each target rat is evaluated by scoring its locomotor activity and frequencies of performing rearing, body grooming and mounting actions. Additionally, the frequency of being mounted by other rats is also measured. Experimental results show that the target becomes more active after interaction. The rat species, with more active behavioral characteristics, is more susceptible to being adjusted by the robot. The increased time spent by the outside observers in the vicinity of the robot indicates that a biomimetic robot has the promise for modulating rat behavior even without direct interaction. Thus, this study provide a novel approach to shaping the sociality of animals living in groups.

  4. Measuring Selective Estrogen Receptor Modulator (SERM)–Membrane Interactions with Second Harmonic Generation

    PubMed Central

    2015-01-01

    The interaction of selective estrogen receptor modulators (SERMs) with lipid membranes has been measured at clinically relevant serum concentrations using the label-free technique of second harmonic generation (SHG). The SERMs investigated in this study include raloxifene, tamoxifen, and the tamoxifen metabolites 4-hydroxytamoxifen, N-desmethyltamoxifen, and endoxifen. Equilibrium association constants (Ka) were measured for SERMs using varying lipid compositions to examine how lipid phase, packing density, and cholesterol content impact SERM-membrane interactions. Membrane-binding properties of tamoxifen and its metabolites were compared on the basis of hydroxyl group substitution and amine ionization to elucidate how the degree of drug ionization impacts membrane partitioning. SERM-membrane interactions were probed under multiple pH conditions, and drug adsorption was observed to vary with the concentration of soluble neutral species. The agreement between Ka values derived from SHG measurements of the interactions between SERMs and artificial cell membranes and independent observations of the SERMs efficacy from clinical studies suggests that quantifying membrane adsorption properties may be important for understanding SERM action in vivo. PMID:24410282

  5. Interaction of NIMIN1 with NPR1 Modulates PR Gene Expression in Arabidopsis

    PubMed Central

    Weigel, Ralf R.; Pfitzner, Ursula M.; Gatz, Christiane

    2005-01-01

    The Arabidopsis thaliana NONEXPRESSER OF PR GENES1 (NPR1, also known as NIM1) protein is an essential positive regulator of salicylic acid (SA)-induced PATHOGENESIS-RELATED (PR) gene expression and systemic acquired resistance (SAR). PR gene activity is regulated at the level of redox-dependent nuclear transport of NPR1. NPR1 interacts with members of the TGA family of transcription factors that are known to bind to SA-responsive elements in the PR-1 promoter. In an attempt to identify proteins involved in SA-mediated signal transduction, we previously described the isolation of three novel genes encoding distinct albeit structurally related proteins designated NIMIN1 (for NIM1-INTERACTING1), NIMIN2, and NIMIN3 that interact with NPR1 in the yeast two-hybrid system. Here, we show that NIMIN1 and NPR1 can be copurified from plant extracts, providing biochemical evidence for their interaction. We provide functional evidence for this interaction by describing transgenic plants constitutively expressing high amounts of NIMIN1. These plants show reduced SA-mediated PR gene induction and a compromised SAR, thus mimicking the described phenotype conferred by npr1. Moreover, they showed reduced RESISTANCE gene–mediated protection. These effects were dependent on the ability of NIMIN1 to interact with NPR1. Mutant plants with a T-DNA insertion in NIMIN1 as well as transgenic plants with reduced NIMIN1 mRNA levels showed hyperactivation of PR-1 gene expression after SA treatment but no effect on the disease resistance phenotype. Our results strongly suggest that NIMIN1 negatively regulates distinct functions of NPR1, providing a mechanism to modulate specific features of SAR. PMID:15749762

  6. Neuroticism Modulates the Effects of Intranasal Vasopressin Treatment on the Neural Response to Positive and Negative Social Interactions

    PubMed Central

    Feng, Chunliang; DeMarco, Ashley C.; Haroon, Ebrahim; Rilling, James K.

    2015-01-01

    Neuroticism is a fundamental personality trait associated with proneness to feel negative affect. Here we ask how Neuroticism influences the neural response to positive and negative social interactions and how Neuroticism modulates the effect of intranasal oxytocin (OT) and vasopressin (AVP) on the neural response to social interactions. In a double-blind, placebo-controlled study, 153 male participants were randomized to receive 24 IU intranasal OT, 20 IU AVP or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner’s Dilemma Game. On a different day, subjects completed the NEO personality inventory to measure Neuroticism. Neuroticism was positively correlated with the neural response to negative social interactions in the anterior cingulate cortex/medial prefrontal cortex and with the neural response to positive social interactions in the insula, indicating that Neuroticism modulates neuropsychological processing of both negative and positive social interactions. Neuroticism did not modulate the effect of intranasal OT treatment on the neural response to either positive or negative social interactions. On the other hand, AVP treatment significantly interacted with Neuroticism to modulate the BOLD response to both positive and negative social interactions. Specifically, AVP increased anterior cingulate cortex/medial prefrontal cortex and lateral temporal lobe responses to negative social interactions to a greater extent in participants scoring high rather than low on Neuroticism. AVP also increased the insula response to positive social interactions to a greater extent in participants scoring high rather than low on Neuroticism. These results imply that AVP may increase emotion regulation in response to negative social interactions and the salience of positive social interactions to a greater extent in individuals high compared to low in Neuroticism. The current findings urge caution against uniform clinical application of

  7. Quantification of chemical mixture interactions modulating dermal absorption using a multiple membrane fiber array.

    PubMed

    Baynes, Ronald E; Xia, Xin Rui; Imran, Mudassar; Riviere, Jim E

    2008-03-01

    Dermal exposures to chemical mixtures can potentially increase or decrease systemic bioavailability of toxicants in the mixture. Changes in dermal permeability can be attributed to changes in physicochemical interactions between the mixture, the skin, and the solute of interest. These physicochemical interactions can be described as changes in system coefficients associated with molecular descriptors described by Abraham's linear solvation energy relationship (LSER). This study evaluated the effects of chemical mixtures containing either a solvent (ethanol) or a surfactant (sodium lauryl sulfate, SLS) on solute permeability and partitioning by quantifying changes in system coefficients in skin and a three-membrane-coated fiber (MCF) system, respectively. Regression analysis demonstrated that changes in system coefficients in skin were strongly correlated ( R2 = 0.89-0.98) to changes in system coefficients in the three-membrane MCF array with mixtures containing either 1% SLS or 50% ethanol. The PDMS fiber appeared to play a significant role (R2 = 0.84-0.85) in the MCF array in predicting changes in solute permeability, while the WAX fiber appeared to contribute less (R2 = 0.59-0.77) to the array than the other two fibers. On the basis of changes in system coefficients that are part of a LSER, these experiments were able to link physicochemical interactions in the MCF with those interactions in skin when either system is exposed to 1% SLS or 50% ethanol. These experiments further demonstrated the utility of a MCF array to adequately predict changes in dermal permeability when skin is exposed to mixtures containing either a surfactant or a solvent and provide some insight into the nature of the physiochemical interactions that modulate dermal absorptions.

  8. Identification of tissue-specific cis-regulatory modules based on interactions between transcription factors

    PubMed Central

    Yu, Xueping; Lin, Jimmy; Zack, Donald J; Qian, Jiang

    2007-01-01

    Background Evolutionary conservation has been used successfully to help identify cis-acting DNA regions that are important in regulating tissue-specific gene expression. Motivated by increasing evidence that some DNA regulatory regions are not evolutionary conserved, we have developed an approach for cis-regulatory region identification that does not rely upon evolutionary sequence conservation. Results The conservation-independent approach is based on an empirical potential energy between interacting transcription factors (TFs). In this analysis, the potential energy is defined as a function of the number of TF interactions in a genomic region and the strength of the interactions. By identifying sets of interacting TFs, the analysis locates regions enriched with the binding sites of these interacting TFs. We applied this approach to 30 human tissues and identified 6232 putative cis-regulatory modules (CRMs) regulating 2130 tissue-specific genes. Interestingly, some genes appear to be regulated by different CRMs in different tissues. Known regulatory regions are highly enriched in our predicted CRMs. In addition, DNase I hypersensitive sites, which tend to be associated with active regulatory regions, significantly overlap with the predicted CRMs, but not with more conserved regions. We also find that conserved and non-conserved CRMs regulate distinct gene groups. Conserved CRMs control more essential genes and genes involved in fundamental cellular activities such as transcription. In contrast, non-conserved CRMs, in general, regulate more non-essential genes, such as genes related to neural activity. Conclusion These results demonstrate that identifying relevant sets of binding motifs can help in the mapping of DNA regulatory regions, and suggest that non-conserved CRMs play an important role in gene regulation. PMID:17996093

  9. Vinculin modulation of paxillin–FAK interactions regulates ERK to control survival and motility

    PubMed Central

    Subauste, M. Cecilia; Pertz, Olivier; Adamson, Eileen D.; Turner, Christopher E.; Junger, Sachiko; Hahn, Klaus M.

    2004-01-01

    Cells lacking vinculin are highly metastatic and motile. The reasons for this finding have remained unclear. Both enhanced survival and motility are critical to metastasis. Here, we show that vinculin null (vin−/−) cells and cells expressing a vinculin Y822F mutant have increased survival due to up-regulated activity of extracellular signal–regulated kinase (ERK). This increase is shown to result from vinculin's modulation of paxillin–FAK interactions. A vinculin fragment (amino acids 811–1066) containing the paxillin binding site restored apoptosis and suppressed ERK activity in vin−/− cells. Both vinY822F and vin−/− cells exhibit increased interaction between paxillin and focal adhesion kinase (FAK) and increased paxillin and FAK phosphorylation. Transfection with paxillin Y31FY118F dominant-negative mutant in these cells inhibits ERK activation and restores apoptosis. The enhanced motility of vin−/− and vinY822F cells is also shown to be due to a similar mechanism. Thus, vinculin regulates survival and motility via ERK by controlling the accessibility of paxillin for FAK interaction. PMID:15138291

  10. Is there a possible single mediator in modulating neuroendocrine-thymus interaction in ageing?

    PubMed

    Mocchegiani, Eugenio; Malavolta, Marco; Costarelli, Laura; Giacconi, Robertina; Piacenza, Francesco; Lattanzio, Fabrizia; Basso, Andrea

    2013-02-01

    The restoration of the thymic functions and the thymic re-growth may be achieved in old mice by some endocrinological (melatonin) or nutritional interventions (arginine or zinc), suggesting that the thymic involution in old age is a phenomenon secondary to age-related alterations occurring in neuroendocrine-thymus interactions. The targets for the thymic restoration may be hormone receptors and cytokines, strictly related to the presence of two nutritional factors, such as arginine and zinc, which are in turn essential for the efficiency of neuroendocrine-immune network both in ontogeny and ageing. The effect of melatonin is largely due to the presence of its specific receptors on cell membrane of thymocytes and Thymic Epithelial Cells (TECs). TECs synthesize thymulin peptide that is required for T-cell differentiation and maturation within the thymus gland. In this context, the role of zinc is pivotal because it is involved, through "zinc finger motifs", in the gene expression of melatonin receptors, in cell proliferation, apoptosis and thymulin reactivation. Zinc is also required for the biological action of arginine, via Nitric Oxide pathway. Therefore, the beneficial effect of melatonin or arginine on neuroendocrine-thymus interaction in ageing can also occur via a better zinc pool redistribution within the body where the capability of the zinc-binding proteins Metallothioneins (MT) in zinc release has a key role. These findings suggest that zinc, via MT buffering, can be a single mediator in modulating neuroendocrine-thymus interaction in ageing.

  11. The Thermal Structural Transition of Alpha-Crystallin Modulates Subunit Interactions and Increases Protein Solubility

    PubMed Central

    Maulucci, Giuseppe; De Spirito, Marco; Arcovito, Giuseppe; Papi, Massimiliano

    2012-01-01

    Background Alpha crystallin is an oligomer composed of two types of subunits, alpha-A and alpha-B crystallin, and is the major constituent of human lens. The temperature induced condensation of alpha-crystallin, the main cause for eye lens opacification (cataract), is a two step-process, a nucleation followed by an aggregation phase, and a protective effect towards the aggregation is exhibited over the alpha crystallin phase transition temperature (Tc = 318.16 K). Methods/Results To investigate if a modulation of the subunit interactions over Tc could trigger the protective mechanism towards the aggregation, we followed, by using simultaneously static and dynamic light scattering, the temperature induced condensation of alpha-crystallin. By developing a mathematical model able to uncouple the nucleation and aggregation processes, we find a previously unobserved transition in the nucleation rate constant. Its temperature dependence allows to determine fundamental structural parameters, the chemical potential (Δμ) and the interfacial tension (γ) of the aggregating phase, that characterize subunit interactions. Conclusions/General Significance The decrease of both Δμ and γ at Tc, and a relative increase in solubility, reveal a significative decrease in the strenght of alpha-crystallin subunits interactions, which protects from supramolecolar condensation in hypertermic conditions. On the whole, we suggest a general approach able to understand the structural and kinetic mechanisms involved in aggregation-related diseases and in drugs development and testing. PMID:22347398

  12. Interactive Learning Module Improves Resident Knowledge of Risks of Ionizing Radiation Exposure From Medical Imaging.

    PubMed

    Sheng, Alexander Y; Breaud, Alan H; Schneider, Jeffrey I; Kadom, Nadja; Mitchell, Patricia M; Linden, Judith A

    2016-01-01

    Physician awareness of the risks of ionizing radiation exposure related to medical imaging is poor. Effective educational interventions informing physicians of such risk, especially in emergency medicine (EM), are lacking. The SIEVERT (Suboptimal Ionizing Radiation Exposure Education - A Void in Emergency Medicine Residency Training) learning module was designed to improve provider knowledge of the risks of radiation exposure from medical imaging and comfort in communicating these risks to patients. The 1-hour module consists of introductory lecture, interactive discussion, and role-playing scenarios. In this pilot study, we assessed the educational effect using unmatched, anonymous preintervention and postintervention questionnaires that assessed fund of knowledge, participant self-reported imaging ordering practices in several clinical scenarios, and trainee comfort level in discussing radiation risks with patients. All 25 EM resident participants completed the preintervention questionnaire, and 22 completed the postintervention questionnaire within 4 hours after participation. Correct responses on the 14-question learning assessment increased from 6.32 (standard deviation = 2.36) preintervention to 12.23 (standard deviation = 1.85) post-intervention. Overall, 24% of residents were comfortable with discussing the risks of ionizing radiation exposure with patients preintervention, whereas 41% felt comfortable postintervention. Participants ordered fewer computed tomography scans in 2 of the 4 clinical scenarios after attending the educational intervention. There was improvement in EM residents' knowledge regarding the risks of ionizing radiation exposure from medical imaging, and increased participant self-reported comfort levels in the discussion of these risks with patients after the 1-hour SIEVERT learning module.

  13. Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

    PubMed Central

    Rouwette, Tom; Avenali, Luca; Sondermann, Julia; Narayanan, Pratibha; Gomez-Varela, David; Schmidt, Manuela

    2015-01-01

    In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles. PMID:26039491

  14. Biopolymer-Lipid Bilayer Interaction Modulates the Physical Properties of Liposomes: Mechanism and Structure.

    PubMed

    Tan, Chen; Zhang, Yating; Abbas, Shabbar; Feng, Biao; Zhang, Xiaoming; Xia, Wenshui; Xia, Shuqin

    2015-08-19

    This study was conducted to elucidate the conformational dependence of the modulating ability of chitosan, a positively charged biopolymer, on a new type of liposome composed of mixed lipids including egg yolk phosphatidylcholine (EYPC) and nonionic surfactant (Tween 80). Analysis of the dynamic and structure of bilayer membrane upon interaction with chitosan by fluorescence and electron paramagnetic resonance techniques demonstrated that, in addition to providing a physical barrier for the membrane surface, the adsorption of chitosan extended and crimped chains rigidified the lipid membrane. However, the decrease in relative microviscosity and order parameter suggested that the presence of chitosan coils disturbed the membrane organization. It was also noted that the increase of fluidity in the lipid bilayer center was not pronounced, indicating the shallow penetration of coils into the hydrophobic interior of bilayer. Microscopic observations revealed that chitosan adsorption not only affected the morphology of liposomes but also modulated the particle aggregation and fusion. Especially, a number of very heterogeneous particles were visualized, which tended to confirm the role of chitosan coils as a "polymeric surfactant". In addition to particle deformation, the membrane permeability was also tuned. These findings may provide a new perspective to understand the physiological functionality of biopolymer and design biopolymer-liposome composite structures as delivery systems for bioactive components. PMID:26173584

  15. Environmental factors as modulators of neurodegeneration: insights from gene-environment interactions in Huntington's disease.

    PubMed

    Mo, Christina; Hannan, Anthony J; Renoir, Thibault

    2015-05-01

    Unlike many other neurodegenerative diseases with established gene-environment interactions, Huntington's disease (HD) is viewed as a disorder governed by genetics. The cause of the disease is a highly penetrant tandem repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. In the year 2000, a pioneering study showed that the disease could be delayed in transgenic mice by enriched housing conditions. This review describes subsequent human and preclinical studies identifying environmental modulation of motor, cognitive, affective and other symptoms found in HD. Alongside the behavioral observations we also discuss potential mechanisms and the relevance to other neurodegenerative disorders, including Alzheimer's and Parkinson's disease. In mouse models of HD, increased sensorimotor and cognitive stimulation can delay or ameliorate various endophenotypes. Potential mechanisms include increased trophic support, synaptic plasticity, adult neurogenesis, and other forms of experience-dependent cellular plasticity. Subsequent clinical investigations support a role for lifetime activity levels in modulating the onset and progression of HD. Stress can accelerate memory and olfactory deficits and exacerbate cellular dysfunctions in HD mice. In the absence of effective treatments to slow the course of HD, environmental interventions offer feasible approaches to delay the disease, however further preclinical and human studies are needed in order to generate clinical recommendations. Environmental interventions could be combined with future pharmacological therapies and stimulate the identification of enviromimetics, drugs which mimic or enhance the beneficial effects of cognitive stimulation and physical activity.

  16. Preliminary results from the flight of the Solar Array Module Plasma Interactions Experiment (SAMPIE)

    NASA Technical Reports Server (NTRS)

    Ferguson, Dale C.; Hillard, G. Barry

    1994-01-01

    SAMPIE, the Solar Array Module Plasma Interactions Experiment, flew in the Space Shuttle Columbia payload bay as part of the Office of Aeronautics and Space Technology-2 (OAST-2) mission on STS-62, March, 1994. SAMPIE biased samples of solar arrays and space power materials to varying potentials with respect to the surrounding space plasma, and recorded the plasma currents collected and the arcs which occurred, along with a set of plasma diagnostics data. A large set of high quality data was obtained on the behavior of solar arrays and space power materials in the space environment. This paper is the first report on the data SAMPIE telemetered to the ground during the mission. It will be seen that the flight data promise to help determine arcing thresholds, snapover potentials, and floating potentials for arrays and spacecraft in LEO.

  17. Observation of interaction-induced modulations of a quantum Hall liquid's area

    PubMed Central

    Sivan, I.; Choi, H. K.; Park, Jinhong; Rosenblatt, A.; Gefen, Yuval; Mahalu, D.; Umansky, V.

    2016-01-01

    Studies of electronic interferometers, based on edge-channel transport in the quantum Hall effect regime, have been stimulated by the search for evidence of abelian and non-abelian anyonic statistics of fractional charges. In particular, the electronic Fabry–Pérot interferometer has been found to be Coulomb dominated, thus masking coherent Aharonov–Bohm interference patterns: the flux trapped within the interferometer remains unchanged as the applied magnetic field is varied, barring unobservable modulations of the interference area. Here we report on conductance measurements indicative of the interferometer's area ‘breathing' with the variation of the magnetic field, associated with observable (a fraction of a flux quantum) variations of the trapped flux. This is the result of partial (controlled) screening of Coulomb interactions. Our results introduce a novel experimental tool for probing anyonic statistics. PMID:27396234

  18. Observation of interaction-induced modulations of a quantum Hall liquid's area

    NASA Astrophysics Data System (ADS)

    Sivan, I.; Choi, H. K.; Park, Jinhong; Rosenblatt, A.; Gefen, Yuval; Mahalu, D.; Umansky, V.

    2016-07-01

    Studies of electronic interferometers, based on edge-channel transport in the quantum Hall effect regime, have been stimulated by the search for evidence of abelian and non-abelian anyonic statistics of fractional charges. In particular, the electronic Fabry-Pérot interferometer has been found to be Coulomb dominated, thus masking coherent Aharonov-Bohm interference patterns: the flux trapped within the interferometer remains unchanged as the applied magnetic field is varied, barring unobservable modulations of the interference area. Here we report on conductance measurements indicative of the interferometer's area `breathing' with the variation of the magnetic field, associated with observable (a fraction of a flux quantum) variations of the trapped flux. This is the result of partial (controlled) screening of Coulomb interactions. Our results introduce a novel experimental tool for probing anyonic statistics.

  19. Presynaptic modulation of transmitter release via alpha2-adrenoceptors: nonsynaptic interactions.

    PubMed

    Vizi, E S

    1999-01-01

    It is generally accepted that neurochemical transmission occurring at the synapse is the primary way of sending messages from one neuron to another. Neurotransmitters released from axon terminal in a [Ca2+]0-dependent manner act transsynaptically on the postsynaptic site. The past 30 years have witnessed something of a revolution in the understanding of how neurons communicate with each other. It has been shown that the exocytotic release of transmitters from axon terminals is subject to presynaptic modulation via presynatic hetero- and auto-receptors. For example via stimulation of alpha2-adrenoceptors expressed on varicosities and coupled to G-protein the stimulation-evoked release of different transmitters can be inhibited. This review will focus on nonsynaptic interactions between axon terminals. The present data clearly show that transmitters released from axon terminals without synaptic contact play an important role in the fine tuning of communication between neurons within a neuronal circuit.

  20. Preliminary Results from the Flight of the Solar Array Module Plasma Interactions Experiment (SAMPIE)

    NASA Technical Reports Server (NTRS)

    Ferguson, Dale C.; Hillard, G. Barry

    1994-01-01

    SAMPIE, the Solar Array Module Plasma Interactions Experiment, flew in the Space Shuttle Columbia payload bay as part of the OAST-2 mission on STS-62, March, 1994. SAMPIE biased samples of solar arrays and space power materials to varying potentials with respect to the surrounding space plasma, and recorded the plasma currents collected and the arcs which occurred, along with a set of plasma diagnostics data. A large set of high quality data was obtained on the behavior of solar arrays and space power materials in the space environment. This paper is the first report on the data SAMPIE telemetered to the ground during the mission. It will be seen that the flight data promise to help determine arcing thresholds, snapover potentials and floating potentials for arrays and spacecraft in LEO.

  1. Modulation of Protein–Protein Interactions for the Development of Novel Therapeutics

    PubMed Central

    Petta, Ioanna; Lievens, Sam; Libert, Claude; Tavernier, Jan; De Bosscher, Karolien

    2016-01-01

    Protein–protein interactions (PPIs) underlie most biological processes. An increasing interest to investigate the unexplored potential of PPIs in drug discovery is driven by the need to find novel therapeutic targets for a whole range of diseases with a high unmet medical need. To date, PPI inhibition with small molecules is the mechanism that has most often been explored, resulting in significant progress towards drug development. However, also PPI stabilization is gradually gaining ground. In this review, we provide a focused overview of a number of PPIs that control critical regulatory pathways and constitute targets for the design of novel therapeutics. We discuss PPI-modulating small molecules that are already pursued in clinical trials. In addition, we review a number of PPIs that are still under preclinical investigation but for which preliminary data support their use as therapeutic targets. PMID:26675501

  2. Interaction between cyclodextrin and neuronal membrane results in modulation of GABAA receptor conformational transitions

    PubMed Central

    Pytel, Maria; Mercik, Katarzyna; Mozrzymas, Jerzy W

    2006-01-01

    Cyclodextrins (CDs) are nanostructures widely applied in biotechnology and chemistry. Owing to partially hydrophobic character, CDs interact with biological membranes. While the mechanisms of CDs interactions with lipids were widely studied, their effects on proteins are less understood. In the present study we investigated the effects of beta cyclodextrin (βCD) on GABAA receptor (GABAAR) gating. To reliably resolve the kinetics of conformational transitions, currents were elicited by ultrafast gamma-aminobutyric acid (GABA) applications to outside-out patches from rat cultured hippocampal neurons. βCD increased the amplitude of responses to saturating GABA concentration ([GABA]) in a dose-dependent manner and this effect was accompanied by profound alterations in the current kinetics. Current deactivation was slowed down by βCD but this effect was biphasic with a maximum at around 0.5 mM βCD. While the fast deactivation time constant was monotonically slowed down within considered βCD concentration range, the slow component first increased and then, at millimolar βCD concentration, decreased. The rate and extent of desensitization was decreased by βCD in a dose-dependent manner. The analysis of current responses to nonsaturating [GABA] indicated that βCD affected the GABAAR agonist binding site by slowing down the unbinding rate. Modulation of GABAAR desensitization and binding showed different concentration-dependence suggesting different modualtory sites with higher affinity of the latter one. All the βCD effects were fully reversible indicating that cholesterol uptake into βCD was not the primary mechanism. We conclude that βCD is a strong modulator of GABAAR conformational transitions. PMID:16702996

  3. Interaction between cyclodextrin and neuronal membrane results in modulation of GABA(A) receptor conformational transitions.

    PubMed

    Pytel, Maria; Mercik, Katarzyna; Mozrzymas, Jerzy W

    2006-06-01

    Cyclodextrins (CDs) are nanostructures widely applied in biotechnology and chemistry. Owing to partially hydrophobic character, CDs interact with biological membranes. While the mechanisms of CDs interactions with lipids were widely studied, their effects on proteins are less understood. In the present study we investigated the effects of beta cyclodextrin (betaCD) on GABA(A) receptor (GABA(A)R) gating. To reliably resolve the kinetics of conformational transitions, currents were elicited by ultrafast gamma-aminobutyric acid (GABA) applications to outside-out patches from rat cultured hippocampal neurons. betaCD increased the amplitude of responses to saturating GABA concentration ([GABA]) in a dose-dependent manner and this effect was accompanied by profound alterations in the current kinetics. Current deactivation was slowed down by betaCD but this effect was biphasic with a maximum at around 0.5 mM betaCD. While the fast deactivation time constant was monotonically slowed down within considered betaCD concentration range, the slow component first increased and then, at millimolar betaCD concentration, decreased. The rate and extent of desensitization was decreased by betaCD in a dose-dependent manner. The analysis of current responses to nonsaturating [GABA] indicated that betaCD affected the GABA(A)R agonist binding site by slowing down the unbinding rate. Modulation of GABA(A)R desensitization and binding showed different concentration-dependence suggesting different modualtory sites with higher affinity of the latter one. All the betaCD effects were fully reversible indicating that cholesterol uptake into betaCD was not the primary mechanism. We conclude that betaCD is a strong modulator of GABA(A)R conformational transitions.

  4. Plume-Free Stream Interaction Heating Effects During Orion Crew Module Reentry

    NASA Technical Reports Server (NTRS)

    Marichalar, J.; Lumpkin, F.; Boyles, K.

    2012-01-01

    During reentry of the Orion Crew Module (CM), vehicle attitude control will be performed by firing reaction control system (RCS) thrusters. Simulation of RCS plumes and their interaction with the oncoming flow has been difficult for the analysis community due to the large scarf angles of the RCS thrusters and the unsteady nature of the Orion capsule backshell environments. The model for the aerothermal database has thus relied on wind tunnel test data to capture the heating effects of thruster plume interactions with the freestream. These data are only valid for the continuum flow regime of the reentry trajectory. A Direct Simulation Monte Carlo (DSMC) analysis was performed to study the vehicle heating effects that result from the RCS thruster plume interaction with the oncoming freestream flow at high altitudes during Orion CM reentry. The study was performed with the DSMC Analysis Code (DAC). The inflow boundary conditions for the jets were obtained from Data Parallel Line Relaxation (DPLR) computational fluid dynamics (CFD) solutions. Simulations were performed for the roll, yaw, pitch-up and pitch-down jets at altitudes of 105 km, 125 km and 160 km as well as vacuum conditions. For comparison purposes (see Figure 1), the freestream conditions were based on previous DAC simulations performed without active RCS to populate the aerodynamic database for the Orion CM. Other inputs to the analysis included a constant Orbital reentry velocity of 7.5 km/s and angle of attack of 160 degrees. The results of the study showed that the interaction effects decrease quickly with increasing altitude. Also, jets with highly scarfed nozzles cause more severe heating compared to the nozzles with lower scarf angles. The difficulty of performing these simulations was based on the maximum number density and the ratio of number densities between the freestream and the plume for each simulation. The lowest altitude solutions required a substantial amount of computational resources

  5. Time-dependent modulation of galactic cosmic rays by merged interaction regions

    NASA Technical Reports Server (NTRS)

    Perko, J. S.

    1993-01-01

    Models that solve the one-dimensional, solar modulation equation have reproduced the 11-year galactic cosmic ray using functional representations of global merged interaction regions (MIRs). This study extends those results to the solution of the modulation equation with explicit time dependence. The magnetometers on Voyagers 1 and 2 provide local magnetic field intensities at regular intervals, from which one calculates the ratio of the field intensity to the average local field. These ratios in turn are inverted to form diffusion coefficients. Strung together in radius and time, these coefficents then fall and rise with the strength of the interplanetary magnetic field, becoming representations of MIRs. These diffusion coefficients, calculated locally, propagate unchanged from approx. 10 AU to the outer boundary (120 AU). Inside 10 AU, all parameters, including the diffusion coefficient are assumed constant in time and space. The model reproduces the time-intensity profiles of Voyager 2 and Pioneer 10. Radial gradient data from 1982-1990 between Pioneer 10 and Voyager 2 are about the same magnitude as those calculated in the model. It is also shows agreement in rough magnitude with the radial gradient between Pioneer 10 and 1 AU. When coupled with enhanced, time-dependent solar wind speed at the probe's high latitude, as measured by independent observers, the model also follows Voyager 1's time-intensity profile reasonably well, providing a natural source the model also follows Voyager 1's time-intensity profile reasonably well, providing a natural source for the observed negative latitudinal gradients. The model exhibits the 11-year cyclical cosmic ray intensity behavior at all radii, including 1 AU, not just at the location of the spacecraft where the magnetic fields are measured. In addition, the model's point of cosmic ray maximum correctly travels at the solar wind speed, illustrating the well-known propagation of modulation. Finally, at least in the inner

  6. Sclerostin-erbB-3 interactions: modulation of erbB-3 activity by sclerostin.

    PubMed

    Craig, Theodore A; Kumar, Rajiv

    2010-11-12

    To gain insights into the mechanism of action of sclerostin, a protein that regulates bone mass, we performed yeast two-hybrid analyses using human SOST (sclerostin) cDNA cloned into pGBKT7 DNA-binding domain vector as a bait, and a normalized, high-complexity, universal cDNA library in a GAL4 activating domain vector. We identified an interaction between sclerostin and the carboxyl-terminal portion of the receptor tyrosine-protein kinase erbB-3. To determine the biological relevance of this interaction, we treated MC3T3-E1 mouse osteoblast cells transfected with either a SOST expression plasmid or a control vector, with recombinant heregulin/neuregulin. Phospho-p44/42 (Thr202/Tyr204) MAPK was assessed in heregulin/neuregulin treated cells. We observed an increase in phospho-p44/42 (Thr202/Tyr204) MAPK concentrations in SOST transfected cells but not in cells transfected with a control vector, thus demonstrating a modulatory effect of sclerostin on heregulin/neuregulin signaling in osteoblasts. The data demonstrate that sclerostin functions in part, by modulating the activity of erbB-3.

  7. Complex interactions between cis-regulatory modules in native conformation are critical for Drosophila snail expression.

    PubMed

    Dunipace, Leslie; Ozdemir, Anil; Stathopoulos, Angelike

    2011-09-01

    It has been shown in several organisms that multiple cis-regulatory modules (CRMs) of a gene locus can be active concurrently to support similar spatiotemporal expression. To understand the functional importance of such seemingly redundant CRMs, we examined two CRMs from the Drosophila snail gene locus, which are both active in the ventral region of pre-gastrulation embryos. By performing a deletion series in a ∼25 kb DNA rescue construct using BAC recombineering and site-directed transgenesis, we demonstrate that the two CRMs are not redundant. The distal CRM is absolutely required for viability, whereas the proximal CRM is required only under extreme conditions such as high temperature. Consistent with their distinct requirements, the CRMs support distinct expression patterns: the proximal CRM exhibits an expanded expression domain relative to endogenous snail, whereas the distal CRM exhibits almost complete overlap with snail except at the anterior-most pole. We further show that the distal CRM normally limits the increased expression domain of the proximal CRM and that the proximal CRM serves as a `damper' for the expression levels driven by the distal CRM. Thus, the two CRMs interact in cis in a non-additive fashion and these interactions may be important for fine-tuning the domains and levels of gene expression. PMID:21813571

  8. Olfactory Sensory Activity Modulates Microglial-Neuronal Interactions during Dopaminergic Cell Loss in the Olfactory Bulb

    PubMed Central

    Grier, Bryce D.; Belluscio, Leonardo; Cheetham, Claire E. J.

    2016-01-01

    The mammalian olfactory bulb (OB) displays robust activity-dependent plasticity throughout life. Dopaminergic (DA) neurons in the glomerular layer (GL) of the OB are particularly plastic, with loss of sensory input rapidly reducing tyrosine hydroxylase (TH) expression and dopamine production, followed by a substantial reduction in DA neuron number. Here, we asked whether microglia participate in activity-dependent elimination of DA neurons in the mouse OB. Interestingly, we found a significant reduction in the number of both DA neurons and their synapses in the OB ipsilateral to the occluded naris (occluded OB) within just 7 days of sensory deprivation. Concomitantly, the volume of the occluded OB decreased, resulting in an increase in microglial density. Microglia in the occluded OB also adopted morphologies consistent with activation. Using in vivo 2-photon imaging and histological analysis we then showed that loss of olfactory input markedly altered microglial-neuronal interactions during the time that DA neurons are being eliminated: both microglial process motility and the frequency of wrapping of DA neuron somata by activated microglia increased significantly in the occluded OB. Furthermore, we found microglia in the occluded OB that had completely engulfed components of DA neurons. Together, our data provide evidence that loss of olfactory input modulates microglial-DA neuron interactions in the OB, thereby suggesting an important role for microglia in the activity-dependent elimination of DA neurons and their synapses. PMID:27471450

  9. iPPI-DB: an online database of modulators of protein-protein interactions.

    PubMed

    Labbé, Céline M; Kuenemann, Mélaine A; Zarzycka, Barbara; Vriend, Gert; Nicolaes, Gerry A F; Lagorce, David; Miteva, Maria A; Villoutreix, Bruno O; Sperandio, Olivier

    2016-01-01

    In order to boost the identification of low-molecular-weight drugs on protein-protein interactions (PPI), it is essential to properly collect and annotate experimental data about successful examples. This provides the scientific community with the necessary information to derive trends about privileged physicochemical properties and chemotypes that maximize the likelihood of promoting a given chemical probe to the most advanced stages of development. To this end we have developed iPPI-DB (freely accessible at http://www.ippidb.cdithem.fr), a database that contains the structure, some physicochemical characteristics, the pharmacological data and the profile of the PPI targets of several hundreds modulators of protein-protein interactions. iPPI-DB is accessible through a web application and can be queried according to two general approaches: using physicochemical/pharmacological criteria; or by chemical similarity to a user-defined structure input. In both cases the results are displayed as a sortable and exportable datasheet with links to external databases such as Uniprot, PubMed. Furthermore each compound in the table has a link to an individual ID card that contains its physicochemical and pharmacological profile derived from iPPI-DB data. This includes information about its binding data, ligand and lipophilic efficiencies, location in the PPI chemical space, and importantly similarity with known drugs, and links to external databases like PubChem, and ChEMBL.

  10. DHCVIM - a direct heating containment vessel interactions module: applications to Sandia National Laboratories Surtsey experiments

    SciTech Connect

    Ginsberg, T.; Tutu, N.K.

    1987-01-01

    Direct containment heating is the mechanism of severe nuclear reactor accident containment loading that results from transfer of thermal and chemical energy from high-temperature, finely divided, molten core material to the containment atmosphere. The direct heating containment vessel interactions module (DHCVIM) has been developed at Brookhaven National Laboratory to model the mechanisms of containment loading resulting from the direct heating accident sequence. The calculational procedure is being used at present to model the Sandia National Laboratories one-tenth-scale Surtsey direct containment heating experiments. The objective of the code is to provide a test bed for detailed modeling of various aspects of the thermal, chemical, and hydrodynamic interactions that are expected to occur in three regions of a containment building: reactor cavity, intermediate subcompartments, and containment dome. Major emphasis is placed on the description of reactor cavity dynamics. This paper summarizes the modeling principles that are incorporated in DHCVIM and presents a prediction of the Surtsey Test DCH-2 that was made prior to execution of the experiment.

  11. DHCVIM: A direct heating containment vessel interactions module: Applications to Sandia National Laboratory Surtsey experiments

    SciTech Connect

    Ginsberg, T.; Tutu, N.K.

    1987-01-01

    Direct containment heating is the mechanism of severe nuclear reactor accident containment loading which results from transfer of thermal and chemical energy from high temperature, finely divided, molten core material to the containment atmosphere. The Direct Heating Containment Vessel Interactions Module, DHCVIM, has been developed at BNL to mechanistically model the mechanisms of containment loading resulting from the direct heating accident sequence. The calculational procedure is being used at present to model the Sandia National Laboratory 1/10th-scale Surtsey direct containment heating experiments. The objective of the code is to provide a test bed for detailed modeling of various aspects of the thermal, chemical and hydrodynamic interactions which are expected to occur in three regions of a containment building: reactor cavity, intermediate subcompartments and containment done. Major emphasis is placed, at present, on the description of reactor cavity dynamics. This paper summarizes the modeling principles which are incorporated in DHCVIM and presents a prediction of the Surtsey Test DCH-2 which was made prior to execution of the experiment.

  12. Olfactory Sensory Activity Modulates Microglial-Neuronal Interactions during Dopaminergic Cell Loss in the Olfactory Bulb.

    PubMed

    Grier, Bryce D; Belluscio, Leonardo; Cheetham, Claire E J

    2016-01-01

    The mammalian olfactory bulb (OB) displays robust activity-dependent plasticity throughout life. Dopaminergic (DA) neurons in the glomerular layer (GL) of the OB are particularly plastic, with loss of sensory input rapidly reducing tyrosine hydroxylase (TH) expression and dopamine production, followed by a substantial reduction in DA neuron number. Here, we asked whether microglia participate in activity-dependent elimination of DA neurons in the mouse OB. Interestingly, we found a significant reduction in the number of both DA neurons and their synapses in the OB ipsilateral to the occluded naris (occluded OB) within just 7 days of sensory deprivation. Concomitantly, the volume of the occluded OB decreased, resulting in an increase in microglial density. Microglia in the occluded OB also adopted morphologies consistent with activation. Using in vivo 2-photon imaging and histological analysis we then showed that loss of olfactory input markedly altered microglial-neuronal interactions during the time that DA neurons are being eliminated: both microglial process motility and the frequency of wrapping of DA neuron somata by activated microglia increased significantly in the occluded OB. Furthermore, we found microglia in the occluded OB that had completely engulfed components of DA neurons. Together, our data provide evidence that loss of olfactory input modulates microglial-DA neuron interactions in the OB, thereby suggesting an important role for microglia in the activity-dependent elimination of DA neurons and their synapses. PMID:27471450

  13. Generalized spin-dependent WIMP-nucleus interactions and the DAMA modulation effect

    SciTech Connect

    Scopel, Stefano; Yoon, Kook-Hyun; Yoon, Jong-Hyun E-mail: koreasds@naver.com

    2015-07-01

    Guided by non-relativistic Effective Field Theory (EFT) we classify the most general spin-dependent interactions between a fermionic Weakly Interacting Massive Particle (WIMP) and nuclei, and within this class of models we discuss the viability of an interpretation of the DAMA modulation result in terms of a signal from WIMP elastic scatterings using a halo-independent approach. We find that, although several relativistic EFT's can lead to a spin-dependent cross section, in some cases with an explicit, non-negligible dependence on the WIMP incoming velocity, three main scenarios can be singled out in the non-relativistic limit which approximately encompass them all, and that only differ by their dependence on the transferred momentum. For two of them compatibility between DAMA and other constraints is possible for a WIMP mass below 30 GeV, but only for a WIMP velocity distribution in the halo of our Galaxy which departs from a Maxwellian. This is achieved by combining a suppression of the WIMP effective coupling to neutrons (to evade constraints from xenon and germanium detectors) to an explicit quadratic or quartic dependence of the cross section on the transferred momentum (that leads to a relative enhancement of the expected rate off sodium in DAMA compared to that off fluorine in droplet detectors and bubble chambers). For larger WIMP masses the same scenarios are excluded by scatterings off iodine in COUPP.

  14. iPPI-DB: an online database of modulators of protein-protein interactions.

    PubMed

    Labbé, Céline M; Kuenemann, Mélaine A; Zarzycka, Barbara; Vriend, Gert; Nicolaes, Gerry A F; Lagorce, David; Miteva, Maria A; Villoutreix, Bruno O; Sperandio, Olivier

    2016-01-01

    In order to boost the identification of low-molecular-weight drugs on protein-protein interactions (PPI), it is essential to properly collect and annotate experimental data about successful examples. This provides the scientific community with the necessary information to derive trends about privileged physicochemical properties and chemotypes that maximize the likelihood of promoting a given chemical probe to the most advanced stages of development. To this end we have developed iPPI-DB (freely accessible at http://www.ippidb.cdithem.fr), a database that contains the structure, some physicochemical characteristics, the pharmacological data and the profile of the PPI targets of several hundreds modulators of protein-protein interactions. iPPI-DB is accessible through a web application and can be queried according to two general approaches: using physicochemical/pharmacological criteria; or by chemical similarity to a user-defined structure input. In both cases the results are displayed as a sortable and exportable datasheet with links to external databases such as Uniprot, PubMed. Furthermore each compound in the table has a link to an individual ID card that contains its physicochemical and pharmacological profile derived from iPPI-DB data. This includes information about its binding data, ligand and lipophilic efficiencies, location in the PPI chemical space, and importantly similarity with known drugs, and links to external databases like PubChem, and ChEMBL. PMID:26432833

  15. Modulation of social interactions by immune stimulation in honey bee, Apis mellifera, workers

    PubMed Central

    Richard, F-J; Aubert, A; Grozinger, CM

    2008-01-01

    Background Immune response pathways have been relatively well-conserved across animal species, with similar systems in both mammals and invertebrates. Interestingly, honey bees have substantially reduced numbers of genes associated with immune function compared with solitary insect species. However, social species such as honey bees provide an excellent environment for pathogen or parasite transmission with controlled environmental conditions in the hive, high population densities, and frequent interactions. This suggests that honey bees may have developed complementary mechanisms, such as behavioral modifications, to deal with disease. Results Here, we demonstrate that activation of the immune system in honey bees (using bacterial lipopolysaccharides as a non-replicative pathogen) alters the social responses of healthy nestmates toward the treated individuals. Furthermore, treated individuals expressed significant differences in overall cuticular hydrocarbon profiles compared with controls. Finally, coating healthy individuals with extracts containing cuticular hydrocarbons of immunostimulated individuals significantly increased the agonistic responses of nestmates. Conclusion Since cuticular hydrocarbons play a critical role in nestmate recognition and other social interactions in a wide variety of insect species, modulation of such chemical profiles by the activation of the immune system could play a crucial role in the social regulation of pathogen dissemination within the colony. PMID:19014614

  16. Complex interactions between cis-regulatory modules in native conformation are critical for Drosophila snail expression

    PubMed Central

    Dunipace, Leslie; Ozdemir, Anil; Stathopoulos, Angelike

    2011-01-01

    It has been shown in several organisms that multiple cis-regulatory modules (CRMs) of a gene locus can be active concurrently to support similar spatiotemporal expression. To understand the functional importance of such seemingly redundant CRMs, we examined two CRMs from the Drosophila snail gene locus, which are both active in the ventral region of pre-gastrulation embryos. By performing a deletion series in a ∼25 kb DNA rescue construct using BAC recombineering and site-directed transgenesis, we demonstrate that the two CRMs are not redundant. The distal CRM is absolutely required for viability, whereas the proximal CRM is required only under extreme conditions such as high temperature. Consistent with their distinct requirements, the CRMs support distinct expression patterns: the proximal CRM exhibits an expanded expression domain relative to endogenous snail, whereas the distal CRM exhibits almost complete overlap with snail except at the anterior-most pole. We further show that the distal CRM normally limits the increased expression domain of the proximal CRM and that the proximal CRM serves as a `damper' for the expression levels driven by the distal CRM. Thus, the two CRMs interact in cis in a non-additive fashion and these interactions may be important for fine-tuning the domains and levels of gene expression. PMID:21813571

  17. Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations

    PubMed Central

    Yang, Liu; Munck, Martina; Swaminathan, Karthic; Kapinos, Larisa E.; Noegel, Angelika A.; Neumann, Sascha

    2013-01-01

    Background In eukaryotes the genetic material is enclosed by a continuous membrane system, the nuclear envelope (NE). Along the NE specific proteins assemble to form meshworks and mutations in these proteins have been described in a group of human diseases called laminopathies. Laminopathies include lipodystrophies, muscle and cardiac diseases as well as metabolic or progeroid syndromes. Most laminopathies are caused by mutations in the LMNAgene encoding lamins A/C. Together with Nesprins (Nuclear Envelope Spectrin Repeat Proteins) they are core components of the LINC complex (Linker of Nucleoskeleton and Cytoskeleton). The LINC complex connects the nucleoskeleton and the cytoskeleton and plays a role in the transfer of mechanically induced signals along the NE into the nucleus, and its components have been attributed functions in maintaining nuclear and cellular organization as well as signal transduction. Results Here we narrowed down the interaction sites between lamin A and Nesprin-2 to aa 403–425 in lamin A and aa 6146–6347 in Nesprin-2. Laminopathic mutations in and around the involved region of lamin A (R401C, G411D, G413C, V415I, R419C, L421P, R427G, Q432X) modulate the interaction with Nesprin-2 and this may contribute to the disease phenotype. The most notable mutation is the lamin A mutation Q432X that alters LINC complex protein assemblies and causes chromosomal and transcription factor rearrangements. Conclusion Mutations in Nesprin-2 and lamin A are characterised by complex genotype phenotype relations. Our data show that each mutation in LMNAanalysed here has a distinct impact on the interaction among both proteins that substantially explains how distinct mutations in widely expressed genes lead to the formation of phenotypically different diseases. PMID:23977161

  18. Bisphosphonates modulate vital functions of human osteoblasts and affect their interactions with breast cancer cells.

    PubMed

    Kaiser, Tatjana; Teufel, Ingrid; Geiger, Konstanze; Vater, Yvonne; Aicher, Wilhelm K; Klein, Gerd; Fehm, Tanja

    2013-07-01

    Bisphosphonates (BPs) are in clinical use for the treatment of breast cancer patients with bone metastases. Their anti-resorptive effect is mainly explained by inhibition of osteoclast activity, but recent evidence also points to a direct action of BPs on bone-forming osteoblasts. However, the mechanisms how BPs influence osteoblasts and their interactions with breast cancer cells are still poorly characterized. Human osteoblasts isolated from bone specimens were characterized in depth by their expression of osteogenic marker genes. The influence of the nitrogen-containing BPs zoledronate (Zol), ibandronate (Iban), and pamidronate (Pam) on molecular and cellular functions of osteoblasts was assessed focusing on cell proliferation and viability, apoptosis, cytokine secretion, and osteogenic-associated genes. Furthermore, effects of BPs on osteoblast-breast tumor cell interactions were examined in an established in vitro model system. The BPs Zol and Pam inhibited cell viability of osteoblasts. This effect was mediated by an induction of caspase-dependent apoptosis in osteoblasts. By interfering with the mevalonate pathway, Zol also reduces the proliferation of osteoblasts. The expression of phenotypic markers of osteogenic differentiation was altered by Zol and Pam. In addition, both BPs strongly influenced the secretion of the chemokine CCL2 by osteoblasts. Breast cancer cells also responded to Zol and Pam with a reduced cell adhesion to osteoblast-derived extracellular matrix molecules and with a decreased migration in response to osteoblast-secreted factors. BPs revealed prominent effects on human osteoblasts. Zol and Pam as the most potent BPs affected not only the expression of osteogenic markers, osteoblast viability, and proliferation but also important osteoblast-tumor cell interactions. Changing the osteoblast metabolism by BPs modulates migration and adhesion of breast cancer cells as well. PMID:23807419

  19. Reversibly Switching Bilayer Permeability and Release Modules of Photochromic Polymersomes Stabilized by Cooperative Noncovalent Interactions.

    PubMed

    Wang, Xiaorui; Hu, Jinming; Liu, Guhuan; Tian, Jie; Wang, Huijuan; Gong, Ming; Liu, Shiyong

    2015-12-01

    We report on the fabrication of photochromic polymersomes exhibiting photoswitchable and reversible bilayer permeability from newly designed poly(ethylene oxide)-b-PSPA (PEO-b-PSPA) diblock copolymers, where SPA is spiropyran (SP)-based monomer containing a unique carbamate linkage. Upon self-assembling into polymersomes, SP moieties within vesicle bilayers undergo reversible phototriggered isomerization between hydrophobic spiropyran (SP, λ2 > 450 nm irradiation) and zwitterionic merocyanine (MC, λ1 < 420 nm irradiation) states. For both SP and MC polymersomes, their microstructures are stabilized by multiple cooperative noncovalent interactions including hydrophobic, hydrogen bonding, π-π stacking, and paired electrostatic (zwitterionic) interactions, with the latter two types being exclusive for MC polymersomes. Control experiments using analogous block copolymers of hydrophobic SP monomer with a carbonate linkage (SPO) and conventional spiropyran methacrylate monomer (SPMA) containing a single ester functionality were then conducted, revealing that carbamate-incurred hydrogen bonding interactions in PEO-b-PSPA are crucial for polymersome stabilization in the zwitterionic MC state. Moreover, reversible phototriggered SP-to-MC polymersome transition is accompanied by membrane polarity and permeability switching from being nonimpermeable to selectively permeable toward noncharged, charged, and zwitterionic small molecule species below critical molar masses. Intriguingly, UV-actuated MC polymersomes possess two types of release modules: (1) sustained release upon short UV irradiation duration by taking advantage of the unexpectedly slow spontaneous MC-to-SP transition kinetics (t1/2 > 20 h) under dark conditions; (2) on-demand and switchable release under alternated UV-vis light irradiation. We further demonstrate photoswitchable spatiotemporal release of 4',6-diamidino-2-phenylindole (DAPI, cell nuclei-staining dye) within living HeLa cells.

  20. Mechanics of interaction and atomic-scale wear of amplitude modulation atomic force microscopy probes.

    PubMed

    Vahdat, Vahid; Grierson, David S; Turner, Kevin T; Carpick, Robert W

    2013-04-23

    Wear is one of the main factors that hinders the performance of probes for atomic force microscopy (AFM), including for the widely used amplitude modulation (AM-AFM) mode. Unfortunately, a comprehensive scientific understanding of nanoscale wear is lacking. We have developed a protocol for conducting consistent and quantitative AM-AFM wear experiments. The protocol involves controlling the tip-sample interaction regime during AM-AFM scanning, determining the tip-sample contact geometry, calculating the peak repulsive force and normal stress over the course of the wear test, and quantifying the wear volume using high-resolution transmission electron microscopy imaging. The peak repulsive tip-sample interaction force is estimated from a closed-form equation accompanied by an effective tip radius measurement procedure, which combines transmission electron microscopy and blind tip reconstruction. The contact stress is estimated by applying Derjaguin-Müller-Toporov contact mechanics model and also numerically solving a general contact mechanics model recently developed for the adhesive contact of arbitrary axisymmetric punch shapes. We discuss the important role that the assumed tip shape geometry plays in calculating both the interaction forces and the contact stresses. Contact stresses are significantly affected by the tip geometry while the peak repulsive force is mainly determined by experimentally controlled parameters, specifically, the free oscillation amplitude and amplitude ratio. The applicability of this protocol is demonstrated experimentally by assessing the performance of diamond-like carbon-coated and silicon-nitride-coated silicon probes scanned over ultrananocrystalline diamond substrates in repulsive mode AM-AFM. There is no sign of fracture or plastic deformation in the case of diamond-like carbon; wear could be characterized as a gradual atom-by-atom process. In contrast, silicon nitride wears through removal of the cluster of atoms and plastic

  1. Reversibly Switching Bilayer Permeability and Release Modules of Photochromic Polymersomes Stabilized by Cooperative Noncovalent Interactions.

    PubMed

    Wang, Xiaorui; Hu, Jinming; Liu, Guhuan; Tian, Jie; Wang, Huijuan; Gong, Ming; Liu, Shiyong

    2015-12-01

    We report on the fabrication of photochromic polymersomes exhibiting photoswitchable and reversible bilayer permeability from newly designed poly(ethylene oxide)-b-PSPA (PEO-b-PSPA) diblock copolymers, where SPA is spiropyran (SP)-based monomer containing a unique carbamate linkage. Upon self-assembling into polymersomes, SP moieties within vesicle bilayers undergo reversible phototriggered isomerization between hydrophobic spiropyran (SP, λ2 > 450 nm irradiation) and zwitterionic merocyanine (MC, λ1 < 420 nm irradiation) states. For both SP and MC polymersomes, their microstructures are stabilized by multiple cooperative noncovalent interactions including hydrophobic, hydrogen bonding, π-π stacking, and paired electrostatic (zwitterionic) interactions, with the latter two types being exclusive for MC polymersomes. Control experiments using analogous block copolymers of hydrophobic SP monomer with a carbonate linkage (SPO) and conventional spiropyran methacrylate monomer (SPMA) containing a single ester functionality were then conducted, revealing that carbamate-incurred hydrogen bonding interactions in PEO-b-PSPA are crucial for polymersome stabilization in the zwitterionic MC state. Moreover, reversible phototriggered SP-to-MC polymersome transition is accompanied by membrane polarity and permeability switching from being nonimpermeable to selectively permeable toward noncharged, charged, and zwitterionic small molecule species below critical molar masses. Intriguingly, UV-actuated MC polymersomes possess two types of release modules: (1) sustained release upon short UV irradiation duration by taking advantage of the unexpectedly slow spontaneous MC-to-SP transition kinetics (t1/2 > 20 h) under dark conditions; (2) on-demand and switchable release under alternated UV-vis light irradiation. We further demonstrate photoswitchable spatiotemporal release of 4',6-diamidino-2-phenylindole (DAPI, cell nuclei-staining dye) within living HeLa cells. PMID:26583385

  2. Epigenetic Modulation in Periodontitis: Interaction of Adiponectin and JMJD3-IRF4 Axis in Macrophages.

    PubMed

    Xuan, Dongying; Han, Qianqian; Tu, Qisheng; Zhang, Lan; Yu, Liming; Murry, Dana; Tu, Tianchi; Tang, Yin; Lian, Jane B; Stein, Gary S; Valverde, Paloma; Zhang, Jincai; Chen, Jake

    2016-05-01

    Emerging evidence suggests an important role for epigenetic mechanisms in modulating signals during macrophage polarization and inflammation. JMJD3, a JmjC family histone demethylase necessary for M2 polarization is also required for effective induction of multiple M1 genes by lipopolysaccharide (LPS). However, the effects of JMJD3 to inflammation in the context of obesity remains unknown. To address this deficiency, we firstly examined the expression of JMJD3 in macrophage isolated from bone marrow and adipose tissue of diet induced obesity (DIO) mice. The results indicated that JMJD3 was down-regulated in obesity. Adiponectin (APN), a factor secreted by adipose tissue which is down-regulated in obesity, functions to switch macrophage polarization from M1 to M2, thereby attenuating chronic inflammation. Intriguingly, our results indicated that APN contributed to JMJD3 up-regulation, reduced macrophage infiltration in obese adipose tissue, and abolished the up-regulation of JMJD3 in peritoneal macrophages isolated from DIO mice when challenged with Porphyromonas gingivalis LPS (pg.lps). To elucidate the interaction of APN and JMJD3 involved in macrophage transformation in the context of inflammation, we designed the loss and gain-function experiments of APN in vivo with APN(-/-) mice with experimental periodontitis and in vitro with macrophage isolated from APN(-/-) mice. For the first time, we found that APN can help to reduce periodontitis-related bone loss, modulate JMJD3 and IRF4 expression, and macrophage infiltration. Therefore, it can be inferred that APN may contribute to anti-inflammation macrophage polarization by regulating JMJD3 expression, which provides a basis for macrophage-centered epigenetic therapeutic strategies.

  3. Integrating Anatomy Training into Radiation Oncology Residency: Considerations for Developing a Multidisciplinary, Interactive Learning Module for Adult Learners

    ERIC Educational Resources Information Center

    Labranche, Leah; Johnson, Marjorie; Palma, David; D'Souza, Leah; Jaswal, Jasbir

    2015-01-01

    Radiation oncologists require an in-depth understanding of anatomical relationships for modern clinical practice, although most do not receive formal anatomy training during residency. To fulfill the need for instruction in relevant anatomy, a series of four multidisciplinary, interactive learning modules were developed for a cohort of radiation…

  4. Improving Intercultural Interactions. Modules for Cross-Cultural Training Programs. Multicultural Aspects of Counseling Series 3.

    ERIC Educational Resources Information Center

    Brislin, Richard W., Ed.; Yoshida, Tomoko, Ed.

    This book contains modules for use in cross-cultural training programs. A module differs from a chapter in that it is a collection of materials that guide the reader both on the content of a defined unit of training and the method of delivery of that content. The modules are grouped into four sections, three corresponding to organizations in which…

  5. Role of IGF1R+ MSCs in modulating neuroplasticity via CXCR4 cross-interaction

    PubMed Central

    Lee, Hsu-Tung; Chang, Hao-Teng; Lee, Sophie; Lin, Chen-Huan; Fan, Jia-Rong; Lin, Shinn-Zong; Hsu, Chung Y.; Hsieh, Chia-Hung; Shyu, Woei-Cherng

    2016-01-01

    To guide the use of human mesenchymal stem cells (MSCs) toward clinical applications, identifying pluripotent-like-markers for selecting MSCs that retain potent self-renewal-ability should be addressed. Here, an insulin-like growth factor 1 receptor (IGF1R)–expressing sub-population in human dental pulp MSCs (hDSCs), displayed multipotent properties. IGF1R expression could be maintained in hDSCs when they were cultured in 2% human cord blood serum (hUCS) in contrast to that in 10% fetal calf serum (FCS). Cytokine array showed that hUCS contained higher amount of several growth factors compared to FCS, including IGF-1 and platelet-derived growth factor (PDGF-BB). These cytokines modulates the signaling events in the hDSCs and potentially enhances engraftment upon transplantation. Specifically, a bidirectional cross-talk between IGF1R/IGF1 and CXCR4/SDF-1α signaling pathways in hDSCs, as revealed by interaction of the two receptors and synergistic activation of both signaling pathways. In rat stroke model, animals receiving IGF1R+ hDSCs transplantation, interaction between IGF1R and CXCR4 was demonstrated to promote neuroplasticity, therefore improving neurological function through increasing glucose metabolic activity, enhancing angiogenesis and anti-inflammatiory effects. Therefore, PDGF in hUCS-culture system contributed to the maintenance of the expression of IGF1R in hDSCs. Furthermore, implantation of IGF1R+ hDSCs exerted enhanced neuroplasticity via integrating inputs from both CXCR4 and IGF1R signaling pathways. PMID:27586516

  6. Metabolic and trophic interactions modulate methane production by Arctic peat microbiota in response to warming.

    PubMed

    Tveit, Alexander Tøsdal; Urich, Tim; Frenzel, Peter; Svenning, Mette Marianne

    2015-05-12

    Arctic permafrost soils store large amounts of soil organic carbon (SOC) that could be released into the atmosphere as methane (CH4) in a future warmer climate. How warming affects the complex microbial network decomposing SOC is not understood. We studied CH4 production of Arctic peat soil microbiota in anoxic microcosms over a temperature gradient from 1 to 30 °C, combining metatranscriptomic, metagenomic, and targeted metabolic profiling. The CH4 production rate at 4 °C was 25% of that at 25 °C and increased rapidly with temperature, driven by fast adaptations of microbial community structure, metabolic network of SOC decomposition, and trophic interactions. Below 7 °C, syntrophic propionate oxidation was the rate-limiting step for CH4 production; above this threshold temperature, polysaccharide hydrolysis became rate limiting. This change was associated with a shift within the functional guild for syntrophic propionate oxidation, with Firmicutes being replaced by Bacteroidetes. Correspondingly, there was a shift from the formate- and H2-using Methanobacteriales to Methanomicrobiales and from the acetotrophic Methanosarcinaceae to Methanosaetaceae. Methanogenesis from methylamines, probably stemming from degradation of bacterial cells, became more important with increasing temperature and corresponded with an increased relative abundance of predatory protists of the phylum Cercozoa. We concluded that Arctic peat microbiota responds rapidly to increased temperatures by modulating metabolic and trophic interactions so that CH4 is always highly produced: The microbial community adapts through taxonomic shifts, and cascade effects of substrate availability cause replacement of functional guilds and functional changes within taxa.

  7. Metabolic and trophic interactions modulate methane production by Arctic peat microbiota in response to warming

    PubMed Central

    Tveit, Alexander Tøsdal; Urich, Tim; Frenzel, Peter; Svenning, Mette Marianne

    2015-01-01

    Arctic permafrost soils store large amounts of soil organic carbon (SOC) that could be released into the atmosphere as methane (CH4) in a future warmer climate. How warming affects the complex microbial network decomposing SOC is not understood. We studied CH4 production of Arctic peat soil microbiota in anoxic microcosms over a temperature gradient from 1 to 30 °C, combining metatranscriptomic, metagenomic, and targeted metabolic profiling. The CH4 production rate at 4 °C was 25% of that at 25 °C and increased rapidly with temperature, driven by fast adaptations of microbial community structure, metabolic network of SOC decomposition, and trophic interactions. Below 7 °C, syntrophic propionate oxidation was the rate-limiting step for CH4 production; above this threshold temperature, polysaccharide hydrolysis became rate limiting. This change was associated with a shift within the functional guild for syntrophic propionate oxidation, with Firmicutes being replaced by Bacteroidetes. Correspondingly, there was a shift from the formate- and H2-using Methanobacteriales to Methanomicrobiales and from the acetotrophic Methanosarcinaceae to Methanosaetaceae. Methanogenesis from methylamines, probably stemming from degradation of bacterial cells, became more important with increasing temperature and corresponded with an increased relative abundance of predatory protists of the phylum Cercozoa. We concluded that Arctic peat microbiota responds rapidly to increased temperatures by modulating metabolic and trophic interactions so that CH4 is always highly produced: The microbial community adapts through taxonomic shifts, and cascade effects of substrate availability cause replacement of functional guilds and functional changes within taxa. PMID:25918393

  8. Role of IGF1R(+) MSCs in modulating neuroplasticity via CXCR4 cross-interaction.

    PubMed

    Lee, Hsu-Tung; Chang, Hao-Teng; Lee, Sophie; Lin, Chen-Huan; Fan, Jia-Rong; Lin, Shinn-Zong; Hsu, Chung Y; Hsieh, Chia-Hung; Shyu, Woei-Cherng

    2016-01-01

    To guide the use of human mesenchymal stem cells (MSCs) toward clinical applications, identifying pluripotent-like-markers for selecting MSCs that retain potent self-renewal-ability should be addressed. Here, an insulin-like growth factor 1 receptor (IGF1R)-expressing sub-population in human dental pulp MSCs (hDSCs), displayed multipotent properties. IGF1R expression could be maintained in hDSCs when they were cultured in 2% human cord blood serum (hUCS) in contrast to that in 10% fetal calf serum (FCS). Cytokine array showed that hUCS contained higher amount of several growth factors compared to FCS, including IGF-1 and platelet-derived growth factor (PDGF-BB). These cytokines modulates the signaling events in the hDSCs and potentially enhances engraftment upon transplantation. Specifically, a bidirectional cross-talk between IGF1R/IGF1 and CXCR4/SDF-1α signaling pathways in hDSCs, as revealed by interaction of the two receptors and synergistic activation of both signaling pathways. In rat stroke model, animals receiving IGF1R(+) hDSCs transplantation, interaction between IGF1R and CXCR4 was demonstrated to promote neuroplasticity, therefore improving neurological function through increasing glucose metabolic activity, enhancing angiogenesis and anti-inflammatiory effects. Therefore, PDGF in hUCS-culture system contributed to the maintenance of the expression of IGF1R in hDSCs. Furthermore, implantation of IGF1R(+) hDSCs exerted enhanced neuroplasticity via integrating inputs from both CXCR4 and IGF1R signaling pathways. PMID:27586516

  9. Rosetta stone method for detecting protein function and protein-protein interactions from genome sequences

    DOEpatents

    Eisenberg, David; Marcotte, Edward M.; Pellegrini, Matteo; Thompson, Michael J.; Yeates, Todd O.

    2002-10-15

    A computational method system, and computer program are provided for inferring functional links from genome sequences. One method is based on the observation that some pairs of proteins A' and B' have homologs in another organism fused into a single protein chain AB. A trans-genome comparison of sequences can reveal these AB sequences, which are Rosetta Stone sequences because they decipher an interaction between A' and B. Another method compares the genomic sequence of two or more organisms to create a phylogenetic profile for each protein indicating its presence or absence across all the genomes. The profile provides information regarding functional links between different families of proteins. In yet another method a combination of the above two methods is used to predict functional links.

  10. Lipid-mediated Protein-protein Interactions Modulate Respiration-driven ATP Synthesis

    PubMed Central

    Nilsson, Tobias; Lundin, Camilla Rydström; Nordlund, Gustav; Ädelroth, Pia; von Ballmoos, Christoph; Brzezinski, Peter

    2016-01-01

    Energy conversion in biological systems is underpinned by membrane-bound proton transporters that generate and maintain a proton electrochemical gradient across the membrane which used, e.g. for generation of ATP by the ATP synthase. Here, we have co-reconstituted the proton pump cytochrome bo3 (ubiquinol oxidase) together with ATP synthase in liposomes and studied the effect of changing the lipid composition on the ATP synthesis activity driven by proton pumping. We found that for 100 nm liposomes, containing 5 of each proteins, the ATP synthesis rates decreased significantly with increasing fractions of DOPA, DOPE, DOPG or cardiolipin added to liposomes made of DOPC; with e.g. 5% DOPG, we observed an almost 50% decrease in the ATP synthesis rate. However, upon increasing the average distance between the proton pumps and ATP synthases, the ATP synthesis rate dropped and the lipid dependence of this activity vanished. The data indicate that protons are transferred along the membrane, between cytochrome bo3 and the ATP synthase, but only at sufficiently high protein densities. We also argue that the local protein density may be modulated by lipid-dependent changes in interactions between the two proteins complexes, which points to a mechanism by which the cell may regulate the overall activity of the respiratory chain. PMID:27063297

  11. Platelet interactions with titanium: modulation of platelet activity by surface topography.

    PubMed

    Park, J Y; Gemmell, C H; Davies, J E

    2001-10-01

    Endosseous implants initially come into contact with blood. Thus, the nature of the interactions between blood and implanted endosseous implants may influence subsequent bone healing events in the peri-implant healing compartment. We conducted studies to address the following question: Does implant surface microtexture modulate platelet activity? We used commercially pure Ti (cpTi) disks with four different surface finishes: dual acid-etched (DAE), 320 grit (320G) abraded, machined, and p1200 polished cpTi. Surfaces were characterized by scanning electron microscopy (SEM) and optical profilometry. The DAE and 320G surfaces presented more complex microtextures than the machined or polished surfaces. Platelet activities were measured by quantifying platelet adherence, platelet-derived microparticle (MP) formation, and P-selectin expression as function of surface type. Platelet adhesion, measured using a lactate dehydrogenase (LDH) assay. was increased on DAE and 320G surfaces compared to machined and polished surfaces (p < 0.05). M P formation and P-selectin expression, assayed by flow cytometry, also showed increased activation of platelets on DAE and 320G surfaces. Because increased activation of platelets may lead to up-regulation of osteogenic responses during bone healing, these results may explain the enhanced osteoconductivity known to occur with DAE cpTi surfaces in comparison with machined cpTi surfaces. PMID:11519787

  12. Program EPICP: Electron photon interaction code, photon test module. Version 94.2

    SciTech Connect

    Cullen, D.E.

    1994-09-01

    The computer code EPICP performs Monte Carlo photon transport calculations in a simple one zone cylindrical detector. Results include deposition within the detector, transmission, reflection and lateral leakage from the detector, as well as events and energy deposition as a function of the depth into the detector. EPICP is part of the EPIC (Electron Photon Interaction Code) system. EPICP is designed to perform both normal transport calculations and diagnostic calculations involving only photons, with the objective of developing optimum algorithms for later use in EPIC. The EPIC system includes other modules that are designed to develop optimum algorithms for later use in EPIC; this includes electron and positron transport (EPICE), neutron transport (EPICN), charged particle transport (EPICC), geometry (EPICG), source sampling (EPICS). This is a modular system that once optimized can be linked together to consider a wide variety of particles, geometries, sources, etc. By design EPICP only considers photon transport. In particular it does not consider electron transport so that later EPICP and EPICE can be used to quantitatively evaluate the importance of electron transport when starting from photon sources. In this report I will merely mention where we expect the results to significantly differ from those obtained considering only photon transport from that obtained using coupled electron-photon transport.

  13. Interactive Scene Analysis Module - A sensor-database fusion system for telerobotic environments

    NASA Technical Reports Server (NTRS)

    Cooper, Eric G.; Vazquez, Sixto L.; Goode, Plesent W.

    1992-01-01

    Accomplishing a task with telerobotics typically involves a combination of operator control/supervision and a 'script' of preprogrammed commands. These commands usually assume that the location of various objects in the task space conform to some internal representation (database) of that task space. The ability to quickly and accurately verify the task environment against the internal database would improve the robustness of these preprogrammed commands. In addition, the on-line initialization and maintenance of a task space database is difficult for operators using Cartesian coordinates alone. This paper describes the Interactive Scene' Analysis Module (ISAM) developed to provide taskspace database initialization and verification utilizing 3-D graphic overlay modelling, video imaging, and laser radar based range imaging. Through the fusion of taskspace database information and image sensor data, a verifiable taskspace model is generated providing location and orientation data for objects in a task space. This paper also describes applications of the ISAM in the Intelligent Systems Research Laboratory (ISRL) at NASA Langley Research Center, and discusses its performance relative to representation accuracy and operator interface efficiency.

  14. Explicit authenticity and stimulus features interact to modulate BOLD response induced by emotional speech.

    PubMed

    Drolet, Matthis; Schubotz, Ricarda I; Fischer, Julia

    2013-06-01

    Context has been found to have a profound effect on the recognition of social stimuli and correlated brain activation. The present study was designed to determine whether knowledge about emotional authenticity influences emotion recognition expressed through speech intonation. Participants classified emotionally expressive speech in an fMRI experimental design as sad, happy, angry, or fearful. For some trials, stimuli were cued as either authentic or play-acted in order to manipulate participant top-down belief about authenticity, and these labels were presented both congruently and incongruently to the emotional authenticity of the stimulus. Contrasting authentic versus play-acted stimuli during uncued trials indicated that play-acted stimuli spontaneously up-regulate activity in the auditory cortex and regions associated with emotional speech processing. In addition, a clear interaction effect of cue and stimulus authenticity showed up-regulation in the posterior superior temporal sulcus and the anterior cingulate cortex, indicating that cueing had an impact on the perception of authenticity. In particular, when a cue indicating an authentic stimulus was followed by a play-acted stimulus, additional activation occurred in the temporoparietal junction, probably pointing to increased load on perspective taking in such trials. While actual authenticity has a significant impact on brain activation, individual belief about stimulus authenticity can additionally modulate the brain response to differences in emotionally expressive speech.

  15. Hippocampal cannabinoid transmission modulates dopamine neuron activity: impact on rewarding memory formation and social interaction.

    PubMed

    Loureiro, Michael; Renard, Justine; Zunder, Jordan; Laviolette, Steven R

    2015-05-01

    Disturbances in cannabinoid type 1 receptor (CB1R) signaling have been linked to emotional and cognitive deficits characterizing neuropsychiatric disorders, including schizophrenia. Thus, there is growing interest in characterizing the relationship between cannabinoid transmission, emotional processing, and dopamine (DA)-dependent behavioral deficits. The CB1R is highly expressed in the mammalian nervous system, particularly in the hippocampus. Activation of the ventral hippocampal subregion (vHipp) is known to increase both the activity of DAergic neurons located in the ventral tegmental area (VTA) and DA levels in reward-related brain regions, particularly the nucleus accumbens (NAc). However, the possible functional relationship between hippocampal CB1R transmission and VTA DA neuronal activity is not currently understood. In this study, using in vivo neuronal recordings in rats, we demonstrate that activation of CB1R in the vHipp strongly increases VTA DA neuronal firing and bursting activity, while simultaneously decreasing the activity of VTA non-DA neurons. Furthermore, using a conditioned place preference procedure and a social interaction test, we report that intra-vHipp CB1R activation potentiates the reward salience of normally sub-threshold conditioning doses of opiates and induces deficits in natural sociability and social recognition behaviors. Finally, these behavioral effects were prevented by directly blocking NAc DAergic transmission. Collectively, these findings identify hippocampal CB1R transmission as a critical modulator of the mesolimbic DA pathway and in the processing of reward and social-related behavioral phenomena. PMID:25510937

  16. Fast Quantum Nondemolition Readout by Parametric Modulation of Longitudinal Qubit-Oscillator Interaction

    NASA Astrophysics Data System (ADS)

    Bourassa, Jérôme; Didier, Nicolas; Blais, Alexandre

    For quantum information processing, qubit readout must be fast, of high-fidelity and ideally quantum non-demolition (QND). To rapidly reuse the measured qubit, fast reset of the measurement pointer states is also needed. Combining these characteristics is essential to meet the stringent requirements of fault-tolerant quantum computation. For superconducting qubits, a common strategy is the dispersive readout where the qubit is coupled to an oscillator acting as pointer. In this talk, we present an alternative strategy based on parametric modulation of longitudinal qubit-oscillator interaction. We show that compared to dispersive readout it leads to a faster, high-fidelity and ideally QND qubit readout with a simple reset mechanism. We moreover show how to exponentially improve the signal-to-noise ratio (SNR) of this measurement with the help of single-mode squeezed input state on the oscillator. We present an implementation of this longitudinal parametric readout in circuit quantum electrodynamics along with results using realistic experimental parameters Now at Quantic team, INRIA Paris.

  17. Purification of scatter factor, a fibroblast-derived basic protein that modulates epithelial interactions and movement.

    PubMed Central

    Gherardi, E; Gray, J; Stoker, M; Perryman, M; Furlong, R

    1989-01-01

    Scatter factor is a fibroblast-derived protein that causes separation of contiguous epithelial cells and increased local mobility of unanchored cells. Highly purified scatter factor has been obtained by a combination of ion-exchange and reverse-phase chromatography from serum-free medium conditioned by a ras-transformed clone (D4) of mouse NIH 3T3 fibroblasts. Under nonreducing conditions scatter factor has a pI of approximately 9.5 and migrates in SDS/polyacrylamide gels as a single band at approximately 62 kDa from which epithelial scatter activity can be recovered. Treatment with reducing agents destroys biological activity and is associated with the appearance of two major bands at approximately 57 and approximately 30 kDa. Whether both the 57-kDa and 30-kDa polypeptides are required for biological activity remains to be established. All the activities observed in crude medium conditioned by cells producing scatter factor are retained by highly purified preparations of scatter factor. These include (i) increased local movement, modulation of morphology, and inhibition of junction formation by single epithelial cells and (ii) disruption of epithelial interactions and cell scattering from preformed epithelial sheets. These changes occur with picomolar concentrations of purified scatter factor and without an effect on cell growth. Images PMID:2527367

  18. Elevated Ozone Modulates Herbivore-Induced Volatile Emissions of Brassica nigra and Alters a Tritrophic Interaction.

    PubMed

    Khaling, Eliezer; Li, Tao; Holopainen, Jarmo K; Blande, James D

    2016-05-01

    Plants damaged by herbivores emit volatile organic compounds (VOCs) that are used by parasitoids for host location. In nature, however, plants are exposed to multiple abiotic and biotic stresses of varying intensities, which may affect tritrophic interactions. Here, we studied the effects of ozone exposure and feeding by Pieris brassicae larvae on the VOCs emitted by Brassica nigra and the effects on oriented flight of the parasitoid Cotesia glomerata. We also investigated the oriented flight of C. glomerata in a wind-tunnel with elevated ozone levels. Herbivore-feeding induced the emission of several VOCs, while ozone alone had no significant effect. However, exposure to 120 ppb ozone, followed by 24 hr of herbivore-feeding, induced higher emissions of all VOCs as compared to herbivore-feeding alone. In accordance, herbivore-damaged plants elicited more oriented flights than undamaged plants, whereas plants exposed to 120 ppb ozone and 24 hr of herbivore-feeding elicited more oriented flights than plants subjected to herbivore-feeding alone. Ozone enrichment of the wind-tunnel air appeared to negatively affect orientation of parasitoids at 70 ppb, but not at 120 ppb. These results suggest that the combination of ozone and P. brassicae-feeding modulates VOC emissions, which significantly influence foraging efficiency of C. glomerata. PMID:27167383

  19. Lipid-mediated Protein-protein Interactions Modulate Respiration-driven ATP Synthesis.

    PubMed

    Nilsson, Tobias; Lundin, Camilla Rydström; Nordlund, Gustav; Ädelroth, Pia; von Ballmoos, Christoph; Brzezinski, Peter

    2016-04-11

    Energy conversion in biological systems is underpinned by membrane-bound proton transporters that generate and maintain a proton electrochemical gradient across the membrane which used, e.g. for generation of ATP by the ATP synthase. Here, we have co-reconstituted the proton pump cytochrome bo3 (ubiquinol oxidase) together with ATP synthase in liposomes and studied the effect of changing the lipid composition on the ATP synthesis activity driven by proton pumping. We found that for 100 nm liposomes, containing 5 of each proteins, the ATP synthesis rates decreased significantly with increasing fractions of DOPA, DOPE, DOPG or cardiolipin added to liposomes made of DOPC; with e.g. 5% DOPG, we observed an almost 50% decrease in the ATP synthesis rate. However, upon increasing the average distance between the proton pumps and ATP synthases, the ATP synthesis rate dropped and the lipid dependence of this activity vanished. The data indicate that protons are transferred along the membrane, between cytochrome bo3 and the ATP synthase, but only at sufficiently high protein densities. We also argue that the local protein density may be modulated by lipid-dependent changes in interactions between the two proteins complexes, which points to a mechanism by which the cell may regulate the overall activity of the respiratory chain.

  20. A novel GRK2/HDAC6 interaction modulates cell spreading and motility

    PubMed Central

    Lafarga, Vanesa; Aymerich, Ivette; Tapia, Olga; Mayor, Federico; Penela, Petronila

    2012-01-01

    Cell motility and adhesion involves dynamic microtubule (MT) acetylation/deacetylation, a process regulated by enzymes as HDAC6, a major cytoplasmic α-tubulin deacetylase. We identify G protein-coupled receptor kinase 2 (GRK2) as a key novel stimulator of HDAC6. GRK2, which levels inversely correlate with the extent of α-tubulin acetylation in epithelial cells and fibroblasts, directly associates with and phosphorylates HDAC6 to stimulate α-tubulin deacetylase activity. Remarkably, phosphorylation of GRK2 itself at S670 specifically potentiates its ability to regulate HDAC6. GRK2 and HDAC6 colocalize in the lamellipodia of migrating cells, leading to local tubulin deacetylation and enhanced motility. Consistently, cells expressing GRK2-K220R or GRK2-S670A mutants, unable to phosphorylate HDAC6, exhibit highly acetylated cortical MTs and display impaired migration and protrusive activity. Finally, we find that a balanced, GRK2/HDAC6-mediated regulation of tubulin acetylation differentially modulates the early and late stages of cellular spreading. This novel GRK2/HDAC6 functional interaction may have important implications in pathological contexts. PMID:22193721

  1. Structure-based design of small-molecule protein-protein interaction modulators: the story so far.

    PubMed

    Falchi, Federico; Caporuscio, Fabiana; Recanatini, Maurizio

    2014-03-01

    As the pivotal role of protein-protein interactions in cell growth, transcriptional activity, intracellular trafficking, signal transduction and pathological conditions has been assessed, experimental and in silico strategies have been developed to design protein-protein interaction modulators. State-of-the-art structure-based design methods, mainly pharmacophore modeling and docking, which have succeeded in the identification of enzyme inhibitors, receptor agonists and antagonists, and new tools specifically conceived to target protein-protein interfaces (e.g., hot-spot and druggable pocket prediction methods) have been applied in the search for small-molecule protein-protein interaction modulators. Many successful applications of structure-based design approaches that, despite the challenge of targeting protein-protein interfaces with small molecules, have led to the identification of micromolar and submicromolar hits are reviewed here.

  2. Interactions between endothelial cells and T cells modulate responses to mixed neutron/gamma radiation.

    PubMed

    Cary, Lynnette H; Noutai, Daniel; Salber, Rudolph E; Williams, Margaret S; Ngudiankama, Barbara F; Whitnall, Mark H

    2014-06-01

    Detonation of an improvised nuclear device near a population center would cause significant casualties from the acute radiation syndrome (ARS) due to exposure to mixed neutron/gamma fields (MF). The pathophysiology of ARS involves inflammation, microvascular damage and alterations in immune function. Interactions between endothelial cells (EC) and hematopoietic cells are important not only for regulating immune cell traffic and function, but also for providing the microenvironment that controls survival, differentiation and migration of hematopoietic stem and progenitor cells in blood-forming tissues. Endothelial cells/leukocyte interactions also influence tumor progression and the results of anticancer therapies. In this study, we hypothesized that irradiation of endothelial cells would modulate their effects on hematopoietic cells and vice versa. Human umbilical vein endothelial cells (HUVEC) and immortalized T lymphocytes (Jurkat cells) were cultured individually and in co-culture after exposure to mixed fields. Effects of nonirradiated cells were compared to effects of irradiated cells and alterations in signaling pathways were determined. Mitogen-activated protein kinases (MAPKs) p38 and p44/42 (ERK1/2) in HUVEC exhibited higher levels of phosphorylated protein after exposure to mixed field radiation. IL-6, IL-8, G-CSF, platelet derived growth factor (PDGF) and angiopoietin 2 (ANG2) protein expression were upregulated in HUVEC by exposure to mixed field radiation. PCR arrays using HUVEC mRNA revealed alterations in gene expression after exposure to mixed fields and/or co-culture with Jurkat cells. The presence of HUVEC also influenced the function of Jurkat cells. Nonirradiated Jurkat cells showed an increase in proliferation when co-cultured with nonirradiated HUVEC, and a decrease in proliferation when co-cultured with irradiated HUVEC. Additionally, nonirradiated Jurkat cells incubated in media from irradiated HUVEC exhibited upregulation of activated

  3. Teaching dental students to interact with survivors of traumatic events: development of a two-day module.

    PubMed

    Raja, Sheela; Rajagopalan, Chelsea F; Kruthoff, Mariela; Kuperschmidt, Alexandra; Chang, Priscilla; Hoersch, Michelle

    2015-01-01

    Dentists are likely to treat patients who have experienced a wide range of traumatic life events, including child abuse and neglect, domestic violence, sexual assault, elder abuse, and exposure to combat. In order to effectively treat survivors of traumatic events, dentists must understand how these patients may present in oral health settings, the basic mandated reporting requirements related to abuse and neglect, and communication strategies to help engage trauma survivors in dental treatment. A traditional lecture-format educational module on trauma-informed care was developed and implemented for second-year dental students (N=92) at one U.S. dental school, after which a needs assessment was performed (all 92 students participated). This assessment then informed development of an enhanced module for the subsequent group of second-year dental students (N=102) at the same school. The revised (final) module was more interactive in nature, expanded to multiple sessions, and included more discussion of mandated reporting and appropriate dentist-patient communication in relation to traumatic events. All 102 students participated in assessments of the revised module. Comparison of pre and post tests and needs assessments between the initial and final modules indicated that the extended, more interactive final module was more effective in meeting the educational objectives. Results showed that the final module increased the students' knowledge in the health-related manifestations of traumatic events and slightly improved their confidence levels in treating survivors of trauma. Dentists who are prepared to deliver trauma-informed care may help individual patients feel more at ease and increase engagement in regular preventive care. Suggestions for future educational efforts in this area are discussed.

  4. Teaching dental students to interact with survivors of traumatic events: development of a two-day module.

    PubMed

    Raja, Sheela; Rajagopalan, Chelsea F; Kruthoff, Mariela; Kuperschmidt, Alexandra; Chang, Priscilla; Hoersch, Michelle

    2015-01-01

    Dentists are likely to treat patients who have experienced a wide range of traumatic life events, including child abuse and neglect, domestic violence, sexual assault, elder abuse, and exposure to combat. In order to effectively treat survivors of traumatic events, dentists must understand how these patients may present in oral health settings, the basic mandated reporting requirements related to abuse and neglect, and communication strategies to help engage trauma survivors in dental treatment. A traditional lecture-format educational module on trauma-informed care was developed and implemented for second-year dental students (N=92) at one U.S. dental school, after which a needs assessment was performed (all 92 students participated). This assessment then informed development of an enhanced module for the subsequent group of second-year dental students (N=102) at the same school. The revised (final) module was more interactive in nature, expanded to multiple sessions, and included more discussion of mandated reporting and appropriate dentist-patient communication in relation to traumatic events. All 102 students participated in assessments of the revised module. Comparison of pre and post tests and needs assessments between the initial and final modules indicated that the extended, more interactive final module was more effective in meeting the educational objectives. Results showed that the final module increased the students' knowledge in the health-related manifestations of traumatic events and slightly improved their confidence levels in treating survivors of trauma. Dentists who are prepared to deliver trauma-informed care may help individual patients feel more at ease and increase engagement in regular preventive care. Suggestions for future educational efforts in this area are discussed. PMID:25576552

  5. Facile modulation of optical properties of octagold clusters through the control of ligand-mediated interactions.

    PubMed

    Iwasaki, Mitsuhiro; Kobayashi, Naoki; Shichibu, Yukatsu; Konishi, Katsuaki

    2016-07-28

    In the recent development of structurally defined ligand-stabilized gold clusters, it has been revealed that not only the inorganic units but also the surrounding organic ligands substantially affect their electronic/optical properties. In this work, a series of core + exo type Au8 clusters decorated by dppp (Ph2P(CH2)3PPh2) and arylthiolate ligands ([Au8(dppp)4(SR)2](2+), 1-5) were synthesized, and their optical properties were studied in order to gain insights into the perturbation effects of the organic ligands. 1-5 showed visible absorption and photoluminescence emission bands at longer wavelengths compared to their chloro- and acetylide-modified analogues, suggesting the contribution of weak non-bonding interactions of the Au framework with the ligand heteroatoms. Upon acid treatment, 2- and 4-pyridinethiolate clusters (R = Py, 2 and 4) showed larger red shifts of the absorption and emission bands than the 3-pyridyl isomer (3), implying the involvement of the resonance structures of the SPy units. On the other hand, all regioisomers (2-4) showed large photoluminescence enhancements upon pyridine protonation. X-ray crystallographic and NMR analyses of 4 and its protonated form (4') showed that the electron-deficient pyridinium rings of 4' form π-stacks with neighbouring phenyl groups of dppp, suggesting that the orientation of the surface aromatics is a plausible factor governing the emission efficiency. These observations provide examples of successful modulation of optical properties of small gold clusters through the electronic and/or steric perturbation by the proximal organic ligands, highlighting the importance of the ligand design in the fine tuning of cluster properties directed for optical chemosensors and luminescent materials. PMID:27378218

  6. Leptospiral LruA Is Required for Virulence and Modulates an Interaction with Mammalian Apolipoprotein AI

    PubMed Central

    Zhang, Kunkun; Murray, Gerald L.; Seemann, Torsten; Srikram, Amporn; Bartpho, Thanatchaporn; Sermswan, Rasana W.; Hoke, David E.

    2013-01-01

    Leptospirosis is a worldwide zoonosis caused by spirochetes of the genus Leptospira. While understanding of pathogenesis remains limited, the development of mutagenesis in Leptospira has provided a powerful tool for identifying novel virulence factors. LruA is a lipoprotein that has been implicated in leptospiral uveitis as a target of the immune response. In this study, two lruA mutants, M754 and M765, generated by transposon mutagenesis from Leptospira interrogans serovar Manilae, were characterized. In M754, the transposon inserted in the middle of lruA, resulting in no detectable expression of LruA. In M765, the transposon inserted toward the 3′ end of the gene, resulting in expression of a truncated protein. LruA was demonstrated to be on the cell surface in M765 and the wild type (WT). M754, but not M765, was attenuated in a hamster model of acute infection. A search for differential binding to human serum proteins identified a serum protein of around 30 kDa bound to the wild type and the LruA deletion mutant (M754), but not to the LruA truncation mutant (M765). Two-dimensional separation of proteins from leptospiral cells incubated with guinea pig serum identified the 28-kDa apolipoprotein A-I (ApoA-I) as a major mammalian serum protein that binds Leptospira in vitro. Interestingly, M754 (with no detectable LruA) bound more ApoA-I than did the LruA-expressing strains Manilae wild type and M765. Our data thus identify LruA as a surface-exposed leptospiral virulence factor that contributes to leptospiral pathogenesis, possibly by modulating cellular interactions with serum protein ApoA-I. PMID:23918777

  7. Bio::Homology::InterologWalk - A Perl module to build putative protein-protein interaction networks through interolog mapping

    PubMed Central

    2011-01-01

    Background Protein-protein interaction (PPI) data are widely used to generate network models that aim to describe the relationships between proteins in biological systems. The fidelity and completeness of such networks is primarily limited by the paucity of protein interaction information and by the restriction of most of these data to just a few widely studied experimental organisms. In order to extend the utility of existing PPIs, computational methods can be used that exploit functional conservation between orthologous proteins across taxa to predict putative PPIs or 'interologs'. To date most interolog prediction efforts have been restricted to specific biological domains with fixed underlying data sources and there are no software tools available that provide a generalised framework for 'on-the-fly' interolog prediction. Results We introduce Bio::Homology::InterologWalk, a Perl module to retrieve, prioritise and visualise putative protein-protein interactions through an orthology-walk method. The module uses orthology and experimental interaction data to generate putative PPIs and optionally collates meta-data into an Interaction Prioritisation Index that can be used to help prioritise interologs for further analysis. We show the application of our interolog prediction method to the genomic interactome of the fruit fly, Drosophila melanogaster. We analyse the resulting interaction networks and show that the method proposes new interactome members and interactions that are candidates for future experimental investigation. Conclusions Our interolog prediction tool employs the Ensembl Perl API and PSICQUIC enabled protein interaction data sources to generate up to date interologs 'on-the-fly'. This represents a significant advance on previous methods for interolog prediction as it allows the use of the latest orthology and protein interaction data for all of the genomes in Ensembl. The module outputs simple text files, making it easy to customise the results by

  8. Identification of lncRNA functions in lung cancer based on associated protein-protein interaction modules

    PubMed Central

    Wu, Chih-Hsun; Hsu, Chia-Lang; Lu, Pei-Chun; Lin, Wen-Chang; Juan, Hsueh-Fen; Huang, Hsuan-Cheng

    2016-01-01

    Long non-coding RNAs (lncRNAs) have been found to play important roles in various biological processes; however, many of their functions remain unclear. In this study, we present a novel approach to identify the lncRNA-associated protein-protein interaction (PPI) modules and ascertain their functions in human lung squamous cell carcinoma. We collected lncRNA and mRNA expression profiles of lung squamous cell carcinoma from The Cancer Genome Atlas. To identify the lncRNA-associated PPI modules, lncRNA-mRNA co-expression networks were first constructed based on the mutual ranks of expression correlations. Next, we examined whether the co-expressed mRNAs of a specific lncRNA were closely connected by PPIs. For this, a significantly connected mRNA set was considered to be the lncRNA-associated PPI module. Finally, the prospective functions of a lncRNA was inferred using Gene Ontology enrichment analysis on the associated module. We found that lncRNA-associated PPI modules were subtype-dependent and each subtype had unique molecular mechanisms. In addition, antisense lncRNAs and sense genes tended to be functionally associated. Our results might provide new directions for understanding lncRNA regulations in lung cancer. The analysis pipeline was implemented in a web tool, available at http://lncin.ym.edu.tw/. PMID:27786280

  9. Modulation instability of ion acoustic waves, solitons, and their interactions in nonthermal electron-positron-ion plasmas

    SciTech Connect

    Zhang Jiefang; Wang Yueyue; Wu Lei

    2009-06-15

    The propagation of ion acoustic waves in plasmas composed of ions, positrons, and nonthermally distributed electrons is investigated. By means of the reduction perturbation technique, a nonlinear Schroedinger equation is derived and the modulation instability of ion acoustic wave is analyzed, where the nonthermal parameter is found to be of significant importance. Furthermore, analytical expressions for the bright and dark solitons are obtained, and the interaction of multiple solitons is discussed.

  10. Corticospinal interaction during isometric compensation for modulated forces with different frequencies

    PubMed Central

    2010-01-01

    Background During isometric compensation of modulated low-level forces corticomuscular coherence (CMC) has been shown to occur in high-beta or gamma-range. The influence of the frequency of force modulation on CMC has up to now remained unexplored. We addressed this question by investigating CMC, motor performance, and cortical spectral power during a visuomotor task in which subjects had to compensate a modulated force of 8% of the maximum voluntary contraction exerted on their right index finger. The effect of three frequencies of force modulation (0.6, 1.0 and 1.6 Hz) was tested. EEG, EMG from first dorsal interosseus, hand flexor and extensor muscles, and finger position were recorded in eight right-handed women. Results Five subjects showed CMC in gamma- (28-45 Hz) and three in beta-range (15-30 Hz). Beta- and gamma-range CMC and cortical motor spectral power were not modulated by the various frequencies. However, a sharp bilateral CMC peak at 1.6 Hz was observed, but only in the five gamma-range CMC subjects. The performance error increased linearly with the frequency. Conclusions Our findings suggest that the frequency of force modulation has no effect on the beta- and gamma-range CMC during isometric compensation for modulated forces at 8% MVC. The beta- and gamma-range CMC may be related to interindividual differences and possibly to strategy differences. PMID:21194447

  11. Interaction between electrical modulation of the brain and pharmacotherapy to control pharmacoresistant epilepsy.

    PubMed

    Rocha, Luisa

    2013-05-01

    In spite of the high success rate of many surgical procedures for pharmacoresistant epilepsy, a substantial number of patients do not become seizure-free. Different strategies for electrical modulation of the brain such as Deep Brain Stimulation, Vagal Nerve Stimulation and Transcraneal Magnetic Stimulation have gained considerable interest in the last decade as alternative therapies for patients with medically refractory epilepsy. Research into the mechanism of action of the strategies for electrical modulation of the brain suggests a crucial role of different molecules and channels such as glutamate, γ-aminobutyric acid, adenosine, brain-derived neurotrophic factor, calcium channels, sodium channels as well as extracellular potassium. Electrical modulation of the brain may reduce the overexpression of P-glycoprotein, a drug efflux transporter that reduces the absorption of antiepileptic drugs. Electrical modulation of the brain induces long-term effects associated with beneficial consequences on clinical symptoms observed during the postictal state. In addition, electrical modulation of the brain might also promote the neurogenesis in subjects with pharmacoresistant epilepsy in whom this process is decreased. Targeting the regulatory pathways in charge of the effects of electrical modulation of the brain is discussed as a means to improve its efficacy. Electrical modulation of the brain combined with pharmacotherapy may represent an innovative approach to avoid epileptogenesis, reduce seizure activity, induce beneficial effects during the postictal state, diminish the amount of antiepileptic drugs, and improve alertness, memory and mood in pharmacoresistant epilepsy.

  12. Modulating non-native aggregation and electrostatic protein-protein interactions with computationally designed single-point mutations.

    PubMed

    O'Brien, C J; Blanco, M A; Costanzo, J A; Enterline, M; Fernandez, E J; Robinson, A S; Roberts, C J

    2016-06-01

    Non-native protein aggregation is a ubiquitous challenge in the production, storage and administration of protein-based biotherapeutics. This study focuses on altering electrostatic protein-protein interactions as a strategy to modulate aggregation propensity in terms of temperature-dependent aggregation rates, using single-charge variants of human γ-D crystallin. Molecular models were combined to predict amino acid substitutions that would modulate protein-protein interactions with minimal effects on conformational stability. Experimental protein-protein interactions were quantified by the Kirkwood-Buff integrals (G22) from laser scattering, and G22 showed semi-quantitative agreement with model predictions. Experimental initial-rates for aggregation showed that increased (decreased) repulsive interactions led to significantly increased (decreased) aggregation resistance, even based solely on single-point mutations. However, in the case of a particular amino acid (E17), the aggregation mechanism was altered by substitution with R or K, and this greatly mitigated improvements in aggregation resistance. The results illustrate that predictions based on native protein-protein interactions can provide a useful design target for engineering aggregation resistance; however, this approach needs to be balanced with consideration of how mutations can impact aggregation mechanisms. PMID:27160179

  13. Drug-Like Protein–Protein Interaction Modulators: Challenges and Opportunities for Drug Discovery and Chemical Biology

    PubMed Central

    Villoutreix, Bruno O; Kuenemann, Melaine A; Poyet, Jean-Luc; Bruzzoni-Giovanelli, Heriberto; Labbé, Céline; Lagorce, David; Sperandio, Olivier; Miteva, Maria A

    2014-01-01

    Fundamental processes in living cells are largely controlled by macromolecular interactions and among them, protein–protein interactions (PPIs) have a critical role while their dysregulations can contribute to the pathogenesis of numerous diseases. Although PPIs were considered as attractive pharmaceutical targets already some years ago, they have been thus far largely unexploited for therapeutic interventions with low molecular weight compounds. Several limiting factors, from technological hurdles to conceptual barriers, are known, which, taken together, explain why research in this area has been relatively slow. However, this last decade, the scientific community has challenged the dogma and became more enthusiastic about the modulation of PPIs with small drug-like molecules. In fact, several success stories were reported both, at the preclinical and clinical stages. In this review article, written for the 2014 International Summer School in Chemoinformatics (Strasbourg, France), we discuss in silico tools (essentially post 2012) and databases that can assist the design of low molecular weight PPI modulators (these tools can be found at www.vls3d.com). We first introduce the field of protein–protein interaction research, discuss key challenges and comment recently reported in silico packages, protocols and databases dedicated to PPIs. Then, we illustrate how in silico methods can be used and combined with experimental work to identify PPI modulators. PMID:25254076

  14. Drug-Like Protein-Protein Interaction Modulators: Challenges and Opportunities for Drug Discovery and Chemical Biology.

    PubMed

    Villoutreix, Bruno O; Kuenemann, Melaine A; Poyet, Jean-Luc; Bruzzoni-Giovanelli, Heriberto; Labbé, Céline; Lagorce, David; Sperandio, Olivier; Miteva, Maria A

    2014-06-01

    [Formula: see text] Fundamental processes in living cells are largely controlled by macromolecular interactions and among them, protein-protein interactions (PPIs) have a critical role while their dysregulations can contribute to the pathogenesis of numerous diseases. Although PPIs were considered as attractive pharmaceutical targets already some years ago, they have been thus far largely unexploited for therapeutic interventions with low molecular weight compounds. Several limiting factors, from technological hurdles to conceptual barriers, are known, which, taken together, explain why research in this area has been relatively slow. However, this last decade, the scientific community has challenged the dogma and became more enthusiastic about the modulation of PPIs with small drug-like molecules. In fact, several success stories were reported both, at the preclinical and clinical stages. In this review article, written for the 2014 International Summer School in Chemoinformatics (Strasbourg, France), we discuss in silico tools (essentially post 2012) and databases that can assist the design of low molecular weight PPI modulators (these tools can be found at www.vls3d.com). We first introduce the field of protein-protein interaction research, discuss key challenges and comment recently reported in silico packages, protocols and databases dedicated to PPIs. Then, we illustrate how in silico methods can be used and combined with experimental work to identify PPI modulators.

  15. Interactive E-learning module in pharmacology: a pilot project at a rural medical college in India.

    PubMed

    Gaikwad, Nitin; Tankhiwale, Suresh

    2014-01-01

    Many medical educators are experimenting with innovative ways of E-learning. E-learning provides opportunities to students for self-directed learning in addition to other advantages. In this study, we designed and evaluated an interactive E-learning module in pharmacology for effectiveness, acceptability and feasibility, with the aim of promoting active learning in this fact-filled subject. A quasi-experimental single-group pre-test/post-test study was conducted with fourth-semester students of the second professionals course (II MBBS), selected using non-probability convenience sampling method. An E-learning module in endocrine pharmacology was designed to comprise three units of interactive PowerPoint presentations. The pre-validated presentations were uploaded on the website according to a predefined schedule and the 42 registered students were encouraged to self-learning using these interactive presentations. Cognitive gain was assessed using an online pre- and post-test for each unit. Students' perceptions were recorded using an online feedback questionnaire on a 5-point Likert scale. Finally, focused group discussion was conducted to further explore students' views on E-learning activity. Significant attrition was observed during the E-learning activity. Of the 42 registered students, only 16 students completed the entire E-learning module. The summed average score of all three units (entire module) was increased significantly from 38.42 % (summed average pre-test score: 11.56/30 ± 2.90) to 66.46 % (summed average post-test score: 19.94/30 ± 6.13). The class-average normalized gain for the entire module was 0.4542 (45.42). The students accepted this E-learning activity well as they perceived it to be innovative, convenient, flexible and useful. The average rating was between 4 (agree) and 5 (strongly agree). The interactive E-learning module in pharmacology was moderately effective and well perceived by the students. The simple, cost-effective and

  16. A systems biology approach using metabolomic data reveals genes and pathways interacting to modulate divergent growth in cattle

    PubMed Central

    2013-01-01

    Background Systems biology enables the identification of gene networks that modulate complex traits. Comprehensive metabolomic analyses provide innovative phenotypes that are intermediate between the initiator of genetic variability, the genome, and raw phenotypes that are influenced by a large number of environmental effects. The present study combines two concepts, systems biology and metabolic analyses, in an approach without prior functional hypothesis in order to dissect genes and molecular pathways that modulate differential growth at the onset of puberty in male cattle. Furthermore, this integrative strategy was applied to specifically explore distinctive gene interactions of non-SMC condensin I complex, subunit G (NCAPG) and myostatin (GDF8), known modulators of pre- and postnatal growth that are only partially understood for their molecular pathways affecting differential body weight. Results Our study successfully established gene networks and interacting partners affecting growth at the onset of puberty in cattle. We demonstrated the biological relevance of the created networks by comparison to randomly created networks. Our data showed that GnRH (Gonadotropin-releasing hormone) signaling is associated with divergent growth at the onset of puberty and revealed two highly connected hubs, BTC and DGKH, within the network. Both genes are known to directly interact with the GnRH signaling pathway. Furthermore, a gene interaction network for NCAPG containing 14 densely connected genes revealed novel information concerning the functional role of NCAPG in divergent growth. Conclusions Merging both concepts, systems biology and metabolomic analyses, successfully yielded new insights into gene networks and interacting partners affecting growth at the onset of puberty in cattle. Genetic modulation in GnRH signaling was identified as key modifier of differential cattle growth at the onset of puberty. In addition, the benefit of our innovative concept without prior

  17. Modulation of Interleukin-1 Transcriptional Response by the Interaction between VRK2 and the JIP1 Scaffold Protein

    PubMed Central

    Blanco, Sandra; Sanz-García, Marta; Santos, Claudio R.; Lazo, Pedro A.

    2008-01-01

    Background Cellular biological responses to specific stimulation are determined by a balance among signaling pathways. Protein interactions are likely to modulate these pathways. Vaccinia-related kinase-2 (VRK2) is a novel human kinase that can modulate different signaling pathways. Principal Findings We report that in vivo, the activity of JIP1-JNK complexes is downregulated by VRK2 in response to interleukin-1β. Also the reduction of endogenous VRK2 with shRNA increases the transcriptional response to IL-1β. The JIP1 scaffold protein assembles three consecutive members of a given MAPK pathway forming signaling complexes and their signal can be modulated by interactions with regulatory proteins that remain to be identified. Knocking-down JIP1 with siRNA resulted in elimination of the AP1 transcriptional response to IL-1β. VRK2, a member of novel Ser-Thr kinase family, is able to stably interact with JIP1, TAK1 and MKK7, but not JNK, and can be isolated forming oligomeric complexes with different proportions of TAK1, MKK7β1 and JNK. JIP1 assembles all these proteins in an oligomeric signalosome. VRK2 binding to the JIP1 signalosome prevents the association of JNK and results in a reduction in its phosphorylation and downregulation of AP1-dependent transcription. Conclusions/Significance This work suggests that the intracellular level of VRK2 protein can modulate the flow through a signaling pathway and alter the response from a receptor that can be distributed by more than one pathway, and thus contribute to the cellular specificity of the response by forming alternative signaling complexes. Furthermore, the effect might be more general and affect other signaling routes assembled on the JIP1 scaffold protein for which a model is proposed. PMID:18286207

  18. Screening for Small-Molecule Modulators of Long Noncoding RNA-Protein Interactions Using AlphaScreen

    PubMed Central

    Pedram Fatemi, Roya; Salah-Uddin, Sultan; Modarresi, Farzaneh; Khoury, Nathalie; Wahlestedt, Claes

    2015-01-01

    Long non–protein coding RNAs (lncRNAs) are an important class of molecules that help orchestrate key cellular events. Although their functional roles in cells are not well understood, thousands of lncRNAs and a number of possible mechanisms by which they act have been reported. LncRNAs can exert their regulatory function in cells by interacting with epigenetic enzymes. In this study, we developed a tool to study lncRNA-protein interactions for high-throughput screening of small-molecule modulators using AlphaScreen technology. We tested the interaction of two lncRNAs: brain-derived neurotrophic factor antisense (BDNF-AS) and Hox transcript antisense RNA (HOTAIR), with Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase against a phytochemical library, to look for small-molecule inhibitors that can alter the expression of downstream target genes. We identified ellipticine, a compound that up-regulates BDNF transcription. Our study shows the feasibility of using high-throughput screening to identify modulators of lncRNA-protein interactions and paves the road for targeting lncRNAs that are dysregulated in human disorders using small-molecule therapies. PMID:26173710

  19. Interaction of Motility, Directional Sensing, and Polarity Modules Recreates the Behaviors of Chemotaxing Cells

    PubMed Central

    Shi, Changji; Huang, Chuan-Hsiang; Devreotes, Peter N.; Iglesias, Pablo A.

    2013-01-01

    Chemotaxis involves the coordinated action of separable but interrelated processes: motility, gradient sensing, and polarization. We have hypothesized that these are mediated by separate modules that account for these processes individually and that, when combined, recreate most of the behaviors of chemotactic cells. Here, we describe a mathematical model where the modules are implemented in terms of reaction-diffusion equations. Migration and the accompanying changes in cellular morphology are demonstrated in simulations using a mechanical model of the cell cortex implemented in the level set framework. The central module is an excitable network that accounts for random migration. The response to combinations of uniform stimuli and gradients is mediated by a local excitation, global inhibition module that biases the direction in which excitability is directed. A polarization module linked to the excitable network through the cytoskeleton allows unstimulated cells to move persistently and, for cells in gradients, to gradually acquire distinct sensitivity between front and back. Finally, by varying the strengths of various feedback loops in the model we obtain cellular behaviors that mirror those of genetically altered cell lines. PMID:23861660

  20. Mutual interplay of non-covalent interactions in modulating the geometry of organic linkers in their salts

    NASA Astrophysics Data System (ADS)

    Tripuramallu, Bharat Kumar

    2014-08-01

    Two ion-pair compounds (Hhfipbb)2·(H2px2ampy) (1) and (H2pxph)·(4-Hptz)2 (2) have been synthesized, based on the ligands 4,4‧-(hexafluoroisopropylidene)-bis(benzoic acid) (H2hfipbb), 1,4-bis(2-pyridylaminomethyl)benzene (px2ampy), p-xylylenediphosphonic acid (H4pxph) and (5-(4-pyridyl) tetrazole) (4-ptz). Both the compounds 1 and 2 are characterized by routine elemental analyses, IR-, thermogravimetric studies and unambiguously characterized by single crystal X-ray crystallography. The mutual supramolecular interactions, exhibited by the individual ligands in the organic salts, modulate their geometries to form higher dimensional supramolecular architectures in the crystals of organic salts 1 and 2. In compound 1, the di-cation H2px2ampy2+ modulates its potential hydrogen donor sites in a cis conformation to form a R22(8) hetero synthon with carboxylate oxygen atoms of singly deprotonated Hhfipbb1- anion and thereby restricts the twisting between two benzene rings in the Hhfipbb1- skeleton to form 3D intricate supramolecular architecture. The trans-conformations of H4pxph (compound 2) forms 1D chain through R22(8) homo synthons, which extends to a 3D porous supramolecular network through interactions with 4-Hptz+ cations (by twisting them). The ion components, that are present in both compounds, modulate their geometry from their classical geometries, displayed by them in the metal coordination architectures and inorganic salts.

  1. Affect-modulated startle: interactive influence of catechol-O-methyltransferase Val158Met genotype and childhood trauma.

    PubMed

    Klauke, Benedikt; Winter, Bernward; Gajewska, Agnes; Zwanzger, Peter; Reif, Andreas; Herrmann, Martin J; Dlugos, Andrea; Warrings, Bodo; Jacob, Christian; Mühlberger, Andreas; Arolt, Volker; Pauli, Paul; Deckert, Jürgen; Domschke, Katharina

    2012-01-01

    The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system--partly conferred by catechol-O-methyltransferase (COMT) gene variation--for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.

  2. Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma

    PubMed Central

    Klauke, Benedikt; Winter, Bernward; Gajewska, Agnes; Zwanzger, Peter; Reif, Andreas; Herrmann, Martin J.; Dlugos, Andrea; Warrings, Bodo; Jacob, Christian; Mühlberger, Andreas; Arolt, Volker; Pauli, Paul; Deckert, Jürgen; Domschke, Katharina

    2012-01-01

    The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system – partly conferred by catechol-O-methyltransferase (COMT) gene variation – for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders. PMID:22745815

  3. Siderophore biosynthesis coordinately modulated the virulence-associated interactive metabolome of uropathogenic Escherichia coli and human urine

    PubMed Central

    Su, Qiao; Guan, Tianbing; Lv, Haitao

    2016-01-01

    Uropathogenic Escherichia coli (UPEC) growth in women’s bladders during urinary tract infection (UTI) incurs substantial chemical exchange, termed the “interactive metabolome”, which primarily accounts for the metabolic costs (utilized metabolome) and metabolic donations (excreted metabolome) between UPEC and human urine. Here, we attempted to identify the individualized interactive metabolome between UPEC and human urine. We were able to distinguish UPEC from non-UPEC by employing a combination of metabolomics and genetics. Our results revealed that the interactive metabolome between UPEC and human urine was markedly different from that between non-UPEC and human urine, and that UPEC triggered much stronger perturbations in the interactive metabolome in human urine. Furthermore, siderophore biosynthesis coordinately modulated the individualized interactive metabolome, which we found to be a critical component of UPEC virulence. The individualized virulence-associated interactive metabolome contained 31 different metabolites and 17 central metabolic pathways that were annotated to host these different metabolites, including energetic metabolism, amino acid metabolism, and gut microbe metabolism. Changes in the activities of these pathways mechanistically pinpointed the virulent capability of siderophore biosynthesis. Together, our findings provide novel insights into UPEC virulence, and we propose that siderophores are potential targets for further discovery of drugs to treat UPEC-induced UTI. PMID:27076285

  4. Siderophore biosynthesis coordinately modulated the virulence-associated interactive metabolome of uropathogenic Escherichia coli and human urine.

    PubMed

    Su, Qiao; Guan, Tianbing; Lv, Haitao

    2016-04-14

    Uropathogenic Escherichia coli (UPEC) growth in women's bladders during urinary tract infection (UTI) incurs substantial chemical exchange, termed the "interactive metabolome", which primarily accounts for the metabolic costs (utilized metabolome) and metabolic donations (excreted metabolome) between UPEC and human urine. Here, we attempted to identify the individualized interactive metabolome between UPEC and human urine. We were able to distinguish UPEC from non-UPEC by employing a combination of metabolomics and genetics. Our results revealed that the interactive metabolome between UPEC and human urine was markedly different from that between non-UPEC and human urine, and that UPEC triggered much stronger perturbations in the interactive metabolome in human urine. Furthermore, siderophore biosynthesis coordinately modulated the individualized interactive metabolome, which we found to be a critical component of UPEC virulence. The individualized virulence-associated interactive metabolome contained 31 different metabolites and 17 central metabolic pathways that were annotated to host these different metabolites, including energetic metabolism, amino acid metabolism, and gut microbe metabolism. Changes in the activities of these pathways mechanistically pinpointed the virulent capability of siderophore biosynthesis. Together, our findings provide novel insights into UPEC virulence, and we propose that siderophores are potential targets for further discovery of drugs to treat UPEC-induced UTI.

  5. The Interaction of Heparin Tetrasaccharides with Chemokine CCL5 Is Modulated by Sulfation Pattern and pH*

    PubMed Central

    Singh, Arunima; Kett, Warren C.; Severin, India C.; Agyekum, Isaac; Duan, Jiana; Amster, I. Jonathan; Proudfoot, Amanda E. I.; Coombe, Deirdre R.; Woods, Robert J.

    2015-01-01

    Interactions between chemokines such as CCL5 and glycosaminoglycans (GAGs) are essential for creating haptotactic gradients to guide the migration of leukocytes into inflammatory sites, and the GAGs that interact with CCL5 with the highest affinity are heparan sulfates/heparin. The interaction between CCL5 and its receptor on monocytes, CCR1, is mediated through residues Arg-17 and -47 in CCL5, which overlap with the GAG-binding 44RKNR47 “BBXB” motifs. Here we report that heparin and tetrasaccharide fragments of heparin are able to inhibit CCL5-CCR1 binding, with IC50 values showing strong dependence on the pattern and extent of sulfation. Modeling of the CCL5-tetrasaccharide complexes suggested that interactions between specific sulfate and carboxylate groups of heparin and residues Arg-17 and -47 of the protein are essential for strong inhibition; tetrasaccharides lacking the specific sulfation pattern were found to preferentially bind CCL5 in positions less favorable for inhibition of the interaction with CCR1. Simulations of a 12-mer heparin fragment bound to CCL5 indicated that the oligosaccharide preferred to interact simultaneously with both 44RKNR47 motifs in the CCL5 homodimer and engaged residues Arg-47 and -17 from both chains. Direct engagement of these residues by the longer heparin oligosaccharide provides a rationalization for its effectiveness as an inhibitor of CCL5-CCR1 interaction. In this mode, histidine (His-23) may contribute to CCL5-GAG interactions when the pH drops just below neutral, as occurs during inflammation. Additionally, an examination of the contribution of pH to modulating CCL5-heparin interactions suggested a need for careful interpretation of experimental results when experiments are performed under non-physiological conditions. PMID:25907556

  6. The Interaction of Heparin Tetrasaccharides with Chemokine CCL5 Is Modulated by Sulfation Pattern and pH.

    PubMed

    Singh, Arunima; Kett, Warren C; Severin, India C; Agyekum, Isaac; Duan, Jiana; Amster, I Jonathan; Proudfoot, Amanda E I; Coombe, Deirdre R; Woods, Robert J

    2015-06-19

    Interactions between chemokines such as CCL5 and glycosaminoglycans (GAGs) are essential for creating haptotactic gradients to guide the migration of leukocytes into inflammatory sites, and the GAGs that interact with CCL5 with the highest affinity are heparan sulfates/heparin. The interaction between CCL5 and its receptor on monocytes, CCR1, is mediated through residues Arg-17 and -47 in CCL5, which overlap with the GAG-binding (44)RKNR(47) "BBXB" motifs. Here we report that heparin and tetrasaccharide fragments of heparin are able to inhibit CCL5-CCR1 binding, with IC50 values showing strong dependence on the pattern and extent of sulfation. Modeling of the CCL5-tetrasaccharide complexes suggested that interactions between specific sulfate and carboxylate groups of heparin and residues Arg-17 and -47 of the protein are essential for strong inhibition; tetrasaccharides lacking the specific sulfation pattern were found to preferentially bind CCL5 in positions less favorable for inhibition of the interaction with CCR1. Simulations of a 12-mer heparin fragment bound to CCL5 indicated that the oligosaccharide preferred to interact simultaneously with both (44)RKNR(47) motifs in the CCL5 homodimer and engaged residues Arg-47 and -17 from both chains. Direct engagement of these residues by the longer heparin oligosaccharide provides a rationalization for its effectiveness as an inhibitor of CCL5-CCR1 interaction. In this mode, histidine (His-23) may contribute to CCL5-GAG interactions when the pH drops just below neutral, as occurs during inflammation. Additionally, an examination of the contribution of pH to modulating CCL5-heparin interactions suggested a need for careful interpretation of experimental results when experiments are performed under non-physiological conditions.

  7. Impact of Oceanic Scale-Interactions on the Seasonal Modulation of Ocean Dynamics By the Atmosphere

    NASA Astrophysics Data System (ADS)

    Sasaki, H.; Klein, P.; Qiu, B.; Sasai, Y.

    2014-12-01

    A realistic North Pacific simulation at high-resolution (1/30 degree in the horizontal and 100 vertical levels) highlights an efficient energy pathway, involving winter frontal instabilities at submesoscale set up by large-scale atmospheric forcings: these instabilities, through an inverse kinetic energy cascade, lead to a significant seasonal modulation of the kinetic energy over a broad scale range including submesoscales and mesoscales. The kinetic energy within the scale band of 10-200km is doubled in winter relatively to summer. This suggests a significant seasonal modulation of dispersion and transport of heat and tracers triggered by atmospheric forcings through this energy pathway. Monitoring such seasonal modulation is a major challenge because of the lack of high-resolution observations on a global scale. However the resulting meso/submesoscale field has been found to be statistically in geostrophic equilibrium at all seasons. This means that such modulation can be diagnosed, using the geostrophic approximation, from SSH data from the future SWOT and COMPIRA wide-swath altimeter missions.

  8. Investigation of allosteric modulation mechanism of metabotropic glutamate receptor 1 by molecular dynamics simulations, free energy and weak interaction analysis

    NASA Astrophysics Data System (ADS)

    Bai, Qifeng; Yao, Xiaojun

    2016-02-01

    Metabotropic glutamate receptor 1 (mGlu1), which belongs to class C G protein-coupled receptors (GPCRs), can be coupled with G protein to transfer extracellular signal by dimerization and allosteric regulation. Unraveling the dimer packing and allosteric mechanism can be of great help for understanding specific regulatory mechanism and designing more potential negative allosteric modulator (NAM). Here, we report molecular dynamics simulation studies of the modulation mechanism of FITM on the wild type, T815M and Y805A mutants of mGlu1 through weak interaction analysis and free energy calculation. The weak interaction analysis demonstrates that van der Waals (vdW) and hydrogen bonding play an important role on the dimer packing between six cholesterol molecules and mGlu1 as well as the interaction between allosteric sites T815, Y805 and FITM in wild type, T815M and Y805A mutants of mGlu1. Besides, the results of free energy calculations indicate that secondary binding pocket is mainly formed by the residues Thr748, Cys746, Lys811 and Ser735 except for FITM-bound pocket in crystal structure. Our results can not only reveal the dimer packing and allosteric regulation mechanism, but also can supply useful information for the design of potential NAM of mGlu1.

  9. Modulation of pineal melatonin synthesis by glutamate involves paracrine interactions between pinealocytes and astrocytes through NF-κB activation.

    PubMed

    Villela, Darine; Atherino, Victoria Fairbanks; Lima, Larissa de Sá; Moutinho, Anderson Augusto; do Amaral, Fernanda Gaspar; Peres, Rafael; Martins de Lima, Thais; Torrão, Andréa da Silva; Cipolla-Neto, José; Scavone, Cristóforo; Afeche, Solange Castro

    2013-01-01

    The glutamatergic modulation of melatonin synthesis is well known, along with the importance of astrocytes in mediating glutamatergic signaling in the central nervous system. Pinealocytes and astrocytes are the main cell types in the pineal gland. The objective of this work was to investigate the interactions between astrocytes and pinealocytes as a part of the glutamate inhibitory effect on melatonin synthesis. Rat pinealocytes isolated or in coculture with astrocytes were incubated with glutamate in the presence of norepinephrine, and the melatonin content, was quantified. The expression of glutamate receptors, the intracellular calcium content and the NF- κ B activation were analyzed in astrocytes and pinealocytes. TNF- α 's possible mediation of the effect of glutamate was also investigated. The results showed that glutamate's inhibitory effect on melatonin synthesis involves interactions between astrocytes and pinealocytes, possibly through the release of TNF- α . Moreover, the activation of the astrocytic NF- κ B seems to be a necessary step. In astrocytes and pinealocytes, AMPA, NMDA, and group I metabotropic glutamate receptors were observed, as well as the intracellular calcium elevation. In conclusion, there is evidence that the modulation of melatonin synthesis by glutamate involves paracrine interactions between pinealocytes and astrocytes through the activation of the astrocytic NF- κ B transcription factor and possibly by subsequent TNF- α release.

  10. Dipicrylamine Modulates GABAρ1 Receptors through Interactions with Residues in the TM4 and Cys-Loop Domains.

    PubMed

    Limon, Agenor; Estrada-Mondragón, Argel; Ruiz, Jorge M Reyes; Miledi, Ricardo

    2016-04-01

    Dipicrylamine (DPA) is a commonly used acceptor agent in Förster resonance energy transfer experiments that allows the study of high-frequency neuronal activity in the optical monitoring of voltage in living cells. However, DPA potently antagonizes GABAA receptors that contain α1 and β2 subunits by a mechanism which is not clearly understood. In this work, we aimed to determine whether DPA modulation is a general phenomenon of Cys-loop ligand-gated ion channels (LGICs), and whether this modulation depends on particular amino acid residues. For this, we studied the effects of DPA on human homomeric GABAρ1, α7 nicotinic, and 5-HT3A serotonin receptors expressed in Xenopus oocytes. Our results indicate that DPA is an allosteric modulator of GABAρ1 receptors with an IC50 of 1.6 µM, an enhancer of α7 nicotinic receptors at relatively high concentrations of DPA, and has little, if any, effect on 5-HT3A receptors. DPA antagonism of GABAρ1 was strongly enhanced by preincubation, was slightly voltage-dependent, and its washout was accelerated by bovine serum albumin. These results indicate that DPA modulation is not a general phenomenon of LGICs, and structural differences between receptors may account for disparities in DPA effects. In silico modeling of DPA docking to GABAρ1, α7 nicotinic, and 5-HT3A receptors suggests that a hydrophobic pocket within the Cys-loop and the M4 segment in GABAρ1, located at the extracellular/membrane interface, facilitates the interaction with DPA that leads to inhibition of the receptor. Functional examinations of mutant receptors support the involvement of the M4 segment in the allosteric modulation of GABAρ1 by DPA. PMID:26869399

  11. Mycoplasma fermentans and TNF-β interact to amplify immune-modulating cytokines in human lung fibroblasts

    PubMed Central

    Fabisiak, James P.; Gao, Fei; Thomson, Robyn G.; Strieter, Robert M.; Watkins, Simon C.; Dauber, James H.

    2010-01-01

    Mycoplasma can establish latent infections and are associated with arthritis, leukemia, and chronic lung disease. We developed an experimental model in which lung cells are deliberately infected with Mycoplasma fermentans. Human lung fibroblasts (HLF) were exposed to live M. fermentans and immune-modulating cytokine release was assessed with and without known inducers of cytokine production. M. fermentans increased IL-6, IL-8/CXCL8, MCP-1/CCL2, and Gro-α/CXCL1 production. M. fermentans interacted with TNF-β to release more IL-6, CXCL8, and CXCL1 than predicted by the responses to either stimulus alone. The effects of live infection were recapitulated by exposure to M. fermentans-derived macrophage-activating lipopeptide-2 (MALP-2), a Toll-like receptor-2- and receptor-6-specific ligand. The synergistic effect of combined stimuli was more pronounced with prolonged incubations. Preexposure to TNF-β sensitized the cells to subsequent MALP-2 challenge, but preexposure to MALP-2 did not alter the IL-6 response to TNF-β. Exposure to M. fermentans or MALP-2 did not enhance nuclear localization, DNA binding, or transcriptional activity of NF-κB and did not modulate early NF-κB activation in response to TNF-β. Application of specific inhibitors of various MAPKs suggested that p38 and JNK/stress-activated protein kinase were involved in early IL-6 release after exposure to TNF-β and M. fermentans, respectively. The combined response to M. fermentans and TNF-β, however, was uniquely sensitive to delayed application of SP-600125, suggesting that JNK/stress-activated protein kinase contributes to the amplification of IL-6 release. Thus M. fermentans interacts with stimuli such as TNF-β to amplify lung cell production of immune-modulating cytokines. The mechanisms accounting for this interaction can now be dissected with the use of this in vitro model. PMID:16751226

  12. Four imidazolium iodocuprates based on anion-π and π-π interactions: Structural and spectral modulation

    NASA Astrophysics Data System (ADS)

    Liu, Fang; Hao, Pengfei; Yu, Tanlai; Guan, Qi; Fu, Yunlong

    2016-09-01

    Four imidazolium iodocuprates, [(1,3-dimethylimidazole)(Cu2I3)]n (1), [(1,2,3-trimethylimidazole)(Cu2I3)]n (2), [(1,3-dimethylimidazole)(Cu3I5)]n (3) and [(1,3-dimethylbenzimidazole)(CuI2)]n (4) have been solvothermally synthesized and optically characterized. Results exhibit that cationic spatial orientation, anion-π and π-π interactions are beneficial to structural diversity and band gap modulation of iodocuprate hybrids. The UV-vis diffuse reflectance spectra show that compounds 1-4 are potential semiconductor materials.

  13. Supramolecular interactions between library members modulate the behavior of dynamic combinatorial libraries.

    PubMed

    Orrillo, A Gastón; Furlan, Ricardo L E

    2010-01-01

    The presence of a supramolecular network of interactions between library members can lead to very different responses when libraries with identical molecular composition are exposed to the same template. Numerical simulations demonstrate that supramolecular interactions between library members of covalent dynamic combinatorial libraries (DCLs) can affect both degree and selectivity of the response of the library when a template molecule is added.

  14. Endosome-mitochondria interactions are modulated by iron release from transferrin.

    PubMed

    Das, Anupam; Nag, Sagarika; Mason, Anne B; Barroso, Margarida M

    2016-09-26

    Transient "kiss and run" interactions between endosomes containing iron-bound transferrin (Tf) and mitochondria have been shown to facilitate direct iron transfer in erythroid cells. In this study, we used superresolution three-dimensional (3D) direct stochastic optical reconstruction microscopy to show that Tf-containing endosomes directly interact with mitochondria in epithelial cells. We used live-cell time-lapse fluorescence microscopy, followed by 3D rendering, object tracking, and a distance transformation algorithm, to track Tf-endosomes and characterize the dynamics of their interactions with mitochondria. Quenching of iron sensor RDA-labeled mitochondria confirmed functional iron transfer by an interacting Tf-endosome. The motility of Tf-endosomes is significantly reduced upon interaction with mitochondria. To further assess the functional role of iron in the ability of Tf-endosomes to interact with mitochondria, we blocked endosomal iron release by using a Tf K206E/K534A mutant. Blocking intraendosomal iron release led to significantly increased motility of Tf-endosomes and increased duration of endosome-mitochondria interactions. Thus, intraendosomal iron regulates the kinetics of the interactions between Tf-containing endosomes and mitochondria in epithelial cells. PMID:27646275

  15. Endosome-mitochondria interactions are modulated by iron release from transferrin.

    PubMed

    Das, Anupam; Nag, Sagarika; Mason, Anne B; Barroso, Margarida M

    2016-09-26

    Transient "kiss and run" interactions between endosomes containing iron-bound transferrin (Tf) and mitochondria have been shown to facilitate direct iron transfer in erythroid cells. In this study, we used superresolution three-dimensional (3D) direct stochastic optical reconstruction microscopy to show that Tf-containing endosomes directly interact with mitochondria in epithelial cells. We used live-cell time-lapse fluorescence microscopy, followed by 3D rendering, object tracking, and a distance transformation algorithm, to track Tf-endosomes and characterize the dynamics of their interactions with mitochondria. Quenching of iron sensor RDA-labeled mitochondria confirmed functional iron transfer by an interacting Tf-endosome. The motility of Tf-endosomes is significantly reduced upon interaction with mitochondria. To further assess the functional role of iron in the ability of Tf-endosomes to interact with mitochondria, we blocked endosomal iron release by using a Tf K206E/K534A mutant. Blocking intraendosomal iron release led to significantly increased motility of Tf-endosomes and increased duration of endosome-mitochondria interactions. Thus, intraendosomal iron regulates the kinetics of the interactions between Tf-containing endosomes and mitochondria in epithelial cells.

  16. A conserved patch of hydrophobic amino acids modulates Myb activity by mediating protein-protein interactions.

    PubMed

    Dukare, Sandeep; Klempnauer, Karl-Heinz

    2016-07-01

    The transcription factor c-Myb plays a key role in the control of proliferation and differentiation in hematopoietic progenitor cells and has been implicated in the development of leukemia and certain non-hematopoietic tumors. c-Myb activity is highly dependent on the interaction with the coactivator p300 which is mediated by the transactivation domain of c-Myb and the KIX domain of p300. We have previously observed that conservative valine-to-isoleucine amino acid substitutions in a conserved stretch of hydrophobic amino acids have a profound effect on Myb activity. Here, we have explored the function of the hydrophobic region as a mediator of protein-protein interactions. We show that the hydrophobic region facilitates Myb self-interaction and binding of the histone acetyl transferase Tip60, a previously identified Myb interacting protein. We show that these interactions are affected by the valine-to-isoleucine amino acid substitutions and suppress Myb activity by interfering with the interaction of Myb and the KIX domain of p300. Taken together, our work identifies the hydrophobic region in the Myb transactivation domain as a binding site for homo- and heteromeric protein interactions and leads to a picture of the c-Myb transactivation domain as a composite protein binding region that facilitates interdependent protein-protein interactions of Myb with regulatory proteins.

  17. Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin.

    PubMed

    Coss, Christopher C; Jones, Amanda; Dalton, James T

    2016-08-01

    GTx-024 (also known as enobosarm) is a first in class selective androgen receptor modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metabolite (GTx-024 glucuronide), and each substrate were characterized in detail. Itraconazole administration had no effect on GTx-024 pharmacokinetics. Likewise, GTx-024 administration did not significantly change the pharmacokinetics of celecoxib or rosuvastatin. Rifampin administration had the largest impact on GTx-024 pharmacokinetics of any co-administered agent and reduced the maximal plasma concentration (Cmax) by 23 % and the area under the curve (AUC∞) by 43 %. Probenecid had a complex interaction with GTx-024 whereby both GTx-024 plasma levels and GTx-024 glucuronide plasma levels (AUC∞) were increased by co-administration of the UGT inhibitor (50 and 112 %, respectively). Overall, GTx-024 was well tolerated and poses very little risk of generating clinically relevant drug-drug interactions.

  18. Do biotic interactions modulate ecosystem functioning along stress gradients? Insights from semi-arid plant and biological soil crust communities

    PubMed Central

    Maestre, Fernando T.; Bowker, Matthew A.; Escolar, Cristina; Puche, María D.; Soliveres, Santiago; Maltez-Mouro, Sara; García-Palacios, Pablo; Castillo-Monroy, Andrea P.; Martínez, Isabel; Escudero, Adrián

    2010-01-01

    Climate change will exacerbate the degree of abiotic stress experienced by semi-arid ecosystems. While abiotic stress profoundly affects biotic interactions, their potential role as modulators of ecosystem responses to climate change is largely unknown. Using plants and biological soil crusts, we tested the relative importance of facilitative–competitive interactions and other community attributes (cover, species richness and species evenness) as drivers of ecosystem functioning along stress gradients in semi-arid Mediterranean ecosystems. Biotic interactions shifted from facilitation to competition along stress gradients driven by water availability and temperature. These changes were, however, dependent on the spatial scale and the community considered. We found little evidence to suggest that biotic interactions are a major direct influence upon indicators of ecosystem functioning (soil respiration, organic carbon, water-holding capacity, compaction and the activity of enzymes related to the carbon, nitrogen and phosphorus cycles) along stress gradients. However, attributes such as cover and species richness showed a direct effect on ecosystem functioning. Our results do not agree with predictions emphasizing that the importance of plant–plant interactions will be increased under climate change in dry environments, and indicate that reductions in the cover of plant and biological soil crust communities will negatively impact ecosystems under future climatic conditions. PMID:20513714

  19. Contextual task difficulty modulates stimulus discrimination: electrophysiological evidence for interaction between sensory and executive processes.

    PubMed

    Fedota, John R; McDonald, Craig G; Roberts, Daniel M; Parasuraman, Raja

    2012-10-01

    The occipital-temporal N1 component of the event-related potential (ERP) has previously been shown to index a stimulus discrimination process. However, the N1 has not consistently been shown to be sensitive to the difficulty of stimulus discrimination. Here, we manipulated the difficulty of stimulus discrimination by modulating the similarity between serially presented targets and nontargets. The same target stimulus was employed in both easy and difficult discrimination contexts, and these physically identical target stimuli elicited a larger N1 and smaller P3b in the difficult task context. Moreover, when targets were incorrectly categorized, N1 amplitude was diminished and a P3b was not elicited. These findings provide evidence that the N1 component reflects a sensory discrimination process that is modulated by executive control, and that this component can index discrimination errors when stimulus discrimination is difficult.

  20. Contextual task difficulty modulates stimulus discrimination: Electrophysiological evidence for interaction between sensory and executive processes

    PubMed Central

    Fedota, John R.; McDonald, Craig G.; Roberts, Daniel M.; Parasuraman, Raja

    2012-01-01

    The occipital-temporal N1 component of the event-related potential (ERP) has previously been shown to index a stimulus discrimination process. However, the N1 has not consistently been shown to be sensitive to the difficulty of stimulus discrimination. Here we manipulated the difficulty of stimulus discrimination by modulating the similarity between serially presented targets and non-targets. The same target stimulus was employed in both easy and difficult discrimination contexts, and these physically identical target stimuli elicited a larger N1 and smaller P3b in the difficult task context. Moreover, when targets were incorrectly categorized, N1 amplitude was diminished and a P3b was not elicited. These findings provide evidence that the N1 component reflects a sensory discrimination process that is modulated by executive control, and that this component can index discrimination errors when stimulus discrimination is difficult. PMID:22906001

  1. Target-object integration, attention distribution, and object orientation interactively modulate object-based selection.

    PubMed

    Al-Janabi, Shahd; Greenberg, Adam S

    2016-10-01

    The representational basis of attentional selection can be object-based. Various studies have suggested, however, that object-based selection is less robust than spatial selection across experimental paradigms. We sought to examine the manner by which the following factors might explain this variation: Target-Object Integration (targets 'on' vs. part 'of' an object), Attention Distribution (narrow vs. wide), and Object Orientation (horizontal vs. vertical). In Experiment 1, participants discriminated between two targets presented 'on' an object in one session, or presented as a change 'of' an object in another session. There was no spatial cue-thus, attention was initially focused widely-and the objects were horizontal or vertical. We found evidence of object-based selection only when targets constituted a change 'of' an object. Additionally, object orientation modulated the sign of object-based selection: We observed a same-object advantage for horizontal objects, but a same-object cost for vertical objects. In Experiment 2, an informative cue preceded a single target presented 'on' an object or as a change 'of' an object (thus, attention was initially focused narrowly). Unlike in Experiment 1, we found evidence of object-based selection independent of target-object integration. We again found that the sign of selection was modulated by the objects' orientation. This result may reflect a meridian effect, which emerged due to anisotropies in the cortical representations when attention is oriented endogenously. Experiment 3 revealed that object orientation did not modulate object-based selection when attention was oriented exogenously. Our findings suggest that target-object integration, attention distribution, and object orientation modulate object-based selection, but only in combination.

  2. Target-object integration, attention distribution, and object orientation interactively modulate object-based selection.

    PubMed

    Al-Janabi, Shahd; Greenberg, Adam S

    2016-10-01

    The representational basis of attentional selection can be object-based. Various studies have suggested, however, that object-based selection is less robust than spatial selection across experimental paradigms. We sought to examine the manner by which the following factors might explain this variation: Target-Object Integration (targets 'on' vs. part 'of' an object), Attention Distribution (narrow vs. wide), and Object Orientation (horizontal vs. vertical). In Experiment 1, participants discriminated between two targets presented 'on' an object in one session, or presented as a change 'of' an object in another session. There was no spatial cue-thus, attention was initially focused widely-and the objects were horizontal or vertical. We found evidence of object-based selection only when targets constituted a change 'of' an object. Additionally, object orientation modulated the sign of object-based selection: We observed a same-object advantage for horizontal objects, but a same-object cost for vertical objects. In Experiment 2, an informative cue preceded a single target presented 'on' an object or as a change 'of' an object (thus, attention was initially focused narrowly). Unlike in Experiment 1, we found evidence of object-based selection independent of target-object integration. We again found that the sign of selection was modulated by the objects' orientation. This result may reflect a meridian effect, which emerged due to anisotropies in the cortical representations when attention is oriented endogenously. Experiment 3 revealed that object orientation did not modulate object-based selection when attention was oriented exogenously. Our findings suggest that target-object integration, attention distribution, and object orientation modulate object-based selection, but only in combination. PMID:27198915

  3. Interaction of cannabinoid receptor 2 and social environment modulates chronic alcohol consumption.

    PubMed

    Pradier, Bruno; Erxlebe, Edda; Markert, Astrid; Rácz, Ildikó

    2015-01-01

    Genetic and environmental factors contribute nearly in equal power to the development of alcoholism. Environmental factors, such as negative life events or emotionally disruptive conditions, initiate and promote alcohol drinking and relapse. The endocannabinoid system is involved in hedonic control and modulates stress reactivity. Furthermore, chronic alcohol drinking alters endocannabinoid signalling, which in turn influences the stress reactivity. Recently, it has been shown that CB2 receptor activity influences stress sensitivity and alcohol drinking. We hypothesized that CB2 receptors influence the impact of environmental risk factors on alcohol preference and consumption. Therefore, in this study, we investigated the alcohol-drinking pattern of wild-type and CB2-deficient animals under single- and group-housing conditions using different alcohol-drinking models, such as forced drinking, intermittent forced drinking and two-bottle choice paradigms. Our data showed that CB2 receptor modulates alcohol consumption and reward. Interestingly, we detected that lack of CB2 receptors led to increased alcohol drinking in the intermittent forced drinking paradigm under group-housing conditions. Furthermore, we found that CB2 knockout mice consumed more food and that their body weight gain was modulated by social environment. On the basis of these data, we conclude that social environment critically affects the modulatory function of CB2 receptors, especially in alcohol intake. These findings suggest that a treatment strategy targeting CB2 receptors may have a beneficial effect on pathological drinking, particularly in situations of social stress and discomfort.

  4. Use of Live Interactive Webcasting for an International Postgraduate Module in eHealth: Case Study Evaluation

    PubMed Central

    Maramba, Inocencio; Boulos, Maged N Kamel; Alexander, Tara

    2009-01-01

    Background Producing “traditional” e-learning can be time consuming, and in a topic such as eHealth, it may have a short shelf-life. Students sometimes report feeling isolated and lacking in motivation. Synchronous methods can play an important part in any blended approach to learning. Objective The aim was to develop, deliver, and evaluate an international postgraduate module in eHealth using live interactive webcasting. Methods We developed a hybrid solution for live interactive webcasting using a scan converter, mixer, and digitizer, and video server to embed a presenter-controlled talking head or copy of the presenter’s computer screen (normally a PowerPoint slide) in a student chat room. We recruited 16 students from six countries and ran weekly 2.5-hour live sessions for 10 weeks. The content included the use of computers by patients, patient access to records, different forms of e-learning for patients and professionals, research methods in eHealth, geographic information systems, and telehealth. All sessions were recorded—presentations as video files and the student interaction as text files. Students were sent an email questionnaire of mostly open questions seeking their views of this form of learning. Responses were collated and anonymized by a colleague who was not part of the teaching team. Results Sessions were generally very interactive, with most students participating actively in breakout or full-class discussions. In a typical 2.5-hour session, students posted about 50 messages each. Two students did not complete all sessions; one withdrew from the pressure of work after session 6, and one from illness after session 7. Fourteen of the 16 responded to the feedback questionnaire. Most students (12/14) found the module useful or very useful, and all would recommend the module to others. All liked the method of delivery, in particular the interactivity, the variety of students, and the “closeness” of the group. Most (11/14) felt

  5. Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module.

    PubMed

    Yim, Nambin; Ryu, Seung-Wook; Choi, Kyungsun; Lee, Kwang Ryeol; Lee, Seunghee; Choi, Hojun; Kim, Jeongjin; Shaker, Mohammed R; Sun, Woong; Park, Ji-Ho; Kim, Daesoo; Heo, Won Do; Choi, Chulhee

    2016-01-01

    Nanoparticle-mediated delivery of functional macromolecules is a promising method for treating a variety of human diseases. Among nanoparticles, cell-derived exosomes have recently been highlighted as a new therapeutic strategy for the in vivo delivery of nucleotides and chemical drugs. Here we describe a new tool for intracellular delivery of target proteins, named 'exosomes for protein loading via optically reversible protein-protein interactions' (EXPLORs). By integrating a reversible protein-protein interaction module controlled by blue light with the endogenous process of exosome biogenesis, we are able to successfully load cargo proteins into newly generated exosomes. Treatment with protein-loaded EXPLORs is shown to significantly increase intracellular levels of cargo proteins and their function in recipient cells in vitro and in vivo. These results clearly indicate the potential of EXPLORs as a mechanism for the efficient intracellular transfer of protein-based therapeutics into recipient cells and tissues. PMID:27447450

  6. Design of Peptide-Membrane Interactions to Modulate Single-File Water Transport through Modified Gramicidin Channels

    PubMed Central

    Portella, Guillem; Polupanow, Tanja; Zocher, Florian; Boytsov, Danila A.; Pohl, Peter; Diederichsen, Ulf; de Groot, Bert L.

    2012-01-01

    Water permeability through single-file channels is affected by intrinsic factors such as their size and polarity and by external determinants like their lipid environment in the membrane. Previous computational studies revealed that the obstruction of the channel by lipid headgroups can be long-lived, in the range of nanoseconds, and that pore-length-matching membrane mimetics could speed up water permeability. To test the hypothesis of lipid-channel interactions modulating channel permeability, we designed different gramicidin A derivatives with attached acyl chains. By combining extensive molecular-dynamics simulations and single-channel water permeation measurements, we show that by tuning lipid-channel interactions, these modifications reduce the presence of lipid headgroups in the pore, which leads to a clear and selective increase in their water permeability. PMID:23083713

  7. Design of peptide-membrane interactions to modulate single-file water transport through modified gramicidin channels.

    PubMed

    Portella, Guillem; Polupanow, Tanja; Zocher, Florian; Boytsov, Danila A; Pohl, Peter; Diederichsen, Ulf; de Groot, Bert L

    2012-10-17

    Water permeability through single-file channels is affected by intrinsic factors such as their size and polarity and by external determinants like their lipid environment in the membrane. Previous computational studies revealed that the obstruction of the channel by lipid headgroups can be long-lived, in the range of nanoseconds, and that pore-length-matching membrane mimetics could speed up water permeability. To test the hypothesis of lipid-channel interactions modulating channel permeability, we designed different gramicidin A derivatives with attached acyl chains. By combining extensive molecular-dynamics simulations and single-channel water permeation measurements, we show that by tuning lipid-channel interactions, these modifications reduce the presence of lipid headgroups in the pore, which leads to a clear and selective increase in their water permeability.

  8. Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein–protein interaction module

    PubMed Central

    Yim, Nambin; Ryu, Seung-Wook; Choi, Kyungsun; Lee, Kwang Ryeol; Lee, Seunghee; Choi, Hojun; Kim, Jeongjin; Shaker, Mohammed R.; Sun, Woong; Park, Ji-Ho; Kim, Daesoo; Do Heo, Won; Choi, Chulhee

    2016-01-01

    Nanoparticle-mediated delivery of functional macromolecules is a promising method for treating a variety of human diseases. Among nanoparticles, cell-derived exosomes have recently been highlighted as a new therapeutic strategy for the in vivo delivery of nucleotides and chemical drugs. Here we describe a new tool for intracellular delivery of target proteins, named ‘exosomes for protein loading via optically reversible protein–protein interactions' (EXPLORs). By integrating a reversible protein–protein interaction module controlled by blue light with the endogenous process of exosome biogenesis, we are able to successfully load cargo proteins into newly generated exosomes. Treatment with protein-loaded EXPLORs is shown to significantly increase intracellular levels of cargo proteins and their function in recipient cells in vitro and in vivo. These results clearly indicate the potential of EXPLORs as a mechanism for the efficient intracellular transfer of protein-based therapeutics into recipient cells and tissues. PMID:27447450

  9. 2P2Idb v2: update of a structural database dedicated to orthosteric modulation of protein-protein interactions.

    PubMed

    Basse, Marie-Jeanne; Betzi, Stéphane; Morelli, Xavier; Roche, Philippe

    2016-01-01

    2P2Idb is a hand-curated structural database dedicated to protein-protein interactions with known small molecule orthosteric modulators. It compiles the structural information related to orthosteric inhibitors and their target [i.e. related 3D structures available in the RCSB Protein Data Bank (PDB)] and provides links to other useful databases. 2P2Idb includes all interactions for which both the protein-protein and protein-inhibitor complexes have been structurally characterized. Since its first release in 2010, the database has grown constantly and the current version contains 27 protein-protein complexes and 274 protein-inhibitor complexes corresponding to 242 unique small molecule inhibitors which represent almost a 5-fold increase compared to the previous version. A number of new data have been added, including new protein-protein complexes, binding affinities, molecular descriptors, precalculated interface parameters and links to other webservers. A new query tool has been implemented to search for inhibitors within the database using standard molecular descriptors. A novel version of the 2P2I-inspector tool has been implemented to calculate a series of physical and chemical parameters of the protein interfaces. Several geometrical parameters including planarity, eccentricity and circularity have been added as well as customizable distance cutoffs. This tool has also been extended to protein-ligand interfaces. The 2P2I database thus represents a wealth of structural source of information for scientists interested in the properties of protein-protein interactions and the design of protein-protein interaction modulators. Database URL: http://2p2idb.cnrs-mrs.fr.

  10. 2P2Idb v2: update of a structural database dedicated to orthosteric modulation of protein–protein interactions

    PubMed Central

    Basse, Marie-Jeanne; Betzi, Stéphane; Morelli, Xavier; Roche, Philippe

    2016-01-01

    2P2Idb is a hand-curated structural database dedicated to protein–protein interactions with known small molecule orthosteric modulators. It compiles the structural information related to orthosteric inhibitors and their target [i.e. related 3D structures available in the RCSB Protein Data Bank (PDB)] and provides links to other useful databases. 2P2Idb includes all interactions for which both the protein–protein and protein–inhibitor complexes have been structurally characterized. Since its first release in 2010, the database has grown constantly and the current version contains 27 protein–protein complexes and 274 protein–inhibitor complexes corresponding to 242 unique small molecule inhibitors which represent almost a 5-fold increase compared to the previous version. A number of new data have been added, including new protein–protein complexes, binding affinities, molecular descriptors, precalculated interface parameters and links to other webservers. A new query tool has been implemented to search for inhibitors within the database using standard molecular descriptors. A novel version of the 2P2I-inspector tool has been implemented to calculate a series of physical and chemical parameters of the protein interfaces. Several geometrical parameters including planarity, eccentricity and circularity have been added as well as customizable distance cutoffs. This tool has also been extended to protein–ligand interfaces. The 2P2I database thus represents a wealth of structural source of information for scientists interested in the properties of protein–protein interactions and the design of protein–protein interaction modulators. Database URL: http://2p2idb.cnrs-mrs.fr PMID:26980515

  11. The HMI™ module: a new tool to study the Host-Microbiota Interaction in the human gastrointestinal tract in vitro

    PubMed Central

    2014-01-01

    Background Recent scientific developments have shed more light on the importance of the host-microbe interaction, particularly in the gut. However, the mechanistic study of the host-microbe interplay is complicated by the intrinsic limitations in reaching the different areas of the gastrointestinal tract (GIT) in vivo. In this paper, we present the technical validation of a new device - the Host-Microbiota Interaction (HMI) module - and the evidence that it can be used in combination with a gut dynamic simulator to evaluate the effect of a specific treatment at the level of the luminal microbial community and of the host surface colonization and signaling. Results The HMI module recreates conditions that are physiologically relevant for the GIT: i) a mucosal area to which bacteria can adhere under relevant shear stress (3 dynes cm−2); ii) the bilateral transport of low molecular weight metabolites (4 to 150 kDa) with permeation coefficients ranging from 2.4 × 10−6 to 7.1 × 10−9 cm sec−1; and iii) microaerophilic conditions at the bottom of the growing biofilm (PmO2 = 2.5 × 10−4 cm sec−1). In a long-term study, the host’s cells in the HMI module were still viable after a 48-hour exposure to a complex microbial community. The dominant mucus-associated microbiota differed from the luminal one and its composition was influenced by the treatment with a dried product derived from yeast fermentation. The latter - with known anti-inflammatory properties - induced a decrease of pro-inflammatory IL-8 production between 24 and 48 h. Conclusions The study of the in vivo functionality of adhering bacterial communities in the human GIT and of the localized effect on the host is frequently hindered by the complexity of reaching particular areas of the GIT. The HMI module offers the possibility of co-culturing a gut representative microbial community with enterocyte-like cells up to 48 h and may therefore contribute to the mechanistic understanding of

  12. Destabilization of interaction between cytokinin signaling intermediates AHP1 and ARR4 modulates Arabidopsis development.

    PubMed

    Verma, Vivek; Sivaraman, Jayaraman; Srivastava, Anjil Kumar; Sadanandom, Ari; Kumar, Prakash P

    2015-04-01

    Eukaryotic two-component signaling involves the His-Asp-His-Asp multistep phosphorelay (MSP). In Arabidopsis thaliana, cytokinin-mediated MSP signaling intermediates include histidine kinases (HKs), histidine phosphotransfer proteins (Hpts) and response regulators (RRs). The structure-function relationship of interaction between Hpt (e.g. AHP1) and RR (e.g. ARR4) is poorly understood. Using a homology model and yeast two-hybrid analysis, we identified key amino acids of ARR4 at the AHP1-ΔARR4((16-175)) interaction interface. Mutating them in Arabidopsis (arr3,4,5,6,8,9 hextuple mutant background) and performing root length assays provided functional relevance, and coimmunoprecipitation (coIP) assay provided biochemical evidence for the interaction. The homology model mimics crystal structures of Hpt-RR complexes. Mutating selected interface residues of ARR4 either abolished or destabilized the interaction. D45A and Y96A mutations weakened interaction with AHP1, and exhibited weaker rescue of root elongation in the hextuple mutants. CoIP analysis using cytokinin-treated transgenic Arabidopsis seedlings provided biochemical evidence for weakened AHP1-ARR4 interaction. The relevance of the selected residues for the interaction was further validated in two independent pairs of Hpt-RR proteins from Arabidopsis and rice (Oryza sativa). Our data provide evidence of a link between Hpt-RR interaction affinity and regulation of downstream functions of RRs. This establishes a structure-function relationship for the final step of a eukaryotic MSP signal cascade.

  13. PfCRT and PfMDR1 modulate interactions of artemisinin derivatives and ion channel blockers

    PubMed Central

    Eastman, Richard T.; Khine, Pwint; Huang, Ruili; Thomas, Craig J.; Su, Xin-zhuan

    2016-01-01

    Treatment of the symptomatic asexual stage of Plasmodium falciparum relies almost exclusively on artemisinin (ART) combination therapies (ACTs) in endemic regions. ACTs combine ART or its derivative with a long-acting partner drug to maximize efficacy during the typical three-day regimen. Both laboratory and clinical studies have previously demonstrated that the common drug resistance determinants P. falciparum chloroquine resistance transporter (PfCRT) and multidrug resistance transporter (PfMDR1) can modulate the susceptibility to many current antimalarial drugs and chemical compounds. Here we investigated the parasite responses to dihydroartemisinin (DHA) and various Ca2+ and Na+ channel blockers and showed positively correlated responses between DHA and several channel blockers, suggesting potential shared transport pathways or mode of action. Additionally, we demonstrated that PfCRT and PfMDR1 could also significantly modulate the pharmacodynamic interactions of the compounds and that the interactions were influenced by the parasite genetic backgrounds. These results provide important information for better understanding of drug resistance and for assessing the overall impact of drug resistance markers on parasite response to ACTs. PMID:27147113

  14. Thermal acclimation modulates the impacts of temperature and enrichment on trophic interaction strengths and population dynamics.

    PubMed

    Sentis, Arnaud; Morisson, Julie; Boukal, David S

    2015-09-01

    Global change affects individual phenotypes and biotic interactions, which can have cascading effects up to the ecosystem level. However, the role of environmentally induced phenotypic plasticity in species interactions is poorly understood, leaving a substantial gap in our knowledge of the impacts of global change on ecosystems. Using a cladoceran-dragonfly system, we experimentally investigated the effects of thermal acclimation, acute temperature change and enrichment on predator functional response and metabolic rate. Using our experimental data, we next parameterized a population dynamics model to determine the consequences of these effects on trophic interaction strength and food-chain stability. We found that (1) predation and metabolic rates of the dragonfly larvae increase with acute warming, (2) warm-acclimated larvae have a higher maximum predation rate than cold-acclimated ones, and (3) long-term interaction strength increases with enrichment but decreases with both acclimation and acute temperatures. Overall, our experimental results show that thermal acclimation can buffer negative impacts of environmental change on predators and increase food-web stability and persistence. We conclude that the effect of acclimation and, more generally, phenotypic plasticity on trophic interactions should not be overlooked if we aim to understand the effects of climate change and enrichment on species interaction strength and food-web stability. PMID:25808556

  15. Functional interactions between the nucleus tractus solitarius (NTS) and nucleus accumbens shell in modulating memory for arousing experiences.

    PubMed

    Kerfoot, Erin C; Chattillion, Elizabeth A; Williams, Cedric L

    2008-01-01

    The shell division of the nucleus accumbens receives noradrenergic input from neurons in the nucleus of the solitary tract (NTS) that transmit information regarding fluctuations in peripheral hormonal and autonomic activity. Accumbens shell neurons also receive converging inputs from limbic areas such as the hippocampus and amygdala that process newly acquired information. However, few studies have explored whether peripheral information regarding changes in emotional arousal contributes to memory processing in the accumbens. The beneficial effects on memory produced by emotional arousal and the corresponding activation of NTS neurons may be mediated through influences on neuronal activity in the accumbens shell during memory encoding. To explore this putative relationship, Experiment 1 examined interactions between the NTS and the accumbens shell in modulating memory for responses acquired after footshock training in a water-motivated inhibitory avoidance task. Memory for the noxious shock was significantly improved by posttraining excitation of noradrenergic NTS neurons. The enhanced retention produced by activating NTS neurons was attenuated by suppressing neuronal activity in the accumbens shell with bupivacaine (0.25%/0.5 microl). Experiment 2 examined the direct involvement of accumbens shell noradrenergic activation in the modulation of memory for psychologically arousing events such as a reduction in perceived reward value. Noradrenergic activation of the accumbens shell with phenylephrine (1.0 microg/0.5 microl) produced an enhancement in memory for the frustrating experience relative to control injections as evidenced by runway performance on an extended seven-day retention test. These findings demonstrate a functional relationship between NTS neurons and the accumbens shell in modulating memory following physiological arousal and identifies a role of norepinephrine in modulating synaptic activity in the accumbens shell to facilitate this process.

  16. Interaction between positive allosteric modulators and trapping blockers of the NMDA receptor channel

    PubMed Central

    Emnett, Christine M; Eisenman, Lawrence N; Mohan, Jayaram; Taylor, Amanda A; Doherty, James J; Paul, Steven M; Zorumski, Charles F; Mennerick, Steven

    2015-01-01

    Background and Purpose Memantine and ketamine are clinically used, open-channel blockers of NMDA receptors exhibiting remarkable pharmacodynamic similarities despite strikingly different clinical profiles. Although NMDA channel gating constitutes an important difference between memantine and ketamine, it is unclear how positive allosteric modulators (PAMs) might affect the pharmacodynamics of these NMDA blockers. Experimental Approach We used two different PAMs: SGE-201, an analogue of an endogenous oxysterol, 24S-hydroxycholesterol, along with pregnenolone sulphate (PS), to test on memantine and ketamine responses in single cells (oocytes and cultured neurons) and networks (hippocampal slices), using standard electrophysiological techniques. Key Results SGE-201 and PS had no effect on steady-state block or voltage dependence of a channel blocker. However, both PAMs increased the actions of memantine and ketamine on phasic excitatory post-synaptic currents, but neither revealed underlying pharmacodynamic differences. SGE-201 accelerated the re-equilibration of blockers during voltage jumps. SGE-201 also unmasked differences among the blockers in neuronal networks – measured either by suppression of activity in multi-electrode arrays or by neuroprotection against a mild excitotoxic insult. Either potentiating NMDA receptors while maintaining the basal activity level or increasing activity/depolarization without potentiating NMDA receptor function is sufficient to expose pharmacodynamic blocker differences in suppressing network function and in neuroprotection. Conclusions and Implications Positive modulation revealed no pharmacodynamic differences between NMDA receptor blockers at a constant voltage, but did expose differences during spontaneous network activity. Endogenous modulator tone of NMDA receptors in different brain regions may underlie differences in the effects of NMDA receptor blockers on behaviour. PMID:25377730

  17. Equilibrium-fluctuation-analysis of single liposome binding events reveals how cholesterol and Ca2+ modulate glycosphingolipid trans-interactions.

    PubMed

    Kunze, Angelika; Bally, Marta; Höök, Fredrik; Larson, Göran

    2013-01-01

    Carbohydrate-carbohydrate interactions (CCIs) are of central importance for several biological processes. However, the ultra-weak nature of CCIs generates difficulties in studying this interaction, thus only little is known about CCIs. Here we present a highly sensitive equilibrium-fluctuation-analysis of single liposome binding events to supported lipid bilayers (SLBs) based on total internal reflection fluorescence (TIRF) microscopy that allows us to determine apparent kinetic rate constants of CCIs. The liposomes and SLBs both contained natural Le(x) glycosphingolipids (Galβ4(Fucα3)GlcNAcβ3Galβ4Glcβ1Cer), which were employed to mimic cell-cell contacts. The kinetic parameters of the self-interaction between Le(x)-containing liposomes and SLBs were measured and found to be modulated by bivalent cations. Even more interestingly, upon addition of cholesterol, the strength of the CCIs increases, suggesting that this interaction is strongly influenced by a cholesterol-dependent presentation and/or spatial organization of glycosphingolipids in cell membranes. PMID:23486243

  18. Several lipid-related gene polymorphisms interact with overweight/obesity to modulate blood pressure levels.

    PubMed

    Yin, Rui-Xing; Wu, Dong-Feng; Aung, Lynn Htet Htet; Yan, Ting-Ting; Cao, Xiao-Li; Long, Xing-Jiang; Miao, Lin; Liu, Wan-Ying; Zhang, Lin; Li, Meng

    2012-01-01

    Little is known about the interactions of single nucleotide polymorphisms (SNPs) and overweight/obesity on blood pressure levels. The present study was undertaken to detect 10 lipid-related gene SNPs and their interactions with overweight/obesity on blood pressure levels. Genotyping of ATP-binding cassette transporter A1 (ABCA-1) V825I, acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) rs1044925, low density lipoprotein receptor (LDL-R) AvaII hepatic lipase gene (LIPC) -250G > A, endothelial lipase gene (LIPG) 584C > T, methylenetetrahydrofolate reductase (MTHFR) 677C > T, the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP) rs3757354, proprotein convertase subtilisin-like kexin type 9 (PCSK9) E670G, peroxisome proliferator-activated receptor delta (PPARD) +294T > C, and Scavenger receptor class B type 1 (SCARB1) rs5888 was performed in 978 normal weight and 751 overweight/obese subjects. The interactions were detected by factorial regression analysis. The genotypes of ACAT-1 AC, LIPC GA and AA, and SCARB1 TT; LDL-R A-A- and LIPC GA; and SCARB1 TT were interacted with overweight/obesity to increase systolic, diastolic blood pressure (SBP, DBP) and pulse pressure (PP) levels; respectively. The genotypes of ACAT-1 CC; ACAT-1 AA and CC were interacted with overweight/obesity to decrease SBP, PP levels (p < 0.01-0.001); respectively. The differences in blood pressure levels between normal weight and overweight/obese subjects might partly result from different interactions of several SNPs and overweight/obesity. PMID:23109900

  19. Developing Classroom Interactions Which Signal Effective Teaching. A Module for Undergraduate Instruction in Teacher Education in the RAFT Program at Mississippi State University.

    ERIC Educational Resources Information Center

    Handley, Herbert M., Ed.

    In this module, developed by the Research Applications for Teaching (RAFT) project, preservice teachers study the major types of classroom interactions which occur between teachers and students and review the research findings showing how these interactions are related to effective teaching. Much effort is spent on describing procedures for…

  20. The physical interaction of Mcm10 with Cdc45 modulates their DNA-binding properties.

    PubMed

    Di Perna, Roberta; Aria, Valentina; De Falco, Mariarosaria; Sannino, Vincenzo; Okorokov, Andrei L; Pisani, Francesca M; De Felice, Mariarita

    2013-09-01

    The eukaryotic DNA replication protein Mcm10 (mini-chromosome maintenance 10) associates with chromatin in early S-phase and is required for assembly and function of the replication fork protein machinery. Another essential component of the eukaryotic replication fork is Cdc45 (cell division cycle 45), which is required for both initiation and elongation of DNA replication. In the present study we characterize, for the first time, the physical and functional interactions of human Mcm10 and Cdc45. First we demonstrated that Mcm10 and Cdc45 interact in cell-free extracts. We then analysed the role of each of the Mcm10 domains: N-terminal, internal and C-terminal (NTD, ID and CTD respectively). We have detected a direct physical interaction between CTD and Cdc45 by both in vitro co-immunoprecipitation and surface plasmon resonance experiments. On the other hand, we have found that the interaction of the Mcm10 ID with Cdc45 takes place only in the presence of DNA. Furthermore, we found that the isolated ID and CTD domains are fully functional, retaining DNA-binding capability with a clear preference for bubble and fork structures, and that they both enhance Cdc45 DNA-binding affinity. The results of the present study demonstrate that human Mcm10 and Cdc45 directly interact and establish a mutual co-operation in DNA binding.

  1. Selective interaction between microbubbles and modulating waves in a Taylor-Couette flow

    NASA Astrophysics Data System (ADS)

    Watamura, Tomoaki; Tasaka, Yuji; Murai, Yuichi

    2012-11-01

    Modifications of a coherent vortical structure by dispersed microbubbles have been investigated in a vertical Taylor-Couette flow, which is the flow generated between coaxial-rotating double cylinders. Radii of the inner and outer cylinders are 95 mm and 105 mm, respectively. The radius ratio and aspect ratio are 0.905 and 20, respectively. Flow mode in the experiments represents wavy vortex flow and modulated wavy vortex flow. Hydrogen bubbles with 60 μm in the mean diameter were generated by water electrolysis and dispersed from a platinum-wire electrode mounted at the bottom of the fluid layer. Maximum void fraction estimated by input power is smaller than 0.01%. Velocity distribution of microbubbles in a Taylor vortex array is determined by image analysis, and show preferential distribution and motion in the oscillating vortex tube. The fluctuation power of the basic wave was increased by adding microbubbles, while the power of its modulation was decreased. The gradient of the azimuthal velocity in the radial direction, i.e. origin of skin frictional drag acting on the cylinder walls, was decreased. These modifications of flow structure represent the suppression of the flow transition, due to the excitation of the basic wave oscillation and increase of momentum transfer by bubble swarm.

  2. Ultrafast spontaneous emission modulation of graphene quantum dots interacting with Ag nanoparticles in solution

    NASA Astrophysics Data System (ADS)

    Zhao, Jianwei; Lu, Jian; Wang, Liang; Tian, Linfan; Deng, Xingxia; Tian, Lijun; Pan, Dengyu; Wang, Zhongyang

    2016-07-01

    We investigated the strong interaction between graphene quantum dots and silver nanoparticles in solution using time-resolved photoluminescence techniques. In solution, the silver nanoparticles are surrounded by graphene quantum dots and interacted with graphene quantum dots through exciton-plasmon coupling. An ultrafast spontaneous emission process (lifetime 27 ps) was observed in such a mixed solution. This ultrafast lifetime corresponds to the emission rate exceeding 35 GHz, with the purcell enhancement by a factor of ˜12. These experiment results pave the way for the realization of future high speed light sources applications.

  3. Capsule expression in Streptococcus mitis modulates interaction with oral keratinocytes and alters susceptibility to human antimicrobial peptides.

    PubMed

    Rukke, H V; Engen, S A; Schenck, K; Petersen, F C

    2016-08-01

    Streptococcus mitis is a colonizer of the oral cavity and the nasopharynx, and is closely related to Streptococcus pneumoniae. Both species occur in encapsulated and unencapsulated forms, but in S. mitis the role of the capsule in host interactions is mostly unknown. Therefore, the aim of this study was to examine how capsule expression in S. mitis can modulate interactions with the host with relevance for colonization. The S. mitis type strain, as well as two mutants of the type strain, an isogenic capsule deletion mutant, and a capsule switch mutant expressing the serotype 4 capsule of S. pneumoniae TIGR4, were used. Wild-type and capsule deletion strains of S. pneumoniae TIGR4 were included for comparison. We found that capsule production in S. mitis reduced adhesion to oral and lung epithelial cells. Further, exposure of oral epithelial cells to encapsulated S. mitis resulted in higher interleukin-6 and CXCL-8 transcription levels relative to the unencapsulated mutant. Capsule expression in S. mitis increased the sensitivity to human neutrophil peptide 1-3 but reduced the sensitivity to human β-defensin-3 and cathelicidin. This was in contrast with S. pneumoniae in which capsule expression has been generally associated with increased sensitivity to human antimicrobial peptides (AMPs). Collectively, these findings indicate that capsule expression in S. mitis is important in modulating interactions with epithelial cells, and is associated with increased or reduced susceptibility to AMPs depending on the nature of the AMP.

  4. Modulation of Magnetic Heating via Dipolar Magnetic Interactions in Monodisperse and Crystalline Iron Oxide Nanoparticles

    DOE PAGES

    Salas, Gorka; Camarero, Julio; Cabrera, David; Takacs, Hélène; Varela, María; Ludwig, Robert; Dähring, Heidi; Hilger, Ingrid; Miranda, Rodolfo; Morales, María del Puerto; et al

    2014-07-23

    Here, we report on the study of heat dissipation power in monodisperse and crystalline magnetite nanoparticles as function of particle and aggregate sizes, magnetic field frequencies (up to 435 kHz) and amplitudes (up to 50 mT), media viscosity and particle concentration. These nanoparticles display specific absorption rate values of few hundreds of WgFe-1 at moderate frequencies (~100 kHz), increasing up to 3632 WgFe-1 at more extreme field conditions (430 kHz and 40 mT) for the largest size. We have found that Néelian relaxation processes are dominant for all nanoparticle sizes, whereas Brownian contribution dominates only for the largest size (22more » nm) at high particle concentrations when dipolar interactions enhance the effective magnetic anisotropy. Besides, the particle concentration dependence of the specific absorption rate reflects the importance of magnetic dipolar interactions which strongly depend on aggregate and particle size. Our results show that dipolar interactions tune the effective magnetic anisotropy determining the Néelian and Brownian contributions into SAR values. The possibility of switching between heating mechanisms via dipolar interactions is of great importance towards controlling the heat exposure supplied by IONP as intracellular heating mediators.« less

  5. GGA3 Interacts with a G Protein-Coupled Receptor and Modulates Its Cell Surface Export

    PubMed Central

    Zhang, Maoxiang; Davis, Jason E.; Li, Chunman; Gao, Jie; Huang, Wei; Lambert, Nevin A.; Terry, Alvin V.

    2016-01-01

    Molecular mechanisms governing the anterograde trafficking of nascent G protein-coupled receptors (GPCRs) are poorly understood. Here, we have studied the regulation of cell surface transport of α2-adrenergic receptors (α2-ARs) by GGA3 (Golgi-localized, γ-adaptin ear domain homology, ADP ribosylation factor-binding protein 3), a multidomain clathrin adaptor protein that sorts cargo proteins at the trans-Golgi network (TGN) to the endosome/lysosome pathway. By using an inducible system, we demonstrated that GGA3 knockdown significantly inhibited the cell surface expression of newly synthesized α2B-AR without altering overall receptor synthesis and internalization. The receptors were arrested in the TGN. Furthermore, GGA3 knockdown attenuated α2B-AR-mediated signaling, including extracellular signal-regulated kinase 1/2 (ERK1/2) activation and cyclic AMP (cAMP) inhibition. More interestingly, GGA3 physically interacted with α2B-AR, and the interaction sites were identified as the triple Arg motif in the third intracellular loop of the receptor and the acidic motif EDWE in the VHS domain of GGA3. In contrast, α2A-AR did not interact with GGA3 and its cell surface export and signaling were not affected by GGA3 knockdown. These data reveal a novel function of GGA3 in export trafficking of a GPCR that is mediated via a specific interaction with the receptor. PMID:26811329

  6. PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions

    PubMed Central

    Matsuzawa, Kenji; Akita, Hiroki; Watanabe, Takashi; Kakeno, Mai; Matsui, Toshinori; Wang, Shujie; Kaibuchi, Kozo

    2016-01-01

    Tiam1 is one of the most extensively analyzed activators of the small GTPase Rac. However, fundamental aspects of its regulation are poorly understood. Here we demonstrate that Tiam1 is functionally suppressed by internal interactions and that the PAR complex participates in its full activation. The N-terminal region of Tiam1 binds to the protein-binding and catalytic domains to inhibit its localization and activation. Atypical PKCs phosphorylate Tiam1 to relieve its intramolecular interactions, and the subsequent stabilization of its interaction with PAR3 allows it to exert localized activity. By analyzing Tiam1 regulation by PAR3-aPKC within the context of PDGF signaling, we also show that PAR3 directly binds PDGF receptor β. Thus we provide the first evidence for the negative regulation of Tiam1 by internal interactions, elucidate the nature of Tiam1 regulation by the PAR complex, and reveal a novel role for the PAR complex in PDGF signaling. PMID:26941335

  7. Genetic variants at PSMD3 interact with dietary fat and carbohydrate to modulate insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Proteasome (prosome, macropain) 26S subunit, non-ATPase, 3 (PSMD3) encodes subunit 3 of the 26S proteasome, which is involved in regulating insulin signal transduction. We aimed to investigate the associations of PSMD3 variants with glucose-related traits and the interactions of those variants with ...

  8. Modulation of Additive and Interactive Effects in Lexical Decision by Trial History

    ERIC Educational Resources Information Center

    Masson, Michael E. J.; Kliegl, Reinhold

    2013-01-01

    Additive and interactive effects of word frequency, stimulus quality, and semantic priming have been used to test theoretical claims about the cognitive architecture of word-reading processes. Additive effects among these factors have been taken as evidence for discrete-stage models of word reading. We present evidence from linear mixed-model…

  9. A New Approach to Developing Interactive Software Modules through Graduate Education

    ERIC Educational Resources Information Center

    Sanders, Nathan E.; Faesi, Chris; Goodman, Alyssa A.

    2014-01-01

    Educational technology has attained significant importance as a mechanism for supporting experiential learning of science concepts. However, the growth of this mechanism is limited by the significant time and technical expertise needed to develop such products, particularly in specialized fields of science. We sought to test whether interactive,…

  10. Stimulus set size modulates the sex-emotion interaction in face categorization.

    PubMed

    Lipp, Ottmar V; Karnadewi, Fika; Craig, Belinda M; Cronin, Sophie L

    2015-05-01

    Previous research has shown that invariant facial features-for example, sex-and variant facial features-for example, emotional expressions-interact during face categorization. The nature of this interaction is a matter of dispute, however, and has been reported as either asymmetrical, such that sex cues influence emotion perception but emotional expressions do not affect the perception of sex, or symmetrical, such that sex and emotion cues each reciprocally influence the categorization of the other. In the present research, we identified stimulus set size as the critical factor leading to this disparity. Using faces drawn from different databases, in two separate experiments we replicated the finding of a symmetrical interaction between face sex and emotional expression when larger sets of posers were used. Using a subset of four posers, in the same setups, however, did not provide evidence for a symmetrical interaction, which is also consistent with prior research. This pattern of results suggests that different strategies may be used to categorize aspects of faces that are encountered repeatedly. PMID:25737259

  11. Interactions between Gut Microbiota, Host Genetics and Diet Modulate the Predisposition to Obesity and Metabolic Syndrome.

    PubMed

    Ussar, Siegfried; Griffin, Nicholas W; Bezy, Olivier; Fujisaka, Shiho; Vienberg, Sara; Softic, Samir; Deng, Luxue; Bry, Lynn; Gordon, Jeffrey I; Kahn, C Ronald

    2015-09-01

    Obesity, diabetes, and metabolic syndrome result from complex interactions between genetic and environmental factors, including the gut microbiota. To dissect these interactions, we utilized three commonly used inbred strains of mice-obesity/diabetes-prone C57Bl/6J mice, obesity/diabetes-resistant 129S1/SvImJ from Jackson Laboratory, and obesity-prone but diabetes-resistant 129S6/SvEvTac from Taconic-plus three derivative lines generated by breeding these strains in a new, common environment. Analysis of metabolic parameters and gut microbiota in all strains and their environmentally normalized derivatives revealed strong interactions between microbiota, diet, breeding site, and metabolic phenotype. Strain-dependent and strain-independent correlations were found between specific microbiota and phenotypes, some of which could be transferred to germ-free recipient animals by fecal transplantation. Environmental reprogramming of microbiota resulted in 129S6/SvEvTac becoming obesity resistant. Thus, development of obesity/metabolic syndrome is the result of interactions between gut microbiota, host genetics, and diet. In permissive genetic backgrounds, environmental reprograming of microbiota can ameliorate development of metabolic syndrome.

  12. Modulation of Magnetic Heating via Dipolar Magnetic Interactions in Monodisperse and Crystalline Iron Oxide Nanoparticles

    SciTech Connect

    Salas, Gorka; Camarero, Julio; Cabrera, David; Takacs, Hélène; Varela, María; Ludwig, Robert; Dähring, Heidi; Hilger, Ingrid; Miranda, Rodolfo; Morales, María del Puerto; Teran, Francisco Jose

    2014-07-23

    Here, we report on the study of heat dissipation power in monodisperse and crystalline magnetite nanoparticles as function of particle and aggregate sizes, magnetic field frequencies (up to 435 kHz) and amplitudes (up to 50 mT), media viscosity and particle concentration. These nanoparticles display specific absorption rate values of few hundreds of WgFe-1 at moderate frequencies (~100 kHz), increasing up to 3632 WgFe-1 at more extreme field conditions (430 kHz and 40 mT) for the largest size. We have found that Néelian relaxation processes are dominant for all nanoparticle sizes, whereas Brownian contribution dominates only for the largest size (22 nm) at high particle concentrations when dipolar interactions enhance the effective magnetic anisotropy. Besides, the particle concentration dependence of the specific absorption rate reflects the importance of magnetic dipolar interactions which strongly depend on aggregate and particle size. Our results show that dipolar interactions tune the effective magnetic anisotropy determining the Néelian and Brownian contributions into SAR values. The possibility of switching between heating mechanisms via dipolar interactions is of great importance towards controlling the heat exposure supplied by IONP as intracellular heating mediators.

  13. Establishment of a Developmental Compartment Requires Interactions between Three Synergistic Cis-regulatory Modules

    PubMed Central

    Bieli, Dimitri; Kanca, Oguz; Requena, David; Hamaratoglu, Fisun; Gohl, Daryl; Schedl, Paul; Affolter, Markus; Slattery, Matthew; Müller, Martin; Estella, Carlos

    2015-01-01

    The subdivision of cell populations in compartments is a key event during animal development. In Drosophila, the gene apterous (ap) divides the wing imaginal disc in dorsal vs ventral cell lineages and is required for wing formation. ap function as a dorsal selector gene has been extensively studied. However, the regulation of its expression during wing development is poorly understood. In this study, we analyzed ap transcriptional regulation at the endogenous locus and identified three cis-regulatory modules (CRMs) essential for wing development. Only when the three CRMs are combined, robust ap expression is obtained. In addition, we genetically and molecularly analyzed the trans-factors that regulate these CRMs. Our results propose a three-step mechanism for the cell lineage compartment expression of ap that includes initial activation, positive autoregulation and Trithorax-mediated maintenance through separable CRMs. PMID:26468882

  14. Accurate formula for dissipative interaction in frequency modulation atomic force microscopy

    NASA Astrophysics Data System (ADS)

    Suzuki, Kazuhiro; Kobayashi, Kei; Labuda, Aleksander; Matsushige, Kazumi; Yamada, Hirofumi

    2014-12-01

    Much interest has recently focused on the viscosity of nano-confined liquids. Frequency modulation atomic force microscopy (FM-AFM) is a powerful technique that can detect variations in the conservative and dissipative forces between a nanometer-scale tip and a sample surface. We now present an accurate formula to convert the dissipation power of the cantilever measured during the experiment to damping of the tip-sample system. We demonstrated the conversion of the dissipation power versus tip-sample separation curve measured using a colloidal probe cantilever on a mica surface in water to the damping curve, which showed a good agreement with the theoretical curve. Moreover, we obtained the damping curve from the dissipation power curve measured on the hydration layers on the mica surface using a nanometer-scale tip, demonstrating that the formula allows us to quantitatively measure the viscosity of a nano-confined liquid using FM-AFM.

  15. Modulated interaction in double-layer shape memory-based micro-designed actuators

    NASA Astrophysics Data System (ADS)

    Crăciunescu, Corneliu; Ercuta, Aurel

    2015-12-01

    The effect of superposed transitions in actuators with layered shape memory alloy (SMA) films undergoing martensitic phase transformation is analyzed in terms of a model developed for two layers of different composition, deposited at the same temperature on a substrate. A significant difference is observed in the actuation versus temperature relationship, depending on the thermal and elastic properties of the SMA layers and their martensitic transformation temperature. The prediction of the actuation is exemplified using a multilayer model and is verified for a cantilever actuator with NiTi and NiMnGa layers deposited on a Si substrate. The model sets the ground for a smart selection of SMAs in order to achieve a modulated actuation.

  16. Accurate formula for dissipative interaction in frequency modulation atomic force microscopy

    SciTech Connect

    Suzuki, Kazuhiro; Matsushige, Kazumi; Yamada, Hirofumi; Kobayashi, Kei; Labuda, Aleksander

    2014-12-08

    Much interest has recently focused on the viscosity of nano-confined liquids. Frequency modulation atomic force microscopy (FM-AFM) is a powerful technique that can detect variations in the conservative and dissipative forces between a nanometer-scale tip and a sample surface. We now present an accurate formula to convert the dissipation power of the cantilever measured during the experiment to damping of the tip-sample system. We demonstrated the conversion of the dissipation power versus tip-sample separation curve measured using a colloidal probe cantilever on a mica surface in water to the damping curve, which showed a good agreement with the theoretical curve. Moreover, we obtained the damping curve from the dissipation power curve measured on the hydration layers on the mica surface using a nanometer-scale tip, demonstrating that the formula allows us to quantitatively measure the viscosity of a nano-confined liquid using FM-AFM.

  17. Interactive Learning Modules: Enabling Near Real-Time Oceanographic Data Use In Undergraduate Education

    NASA Astrophysics Data System (ADS)

    Kilb, D. L.; Fundis, A. T.; Risien, C. M.

    2012-12-01

    The focus of the Education and Public Engagement (EPE) component of the NSF's Ocean Observatories Initiative (OOI) is to provide a new layer of cyber-interactivity for undergraduate educators to bring near real-time data from the global ocean into learning environments. To accomplish this, we are designing six online services including: 1) visualization tools, 2) a lesson builder, 3) a concept map builder, 4) educational web services (middleware), 5) collaboration tools and 6) an educational resource database. Here, we report on our Fall 2012 release that includes the first four of these services: 1) Interactive visualization tools allow users to interactively select data of interest, display the data in various views (e.g., maps, time-series and scatter plots) and obtain statistical measures such as mean, standard deviation and a regression line fit to select data. Specific visualization tools include a tool to compare different months of data, a time series explorer tool to investigate the temporal evolution of select data parameters (e.g., sea water temperature or salinity), a glider profile tool that displays ocean glider tracks and associated transects, and a data comparison tool that allows users to view the data either in scatter plot view comparing one parameter with another, or in time series view. 2) Our interactive lesson builder tool allows users to develop a library of online lesson units, which are collaboratively editable and sharable and provides starter templates designed from learning theory knowledge. 3) Our interactive concept map tool allows the user to build and use concept maps, a graphical interface to map the connection between concepts and ideas. This tool also provides semantic-based recommendations, and allows for embedding of associated resources such as movies, images and blogs. 4) Education web services (middleware) will provide an educational resource database API.

  18. Label-Free Detection of G Protein–SNARE Interactions and Screening for Small Molecule Modulators

    PubMed Central

    2011-01-01

    Gi/o-coupled presynaptic GPCRs are major targets in neuropsychiatric diseases. For example, presynaptic auto- or heteroreceptors include the D2 dopamine receptor, H3 histamine receptor, 5HT1 serotonin receptors, M4 acetylcholine receptors, GABAB receptors, Class II and III metabotropic glutamate receptors, opioid receptors, as well as many other receptors. These GPCRs exert their influence by decreasing exocytosis of synaptic vesicles. One mechanism by which they act is through direct interaction of the Gβγ subunit with members of the SNARE complex downstream of voltage-dependent calcium channels, and specifically with the C-terminus of SNAP25 and the H3 domain of syntaxin1A. (Gerachshenko, T., Blackmer, T., Yoon, E. J., Bartleson, C., Hamm, H. E., and Alford, S. (2005) Gβγ acts at the C terminus of SNAP-25 to mediate presynaptic inhibition, Nat. Neurosci.8, 597–605; Yoon, E. J., Gerachshenko, T., Spiegelberg, B. D., Alford, S., and Hamm, H. E. (2007) Gβγ interferes with Ca2+-dependent binding of synaptotagmin to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, Mol. Pharmacol.72, 1210–1219; Blackmer, T., Larsen, E. C., Bartleson, C., Kowalchyk, J. A., Yoon, E. J., Preininger, A. M., Alford, S., Hamm, H. E., and Martin, T. F. (2005) G protein βγ directly regulates SNARE protein fusion machinery for secretory granule exocytosis, Nat. Neurosci.8, 421–425).1−3 Small molecule inhibitors of the Gβγ–SNARE interaction would allow the study of the relative importance of this mechanism in more detail. We have utilized novel, label-free technology to detect this protein–protein interaction and screen for several small molecule compounds that perturb the interaction, demonstrating the viability of this approach. Interestingly, the screen also produced enhancers of the Gβγ–SNARE interaction. PMID:22368765

  19. Interdomain Hydrophobic Interactions Modulate the Thermostability of Microbial Esterases from the Hormone-Sensitive Lipase Family*

    PubMed Central

    Li, Ping-Yi; Chen, Xiu-Lan; Ji, Peng; Li, Chun-Yang; Wang, Peng; Zhang, Yi; Xie, Bin-Bin; Qin, Qi-Long; Su, Hai-Nan; Zhou, Bai-Cheng; Zhang, Yu-Zhong; Zhang, Xi-Ying

    2015-01-01

    Microbial hormone-sensitive lipases (HSLs) contain a CAP domain and a catalytic domain. However, it remains unclear how the CAP domain interacts with the catalytic domain to maintain the stability of microbial HSLs. Here, we isolated an HSL esterase, E40, from a marine sedimental metagenomic library. E40 exhibited the maximal activity at 45 °C and was quite thermolabile, with a half-life of only 2 min at 40 °C, which may be an adaptation of E40 to the permanently cold sediment environment. The structure of E40 was solved to study its thermolability. Structural analysis showed that E40 lacks the interdomain hydrophobic interactions between loop 1 of the CAP domain and α7 of the catalytic domain compared with its thermostable homologs. Mutational analysis showed that the introduction of hydrophobic residues Trp202 and Phe203 in α7 significantly improved E40 stability and that a further introduction of hydrophobic residues in loop 1 made E40 more thermostable because of the formation of interdomain hydrophobic interactions. Altogether, the results indicate that the absence of interdomain hydrophobic interactions between loop 1 and α7 leads to the thermolability of E40. In addition, a comparative analysis of the structures of E40 and other thermolabile and thermostable HSLs suggests that the interdomain hydrophobic interactions between loop 1 and α7 are a key element for the thermostability of microbial HSLs. Therefore, this study not only illustrates the structural element leading to the thermolability of E40 but also reveals a structural determinant for HSL thermostability. PMID:25771540

  20. A yeast phenomic model for the gene interaction network modulating CFTR-ΔF508 protein biogenesis

    PubMed Central

    2012-01-01

    Background The overall influence of gene interaction in human disease is unknown. In cystic fibrosis (CF) a single allele of the cystic fibrosis transmembrane conductance regulator (CFTR-ΔF508) accounts for most of the disease. In cell models, CFTR-ΔF508 exhibits defective protein biogenesis and degradation rather than proper trafficking to the plasma membrane where CFTR normally functions. Numerous genes function in the biogenesis of CFTR and influence the fate of CFTR-ΔF508. However it is not known whether genetic variation in such genes contributes to disease severity in patients. Nor is there an easy way to study how numerous gene interactions involving CFTR-ΔF would manifest phenotypically. Methods To gain insight into the function and evolutionary conservation of a gene interaction network that regulates biogenesis of a misfolded ABC transporter, we employed yeast genetics to develop a 'phenomic' model, in which the CFTR-ΔF508-equivalent residue of a yeast homolog is mutated (Yor1-ΔF670), and where the genome is scanned quantitatively for interaction. We first confirmed that Yor1-ΔF undergoes protein misfolding and has reduced half-life, analogous to CFTR-ΔF. Gene interaction was then assessed quantitatively by growth curves for approximately 5,000 double mutants, based on alteration in the dose response to growth inhibition by oligomycin, a toxin extruded from the cell at the plasma membrane by Yor1. Results From a comparative genomic perspective, yeast gene interactions influencing Yor1-ΔF biogenesis were representative of human homologs previously found to modulate processing of CFTR-ΔF in mammalian cells. Additional evolutionarily conserved pathways were implicated by the study, and a ΔF-specific pro-biogenesis function of the recently discovered ER membrane complex (EMC) was evident from the yeast screen. This novel function was validated biochemically by siRNA of an EMC ortholog in a human cell line expressing CFTR-ΔF508. The precision and

  1. Interaction of the Human Papillomavirus E6 Oncoprotein with Sorting Nexin 27 Modulates Endocytic Cargo Transport Pathways.

    PubMed

    Ganti, Ketaki; Massimi, Paola; Manzo-Merino, Joaquin; Tomaić, Vjekoslav; Pim, David; Playford, Martin P; Lizano, Marcela; Roberts, Sally; Kranjec, Christian; Doorbar, John; Banks, Lawrence

    2016-09-01

    A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways. This interaction is highly conserved across E6 proteins from multiple high-risk HPV types and is mediated by a classical PBM-PDZ interaction but unlike many E6 targets, SNX27 is not targeted for degradation by E6. Rather, in HPV-18 positive cell lines the association of SNX27 with components of the retromer complex and the endocytic transport machinery is altered in an E6 PBM-dependent manner. Analysis of a SNX27 cargo, the glucose transporter GLUT1, reveals an E6-dependent maintenance of GLUT1 expression and alteration in its association with components of the endocytic transport machinery. Furthermore, knockdown of E6 in HPV-18 positive cervical cancer cells phenocopies the loss of SNX27, both in terms of GLUT1 expression levels and its vesicular localization, with a concomitant marked reduction in glucose uptake, whilst loss of SNX27 results in slower cell proliferation in low nutrient conditions. These results demonstrate that E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells. PMID:27649450

  2. Interaction of the Human Papillomavirus E6 Oncoprotein with Sorting Nexin 27 Modulates Endocytic Cargo Transport Pathways.

    PubMed

    Ganti, Ketaki; Massimi, Paola; Manzo-Merino, Joaquin; Tomaić, Vjekoslav; Pim, David; Playford, Martin P; Lizano, Marcela; Roberts, Sally; Kranjec, Christian; Doorbar, John; Banks, Lawrence

    2016-09-01

    A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways. This interaction is highly conserved across E6 proteins from multiple high-risk HPV types and is mediated by a classical PBM-PDZ interaction but unlike many E6 targets, SNX27 is not targeted for degradation by E6. Rather, in HPV-18 positive cell lines the association of SNX27 with components of the retromer complex and the endocytic transport machinery is altered in an E6 PBM-dependent manner. Analysis of a SNX27 cargo, the glucose transporter GLUT1, reveals an E6-dependent maintenance of GLUT1 expression and alteration in its association with components of the endocytic transport machinery. Furthermore, knockdown of E6 in HPV-18 positive cervical cancer cells phenocopies the loss of SNX27, both in terms of GLUT1 expression levels and its vesicular localization, with a concomitant marked reduction in glucose uptake, whilst loss of SNX27 results in slower cell proliferation in low nutrient conditions. These results demonstrate that E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells.

  3. In vivo modulation of interacting central pattern generators in lobster stomatogastric ganglion: influence of feeding and partial pressure of oxygen.

    PubMed

    Clemens, S; Massabuau, J C; Legeay, A; Meyrand, P; Simmers, J

    1998-04-01

    The stomatogastric ganglion (STG) of the European lobster Homarus gammarus contains two rhythm-generating networks (the gastric and pyloric circuits) that in resting, unfed animals produce two distinct, yet strongly interacting, motor patterns. By using simultaneous EMG recordings from the gastric and pyloric muscles in vivo, we found that after feeding, the gastropyloric interaction disappears as the two networks express accelerated motor rhythms. The return to control levels of network activity occurs progressively over the following 1-2 d and is associated with a gradual reappearance of the gastropyloric interaction. In parallel with this change in network activity is an alteration of oxygen levels in the blood. In resting, unfed animals, arterial partial pressure of oxygen (PO2) is most often between 1 and 2 kPa and then doubles within 1 hr after feeding, before returning to control values some 24 hr later. In vivo, experimental prevention of the arterial PO2 increase after feeding leads to a slowing of pyloric rhythmicity toward control values and a reappearance of the gastropyloric interaction, without apparent effect on gastric network operation. Using in vitro preparations of the stomatogastric nervous system and by changing oxygen levels uniquely at the level of the STG within the range observed in the intact animal, we were able to mimic most of the effects observed in vivo. Our data indicate that the gastropyloric interaction appears only during a "free run" mode of foregut activity and that the coordinated operation of multiple neural networks may be modulated by local changes in oxygenation. PMID:9502835

  4. Arabidopsis thaliana AHL family modulates hypocotyl growth redundantly by interacting with each other via the PPC/DUF296 domain

    PubMed Central

    Zhao, Jianfei; Favero, David S.; Peng, Hao; Neff, Michael M.

    2013-01-01

    The Arabidopsis thaliana genome encodes 29 AT-HOOK MOTIF CONTAINING NUCLEAR LOCALIZED (AHL) genes, which evolved into two phylogenic clades. The AHL proteins contain one or two AT-hook motif(s) and one plant and prokaryote conserved (PPC)/domain of unknown function #296 (DUF296) domain. Seedlings lacking both SOB3/AHL29 and ESC/AHL27 confer a subtle long-hypocotyl phenotype compared with the WT or either single-null mutant. In contrast, the missense allele sob3-6 confers a dramatic long-hypocotyl phenotype in the light. In this study, we examined the dominant-negative feature of sob3-6 and found that it encodes a protein with a disrupted AT-hook motif that abolishes binding to AT-rich DNA. A loss-of-function approach demonstrated different, yet redundant, contributions of additional AHL genes in suppressing hypocotyl elongation in the light. We showed that AHL proteins interact with each other and themselves via the PPC/DUF296 domain. AHLs also share interactions with other nuclear proteins, such as transcription factors, suggesting that these interactions also contribute to the functional redundancy within this gene family. The coordinated action of AHLs requires an AT-hook motif capable of binding AT-rich DNA, as well as a PPC/DUF296 domain containing a conserved Gly-Arg-Phe-Glu-Ile-Leu region. Alteration of this region abolished SOB3/AHL29’s physical interaction with transcription factors and resulted in a dominant-negative allele in planta that was phenotypically similar to sob3-6. We propose a molecular model where AHLs interact with each other and themselves, as well as other nuclear proteins, to form complexes which modulate plant growth and development. PMID:24218605

  5. Interaction of the Human Papillomavirus E6 Oncoprotein with Sorting Nexin 27 Modulates Endocytic Cargo Transport Pathways

    PubMed Central

    Ganti, Ketaki; Massimi, Paola; Manzo-Merino, Joaquin; Tomaić, Vjekoslav; Pim, David; Playford, Martin P.; Lizano, Marcela; Roberts, Sally; Kranjec, Christian; Doorbar, John; Banks, Lawrence

    2016-01-01

    A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways. This interaction is highly conserved across E6 proteins from multiple high-risk HPV types and is mediated by a classical PBM-PDZ interaction but unlike many E6 targets, SNX27 is not targeted for degradation by E6. Rather, in HPV-18 positive cell lines the association of SNX27 with components of the retromer complex and the endocytic transport machinery is altered in an E6 PBM-dependent manner. Analysis of a SNX27 cargo, the glucose transporter GLUT1, reveals an E6-dependent maintenance of GLUT1 expression and alteration in its association with components of the endocytic transport machinery. Furthermore, knockdown of E6 in HPV-18 positive cervical cancer cells phenocopies the loss of SNX27, both in terms of GLUT1 expression levels and its vesicular localization, with a concomitant marked reduction in glucose uptake, whilst loss of SNX27 results in slower cell proliferation in low nutrient conditions. These results demonstrate that E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells. PMID:27649450

  6. Interaction of multiple networks modulated by the working memory training based on real-time fMRI

    NASA Astrophysics Data System (ADS)

    Shen, Jiahui; Zhang, Gaoyan; Zhu, Chaozhe; Yao, Li; Zhao, Xiaojie

    2015-03-01

    Neuroimaging studies of working memory training have identified the alteration of brain activity as well as the regional interactions within the functional networks such as central executive network (CEN) and default mode network (DMN). However, how the interaction within and between these multiple networks is modulated by the training remains unclear. In this paper, we examined the interaction of three training-induced brain networks during working memory training based on real-time functional magnetic resonance imaging (rtfMRI). Thirty subjects assigned to the experimental and control group respectively participated in two times training separated by seven days. Three networks including silence network (SN), CEN and DMN were identified by the training data with the calculated function connections within each network. Structural equation modeling (SEM) approach was used to construct the directional connectivity patterns. The results showed that the causal influences from the percent signal changes of target ROI to the SN were positively changed in both two groups, as well as the causal influence from the SN to CEN was positively changed in experimental group but negatively changed in control group from the SN to DMN. Further correlation analysis of the changes in each network with the behavioral improvements showed that the changes in SN were stronger positively correlated with the behavioral improvement of letter memory task. These findings indicated that the SN was not only a switch between the target ROI and the other networks in the feedback training but also an essential factor to the behavioral improvement.

  7. Propoxylation of cationic polymers provides a novel approach to controllable modulation of their cellular toxicity and interaction with nucleic acids.

    PubMed

    Shevchenko, Vesta D; Salakhieva, Diana V; Yergeshov, Abdulla A; Badeev, Yuriy V; Shtyrlin, Yurii G; Abdullin, Timur I

    2016-12-01

    An effective chemical approach to modulation of biological interactions of cationic polymers was proposed and tested using polyethyleneimine (PEI) as a drug carrier. Branched 25kDa PEI was modified in the reaction with propylene oxide (PO) to produce a series of propoxylated PEIs with NH groups grafted by single or oligomer PO units. Clear relationships between the propoxylation degree and biological effects, such as interaction with plasmid DNA, hemolytic, cytotoxic, and pro-apoptotic activities were revealed for PEIs modified upon PO/NH molar ratio of 0.5, 0.75, 1.0 and 3.0. The partial modification of available cationic centers up to 100% is predominantly accompanied by a significant gradual reduction in polycation adverse effects, while ability of complex formation with plasmid DNA is being preserved. Grafted PEI with 0.75 PO/NH ratio provides better protection from nuclease degradation and transfection activity compared with other modified PEIs. Revealed relationships contribute to the development of safe polymeric systems with controllable physicochemical properties and biological interactions.

  8. LHX3 Interacts with Inhibitor of Histone Acetyltransferase Complex Subunits LANP and TAF-1β to Modulate Pituitary Gene Regulation

    PubMed Central

    Witzmann, Frank A.; Rhodes, Simon J.

    2013-01-01

    LIM-homeodomain 3 (LHX3) is a transcription factor required for mammalian pituitary gland and nervous system development. Human patients and animal models with LHX3 gene mutations present with severe pediatric syndromes that feature hormone deficiencies and symptoms associated with nervous system dysfunction. The carboxyl terminus of the LHX3 protein is required for pituitary gene regulation, but the mechanism by which this domain operates is unknown. In order to better understand LHX3-dependent pituitary hormone gene transcription, we used biochemical and mass spectrometry approaches to identify and characterize proteins that interact with the LHX3 carboxyl terminus. This approach identified the LANP/pp32 and TAF-1β/SET proteins, which are components of the inhibitor of histone acetyltransferase (INHAT) multi-subunit complex that serves as a multifunctional repressor to inhibit histone acetylation and modulate chromatin structure. The protein domains of LANP and TAF-1β that interact with LHX3 were mapped using biochemical techniques. Chromatin immunoprecipitation experiments demonstrated that LANP and TAF-1β are associated with LHX3 target genes in pituitary cells, and experimental alterations of LANP and TAF-1β levels affected LHX3-mediated pituitary gene regulation. Together, these data suggest that transcriptional regulation of pituitary genes by LHX3 involves regulated interactions with the INHAT complex. PMID:23861948

  9. Propoxylation of cationic polymers provides a novel approach to controllable modulation of their cellular toxicity and interaction with nucleic acids.

    PubMed

    Shevchenko, Vesta D; Salakhieva, Diana V; Yergeshov, Abdulla A; Badeev, Yuriy V; Shtyrlin, Yurii G; Abdullin, Timur I

    2016-12-01

    An effective chemical approach to modulation of biological interactions of cationic polymers was proposed and tested using polyethyleneimine (PEI) as a drug carrier. Branched 25kDa PEI was modified in the reaction with propylene oxide (PO) to produce a series of propoxylated PEIs with NH groups grafted by single or oligomer PO units. Clear relationships between the propoxylation degree and biological effects, such as interaction with plasmid DNA, hemolytic, cytotoxic, and pro-apoptotic activities were revealed for PEIs modified upon PO/NH molar ratio of 0.5, 0.75, 1.0 and 3.0. The partial modification of available cationic centers up to 100% is predominantly accompanied by a significant gradual reduction in polycation adverse effects, while ability of complex formation with plasmid DNA is being preserved. Grafted PEI with 0.75 PO/NH ratio provides better protection from nuclease degradation and transfection activity compared with other modified PEIs. Revealed relationships contribute to the development of safe polymeric systems with controllable physicochemical properties and biological interactions. PMID:27612689

  10. Modulation of water efflux through functional interaction between TRPV4 and TMEM16A/anoctamin 1.

    PubMed

    Takayama, Yasunori; Shibasaki, Koji; Suzuki, Yoshiro; Yamanaka, Akihiro; Tominaga, Makoto

    2014-05-01

    Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable channel, is highly expressed in the apical membrane of choroid plexus epithelial cells (CPECs) in the brain. The function of TRPV4 is unknown. Here, we show physical and functional interaction between TRPV4 and anoctamin 1 (ANO1) in HEK293T cells and CPECs. Chloride currents induced by a TRPV4 activator (GSK1016790A) were markedly increased in an extracellular calcium-dependent manner in HEK293T cells expressing TRPV4 with ANO1, but not with ANO4, ANO6, or ANO10, the mRNAs of which were expressed in the choroid plexus. We also found physical interaction between TRPV4 and ANO1 in both HEK293T cells and choroid plexus. We observed that ANO1 was activated at a warm temperature (37°C) in HEK293T cells and that the heat-evoked chloride currents were markedly enhanced after GSK1016790A application in CPECs. Simultaneous stimulation by warmth and hyposmosis induced chloride current activation in wild-type, but not in TRPV4-deficient, CPECs. Cell volume changes were induced by ANO1-mediated chloride currents in parallel with membrane potential changes, and the cell volume was significantly decreased at negative membrane potentials by TRPV4-induced ANO1 activation. Thus, physical and functional interactions between TRPV4 and ANO1 can modulate water transport in the choroid plexus. PMID:24509911

  11. Multiaddressable molecular rectangles with reversible host–guest interactions: Modulation of pH-controlled guest release and capture

    PubMed Central

    Chan, Alan Kwun-Wa; Lam, Wai Han; Tanaka, Yuya; Wong, Keith Man-Chung; Yam, Vivian Wing-Wah

    2015-01-01

    A series of multiaddressable platinum(II) molecular rectangles with different rigidities and cavity sizes has been synthesized by endcapping the U-shaped diplatinum(II) terpyridine moiety with various bis-alkynyl ligands. The studies of the host–guest association with various square planar platinum(II), palladium(II), and gold(III) complexes and the related low-dimensional gold(I) complexes, most of which are potential anticancer therapeutics, have been performed. Excellent guest confinement and selectivity of the rectangular architecture have been shown. Introduction of pH-responsive functionalities to the ligand backbone generates multifunctional molecular rectangles that exhibit reversible guest release and capture on the addition of acids and bases, indicating their potential in controlled therapeutics delivery on pH modulation. The reversible host–guest interactions are found to be strongly perturbed by metal–metal and π–π interactions and to a certain extent, electrostatic interactions, giving rise to various spectroscopic changes depending on the nature of the guest molecules. Their binding mode and thermodynamic parameters have been determined by 2D NMR and van’t Hoff analysis and supported by computational study. PMID:25568083

  12. Studies of Peptide:N-glycnase-p97 Interaction Suggest that p97 Phosphorylation Modulates Endoplasmic Reticulum-Associated Degradation

    SciTech Connect

    Zhao,G.; Zhou, X.; Wang, L.; Li, G.; Schindelin, H.; Lennarz, W.

    2007-01-01

    During endoplasmic reticulum-associated degradation, the multifunctional AAA ATPase p97 is part of a protein degradation complex. p97 associates via its N-terminal domain with various cofactors to recruit ubiquitinated substrates. It also interacts with alternative substrate-processing cofactors, such as Ufd2, Ufd3, and peptide:N-glycanase (PNGase) in higher eukaryotes. These cofactors determine different fates of the substrates and they all bind outside of the N-terminal domain of p97. Here, we describe a cofactor-binding motif of p97 contained within the last 10 amino acid residues of the C terminus, which is both necessary and sufficient to mediate interactions of p97 with PNGase and Ufd3. The crystal structure of the N-terminal domain of PNGase in complex with this motif provides detailed insight into the interaction between p97 and its substrate-processing cofactors. Phosphorylation of p97's highly conserved penultimate tyrosine residue, which is the main phosphorylation site during T cell receptor stimulation, completely blocks binding of either PNGase or Ufd3 to p97. This observation suggests that phosphorylation of this residue modulates endoplasmic reticulum-associated protein degradation activity by discharging substrate-processing cofactors.

  13. Modulated growth, stability and interactions of liquid-like coacervate assemblies of elastin.

    PubMed

    Muiznieks, Lisa D; Cirulis, Judith T; van der Horst, Astrid; Reinhardt, Dieter P; Wuite, Gijs J L; Pomès, Régis; Keeley, Fred W

    2014-06-01

    Elastin self-assembles from monomers into polymer networks that display elasticity and resilience. The first major step in assembly is a liquid-liquid phase separation known as coacervation. This process represents a continuum of stages from initial phase separation to early growth of droplets by coalescence and later "maturation" leading to fiber formation. Assembly of tropoelastin-rich globules is on pathway for fiber formation in vivo. However, little is known about these intermediates beyond their size distribution. Here we investigate the contribution of sequence and structural motifs from full-length tropoelastin and a set of elastin-like polypeptides to the maturation of coacervate assemblies, observing their growth, stability and interaction behavior, and polypeptide alignment within matured globules. We conclude that maturation is driven by surface properties, leading to stabilization of the interface between the hydrophobic interior and aqueous solvent, potentially through structural motifs, and discuss implications for droplet interactions in fiber formation.

  14. KDM5 Interacts with Foxo to Modulate Cellular Levels of Oxidative Stress

    PubMed Central

    Liu, Xingyin; Greer, Christina; Secombe, Julie

    2014-01-01

    Increased cellular levels of oxidative stress are implicated in a large number of human diseases. Here we describe the transcription co-factor KDM5 (also known as Lid) as a new critical regulator of cellular redox state. Moreover, this occurs through a novel KDM5 activity whereby it alters the ability of the transcription factor Foxo to bind to DNA. Our microarray analyses of kdm5 mutants revealed a striking enrichment for genes required to regulate cellular levels of oxidative stress. Consistent with this, loss of kdm5 results in increased sensitivity to treatment with oxidizers, elevated levels of oxidized proteins, and increased mutation load. KDM5 activates oxidative stress resistance genes by interacting with Foxo to facilitate its recruitment to KDM5-Foxo co-regulated genes. Significantly, this occurs independently of KDM5's well-characterized demethylase activity. Instead, KDM5 interacts with the lysine deacetylase HDAC4 to promote Foxo deacetylation, which affects Foxo DNA binding. PMID:25329053

  15. Spin-wave propagation steered by electric field modulated exchange interaction

    NASA Astrophysics Data System (ADS)

    Wang, Sheng; Guan, Xiawei; Cheng, Xiaomin; Lian, Chen; Huang, Ting; Miao, Xiangshui

    2016-09-01

    Combined ab initio and micromagnetic simulations are carried out to demonstrate the feasibility on the electrical manipulation of spin-wave propagation in ultrathin Fe films. It is discovered that the exchange interaction can be substantially weakened under the influence of electric field applied perpendicular to the magnetic film surface. Furthermore, we demonstrate that the electric field modified exchange constant could effectively control the propagation of spin waves. To be specific, an external applied electric field of 5 V/nm can effectively weaken exchange interaction by 80% and is sufficient to induce nearly twofold change of the wavenumber. This discovery may open a door to energy-efficient local manipulation of the spin wave propagation utilizing electric fields, which is crucial for both fundamental research and spin wave based logic applications.

  16. Spin-wave propagation steered by electric field modulated exchange interaction.

    PubMed

    Wang, Sheng; Guan, Xiawei; Cheng, Xiaomin; Lian, Chen; Huang, Ting; Miao, Xiangshui

    2016-01-01

    Combined ab initio and micromagnetic simulations are carried out to demonstrate the feasibility on the electrical manipulation of spin-wave propagation in ultrathin Fe films. It is discovered that the exchange interaction can be substantially weakened under the influence of electric field applied perpendicular to the magnetic film surface. Furthermore, we demonstrate that the electric field modified exchange constant could effectively control the propagation of spin waves. To be specific, an external applied electric field of 5 V/nm can effectively weaken exchange interaction by 80% and is sufficient to induce nearly twofold change of the wavenumber. This discovery may open a door to energy-efficient local manipulation of the spin wave propagation utilizing electric fields, which is crucial for both fundamental research and spin wave based logic applications. PMID:27587083

  17. Spin-wave propagation steered by electric field modulated exchange interaction

    PubMed Central

    Wang, Sheng; Guan, Xiawei; Cheng, Xiaomin; Lian, Chen; Huang, Ting; Miao, Xiangshui

    2016-01-01

    Combined ab initio and micromagnetic simulations are carried out to demonstrate the feasibility on the electrical manipulation of spin-wave propagation in ultrathin Fe films. It is discovered that the exchange interaction can be substantially weakened under the influence of electric field applied perpendicular to the magnetic film surface. Furthermore, we demonstrate that the electric field modified exchange constant could effectively control the propagation of spin waves. To be specific, an external applied electric field of 5 V/nm can effectively weaken exchange interaction by 80% and is sufficient to induce nearly twofold change of the wavenumber. This discovery may open a door to energy-efficient local manipulation of the spin wave propagation utilizing electric fields, which is crucial for both fundamental research and spin wave based logic applications. PMID:27587083

  18. Biomolecular interactions modulate macromolecular structure and dynamics in atomistic model of a bacterial cytoplasm

    PubMed Central

    Yu, Isseki; Mori, Takaharu; Ando, Tadashi; Harada, Ryuhei; Jung, Jaewoon; Sugita, Yuji; Feig, Michael

    2016-01-01

    Biological macromolecules function in highly crowded cellular environments. The structure and dynamics of proteins and nucleic acids are well characterized in vitro, but in vivo crowding effects remain unclear. Using molecular dynamics simulations of a comprehensive atomistic model cytoplasm we found that protein-protein interactions may destabilize native protein structures, whereas metabolite interactions may induce more compact states due to electrostatic screening. Protein-protein interactions also resulted in significant variations in reduced macromolecular diffusion under crowded conditions, while metabolites exhibited significant two-dimensional surface diffusion and altered protein-ligand binding that may reduce the effective concentration of metabolites and ligands in vivo. Metabolic enzymes showed weak non-specific association in cellular environments attributed to solvation and entropic effects. These effects are expected to have broad implications for the in vivo functioning of biomolecules. This work is a first step towards physically realistic in silico whole-cell models that connect molecular with cellular biology. DOI: http://dx.doi.org/10.7554/eLife.19274.001 PMID:27801646

  19. Plasminogen activator inhibitor type 1 interacts with alpha3 subunit of proteasome and modulates its activity.

    PubMed

    Boncela, Joanna; Przygodzka, Patrycja; Papiewska-Pajak, Izabela; Wyroba, Elzbieta; Osinska, Magdalena; Cierniewski, Czeslaw S

    2011-02-25

    Plasminogen activator inhibitor type-1 (PAI-1), a multifunctional protein, is an important physiological regulator of fibrinolysis, extracellular matrix homeostasis, and cell motility. Recent observations show that PAI-1 may also be implicated in maintaining integrity of cells, especially with respect to cellular proliferation or apoptosis. In the present study we provide evidence that PAI-1 interacts with proteasome and affects its activity. First, by using the yeast two-hybrid system, we found that the α3 subunit of proteasome directly interacts with PAI-1. Then, to ensure that the PAI-1-proteasome complex is formed in vivo, both proteins were coimmunoprecipitated from endothelial cells and identified with specific antibodies. The specificity of this interaction was evidenced after transfection of HeLa cells with pCMV-PAI-1 and coimmunoprecipitation of both proteins with anti-PAI-1 antibodies. Subsequently, cellular distribution of the PAI-1-proteasome complexes was established by immunogold staining and electron microscopy analyses. Both proteins appeared in a diffuse cytosolic pattern but also could be found in a dense perinuclear and nuclear location. Furthermore, PAI-1 induced formation of aggresomes freely located in endothelial cytoplasm. Increased PAI-1 expression abrogated degradation of degron analyzed after cotransfection of HeLa cells with pCMV-PAI-1 and pd2EGFP-N1 and prevented degradation of p53 as well as IκBα, as evidenced both by confocal microscopy and Western immunoblotting.

  20. Plasminogen Activator Inhibitor Type 1 Interacts with α3 Subunit of Proteasome and Modulates Its Activity*

    PubMed Central

    Boncela, Joanna; Przygodzka, Patrycja; Papiewska-Pajak, Izabela; Wyroba, Elzbieta; Osinska, Magdalena; Cierniewski, Czeslaw S.

    2011-01-01

    Plasminogen activator inhibitor type-1 (PAI-1), a multifunctional protein, is an important physiological regulator of fibrinolysis, extracellular matrix homeostasis, and cell motility. Recent observations show that PAI-1 may also be implicated in maintaining integrity of cells, especially with respect to cellular proliferation or apoptosis. In the present study we provide evidence that PAI-1 interacts with proteasome and affects its activity. First, by using the yeast two-hybrid system, we found that the α3 subunit of proteasome directly interacts with PAI-1. Then, to ensure that the PAI-1-proteasome complex is formed in vivo, both proteins were coimmunoprecipitated from endothelial cells and identified with specific antibodies. The specificity of this interaction was evidenced after transfection of HeLa cells with pCMV-PAI-1 and coimmunoprecipitation of both proteins with anti-PAI-1 antibodies. Subsequently, cellular distribution of the PAI-1-proteasome complexes was established by immunogold staining and electron microscopy analyses. Both proteins appeared in a diffuse cytosolic pattern but also could be found in a dense perinuclear and nuclear location. Furthermore, PAI-1 induced formation of aggresomes freely located in endothelial cytoplasm. Increased PAI-1 expression abrogated degradation of degron analyzed after cotransfection of HeLa cells with pCMV-PAI-1 and pd2EGFP-N1 and prevented degradation of p53 as well as IκBα, as evidenced both by confocal microscopy and Western immunoblotting. PMID:21135093

  1. Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans.

    PubMed

    Papaleo, F; Burdick, M C; Callicott, J H; Weinberger, D R

    2014-03-01

    Cognitive functions are highly heritable and the impact of complex genetic interactions, though undoubtedly important, has received little investigation. Here we show in an animal model and in a human neuroimaging experiment a consistent non-linear interaction between two genes--catechol-O-methyl transferase (COMT) and dysbindin (dys; dystrobrevin-binding protein 1 (DTNBP1))--implicated through different mechanisms in cortical dopamine signaling and prefrontal cognitive function. In mice, we found that a single genetic mutation reducing expression of either COMT or DTNBP1 alone produced working memory advantages, while, in dramatic contrast, genetic reduction of both in the same mouse produced working memory deficits. We found evidence of the same non-linear genetic interaction in prefrontal cortical function in humans. In healthy volunteers (N=176) studied with functional magnetic resonance imaging during a working memory paradigm, individuals homozygous for the COMT rs4680 Met allele that reduces COMT enzyme activity showed a relatively more efficient prefrontal engagement. In contrast, we found that the same genotype was less efficient on the background of a dys haplotype associated with decreased DTNBP1 expression. These results illustrate that epistasis can be functionally multi-directional and non-linear and that a putatively beneficial allele in one epistastic context is a relatively deleterious one in another. These data also have important implications for single-locus association analyses of complex traits.

  2. Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR

    PubMed Central

    Thelin, William R.; Chen, Yun; Gentzsch, Martina; Kreda, Silvia M.; Sallee, Jennifer L.; Scarlett, Cameron O.; Borchers, Christoph H.; Jacobson, Ken; Stutts, M. Jackson; Milgram, Sharon L.

    2007-01-01

    The role of the cystic fibrosis transmembrane conductance regulator (CFTR) as a cAMP-dependent chloride channel on the apical membrane of epithelia is well established. However, the processes by which CFTR is regulated on the cell surface are not clear. Here we report the identification of a protein-protein interaction between CFTR and the cytoskeletal filamin proteins. Using proteomic approaches, we identified filamins as proteins that associate with the extreme CFTR N terminus. Furthermore, we identified a disease-causing missense mutation in CFTR, serine 13 to phenylalanine (S13F), which disrupted this interaction. In cells, filamins tethered plasma membrane CFTR to the underlying actin network. This interaction stabilized CFTR at the cell surface and regulated the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR was internalized from the cell surface, where it prematurely accumulated in lysosomes and was ultimately degraded. Our data demonstrate what we believe to be a previously unrecognized role for the CFTR N terminus in the regulation of the plasma membrane stability and metabolic stability of CFTR. In addition, we elucidate the molecular defect associated with the S13F mutation. PMID:17235394

  3. GSK-3β: a signaling pathway node modulating neural stem cell and endothelial cell interactions.

    PubMed

    Li, Qi; Michaud, Michael; Canosa, Sandra; Kuo, Andrew; Madri, Joseph A

    2011-05-01

    The neurogenic areas of the brain are highly organized structures in which there is dynamic reciprocal modulation of neural stem cells (NSC) and microvascular endothelial cells (BEC) resulting in control of neural stem cell and vascular proliferation, survival and differentiation throughout the life of the individual. Select molecules such as GSK-3β, functioning as signaling nodes, and their downstream signaling components including HIF-1α, HIF-2α and β-catenin participate in regulating and orchestrating the diverse responses involved in this complex process. In this report we demonstrate GSK-3β's role as a signaling node in two mouse strains (C57BL/6, which have been found to respond to and recover from a hypoxic insult from P3 to P11 poorly and CD-1, which have been found to respond to and recover from a hypoxic insult from P3 to P11 well both in vivo and in vitro) which mimic the wide range of responsiveness to hypoxic insult observed in the very low birth weight premature infant population. Differences in levels of neural stem cell and microvascular endothelial cell GSK-3β activation, β-catenin serine phosphorylation, HIF-1α and 2α, BDNF, SDF-1 and VEGF, β-III-tubulin and cleaved notch-1 expression in C57BL/6 and CD-1 subventricular zone tissues, and cultured NSC and BEC were noted. Specifically, CD1 pups, SVZ tissues and isolated NSC and BEC exhibit less GSK-3β and β-catenin serine phoslphorylation and greater HIF-1α and 2α, BDNF, SDF-1 and VEGF, β-III-tubulin and cleaved notch-1 expression compared to C57BL/6. Correlating with these changes were differences of several neural stem cell and microvascular endothelial cell behaviors including proliferation, apoptosis, migration and differentiation with CD1 NSC exhibiting greater proliferation and migration and decreased apoptosis and differentiation and CD1 BEC exhibiting greater angiogenesis. Further, upon treatment with nanomolar concentrations of a GSK-3β inhibitor (SB412682), C57 NSC and BEC

  4. A Mitochondrial ATP synthase Subunit Interacts with TOR Signaling to Modulate Protein Homeostasis and Lifespan in Drosophila

    PubMed Central

    Sun, Xiaoping; Wheeler, Charles T.; Yolitz, Jason; Laslo, Mara; Alberico, Thomas; Sun, Yaning; Song, Qisheng; Zou, Sige

    2014-01-01

    SUMMARY Diet composition is a critical determinant of lifespan and nutrient imbalance is detrimental health. However, how nutrients interact with genetic factors to modulate lifespan remains elusive. We investigated how diet composition influences mitochondrial ATP synthase subunit d (ATPsyn-d) in modulating lifespan in Drosophila. ATPsyn-d knockdown extended lifespan in females fed low carbohydrate-to-protein (C:P) diets, but not the high C:P ratio diet. This extension was associated with increased resistance to oxidative stress, transcriptional changes in metabolism, proteostasis and immune genes, reduced protein damage and aggregation, and reduced phosphorylation of S6K and ERK in TOR and MAPK signaling, respectively. ATPsyn-d knockdown did not extend lifespan in females with reduced TOR signaling induced genetically by Tsc2 overexpression or pharmacologically by rapamycin. Our data reveal a link among diet, mitochondria, MAPK and TOR signaling in aging and stresses the importance of considering genetic background and diet composition in implementing interventions for promoting healthy aging. PMID:25220459

  5. Two modules in the BRC repeats of BRCA2 mediate structural and functional interactions with the RAD51 recombinase.

    PubMed

    Rajendra, Eeson; Venkitaraman, Ashok R

    2010-01-01

    The breast and ovarian cancer suppressor protein BRCA2 controls the RAD51 recombinase in reactions that lead to homologous DNA recombination (HDR). BRCA2 binds RAD51 via eight conserved BRC repeat motifs of approximately 35 amino acids, each with a varying capacity to bind RAD51. BRC repeats both promote and inhibit RAD51 assembly on different DNA substrates to regulate HDR, but the structural basis for these functions is unclear. Here, we demarcate two tetrameric clusters of hydrophobic residues in the BRC repeats, interacting with distinct pockets in RAD51, and show that the co-location of both modules within a single BRC repeat is necessary for BRC-RAD51 binding and function. The two modules comprise the sequence FxxA, known to inhibit RAD51 assembly by blocking the oligomerization interface, and a previously unrecognized tetramer with the consensus sequence LFDE, which binds to a RAD51 pocket distinct from this interface. The LFDE motif is essential in BRC repeats for modes of RAD51 binding both permissive and inhibitory to RAD51 oligomerization. Targeted insertion of point mutations in RAD51 that disrupt the LFDE-binding pocket impair its assembly at DNA damage sites in living cells. Our findings suggest a model for the modular architecture of BRC repeats that provides fresh insight into the mechanisms regulating homologous DNA recombination.

  6. Aspheric Solute Ions Modulate Gold Nanoparticle Interactions in an Aqueous Solution: An Optimal Way To Reversibly Concentrate Functionalized Nanoparticles.

    PubMed

    Villarreal, Oscar D; Chen, Liao Y; Whetten, Robert L; Demeler, Borries

    2015-12-17

    Nanometer-sized gold particles (AuNPs) are of peculiar interest because their behaviors in an aqueous solution are sensitive to changes in environmental factors including the size and shape of the solute ions. In order to determine these important characteristics, we performed all-atom molecular dynamics simulations on the icosahedral Au144 nanoparticles each coated with a homogeneous set of 60 thiolates (4-mercaptobenzoate, pMBA) in eight aqueous solutions having ions of varying sizes and shapes (Na(+), K(+), tetramethylamonium cation TMA(+), tris-ammonium cation TRS(+), Cl(-), and OH(-)). For each solution, we computed the reversible work (potential of mean of force) to bring two nanoparticles together as a function of their separation distance. We found that the behavior of pMBA protected Au144 nanoparticles can be readily modulated by tuning their aqueous environmental factors (pH and solute ion combinations). We examined the atomistic details on how the sizes and shapes of solute ions quantitatively factor in the definitive characteristics of nanoparticle-environment and nanoparticle-nanoparticle interactions. We predict that tuning the concentrations of nonspherical composite ions such as TRS(+) in an aqueous solution of AuNPs be an effective means to modulate the aggregation propensity desired in biomedical and other applications of small charged nanoparticles.

  7. Fluid-Structure Interactions Analysis of Shear-Induced Modulation of a Mesenchymal Stem Cell: An Image-Based Study.

    PubMed

    Ghaemi, Roza Vaez; Vahidi, Bahman; Sabour, Mohammad Hossein; Haghighipour, Nooshin; Alihemmati, Zakieh

    2016-03-01

    Although effects of biochemical modulation of stem cells have been widely investigated, only recent advances have been made in the identification of mechanical conditioning on cell signaling pathways. Experimental investigations quantifying the micromechanical environment of mesenchymal stem cells (MSCs) are challenging while computational approaches can predict their behavior due to in vitro stimulations. This study introduces a 3D cell-specific finite element model simulating large deformations of MSCs. Here emphasizing cell mechanical modulation which represents the most challenging multiphysics phenomena in sub-cellular level, we focused on an approach attempting to elicit unique responses of a cell under fluid flow. Fluorescent staining of MSCs was performed in order to visualize the MSC morphology and develop a geometrically accurate model of it based on a confocal 3D image. We developed a 3D model of a cell fixed in a microchannel under fluid flow and then solved the numerical model by fluid-structure interactions method. By imposing flow characteristics representative of vigorous in vitro conditions, the model predicts that the employed external flow induces significant localized effective stress in the nucleo-cytoplasmic interface and average cell deformation of about 40%. Moreover, it can be concluded that a lower strain level is made in the cell by the oscillatory flow as compared with steady flow, while same ranges of effective stress are recorded inside the cell in both conditions. The deeper understanding provided by this study is beneficial for better design of single cell in vitro studies. PMID:26333040

  8. Fluid-Structure Interactions Analysis of Shear-Induced Modulation of a Mesenchymal Stem Cell: An Image-Based Study.

    PubMed

    Ghaemi, Roza Vaez; Vahidi, Bahman; Sabour, Mohammad Hossein; Haghighipour, Nooshin; Alihemmati, Zakieh

    2016-03-01

    Although effects of biochemical modulation of stem cells have been widely investigated, only recent advances have been made in the identification of mechanical conditioning on cell signaling pathways. Experimental investigations quantifying the micromechanical environment of mesenchymal stem cells (MSCs) are challenging while computational approaches can predict their behavior due to in vitro stimulations. This study introduces a 3D cell-specific finite element model simulating large deformations of MSCs. Here emphasizing cell mechanical modulation which represents the most challenging multiphysics phenomena in sub-cellular level, we focused on an approach attempting to elicit unique responses of a cell under fluid flow. Fluorescent staining of MSCs was performed in order to visualize the MSC morphology and develop a geometrically accurate model of it based on a confocal 3D image. We developed a 3D model of a cell fixed in a microchannel under fluid flow and then solved the numerical model by fluid-structure interactions method. By imposing flow characteristics representative of vigorous in vitro conditions, the model predicts that the employed external flow induces significant localized effective stress in the nucleo-cytoplasmic interface and average cell deformation of about 40%. Moreover, it can be concluded that a lower strain level is made in the cell by the oscillatory flow as compared with steady flow, while same ranges of effective stress are recorded inside the cell in both conditions. The deeper understanding provided by this study is beneficial for better design of single cell in vitro studies.

  9. Rabaptin-5 and Rabex-5 are neoplastic tumour suppressor genes that interact to modulate Rab5 dynamics in Drosophila melanogaster☆

    PubMed Central

    Thomas, Chloe; Strutt, David

    2014-01-01

    Endocytosis plays an important role in the regulation of tumour growth and metastasis. In Drosophila, a number of endocytic neoplastic tumour suppressor genes have been identified that when mutated cause epithelial disruption and over-proliferation. Here we characterise the Drosophila homologue of the Rab5 effector Rabaptin-5, and show that it is a novel neoplastic tumour suppressor. Its ability to bind Rab5 and modulate early endosomal dynamics is conserved in Drosophila, as is its interaction with the Rab5 GEF Rabex5, for which we also demonstrate neoplastic tumour suppressor characteristics. Surprisingly, we do not observe disruption of apico-basal polarity in Rabaptin-5 and Rabex-5 mutant tissues; instead the tumour phenotype is associated with upregulation of Jun N-terminal Kinase (JNK) and Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signalling. PMID:24104056

  10. Design and Development of High Voltage Direct Current (DC) Sources for the Solar Array Module Plasma Interaction Experiment

    NASA Technical Reports Server (NTRS)

    Bibyk, Irene K.; Wald, Lawrence W.

    1995-01-01

    Two programmable, high voltage DC power supplies were developed as part of the flight electronics for the Solar Array Module Plasma Interaction Experiment (SAMPIE). SAMPIE's primary objectives were to study and characterize the high voltage arcing and parasitic current losses of various solar cells and metal samples within the space plasma of low earth orbit (LEO). High voltage arcing can cause large discontinuous changes in spacecraft potential which lead to damage of the power system materials and significant Electromagnetic Interference (EMI). Parasitic currents cause a change in floating potential which lead to reduced power efficiency. These primary SAMPIE objectives were accomplished by applying artificial biases across test samples over a voltage range from -600 VDC to +300 VDC. This paper chronicles the design, final development, and test of the two programmable high voltage sources for SAMPIE. The technical challenges to the design for these power supplies included vacuum, space plasma effects, thermal protection, Shuttle vibrations and accelerations.

  11. Social top-down response modulation (STORM): a model of the control of mimicry in social interaction

    PubMed Central

    Wang, Yin; Hamilton, Antonia F. de C.

    2012-01-01

    As a distinct feature of human social interactions, spontaneous mimicry has been widely investigated in the past decade. Research suggests that mimicry is a subtle and flexible social behavior which plays an important role for communication and affiliation. However, fundamental questions like why and how people mimic still remain unclear. In this paper, we evaluate past theories of why people mimic and the brain systems that implement mimicry in social psychology and cognitive neuroscience. By reviewing recent behavioral and neuroimaging studies on the control of mimicry by social signals, we conclude that the subtlety and sophistication of mimicry in social contexts reflect a social top-down response modulation (STORM) which increases one's social advantage and this mechanism is most likely implemented by medial prefrontal cortex (mPFC). We suggest that this STORM account of mimicry is important for our understanding of social behavior and social cognition, and provides implications for future research in autism. PMID:22675295

  12. Social top-down response modulation (STORM): a model of the control of mimicry in social interaction.

    PubMed

    Wang, Yin; Hamilton, Antonia F de C

    2012-01-01

    As a distinct feature of human social interactions, spontaneous mimicry has been widely investigated in the past decade. Research suggests that mimicry is a subtle and flexible social behavior which plays an important role for communication and affiliation. However, fundamental questions like why and how people mimic still remain unclear. In this paper, we evaluate past theories of why people mimic and the brain systems that implement mimicry in social psychology and cognitive neuroscience. By reviewing recent behavioral and neuroimaging studies on the control of mimicry by social signals, we conclude that the subtlety and sophistication of mimicry in social contexts reflect a social top-down response modulation (STORM) which increases one's social advantage and this mechanism is most likely implemented by medial prefrontal cortex (mPFC). We suggest that this STORM account of mimicry is important for our understanding of social behavior and social cognition, and provides implications for future research in autism.

  13. Progesterone-induced agrin expression in astrocytes modulates glia-neuron interactions leading to synapse formation.

    PubMed

    Tournell, C E; Bergstrom, R A; Ferreira, A

    2006-09-01

    Experimental evidence recently obtained suggests that synaptogenesis is a tripartite event in which not only pre- and post-synaptic neurons but also glial cells play a key role. However, the molecular mechanisms by which glia modulate the formation of synapses in the CNS remain poorly understood. In the present study, we analyzed the role of astrocytes in synapse formation in cultured hippocampal rat neurons. For these experiments, hippocampal neurons were cultured in the presence or absence of a monolayer of astrocytes. Our results indicated that hippocampal neurons cultured in the presence of astrocytes formed more synapses than the ones cultured in their absence only when kept in N2 serum-free medium. To get insights into the potential molecular mechanisms underlying this effect, we analyzed the expression of proteins known to induce synapse formation in hippocampal neurons. A significant increase in agrin expression was detected in astrocytes cultured in N2 serum-free medium when compared with the ones cultured in serum containing medium. Experiments performed using different components of the N2 mixture indicated that progesterone induced the expression of agrin in astrocytes. Taken collectively, these results provide evidence supporting a role for astrocytes in synapse formation in central neurons. Furthermore, they identified agrin as a potential mediator of this effect, and astrocytes as a bridge between the endocrine and nervous systems during synaptogenesis.

  14. H3 Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

    PubMed Central

    Rice, Frank L.

    2011-01-01

    Histamine H3 receptors (H3Rs), distributed within the brain, the spinal cord, and on specific types of primary sensory neurons, can modulate pain transmission by several mechanisms. In the skin, H3Rs are found on certain Aβ fibers, and on keratinocytes and Merkel cells, as well as on deep dermal, peptidergic Aδ fibers terminating on deep dermal blood vessels. Activation of H3Rs on the latter in the skin, heart, lung, and dura mater reduces calcitonin gene-related peptide and substance P release, leading to anti-inflammatory (but not antinociceptive) actions. However, activation of H3Rs on the spinal terminals of these sensory fibers reduces nociceptive responding to low-intensity mechanical stimuli and inflammatory stimuli such as formalin. These findings suggest that H3R agonists might be useful analgesics, but these drugs have not been tested in clinically relevant pain models. Paradoxically, H3 antagonists/inverse agonists have also been reported to attenuate several types of pain responses, including phase II responses to formalin. In the periaqueductal gray (an important pain regulatory center), the H3 inverse agonist thioperamide releases neuronal histamine and mimics histamine's biphasic modulatory effects in thermal nociceptive tests. Newer H3 inverse agonists with potent, selective, and brain-penetrating properties show efficacy in several neuropathic and arthritis pain models, but the sites and mechanisms for these actions remain poorly understood. PMID:20864501

  15. Modulating charge-transfer interactions in topologically different porphyrin-C60 dyads.

    PubMed

    Guldi, Dirk M; Hirsch, Andreas; Scheloske, Michael; Dietel, Elke; Troisi, Alessandro; Zerbetto, Francesco; Prato, Maurizio

    2003-10-17

    Control over the interchromophore separation, their angular relationship, and the spatial overlap of their electronic clouds in several ZnP-C(60) dyads (ZnP=zinc porphyrin) is used to modulate the rates of intramolecular electron transfer. For the first time, a detailed analysis of the charge transfer absorption and emission spectra, time-dependent spectroscopic measurements, and molecular dynamics simulations prove quantitatively that the same two moieties can produce widely different electron-transfer regimes. This investigation also shows that the combination of ZnP and C(60) consistently produces charge recombination in the inverted Marcus region, with reorganization energies that are remarkably low, regardless of the solvent polarity. The time constants of electron transfer range from the mus to the ps regime, the electronic couplings from a few tens to several hundreds of cm(-1), and the reorganization energies remain below 0.54 eV and can be as low as 0.16 eV.

  16. “iBIM” — Internet-based interactive modules: an easy and interesting learning tool for general surgery residents

    PubMed Central

    Azer, Nader; Shi, Xinzhe; de Gara, Chris; Karmali, Shahzeer; Birch, Daniel W.

    2014-01-01

    Background The increased use of information technology supports a resident-centred educational approach that promotes autonomy, flexibility and time management and helps residents to assess their competence, promoting self-awareness. We established a web-based e-learning tool to introduce general surgery residents to bariatric surgery and evaluate them to determine the most appropriate implementation strategy for Internet-based interactive modules (iBIM) in surgical teaching. Methods Usernames and passwords were assigned to general surgery residents at the University of Alberta. They were directed to the Obesity101 website and prompted to complete a multiple-choice precourse test. Afterwards, they were able to access the interactive modules. Residents could review the course material as often as they wanted before completing a multiple-choice postcourse test and exit survey. We used paired t tests to assess the difference between pre- and postcourse scores. Results Out of 34 residents who agreed to participate in the project, 12 completed the project (35.3%). For these 12 residents, the precourse mean score was 50 ± 17.3 and the postcourse mean score was 67 ± 14 (p = 0.020). Conclusion Most residents who participated in this study recommended using the iBIMs as a study tool for bariatric surgery. Course evaluation scores suggest this novel approach was successful in transferring knowledge to surgical trainees. Further development of this tool and assessment of implementation strategies will determine how iBIM in bariatric surgery may be integrated into the curriculum. PMID:24666457

  17. Liquid-Structure Forces and Electrostatic Modulation of Biomolecular Interactions in Solution

    PubMed Central

    Hassan, Sergio A.

    2008-01-01

    Molecular interactions in solution are controlled by the bulk medium and by the forces originating in the structured region of the solvent close to the solutes. In this paper, a model of electrostatic and liquid-structure forces for dynamics simulations of biomolecules is presented. The model introduces information on the microscopic nature of the liquid in the vicinity of polar and charged groups and the associated non-pairwise character of the forces, thus improving upon conventional continuum representations. The solvent is treated as a polar and polarizable medium, with dielectric properties described by an inhomogeneous version of the Onsager theory. This treatment leads to an effective position-dependent dielectric permittivity that incorporates saturation effects of the electric field and the spatial variation of the liquid density. The non-pairwise additivity of the liquid-structure forces is represented by centers of force located at specific points in the liquid phase. These out-of-the-solute centers are positioned at the peaks of liquid density and exert local, external forces on the atoms of the solute. The density is calculated from a barometric law, using a Lennard-Jones-type solute–liquid effective interaction potential. The conceptual aspects of the model and its exact numerical solutions are discussed for single alkali and halide ions and for ion-pair interactions. The practical aspects of the model and the simplifications introduced for efficient computation of forces in molecular solutes are discussed in the context of polar and charged amino acid dimers. The model reproduces the contact and solvent-separated minima and the desolvation barriers of intermolecular potentials of mean force of amino acid dimers, as observed in atomistic dynamics simulations. Possible refinements based on an improved treatment of molecular correlations are discussed. PMID:17201447

  18. Cellular Zinc Levels are Modulated by Trpml1-Tmem163 Interaction

    PubMed Central

    Cuajungco, Math P.; Basilio, Luigi C.; Silva, Joshua; Hart, Thomas; Tringali, Jonathan; Chen, Cheng-Chang; Biel, Martin; Grimm, Christian

    2014-01-01

    Mucolipidosis type IV (MLIV) is caused by loss of function mutations in the TRPML1 ion channel. We previously reported that tissue zinc levels in MLIV were abnormally elevated; however, the mechanism behind this pathologic accumulation remains unknown. Here, we identify transmembrane (TMEM)-163 protein, a putative zinc transporter, as a novel interacting partner for TRPML1. Evidence from yeast two-hybrid, tissue expression pattern, co-immunoprecipitation, mass spectrometry, and confocal microscopy studies confirmed the physical association of TMEM163 with TRPML1. This interaction is disrupted when a part of TMEM163's N-terminus was deleted. Further studies to define the relevance of their interaction revealed that the plasma membrane (PM) levels of TMEM163 significantly decrease when TRPML1 is co-expressed in HEK-293 cells, while it mostly localizes within the PM when co-expressed with a mutant TRPML1 that distributes mostly in the PM. Meanwhile, co-expression of TMEM163 does not alter TRPML1 channel activity, but its expression levels in MLIV patient fibroblasts are reduced, which correlate with marked accumulation of zinc in lysosomes when these cells are acutely exposed to exogenous zinc (100 μM). When TMEM163 is knocked down or when TMEM163 and TRPML1 are co-knocked down in HEK-293 cells treated overnight with 100 nM zinc, the cells have significantly higher intracellular zinc levels than untreated control. Overall, these findings suggest that TMEM163 and TRPML1 proteins play a critical role in cellular zinc homeostasis, and thus possibly explain a novel mechanism for the pathological overload of zinc in MLIV disease. PMID:25130899

  19. Tailoring biomaterial surface properties to modulate host-implant interactions: implication in cardiovascular and bone therapy

    PubMed Central

    Pacelli, Settimio; Manoharan, Vijayan; Desalvo, Anna; Lomis, Nikita; Jodha, Kartikeya Singh

    2016-01-01

    Host body response to a foreign medical device plays a critical role in defining its fate post implantation. It is thus important to control host-material interactions by designing innovative implant surfaces. In the recent years, biochemical and topographical features have been explored as main target to produce this new type of bioinert or bioresponsive implants. The review discusses specific biofunctional materials and strategies to achieve a precise control over implant surface properties and presents possible solutions to develop next generation of implants, particularly in the fields of bone and cardiovascular therapy. PMID:27630769

  20. Tailoring biomaterial surface properties to modulate host-implant interactions: implication in cardiovascular and bone therapy

    PubMed Central

    Pacelli, Settimio; Manoharan, Vijayan; Desalvo, Anna; Lomis, Nikita; Jodha, Kartikeya Singh

    2016-01-01

    Host body response to a foreign medical device plays a critical role in defining its fate post implantation. It is thus important to control host-material interactions by designing innovative implant surfaces. In the recent years, biochemical and topographical features have been explored as main target to produce this new type of bioinert or bioresponsive implants. The review discusses specific biofunctional materials and strategies to achieve a precise control over implant surface properties and presents possible solutions to develop next generation of implants, particularly in the fields of bone and cardiovascular therapy.

  1. Prenatal exposure to cigarette smoke interacts with OPRM1 to modulate dietary preference for fat

    PubMed Central

    Lee, Ken W.K.; Abrahamowicz, Michal; Leonard, Gabriel T.; Richer, Louis; Perron, Michel; Veillette, Suzanne; Reischl, Eva; Bouchard, Luigi; Gaudet, Daniel; Paus, Tomas; Pausova, Zdenka

    2015-01-01

    Background Preference for fatty foods is a risk factor for obesity. It is a complex behaviour that involves the brain reward system and is regulated by genetic and environmental factors, such as the opioid receptor mu-1 gene (OPRM1) and prenatal exposure to maternal cigarette smoking (PEMCS). We examined whether OPRM1 and PEMCS interact in influencing fat intake and whether exposure-associated epigenetic modifications of OPRM1 may mediate this gene–environment interaction. Methods We studied adolescents from a French Canadian genetic founder population, half of whom were exposed prenatally to maternal cigarette smoking. Fat intake was assessed with a 24-hour food recall in the form of a structured interview conducted by a trained nutritionist. The OPRM1 variant rs2281617 was genotyped for the whole sample with the Illumina Human610-Quad and HumanOmniExpress BeadChips. Methylation of blood DNA was assessed at 21 CpGs across OPRM1 in a subset of the sample using the Illumina HumanMethylation450 BeadChip. Results We included 956 adolescents in our study. In the whole sample, OPRM1 (T carrier in rs2281617) was associated with lower fat intake (−1.6%, p = 0.017), and PEMCS was associated with higher fat intake (+1.6%, p = 0.005). OPRM1 and PEMCS interacted with each other (p = 0.003); the “protective” (fat intake–lowering) allele of OPRM1 was associated with lower fat intake in nonexposed (−3.2%, p < 0.001) but not in exposed individuals (+0.8%, p = 0.42). Further, PEMCS was associated with lower DNA methylation across multiple CpGs across OPRM1 in exposed versus nonexposed individuals (p = 0.031). Limitations A limitation of our study was its cross-sectional design. Conclusion Our study suggests that PEMCS may interact with OPRM1 in increasing fat preference. Silencing of the protective OPRM1 allele in exposed adolescents might be related to epigenetic modification of this gene. PMID:25266401

  2. HuR interacts with human immunodeficiency virus type 1 reverse transcriptase, and modulates reverse transcription in infected cells

    PubMed Central

    Lemay, Julie; Maidou-Peindara, Priscilla; Bader, Thomas; Ennifar, Eric; Rain, Jean-Christophe; Benarous, Richard; Liu, Lang Xia

    2008-01-01

    Reverse transcription of the genetic material of human immunodeficiency virus type 1 (HIV-1) is a critical step in the replication cycle of this virus. This process, catalyzed by reverse transcriptase (RT), is well characterized at the biochemical level. However, in infected cells, reverse transcription occurs in a multiprotein complex – the reverse transcription complex (RTC) – consisting of viral genomic RNA associated with viral proteins (including RT) and, presumably, as yet uncharacterized cellular proteins. Very little is known about the cellular proteins interacting with the RTC, and with reverse transcriptase in particular. We report here that HIV-1 reverse transcription is affected by the levels of a nucleocytoplasmic shuttling protein – the RNA-binding protein HuR. A direct protein-protein interaction between RT and HuR was observed in a yeast two-hybrid screen and confirmed in vitro by homogenous time-resolved fluorescence (HTRF). We mapped the domain interacting with HuR to the RNAse H domain of RT, and the binding domain for RT to the C-terminus of HuR, partially overlapping the third RRM RNA-binding domain of HuR. HuR silencing with specific siRNAs greatly impaired early and late steps of reverse transcription, significantly inhibiting HIV-1 infection. Moreover, by mutagenesis and immunoprecipitation studies, we could not detect the binding of HuR to the viral RNA. These results suggest that HuR may be involved in and may modulate the reverse transcription reaction of HIV-1, by an as yet unknown mechanism involving a protein-protein interaction with HIV-1 RT. PMID:18544151

  3. Male mate preferences in mutual mate choice: finches modulate their songs across and within male-female interactions.

    PubMed

    Heinig, Abbie; Pant, Santosh; Dunning, Jeffery; Bass, Aaron; Coburn, Zachary; Prather, Jonathan F

    2014-10-01

    Male songbirds use song to advertise their attractiveness as potential mates, and the properties of those songs have a powerful influence on female mate preferences. One idea is that males may exert themselves maximally in each song performance, consistent with female evaluation and formation of mate preferences being the primary contributors to mate choice. Alternatively, males may modulate their song behaviour to different degrees in the presence of different females, consistent with both male and female mate preferences contributing to mutual mate choice. Here we consider whether male Bengalese finches, Lonchura striata domestica, express mate preferences at the level of individual females, and whether those preferences are manifest as changes in song behaviour that are sufficient to influence female mate choice. We tested this idea by recording songs performed by individual unmated males during a series of 1 h interactions with each of many unmated females. Across recording sessions, males systematically varied both the quantity and the quality of the songs that they performed to different females. Males also varied their song properties throughout the course of each interaction, and behavioural tests using female birds revealed that songs performed at the onset of each interaction were significantly more attractive than songs performed by the same male later during the same interaction. This demonstration of context-specific variation in the properties of male reproductive signals and a role for that variation in shaping female mate preference reveals that male mate preferences play an important role in mutual mate choice in this species. Because these birds thrive so well in the laboratory and are so amenable to observation and experimentation across generations, these results yield a new model system that may prove especially advantageous in disentangling the role of male and female mate preferences in shaping mutual mate choice and its long-term benefits or

  4. Male mate preferences in mutual mate choice: finches modulate their songs across and within male-female interactions.

    PubMed

    Heinig, Abbie; Pant, Santosh; Dunning, Jeffery; Bass, Aaron; Coburn, Zachary; Prather, Jonathan F

    2014-10-01

    Male songbirds use song to advertise their attractiveness as potential mates, and the properties of those songs have a powerful influence on female mate preferences. One idea is that males may exert themselves maximally in each song performance, consistent with female evaluation and formation of mate preferences being the primary contributors to mate choice. Alternatively, males may modulate their song behaviour to different degrees in the presence of different females, consistent with both male and female mate preferences contributing to mutual mate choice. Here we consider whether male Bengalese finches, Lonchura striata domestica, express mate preferences at the level of individual females, and whether those preferences are manifest as changes in song behaviour that are sufficient to influence female mate choice. We tested this idea by recording songs performed by individual unmated males during a series of 1 h interactions with each of many unmated females. Across recording sessions, males systematically varied both the quantity and the quality of the songs that they performed to different females. Males also varied their song properties throughout the course of each interaction, and behavioural tests using female birds revealed that songs performed at the onset of each interaction were significantly more attractive than songs performed by the same male later during the same interaction. This demonstration of context-specific variation in the properties of male reproductive signals and a role for that variation in shaping female mate preference reveals that male mate preferences play an important role in mutual mate choice in this species. Because these birds thrive so well in the laboratory and are so amenable to observation and experimentation across generations, these results yield a new model system that may prove especially advantageous in disentangling the role of male and female mate preferences in shaping mutual mate choice and its long-term benefits or

  5. The Effects of Noncellulosic Compounds on the Nanoscale Interaction Forces Measured between Carbohydrate-Binding Module and Lignocellulosic Biomass.

    PubMed

    Arslan, Baran; Colpan, Mert; Ju, Xiaohui; Zhang, Xiao; Kostyukova, Alla; Abu-Lail, Nehal I

    2016-05-01

    The lack of fundamental understanding of the types of forces that govern how cellulose-degrading enzymes interact with cellulosic and noncellulosic components of lignocellulosic surfaces limits the design of new strategies for efficient conversion of biomass to bioethanol. In a step to improve our fundamental understanding of such interactions, nanoscale forces acting between a model cellulase-a carbohydrate-binding module (CBM) of cellobiohydrolase I (CBH I)-and a set of lignocellulosic substrates with controlled composition were measured using atomic force microscopy (AFM). The three model substrates investigated were kraft (KP), sulfite (SP), and organosolv (OPP) pulped substrates. These substrates varied in their surface lignin coverage, lignin type, and xylan and acetone extractives' content. Our results indicated that the overall adhesion forces of biomass to CBM increased linearly with surface lignin coverage with kraft lignin showing the highest forces among lignin types investigated. When the overall adhesion forces were decoupled into specific and nonspecific component forces via the Poisson statistical model, hydrophobic and Lifshitz-van der Waals (LW) forces dominated the binding forces of CBM to kraft lignin, whereas permanent dipole-dipole interactions and electrostatic forces facilitated the interactions of lignosulfonates to CBM. Xylan and acetone extractives' content increased the attractive forces between CBM and lignin-free substrates, most likely through hydrogen bonding forces. When the substrates treated differently were compared, it was found that both the differences in specific and nonspecific forces between lignin-containing and lignin-free substrates were the least for OPP. Therefore, cellulase enzymes represented by CBM would weakly bind to organosolv lignin. This will facilitate an easy enzyme recovery compared to other substrates treated with kraft or sulfite pulping. Our results also suggest that altering the surface hydrophobicity

  6. Male mate preferences in mutual mate choice: finches modulate their songs across and within male–female interactions

    PubMed Central

    Heinig, Abbie; Pant, Santosh; Dunning, Jeffery; Bass, Aaron; Coburn, Zachary; Prather, Jonathan F.

    2014-01-01

    Male songbirds use song to advertise their attractiveness as potential mates, and the properties of those songs have a powerful influence on female mate preferences. One idea is that males may exert themselves maximally in each song performance, consistent with female evaluation and formation of mate preferences being the primary contributors to mate choice. Alternatively, males may modulate their song behaviour to different degrees in the presence of different females, consistent with both male and female mate preferences contributing to mutual mate choice. Here we consider whether male Bengalese finches, Lonchura striata domestica, express mate preferences at the level of individual females, and whether those preferences are manifest as changes in song behaviour that are sufficient to influence female mate choice. We tested this idea by recording songs performed by individual unmated males during a series of 1 h interactions with each of many unmated females. Across recording sessions, males systematically varied both the quantity and the quality of the songs that they performed to different females. Males also varied their song properties throughout the course of each interaction, and behavioural tests using female birds revealed that songs performed at the onset of each interaction were significantly more attractive than songs performed by the same male later during the same interaction. This demonstration of context-specific variation in the properties of male reproductive signals and a role for that variation in shaping female mate preference reveals that male mate preferences play an important role in mutual mate choice in this species. Because these birds thrive so well in the laboratory and are so amenable to observation and experimentation across generations, these results yield a new model system that may prove especially advantageous in disentangling the role of male and female mate preferences in shaping mutual mate choice and its long-term benefits or

  7. Staphylokinase has distinct modes of interaction with antimicrobial peptides, modulating its plasminogen-activation properties.

    PubMed

    Nguyen, Leonard T; Vogel, Hans J

    2016-01-01

    Staphylokinase (Sak) is a plasminogen activator protein that is secreted by many Staphylococcus aureus strains. Sak also offers protection by binding and inhibiting specific antimicrobial peptides (AMPs). Here, we evaluate Sak as a more general interaction partner for AMPs. Studies with melittin, mCRAMP, tritrpticin and bovine lactoferricin indicate that the truncation of the first ten residues of Sak (SakΔN10), which occurs in vivo and uncovers important residues in a bulge region, improves its affinity for AMPs. Melittin and mCRAMP have a lower affinity for SakΔN10, and in docking studies, they bind to the N-terminal segment and bulge region of SakΔN10. By comparison, lactoferricin and tritrpticin form moderately high affinity 1:1 complexes with SakΔN10 and their cationic residues form several electrostatic interactions with the protein's α-helix. Overall, our work identifies two distinct AMP binding surfaces on SakΔN10 whose occupation would lead to either inhibition or promotion of its plasminogen activating properties. PMID:27554435

  8. Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors.

    PubMed

    Konya, Viktoria; Philipose, Sonia; Bálint, Zoltán; Olschewski, Andrea; Marsche, Gunther; Sturm, Eva M; Schicho, Rudolf; Peskar, Bernhard A; Schuligoi, Rufina; Heinemann, Akos

    2011-08-01

    Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE(2) and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE(2) and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxin-induced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures. These inhibitory effects were reversed by a selective EP4 receptor antagonist, ONO AE3-208. PGE(2) and the EP4 agonist prevented the activation and cell-surface clustering of β2 integrins, and L-selectin shedding of eosinophils. Under physiological flow conditions, eosinophils that were treated with the EP4 agonist showed reduced adhesion to endothelial monolayers upon stimulation with eotaxin, as well as after TNF-α-induced activation of the endothelial cells. Selective activation of EP1, EP2, and EP3 receptors did not alter eosinophil adhesion to endothelial cells, whereas the EP4 antagonist prevented PGE(2) from decreasing eosinophil adhesion. Finally, eosinophil transmigration across thrombin- and TNF-α-activated endothelial cells was effectively reduced by the EP4 agonist. These data suggest that PGE(2) -EP4 signaling might be protective against allergic responses by inhibiting the interaction of eosinophils with the endothelium and might hence be a useful therapeutic option for controlling inappropriate eosinophil infiltration.

  9. PKCι interacts with Rab14 and modulates epithelial barrier function through regulation of claudin-2 levels

    PubMed Central

    Lu, Ruifeng; Dalgalan, Dogukan; Mandell, Edward K.; Parker, Sara S.; Ghosh, Sourav; Wilson, Jean M.

    2015-01-01

    PKCι is essential for the establishment of epithelial polarity and the normal assembly of tight junctions. We find that PKCι knockdown does not compromise the steady-state distribution of most tight junction proteins but results in increased transepithelial resistance (TER) and decreased paracellular permeability. Analysis of the levels of tight junction components demonstrates that claudin-2 protein levels are decreased. However, other tight junction proteins, such as claudin-1, ZO-1, and occludin, are unchanged. Incubation with an aPKC pseudosubstrate recapitulates the phenotype of PKCι knockdown, including increased TER and decreased levels of claudin-2. In addition, overexpression of PKCι results in increased claudin-2 levels. ELISA and coimmunoprecipitation show that the TGN/endosomal small GTPase Rab14 and PKCι interact directly. Immunolabeling shows that PKCι and Rab14 colocalize in both intracellular puncta and at the plasma membrane and that Rab14 expression is required for normal PKCι distribution in cysts in 3D culture. We showed previously that knockdown of Rab14 results in increased TER and decreased claudin-2. Our results suggest that Rab14 and aPKC interact to regulate trafficking of claudin-2 out of the lysosome-directed pathway. PMID:25694446

  10. Dynamics of Responses in Compatible Potato - Potato virus Y Interaction Are Modulated by Salicylic Acid

    PubMed Central

    Baebler, Špela; Stare, Katja; Kovač, Maja; Blejec, Andrej; Prezelj, Nina; Stare, Tjaša; Kogovšek, Polona; Pompe-Novak, Maruša; Rosahl, Sabine; Ravnikar, Maja; Gruden, Kristina

    2011-01-01

    To investigate the dynamics of the potato – Potato virus Y (PVY) compatible interaction in relation to salicylic acid - controlled pathways we performed experiments using non-transgenic potato cv. Désirée, transgenic NahG-Désirée, cv. Igor and PVYNTN, the most aggressive strain of PVY. The importance of salicylic acid in viral multiplication and symptom development was confirmed by pronounced symptom development in NahG-Désirée, depleted in salicylic acid, and reversion of the effect after spraying with 2,6-dichloroisonicotinic acid (a salicylic acid - analogue). We have employed quantitative PCR for monitoring virus multiplication, as well as plant responses through expression of selected marker genes of photosynthetic activity, carbohydrate metabolism and the defence response. Viral multiplication was the slowest in inoculated potato of cv. Désirée, the only asymptomatic genotype in the study. The intensity of defence-related gene expression was much stronger in both sensitive genotypes (NahG-Désirée and cv. Igor) at the site of inoculation than in asymptomatic plants (cv. Désirée). Photosynthesis and carbohydrate metabolism gene expression differed between the symptomatic and asymptomatic phenotypes. The differential gene expression pattern of the two sensitive genotypes indicates that the outcome of the interaction does not rely simply on one regulatory component, but similar phenotypical features can result from distinct responses at the molecular level. PMID:22194976

  11. Interaction of ascorbic acid and tocopherol on beta-carotene modulated carcinogenesis.

    PubMed

    Black, Homer S

    2010-06-01

    Epidemiological studies suggested that above average intake of beta-carotene (betaC) might reduce cancer risks. However, clinical trials found that betaC supplementation did not reduce the occurrence of non-melanoma skin cancer and that smokers suffered a significant increase in lung cancer incidence. Further, supplementing semi-defined diets with betaC failed to provide photoprotection as reported earlier for closed-formula rations, but actually exacerbated carcinogenesis. A redox mechanism, based upon one-electron transfer rate constants, proposed interactions between tocopherol, betaC and ascorbic acid in which the carotenoid radical cation, a strongly oxidizing radical, would be repaired by ascorbic acid. If the carotenoid radical cation remained unrepaired, this strongly oxidizing species could account for the pro-carcinogenic activity of betaC. Data from nutritional studies supported an interaction of tocopherol and betaC but not with ascorbic acid. The repair of the betaC radical cation must be dependent on factors other than ascorbic acid, e.g., other carotenoids or unidentified phytochemical(s).

  12. Levels of the E2 interacting protein TopBP1 modulate papillomavirus maintenance stage replication

    SciTech Connect

    Kanginakudru, Sriramana; DeSmet, Marsha; Thomas, Yanique; Morgan, Iain M.; Androphy, Elliot J.

    2015-04-15

    The evolutionarily conserved DNA topoisomerase II beta-binding protein 1 (TopBP1) functions in DNA replication, DNA damage response, and cell survival. We analyzed the role of TopBP1 in human and bovine papillomavirus genome replication. Consistent with prior reports, TopBP1 co-localized in discrete nuclear foci and was in complex with papillomavirus E2 protein. Similar to E2, TopBP1 is recruited to the region of the viral origin of replication during G1/S and early S phase. TopBP1 knockdown increased, while over-expression decreased transient virus replication, without affecting cell cycle. Similarly, using cell lines harboring HPV-16 or HPV-31 genome, TopBP1 knockdown increased while over-expression reduced viral copy number relative to genomic DNA. We propose a model in which TopBP1 serves dual roles in viral replication: it is essential for initiation of replication yet it restricts viral copy number. - Highlights: • Protein interaction study confirmed In-situ interaction between TopBP1 and E2. • TopBP1 present at papillomavirus ori in G1/S and early S phase of cell cycle. • TopBP1 knockdown increased, over-expression reduced virus replication. • TopBP1 protein level change did not influence cell survival or cell cycle. • TopBP1 displaced from papillomavirus ori after initiation of replication.

  13. Hearing (rivaling) lips and seeing voices: how audiovisual interactions modulate perceptual stabilization in binocular rivalry

    PubMed Central

    Vidal, Manuel; Barrès, Victor

    2014-01-01

    In binocular rivalry (BR), sensory input remains the same yet subjective experience fluctuates irremediably between two mutually exclusive representations. We investigated the perceptual stabilization effect of an additional sound on the BR dynamics using speech stimuli known to involve robust audiovisual (AV) interactions at several cortical levels. Subjects sensitive to the McGurk effect were presented looping videos of rivaling faces uttering /aba/ and /aga/, respectively, while synchronously hearing the voice /aba/. They reported continuously the dominant percept, either observing passively or trying actively to promote one of the faces. The few studies that investigated the influence of information from an external modality on perceptual competition reported results that seem at first sight inconsistent. Since these differences could stem from how well the modalities matched, we addressed this by comparing two levels of AV congruence: real (/aba/ viseme) vs. illusory (/aga/ viseme producing the /ada/ McGurk fusion). First, adding the voice /aba/ stabilized both real and illusory congruent lips percept. Second, real congruence of the added voice improved volitional control whereas illusory congruence did not, suggesting a graded contribution to the top-down sensitivity control of selective attention. In conclusion, a congruent sound enhanced considerably attentional control over the perceptual outcome selection; however, differences between passive stabilization and active control according to AV congruency suggest these are governed by two distinct mechanisms. Based on existing theoretical models of BR, selective attention and AV interaction in speech perception, we provide a general interpretation of our findings. PMID:25237302

  14. ACTH Modulates PTP-PEST Activity and Promotes Its Interaction With Paxillin.

    PubMed

    Gorostizaga, Alejandra Beatriz; Mori Sequeiros Garcia, M Mercedes; Acquier, Andrea B; Lopez-Costa, Juan J; Mendez, Carlos F; Maloberti, Paula M; Paz, Cristina

    2016-09-01

    Adrenocorticotropic hormone (ACTH) treatment has been proven to promote paxillin dephosphorylation and increase soluble protein tyrosine phosphatase (PTP) activity in rat adrenal zona fasciculata (ZF). Also, in-gel PTP assays have shown the activation of a 115-kDa PTP (PTP115) by ACTH. In this context, the current work presents evidence that PTP115 is PTP-PEST, a PTP that recognizes paxillin as substrate. PTP115 was partially purified from rat adrenal ZF and PTP-PEST was detected through Western blot in bioactive samples taken in each purification step. Immunohistochemical and RT-PCR studies revealed PTP-PEST expression in rat ZF and Y1 adrenocortical cells. Moreover, a PTP-PEST siRNA decreased the expression of this phosphatase. PKA phosphorylation of purified PTP115 isolated from non-ACTH-treated rats increased KM and VM . Finally, in-gel PTP assays of immunoprecipitated paxillin from control and ACTH-treated rats suggested a hormone-mediated increase in paxillin-PTP115 interaction, while PTP-PEST and paxillin co-localize in Y1 cells. Taken together, these data demonstrate PTP-PEST expression in adrenal ZF and its regulation by ACTH/PKA and also suggest an ACTH-induced PTP-PEST-paxillin interaction. J. Cell. Biochem. 117: 2170-2181, 2016. © 2016 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.

  15. Polypeptide Modulators of Caspase Recruitment Domain (CARD)-CARD-mediated Protein-Protein Interactions*

    PubMed Central

    Palacios-Rodríguez, Yadira; García-Laínez, Guillermo; Sancho, Mónica; Gortat, Anna; Orzáez, Mar; Pérez-Payá, Enrique

    2011-01-01

    The caspase recruitment domain (CARD) is present in a large number of proteins. Initially, the CARD was recognized as part of the caspase activation machinery. CARD-CARD interactions play a role in apoptosis and are responsible for the Apaf-1-mediated activation of procaspase-9 in the apoptosome. CARD-containing proteins mediate the inflammasome-dependent activation of proinflammatory caspase-1. More recently, new roles for CARD-containing proteins have been reported in signaling pathways associated with immune responses. The functional role of CARD-containing proteins and CARDs in coordinating apoptosis and inflammatory and immune responses is not completely understood. We have explored the putative cross-talk between apoptosis and inflammation by analyzing the modulatory activity on both the Apaf-1/procaspase-9 interaction and the inflammasome-mediated procaspase-1 activation of CARD-derived polypeptides. To this end, we analyzed the activity of individual recombinant CARDs, rationally designed CARD-derived peptides, and peptides derived from phage display. PMID:22065589

  16. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.

    PubMed

    Lenz, Tobias L; Deutsch, Aaron J; Han, Buhm; Hu, Xinli; Okada, Yukinori; Eyre, Stephen; Knapp, Michael; Zhernakova, Alexandra; Huizinga, Tom W J; Abecasis, Gonçalo; Becker, Jessica; Boeckxstaens, Guy E; Chen, Wei-Min; Franke, Andre; Gladman, Dafna D; Gockel, Ines; Gutierrez-Achury, Javier; Martin, Javier; Nair, Rajan P; Nöthen, Markus M; Onengut-Gumuscu, Suna; Rahman, Proton; Rantapää-Dahlqvist, Solbritt; Stuart, Philip E; Tsoi, Lam C; van Heel, David A; Worthington, Jane; Wouters, Mira M; Klareskog, Lars; Elder, James T; Gregersen, Peter K; Schumacher, Johannes; Rich, Stephen S; Wijmenga, Cisca; Sunyaev, Shamil R; de Bakker, Paul I W; Raychaudhuri, Soumya

    2015-09-01

    Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10(-12); T1D, P = 2.4 × 10(-10); psoriasis, P = 5.9 × 10(-6); celiac disease, P = 1.2 × 10(-87)). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 × 10(-3); T1D, P = 8.6 × 10(-27); celiac disease, P = 6.0 × 10(-100)). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model. PMID:26258845

  17. Dynein light chain interaction with the peroxisomal import docking complex modulates peroxisome biogenesis in yeast.

    PubMed

    Chang, Jinlan; Tower, Robert J; Lancaster, David L; Rachubinski, Richard A

    2013-10-15

    Dynein is a large macromolecular motor complex that moves cargo along microtubules. A motor-independent role for the light chain of dynein, Dyn2p, in peroxisome biology in Saccharomyces cerevisiae was suggested from its interaction with Pex14p, a component of the peroxisomal matrix protein import docking complex. Here we show that cells of the yeast Yarrowia lipolytica deleted for the gene encoding the homologue of Dyn2p are impaired in peroxisome function and biogenesis. These cells exhibit compromised growth on medium containing oleic acid as the carbon source, the metabolism of which requires functional peroxisomes. Their peroxisomes have abnormal morphology, atypical matrix protein localization, and an absence of proteolytic processing of the matrix enzyme thiolase, which normally occurs upon its import into the peroxisome. We also show physical and genetic interactions between Dyn2p and members of the docking complex, particularly Pex17p. Together, our results demonstrate a role for Dyn2p in the assembly of functional peroxisomes and provide evidence that Dyn2p acts in cooperation with the peroxisomal matrix protein import docking complex to effect optimal matrix protein import.

  18. Staphylokinase has distinct modes of interaction with antimicrobial peptides, modulating its plasminogen-activation properties

    PubMed Central

    Nguyen, Leonard T.; Vogel, Hans J.

    2016-01-01

    Staphylokinase (Sak) is a plasminogen activator protein that is secreted by many Staphylococcus aureus strains. Sak also offers protection by binding and inhibiting specific antimicrobial peptides (AMPs). Here, we evaluate Sak as a more general interaction partner for AMPs. Studies with melittin, mCRAMP, tritrpticin and bovine lactoferricin indicate that the truncation of the first ten residues of Sak (SakΔN10), which occurs in vivo and uncovers important residues in a bulge region, improves its affinity for AMPs. Melittin and mCRAMP have a lower affinity for SakΔN10, and in docking studies, they bind to the N-terminal segment and bulge region of SakΔN10. By comparison, lactoferricin and tritrpticin form moderately high affinity 1:1 complexes with SakΔN10 and their cationic residues form several electrostatic interactions with the protein’s α-helix. Overall, our work identifies two distinct AMP binding surfaces on SakΔN10 whose occupation would lead to either inhibition or promotion of its plasminogen activating properties. PMID:27554435

  19. Interpersonal interactions and empathy modulate perception of threat and defensive responses.

    PubMed

    Fossataro, C; Sambo, C F; Garbarini, F; Iannetti, G D

    2016-01-01

    The defensive peripersonal space (DPPS) is a vital "safety margin" surrounding the body. When a threatening stimulus is delivered inside the DPPS, subcortical defensive responses like the hand-blink reflex (HBR) are adjusted depending on the perceived threat content. In three experiments, we explored whether and how defensive responses are affected by the interpersonal interaction within the DPPS of the face. In Experiment 1, we found that the HBR is enhanced when the threat is brought close to the face not only by one's own stimulated hand, but also by another person's hand, although to a significantly lesser extent. In Experiments 2 and 3, we found that the HBR is also enhanced when the hand of the participant enters the DPPS of another individual, either in egocentric or in allocentric perspective. This enhancement is larger in participants with strong empathic tendency when the other individual is in a third person perspective. These results indicate that interpersonal interactions shape perception of threat and defensive responses. These effects are particularly evident in individuals with greater tendency to having empathic concern to other people. PMID:26839143

  20. Ring1B Contains a Ubiquitin-Like Docking Module for Interaction with Cbx Proteins

    SciTech Connect

    Bezsonova, Irina; Walker, John R.; Bacik, John P.; Duan, Shili; Dhe-Paganon, Sirano; Arrowsmith, Cheryl H.

    2010-04-19

    Polycomb group (PcG) proteins are a special set of repressive transcription factors involved in epigenetic modifications of chromatin. They form two functionally distinct groups of catalytically active complexes: Polycomb repressive complex 1 (PRC1) and 2 (PRC2). The PRC1 complex is an important yet poorly characterized multiprotein histone ubiquitylation machine responsible for maintaining transcriptionally silent states of genes through histone H2A K119 modification. The Ring domain containing subunits of PRC1 also have substrate-targeting domains that interact with Cbx proteins, which have been implicated in chromatin and RNA binding. In this work, we present a high resolution structure of the C-terminal domain of Ring1B, revealing a variant ubiquitin-like fold with a distinct conserved surface region. On the basis of crystal structure and mutational analysis of this domain we show that the conserved surface is responsible for interaction with Cbx members of the PRC1 and homodimer formation. These data suggest a mechanism by which Ring1B serves as an adaptor that mediates binding between the members of the PRC1 complex and the nucleosome.

  1. Interaction between anti-Alzheimer and antipsychotic drugs in modulating extrapyramidal motor disorders in mice.

    PubMed

    Shimizu, Saki; Mizuguchi, Yuto; Sobue, Akira; Fujiwara, Mai; Morimoto, Tomoki; Ohno, Yukihiro

    2015-04-01

    Antipsychotics are often used in conjunction with anti-Alzheimer drugs to treat the behavioral and psychological symptoms of dementia (BPSD). Here, we examined the effects of cholinesterase inhibitors (ChEIs), donepezil and galantamine, on antipsychotic-induced extrapyramidal side effects (EPS) in mice. The effects of serotonergic agents on the EPS drug interaction were also evaluated. Donepezil (0.3-3 mg/kg) did not induce EPS signs by itself; however, it significantly potentiated bradykinesia induction with a low dose of haloperidol (0.5 mg/kg) in dose-dependent and synergistic manners. Galantamine (0.3-3 mg/kg) elicited mild bradykinesia at a high dose and dose-dependently augmented haloperidol-induced bradykinesia. The EPS potentiation by galantamine was blocked by trihexyphenidyl (a muscarinic antagonist), but not by mecamylamine (a nicotinic antagonist). In addition, the bradykinesia potentiation by galantamine was significantly reduced by (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (a 5-HT1A agonist), ritanserin (a 5-HT2 antagonist), and SB-258585 (a 5-HT6 antagonist). The present results give us a caution for the antipsychotics and ChEIs interaction in inducing EPS in the treatment of BPSD. In addition, second generation antipsychotics, which can stimulate 5-HT1A receptors or antagonize 5-HT2 and 5-HT6 receptors, seem to be favorable as an adjunctive therapy for BPSD. PMID:25850380

  2. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

    PubMed Central

    Lenz, Tobias L.; Deutsch, Aaron J.; Han, Buhm; Hu, Xinli; Okada, Yukinori; Eyre, Stephen; Knapp, Michael; Zhernakova, Alexandra; Huizinga, Tom W.J.; Abecasis, Goncalo; Becker, Jessica; Boeckxstaens, Guy E.; Chen, Wei-Min; Franke, Andre; Gladman, Dafna D.; Gockel, Ines; Gutierrez-Achury, Javier; Martin, Javier; Nair, Rajan P.; Nöthen, Markus M.; Onengut-Gumuscu, Suna; Rahman, Proton; Rantapää-Dahlqvist, Solbritt; Stuart, Philip E.; Tsoi, Lam C.; Van Heel, David A.; Worthington, Jane; Wouters, Mira M.; Klareskog, Lars; Elder, James T.; Gregersen, Peter K.; Schumacher, Johannes; Rich, Stephen S.; Wijmenga, Cisca; Sunyaev, Shamil R.; de Bakker, Paul I.W.; Raychaudhuri, Soumya

    2015-01-01

    Human leukocyte antigen (HLA) genes confer strong risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen binding repertoires between a heterozygote’s two expressed HLA variants may result in additional non-additive risk effects. We tested non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (RA, Ncases=5,337), type 1 diabetes (T1D, Ncases=5,567), psoriasis vulgaris (Ncases=3,089), idiopathic achalasia (Ncases=727), and celiac disease (Ncases=11,115). In four out of five diseases, we observed highly significant non-additive dominance effects (RA: P=2.5×1012; T1D: P=2.4×10−10; psoriasis: P=5.9×10−6; celiac disease: P=1.2×10−87). In three of these diseases, the dominance effects were explained by interactions between specific classical HLA alleles (RA: P=1.8×10−3; T1D: P=8.6×1027; celiac disease: P=6.0×10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (RA: 1.4%, T1D: 4.0%, and celiac disease: 4.1%, beyond a simple additive model). PMID:26258845

  3. Development of MCAERO wing design panel method with interactive graphics module

    NASA Technical Reports Server (NTRS)

    Hawk, J. D.; Bristow, D. R.

    1984-01-01

    A reliable and efficient iterative method has been developed for designing wing section contours corresponding to a prescribed subcritical pressure distribution. The design process is initialized by using MCAERO (MCAIR 3-D Subsonic Potential Flow Analysis Code) to analyze a baseline configuration. A second program DMCAERO is then used to calculate a matrix containing the partial derivative of potential at each control point with respect to each unknown geometry parameter by applying a first-order expansion to the baseline equations in MCAERO. This matrix is calculated only once but is used in each iteration cycle to calculate the geometry perturbation and to analyze the perturbed geometry. The potential on the new geometry is calculated by linear extrapolation from the baseline solution. This extrapolated potential is converted to velocity by numerical differentiation, and velocity is converted to pressure by using Bernoulli's equation. There is an interactive graphics option which allows the user to graphically display the results of the design process and to interactively change either the geometry or the prescribed pressure distribution.

  4. Bimodal modulation by nicotine of anxiety in the social interaction test: role of the dorsal hippocampus.

    PubMed

    File, S E; Kenny, P J; Ouagazzal, A M

    1998-12-01

    In conditions generating moderate levels of anxiety in the social interaction test (low light, unfamiliar arena or high light, familiar arena), parenteral administration of nicotine had bimodal actions, low doses (0.01 and 0.1 mg/kg i.p.) had anxiolytic effects and high doses (0.5 and 1.0 mg/kg i.p.) had anxiogenic effects. In test conditions where anxiety was lowest (low light, familiar arena) and highest (high light, unfamiliar arena), nicotine was without effect after intraperitoneal or hippocampal administration. Thus, nicotine plays a modulatory role in which the activity of other neurotransmitters is crucial to its expression. After bilateral administration to the dorsal hippocampus, nicotine (0.1-8.0 microg) had anxiogenic effects in conditions of moderate anxiety; mecamylamine (30 ng) was silent in these conditions, indicating no intrinsic tone. Our results show that the dorsal hippocampus is one area that can mediate anxiogenic effects in the social interaction test, but the brain region mediating anxiolytic effects remains to be identified.

  5. Supramolecular host-guest interaction of trityl-nitroxide biradicals with cyclodextrins: modulation of spin-spin interaction and redox sensitivity

    PubMed Central

    Tan, Xiaoli; Song, Yuguang; Liu, Huiqiang; Zhong, Qinwen; Rockenbauer, Antal; Villamena, Frederick A.; Zweier, Jay L.; Liu, Yangping

    2016-01-01

    Supramolecular host-guest interactions of trityl-nitroxide (TN) biradicals CT02-VT, CT02-AT and CT02-GT with methyl-β-cyclodextrin (M-β-CD), hydroxypropyl-β-cyclodextrin (H-β-CD) and γ-cyclodextrin (γ-CD) were investigated by EPR spectroscopy. In the presence of cyclodextrins (i.e., γ-CD, M-β-CD and H-β-CD), host-guest complexes of CT02-VT are formed where the nitroxide and linker parts possibly interact with the cyclodextrins’ cavities. Complexation with cyclodextrins leads to suppression of the intramolecular through-space spin-spin exchange coupling in CT02-VT, thus allowing determination of the through-bond spin-spin exchange coupling which was calculated to be 1.6 G using EPR simulations. Different types of cyclodextrins have variable binding affinity with CT02-VT with γ-CD (95 M−1) > M-β-CD (70 M−1) > H-β-CD (32 M−1). In addition, the effect of the linkers in TN biradicals on the host-guest interactions was also investigated. Among three TN biradicals studied, CT02-VT has the highest association constant with one designated cyclodextrin derivative. On the other hand, the complexes of CT02-GT (~ 22 G) and CT02-AT (7.7–9.0 G) with cyclodextrins have much higher through-bond spin-spin exchange couplings than that of CT02-VT (1.6 G) due to the shorter linkers than that of CT02-VT. Furthermore, the stability of TN biradicals towards ascorbate was significantly enhanced after the complexation with CDs, with an almost 2-time attenuation of the second-order rate constants for all the biradicals. Therefore, the supramolecular host-guest interactions with cyclodextrins will be an alternative method to modulate the magnitude of the spin-spin interactions and redox sensitivity of TN biradicals and the resulting complexes are promising as highly efficient DNP polarizing agents as well as EPR redox probes. PMID:26700002

  6. DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction

    PubMed Central

    Zou, D.; Chen, L.; Deng, D.; Jiang, D.; Dong, F.; McSweeney, C.; Zhou, Y.; Liu, L.; Chen, G.; Wu, Y.; Mao, Y.

    2016-01-01

    Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PV-positive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3D-Gq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

  7. DREADD in parvalbumin interneurons of the dentate gyrus modulates anxiety, social interaction and memory extinction.

    PubMed

    Zou, D; Chen, L; Deng, D; Jiang, D; Dong, F; McSweeney, C; Zhou, Y; Liu, L; Chen, G; Wu, Y; Mao, Y

    2016-01-01

    Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PVpositive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3DGq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

  8. Extracellular Matrix Ligand and Stiffness Modulate Immature Nucleus Pulposus Cell-Cell Interactions

    PubMed Central

    Gilchrist, Christopher L.; Darling, Eric M.; Chen, Jun; Setton, Lori A.

    2011-01-01

    The nucleus pulposus (NP) of the intervertebral disc functions to provide compressive load support in the spine, and contains cells that play a critical role in the generation and maintenance of this tissue. The NP cell population undergoes significant morphological and phenotypic changes during maturation and aging, transitioning from large, vacuolated immature cells arranged in cell clusters to a sparse population of smaller, isolated chondrocyte-like cells. These morphological and organizational changes appear to correlate with the first signs of degenerative changes within the intervertebral disc. The extracellular matrix of the immature NP is a soft, gelatinous material containing multiple laminin isoforms, features that are unique to the NP relative to other regions of the disc and that change with aging and degeneration. Based on this knowledge, we hypothesized that a soft, laminin-rich extracellular matrix environment would promote NP cell-cell interactions and phenotypes similar to those found in immature NP tissues. NP cells were isolated from porcine intervertebral discs and cultured in matrix environments of varying mechanical stiffness that were functionalized with various matrix ligands; cellular responses to periods of culture were assessed using quantitative measures of cell organization and phenotype. Results show that soft (<720 Pa), laminin-containing extracellular matrix substrates promote NP cell morphologies, cell-cell interactions, and proteoglycan production in vitro, and that this behavior is dependent upon both extracellular matrix ligand and substrate mechanical properties. These findings indicate that NP cell organization and phenotype may be highly sensitive to their surrounding extracellular matrix environment. PMID:22087260

  9. Salmonella–Host InteractionsModulation of the Host Innate Immune System

    PubMed Central

    Hurley, Daniel; McCusker, Matthew P.; Fanning, Séamus; Martins, Marta

    2014-01-01

    Salmonella enterica (S. enterica) are Gram-negative bacteria that can invade a broad range of hosts causing both acute and chronic infections. This phenotype is related to its ability to replicate and persist within non-phagocytic host epithelial cells as well as phagocytic dendritic cells and macrophages of the innate immune system. Infection with S. enterica manifests itself through a broad range of clinical symptoms and can result in asymptomatic carriage, gastroenteritis, systemic disease such as typhoid fever and in severe cases, death (1). Exposure to S. enterica serovars Typhi and Paratyphi exhibits clinical symptoms including diarrhea, fatigue, fever, and temperature fluctuations. Other serovars such as the non-typhoidal Salmonella (NTS), of which there are over 2,500, are commonly contracted as, but not limited to, food-borne sources causing gastrointestinal symptoms, which include diarrhea and vomiting. The availability of complete genome sequences for many S. enterica serovars has facilitated research into the genetic determinants of virulence for this pathogen. This work has led to the identification of important bacterial components, including flagella, type III secretion systems, lipopolysaccharides, and Salmonella pathogenicity islands, all of which support the intracellular life cycle of S. enterica. Studies focusing on the host–pathogen interaction have provided insights into receptor activation of the innate immune system. Therefore, characterizing the host–S. enterica interaction is critical to understand the pathogenicity of the bacteria in a clinically relevant context. This review outlines salmonellosis and the clinical manifestations between typhoidal and NTS infections as well as discussing the host immune response to infection and the models that are being used to elucidate the mechanisms involved in Salmonella pathogenicity. PMID:25339955

  10. The lipid composition of Legionella dumoffii membrane modulates the interaction with Galleria mellonella apolipophorin III.

    PubMed

    Palusińska-Szysz, Marta; Zdybicka-Barabas, Agnieszka; Reszczyńska, Emilia; Luchowski, Rafał; Kania, Magdalena; Gisch, Nicolas; Waldow, Franziska; Mak, Paweł; Danikiewicz, Witold; Gruszecki, Wiesław I; Cytryńska, Małgorzata

    2016-07-01

    Apolipophorin III (apoLp-III), an insect homologue of human apolipoprotein E (apoE), is a widely used model protein in studies on protein-lipid interactions, and anti-Legionella activity of Galleria mellonella apoLp-III has been documented. Interestingly, exogenous choline-cultured Legionella dumoffii cells are considerably more susceptible to apoLp-III than non-supplemented bacteria. In order to explain these differences, we performed, for the first time, a detailed analysis of L. dumoffii lipids and a comparative lipidomic analysis of membranes of bacteria grown without and in the presence of exogenous choline. (31)P NMR analysis of L. dumoffii phospholipids (PLs) revealed a considerable increase in the phosphatidylcholine (PC) content in bacteria cultured on choline medium and a decrease in the phosphatidylethanolamine (PE) content in approximately the same range. The interactions of G. mellonella apoLp-III with lipid bilayer membranes prepared from PLs extracted from non- and choline-supplemented L. dumoffii cells were examined in detail by means of attenuated total reflection- and linear dichroism-Fourier transform infrared spectroscopy. Furthermore, the kinetics of apoLp-III binding to liposomes formed from L. dumoffii PLs was analysed by fluorescence correlation spectroscopy and fluorescence lifetime imaging microscopy using fluorescently labelled G. mellonella apoLp-III. Our results indicated enhanced binding of apoLp-III to and deeper penetration into lipid membranes formed from PLs extracted from the choline-supplemented bacteria, i.e. characterized by an increased PC/PE ratio. This could explain, at least in part, the higher susceptibility of choline-cultured L. dumoffii to G. mellonella apoLp-III. PMID:27094351

  11. The lipid composition of Legionella dumoffii membrane modulates the interaction with Galleria mellonella apolipophorin III.

    PubMed

    Palusińska-Szysz, Marta; Zdybicka-Barabas, Agnieszka; Reszczyńska, Emilia; Luchowski, Rafał; Kania, Magdalena; Gisch, Nicolas; Waldow, Franziska; Mak, Paweł; Danikiewicz, Witold; Gruszecki, Wiesław I; Cytryńska, Małgorzata

    2016-07-01

    Apolipophorin III (apoLp-III), an insect homologue of human apolipoprotein E (apoE), is a widely used model protein in studies on protein-lipid interactions, and anti-Legionella activity of Galleria mellonella apoLp-III has been documented. Interestingly, exogenous choline-cultured Legionella dumoffii cells are considerably more susceptible to apoLp-III than non-supplemented bacteria. In order to explain these differences, we performed, for the first time, a detailed analysis of L. dumoffii lipids and a comparative lipidomic analysis of membranes of bacteria grown without and in the presence of exogenous choline. (31)P NMR analysis of L. dumoffii phospholipids (PLs) revealed a considerable increase in the phosphatidylcholine (PC) content in bacteria cultured on choline medium and a decrease in the phosphatidylethanolamine (PE) content in approximately the same range. The interactions of G. mellonella apoLp-III with lipid bilayer membranes prepared from PLs extracted from non- and choline-supplemented L. dumoffii cells were examined in detail by means of attenuated total reflection- and linear dichroism-Fourier transform infrared spectroscopy. Furthermore, the kinetics of apoLp-III binding to liposomes formed from L. dumoffii PLs was analysed by fluorescence correlation spectroscopy and fluorescence lifetime imaging microscopy using fluorescently labelled G. mellonella apoLp-III. Our results indicated enhanced binding of apoLp-III to and deeper penetration into lipid membranes formed from PLs extracted from the choline-supplemented bacteria, i.e. characterized by an increased PC/PE ratio. This could explain, at least in part, the higher susceptibility of choline-cultured L. dumoffii to G. mellonella apoLp-III.

  12. Interaction of Baroreceptor and Chemoreceptor Reflexes MODULATION OF THE CHEMORECEPTOR REFLEX BY CHANGES IN BARORECEPTOR ACTIVITY

    PubMed Central

    Heistad, Donald D.; Abboud, Francois M.; Mark, Allyn L.; Schmid, Phillip G.

    1974-01-01

    The purpose of this study was to determine whether the level of arterial pressure and degree of baroreceptor activation affect responses to stimulation of chemoreceptors. Chemoreceptors were stimulated by injecting nicotine into the common carotid artery of anesthetized and paralyzed dogs. Responses were observed in the innervated gracilis muscle, perfused at constant flow while perfusion pressure was measured. Arterial pressure was lowered by bleeding the animals and raised by transient occlusion of the descending aorta. Vasoconstrictor responses to stimulation of chemoreceptors were enhanced by hypotension and inhibited by elevation of arterial pressure. Potentiation of the chemoreceptor reflex by hemorrhagic hypotension was not the result of altered vascular resistance in the gracilis muscle, sensitization of chemoreceptors by catecholamines or acidosis, or changes in cerebral perfusion pressure. Additional studies were done in which we excluded the possibility that the changes resulted from direct effects of changes in arterial pressure on chemoreceptors. Both carotid bifurcations were isolated and perfused. On one side, pressure was raised to stimulate the carotid sinus baroreceptors. On the other side, the carotid body chemoreceptors were stimulated by nicotine or by hypoxic and hypercapnic blood. Activation of baroreceptors on one side attenuated the vasoconstrictor response to chemoreceptor stimulation on the other side. This excludes a direct effect of changes in arterial pressure on the chemoreceptors and suggests a central interaction of these reflexes. We conclude that vasoconstrictor responses to stimulation of chemoreceptors are potentiated by hypotension and inhibited by transient hypertension. These effects appear to result at least in part from a central interaction of chemoreceptor and baroreceptor reflexes. PMID:4825222

  13. Salmonella-host interactions - modulation of the host innate immune system.

    PubMed

    Hurley, Daniel; McCusker, Matthew P; Fanning, Séamus; Martins, Marta

    2014-01-01

    Salmonella enterica (S. enterica) are Gram-negative bacteria that can invade a broad range of hosts causing both acute and chronic infections. This phenotype is related to its ability to replicate and persist within non-phagocytic host epithelial cells as well as phagocytic dendritic cells and macrophages of the innate immune system. Infection with S. enterica manifests itself through a broad range of clinical symptoms and can result in asymptomatic carriage, gastroenteritis, systemic disease such as typhoid fever and in severe cases, death (1). Exposure to S. enterica serovars Typhi and Paratyphi exhibits clinical symptoms including diarrhea, fatigue, fever, and temperature fluctuations. Other serovars such as the non-typhoidal Salmonella (NTS), of which there are over 2,500, are commonly contracted as, but not limited to, food-borne sources causing gastrointestinal symptoms, which include diarrhea and vomiting. The availability of complete genome sequences for many S. enterica serovars has facilitated research into the genetic determinants of virulence for this pathogen. This work has led to the identification of important bacterial components, including flagella, type III secretion systems, lipopolysaccharides, and Salmonella pathogenicity islands, all of which support the intracellular life cycle of S. enterica. Studies focusing on the host-pathogen interaction have provided insights into receptor activation of the innate immune system. Therefore, characterizing the host-S. enterica interaction is critical to understand the pathogenicity of the bacteria in a clinically relevant context. This review outlines salmonellosis and the clinical manifestations between typhoidal and NTS infections as well as discussing the host immune response to infection and the models that are being used to elucidate the mechanisms involved in Salmonella pathogenicity.

  14. DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction

    PubMed Central

    Zou, D.; Chen, L.; Deng, D.; Jiang, D.; Dong, F.; McSweeney, C.; Zhou, Y.; Liu, L.; Chen, G.; Wu, Y.; Mao, Y.

    2016-01-01

    Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PV-positive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3D-Gq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus. PMID:26733123

  15. Cis interaction between Semaphorin6A and Plexin-A4 modulates the repulsive response to Sema6A

    PubMed Central

    Haklai-Topper, Liat; Mlechkovich, Guy; Savariego, Dana; Gokhman, Irena; Yaron, Avraham

    2010-01-01

    The correct navigation of axons to their targets depends on guidance molecules in the extra-cellular environment. Differential responsiveness to a particular guidance cue is largely an outcome of disparity in the expression of its receptors on the reacting axons. Here, we show that the differential responsiveness of sympathetic and sensory neurons to the transmembrane Semaphorin Sema6A is mainly determined by its co-expression in the responding neurons. Both sympathetic and sensory neurons express the Sema6A receptor Plexin-A4, but only sympathetic neurons respond to it. The expression of Sema6A counteracts this responsiveness and is detected only in sensory neurons. Remarkably, sensory neurons that lack Sema6A gain sensitivity to it in a Plexin-A4-dependent manner. Using heterologus systems, we show that the co-expression of Sema6A and Plexin-A4 hinders the binding of exogenous ligand, suggesting that a Sema6A–Plexin-A4 cis interaction serves as an inhibitory mechanism. Finally, we provide evidence for differential modes of interaction in cis versus in trans. Thus, co-expression of a transmembrane cue together with its receptor can serve as a guidance response modulator. PMID:20606624

  16. Interactive Online Modules and Videos for Learning Geological Concepts at the University of Toronto Department of Earth Sciences

    NASA Astrophysics Data System (ADS)

    Veglio, E.; Graves, L. W.; Bank, C. G.

    2014-12-01

    We designed various computer-based applications and videos as educational resources for undergraduate courses at the University of Toronto in the Earth Science Department. These resources were developed in effort to enhance students' self-learning of key concepts as identified by educators at the department. The interactive learning modules and videos were created using the programs MATLAB and Adobe Creative Suite 5 (Photoshop and Premiere) and range from optical mineralogy (extinction and Becke line), petrology (equilibrium melting in 2-phase systems), crystallography (crystal systems), geophysics (gravity anomaly), and geologic history (evolution of Canada). These resources will be made available for students on internal course websites as well as through the University of Toronto Earth Science's website (www.es.utoronto.ca) where appropriate; the video platform YouTube.com may be used to reach a wide audience and promote the material. Usage of the material will be monitored and feedback will be collected over the next academic year in order to gage the use of these interactive learning tools and to assess if these computer-based applications and videos foster student engagement and active learning, and thus offer an enriched learning experience.

  17. Vasoactive Intestinal Peptide modulates trophoblast-derived cell line function and interaction with phagocytic cells through autocrine pathways

    PubMed Central

    Vota, Daiana; Paparini, Daniel; Hauk, Vanesa; Toro, Ayelén; Merech, Fatima; Varone, Cecilia; Ramhorst, Rosanna; Pérez Leirós, Claudia

    2016-01-01

    Trophoblast cells migrate and invade the decidual stroma in a tightly regulated process to maintain immune homeostasis at the maternal-placental interface during the first weeks of pregnancy. Locally synthesized factors modulate trophoblast cell function and their interaction with maternal leukocytes to promote the silent clearance of apoptotic cells. The vasoactive intestinal peptide (VIP) is a pleiotropic polypeptide with trophic and anti-inflammatory effects in murine pregnancy models. We explored the effect of VIP on two human first trimester trophoblast cell lines, particularly on their migration, invasiveness and interaction with phagocytic cells, and the signalling and regulatory pathways involved. We found that VIP enhanced trophoblast cell migration and invasion through the activation of high affinity VPAC receptors and PKA-CRE signalling pathways. VIP knocked-down trophoblast cells showed reduced migration in basal and leukemic inhibitor factor (LIF)-elicited conditions. In parallel, VIP-silenced trophoblast cells failed to induce the phagocytosis of apoptotic bodies and the expression of immunosuppressant markers by human monocytes. Our results suggest that VIP-mediated autocrine pathways regulate trophoblast cell function and contribute to immune homeostasis maintenance at placentation and may provide new clues for therapeutic intervention in pregnancies complicated by defective deep placentation. PMID:27212399

  18. Vasoactive Intestinal Peptide modulates trophoblast-derived cell line function and interaction with phagocytic cells through autocrine pathways.

    PubMed

    Vota, Daiana; Paparini, Daniel; Hauk, Vanesa; Toro, Ayelén; Merech, Fatima; Varone, Cecilia; Ramhorst, Rosanna; Pérez Leirós, Claudia

    2016-01-01

    Trophoblast cells migrate and invade the decidual stroma in a tightly regulated process to maintain immune homeostasis at the maternal-placental interface during the first weeks of pregnancy. Locally synthesized factors modulate trophoblast cell function and their interaction with maternal leukocytes to promote the silent clearance of apoptotic cells. The vasoactive intestinal peptide (VIP) is a pleiotropic polypeptide with trophic and anti-inflammatory effects in murine pregnancy models. We explored the effect of VIP on two human first trimester trophoblast cell lines, particularly on their migration, invasiveness and interaction with phagocytic cells, and the signalling and regulatory pathways involved. We found that VIP enhanced trophoblast cell migration and invasion through the activation of high affinity VPAC receptors and PKA-CRE signalling pathways. VIP knocked-down trophoblast cells showed reduced migration in basal and leukemic inhibitor factor (LIF)-elicited conditions. In parallel, VIP-silenced trophoblast cells failed to induce the phagocytosis of apoptotic bodies and the expression of immunosuppressant markers by human monocytes. Our results suggest that VIP-mediated autocrine pathways regulate trophoblast cell function and contribute to immune homeostasis maintenance at placentation and may provide new clues for therapeutic intervention in pregnancies complicated by defective deep placentation. PMID:27212399

  19. Role of further-neighbor interactions in modulating the critical behavior of the Ising model with frustration.

    PubMed

    Liu, R M; Zhuo, W Z; Dong, S; Lu, X B; Gao, X S; Qin, M H; Liu, J-M

    2016-03-01

    In this work, we investigate the phase transitions and critical behaviors of the frustrated J(1)-J(2)-J(3) Ising model on the square lattice using Monte Carlo simulations, and particular attention goes to the effect of the second-next-nearest-neighbor interaction J(3) on the phase transition from a disordered state to the single stripe antiferromagnetic state. A continuous Ashkin-Teller-like transition behavior in a certain range of J(3) is identified, while the four-state Potts-critical end point [J(3)/J(1)](C) is estimated based on the analytic method reported in earlier work [Jin, Sen, and Sandvik, Phys. Rev. Lett. 108, 045702 (2012)]. It is suggested that the interaction J(3) can tune the transition temperature and in turn modulate the critical behaviors of the frustrated model. Furthermore, it is revealed that an antiferromagnetic J(3) can stabilize the staggered dimer state via a phase transition of strong first-order character. PMID:27078299

  20. Using Surface Enhanced Raman Scattering to Analyze the Interactions of Protein Receptors with Bacterial Quorum Sensing Modulators

    PubMed Central

    2015-01-01

    Many members of the LuxR family of quorum sensing (QS) transcriptional activators, including LasR of Pseudomonas aeruginosa, are believed to require appropriate acyl-homoserine lactone (acyl-HSL) ligands to fold into an active conformation. The failure to purify ligand-free LuxR homologues in nonaggregated form at the high concentrations required for their structural characterization has limited the understanding of the mechanisms by which QS receptors are activated. Surface-enhanced Raman scattering (SERS) is a vibrational spectroscopy technique that can be applied to study proteins at extremely low concentrations in their active state. The high sensitivity of SERS has allowed us to detect molecular interactions between the ligand-binding domain of LasR (LasRLBD) as a soluble apoprotein and modulators of P. aeruginosa QS. We found that QS activators and inhibitors produce differential SERS fingerprints in LasRLBD, and in combination with molecular docking analysis provide insight into the relevant interaction mechanism. This study reveals signal-specific structural changes in LasR upon ligand binding, thereby confirming the applicability of SERS to analyze ligand-induced conformational changes in proteins. PMID:25927541

  1. ICE1 of Poncirus trifoliata functions in cold tolerance by modulating polyamine levels through interacting with arginine decarboxylase

    PubMed Central

    Huang, Xiao-San; Zhang, Qinghua; Zhu, Dexin; Fu, Xingzheng; Wang, Min; Zhang, Qian; Moriguchi, Takaya; Liu, Ji-Hong

    2015-01-01

    ICE1 (Inducer of CBF Expression 1) encodes a MYC-like basic helix–loop–helix transcription factor that acts as a central regulator of cold response. In this study, we elucidated the function and underlying mechanisms of PtrICE1 from trifoliate orange [Poncirus trifoliata (L.) Raf.]. PtrICE1 was upregulated by cold, dehydration, and salt, with the greatest induction under cold conditions. PtrICE1 was localized in the nucleus and could bind to a MYC-recognizing sequence. Ectopic expression of PtrICE1 in tobacco and lemon conferred enhanced tolerance to cold stresses at either chilling or freezing temperatures. Yeast two-hybrid screening revealed that 21 proteins belonged to the PtrICE1 interactome, in which PtADC (arginine decarboxylase) was confirmed as a bona fide protein interacting with PtrICE1. Transcript levels of ADC genes in the transgenic lines were slightly elevated under normal growth condition but substantially increased under cold conditions, consistent with changes in free polyamine levels. By contrast, accumulation of the reactive oxygen species, H2O2 and O2 –, was appreciably alleviated in the transgenic lines under cold stress. Higher activities of antioxidant enzymes, such as superoxide dismutase and catalase, were detected in the transgenic lines under cold conditions. Taken together, these results demonstrated that PtrICE1 plays a positive role in cold tolerance, which may be due to modulation of polyamine levels through interacting with the ADC gene. PMID:25873670

  2. ICE1 of Poncirus trifoliata functions in cold tolerance by modulating polyamine levels through interacting with arginine decarboxylase.

    PubMed

    Huang, Xiao-San; Zhang, Qinghua; Zhu, Dexin; Fu, Xingzheng; Wang, Min; Zhang, Qian; Moriguchi, Takaya; Liu, Ji-Hong

    2015-06-01

    ICE1 (Inducer of CBF Expression 1) encodes a MYC-like basic helix-loop-helix transcription factor that acts as a central regulator of cold response. In this study, we elucidated the function and underlying mechanisms of PtrICE1 from trifoliate orange [Poncirus trifoliata (L.) Raf.]. PtrICE1 was upregulated by cold, dehydration, and salt, with the greatest induction under cold conditions. PtrICE1 was localized in the nucleus and could bind to a MYC-recognizing sequence. Ectopic expression of PtrICE1 in tobacco and lemon conferred enhanced tolerance to cold stresses at either chilling or freezing temperatures. Yeast two-hybrid screening revealed that 21 proteins belonged to the PtrICE1 interactome, in which PtADC (arginine decarboxylase) was confirmed as a bona fide protein interacting with PtrICE1. Transcript levels of ADC genes in the transgenic lines were slightly elevated under normal growth condition but substantially increased under cold conditions, consistent with changes in free polyamine levels. By contrast, accumulation of the reactive oxygen species, H2O2 and O2 (-), was appreciably alleviated in the transgenic lines under cold stress. Higher activities of antioxidant enzymes, such as superoxide dismutase and catalase, were detected in the transgenic lines under cold conditions. Taken together, these results demonstrated that PtrICE1 plays a positive role in cold tolerance, which may be due to modulation of polyamine levels through interacting with the ADC gene. PMID:25873670

  3. Variants in the inflammatory IL6 and MPO genes modulate stroke susceptibility through main effects and gene–gene interactions

    PubMed Central

    Manso, Helena; Krug, Tiago; Sobral, João; Albergaria, Isabel; Gaspar, Gisela; Ferro, José M; Oliveira, Sofia A; Vicente, Astrid M

    2011-01-01

    There is substantial evidence that inflammation within the central nervous system contributes to stroke risk and recovery. Inflammatory conditions increase stroke risk, and the inflammatory response is of major importance in recovery and healing processes after stroke. We investigated the role of inflammatory genes IL1B, IL6, MPO, and TNF in stroke susceptibility and recovery in a population sample of 672 patients and 530 controls, adjusting for demographic, clinical and lifestyle risk factors, and stroke severity parameters. We also considered the likely complexity of inflammatory mechanisms in stroke, by assessing the combined effects of multiple genes. Two interleukin 6 (IL6) and one myeloperoxidase (MPO) single-nucleotide polymorphisms were significantly associated with stroke risk (0.022interaction between the IL6 and MPO genes was also identified in association with stroke susceptibility (P=0.031 after 1,000 permutations). In a subset of 546 patients, one IL6 haplotype was associated with stroke outcome at 3 months (correctedP=0.024), an intriguing finding warranting further validation. Our findings support the association of the IL6 gene and present novel evidence for the involvement of MPO in stroke susceptibility, suggesting a modulation of stroke risk by main gene effects, clinical and lifestyle factors, and gene–gene interactions. PMID:21407237

  4. Interaction of gelatin with polyenes modulates antifungal activity and biocompatibility of electrospun fiber mats

    PubMed Central

    Lakshminarayanan, Rajamani; Sridhar, Radhakrishnan; Loh, Xian Jun; Nandhakumar, Muruganantham; Barathi, Veluchamy Amutha; Kalaipriya, Madhaiyan; Kwan, Jia Lin; Liu, Shou Ping; Beuerman, Roger Wilmer; Ramakrishna, Seeram

    2014-01-01

    Topical application of antifungals does not have predictable or well-controlled release characteristics and requires reapplication to achieve therapeutic local concentration in a reasonable time period. In this article, the efficacy of five different US Food and Drug Administration-approved antifungal-loaded (amphotericin B, natamycin, terbinafine, fluconazole, and itraconazole) electrospun gelatin fiber mats were compared. Morphological studies show that incorporation of polyenes resulted in a two-fold increase in fiber diameter and the mats inhibit the growth of yeasts and filamentous fungal pathogens. Terbinafine-loaded mats were effective against three filamentous fungal species. Among the two azole antifungals compared, the itraconazole-loaded mat was potent against Aspergillus strains. However, activity loss was observed for fluconazole-loaded mats against all of the test organisms. The polyene-loaded mats displayed rapid candidacidal activities as well. Biophysical and rheological measurements indicate strong interactions between polyene antifungals and gelatin matrix. As a result, the polyenes stabilized the triple helical conformation of gelatin and the presence of gelatin decreased the hemolytic activity of polyenes. The polyene-loaded fiber mats were noncytotoxic to primary human corneal and sclera fibroblasts. The reduction of toxicity with complete retention of activity of the polyene antifungal-loaded gelatin fiber mats can provide new opportunities in the management of superficial skin infections. PMID:24920895

  5. p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein-Protein Interactions.

    PubMed

    Bulfer, Stacie L; Chou, Tsui-Fen; Arkin, Michelle R

    2016-08-19

    The AAA+ ATPase p97/VCP adopts at least three conformations that depend on the binding of ADP and ATP and alter the orientation of the N-terminal protein-protein interaction (PPI) domain into "up" and "down" conformations. Point mutations that cause multisystem proteinopathy 1 (MSP1) are found at the interface of the N domain and D1-ATPase domain and potentially alter the conformational preferences of p97. Additionally, binding of "adaptor" proteins to the N-domain regulates p97's catalytic activity. We propose that p97/adaptor PPIs are coupled to p97 conformational states. We evaluated the binding of nucleotides and the adaptor proteins p37 and p47 to wild-type p97 and MSP1 mutants. Notably, p47 and p37 bind 8-fold more weakly to the ADP-bound conformation of wild-type p97 compared to the ATP-bound conformation. However, MSP1 mutants lose this nucleotide-induced conformational coupling because they destabilize the ADP-bound, "down" conformation of the N-domain. Loss in conformation coupling to PPIs could contribute to the mechanism of MSP1. PMID:27267671

  6. Chemokine interaction with synergy-inducing molecules: fine tuning modulation of cell trafficking

    PubMed Central

    Cecchinato, Valentina; D’Agostino, Gianluca; Raeli, Lorenzo; Uguccioni, Mariagrazia

    2016-01-01

    Directed migration and arrest of leukocytes during homeostasis, inflammation, and tumor development is mediated by the chemokine system, which governs leukocyte migration and activities. Although we understand well the effects of different chemokines one by one, much less was known about the potential consequences of the concomitant expression of multiple chemokines or of their interaction with inflammatory molecules on leukocyte migration and functions. In the past 10 yr, several studies revealed the existence of additional features of chemokines: they can antagonize chemokine receptors or synergize with other chemokines, also by forming heterocomplexes. Moreover, recent data show that not only chemokines but also the alarmin high-mobility group box 1 can for a complex with CXCL12, enhancing its potency on CXCR4. The molecular mechanism underlying the effect of the heterocomplex has been partially elucidated, whereas its structure is a matter of current investigations. The present review discusses the current knowledge and relevance of the functions of heterocomplexes formed between chemokines or between the chemokine CXCL12 and the alarmin high-mobility group box 1. These studies highlight the importance of taking into account, when approaching innovative therapies targeting the chemokine system, also the fact that some chemokines and molecules released in inflammation, can considerably affect the activity of chemokine receptor agonists. PMID:26715684

  7. Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

    PubMed Central

    Kim, Jonghoon; Jung, Jinjoo; Koo, Jaeyoung; Cho, Wansang; Lee, Won Seok; Kim, Chanwoo; Park, Wonwoo; Park, Seung Bum

    2016-01-01

    Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase–RagD protein–protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure-based DOS strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets. PMID:27774980

  8. Developmental and genetic modulation of arsenic biotransformation: A gene by environment interaction?

    SciTech Connect

    Meza, Mercedes; Gandolfi, A. Jay; Klimecki, Walter T.

    2007-08-01

    The complexity of arsenic toxicology has confounded the identification of specific pathways of disease causation. One focal point of arsenic research is aimed at fully characterizing arsenic biotransformation in humans, a process that appears to be quite variable, producing a mixture of several arsenic species with greatly differing toxic potencies. In an effort to characterize genetic determinants of variability in arsenic biotransformation, a genetic association study of 135 subjects in western Sonora, Mexico was performed by testing 23 polymorphic sites in three arsenic biotransformation candidate genes. One gene, arsenic 3 methyltransferase (AS3MT), was strongly associated with the ratio of urinary dimethylarsinic acid to monomethylarsonic acid (D/M) in children (7-11 years) but not in adults (18-79 years). Subsequent analyses revealed that the high D/M values associated with variant AS3MT alleles were primarily due to lower levels of monomethylarsonic acid as percent of total urinary arsenic (%MMA5). In light of several reports of arsenic-induced disease being associated with relatively high %MMA5 levels, these findings raise the possibility that variant AS3MT individuals may suffer less risk from arsenic exposure than non-variant individuals. These analyses also provide evidence that, in this population, regardless of AS3MT variant status, children tend to have lower %MMA5 values than adults, suggesting that the global developmental regulation of arsenic biotransformation may interact with genetic variants in metabolic genes to result in novel genetic effects such as those in this report.

  9. Impact of oceanic-scale interactions on the seasonal modulation of ocean dynamics by the atmosphere

    PubMed Central

    Sasaki, Hideharu; Klein, Patrice; Qiu, Bo; Sasai, Yoshikazu

    2014-01-01

    Ocean eddies (with a size of 100–300 km), ubiquitous in satellite observations, are known to represent about 80% of the total ocean kinetic energy. Recent studies have pointed out the unexpected role of smaller oceanic structures (with 1–50 km scales) in generating and sustaining these eddies. The interpretation proposed so far invokes the internal instability resulting from the large-scale interaction between upper and interior oceanic layers. Here we show, using a new high-resolution simulation of the realistic North Pacific Ocean, that ocean eddies are instead sustained by a different process that involves small-scale mixed-layer instabilities set up by large-scale atmospheric forcing in winter. This leads to a seasonal evolution of the eddy kinetic energy in a very large part of this ocean, with an amplitude varying by a factor almost equal to 2. Perspectives in terms of the impacts on climate dynamics and future satellite observational systems are briefly discussed. PMID:25501039

  10. Galactic Cosmic-Ray Intensity Modulation by Corotating Interaction Region Stream Interfaces at 1 au

    NASA Astrophysics Data System (ADS)

    Guo, X.; Florinski, V.

    2016-07-01

    We present a new model that couples galactic cosmic-ray (GCR) propagation with magnetic turbulence transport and the MHD background evolution in the heliosphere. The model is applied to the problem of the formation of corotating interaction regions (CIRs) during the last solar minimum from the period between 2007 and 2009. The numerical model simultaneously calculates the large-scale supersonic solar wind properties and its small-scale turbulent content from 0.3 au to the termination shock. Cosmic rays are then transported through the background, and thus computed, with diffusion coefficients derived from the solar wind turbulent properties, using a stochastic Parker approach. Our results demonstrate that GCR variations depend on the ratio of diffusion coefficients in the fast and slow solar winds. Stream interfaces inside the CIRs always lead to depressions of the GCR intensity. On the other hand, heliospheric current sheet (HCS) crossings do not appreciably affect GCR intensities in the model, which is consistent with the two observations under quiet solar wind conditions. Therefore, variations in diffusion coefficients associated with CIR stream interfaces are more important for GCR propagation than the drift effects of the HCS during a negative solar minimum.

  11. Impact of oceanic-scale interactions on the seasonal modulation of ocean dynamics by the atmosphere.

    PubMed

    Sasaki, Hideharu; Klein, Patrice; Qiu, Bo; Sasai, Yoshikazu

    2014-12-15

    Ocean eddies (with a size of 100-300 km), ubiquitous in satellite observations, are known to represent about 80% of the total ocean kinetic energy. Recent studies have pointed out the unexpected role of smaller oceanic structures (with 1-50 km scales) in generating and sustaining these eddies. The interpretation proposed so far invokes the internal instability resulting from the large-scale interaction between upper and interior oceanic layers. Here we show, using a new high-resolution simulation of the realistic North Pacific Ocean, that ocean eddies are instead sustained by a different process that involves small-scale mixed-layer instabilities set up by large-scale atmospheric forcing in winter. This leads to a seasonal evolution of the eddy kinetic energy in a very large part of this ocean, with an amplitude varying by a factor almost equal to 2. Perspectives in terms of the impacts on climate dynamics and future satellite observational systems are briefly discussed.

  12. Interactions between Thaumarchaea, Nitrospira and methanotrophs modulate autotrophic nitrification in volcanic grassland soil

    PubMed Central

    Daebeler, Anne; Bodelier, Paul LE; Yan, Zheng; Hefting, Mariet M; Jia, Zhongjun; Laanbroek, Hendrikus J

    2014-01-01

    Ammonium/ammonia is the sole energy substrate of ammonia oxidizers, and is also an essential nitrogen source for other microorganisms. Ammonia oxidizers therefore must compete with other soil microorganisms such as methane-oxidizing bacteria (MOB) in terrestrial ecosystems when ammonium concentrations are limiting. Here we report on the interactions between nitrifying communities dominated by ammonia-oxidizing archaea (AOA) and Nitrospira-like nitrite-oxidizing bacteria (NOB), and communities of MOB in controlled microcosm experiments with two levels of ammonium and methane availability. We observed strong stimulatory effects of elevated ammonium concentration on the processes of nitrification and methane oxidation as well as on the abundances of autotrophically growing nitrifiers. However, the key players in nitrification and methane oxidation, identified by stable-isotope labeling using 13CO2 and 13CH4, were the same under both ammonium levels, namely type 1.1a AOA, sublineage I and II Nitrospira-like NOB and Methylomicrobium-/Methylosarcina-like MOB, respectively. Ammonia-oxidizing bacteria were nearly absent, and ammonia oxidation could almost exclusively be attributed to AOA. Interestingly, although AOA functional gene abundance increased 10-fold during incubation, there was very limited evidence of autotrophic growth, suggesting a partly mixotrophic lifestyle. Furthermore, autotrophic growth of AOA and NOB was inhibited by active MOB at both ammonium levels. Our results suggest the existence of a previously overlooked competition for nitrogen between nitrifiers and methane oxidizers in soil, thus linking two of the most important biogeochemical cycles in nature. PMID:24858784

  13. Otx2 induction of the gonadotropin-releasing hormone promoter is modulated by direct interactions with Grg co-repressors.

    PubMed

    Larder, Rachel; Mellon, Pamela L

    2009-06-19

    Hormonal communication between the hypothalamus, pituitary, and gonads orchestrates the development and regulation of mammalian reproductive function. In mice, gonadotropin-releasing hormone (GnRH) expression is limited to approximately 1000 neurons that originate in the olfactory placode then migrate to specific positions scattered throughout the hypothalamus. Coordination of the hypothalamic-pituitary-gonadal axis is dependent upon correct migration of GnRH neurons into the hypothalamus followed by the appropriate synthesis and pulsatile secretion of GnRH. Defects in any one of these processes can cause infertility. Recently, substantial progress has been made in identifying transcription factors, and their cofactors, that regulate not only adult expression of GnRH, but also the maturation of GnRH neurons. Here, we show that expression of Otx2, a homeodomain protein required for the formation of the forebrain, is dramatically up-regulated during GnRH neuronal maturation and that overexpression of Otx2 increases GnRH promoter activity in GnRH neuronal cell lines. Furthermore, Otx2 transcriptional activity is modulated by Grg4, a member of the Groucho-related-gene (Grg) family. Using mutational analysis, we show that a WRPW peptide motif within the Otx2 protein is required for physical interaction between Otx2 and Grg4. Without this physical interaction, Grg4 cannot repress Otx2-dependent activation of GnRH gene transcription. Taken together, these data show that Otx2 is important for GnRH expression and that direct interaction between Otx2 and Grg co-repressors regulates GnRH gene expression in hypothalamic neurons.

  14. Differential modulation of transcriptional activity of oestrogen receptors by direct protein-protein interactions with retinoid receptors.

    PubMed Central

    Song, M R; Lee, S K; Seo, Y W; Choi, H S; Lee, J W; Lee, M O

    1998-01-01

    Control of oestradiol-responsive gene regulation by oestrogen receptors (ERs) may involve complex cross-talk with retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Recently, we have shown that ERalpha directly interacts with RARalpha and RXRalpha through their ligand binding domains (LBDs). In the present work, we extend these results by showing that ERbeta binds similarly to RARalpha and RXRalpha but not to the glucocorticoid receptor, as demonstrated by the yeast two-hybrid tests and glutathione S-transferase pull-down assays. These direct interactions were also demonstrated in gel-shift assays, in which the oestrogen response element (ERE) binding by ERalpha was enhanced by the RXRalpha LBD but was abolished by the RARalpha LBD. In addition, we showed that RARalpha and RXRalpha bound the ERE as efficiently as ERalpha, suggesting that competition for DNA binding may affect the transactivation function of the ER. In transient transfection experiments, co-expression of RARalpha or RXRalpha, along with ERalpha or ERbeta, revealed differential modulation of the ERE-dependent transactivation, which was distinct from the results when each receptor alone was co-transfected. Importantly, when the LBD of RARalpha was co-expressed with ERalpha, transactivation of ERalpha on the ERE was repressed as efficiently as when wild-type RARalpha was co-expressed. Furthermore, liganded RARalpha or unliganded RXRalpha enhanced the ERalpha transactivation, suggesting the formation of transcriptionally active heterodimer complexes between the ER and retinoid receptors. Taken together, these results suggest that direct protein-protein interactions may play major roles in the determination of the biological consequences of cross-talk between ERs and RARalpha or RXRalpha. PMID:9841885

  15. Interactive properties of human glioblastoma cells with brain neurons in culture and neuronal modulation of glial laminin organization.

    PubMed

    Faria, Jane; Romão, Luciana; Martins, Sheila; Alves, Tércia; Mendes, Fabio A; de Faria, Giselle Pinto; Hollanda, Rosenilde; Takiya, Christina; Chimelli, Leila; Morandi, Veronica; de Souza, Jorge Marcondes; Abreu, Jose Garcia; Moura Neto, Vivaldo

    2006-12-01

    The harmonious development of the central nervous system depends on the interactions of the neuronal and glial cells. Extracellular matrix elements play important roles in these interactions, especially laminin produced by astrocytes, which has been shown to be a good substrate for neuron growth and axonal guidance. Glioblastomas are the most common subtypes of primary brain tumors and may be astrocytes in origin. As normal laminin-producing glial cells are the preferential substrate for neurons, and glial tumors have been shown to produce laminin, we questioned whether glioblastoma retained the same normal glial-neuron interactive properties with respect to neuronal growth and differentiation. Then, rat neurons were co-cultured onto rat normal astrocytes or onto three human glioblastoma cell lines obtained from neurosurgery. The co-culture confirmed that human glioblastoma cells as well as astrocytes maintained the ability to support neuritogenesis, but non-neural normal or tumoral cells failed to do so. However, glioblastoma cells did not distinguish embryonic from post-natal neurons in relation to neurite pattern in the co-cultures, as normal astrocytes did. Further, the laminin organization on both normal and tumoral glial cells was altered from a filamentous arrangement to a mixed punctuate/filamentous pattern when in co-culture with neurons. Together, these results suggest that glioblastoma cells could identify neuronal cells as partners, to support their growth and induce complex neurites, but they lost the normal glia property to distinguish neuronal age. In addition, our results show for the first time that neurons modulate the organization of astrocytes and glioblastoma laminin on the extracellular matrix.

  16. The interaction of eugenol with cell membrane models at the air-water interface is modulated by the lipid monolayer composition.

    PubMed

    Gonçalves, Giulia E G; de Souza, Fernanda S; Lago, João Henrique G; Caseli, Luciano

    2015-12-01

    Eugenol, a natural phenylpropanoid derivative with possible action in biological surfaces as microbicide, anesthetic and antioxidant, was incorporated in lipid monolayers of selected lipids at the air-water interface, representing cell membrane models. Interaction of eugenol with the lipids dipalmitoylphosphatidylcholine (DPPC), dioctadecyldimethylammonium bromide (DODAB), and dipalmitoylphosphatidylserine (DPPS) could be inferred by means of surface pressure-area isotherms and Polarization-Modulation Reflection-Absorption Spectroscopy. The interaction showed different effects on the different lipids. A higher monolayer expansion was observed for DPPS and DODAB, while more significant effects on the polar groups of the lipids were observed for DPPS and DPPC. These results pointed to the fact that the interaction of eugenol with lipid monolayers at the air-water interface is modulated by the lipid composition, which may be important to comprehend at the molecular level the interaction of this drug with biological surfaces.

  17. Beyond aggression: Androgen-receptor blockade modulates social interaction in wild meerkats.

    PubMed

    delBarco-Trillo, Javier; Greene, Lydia K; Goncalves, Ines Braga; Fenkes, Miriam; Wisse, Jillian H; Drewe, Julian A; Manser, Marta B; Clutton-Brock, Tim; Drea, Christine M

    2016-02-01

    In male vertebrates, androgens are inextricably linked to reproduction, social dominance, and aggression, often at the cost of paternal investment or prosociality. Testosterone is invoked to explain rank-related reproductive differences, but its role within a status class, particularly among subordinates, is underappreciated. Recent evidence, especially for monogamous and cooperatively breeding species, suggests broader androgenic mediation of adult social interaction. We explored the actions of androgens in subordinate, male members of a cooperatively breeding species, the meerkat (Suricata suricatta). Although male meerkats show no rank-related testosterone differences, subordinate helpers rarely reproduce. We blocked androgen receptors, in the field, by treating subordinate males with the antiandrogen, flutamide. We monitored androgen concentrations (via baseline serum and time-sequential fecal sampling) and recorded behavior within their groups (via focal observation). Relative to controls, flutamide-treated animals initiated less and received more high-intensity aggression (biting, threatening, feeding competition), engaged in more prosocial behavior (social sniffing, grooming, huddling), and less frequently initiated play or assumed a 'dominant' role during play, revealing significant androgenic effects across a broad range of social behavior. By contrast, guarding or vigilance and measures of olfactory and vocal communication in subordinate males appeared unaffected by flutamide treatment. Thus, androgens in male meerkat helpers are aligned with the traditional trade-off between promoting reproductive and aggressive behavior at a cost to affiliation. Our findings, based on rare endocrine manipulation in wild mammals, show a more pervasive role for androgens in adult social behavior than is often recognized, with possible relevance for understanding tradeoffs in cooperative systems.

  18. Antagonistic interactions between dexamethasone and fluoxetine modulate morphodynamics and expression of cytokines in astrocytes.

    PubMed

    Henkel, A W; Alali, H; Devassy, A; Alawadi, M M; Redzic, Z B

    2014-11-01

    The "plasticity hypothesis" proposes that major depression is caused by morphological and biochemical modifications in neurons and astrocytes and those beneficial pharmacological effects of selective-serotonin-reuptake-inhibitors (SSRI) are at least partially associated with modifications of cellular communications between these cells. In this study we examined effects of the antidepressant fluoxetine on cultured astrocytes that were, in some cases, pretreated with dexamethasone, a cortisol analog known to trigger depressive disorder. Primary rat astrocytes were purified and treated with dexamethasone and the SSRI fluoxetine in physiological concentrations so that both drugs did not affect cell viability. Expression of interleukin-2 (IL-2) and glia-derived-neurotrophic-factor (GDNF) were analyzed and monitored and cell viability, apoptosis, cluster formation, particle-removing capacity and cell mobility were also monitored. Pre-studies without any drugs on mixed neuron-astrocyte co-cultures suggested that astrocytes interacted with neurons and other brain cells in vitro by actively assembling them into clusters. Treatment of purified astrocytes with dexamethasone significantly decreased their mobility compared to controls but had no effect on cluster formation. Dexamethasone-treated cells removed fewer extracellular particles derived from dead cells and cell debris. Both effects were abolished by simultaneous application of fluoxetine. Intracellular IL-2 increased, while GDNF amount expression was diminished following dexamethasone treatment. Simultaneous administration of fluoxetine reversed dexamethasone-triggered IL-2 elevation but had no effect on decreased GDNF concentration. These results suggest that mobility and growth factor equilibrium of astrocytes are affected by dexamethasone and by fluoxetine and that fluoxetine could reverse some changes induced by dexamethasone. PMID:25242644

  19. Utilizing cell-matrix interactions to modulate gene transfer to stem cells inside hyaluronic acid hydrogels.

    PubMed

    Gojgini, Shiva; Tokatlian, Talar; Segura, Tatiana

    2011-10-01

    The effective delivery of DNA locally would increase the applicability of gene therapy in tissue regeneration, where diseased tissue is to be repaired in situ. One promising approach is to use hydrogel scaffolds to encapsulate and deliver plasmid DNA in the form of nanoparticles to the diseased tissue, so that cells infiltrating the scaffold are transfected to induce regeneration. This study focuses on the design of a DNA nanoparticle-loaded hydrogel scaffold. In particular, this study focuses on understanding how cell-matrix interactions affect gene transfer to adult stem cells cultured inside matrix metalloproteinase (MMP) degradable hyaluronic acid (HA) hydrogel scaffolds. HA was cross-linked to form a hydrogel material using a MMP degradable peptide and Michael addition chemistry. Gene transfer inside these hydrogel materials was assessed as a function of polyplex nitrogen to phosphate ratio (N/P = 5 to 12), matrix stiffness (100-1700 Pa), RGD (Arg-Gly-Asp) concentration (10-400 μM), and RGD presentation (0.2-4.7 RGDs per HA molecule). All variables were found to affect gene transfer to mouse mensenchymal stem cells culture inside the DNA loaded hydrogels. As expected, higher N/P ratios lead to higher gene transfer efficiency but also higher toxicity; softer hydrogels resulted in higher transgene expression than stiffer hydrogels, and an intermediate RGD concentration and RGD clustering resulted in higher transgene expression. We believe that the knowledge gained through this in vitro model can be utilized to design better scaffold-mediated gene delivery for local gene therapy.

  20. Beyond aggression: Androgen-receptor blockade modulates social interaction in wild meerkats.

    PubMed

    delBarco-Trillo, Javier; Greene, Lydia K; Goncalves, Ines Braga; Fenkes, Miriam; Wisse, Jillian H; Drewe, Julian A; Manser, Marta B; Clutton-Brock, Tim; Drea, Christine M

    2016-02-01

    In male vertebrates, androgens are inextricably linked to reproduction, social dominance, and aggression, often at the cost of paternal investment or prosociality. Testosterone is invoked to explain rank-related reproductive differences, but its role within a status class, particularly among subordinates, is underappreciated. Recent evidence, especially for monogamous and cooperatively breeding species, suggests broader androgenic mediation of adult social interaction. We explored the actions of androgens in subordinate, male members of a cooperatively breeding species, the meerkat (Suricata suricatta). Although male meerkats show no rank-related testosterone differences, subordinate helpers rarely reproduce. We blocked androgen receptors, in the field, by treating subordinate males with the antiandrogen, flutamide. We monitored androgen concentrations (via baseline serum and time-sequential fecal sampling) and recorded behavior within their groups (via focal observation). Relative to controls, flutamide-treated animals initiated less and received more high-intensity aggression (biting, threatening, feeding competition), engaged in more prosocial behavior (social sniffing, grooming, huddling), and less frequently initiated play or assumed a 'dominant' role during play, revealing significant androgenic effects across a broad range of social behavior. By contrast, guarding or vigilance and measures of olfactory and vocal communication in subordinate males appeared unaffected by flutamide treatment. Thus, androgens in male meerkat helpers are aligned with the traditional trade-off between promoting reproductive and aggressive behavior at a cost to affiliation. Our findings, based on rare endocrine manipulation in wild mammals, show a more pervasive role for androgens in adult social behavior than is often recognized, with possible relevance for understanding tradeoffs in cooperative systems. PMID:26545817

  1. Interaction between protein kinase C and protein kinase A can modulate transmitter release at the rat neuromuscular synapse.

    PubMed

    Santafé, M M; Garcia, N; Lanuza, M A; Tomàs, M; Tomàs, J

    2009-02-15

    We used intracellular recording to investigate the functional interaction between protein kinase C (PKC) and protein kinase A (PKA) signal transduction cascades in the control of transmitter release in the neuromuscular synapses from adult rats. Our results indicate that: 1) PKA and PKC are independently involved in asynchronous release. 2) Evoked acetylcholine (ACh) release is enhanced with the PKA agonist Sp-8-BrcAMP and the PKC agonist phorbol ester (PMA). 3) PKA has a constitutive role in promoting a component of normal evoked transmitter release because, when the kinase is inhibited with H-89, the release diminishes. However, the PKC inhibitor calphostin C (CaC) does not affect ACh release. 4) PKA regulates neurotransmission without PKC involvement because, after PMA or CaC modulation of the PKC activity, coupling to the ACh release of PKA can normally be stimulated with Sp-8-BrcAMP or inhibited with H-89. 5) After PKA inhibition with H-89, PKC stimulation with PMA (or inhibition with CaC) does not lead to any change in evoked ACh release. However, in PKA-stimulated preparations with Sp-8-BrcAMP, PKC becomes tonically active, thus potentiating a component of release that can now be blocked with CaC. In normal conditions, therefore, PKA was able to modulate ACh release independently of PKC activity, whereas PKA stimulation caused the PKC coupling to evoked release. In contrast, PKA inhibition prevent PKC stimulation (with the phorbol ester) and coupling to ACh output. There was therefore some dependence of PKC on PKA activity in the fine control of the neuromuscular synaptic functionalism and ACh release.

  2. Electrostatic Interactions Involving the Extreme C Terminus of Nuclear Export Factor CRM1 Modulate Its Affinity for Cargo*

    PubMed Central

    Fox, Abigail M.; Ciziene, Danguole; McLaughlin, Stephen H.; Stewart, Murray

    2011-01-01

    The toroid-shaped nuclear protein export factor CRM1 is constructed from 21 tandem HEAT repeats, each of which contains an inner (B) and outer (A) α-helix joined by loops. Proteins targeted for export have a nuclear export signal (NES) that binds between the A-helices of HEAT repeats 11 and 12 on the outer surface of CRM1. RanGTP binding increases the affinity of CRM1 for NESs. In the absence of RanGTP, the CRM1 C-terminal helix, together with the HEAT repeat 9 loop, modulates its affinity for NESs. Here we show that there is an electrostatic interaction between acidic residues at the extreme distal tip of the C-terminal helix and basic residues on the HEAT repeat 12 B-helix that lies on the inner surface of CRM1 beneath the NES binding site. Small angle x-ray scattering indicates that the increased affinity for NESs generated by mutations in the C-terminal helix is not associated with large scale changes in CRM1 conformation, consistent with the modulation of NES affinity being mediated by a local change in CRM1 near the NES binding site. These data also suggest that in the absence of RanGTP, the C-terminal helix lies across the CRM1 toroid in a position similar to that seen in the CRM1-Snurportin crystal structure. By creating local changes that stabilize the NES binding site in its closed conformation and thereby reducing the affinity of CRM1 for NESs, the C-terminal helix and HEAT 9 loop facilitate release of NES-containing cargo in the cytoplasm and also inhibit their return to the nucleus. PMID:21708948

  3. Cannabinoid Receptor–Interacting Protein 1a Modulates CB1 Receptor Signaling and Regulation

    PubMed Central

    Smith, Tricia H.; Blume, Lawrence C.; Straiker, Alex; Cox, Jordan O.; David, Bethany G.; McVoy, Julie R. Secor; Sayers, Katherine W.; Poklis, Justin L.; Abdullah, Rehab A.; Egertová, Michaela; Chen, Ching-Kang; Mackie, Ken; Elphick, Maurice R.; Howlett, Allyn C.

    2015-01-01

    Cannabinoid CB1 receptors (CB1Rs) mediate the presynaptic effects of endocannabinoids in the central nervous system (CNS) and most behavioral effects of exogenous cannabinoids. Cannabinoid receptor–interacting protein 1a (CRIP1a) binds to the CB1R C-terminus and can attenuate constitutive CB1R-mediated inhibition of Ca2+ channel activity. We now demonstrate cellular colocalization of CRIP1a at neuronal elements in the CNS and show that CRIP1a inhibits both constitutive and agonist-stimulated CB1R-mediated guanine nucleotide–binding regulatory protein (G-protein) activity. Stable overexpression of CRIP1a in human embryonic kidney (HEK)-293 cells stably expressing CB1Rs (CB1-HEK), or in N18TG2 cells endogenously expressing CB1Rs, decreased CB1R-mediated G-protein activation (measured by agonist-stimulated [35S]GTPγS (guanylyl-5′-[O-thio]-triphosphate) binding) in both cell lines and attenuated inverse agonism by rimonabant in CB1-HEK cells. Conversely, small-interfering RNA–mediated knockdown of CRIP1a in N18TG2 cells enhanced CB1R-mediated G-protein activation. These effects were not attributable to differences in CB1R expression or endocannabinoid tone because CB1R levels did not differ between cell lines varying in CRIP1a expression, and endocannabinoid levels were undetectable (CB1-HEK) or unchanged (N18TG2) by CRIP1a overexpression. In CB1-HEK cells, 4-hour pretreatment with cannabinoid agonists downregulated CB1Rs and desensitized agonist-stimulated [35S]GTPγS binding. CRIP1a overexpression attenuated CB1R downregulation without altering CB1R desensitization. Finally, in cultured autaptic hippocampal neurons, CRIP1a overexpression attenuated both depolarization-induced suppression of excitation and inhibition of excitatory synaptic activity induced by exogenous application of cannabinoid but not by adenosine A1 agonists. These results confirm that CRIP1a inhibits constitutive CB1R activity and demonstrate that CRIP1a can also inhibit agonist

  4. Touch and gravitropic set-point angle interact to modulate gravitropic growth in roots.

    PubMed

    Massa, G D; Gilroy, S

    2003-01-01

    /tracking response as the curve of the surface changed. We propose that the interaction of touch and gravity sensing/response systems combine to strictly control the tropic growth of the root. Such signal integration is likely a critical part of growth control in the stimulus-rich environment of the soil.

  5. Touch and gravitropic set-point angle interact to modulate gravitropic growth in roots

    NASA Technical Reports Server (NTRS)

    Massa, G. D.; Gilroy, S.

    2003-01-01

    /tracking response as the curve of the surface changed. We propose that the interaction of touch and gravity sensing/response systems combine to strictly control the tropic growth of the root. Such signal integration is likely a critical part of growth control in the stimulus-rich environment of the soil. c2003 COSPAR. Published by Elsevier Ltd. All rights reserved.

  6. Cannabinoid receptor-interacting protein 1a modulates CB1 receptor signaling and regulation.

    PubMed

    Smith, Tricia H; Blume, Lawrence C; Straiker, Alex; Cox, Jordan O; David, Bethany G; McVoy, Julie R Secor; Sayers, Katherine W; Poklis, Justin L; Abdullah, Rehab A; Egertová, Michaela; Chen, Ching-Kang; Mackie, Ken; Elphick, Maurice R; Howlett, Allyn C; Selley, Dana E

    2015-04-01

    Cannabinoid CB1 receptors (CB1Rs) mediate the presynaptic effects of endocannabinoids in the central nervous system (CNS) and most behavioral effects of exogenous cannabinoids. Cannabinoid receptor-interacting protein 1a (CRIP1a) binds to the CB1R C-terminus and can attenuate constitutive CB1R-mediated inhibition of Ca(2+) channel activity. We now demonstrate cellular colocalization of CRIP1a at neuronal elements in the CNS and show that CRIP1a inhibits both constitutive and agonist-stimulated CB1R-mediated guanine nucleotide-binding regulatory protein (G-protein) activity. Stable overexpression of CRIP1a in human embryonic kidney (HEK)-293 cells stably expressing CB1Rs (CB1-HEK), or in N18TG2 cells endogenously expressing CB1Rs, decreased CB1R-mediated G-protein activation (measured by agonist-stimulated [(35)S]GTPγS (guanylyl-5'-[O-thio]-triphosphate) binding) in both cell lines and attenuated inverse agonism by rimonabant in CB1-HEK cells. Conversely, small-interfering RNA-mediated knockdown of CRIP1a in N18TG2 cells enhanced CB1R-mediated G-protein activation. These effects were not attributable to differences in CB1R expression or endocannabinoid tone because CB1R levels did not differ between cell lines varying in CRIP1a expression, and endocannabinoid levels were undetectable (CB1-HEK) or unchanged (N18TG2) by CRIP1a overexpression. In CB1-HEK cells, 4-hour pretreatment with cannabinoid agonists downregulated CB1Rs and desensitized agonist-stimulated [(35)S]GTPγS binding. CRIP1a overexpression attenuated CB1R downregulation without altering CB1R desensitization. Finally, in cultured autaptic hippocampal neurons, CRIP1a overexpression attenuated both depolarization-induced suppression of excitation and inhibition of excitatory synaptic activity induced by exogenous application of cannabinoid but not by adenosine A1 agonists. These results confirm that CRIP1a inhibits constitutive CB1R activity and demonstrate that CRIP1a can also inhibit agonist

  7. High and Low Computer Self-Efficacy Groups and Their Learning Behavior from Self-Regulated Learning Perspective While Engaged in Interactive Learning Modules

    ERIC Educational Resources Information Center

    Santoso, Harry B.; Lawanto, Oenardi; Becker, Kurt; Fang, Ning; Reeve, Edward M.

    2014-01-01

    The purpose of this research was to investigate high school students' computer self-efficacy (CSE) and learning behavior in a self-regulated learning (SRL) framework while utilizing an interactive learning module. The researcher hypothesizes that CSE is reflected on cognitive actions and metacognitive strategies while the students are engaged with…

  8. Different impressions of other agents obtained through social interaction uniquely modulate dorsal and ventral pathway activities in the social human brain.

    PubMed

    Takahashi, Hideyuki; Terada, Kazunori; Morita, Tomoyo; Suzuki, Shinsuke; Haji, Tomoki; Kozima, Hideki; Yoshikawa, Masahiro; Matsumoto, Yoshio; Omori, Takashi; Asada, Minoru; Naito, Eiichi

    2014-09-01

    Internal (neuronal) representations in the brain are modified by our experiences, and this phenomenon is not unique to sensory and motor systems. Here, we show that different impressions obtained through social interaction with a variety of agents uniquely modulate activity of dorsal and ventral pathways of the brain network that mediates human social behavior. We scanned brain activity with functional magnetic resonance imaging (fMRI) in 16 healthy volunteers when they performed a simple matching-pennies game with a human, human-like android, mechanical robot, interactive robot, and a computer. Before playing this game in the scanner, participants experienced social interactions with each opponent separately and scored their initial impressions using two questionnaires. We found that the participants perceived opponents in two mental dimensions: one represented "mind-holderness" in which participants attributed anthropomorphic impressions to some of the opponents that had mental functions, while the other dimension represented "mind-readerness" in which participants characterized opponents as intelligent. Interestingly, this "mind-readerness" dimension correlated to participants frequently changing their game tactic to prevent opponents from envisioning their strategy, and this was corroborated by increased entropy during the game. We also found that the two factors separately modulated activity in distinct social brain regions. Specifically, mind-holderness modulated activity in the dorsal aspect of the temporoparietal junction (TPJ) and medial prefrontal and posterior paracingulate cortices, while mind-readerness modulated activity in the ventral aspect of TPJ and the temporal pole. These results clearly demonstrate that activity in social brain networks is modulated through pre-scanning experiences of social interaction with a variety of agents. Furthermore, our findings elucidated the existence of two distinct functional networks in the social human brain

  9. Palmitoylation as a key factor to modulate SP-C-lipid interactions in lung surfactant membrane multilayers.

    PubMed

    Roldan, Nuria; Goormaghtigh, Erik; Pérez-Gil, Jesús; Garcia-Alvarez, Begoña

    2015-01-01

    Surfactant protein C (SP-C) has been regarded as the most specific protein linked to development of mammalian lungs, and great efforts have been done to understand its structure-function relationships. Previous evidence has outlined the importance of SP-C palmitoylation to sustain the proper dynamics of lung surfactant, but the mechanism by which this posttranslational modification aids SP-C to stabilize the interfacial surfactant film along the compression-expansion breathing cycles, is still unrevealed. In this work we have compared the structure, orientation and lipid-protein interactions of a native palmitoylated SP-C with those of a non-palmitoylated recombinant SP-C (rSP-C) form in air-exposed multilayer membrane environments, by means of ATR-FTIR spectroscopy. Palmitoylation does not affect the secondary structure of the protein, which exhibits a full α-helical conformation in partly dehydrated phospholipid multilayer films. However, differences between the Amide I band of the IR spectrum of palmitoylated and non-palmitoylated proteins suggest subtle differences affecting the environment of their helical component. These differences are accompanied by differential effects on the IR bands from phospholipid phosphates, indicating that palmitoylation modulates lipid-protein interactions at the headgroup region of phospholipid layers. On the other hand, the relative dichroic absorption of polarized IR has allowed calculating that the palmitoylated protein adopts a more tilted transmembrane orientation than the non-palmitoylated SP-C, likely contributing to more compact, dehydrated and possibly stable multilayer lipid-protein films. As a whole, the behavior of multilayer films containing palmitoylated SP-C may reflect favorable structural properties for surfactant reservoirs at the air-liquid respiratory interface.

  10. Competitive interactions between methane- and ammonia-oxidizing bacteria modulate carbon and nitrogen cycling in paddy soil

    NASA Astrophysics Data System (ADS)

    Zheng, Y.; Huang, R.; Wang, B. Z.; Bodelier, P. L. E.; Jia, Z. J.

    2014-06-01

    Pure culture studies have demonstrated that methanotrophs and ammonia oxidizers can both carry out the oxidation of methane and ammonia. However, the expected interactions resulting from these similarities are poorly understood, especially in complex, natural environments. Using DNA-based stable isotope probing and pyrosequencing of 16S rRNA and functional genes, we report on biogeochemical and molecular evidence for growth stimulation of methanotrophic communities by ammonium fertilization, and that methane modulates nitrogen cycling by competitive inhibition of nitrifying communities in a rice paddy soil. Pairwise comparison between microcosms amended with CH4, CH4+Urea, and Urea indicated that urea fertilization stimulated methane oxidation activity 6-fold during a 19-day incubation period, while ammonia oxidation activity was significantly suppressed in the presence of CH4. Pyrosequencing of the total 16S rRNA genes revealed that urea amendment resulted in rapid growth of Methylosarcina-like MOB, and nitrifying communities appeared to be partially inhibited by methane. High-throughput sequencing of the 13C-labeled DNA further revealed that methane amendment resulted in clear growth of Methylosarcina-related MOB while methane plus urea led to an equal increase in Methylosarcina and Methylobacter-related type Ia MOB, indicating the differential growth requirements of representatives of these genera. An increase in 13C assimilation by microorganisms related to methanol oxidizers clearly indicated carbon transfer from methane oxidation to other soil microbes, which was enhanced by urea addition. The active growth of type Ia methanotrops was significantly stimulated by urea amendment, and the pronounced growth of methanol-oxidizing bacteria occurred in CH4-treated microcosms only upon urea amendment. Methane addition partially inhibited the growth of Nitrosospira and Nitrosomonas in urea-amended microcosms, as well as growth of nitrite-oxidizing bacteria. These

  11. Competitive interactions between methane- and ammonia-oxidizing bacteria modulate carbon and nitrogen cycling in paddy soil

    NASA Astrophysics Data System (ADS)

    Zheng, Y.; Huang, R.; Wang, B. Z.; Bodelier, P. L. E.; Jia, Z. J.

    2014-03-01

    Pure culture studies have demonstrated that methanotrophs and ammonia oxidizers can both carry out the oxidation of methane and ammonia. However, the expected interactions resulting from these similarities are poorly understood, especially in complex, natural environments. Using DNA-based stable isotope probing and pyrosequencing of 16S rRNA and pmoA genes, we report on biogeochemical and molecular evidence for growth stimulation of methanotrophic communities by ammonium fertilization, and that methane modulates nitrogen cycling by competitive inhibition of nitrifying communities in a rice paddy soil. Pairwise comparison between microcosms amended with CH4, CH4+Urea, and Urea indicated that urea fertilization stimulated methane oxidation activity by 6-fold during a 19 day incubation period, while ammonia oxidation activity was significantly inhibited in the presence of CH4. Pyrosequencing of the total 16S rRNA genes revealed that urea amendment resulted in rapid growth of Methylosarcina-like type Ia MOB, and nitrifying communities appeared to be suppressed by methane. High-throughput sequencing of the 13C-labeled DNA further revealed that methane amendment resulted in clear growth of Methylosarcina-related MOB while methane plus urea led to equal increase in Methylosarcina and Methylobacter-related MOB, indicating the differential growth requirements of representatives of these genera. Strikingly, type Ib MOB did not respond to methane nor to urea. Increase in 13C-assimilation by microorganisms related to methanol oxidizers clearly indicated carbon transfer from methane oxidation to other soil microbes, which was enhanced by urea addition. The active growth of type Ia methanotrops was significantly stimulated by urea amendment, and the pronounced growth of methanol-oxidizing bacteria occurred in CH4-treated microcosms only upon urea amendment. Methane addition inhibited the growth of Nitrosospira and Nitrosomonas in urea-amended microcosms, in addition of nitrite

  12. Transport characteristics and transporter-based drug-drug interactions of TM-25659, a novel TAZ modulator.

    PubMed

    Choi, Min-Koo; Kwon, Mihwa; Ahn, Jin Hee; Kim, Nak Jung; Bae, Myung-Ae; Song, Im-Sook

    2014-04-01

    The in vitro metabolic stability and transport mechanism of TM-25659, a novel TAZ modulator, was investigated in human hepatocytes and human liver microsomes (HLMs) based on the preferred hepatobiliary elimination in rats. In addition, the in vitro transport mechanism and transporter-mediated drug-drug interactions were evaluated using oocytes and MDCKII cells overexpressing clinically important drug transporters. After a 1 h incubation in HLMs, 92.9 ± 9.5% and 95.5 ± 11.6% of the initial TM-25659 remained in the presence of NADPH and UDPGA, respectively. Uptake of TM-25659 readily accumulated in human hepatocytes at 37 ºC (i.e. 6.7-fold greater than that at 4 ºC), in which drug transporters such as OATP1B1 and OATP1B3 were involved. TM-25659 had a significantly greater basal to apical transport rate (5.9-fold) than apical to basal transport rate in the Caco-2 cell monolayer, suggesting the involvement of an efflux transport system. Further studies using inhibitors of efflux transporters and overexpressing cells revealed that MRP2 was involved in the transport of TM-25659. These results, taken together, suggested that TM-25659 can be actively influxed into hepatocytes and undergo biliary excretion without substantial metabolism. Additionally, TM-25659 inhibited the transport activities of OATP1B1 and OATP1B3 with IC50 values of 36.3 and 25.9 μm, respectively. TM-25659 (100 μm) increased the accumulation of the probe substrate by 160% and 213%, respectively, through the inhibition of efflux function of P-gp and MRP2. In conclusion, OATP1B1, OATP1B3, P-gp and MRP2 might be major transporters responsible for the pharmacokinetics and drug-drug interaction of TM-25659, although their contribution to in vivo pharmacokinetics needs to be further investigated.

  13. Light-Dependent Phosphorylation of Bardet Biedl Syndrome 5 in Photoreceptor Cells Modulates its Interaction with Arrestin1

    PubMed Central

    Smith, Tyler S.; Spitzbarth, Benjamin; Li, Jian; Dugger, Donald R.; Stern-Schneider, Gabi; Sehn, Elisabeth; Bolch, Susan N.; McDowell, J. Hugh; Tipton, Jeremiah; Wolfrum, Uwe; Smith, W. Clay

    2013-01-01

    Arrestins are dynamic proteins which move between cell compartments triggered by stimulation of G-protein-coupled receptors. Even more dynamically in vertebrate photoreceptors, arrestin1 (Arr1) moves between the inner and outer segments according to the lighting conditions. Previous studies have shown that the light-driven translocation of Arr1 in rod photoreceptors is initiated by rhodopsin through a phospholipase C/protein kinase C (PKC) signaling cascade. The purpose of this study is to identify the PKC substrate that regulates the translocation of Arr1. Mass spectrometry was used to identify the primary phosphorylated proteins in extracts prepared from PKC-stimulated mouse eye cups, confirming the finding with in vitro phosphorylation assays. Our results show that BBS5 is the principal protein phosphorylated either by phorbol ester stimulation or by light stimulation of PKC. Via immunoprecipitation of BBS5 in rod outer segments, Arr1 was pulled down; phosphorylation of BBS5 reduced this co-precipitation of Arr1. Immunofluorescence and immunoelectron microscopy showed that BBS5 principally localizes along the axonemes of rods and cones, but also in photoreceptor inner segments, and synaptic regions. Our principal findings in this study are three-fold. First, we demonstrate that BBS5 is post-translationally regulated by phosphorylation via PKC, an event that is triggered by light in photoreceptor cells. Second, we find a direct interaction between BBS5 and Arr1, an interaction that is modulated by phosphorylation of BBS5. Finally, we show that BBS5 is distributed along the photoreceptor axoneme, co-localizing with Arr1 in the dark. These findings suggest a role for BBS5 in regulating light-dependent translocation of Arr1 and a model describing its role in Arr1 translocation is proposed. PMID:23817741

  14. Nucleotide binding interactions modulate dNTP selectivity and facilitate 8-oxo-dGTP incorporation by DNA polymerase lambda

    PubMed Central

    Burak, Matthew J.; Guja, Kip E.; Garcia-Diaz, Miguel

    2015-01-01

    8-Oxo-7,8,-dihydro-2′-deoxyguanosine triphosphate (8-oxo-dGTP) is a major product of oxidative damage in the nucleotide pool. It is capable of mispairing with adenosine (dA), resulting in futile, mutagenic cycles of base excision repair. Therefore, it is critical that DNA polymerases discriminate against 8-oxo-dGTP at the insertion step. Because of its roles in oxidative DNA damage repair and non-homologous end joining, DNA polymerase lambda (Pol λ) may frequently encounter 8-oxo-dGTP. Here, we have studied the mechanisms of 8-oxo-dGMP incorporation and discrimination by Pol λ. We have solved high resolution crystal structures showing how Pol λ accommodates 8-oxo-dGTP in its active site. The structures indicate that when mispaired with dA, the oxidized nucleotide assumes the mutagenic syn-conformation, and is stabilized by multiple interactions. Steady-state kinetics reveal that two residues lining the dNTP binding pocket, Ala510 and Asn513, play differential roles in dNTP selectivity. Specifically, Ala510 and Asn513 facilitate incorporation of 8-oxo-dGMP opposite dA and dC, respectively. These residues also modulate the balance between purine and pyrimidine incorporation. Our results shed light on the mechanisms controlling 8-oxo-dGMP incorporation in Pol λ and on the importance of interactions with the incoming dNTP to determine selectivity in family X DNA polymerases. PMID:26220180

  15. Phosphorus and magnesium interactively modulate the elongation and directional growth of primary roots in Arabidopsis thaliana (L.) Heynh

    PubMed Central

    Niu, Yaofang; Jin, Gulei; Li, Xin; Tang, Caixian; Zhang, Yongsong; Liang, Yongchao; Yu, Jingquan

    2015-01-01

    A balanced supply of essential nutrients is an important factor influencing root architecture in many plants, yet data related to the interactive effects of two nutrients on root growth are limited. Here, we investigated the interactive effect between phosphorus (P) and magnesium (Mg) on root growth of Arabidopsis grown in pH-buffered agar medium at different P and Mg levels. The results showed that elongation and deviation of primary roots were directly correlated with the amount of P added to the medium but could be modified by the Mg level, which was related to the root meristem activity and stem-cell division. High P enhanced while low P decreased the tip-focused fluorescence signal of auxin biosynthesis, transport, and redistribution during elongation of primary roots; these effects were greater under low Mg than under high Mg. The altered root growth in response to P and Mg supply was correlated with AUX1, PIN2, and PIN3 mRNA abundance and expression and the accumulation of the protein. Application of either auxin influx inhibitor or efflux inhibitor inhibited the elongation and increased the deviation angle of primary roots, and decreased auxin level in root tips. Furthermore, the auxin-transport mutants aux1-22 and eir1-1 displayed reduced root growth and increased the deviation angle. Our data suggest a profound effect of the combined supply of P and Mg on the development of root morphology in Arabidopsis through auxin signals that modulate the elongation and directional growth of primary root and the expression of root differentiation and development genes. PMID:25922494

  16. Phosphorus and magnesium interactively modulate the elongation and directional growth of primary roots in Arabidopsis thaliana (L.) Heynh.

    PubMed

    Niu, Yaofang; Jin, Gulei; Li, Xin; Tang, Caixian; Zhang, Yongsong; Liang, Yongchao; Yu, Jingquan

    2015-07-01

    A balanced supply of essential nutrients is an important factor influencing root architecture in many plants, yet data related to the interactive effects of two nutrients on root growth are limited. Here, we investigated the interactive effect between phosphorus (P) and magnesium (Mg) on root growth of Arabidopsis grown in pH-buffered agar medium at different P and Mg levels. The results showed that elongation and deviation of primary roots were directly correlated with the amount of P added to the medium but could be modified by the Mg level, which was related to the root meristem activity and stem-cell division. High P enhanced while low P decreased the tip-focused fluorescence signal of auxin biosynthesis, transport, and redistribution during elongation of primary roots; these effects were greater under low Mg than under high Mg. The altered root growth in response to P and Mg supply was correlated with AUX1, PIN2, and PIN3 mRNA abundance and expression and the accumulation of the protein. Application of either auxin influx inhibitor or efflux inhibitor inhibited the elongation and increased the deviation angle of primary roots, and decreased auxin level in root tips. Furthermore, the auxin-transport mutants aux1-22 and eir1-1 displayed reduced root growth and increased the deviation angle. Our data suggest a profound effect of the combined supply of P and Mg on the development of root morphology in Arabidopsis through auxin signals that modulate the elongation and directional growth of primary root and the expression of root differentiation and development genes.

  17. Magnesium and manganese interactively modulate parthenolide accumulation and the antioxidant defense system in the leaves of Tanacetum parthenium.

    PubMed

    Farzadfar, Soudeh; Zarinkamar, Fatemeh; Behmanesh, Mehrdad; Hojati, Mostafa

    2016-09-01

    A balanced nutrient supply is a critical factor affecting accumulation of terpenoids in plants, yet data related to the interactive effects of two essential nutrients for the biosynthesis of sesquiterpenes are scarce. Here, the interactional effects between magnesium (Mg) and manganese (Mn) on plant growth, oxidative status, parthenolide accumulation and expression of key genes involved in parthenolide biosynthesis including 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate reductase (HDR), 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGR), germacrene A synthase (GAS), germacrene A oxidase (GAO), costunolide synthase (COS) and parthenolide synthase (PTS) in the leaves of feverfew plants grown at different Mn and Mn levels were assessed. Plant growth and leaf pigment concentrations were associated with the amount of applied Mg but could be modified by the Mn level. Deprivation and the addition of both Mg and Mn induce oxidative stress. Mg supply also alleviated the adverse effects of Mn excess on plant growth and oxidative status. In addition, parthenolide biosynthesis decreased under deprivation of Mg or Mn, but the addition of Mn up to 50μM under 2mM Mg supply considerably increased its accumulation. The parthenolide accumulation trend might reflect the up-regulation of terpenoid-related genes and enzyme activities as well as the oxidative status of feverfew leaves. Our data suggest a profound effect of the combined supply of Mg and Mn on parthenolide biosynthesis through the activation of terpene synthases, which concomitantly modulate by oxidative status. PMID:27450490

  18. Dengue NS3, an RNAi suppressor, modulates the human miRNA pathways through its interacting partner.

    PubMed

    Kakumani, Pavan Kumar; Rajgokul, K S; Ponia, Sanket Singh; Kaur, Inderjeet; Mahanty, Srikrishna; Medigeshi, Guruprasad R; Banerjea, Akhil C; Chopra, Arun Prasad; Malhotra, Pawan; Mukherjee, Sunil K; Bhatnagar, Raj K

    2015-10-01

    RNAi acts as a host immune response against non-self molecules, including viruses. Viruses evolved to neutralize this response by expressing suppressor proteins. In the present study, we investigated dengue virus non structural protein 3 (dvNS3), for its RNAi-suppressor activity in human cell lines. Dengue virus (DV) NS3 reverts the GFP expression in GFP-silenced cell lines. Pull-down assays of dvNS3 revealed that it interacts with the host factor human heat shock cognate 70 (hHSC70). Down-regulation of hHSC70 resulted in accumulation of dengue viral genomic RNA. Also, the interaction of dvNS3 with hHSC70 perturbs the formation of RISC (RNA-induced silencing complex)-loading complex (RLC), by displacing TRBP (TAR RNA-binding protein) and possibly impairing the downstream activity of miRNAs. Interestingly, some of these miRNAs have earlier been reported to be down-regulated upon DV infection in Huh7 cells. Further studies on the miRNA-mRNA relationship along with mRNA profiling of samples overexpressing dvNS3 revealed up-regulation of TAZ (tafazzin) and SYNGR1 (synaptogyrin 1), known dengue viral host factors (DVHFs). Importantly, overexpression of dvNS3 in human embryonic kidney (HEK) 293T cells resulted in modulation of both mature and precursor miRNAs in human cell lines. Subsequent analysis suggested that dvNS3 induced stage-specific down-regulation of miRNAs. Taken together, these results suggest that dvNS3 affects biogenesis and function of host miRNAs to regulate DVHFs for favouring DV replication.

  19. Negatively charged metal oxide nanoparticles interact with the 20S proteasome and differentially modulate its biologic functional effects.

    PubMed

    Falaschetti, Christine A; Paunesku, Tatjana; Kurepa, Jasmina; Nanavati, Dhaval; Chou, Stanley S; De, Mrinmoy; Song, MinHa; Jang, Jung-tak; Wu, Aiguo; Dravid, Vinayak P; Cheon, Jinwoo; Smalle, Jan; Woloschak, Gayle E

    2013-09-24

    The multicatalytic ubiquitin-proteasome system (UPS) carries out proteolysis in a highly orchestrated way and regulates a large number of cellular processes. Deregulation of the UPS in many disorders has been documented. In some cases, such as carcinogenesis, elevated proteasome activity has been implicated in disease development, while the etiology of other diseases, such as neurodegeneration, includes decreased UPS activity. Therefore, agents that alter proteasome activity could suppress as well as enhance a multitude of diseases. Metal oxide nanoparticles, often developed as diagnostic tools, have not previously been tested as modulators of proteasome activity. Here, several types of metal oxide nanoparticles were found to adsorb to the proteasome and show variable preferential binding for particular proteasome subunits with several peptide binding "hotspots" possible. These interactions depend on the size, charge, and concentration of the nanoparticles and affect proteasome activity in a time-dependent manner. Should metal oxide nanoparticles increase proteasome activity in cells, as they do in vitro, unintended effects related to changes in proteasome function can be expected.

  20. Negatively Charged Metal Oxide Nanoparticles Interact with the 20S Proteasome and Differentially Modulate Its Biologic Functional Effects

    PubMed Central

    Falaschetti, Christine A.; Paunesku, Tatjana; Kurepa, Jasmina; Nanavati, Dhaval; Chou, Stanley S.; De, Mrinmoy; Song, MinHa; Jang, Jung-tak; Wu, Aiguo; Dravid, Vinayak P.; Cheon, Jinwoo; Smalle, Jan; Woloschak, Gayle E.

    2013-01-01

    The multicatalytic ubiquitin-proteasome system (UPS) carries out proteolysis in a highly orchestrated way and regulates a large number of cellular processes. Deregulation of the UPS in many disorders has been documented. In some cases, e.g. carcinogenesis, elevated proteasome activity has been implicated in disease development, while the etiology of other diseases, e.g. neurodegeneration, includes decreased UPS activity. Therefore, agents that alter proteasome activity could suppress as well as enhance a multitude of diseases. Metal oxide nanoparticles, often developed as diagnostic tools, have not previously been tested as modulators of proteasome activity. Here, several types of metal oxide nanoparticles were found to adsorb to the proteasome and show variable preferential binding for particular proteasome subunits with several peptide binding “hotspots” possible. These interactions depend on the size, charge, and concentration of the nanoparticles and affect proteasome activity in a time-dependent manner. Should metal oxide nanoparticles increase proteasome activity in cells, as they do in vitro, unintended effects related to changes in proteasome function can be expected. PMID:23930940

  1. The First Residue of the PWWP Motif Modulates HATH Domain Binding, Stability, and Protein-Protein Interaction.

    PubMed

    Hung, Yi-Lin; Lee, Hsia-Ju; Jiang, Ingjye; Lin, Shang-Chi; Lo, Wei-Cheng; Lin, Yi-Jan; Sue, Shih-Che

    2015-07-01

    Hepatoma-derived growth factor (hHDGF) and HDGF-related proteins (HRPs) contain conserved N-terminal HATH domains with a characteristic structural motif, namely the PWWP motif. The HATH domain has attracted attention because of its ability to bind with heparin/heparan sulfate, DNA, and methylated histone peptide. Depending on the sequence of the PWWP motif, HRP HATHs are classified into P-type (Pro-His-Trp-Pro) and A-type (Ala-His-Trp-Pro) forms. A-type HATH is highly unstable and tends to precipitate in solution. We replaced the Pro residue in P-type HATHHDGF with Ala and evaluated the influence on structure, dynamics, and ligand binding. Nuclear magnetic resonance (NMR) hydrogen/deuterium exchange and circular dichroism (CD) measurements revealed reduced stability. Analysis of NMR backbone (15)N relaxations (R1, R2, and nuclear Overhauser effect) revealed additional backbone dynamics in the interface between the β-barrel and the C-terminal helix bundle. The β1-β2 loop, where the AHWP sequence is located, has great structural flexibility, which aids HATH-HATH interaction through the loop. A-type HATH, therefore, shows a stronger tendency to aggregate when binding with heparin and DNA oligomers. This study defines the role of the first residue of the PWWP motif in modulating HATH domain stability and oligomer formation in binding.

  2. Spectro-temporal interactions in auditory-visual perception: How the eyes modulate what the ears hear

    NASA Astrophysics Data System (ADS)

    Grant, Ken W.; van Wassenhove, Virginie

    2001-05-01

    Auditory-visual speech perception has been shown repeatedly to be both more accurate and more robust than auditory speech perception. Attempts to explain these phenomena usually treat acoustic and visual speech information (i.e., accessed via speechreading) as though they were derived from independent processes. Recent electrophysiological (EEG) studies, however, suggest that visual speech processes may play a fundamental role in modulating the way we hear. For example, both the timing and amplitude of auditory-specific event-related potentials as recorded by EEG are systematically altered when speech stimuli are presented audiovisually as opposed to auditorilly. In addition, the detection of a speech signal in noise is more readily accomplished when accompanied by video images of the speaker's production, suggesting that the influence of vision on audition occurs quite early in the perception process. But the impact of visual cues on what we ultimately hear is not limited to speech. Our perceptions of loudness, timbre, and sound source location can also be influenced by visual cues. Thus, for speech and nonspeech stimuli alike, predicting a listener's response to sound based on acoustic engineering principles alone may be misleading. Examples of acoustic-visual interactions will be presented which highlight the multisensory nature of our hearing experience.

  3. Simulation and Design of Vehicle Exhaust Power Generation Systems: The Interaction Between the Heat Exchanger and the Thermoelectric Modules

    NASA Astrophysics Data System (ADS)

    Tao, Cong; Chen, Gang; Mu, Yu; Liu, Lisheng; Zhai, Pengcheng

    2015-06-01

    Vehicle exhaust power generation systems (VEPGS), mainly consisting of a heat exchanger, cooling system, thermoelectric modules (TEMs), and clamping device, have attracted wide interest and attention for power generation from waste heat. In this work, systematical research was conducted to investigate the thermal performance, power output, and thermal stress of a VEPGS by using the multifield coupling method. Different from previous research, this work simulates a model that integrates the heat exchanger and TEMs, focusing on the effect of the TEMs on the thermal performance of the heat exchanger. It is found that the TEMs have a significant effect on the thermal performance of the heat exchanger. When not considering the effects of the TEMs, the hot-end temperature of the TEMs would be seriously underestimated, which would result in underestimation of the power output of the VEPGS and the level of thermal stress of the TEMs. Meanwhile, when considering the effect of the TEMs, the hot-end temperature distribution exhibits significant changes, and its temperature uniformity is significantly improved. The results suggest that, in VEPGS design and optimization, the interaction between the heat exchanger and TEMs should be considered. This study also contributes to a more accurate assessment method for VEPGS design and simulation.

  4. The modulation of the symbiont/host interaction between Wolbachia pipientis and Aedes fluviatilis embryos by glycogen metabolism.

    PubMed

    da Rocha Fernandes, Mariana; Martins, Renato; Pessoa Costa, Evenilton; Pacidônio, Etiene Casagrande; Araujo de Abreu, Leonardo; da Silva Vaz, Itabajara; Moreira, Luciano A; da Fonseca, Rodrigo Nunes; Logullo, Carlos

    2014-01-01

    Wolbachia pipientis, a maternally transmitted bacterium that colonizes arthropods, may affect the general aspects of insect physiology, particularly reproduction. Wolbachia is a natural endosymbiont of Aedes fluviatilis, whose effects in embryogenesis and reproduction have not been addressed so far. In this context, we investigated the correlation between glucose metabolism and morphological alterations during A. fluviatilis embryo development in Wolbachia-positive (W+) and Wolbachia-negative (W-) mosquito strains. While both strains do not display significant morphological and larval hatching differences, larger differences were observed in hexokinase activity and glycogen contents during early and mid-stages of embryogenesis, respectively. To investigate if glycogen would be required for parasite-host interaction, we reduced Glycogen Synthase Kinase-3 (GSK-3) levels in adult females and their eggs by RNAi. GSK-3 knock-down leads to embryonic lethality, lower levels of glycogen and total protein and Wolbachia reduction. Therefore, our results suggest that the relationship between A. fluviatilis and Wolbachia may be modulated by glycogen metabolism.

  5. QM/MM Studies Reveal How Substrate-Substrate and Enzyme-Substrate Interactions Modulate Retaining Glycosyltransferases Catalysis and Mechanism.

    PubMed

    Gómez, Hansel; Mendoza, Fernanda; Lluch, José M; Masgrau, Laura

    2015-01-01

    Glycosyltransferases (GTs) catalyze the biosynthesis of glycosidic linkages by transferring a monosaccharide from a nucleotide sugar donor to an acceptor substrate, and they do that with exquisite regio- and stereospecificity. Retaining GTs act with retention of the configuration at the anomeric carbon of the transferred sugar. Their chemical mechanism has been under debate for long as conclusive experimental data to confirm the mechanism have been elusive. In the past years, quantum mechanical/molecular mechanical (QM/MM) calculations have shed light on the mechanistic discussion. Here, we review the work carried out in our group investigating three of these retaining enzymes (LgtC, α3GalT, and GalNAc-T2). Our results support the controversial front-side attack mechanism as the general mechanism for most retaining GTs. The latest structural data are in agreement with these findings. QM/MM calculations have revealed how enzyme-substrate and substrate-substrate interactions modulate the transfer reaction catalyzed by these enzymes. Moreover, they provide an explanation on why in some cases a strong nucleophilic residue is found on the β-face of the sugar, opening the door to a shift toward a double-displacement mechanism.

  6. The Modulation of the Symbiont/Host Interaction between Wolbachia pipientis and Aedes fluviatilis Embryos by Glycogen Metabolism

    PubMed Central

    da Rocha Fernandes, Mariana; Martins, Renato; Pessoa Costa, Evenilton; Casagrande Pacidônio, Etiene; Araujo de Abreu, Leonardo; da Silva Vaz, Itabajara; Moreira, Luciano A.; da Fonseca, Rodrigo Nunes; Logullo, Carlos

    2014-01-01

    Wolbachia pipientis, a maternally transmitted bacterium that colonizes arthropods, may affect the general aspects of insect physiology, particularly reproduction. Wolbachia is a natural endosymbiont of Aedes fluviatilis, whose effects in embryogenesis and reproduction have not been addressed so far. In this context, we investigated the correlation between glucose metabolism and morphological alterations during A. fluviatilis embryo development in Wolbachia-positive (W+) and Wolbachia-negative (W−) mosquito strains. While both strains do not display significant morphological and larval hatching differences, larger differences were observed in hexokinase activity and glycogen contents during early and mid-stages of embryogenesis, respectively. To investigate if glycogen would be required for parasite-host interaction, we reduced Glycogen Synthase Kinase-3 (GSK-3) levels in adult females and their eggs by RNAi. GSK-3 knock-down leads to embryonic lethality, lower levels of glycogen and total protein and Wolbachia reduction. Therefore, our results suggest that the relationship between A. fluviatilis and Wolbachia may be modulated by glycogen metabolism. PMID:24926801

  7. Prefrontal cortex-nucleus accumbens interaction: in vivo modulation by dopamine and glutamate in the prefrontal cortex.

    PubMed

    Del Arco, Alberto; Mora, Francisco

    2008-08-01

    Previous experimental studies have shown that the prefrontal cortex (PFC) regulates the activity of the nucleus accumbens (NAc), and in particular the release of dopamine in this area of the brain. In the present report we review recent microinjections/microdialysis studies from our laboratory on the effects of stimulation/blockade of dopamine and glutamate receptors in the PFC that modulate dopamine, and also acetylcholine release in the NAc. Stimulation of prefrontal D2 dopamine receptors, but not group I mGlu glutamate receptors, reduces the release of dopamine and acetylcholine in the NAc and spontaneous motor activity. This inhibitory role of prefrontal D2 receptors is not changed by acute systemic injections of the NMDA antagonist phencyclidine. On the other hand, the blockade of NMDA receptors in the PFC increases the release of dopamine and acetylcholine in the NAc as well as motor activity which suggests that the hypofunction of prefrontal NMDA receptors is able to produce the neurochemical and behavioural changes associated with a dysfunction of the corticolimbic circuit. We suggest here that dopamine and glutamate receptors are, in part, segregated in specific cellular circuits in the PFC. Thus, the stimulation/blockade of these receptors would have a different net impact on PFC output projections to regulate dopamine and acetylcholine release in the NAc and in guided behaviour. Finally, it is speculated that environmental enrichment might produce plastic changes that modify the functional interaction between the PFC and the NAc in both physiological and pathological conditions.

  8. Disparate bilingual experiences modulate task-switching advantages: A diffusion-model analysis of the effects of interactional context on switch costs.

    PubMed

    Hartanto, Andree; Yang, Hwajin

    2016-05-01

    Drawing on the adaptive control hypothesis (Green & Abutalebi, 2013), we investigated whether bilinguals' disparate interactional contexts modulate task-switching performance. Fifty-eight bilinguals within the single-language context (SLC) and 75 bilinguals within the dual-language context (DLC) were compared in a typical task-switching paradigm. Given that DLC bilinguals switch between languages within the same context, while SLC bilinguals speak only one language in one environment and therefore rarely switch languages, we hypothesized that the two groups' stark difference in their interactional contexts of conversational exchanges would lead to differences in switch costs. As predicted, DLC bilinguals showed smaller switch costs than SLC bilinguals. Our diffusion-model analyses suggest that DLC bilinguals' benefits in switch costs are more likely driven by task-set reconfiguration than by proactive interference. Our findings underscore the modulating role of the interactional context of conversational exchanges in task switching. PMID:26848731

  9. Differential Modulation of Functional Dynamics and Allosteric Interactions in the Hsp90-Cochaperone Complexes with p23 and Aha1: A Computational Study

    PubMed Central

    Blacklock, Kristin; Verkhivker, Gennady M.

    2013-01-01

    Allosteric interactions of the molecular chaperone Hsp90 with a large cohort of cochaperones and client proteins allow for molecular communication and event coupling in signal transduction networks. The integration of cochaperones into the Hsp90 system is driven by the regulatory mechanisms that modulate the progression of the ATPase cycle and control the recruitment of the Hsp90 clientele. In this work, we report the results of computational modeling of allosteric regulation in the Hsp90 complexes with the cochaperones p23 and Aha1. By integrating protein docking, biophysical simulations, modeling of allosteric communications, protein structure network analysis and the energy landscape theory we have investigated dynamics and stability of the Hsp90-p23 and Hsp90-Aha1 interactions in direct comparison with the extensive body of structural and functional experiments. The results have revealed that functional dynamics and allosteric interactions of Hsp90 can be selectively modulated by these cochaperones via specific targeting of the regulatory hinge regions that could restrict collective motions and stabilize specific chaperone conformations. The protein structure network parameters have quantified the effects of cochaperones on conformational stability of the Hsp90 complexes and identified dynamically stable communities of residues that can contribute to the strengthening of allosteric interactions. According to our results, p23-mediated changes in the Hsp90 interactions may provide “molecular brakes” that could slow down an efficient transmission of the inter-domain allosteric signals, consistent with the functional role of p23 in partially inhibiting the ATPase cycle. Unlike p23, Aha1-mediated acceleration of the Hsp90-ATPase cycle may be achieved via modulation of the equilibrium motions that facilitate allosteric changes favoring a closed dimerized form of Hsp90. The results of our study have shown that Aha1 and p23 can modulate the Hsp90-ATPase activity

  10. A novel role for Gadd45α in base excision repair: Modulation of APE1 activity by the direct interaction of Gadd45α with PCNA

    SciTech Connect

    Kim, Hye Lim; Kim, Sang Uk; Seo, Young Rok

    2013-05-03

    Highlights: ► Emerging critical role for Gadd45α in modulating BER activity. ► Identifying specific PCNA binding site on Gadd45α protein. ► Regulating APE1 activity through interaction between Gadd45α and PCNA. ► Suggesting potential role of Gadd45α–PCNA binding in pancreatic carcinogenesis. -- Abstract: The growth arrest and DNA damage inducible, alpha (Gadd45α) protein regulates DNA repair by interacting with proliferating cell nuclear antigen (PCNA). Our previous study suggested a potential role for Gadd45α in the base excision repair (BER) pathway by affecting apurinic/apyrimidinic endonuclease 1 (APE1) protein in addition to its accepted role in nucleotide excision repair (NER). Here, we investigated whether the interaction of Gadd45α with PCNA affects APE1 activity. To address this issue, we used a siRNA directed to Gadd45α and a form of Gadd45α with a mutation to the predicted site of PCNA binding. There was a reduction of APE1 activity in cells transfected with the Gadd45α siRNA. Furthermore, the interaction of Gadd45α with PCNA and APE1 was lower in cells transfected with mutant Gadd45α compared with cells transfected with wild-type Gadd45α. Indeed, we observed that the APE1 activity in the Gadd45α-interacting complex was significantly lower in cells that overexpress mutant Gadd45α compared with cells that overexpress wild-type Gadd45α. We conclude that the PCNA binding site on Gadd45α plays a critical role in modulating the interaction with PCNA and APE1, affecting BER activity. These results provide novel insights into the mechanisms by which BER activity is modulated, although the interaction of Gadd45α with APE1 needs to be clarified.

  11. Alu-miRNA interactions modulate transcript isoform diversity in stress response and reveal signatures of positive selection.

    PubMed

    Pandey, Rajesh; Bhattacharya, Aniket; Bhardwaj, Vivek; Jha, Vineet; Mandal, Amit K; Mukerji, Mitali

    2016-09-02

    Primate-specific Alus harbor different regulatory features, including miRNA targets. In this study, we provide evidence for miRNA-mediated modulation of transcript isoform levels during heat-shock response through exaptation of Alu-miRNA sites in mature mRNA. We performed genome-wide expression profiling coupled with functional validation of miRNA target sites within exonized Alus, and analyzed conservation of these targets across primates. We observed that two miRNAs (miR-15a-3p and miR-302d-3p) elevated in stress response, target RAD1, GTSE1, NR2C1, FKBP9 and UBE2I exclusively within Alu. These genes map onto the p53 regulatory network. Ectopic overexpression of miR-15a-3p downregulates GTSE1 and RAD1 at the protein level and enhances cell survival. This Alu-mediated fine-tuning seems to be unique to humans as evident from the absence of orthologous sites in other primate lineages. We further analyzed signatures of selection on Alu-miRNA targets in the genome, using 1000 Genomes Phase-I data. We found that 198 out of 3177 Alu-exonized genes exhibit signatures of selection within Alu-miRNA sites, with 60 of them containing SNPs supported by multiple evidences (global-FST > 0.3, pair-wise-FST > 0.5, Fay-Wu's H < -20, iHS > 2.0, high ΔDAF) and implicated in p53 network. We propose that by affecting multiple genes, Alu-miRNA interactions have the potential to facilitate population-level adaptations in response to environmental challenges.

  12. Alu-miRNA interactions modulate transcript isoform diversity in stress response and reveal signatures of positive selection

    PubMed Central

    Pandey, Rajesh; Bhattacharya, Aniket; Bhardwaj, Vivek; Jha, Vineet; Mandal, Amit K.; Mukerji, Mitali

    2016-01-01

    Primate-specific Alus harbor different regulatory features, including miRNA targets. In this study, we provide evidence for miRNA-mediated modulation of transcript isoform levels during heat-shock response through exaptation of Alu-miRNA sites in mature mRNA. We performed genome-wide expression profiling coupled with functional validation of miRNA target sites within exonized Alus, and analyzed conservation of these targets across primates. We observed that two miRNAs (miR-15a-3p and miR-302d-3p) elevated in stress response, target RAD1, GTSE1, NR2C1, FKBP9 and UBE2I exclusively within Alu. These genes map onto the p53 regulatory network. Ectopic overexpression of miR-15a-3p downregulates GTSE1 and RAD1 at the protein level and enhances cell survival. This Alu-mediated fine-tuning seems to be unique to humans as evident from the absence of orthologous sites in other primate lineages. We further analyzed signatures of selection on Alu-miRNA targets in the genome, using 1000 Genomes Phase-I data. We found that 198 out of 3177 Alu-exonized genes exhibit signatures of selection within Alu-miRNA sites, with 60 of them containing SNPs supported by multiple evidences (global-FST > 0.3, pair-wise-FST > 0.5, Fay-Wu’s H < −20, iHS > 2.0, high ΔDAF) and implicated in p53 network. We propose that by affecting multiple genes, Alu-miRNA interactions have the potential to facilitate population-level adaptations in response to environmental challenges. PMID:27586304

  13. The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice

    PubMed Central

    Bermudez-Silva, Francisco J.; Romero-Zerbo, Silvana Y.; Haissaguerre, Magalie; Ruz-Maldonado, Inmaculada; Lhamyani, Said; El Bekay, Rajaa; Tabarin, Antoine; Marsicano, Giovanni; Cota, Daniela

    2016-01-01

    ABSTRACT The endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1) signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1) receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1 µM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6) within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight), which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic β-cell diseases. PMID:26563389

  14. The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice.

    PubMed

    Bermudez-Silva, Francisco J; Romero-Zerbo, Silvana Y; Haissaguerre, Magalie; Ruz-Maldonado, Inmaculada; Lhamyani, Said; El Bekay, Rajaa; Tabarin, Antoine; Marsicano, Giovanni; Cota, Daniela

    2016-01-01

    The endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1) signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1) receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1 µM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6) within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight), which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic β-cell diseases.

  15. The interaction of copper(II) and glycyl-L-histidyl-L-lysine, a growth-modulating tripeptide from plasma.

    PubMed Central

    Lau, S J; Sarkar, B

    1981-01-01

    The interaction between Cu(II) and the growth-modulating tripeptide glycyl-L-histidyl-L-lysine in the presence and absence of L-histidine was investigated by potentiometric titration and visible-absorption spectrophotometry at 25 degrees C in 0.15 M-NaCl. Analyses of the results in the pH range 3.5--10.6 indicated the presence of multiple species in solution in the binary system and extensive amounts of the ternary complexes in the ternary system. The species distribution and the stability constants, as well as the visible-absorption spectra of the species, were evaluated. The combined results were used to propose the structure of some of the complexes. The influence of the epsilon-amino group of the peptide in the enhancement of the stability constants was reflected prominently when compared with those complexes formed by either glycyl-L-histidine or glycyl-L-histidylglycine. The results obtained from the equilibrium-dialysis experiments showed that this tripeptide was able to compete with albumin for Cu(II) at pH 7.5 and 6 degrees C. At equimolar concentrations of albumin and the peptide, about 42% of the Cu(II) was bound to the peptide. At the physiologically relevant concentrations of Cu(II), albumin, L-histidine and this peptide, about 6% of the Cu(II) was associated with the low-molecular-weight components. This distribution could be due to the binary as well as the ternary complexes. The possible physiological role of these complexes in the transportation of Cu(II) from blood to tissues is discussed. PMID:7340824

  16. The interaction of copper(II) and glycyl-L-histidyl-L-lysine, a growth-modulating tripeptide from plasma.

    PubMed

    Lau, S J; Sarkar, B

    1981-12-01

    The interaction between Cu(II) and the growth-modulating tripeptide glycyl-L-histidyl-L-lysine in the presence and absence of L-histidine was investigated by potentiometric titration and visible-absorption spectrophotometry at 25 degrees C in 0.15 M-NaCl. Analyses of the results in the pH range 3.5--10.6 indicated the presence of multiple species in solution in the binary system and extensive amounts of the ternary complexes in the ternary system. The species distribution and the stability constants, as well as the visible-absorption spectra of the species, were evaluated. The combined results were used to propose the structure of some of the complexes. The influence of the epsilon-amino group of the peptide in the enhancement of the stability constants was reflected prominently when compared with those complexes formed by either glycyl-L-histidine or glycyl-L-histidylglycine. The results obtained from the equilibrium-dialysis experiments showed that this tripeptide was able to compete with albumin for Cu(II) at pH 7.5 and 6 degrees C. At equimolar concentrations of albumin and the peptide, about 42% of the Cu(II) was bound to the peptide. At the physiologically relevant concentrations of Cu(II), albumin, L-histidine and this peptide, about 6% of the Cu(II) was associated with the low-molecular-weight components. This distribution could be due to the binary as well as the ternary complexes. The possible physiological role of these complexes in the transportation of Cu(II) from blood to tissues is discussed. PMID:7340824

  17. Alu-miRNA interactions modulate transcript isoform diversity in stress response and reveal signatures of positive selection.

    PubMed

    Pandey, Rajesh; Bhattacharya, Aniket; Bhardwaj, Vivek; Jha, Vineet; Mandal, Amit K; Mukerji, Mitali

    2016-01-01

    Primate-specific Alus harbor different regulatory features, including miRNA targets. In this study, we provide evidence for miRNA-mediated modulation of transcript isoform levels during heat-shock response through exaptation of Alu-miRNA sites in mature mRNA. We performed genome-wide expression profiling coupled with functional validation of miRNA target sites within exonized Alus, and analyzed conservation of these targets across primates. We observed that two miRNAs (miR-15a-3p and miR-302d-3p) elevated in stress response, target RAD1, GTSE1, NR2C1, FKBP9 and UBE2I exclusively within Alu. These genes map onto the p53 regulatory network. Ectopic overexpression of miR-15a-3p downregulates GTSE1 and RAD1 at the protein level and enhances cell survival. This Alu-mediated fine-tuning seems to be unique to humans as evident from the absence of orthologous sites in other primate lineages. We further analyzed signatures of selection on Alu-miRNA targets in the genome, using 1000 Genomes Phase-I data. We found that 198 out of 3177 Alu-exonized genes exhibit signatures of selection within Alu-miRNA sites, with 60 of them containing SNPs supported by multiple evidences (global-FST > 0.3, pair-wise-FST > 0.5, Fay-Wu's H < -20, iHS > 2.0, high ΔDAF) and implicated in p53 network. We propose that by affecting multiple genes, Alu-miRNA interactions have the potential to facilitate population-level adaptations in response to environmental challenges. PMID:27586304

  18. Cancer cell biology: a student-centered instructional module exploring the use of multimedia to enrich interactive, constructivist learning of science.

    PubMed

    Bockholt, Susanne M; West, J Paige; Bollenbacher, Walter E

    2003-01-01

    Multimedia has the potential of providing bioscience education novel learning environments and pedagogy applications to foster student interest, involve students in the research process, advance critical thinking/problem-solving skills, and develop conceptual understanding of biological topics. Cancer Cell Biology, an interactive, multimedia, problem-based module, focuses on how mutations in protooncogenes and tumor suppressor genes can lead to uncontrolled cell proliferation by engaging students as research scientists/physicians with the task of diagnosing the molecular basis of tumor growth for a group of patients. The process of constructing the module, which was guided by scientist and student feedback/responses, is described. The completed module and insights gained from its development are presented as a potential "multimedia pedagogy" for the development of other multimedia science learning environments.

  19. The exopolysaccharide matrix modulates the interaction between 3D architecture and virulence of a mixed-species oral biofilm.

    PubMed

    Xiao, Jin; Klein, Marlise I; Falsetta, Megan L; Lu, Bingwen; Delahunty, Claire M; Yates, John R; Heydorn, Arne; Koo, Hyun

    2012-01-01

    Virulent biofilms are responsible for a range of infections, including oral diseases. All biofilms harbor a microbial-derived extracellular-matrix. The exopolysaccharides (EPS) formed on tooth-pellicle and bacterial surfaces provide binding sites for microorganisms; eventually the accumulated EPS enmeshes microbial cells. The metabolic activity of the bacteria within this matrix leads to acidification of the milieu. We explored the mechanisms through which the Streptococcus mutans-produced EPS-matrix modulates the three-dimensional (3D) architecture and the population shifts during morphogenesis of biofilms on a saliva-coated-apatitic surface using a mixed-bacterial species system. Concomitantly, we examined whether the matrix influences the development of pH-microenvironments within intact-biofilms using a novel 3D in situ pH-mapping technique. Data reveal that the production of the EPS-matrix helps to create spatial heterogeneities by forming an intricate network of exopolysaccharide-enmeshed bacterial-islets (microcolonies) through localized cell-to-matrix interactions. This complex 3D architecture creates compartmentalized acidic and EPS-rich microenvironments throughout the biofilm, which triggers the dominance of pathogenic S. mutans within a mixed-species system. The establishment of a 3D-matrix and EPS-enmeshed microcolonies were largely mediated by the S. mutans gtfB/gtfC genes, expression of which was enhanced in the presence of Actinomyces naeslundii and Streptococcus oralis. Acidic pockets were found only in the interiors of bacterial-islets that are protected by EPS, which impedes rapid neutralization by buffer (pH 7.0). As a result, regions of low pH (<5.5) were detected at specific locations along the surface of attachment. Resistance to chlorhexidine was enhanced in cells within EPS-microcolony complexes compared to those outside such structures within the biofilm. Our results illustrate the critical interaction between matrix architecture and p

  20. Fair play doesn't matter: MEP modulation as a neurophysiological signature of status quo bias in economic interactions.

    PubMed

    Pisoni, Alberto; Lo Gerfo, Emanuele; Ottone, Stefania; Ponzano, Ferruccio; Zarri, Luca; Vergallito, Alessandra; Romero Lauro, Leonor Josefina

    2014-11-01

    quo, in the block in which the status quo maintenance occurred more often. Data support the hypothesis that the economic meaning of the observed actions differently modulates MEP amplitude, pointing at an influence on MF exerted by a peculiar interaction between economic outcomes and variation of the subjects' initial status quo. PMID:24983714

  1. Fair play doesn't matter: MEP modulation as a neurophysiological signature of status quo bias in economic interactions.

    PubMed

    Pisoni, Alberto; Lo Gerfo, Emanuele; Ottone, Stefania; Ponzano, Ferruccio; Zarri, Luca; Vergallito, Alessandra; Romero Lauro, Leonor Josefina

    2014-11-01

    quo, in the block in which the status quo maintenance occurred more often. Data support the hypothesis that the economic meaning of the observed actions differently modulates MEP amplitude, pointing at an influence on MF exerted by a peculiar interaction between economic outcomes and variation of the subjects' initial status quo.

  2. The "ram effect": new insights into neural modulation of the gonadotropic axis by male odors and socio-sexual interactions.

    PubMed

    Fabre-Nys, Claude; Kendrick, Keith M; Scaramuzzi, Rex J

    2015-01-01

    Reproduction in mammals is controlled by the hypothalamo-pituitary-gonadal (HPG) axis under the influence of external and internal factors such as photoperiod, stress, nutrition, and social interactions. Sheep are seasonal breeders and stop mating when day length is increasing (anestrus). However, interactions with a sexually active ram during this period can override the steroid negative feedback responsible for the anoestrus state, stimulate luteinizing hormone (LH) secretion and eventually reinstate cyclicity. This is known as the "ram effect" and research into the mechanisms underlying it is shedding new light on HPG axis regulation. The first step in the ram effect is increased LH pulsatile secretion in anestrus ewes exposed to a sexually active male or only to its fleece, the latter finding indicating a "pheromone-like" effect. Estradiol secretion increases in all ewes and this eventually induces a LH surge and ovulation, just as during the breeding season. An exception is a minority of ewes that exhibit a precocious LH surge (within 4 h) with no prior increase in estradiol. The main olfactory system and the cortical nucleus of the amygdala are critical brain structures in mediating the ram effect since it is blocked by their inactivation. Sexual experience is also important since activation (increased c-fos expression) in these and other regions is greatly reduced in sexually naïve ewes. In adult ewes kisspeptin neurons in both arcuate and preoptic regions and some preoptic GnRH neurons are activated 2 h after exposure to a ram. Exposure to rams also activates noradrenergic neurons in the locus coeruleus and A1 nucleus and increased noradrenalin release occurs in the posterior preoptic area. Pharmacological modulation of this system modifies LH secretion in response to the male or his odor. Together these results show that the ram effect can be a fruitful model to promote both a better understanding of the neural and hormonal regulation of the HPG axis in

  3. A "Do-It-Yourself" Interactive Bone Structure Module: Development and Evaluation of an Online Teaching Resource

    ERIC Educational Resources Information Center

    Rich, Peter; Guy, Richard

    2013-01-01

    A stand-alone online teaching module was developed to cover an area of musculoskeletal anatomy (structure of bone) found to be difficult by students. The material presented in the module was not formally presented in any other way, thus providing additional time for other curriculum components, but it was assessed in the final examination. The…

  4. Prefrontal activity during working memory is modulated by the interaction of variation in CB1 and COX2 coding genes and correlates with frequency of cannabis use.

    PubMed

    Taurisano, Paolo; Antonucci, Linda A; Fazio, Leonardo; Rampino, Antonio; Romano, Raffaella; Porcelli, Annamaria; Masellis, Rita; Colizzi, Marco; Quarto, Tiziana; Torretta, Silvia; Di Giorgio, Annabella; Pergola, Giulio; Bertolino, Alessandro; Blasi, Giuseppe

    2016-08-01

    The CB1 cannabinoid receptor is targeted in the brain by endocannabinoids under physiological conditions as well as by delta9-tetrahydrocannabinol under cannabis use. Furthermore, its signaling appears to affect brain cognitive processing. Recent findings highlight a crucial role of cyclooxygenase-2 (COX-2) in the mechanism of intraneuronal CB1 signaling transduction, while others indicate that two single nucleotide polymorphisms (SNPs) (rs1406977 and rs20417) modulate expression of CB1 (CNR1) and COX-2 (PTGS2) coding genes, respectively. Here, our aim was to use fMRI to investigate in healthy humans whether these SNPs interact in modulating prefrontal activity during working memory processing and if this modulation is linked with cannabis use. We recruited 242 healthy subjects genotyped for CNR1 rs1406977 and PTGS2 rs20417 that performed the N-back working memory task during fMRI and were interviewed using the Cannabis Experience Questionnaire (CEQ). We found that the interaction between CNR1 rs1406977 and PTGS2 rs20417 is associated with dorsolateral prefrontal cortex (DLPFC) activity such that specific genotype configurations (CNR1 C carriers/PTGS2 C carriers and CNR1 TT/PTGS2 GG) predict lower cortical response versus others in spite of similar behavioral accuracy. Furthermore, DLPFC activity in the cluster associated with the CNR1 by PTGS2 interaction was negatively correlated with behavioral efficiency and positively correlated with frequency of cannabis use in cannabis users. These results suggest that a genetically modulated balancing of signaling within the CB1-COX-2 pathway may reflect on more or less efficient patterns of prefrontal activity during working memory. Frequency of cannabis use may be a factor for further modulation of CNR1/PTGS2-mediated cortical processing associated with this cognitive process. PMID:27261878

  5. A new level of regulation in gluconeogenesis: metabolic state modulates the intracellular localization of aldolase B and its interaction with liver fructose-1,6-bisphosphatase.

    PubMed

    Droppelmann, Cristian A; Sáez, Doris E; Asenjo, Joel L; Yáñez, Alejandro J; García-Rocha, Mar; Concha, Ilona I; Grez, Manuel; Guinovart, Joan J; Slebe, Juan C

    2015-12-01

    Understanding how glucose metabolism is finely regulated at molecular and cellular levels in the liver is critical for knowing its relationship to related pathologies, such as diabetes. In order to gain insight into the regulation of glucose metabolism, we studied the liver-expressed isoforms aldolase B and fructose-1,6-bisphosphatase-1 (FBPase-1), key enzymes in gluconeogenesis, analysing their cellular localization in hepatocytes under different metabolic conditions and their protein-protein interaction in vitro and in vivo. We observed that glucose, insulin, glucagon and adrenaline differentially modulate the intracellular distribution of aldolase B and FBPase-1. Interestingly, the in vitro protein-protein interaction analysis between aldolase B and FBPase-1 showed a specific and regulable interaction between them, whereas aldolase A (muscle isozyme) and FBPase-1 showed no interaction. The affinity of the aldolase B and FBPase-1 complex was modulated by intermediate metabolites, but only in the presence of K(+). We observed a decreased association constant in the presence of adenosine monophosphate, fructose-2,6-bisphosphate, fructose-6-phosphate and inhibitory concentrations of fructose-1,6-bisphosphate. Conversely, the association constant of the complex increased in the presence of dihydroxyacetone phosphate (DHAP) and non-inhibitory concentrations of fructose-1,6-bisphosphate. Notably, in vivo FRET studies confirmed the interaction between aldolase B and FBPase-1. Also, the co-expression of aldolase B and FBPase-1 in cultured cells suggested that FBPase-1 guides the cellular localization of aldolase B. Our results provide further evidence that metabolic conditions modulate aldolase B and FBPase-1 activity at the cellular level through the regulation of their interaction, suggesting that their association confers a catalytic advantage for both enzymes. PMID:26417114

  6. A new level of regulation in gluconeogenesis: metabolic state modulates the intracellular localization of aldolase B and its interaction with liver fructose-1,6-bisphosphatase.

    PubMed

    Droppelmann, Cristian A; Sáez, Doris E; Asenjo, Joel L; Yáñez, Alejandro J; García-Rocha, Mar; Concha, Ilona I; Grez, Manuel; Guinovart, Joan J; Slebe, Juan C

    2015-12-01

    Understanding how glucose metabolism is finely regulated at molecular and cellular levels in the liver is critical for knowing its relationship to related pathologies, such as diabetes. In order to gain insight into the regulation of glucose metabolism, we studied the liver-expressed isoforms aldolase B and fructose-1,6-bisphosphatase-1 (FBPase-1), key enzymes in gluconeogenesis, analysing their cellular localization in hepatocytes under different metabolic conditions and their protein-protein interaction in vitro and in vivo. We observed that glucose, insulin, glucagon and adrenaline differentially modulate the intracellular distribution of aldolase B and FBPase-1. Interestingly, the in vitro protein-protein interaction analysis between aldolase B and FBPase-1 showed a specific and regulable interaction between them, whereas aldolase A (muscle isozyme) and FBPase-1 showed no interaction. The affinity of the aldolase B and FBPase-1 complex was modulated by intermediate metabolites, but only in the presence of K(+). We observed a decreased association constant in the presence of adenosine monophosphate, fructose-2,6-bisphosphate, fructose-6-phosphate and inhibitory concentrations of fructose-1,6-bisphosphate. Conversely, the association constant of the complex increased in the presence of dihydroxyacetone phosphate (DHAP) and non-inhibitory concentrations of fructose-1,6-bisphosphate. Notably, in vivo FRET studies confirmed the interaction between aldolase B and FBPase-1. Also, the co-expression of aldolase B and FBPase-1 in cultured cells suggested that FBPase-1 guides the cellular localization of aldolase B. Our results provide further evidence that metabolic conditions modulate aldolase B and FBPase-1 activity at the cellular level through the regulation of their interaction, suggesting that their association confers a catalytic advantage for both enzymes.

  7. The simulation of complete 11 and 12 year modulation cycles for cosmic rays in the heliosphere using a drift model with global merged interaction regions

    NASA Technical Reports Server (NTRS)

    Le Roux, J. A.; Potgieter, M. S.

    1995-01-01

    Two-dimensional, time-dependent drift models have done exceptionally well in explaining major modulation features, especially during the A less than 0 magnetic polarity cycle of the heliospheric magnetic field when positively charge particles are drifting in along the heliospheric neutral sheet (HNS). These models were found to do well when the heliospheric 'tilt angles' alpha less than approximately 30 deg (le Roux & Potgeiter). However, they seem to do less well when alpha greater than approximately 30 deg during A less than 0 cycles seem to fail when this happens in A greater than 0 cycles. Progress was made in understanding these phases of the modulation cycle when merged interaction regions (MIRs) were incorporated in time-dependent drift models (Potgieter et al.). It was also explicitly shown that in obtaining large step decreases in cosmic rays, the MIRs had to be global, i.e., having a latitudinal extent of more than approximately 60 deg. Other classes of MIRs, such as local MIRs and co-rotating MIRs were found to be of secondary importance for establishing long-term modulation. In a previous paper we studied the effects of two consecutive, identical global MIRs, together with a changing wavy HNS, on long-term modulation (Potegieter & le Roux). This approach gave a very natural and convincing explanation for the observed step decreases in cosmic-ray modulation. Emphasis was placed in the declining and recovery phases of the 11 yr modulation cycle. In this paper, four consecutive, nonidentical global MIRs, in combination with a varying wavy HNS, were included in our time-dependent drift model in order to do simulations closer to what was observed between 1977 and 1987. By doing this we could model, for the first time, complete 11 and 22 yr cycles in the heliospheric modulation of galactic cosmic-rays, including the solar magnetic polarity reversals.

  8. Extract of Pelargonium sidoides (EPs 7630) displays anti-infective properties by enhanced phagocytosis and differential modulation of host-bacteria interactions.

    PubMed

    Conrad, Andreas; Frank, Uwe

    2008-05-01

    EPs 7630 is an aqueous-ethanolic extract of the roots of PELARGONIUM SIDOIDES that displays well-documented benefits in the treatment of upper respiratory tract infections (URTI). IN VITRO and animal investigations have revealed various anti-infective properties of EPs 7630. The present review sums up recently published IN VITRO investigations that have shown positive effects on the activity of human peripheral blood phagocytes (PBP) and differential modulation of the interactions between group A streptococci and the host's epithelial barrier.

  9. Gene environment interaction in periphery and brain converge to modulate behavioral outcomes: Insights from the SP1 transient early in life interference rat model

    PubMed Central

    Asor, Eyal; Ben-Shachar, Dorit

    2016-01-01

    It is generally assumed that behavior results from an interaction between susceptible genes and environmental stimuli during critical life stages. The present article reviews the main theoretical and practical concepts in the research of gene environment interaction, emphasizing the need for models simulating real life complexity. We review a novel approach to study gene environment interaction in which a brief post-natal interference with the expression of multiple genes, by hindering the activity of the ubiquitous transcription factor specificity protein 1 (Sp1) is followed by later-in-life exposure of rats to stress. Finally, this review discusses the role of peripheral processes in behavioral responses, with the Sp1 model as one example demonstrating how specific behavioral patterns are linked to modulations in both peripheral and central physiological processes. We suggest that models, which take into account the tripartite reciprocal interaction between the central nervous system, peripheral systems and environmental stimuli will advance our understanding of the complexity of behavior.

  10. Nutrimetabonomics:applications for nutritional sciences, with specific reference to gut microbial interactions.

    PubMed

    Claus, Sandrine P; Swann, Jonathan R

    2013-01-01

    Understanding the role of the diet in determining human health and disease is one major objective of modern nutrition. Mammalian biocomplexity necessitates the incorporation of systems biology technologies into contemporary nutritional research. Metabonomics is a powerful approach that simultaneously measures the low-molecular-weight compounds in a biological sample, enabling the metabolic status of a biological system to be characterized. Such biochemical profiles contain latent information relating to inherent parameters, such as the genotype, and environmental factors, including the diet and gut microbiota. Nutritional metabonomics, or nutrimetabonomics, is being increasingly applied to study molecular interactions between the diet and the global metabolic system. This review discusses three primary areas in which nutrimetabonomics has enjoyed successful application in nutritional research: the illumination of molecular relationships between nutrition and biochemical processes; elucidation of biomarker signatures of food components for use in dietary surveillance; and the study of complex trans-genomic interactions between the mammalian host and its resident gut microbiome. Finally, this review illustrates the potential for nutrimetabonomics in nutritional science as an indispensable tool to achieve personalized nutrition.

  11. Altered CYP2C9 Activity Following Modulation of CYP3A4 Levels in Human Hepatocytes: an Example of Protein-Protein Interactions

    PubMed Central

    Tweedie, Donald J.; Chan, Tom S.; Tracy, Timothy S.

    2014-01-01

    Cytochrome P450 (P450) protein-protein interactions resulting in modulation of enzyme activities have been well documented using recombinant isoforms. This interaction has been less clearly demonstrated in a more physiologic in vitro system such as human hepatocytes. As an expansion of earlier work (Subramanian et al., 2010), in which recombinant CYP2C9 activity decreased with increasing levels of CYP3A4, the current study modulated CYP3A4 content in human hepatocytes to determine the impact on CYP2C9. Modulation of CYP3A4 levels in situ was enabled by the use of a long-term human hepatocyte culture model (HepatoPac) shown to retain phenotypic hepatocyte function over a number of weeks. The extended period of culture allowed time for knockdown of CYP3A4 protein by small interfering RNA (siRNA) with subsequent recovery, as well as upregulation through induction with a recovery period. CYP3A4 gene silencing resulted in a 60% decrease in CYP3A4 activity and protein levels with a concomitant 74% increase in CYP2C9 activity, with no change in CYP2C9 mRNA levels. Upon removal of siRNA, both CYP2C9 and CYP3A4 activities returned to pre-knockdown levels. Importantly, modulation of CYP3A4 protein levels had no impact on cytochrome P450 reductase activities or levels. However, the possibility for competition for limiting reductase cannot be ruled out. Interestingly, lowering CYP3A4 levels also increased UDP-glucuronosyltransferase 2B7 activity. These studies clearly demonstrate that alterations in CYP3A4 levels can modulate CYP2C9 activity in situ and suggest that further studies are warranted to evaluate the possible clinical consequences of these findings. PMID:25157098

  12. The interacting MYB75 and KNAT7 transcription factors modulate secondary cell wall deposition both in stems and seed coat in Arabidopsis.

    PubMed

    Bhargava, Apurva; Ahad, Abdul; Wang, Shucai; Mansfield, Shawn D; Haughn, George W; Douglas, Carl J; Ellis, Brian E

    2013-05-01

    The Arabidopsis thaliana KNAT7 (KNOX family) and MYB75 (MYB family) transcription factors were each shown earlier to interact in yeast two-hybrid assays, and to modulate secondary cell wall formation in inflorescence stems. We demonstrate here that their interaction also occurs in vivo, and that specific domains of each protein mediate this process. The participation of these interacting transcription factors in secondary cell wall formation was then extended to the developing seed coat through the use of targeted transcript analysis and SEM in single loss-of-function mutants. Novel genetic and protein-protein interactions of MYB75 and KNAT7 with other transcription factors known to be involved in seed coat regulation were also identified. We propose that a MYB75-associated protein complex is likely to be involved in modulating secondary cell wall biosynthesis in both the Arabidopsis inflorescence stem and seed coat, and that at least some parts of the transcriptional regulatory network in the two tissues are functionally conserved.

  13. Testing the interaction between analytical modules: an example with Roundup Ready® soybean line GTS 40-3-2

    PubMed Central

    2010-01-01

    Background The modular approach to analysis of genetically modified organisms (GMOs) relies on the independence of the modules combined (i.e. DNA extraction and GM quantification). The validity of this assumption has to be proved on the basis of specific performance criteria. Results An experiment was conducted using, as a reference, the validated quantitative real-time polymerase chain reaction (PCR) module for detection of glyphosate-tolerant Roundup Ready® GM soybean (RRS). Different DNA extraction modules (CTAB, Wizard and Dellaporta), were used to extract DNA from different food/feed matrices (feed, biscuit and certified reference material [CRM 1%]) containing the target of the real-time PCR module used for validation. Purity and structural integrity (absence of inhibition) were used as basic criteria that a DNA extraction module must satisfy in order to provide suitable template DNA for quantitative real-time (RT) PCR-based GMO analysis. When performance criteria were applied (removal of non-compliant DNA extracts), the independence of GMO quantification from the extraction method and matrix was statistically proved, except in the case of Wizard applied to biscuit. A fuzzy logic-based procedure also confirmed the relatively poor performance of the Wizard/biscuit combination. Conclusions For RRS, this study recognises that modularity can be generally accepted, with the limitation of avoiding combining highly processed material (i.e. biscuit) with a magnetic-beads system (i.e. Wizard). PMID:20687918

  14. Discovery of novel interacting partners of PSMD9, a proteasomal chaperone: Role of an Atypical and versatile PDZ-domain motif interaction and identification of putative functional modules

    PubMed Central

    Sangith, Nikhil; Srinivasaraghavan, Kannan; Sahu, Indrajit; Desai, Ankita; Medipally, Spandana; Somavarappu, Arun Kumar; Verma, Chandra; Venkatraman, Prasanna

    2014-01-01

    PSMD9 (Proteasome Macropain non-ATPase subunit 9), a proteasomal assembly chaperone, harbors an uncharacterized PDZ-like domain. Here we report the identification of five novel interacting partners of PSMD9 and provide the first glimpse at the structure of the PDZ-domain, including the molecular details of the interaction. We based our strategy on two propositions: (a) proteins with conserved C-termini may share common functions and (b) PDZ domains interact with C-terminal residues of proteins. Screening of C-terminal peptides followed by interactions using full-length recombinant proteins, we discovered hnRNPA1 (an RNA binding protein), S14 (a ribosomal protein), CSH1 (a growth hormone), E12 (a transcription factor) and IL6 receptor as novel PSMD9-interacting partners. Through multiple techniques and structural insights, we clearly demonstrate for the first time that human PDZ domain interacts with the predicted Short Linear Sequence Motif (SLIM) at the C-termini of the client proteins. These interactions are also recapitulated in mammalian cells. Together, these results are suggestive of the role of PSMD9 in transcriptional regulation, mRNA processing and editing, hormone and receptor activity and protein translation. Our proof-of-principle experiments endorse a novel and quick method for the identification of putative interacting partners of similar PDZ-domain proteins from the proteome and for discovering novel functions. PMID:25009770

  15. Dickkopf-1 regulates gastrulation movements by coordinated modulation of Wnt/βcatenin and Wnt/PCP activities, through interaction with the Dally-like homolog Knypek

    PubMed Central

    Caneparo, Luca; Huang, Ya-Lin; Staudt, Nicole; Tada, Masasumi; Ahrendt, Reiner; Kazanskaya, Olga; Niehrs, Christof; Houart, Corinne

    2007-01-01

    Dickkopf-1 (Dkk1) is a secreted protein that negatively modulates the Wnt/βcatenin pathway. Lack of Dkk1 function affects head formation in frog and mice, supporting the idea that Dkk1 acts as a “head inducer” during gastrulation. We show here that lack of Dkk1 function accelerates internalization and rostral progression of the mesendoderm and that gain of function slows down both internalization and convergence extension, indicating a novel role for Dkk1 in modulating these movements. The motility phenotype found in the morphants is not observed in embryos in which the Wnt/βcatenin pathway is overactivated, and that dominant-negative Wnt proteins are not able to rescue the gastrulation movement defect induced by absence of Dkk1. These data strongly suggest that Dkk1 is acting in a βcatenin independent fashion when modulating gastrulation movements. We demonstrate that the glypican 4/6 homolog Knypek (Kny) binds to Dkk1 and that they are able to functionally interact in vivo. Moreover, Dkk1 regulation of gastrulation movements is kny dependent. Kny is a component of the Wnt/planar cell polarity (PCP) pathway. We found that indeed Dkk1 is able to activate this pathway in both Xenopus and zebrafish. Furthermore, concomitant alteration of the βcatenin and PCP activities is able to mimic the morphant accelerated cell motility phenotype. Our data therefore indicate that Dkk1 regulates gastrulation movement through interaction with LRP5/6 and Kny and coordinated modulations of Wnt/βcatenin and Wnt/PCP pathways. PMID:17322405

  16. Electron spin echo modulation study of sodium dodecyl sulfate and dodecyltrimethylammonium bromide micellar solutions in the presence of urea: Evidence for urea interaction at the micellar surface

    SciTech Connect

    Baglioni, P. ); Ferroni, E. ); Kevan, L. )

    1990-05-17

    Electron spin echo studies have been carried out for a series of x-doxylstearic acid (x-DSA, x = 5,7,10,12,16) and 4-octanoyl-2,2,6,6-tetramethylpiperidine-1-oxy (C{sub 8}-TEMPO) spin probes in micellar solutions of anionic sodium dodecyl sulfate (SDS) and cationic dodecyltrimethylammonium bromide (DTAB) in D{sub 2}O and in the presence of 2 or 6 M urea or urea-d{sub 4}. Modulation effects due to the interaction of the unpaired electron with urea and water deuteriums show that urea does not affect the bent conformation of the x-DSA probe in the micelle. The analysis of the deuterium modulation depth and the Fourier transformation of the two-pulse electron spin echo spectra show that urea interacts with the surfactant polar headgroups at the micelle surface. These results support recent molecular dynamics and Monte Carlo calculations of micellar systems and are in agreement with direct interaction of urea at micellar surfaces in which it replaces some water molecules in the surface region.

  17. Two autonomous structural modules in the fimbrial shaft adhesin FimA mediate Actinomyces interactions with streptococci and host cells during oral biofilm development

    SciTech Connect

    Mishra, Arunima; Devarajan, Bharanidharan; Reardon, Melissa E.; Dwivedi, Prabhat; Krishnan, Vengadesan; Cisar, John O.; Das, Asis; Narayana, Sthanam V.L.; Ton-That, Hung

    2011-09-06

    By combining X-ray crystallography and modelling, we describe here the atomic structure of distinct adhesive moieties of FimA, the shaft fimbrillin of Actinomyces type 2 fimbriae, which uniquely mediates the receptor-dependent intercellular interactions between Actinomyces and oral streptococci as well as host cells during the development of oral biofilms. The FimA adhesin is built with three IgG-like domains, each of which harbours an intramolecular isopeptide bond, previously described in several Gram-positive pilins. Genetic and biochemical studies demonstrate that although these isopeptide bonds are dispensable for fimbrial assembly, cell-cell interactions and biofilm formation, they contribute significantly to the proteolytic stability of FimA. Remarkably, FimA harbours two autonomous adhesive modules, which structurally resemble the Staphylococcus aureus Cna B domain. Each isolated module can bind the plasma glycoprotein asialofetuin as well as the polysaccharide receptors present on the surface of oral streptococci and epithelial cells. Thus, FimA should serve as an excellent paradigm for the development of therapeutic strategies and elucidating the precise molecular mechanisms underlying the interactions between cellular receptors and Gram-positive fimbriae.

  18. Protein interaction module-assisted function X (PIMAX) approach to producing challenging proteins including hyperphosphorylated tau and active CDK5/p25 kinase complex.

    PubMed

    Sui, Dexin; Xu, Xinjing; Ye, Xuemei; Liu, Mengyu; Mianecki, Maxwell; Rattanasinchai, Chotirat; Buehl, Christopher; Deng, Xiexiong; Kuo, Min-Hao

    2015-01-01

    Many biomedically critical proteins are underrepresented in proteomics and biochemical studies because of the difficulty of their production in Escherichia coli. These proteins might possess posttranslational modifications vital to their functions, tend to misfold and be partitioned into bacterial inclusion bodies, or act only in a stoichiometric dimeric complex. Successful production of these proteins requires efficient interaction between these proteins and a specific "facilitator," such as a protein-modifying enzyme, a molecular chaperone, or a natural physical partner within the dimeric complex. Here we report the design and application of a protein interaction module-assisted function X (PIMAX) system that effectively overcomes these hurdles. By fusing two proteins of interest to a pair of well-studied protein-protein interaction modules, we were able to potentiate the association of these two proteins, resulting in successful production of an enzymatically active cyclin-dependent kinase complex and hyperphosphorylated tau protein, which is intimately linked to Alzheimer disease. Furthermore, using tau isoforms quantitatively phosphorylated by GSK-3β and CDK5 kinases via PIMAX, we demonstrated the hyperphosphorylation-stimulated tau oligomerization in vitro, paving the way for new Alzheimer disease drug discoveries. Vectors for PIMAX can be easily modified to meet the needs of different applications. This approach thus provides a convenient and modular suite with broad implications for proteomics and biomedical research.

  19. Gene-nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome.

    PubMed

    Phillips, Catherine M; Goumidi, Louisa; Bertrais, Sandrine; Field, Martyn R; Cupples, L Adrienne; Ordovas, Jose M; Defoort, Catherine; Lovegrove, Julie A; Drevon, Christian A; Gibney, Michael J; Blaak, Ellen E; Kiec-Wilk, Beata; Karlstrom, Britta; Lopez-Miranda, Jose; McManus, Ross; Hercberg, Serge; Lairon, Denis; Planells, Richard; Roche, Helen M

    2010-07-01

    Long-chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and triacylglycerol (TAG) synthesis. Disturbance of these pathways may result in dyslipidemia and insulin resistance, hallmarks of the metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genetic determinants of lipid metabolism to affect MetS risk. We investigated the relationship between ACSL1 polymorphisms (rs4862417, rs6552828, rs13120078, rs9997745, and rs12503643) and MetS risk and determined potential interactions with dietary fat in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1,754). GG homozygotes for rs9997745 had increased MetS risk {odds ratio (OR) 1.90 [confidence interval (CI) 1.15, 3.13]; P = 0.01}, displayed elevated fasting glucose (P = 0.001) and insulin concentrations (P = 0.002) and increased insulin resistance (P = 0.03) relative to the A allele carriers. MetS risk was modulated by dietary fat, whereby the risk conferred by GG homozygosity was abolished among individuals consuming either a low-fat (<35% energy) or a high-PUFA diet (>5.5% energy). In conclusion, ACSL1 rs9997745 influences MetS risk, most likely via disturbances in fatty acid metabolism, which was modulated by dietary fat consumption, particularly PUFA intake, suggesting novel gene-nutrient interactions. PMID:20176858

  20. Characterization of Inhibitors and Monoclonal Antibodies That Modulate the Interaction between Plasmodium falciparum Adhesin PfRh4 with Its Erythrocyte Receptor Complement Receptor 1*

    PubMed Central

    Lim, Nicholas T. Y.; Harder, Markus J.; Kennedy, Alexander T.; Lin, Clara S.; Weir, Christopher; Cowman, Alan F.; Call, Melissa J.; Schmidt, Christoph Q.; Tham, Wai-Hong

    2015-01-01

    Plasmodium falciparum parasites must invade red blood cells to survive within humans. Entry into red blood cells is governed by interactions between parasite adhesins and red blood cell receptors. Previously we identified that P. falciparum reticulocyte binding protein-like homologue 4 (PfRh4) binds to complement receptor 1 (CR1) to mediate entry of malaria parasites into human red blood cells. In this report we characterize a collection of anti-PfRh4 monoclonal antibodies and CR1 protein fragments that modulate the interaction between PfRh4 and CR1. We identify an anti-PfRh4 monoclonal that blocks PfRh4-CR1 interaction in vitro, inhibits PfRh4 binding to red blood cells, and as a result abolishes the PfRh4-CR1 invasion pathway in P. falciparum. Epitope mapping of anti-PfRh4 monoclonal antibodies identified distinct functional regions within PfRh4 involved in modulating its interaction with CR1. Furthermore, we designed a set of protein fragments based on extensive mutagenesis analyses of the PfRh4 binding site on CR1 and determined their interaction affinities using surface plasmon resonance. These CR1 protein fragments bind tightly to PfRh4 and also function as soluble inhibitors to block PfRh4 binding to red blood cells and to inhibit the PfRh4-CR1 invasion pathway. Our findings can aid future efforts in designing specific single epitope antibodies to block P. falciparum invasion via complement receptor 1. PMID:26324715

  1. Regulation of β2-adrenergic receptor maturation and anterograde trafficking by an interaction with Rab geranylgeranyltransferase: modulation of Rab geranylgeranylation by the receptor.

    PubMed

    Lachance, Véronik; Cartier, Andréane; Génier, Samuel; Munger, Sandra; Germain, Pascale; Labrecque, Pascale; Parent, Jean-Luc

    2011-11-25

    Previous reports by us and others demonstrated that G protein-coupled receptors interact functionally with Rab GTPases. Here, we show that the β(2)-adrenergic receptor (β(2)AR) interacts with the Rab geranylgeranyltransferase α-subunit (RGGTA). Confocal microscopy showed that β(2)AR co-localizes with RGGTA in intracellular compartments and at the plasma membrane. Site-directed mutagenesis revealed that RGGTA binds to the L(339)L(340) motif in the β(2)AR C terminus known to be involved in the transport of the receptor from the endoplasmic reticulum to the cell surface. Modulation of the cellular levels of RGGTA protein by overexpression or siRNA-mediated knockdown of the endogenous protein demonstrated that RGGTA has a positive role in the maturation and anterograde trafficking of the β(2)AR, which requires the interaction of RGGTA with the β(2)AR L(339)L(340) motif. Furthermore, the β(2)AR modulates the geranylgeranylation of Rab6a, Rab8a, and Rab11a, but not of other Rab proteins tested in this study. Regulation of Rab geranylgeranylation by the β(2)AR was dependent on the RGGTA-interacting L(339)L(340) motif. Interestingly, a RGGTA-Y107F mutant was unable to regulate Rab geranylgeranylation but still promoted β(2)AR maturation, suggesting that RGGTA may have functions independent of Rab geranylgeranylation. We demonstrate for the first time an interaction between a transmembrane receptor and RGGTA which regulates the maturation and anterograde transport of the receptor, as well as geranylgeranylation of Rab GTPases.

  2. The role of merged interaction regions and drafts in the heliospheric modulation of cosmic rays beyond 20 AU - A computer simulation

    NASA Technical Reports Server (NTRS)

    Potgieter, M. S.; Le Roux, J. A.; Burlaga, L. F.; Mcdonald, F. B.

    1993-01-01

    Voyager 2 magnetic field measurements are used to simulate merged interaction and rarefaction regions (MIRs and RRs) for 1985-1989 via numerical solutions of the time-dependent, axially symmetric transport equation of cosmic rays in the heliosphere, together with the concurrent use of the wavy neutral sheet as a time-dependent drift parameter. This drift approach was found to be more successful, because it was able to reproduce the intensity levels, the factor modulation, and latitudinal gradients for 1 GeV protons at 23 AU.

  3. Direct interaction of cellular hnRNP-F and NS1 of influenza A virus accelerates viral replication by modulation of viral transcriptional activity and host gene expression

    SciTech Connect

    Lee, Jun Han; Kim, Sung-Hak; Pascua, Philippe Noriel Q.; Song, Min-Suk; Baek, Yun Hee; Jin, Xun; Choi, Joong-Kook; Kim, Chul-Joong; Kim, Hyunggee; Choi, Young Ki

    2010-02-05

    To investigate novel NS1-interacting proteins, we conducted a yeast two-hybrid analysis, followed by co-immunoprecipitation assays. We identified heterogeneous nuclear ribonucleoprotein F (hnRNP-F) as a cellular protein interacting with NS1 during influenza A virus infection. Co-precipitation assays suggest that interaction between hnRNP-F and NS1 is a common and direct event among human or avian influenza viruses. NS1 and hnRNP-F co-localize in the nucleus of host cells, and the RNA-binding domain of NS1 directly interacts with the GY-rich region of hnRNP-F determined by GST pull-down assays with truncated proteins. Importantly, hnRNP-F expression levels in host cells indicate regulatory role on virus replication. hnRNP-F depletion by small interfering RNA (siRNA) shows 10- to 100-fold increases in virus titers corresponding to enhanced viral RNA polymerase activity. Our results delineate novel mechanism of action by which NS1 accelerates influenza virus replication by modulating normal cellular mRNA processes through direct interaction with cellular hnRNP-F protein.

  4. Alanine-scanning mutagenesis defines a conserved energetic hotspot in the CaVα1 AID-CaVβ interaction site that is critical for channel modulation

    PubMed Central

    Van Petegem, Filip; Duderstadt, Karl E.; Clark, Kimberly A.; Wang, Michelle; Minor, Daniel L.

    2011-01-01

    Voltage-gated calcium channels (CaVs) are large, multisubunit complexes that control cellular calcium entry. CaV pore-forming (CaVα1) and cytoplasmic (CaVβ) subunits associate through a high-affinity interaction between the CaVα1 α-interaction domain (AID) and CaVβ α-binding pocket (ABP). Here, we analyze AID-ABP interaction thermodynamics using isothermal titration calorimetry (ITC). We find that commensurate with their strong sequence similarity, all CaV1 and CaV2 AID peptides bind CaVβ with similar nanomolar affinities. Although the AID-ABP interface encompasses twenty-four sidechains, alanine-scanning mutagenesis reveals that the binding energy is focused in two complementary hotspots comprising four deeply-conserved residues. Electrophysiological experiments show that hotspot interaction disruption prevents trafficking and functional modulation of CaV1.2 by CaVβ. Together, the data support the primacy of the AID-ABP interface for CaVα1-CaVβ association, underscore the idea that hotspots dominate protein-protein interaction affinities, and uncover a target for strategies to control cellular excitability by blocking CaVα1-CaVβ complex formation. PMID:18275819

  5. EWS/FLI and its downstream target NR0B1 interact directly to modulate transcription and oncogenesis in Ewing's sarcoma.

    PubMed

    Kinsey, Michelle; Smith, Richard; Iyer, Anita K; McCabe, Edward R B; Lessnick, Stephen L

    2009-12-01

    Most Ewing's sarcomas harbor chromosomal translocations that encode fusions between EWS and ETS family members. The most common fusion, EWS/FLI, consists of an EWSR1-derived strong transcriptional activation domain fused, in-frame, to the DNA-binding domain-containing portion of FLI1. EWS/FLI functions as an aberrant transcription factor to regulate genes that mediate the oncogenic phenotype of Ewing's sarcoma. One of these regulated genes, NR0B1, encodes a corepressor protein, and likely plays a transcriptional role in tumorigenesis. However, the genes that NR0B1 regulates and the transcription factors it interacts with in Ewing's sarcoma are largely unknown. We used transcriptional profiling and chromatin immunoprecipitation to identify genes that are regulated by NR0B1, and compared these data to similar data for EWS/FLI. Although the transcriptional profile overlapped as expected, we also found that the genome-wide localization of NR0B1 and EWS/FLI overlapped as well, suggesting that they regulate some genes coordinately. Further analysis revealed that NR0B1 and EWS/FLI physically interact. This protein-protein interaction is likely to be relevant for the development of Ewing's sarcoma because mutations in NR0B1 that disrupt the interaction have transcriptional consequences and also abrogate oncogenic transformation. Taken together, these data suggest that EWS/FLI and NR0B1 physically interact, coordinately modulate gene expression, and mediate the transformed phenotype of Ewing's sarcoma. PMID:19920188

  6. Protein-Protein Interactions Modulate the Docking-Dependent E3-Ubiquitin Ligase Activity of Carboxy-Terminus of Hsc70-Interacting Protein (CHIP).

    PubMed

    Narayan, Vikram; Landré, Vivien; Ning, Jia; Hernychova, Lenka; Muller, Petr; Verma, Chandra; Walkinshaw, Malcolm D; Blackburn, Elizabeth A; Ball, Kathryn L

    2015-11-01

    CHIP is a tetratricopeptide repeat (TPR) domain protein that functions as an E3-ubiquitin ligase. As well as linking the molecular chaperones to the ubiquitin proteasome system, CHIP also has a docking-dependent mode where it ubiquitinates native substrates, thereby regulating their steady state levels and/or function. Here we explore the effect of Hsp70 on the docking-dependent E3-ligase activity of CHIP. The TPR-domain is revealed as a binding site for allosteric modulators involved in determining CHIP's dynamic conformation and activity. Biochemical, biophysical and modeling evidence demonstrate that Hsp70-binding to the TPR, or Hsp70-mimetic mutations, regulate CHIP-mediated ubiquitination of p53 and IRF-1 through effects on U-box activity and substrate binding. HDX-MS was used to establish that conformational-inhibition-signals extended from the TPR-domain to the U-box. This underscores inter-domain allosteric regulation of CHIP by the core molecular chaperones. Defining the chaperone-associated TPR-domain of CHIP as a manager of inter-domain communication highlights the potential for scaffolding modules to regulate, as well as assemble, complexes that are fundamental to protein homeostatic control. PMID:26330542

  7. Modulation of Ultrafast Conformational Dynamics in Allosteric Interaction of Gal Repressor Protein with Different Operator DNA Sequences.

    PubMed

    Choudhury, Susobhan; Naiya, Gitashri; Singh, Priya; Lemmens, Peter; Roy, Siddhartha; Pal, Samir Kumar

    2016-04-01

    Although all forms of dynamical behaviour of a protein under allosteric interaction with effectors are predicted, little evidence of ultrafast dynamics in the interaction has been reported. Here, we demonstrate the efficacy of a combined approach involving picosecond-resolved FRET and polarisation-gated fluorescence for the exploration of ultrafast dynamics in the allosteric interaction of the Gal repressor (GalR) protein dimer with DNA operator sequences OE and OI . FRET from the single tryptophan residue to a covalently attached probe IAEDANS at a cysteine residue in the C-terminal domain of GalR shows structural perturbation and conformational dynamics during allosteric interaction. Polarisation-gated fluorescence spectroscopy of IAEDANS and another probe (FITC) covalently attached to the operator directly revealed the essential dynamics for cooperativity in the protein-protein interaction. The ultrafast resonance energy transfer from IAEDANS in the protein to FITC also revealed different dynamic flexibility in the allosteric interaction. An attempt was made to correlate the dynamic changes in the protein dimers with OE and OI with the consequent protein-protein interaction (tetramerisation) to form a DNA loop encompassing the promoter segment.

  8. Integrating Module - NEMS Documentation

    EIA Publications

    2014-01-01

    Provides an overview of the complete National Energy Modeling System (NEMS) model, and includes brief descriptions of the modules with which the Integrating Module interacts. The emphasis and focus, however, is on the structure and function of the Integrating Module of NEMS.

  9. Regulation of the Cav1.2 cardiac channel by redox via modulation of CaM interaction with the channel.

    PubMed

    Sun, Yu; Xu, Jianjun; Minobe, Etsuko; Shimoara, Shoken; Hao, Liying; Kameyama, Masaki

    2015-07-01

    Although it has been well documented that redox can modulate Cav1.2 channel activity, the underlying mechanisms are not fully understood. In our study, we examined the effects of redox on Cav1.2 channel activity and on CaM interaction with the Cav1.2 α1 subunit. Dithiothreitol (DTT, 1 mM) in the cell-attached mode decreased, while hydrogen peroxide (H2O2, 1 mM) increased channel activity to 72 and 303%, respectively. The effects of redox were maintained in the inside-out mode where channel activity was induced by CaM + ATP: DTT (1 mM) decreased, while H2O2 (1 mM) increased the channel activity. These results were mimicked by the thioredoxin and oxidized glutathione system. To test whether the redox state might determine channel activity by affecting the CaM interaction with the channel, we examined the effects of DTT and H2O2 on CaM binding to the N- and C-terminal fragments of the channel. We found that DTT concentration-dependently inhibited CaM binding to the C-terminus (IC50 37 μM), but H2O2 had no effect. Neither DTT nor H2O2 had an effect on CaM interaction with the N-terminus. These results suggest that redox-mediated regulation of the Cav1.2 channel is governed, at least partially, by modulation of the CaM interaction with the channel.

  10. SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells

    PubMed Central

    Myers, Samuel A; Peddada, Sailaja; Chatterjee, Nilanjana; Friedrich, Tara; Tomoda, Kiichrio; Krings, Gregor; Thomas, Sean; Maynard, Jason; Broeker, Michael; Thomson, Matthew; Pollard, Katherine; Yamanaka, Shinya; Burlingame, Alma L; Panning, Barbara

    2016-01-01

    The transcription factor SOX2 is central in establishing and maintaining pluripotency. The processes that modulate SOX2 activity to promote pluripotency are not well understood. Here, we show SOX2 is O-GlcNAc modified in its transactivation domain during reprogramming and in mouse embryonic stem cells (mESCs). Upon induction of differentiation SOX2 O-GlcNAcylation at serine 248 is decreased. Replacing wild type with an O-GlcNAc-deficient SOX2 (S248A) increases reprogramming efficiency. ESCs with O-GlcNAc-deficient SOX2 exhibit alterations in gene expression. This change correlates with altered protein-protein interactions and genomic occupancy of the O-GlcNAc-deficient SOX2 compared to wild type. In addition, SOX2 O-GlcNAcylation impairs the SOX2-PARP1 interaction, which has been shown to regulate ESC self-renewal. These findings show that SOX2 activity is modulated by O-GlcNAc, and provide a novel regulatory mechanism for this crucial pluripotency transcription factor. DOI: http://dx.doi.org/10.7554/eLife.10647.001 PMID:26949256

  11. SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells.

    PubMed

    Myers, Samuel A; Peddada, Sailaja; Chatterjee, Nilanjana; Friedrich, Tara; Tomoda, Kiichrio; Krings, Gregor; Thomas, Sean; Maynard, Jason; Broeker, Michael; Thomson, Matthew; Pollard, Katherine; Yamanaka, Shinya; Burlingame, Alma L; Panning, Barbara

    2016-03-07

    The transcription factor SOX2 is central in establishing and maintaining pluripotency. The processes that modulate SOX2 activity to promote pluripotency are not well understood. Here, we show SOX2 is O-GlcNAc modified in its transactivation domain during reprogramming and in mouse embryonic stem cells (mESCs). Upon induction of differentiation SOX2 O-GlcNAcylation at serine 248 is decreased. Replacing wild type with an O-GlcNAc-deficient SOX2 (S248A) increases reprogramming efficiency. ESCs with O-GlcNAc-deficient SOX2 exhibit alterations in gene expression. This change correlates with altered protein-protein interactions and genomic occupancy of the O-GlcNAc-deficient SOX2 compared to wild type. In addition, SOX2 O-GlcNAcylation impairs the SOX2-PARP1 interaction, which has been shown to regulate ESC self-renewal. These findings show that SOX2 activity is modulated by O-GlcNAc, and provide a novel regulatory mechanism for this crucial pluripotency transcription factor.

  12. Artificial neural network-based exploration of gene-nutrient interactions in folate and xenobiotic metabolic pathways that modulate susceptibility to breast cancer.

    PubMed

    Naushad, Shaik Mohammad; Ramaiah, M Janaki; Pavithrakumari, Manickam; Jayapriya, Jaganathan; Hussain, Tajamul; Alrokayan, Salman A; Gottumukkala, Suryanarayana Raju; Digumarti, Raghunadharao; Kutala, Vijay Kumar

    2016-04-15

    In the current study, an artificial neural network (ANN)-based breast cancer prediction model was developed from the data of folate and xenobiotic pathway genetic polymorphisms along with the nutritional and demographic variables to investigate how micronutrients modulate susceptibility to breast cancer. The developed ANN model explained 94.2% variability in breast cancer prediction. Fixed effect models of folate (400 μg/day) and B12 (6 μg/day) showed 33.3% and 11.3% risk reduction, respectively. Multifactor dimensionality reduction analysis showed the following interactions in responders to folate: RFC1 G80A × MTHFR C677T (primary), COMT H108L × CYP1A1 m2 (secondary), MTR A2756G (tertiary). The interactions among responders to B12 were RFC1G80A × cSHMT C1420T and CYP1A1 m2 × CYP1A1 m4. ANN simulations revealed that increased folate might restore ER and PR expression and reduce the promoter CpG island methylation of extra cellular superoxide dismutase and BRCA1. Dietary intake of folate appears to confer protection against breast cancer through its modulating effects on ER and PR expression and methylation of EC-SOD and BRCA1. PMID:26784656

  13. Artificial neural network-based exploration of gene-nutrient interactions in folate and xenobiotic metabolic pathways that modulate susceptibility to breast cancer.

    PubMed

    Naushad, Shaik Mohammad; Ramaiah, M Janaki; Pavithrakumari, Manickam; Jayapriya, Jaganathan; Hussain, Tajamul; Alrokayan, Salman A; Gottumukkala, Suryanarayana Raju; Digumarti, Raghunadharao; Kutala, Vijay Kumar

    2016-04-15

    In the current study, an artificial neural network (ANN)-based breast cancer prediction model was developed from the data of folate and xenobiotic pathway genetic polymorphisms along with the nutritional and demographic variables to investigate how micronutrients modulate susceptibility to breast cancer. The developed ANN model explained 94.2% variability in breast cancer prediction. Fixed effect models of folate (400 μg/day) and B12 (6 μg/day) showed 33.3% and 11.3% risk reduction, respectively. Multifactor dimensionality reduction analysis showed the following interactions in responders to folate: RFC1 G80A × MTHFR C677T (primary), COMT H108L × CYP1A1 m2 (secondary), MTR A2756G (tertiary). The interactions among responders to B12 were RFC1G80A × cSHMT C1420T and CYP1A1 m2 × CYP1A1 m4. ANN simulations revealed that increased folate might restore ER and PR expression and reduce the promoter CpG island methylation of extra cellular superoxide dismutase and BRCA1. Dietary intake of folate appears to confer protection against breast cancer through its modulating effects on ER and PR expression and methylation of EC-SOD and BRCA1.

  14. Combined effects of potassium chloride and ethanol as mobile phase modulators on hydrophobic interaction and reversed-phase chromatography of three insulin variants.

    PubMed

    Johansson, Karolina; Frederiksen, Søren S; Degerman, Marcus; Breil, Martin P; Mollerup, Jørgen M; Nilsson, Bernt

    2015-02-13

    The two main chromatographic modes based on hydrophobicity, hydrophobic interaction chromatography (HIC) and reversed-phase chromatography (RPC), are widely used for both analytical and preparative chromatography of proteins in the pharmaceutical industry. Despite the extensive application of these separation methods, and the vast amount of studies performed on HIC and RPC over the decades, the underlying phenomena remain elusive. As part of a systematic study of the influence of mobile phase modulators in hydrophobicity-based chromatography, we have investigated the effects of both KCl and ethanol on the retention of three insulin variants on two HIC adsorbents and two RPC adsorbents. The focus was on the linear adsorption range, separating the modulator effects from the capacity effects, but some complementary experiments at higher load were included to further investigate observed phenomena. The results show that the modulators have the same effect on the two RPC adsorbents in the linear range, indicating that the modulator concentration only affects the activity of the solute in the mobile phase, and not that of the solute-ligand complex, or that of the ligand. Unfortunately, the HIC adsorbents did not show the same behavior. However, the insulin variants displayed a strong tendency toward self-association on both HIC adsorbents; on one in particular. Since this causes peak fronting, the retention is affected, and this could probably explain the lack of congruity. This conclusion was supported by the results from the non-linear range experiments which were indicative of double-layer adsorption on the HIC adsorbents, while the RPC adsorbents gave the anticipated increased tailing at higher load.

  15. Heat shock partially dissociates the overlapping modules of the yeast protein-protein interaction network: a systems level model of adaptation.

    PubMed

    Mihalik, Ágoston; Csermely, Peter

    2011-10-01

    Network analysis became a powerful tool giving new insights to the understanding of cellular behavior. Heat shock, the archetype of stress responses, is a well-characterized and simple model of cellular dynamics. S. cerevisiae is an appropriate model organism, since both its protein-protein interaction network (interactome) and stress response at the gene expression level have been well characterized. However, the analysis of the reorganization of the yeast interactome during stress has not been investigated yet. We calculated the changes of the interaction-weights of the yeast interactome from the changes of mRNA expression levels upon heat shock. The major finding of our study is that heat shock induced a significant decrease in both the overlaps and connections of yeast interactome modules. In agreement with this the weighted diameter of the yeast interactome had a 4.9-fold increase in heat shock. Several key proteins of the heat shock response became centers of heat shock-induced local communities, as well as bridges providing a residual connection of modules after heat shock. The observed changes resemble to a 'stratus-cumulus' type transition of the interactome structure, since the unstressed yeast interactome had a globally connected organization, similar to that of stratus clouds, whereas the heat shocked interactome had a multifocal organization, similar to that of cumulus clouds. Our results showed that heat shock induces a partial disintegration of the global organization of the yeast interactome. This change may be rather general occurring in many types of stresses. Moreover, other complex systems, such as single proteins, social networks and ecosystems may also decrease their inter-modular links, thus develop more compact modules, and display a partial disintegration of their global structure in the initial phase of crisis. Thus, our work may provide a model of a general, system-level adaptation mechanism to environmental changes. PMID:22022244

  16. Heat shock partially dissociates the overlapping modules of the yeast protein-protein interaction network: a systems level model of adaptation.

    PubMed

    Mihalik, Ágoston; Csermely, Peter

    2011-10-01

    Network analysis became a powerful tool giving new insights to the understanding of cellular behavior. Heat shock, the archetype of stress responses, is a well-characterized and simple model of cellular dynamics. S. cerevisiae is an appropriate model organism, since both its protein-protein interaction network (interactome) and stress response at the gene expression level have been well characterized. However, the analysis of the reorganization of the yeast interactome during stress has not been investigated yet. We calculated the changes of the interaction-weights of the yeast interactome from the changes of mRNA expression levels upon heat shock. The major finding of our study is that heat shock induced a significant decrease in both the overlaps and connections of yeast interactome modules. In agreement with this the weighted diameter of the yeast interactome had a 4.9-fold increase in heat shock. Several key proteins of the heat shock response became centers of heat shock-induced local communities, as well as bridges providing a residual connection of modules after heat shock. The observed changes resemble to a 'stratus-cumulus' type transition of the interactome structure, since the unstressed yeast interactome had a globally connected organization, similar to that of stratus clouds, whereas the heat shocked interactome had a multifocal organization, similar to that of cumulus clouds. Our results showed that heat shock induces a partial disintegration of the global organization of the yeast interactome. This change may be rather general occurring in many types of stresses. Moreover, other complex systems, such as single proteins, social networks and ecosystems may also decrease their inter-modular links, thus develop more compact modules, and display a partial disintegration of their global structure in the initial phase of crisis. Thus, our work may provide a model of a general, system-level adaptation mechanism to environmental changes.

  17. Dynamic modulation of spatially structured polarization fields for real-time control of ultrafast laser-material interactions.

    PubMed

    Jin, Y; Allegre, O J; Perrie, W; Abrams, K; Ouyang, J; Fearon, E; Edwardson, S P; Dearden, G

    2013-10-21

    The polarization state of an ultrafast laser is dynamically controlled using two Spatial Light Modulators and additional waveplates. Consequently, four states of polarization, linear horizontal and vertical, radial and azimuthal, all with a ring intensity distribution, were dynamically switched at a frequency ν = 12.5 Hz while synchronized with a motion control system. This technique, demonstrated here for the first time, enables a remarkable level of real-time control of the properties of light waves and applied to real-time surface patterning, shows that highly controlled nanostructuring is possible. Laser ablation of Induced Periodic Surface Structures is used to directly verify the state of polarization at the focal plane.

  18. Gene environment interaction in periphery and brain converge to modulate behavioral outcomes: Insights from the SP1 transient early in life interference rat model.

    PubMed

    Asor, Eyal; Ben-Shachar, Dorit

    2016-09-22

    It is generally assumed that behavior results from an interaction between susceptible genes and environmental stimuli during critical life stages. The present article reviews the main theoretical and practical concepts in the research of gene environment interaction, emphasizing the need for models simulating real life complexity. We review a novel approach to study gene environment interaction in which a brief post-natal interference with the expression of multiple genes, by hindering the activity of the ubiquitous transcription factor specificity protein 1 (Sp1) is followed by later-in-life exposure of rats to stress. Finally, this review discusses the role of peripheral processes in behavioral responses, with the Sp1 model as one example demonstrating how specific behavioral patterns are linked to modulations in both peripheral and central physiological processes. We suggest that models, which take into account the tripartite reciprocal interaction between the central nervous system, peripheral systems and environmental stimuli will advance our understanding of the complexity of behavior. PMID:27679768

  19. Gene environment interaction in periphery and brain converge to modulate behavioral outcomes: Insights from the SP1 transient early in life interference rat model

    PubMed Central

    Asor, Eyal; Ben-Shachar, Dorit

    2016-01-01

    It is generally assumed that behavior results from an interaction between susceptible genes and environmental stimuli during critical life stages. The present article reviews the main theoretical and practical concepts in the research of gene environment interaction, emphasizing the need for models simulating real life complexity. We review a novel approach to study gene environment interaction in which a brief post-natal interference with the expression of multiple genes, by hindering the activity of the ubiquitous transcription factor specificity protein 1 (Sp1) is followed by later-in-life exposure of rats to stress. Finally, this review discusses the role of peripheral processes in behavioral responses, with the Sp1 model as one example demonstrating how specific behavioral patterns are linked to modulations in both peripheral and central physiological processes. We suggest that models, which take into account the tripartite reciprocal interaction between the central nervous system, peripheral systems and environmental stimuli will advance our understanding of the complexity of behavior. PMID:27679768

  20. A lipoprotein lipase gene polymorphism interacts with consumption of alcohol and unsaturated fat to modulate serum HDL-cholesterol concentrations.

    PubMed

    Baik, Inkyung; Lee, Seungku; Kim, Seong Hwan; Shin, Chol

    2013-10-01

    There are limited data from prospective studies regarding interactions between lipoprotein lipase gene (LPL) and lifestyle factors in association with HDL-cholesterol (HDL-C) concentrations, a biomarker of coronary heart disease risk. Our prospective cohort study investigated the interactive effects of a common LPL polymorphism and lifestyle factors, including obesity, smoking, alcohol consumption, physical activity, and dietary intake, on follow-up measurements of HDL-C and triglyceride (TG) concentrations. A total of 5314 Korean men and women aged 40-69 y participated in the study. Serum HDL-C and TG concentrations were measured in all participants at baseline and 6-y follow-up examinations. On the basis of genome-wide association data for HDL-C and TG concentrations, we selected the most significant polymorphism (rs10503669), which was in high linkage disequilibrium with the serine 447 stop (S447×) mutation (D' = 0.99) of LPL. We found that carrying the T allele reflecting the LPL ×447 allele was positively associated with follow-up measurement of HDL-C concentrations (P < 0.001). In the linear regression model adjusted for baseline HDL-C concentration and potential risk factors, we observed interactive effects of the polymorphism and consumption of alcohol (P-interaction < 0.01) and unsaturated fat (P-interaction < 0.05) on follow-up measurement of HDL-C concentrations. We also observed interactive effects of the polymorphism and body mass index (P-interaction < 0.01) on follow-up measurement of TG concentrations after adjusting for the baseline level and potential risk factors. Our findings suggest that carriers of the LPL ×447 allele benefit from moderate alcohol consumption and a diet high in unsaturated fat to minimize reduction of blood HDL-C concentrations and that obese persons who do not carry the LPL ×447 allele need to control body weight to prevent hypertriglyceridemia.

  1. Modulating the Copper-Sulfur Interaction in Type 1 Blue Copper Azurin by Replacing Cys112 with Nonproteinogenic Homocysteine

    PubMed Central

    Clark, Kevin M; Yu, Yang; Blackburn, Ninian; Lu, Yi

    2014-01-01

    The Cu-SCys interaction is known to play a dominant role in defining the type 1 (T1) blue copper center with respect to both its electronic structure and electron transfer function. Despite this importance, its role has yet to be probed by mutagenesis studies without dramatic change of its T1 copper character. We herein report replacement of the conserved Cys112 in azurin with the nonproteinogenic amino acid homocysteine. Based on electronic absorption, electron paramagnetic resonance, and extended x-ray absorption fine structural spectroscopic studies, this variant displays typical type 1 copper site features. Surprisingly, instead of increasing the strength of the Cu-sulfur interaction by the introduction of the extra methylene group, the Cys112Hcy azurin showed a decrease in the covalent interaction between SHcy and Cu(II) when compared with the WT SCys-Cu(II) interaction. This is likely due to geometric adjustment of the center that resulted in the copper ion moving out of the trigonal plane defined by two histidines and one Hcy and closer to Met121. These structural changes resulted in an increase of reduction potential by 35 mV, consistent with lower Cu-S covalency. These results suggest that the Cu-SCys interaction is close to being optimal in native blue copper protein. It also demonstrates the power of using nonproteinogenic amino acids in addressing important issues in bioinorganic chemistry. PMID:24707355

  2. Rapeseed calcineurin B-like protein CBL4, interacting with CBL-interacting protein kinase CIPK24, modulates salt tolerance in plants.

    PubMed

    Liu, Wu-Zhen; Deng, Min; Li, Liang; Yang, Bo; Li, Hongwei; Deng, Hanqing; Jiang, Yuan-Qing

    2015-11-20

    Calcium is a ubiquitous intracellular secondary messenger in eukaryotes. Upon stress challenge, cytosolic Ca(2+) fluctuation could be sensed and bound by calcineurin B-like proteins (CBLs), which further regulate a group of Ser/Thr protein kinases called CBL-interacting protein kinases (CIPKs) to relay the signal and induce cellular responses. Although the CBL-CIPK network has been demonstrated to play crucial roles in plant development and responses to various environmental stresses in Arabidopsis, little is known about their function in rapeseed. In the present study, we characterized CBL4 gene from rapeseed. We found that CBL4 is localized at the plasma membrane and it interacted with CIPK24 in both yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays. Unlike the orthologs in Arabidopsis, rapeseed CIPK24 did not interact with CBL10. Furthermore, expression of rapeseed CBL4 rescued the salt-sensitive phenotype of sos3-1 mutant and overexpression of rapeseed CBL4 in Arabidopsis showed enhanced tolerance of salt stress than wild-type. Overall, the results clarified the function of CBL4 in rapeseed.

  3. Modulation of kinase-inhibitor interactions by auxiliary protein binding: Crystallography studies on Aurora A interactions with VX-680 and with TPX2

    SciTech Connect

    Zhao, Baoguang; Smallwood, Angela; Yang, Jingsong; Koretke, Kristin; Nurse, Kelvin; Calamari, Amy; Kirkpatrick, Robert B.; Lai, Zhihong

    2008-10-24

    VX-680, also known as MK-0457, is an ATP-competitive small molecule inhibitor of the Aurora kinases that has entered phase II clinical trials for the treatment of cancer. We have solved the cocrystal structure of AurA/TPX2/VX-680 at 2.3 {angstrom} resolution. In the crystal structure, VX-680 binds to the active conformation of AurA. The glycine-rich loop in AurA adopts a unique bent conformation, forming a {pi}-{pi} interaction with the phenyl group of VX-680. In contrast, in the published AurA/VX-680 structure, VX-680 binds to AurA in the inactive conformation, interacting with a hydrophobic pocket only present in the inactive conformation. These data suggest that TPX2, a protein cofactor, can alter the binding mode of VX-680 with AurA. More generally, the presence of physiologically relevant cofactor proteins can alter the kinetics, binding interactions, and inhibition of enzymes, and studies with these multiprotein complexes may be beneficial to the discovery and optimization of enzyme inhibitors as therapeutic agents.

  4. Dynamic interaction of SARAF with STIM1 and Orai1 to modulate store-operated calcium entry

    PubMed Central

    Albarran, Letizia; Lopez, Jose J.; Amor, Nidhal Ben; Martin-Cano, Francisco E.; Berna-Erro, Alejandro; Smani, Tarik; Salido, Gines M.; Rosado, Juan A.

    2016-01-01

    Ca2+ influx by store-operated Ca2+ channels is a major mechanism for intracellular Ca2+ homeostasis and cellular function. Here we present evidence for the dynamic interaction between the SOCE-associated regulatory factor (SARAF), STIM1 and Orai1. SARAF overexpression attenuated SOCE and the STIM1-Orai1 interaction in cells endogenously expressing STIM1 and Orai1 while RNAi-mediated SARAF silencing induced opposite effects. SARAF impaired the association between Orai1 and the Orai1-activating small fragment of STIM1 co-expressed in the STIM1-deficient NG115-401L cells. Cell treatment with thapsigargin or physiological agonists results in direct association of SARAF with Orai1. STIM1-independent interaction of SARAF with Orai1 leads to activation of this channel. In cells endogenously expressing STIM1 and Orai1, Ca2+ store depletion leads to dissociation of SARAF with STIM1 approximately 30s after treatment with thapsigargin, which paralleled the increase in SARAF-Orai1 interaction, followed by reinteraction with STIM1 and dissociation from Orai1. Co-expression of SARAF and either Orai1 or various N-terminal deletion Orai1 mutants did not alter SARAF-Orai1 interaction; however, expression of C-terminal deletion Orai1 mutants or blockade of the C-terminus of Orai1 impair the interaction with SARAF. These observations suggest that SARAF exerts an initial positive role in the activation of SOCE followed by the facilitation of SCDI of Orai1. PMID:27068144

  5. Calibration methodology for a dual-ended readout silicon photomultiplier based depth-of-interaction PET detector module

    SciTech Connect

    Xi, Wenze; McKisson, John E.; Weisenberger, Andrew G.; Lee, Seung Joon; Taylor, William Mark; Stepanyan, Armenak; Zorn, Carl J.

    2012-11-01

    We developed a novel calibration methodology for a PET detector with dual-ended readout of an LYSO array by two silicon photomultipliers (SiPMs). By introducing a detector gain balancing step in the calibration process, improved depth-of-interaction calibration uniformity and accuracy can be achieved. The entire calibration process has four steps: scintillation crystal array mappings for two SiPM readouts, detector gain balancing, energy calibration, and depth-of-interaction calibration. This document provides a detailed description on the detector calibration system setup.

  6. Kaposi's sarcoma-associated herpesvirus noncoding polyadenylated nuclear RNA interacts with virus- and host cell-encoded proteins and suppresses expression of genes involved in immune modulation.

    PubMed

    Rossetto, Cyprian C; Pari, Gregory S

    2011-12-01

    During lytic infection, Kaposi's sarcoma-associated herpesvirus (KSHV) expresses a polyadenylated nuclear RNA (PAN RNA). This noncoding RNA (ncRNA) is localized to the nucleus and is the most abundant viral RNA during lytic infection; however, to date, the role of PAN RNA in the virus life cycle is unknown. Many examples exist where ncRNAs have a defined key regulatory function controlling gene expression by various mechanisms. Our goal for this study was to identify putative binding partners for PAN RNA in an effort to elucidate a possible function for the transcript in KSHV infection. We employed an in vitro affinity protocol where PAN RNA was used as bait for factors present in BCBL-1 cell nuclear extract to show that PAN RNA interacts with several virus- and host cell-encoded factors, including histones H1 and H2A, mitochondrial and cellular single-stranded binding proteins (SSBPs), and interferon regulatory factor 4 (IRF4). RNA chromatin immunoprecipitation (ChIP) assays confirmed that PAN RNA interacted with these factors in the infected cell environment. A luciferase reporter assay showed that PAN RNA expression interfered with the ability of IRF4/PU.1 to activate the interleukin-4 (IL-4) promoter, strongly suggesting a role for PAN RNA in immune modulation. Since the proteomic screen and functional data suggested a role in immune responses, we investigated if constitutive PAN RNA expression could affect other genes involved in immune responses. PAN RNA expression decreased expression of gamma interferon, interleukin-18, alpha interferon 16, and RNase L. These data strongly suggest that PAN RNA interacts with viral and cellular proteins and can function as an immune modulator. PMID:21957289

  7. Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation*

    PubMed Central

    Monsellier, Elodie; Redeker, Virginie; Ruiz-Arlandis, Gemma; Bousset, Luc; Melki, Ronald

    2015-01-01

    The aggregation of polyglutamine (polyQ)-containing proteins is at the origin of nine neurodegenerative diseases. Molecular chaperones prevent the aggregation of polyQ-containing proteins. The exact mechanism by which they interact with polyQ-containing, aggregation-prone proteins and interfere with their assembly is unknown. Here we dissect the mechanism of interaction between a huntingtin exon 1 fragment of increasing polyQ lengths (HttEx1Qn), the aggregation of which is tightly associated with Huntington's disease, and molecular chaperone Hsc70. We show that Hsc70, together with its Hsp40 co-chaperones, inhibits HttEx1Qn aggregation and modifies the structural, seeding, and infectious properties of the resulting fibrils in a polyQ-independent manner. We demonstrate that Hsc70 binds the 17-residue-long N-terminal flank of HttEx1Qn, and we map Hsc70-HttEx1Qn surface interfaces at the residue level. Finally, we show that this interaction competes with homotypic interactions between the N termini of different HttEx1Qn molecules that trigger the aggregation process. Our results lay the foundations of future therapeutic strategies targeting huntingtin aggregation in Huntington disease. PMID:25505179

  8. SARM modulates MyD88-mediated TLR activation through BB-loop dependent TIR-TIR interactions.

    PubMed

    Carlsson, Emil; Ding, Jeak Ling; Byrne, Bernadette

    2016-02-01

    Toll-like receptors (TLRs) recognise invading pathogens and initiate an innate immune response by recruiting intracellular adaptor proteins via heterotypic Toll/interleukin-1 receptor (TIR) domain interactions. Of the five TIR domain-containing adaptor proteins identified, Sterile α- and armadillo-motif-containing protein (SARM) is functionally unique; suppressing immune signalling instead of promoting it. Here we demonstrate that the recombinantly expressed and purified SARM TIR domain interacts with both the major human TLR adaptors, MyD88 and TRIF. A single glycine residue located in the BB-loop of the SARM TIR domain, G601, was identified as essential for interaction. A short peptide derived from this motif was also found to interact with MyD88 in vitro. SARM expression in HEK293 cells was found to significantly suppress lipopolysaccharide (LPS)-mediated upregulation of inflammatory cytokines, IL-8 and TNF-α, an effect lost in the G601A mutant. The same result was observed with cytokine activation initiated by MyD88 expression and stimulation of TLR2 with lipoteichoic acid (LTA), suggesting that SARM is capable of suppressing both TRIF- and MyD88- dependent TLR signalling. Our findings indicate that SARM acts on a broader set of target proteins than previously thought, and that the BB-loop motif is functionally important, giving further insight into the endogenous mechanisms used to suppress inflammation in immune cells. PMID:26592460

  9. Interactions between Brainstem Noradrenergic Neurons and the Nucleus Accumbens Shell in Modulating Memory for Emotionally Arousing Events

    ERIC Educational Resources Information Center

    Kerfoot, Erin C.; Williams, Cedric L.

    2011-01-01

    The nucleus accumbens shell (NAC) receives axons containing dopamine-[beta]-hydroxylase that originate from brainstem neurons in the nucleus of the solitary tract (NTS). Recent findings show that memory enhancement produced by stimulating NTS neurons after learning may involve interactions with the NAC. However, it is unclear whether these…

  10. Cfh genotype interacts with dietary glycemic index to modulate age-related macular degeneration-like features in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Age-related macular degeneration (AMD) is a leading cause of visual impairment worldwide. Genetics and diet contribute to the relative risk for developing AMD, but their interactions are poorly understood. Genetic variations in Complement Factor H (CFH), and dietary glycemic index (GI) are major ris...

  11. Modulation of the summer hydrological cycle evolution over western Europe by anthropogenic aerosols and soil-atmosphere interactions

    NASA Astrophysics Data System (ADS)

    Boé, J.

    2016-07-01

    Large decadal variations in solar radiation at surface have been observed over Europe for 60 years. These variations might have impacted the hydrological cycle, through a modulation of the energy available for evapotranspiration. Here a large ensemble of climate models is analyzed to characterize the impacts of anthropogenic aerosols on the hydrological cycle over western Europe in summer and the associated uncertainties. Some models simulate strong aerosols-driven changes in evapotranspiration and also precipitation on the historical period, while other models show virtually no impact. These opposed responses are largely determined by two seemingly independent properties of the models: the magnitude of the impact of anthropogenic aerosols on solar radiation and whether evapotranspiration is predominantly water or energy limited. Both properties, characterized on the past climate, are highly uncertain in current climate models and continue to impact the evolution of the hydrological cycle through the 21st century.

  12. Human Mitochondrial Ribosomal Protein MRPL12 Interacts Directly with Mitochondrial RNA Polymerase to Modulate Mitochondrial Gene Expression*

    PubMed Central

    Wang, Zhibo; Cotney, Justin; Shadel, Gerald S.

    2008-01-01

    The core human mitochondrial transcription machinery comprises a single subunit bacteriophage-related RNA polymerase, POLRMT, the high mobility group box DNA-binding protein h-mtTFA/TFAM, and two transcriptional co-activator proteins, h-mtTFB1 and h-mtTFB2 that also have rRNA methyltransferase activity. Recapitulation of specific initiation of transcription in vitro can be achieved by a complex of POLRMT, h-mtTFA, and either h-mtTFB1 or h-mtTFB2. However, the nature of mitochondrial transcription complexes in vivo and the potential involvement of additional proteins in the transcription process in human mitochondria have not been extensively investigated. In Saccharomyces cerevisiae, transcription and translation are physically coupled via the formation of a multiprotein complex nucleated by the binding of Nam1p to the amino-terminal domain of mtRNA polymerase (Rpo41p). This model system paradigm led us to search for proteins that interact with POLRMT to regulate mitochondrial gene expression in humans. Using an affinity capture strategy to identify POLRMT-binding proteins, we identified mitochondrial ribosomal protein L7/L12 (MRPL12) as a protein in HeLa mitochondrial extracts that interacts specifically with POLRMT in vitro. Purified recombinant MRPL12 binds to POLRMT and stimulates mitochondrial transcription activity in vitro, demonstrating that this interaction is both direct and functional. Finally, from HeLa cells that overexpress FLAG epitope-tagged MRPL12, increased steady-state levels of mtDNA-encoded transcripts are observed and MRPL12-POLRMT complexes can be co-immunoprecipitated, providing strong evidence that this interaction enhances mitochondrial transcription or RNA stability in vivo. We speculate that the MRPL12 interaction with POLRMT is likely part of a novel regulatory mechanism that coordinates mitochondrial transcription with translation and/or ribosome biogenesis during human mitochondrial gene expression. PMID:17337445

  13. Hepatocyte Growth Factor Modulates MET Receptor Tyrosine Kinase and β-Catenin Functional Interactions to Enhance Synapse Formation

    PubMed Central

    Xie, Zhihui; Eagleson, Kathie L.

    2016-01-01

    MET, a pleiotropic receptor tyrosine kinase implicated in autism risk, influences multiple neurodevelopmental processes. There is a knowledge gap, however, in the molecular mechanism through which MET mediates developmental events related to disorder risk. In the neocortex, MET is expressed transiently during periods of peak dendritic outgrowth and synaptogenesis, with expression enriched at developing synapses, consistent with demonstrated roles in dendritic morphogenesis, modulation of spine volume, and excitatory synapse development. In a recent coimmunoprecipitation/mass spectrometry screen, β-catenin was identified as part of the MET interactome in developing neocortical synaptosomes. Here, we investigated the influence of the MET/β-catenin complex in mouse neocortical synaptogenesis. Western blot analysis confirms that MET and β-catenin coimmunoprecipitate, but N-cadherin is not associated with the MET complex. Following stimulation with hepatocyte growth factor (HGF), β-catenin is phosphorylated at tyrosine142 (Y142) and dissociates from MET, accompanied by an increase in β-catenin/N-cadherin and MET/synapsin 1 protein complexes. In neocortical neurons in vitro, proximity ligation assays confirmed the close proximity of these proteins. Moreover, in neurons transfected with synaptophysin-GFP, HGF stimulation increases the density of synaptophysin/bassoon (a presynaptic marker) and synaptophysin/PSD-95 (a postsynaptic marker) clusters. Mutation of β-catenin at Y142 disrupts the dissociation of the MET/β-catenin complex and prevents the increase in clusters in response to HGF. The data demonstrate a new mechanism for the modulation of synapse formation, whereby MET activation induces an alignment of presynaptic and postsynaptic elements that are necessary for assembly and formation of functional synapses by subsets of neocortical neurons that express MET/β-catenin complex.

  14. Hepatocyte Growth Factor Modulates MET Receptor Tyrosine Kinase and β-Catenin Functional Interactions to Enhance Synapse Formation.

    PubMed

    Xie, Zhihui; Eagleson, Kathie L; Wu, Hsiao-Huei; Levitt, Pat

    2016-01-01

    MET, a pleiotropic receptor tyrosine kinase implicated in autism risk, influences multiple neurodevelopmental processes. There is a knowledge gap, however, in the molecular mechanism through which MET mediates developmental events related to disorder risk. In the neocortex, MET is expressed transiently during periods of peak dendritic outgrowth and synaptogenesis, with expression enriched at developing synapses, consistent with demonstrated roles in dendritic morphogenesis, modulation of spine volume, and excitatory synapse development. In a recent coimmunoprecipitation/mass spectrometry screen, β-catenin was identified as part of the MET interactome in developing neocortical synaptosomes. Here, we investigated the influence of the MET/β-catenin complex in mouse neocortical synaptogenesis. Western blot analysis confirms that MET and β-catenin coimmunoprecipitate, but N-cadherin is not associated with the MET complex. Following stimulation with hepatocyte growth factor (HGF), β-catenin is phosphorylated at tyrosine(142) (Y142) and dissociates from MET, accompanied by an increase in β-catenin/N-cadherin and MET/synapsin 1 protein complexes. In neocortical neurons in vitro, proximity ligation assays confirmed the close proximity of these proteins. Moreover, in neurons transfected with synaptophysin-GFP, HGF stimulation increases the density of synaptophysin/bassoon (a presynaptic marker) and synaptophysin/PSD-95 (a postsynaptic marker) clusters. Mutation of β-catenin at Y142 disrupts the dissociation of the MET/β-catenin complex and prevents the increase in clusters in response to HGF. The data demonstrate a new mechanism for the modulation of synapse formation, whereby MET activation induces an alignment of presynaptic and postsynaptic elements that are necessary for assembly and formation of functional synapses by subsets of neocortical neurons that express MET/β-catenin complex. PMID:27595133

  15. Hepatocyte Growth Factor Modulates MET Receptor Tyrosine Kinase and β-Catenin Functional Interactions to Enhance Synapse Formation.

    PubMed

    Xie, Zhihui; Eagleson, Kathie L; Wu, Hsiao-Huei; Levitt, Pat

    2016-01-01

    MET, a pleiotropic receptor tyrosine kinase implicated in autism risk, influences multiple neurodevelopmental processes. There is a knowledge gap, however, in the molecular mechanism through which MET mediates developmental events related to disorder risk. In the neocortex, MET is expressed transiently during periods of peak dendritic outgrowth and synaptogenesis, with expression enriched at developing synapses, consistent with demonstrated roles in dendritic morphogenesis, modulation of spine volume, and excitatory synapse development. In a recent coimmunoprecipitation/mass spectrometry screen, β-catenin was identified as part of the MET interactome in developing neocortical synaptosomes. Here, we investigated the influence of the MET/β-catenin complex in mouse neocortical synaptogenesis. Western blot analysis confirms that MET and β-catenin coimmunoprecipitate, but N-cadherin is not associated with the MET complex. Following stimulation with hepatocyte growth factor (HGF), β-catenin is phosphorylated at tyrosine(142) (Y142) and dissociates from MET, accompanied by an increase in β-catenin/N-cadherin and MET/synapsin 1 protein complexes. In neocortical neurons in vitro, proximity ligation assays confirmed the close proximity of these proteins. Moreover, in neurons transfected with synaptophysin-GFP, HGF stimulation increases the density of synaptophysin/bassoon (a presynaptic marker) and synaptophysin/PSD-95 (a postsynaptic marker) clusters. Mutation of β-catenin at Y142 disrupts the dissociation of the MET/β-catenin complex and prevents the increase in clusters in response to HGF. The data demonstrate a new mechanism for the modulation of synapse formation, whereby MET activation induces an alignment of presynaptic and postsynaptic elements that are necessary for assembly and formation of functional synapses by subsets of neocortical neurons that express MET/β-catenin complex.

  16. Hepatocyte Growth Factor Modulates MET Receptor Tyrosine Kinase and β-Catenin Functional Interactions to Enhance Synapse Formation

    PubMed Central

    Xie, Zhihui; Eagleson, Kathie L.

    2016-01-01

    MET, a pleiotropic receptor tyrosine kinase implicated in autism risk, influences multiple neurodevelopmental processes. There is a knowledge gap, however, in the molecular mechanism through which MET mediates developmental events related to disorder risk. In the neocortex, MET is expressed transiently during periods of peak dendritic outgrowth and synaptogenesis, with expression enriched at developing synapses, consistent with demonstrated roles in dendritic morphogenesis, modulation of spine volume, and excitatory synapse development. In a recent coimmunoprecipitation/mass spectrometry screen, β-catenin was identified as part of the MET interactome in developing neocortical synaptosomes. Here, we investigated the influence of the MET/β-catenin complex in mouse neocortical synaptogenesis. Western blot analysis confirms that MET and β-catenin coimmunoprecipitate, but N-cadherin is not associated with the MET complex. Following stimulation with hepatocyte growth factor (HGF), β-catenin is phosphorylated at tyrosine142 (Y142) and dissociates from MET, accompanied by an increase in β-catenin/N-cadherin and MET/synapsin 1 protein complexes. In neocortical neurons in vitro, proximity ligation assays confirmed the close proximity of these proteins. Moreover, in neurons transfected with synaptophysin-GFP, HGF stimulation increases the density of synaptophysin/bassoon (a presynaptic marker) and synaptophysin/PSD-95 (a postsynaptic marker) clusters. Mutation of β-catenin at Y142 disrupts the dissociation of the MET/β-catenin complex and prevents the increase in clusters in response to HGF. The data demonstrate a new mechanism for the modulation of synapse formation, whereby MET activation induces an alignment of presynaptic and postsynaptic elements that are necessary for assembly and formation of functional synapses by subsets of neocortical neurons that express MET/β-catenin complex. PMID:27595133

  17. SlTPR1, a tomato tetratricopeptide repeat protein, interacts with the ethylene receptors NR and LeETR1, modulating ethylene and auxin responses and development

    PubMed Central

    Lin, Zhefeng; Arciga-Reyes, Luis; Zhong, Silin; Alexander, Lucy; Hackett, Rachel; Wilson, Ian; Grierson, Don

    2008-01-01

    The gaseous hormone ethylene is perceived by a family of ethylene receptors which interact with the Raf-like kinase CTR1. SlTPR1 encodes a novel TPR (tetratricopeptide repeat) protein from tomato that interacts with the ethylene receptors NR and LeETR1 in yeast two-hybrid and in vitro protein interaction assays. SlTPR1 protein with a GFP fluorescent tag was localized in the plasmalemma and nuclear membrane in Arabidopsis, and SlTPR1-CFP and NR-YFP fusion proteins were co-localized in the plasmalemma and nuclear membrane following co-bombardment of onion cells. Overexpression of SlTPR1 in tomato resulted in ethylene-related pleiotropic effects including reduced stature, delayed and reduced production of inflorescences, abnormal and infertile flowers with degenerate styles and pollen, epinasty, reduced apical dominance, inhibition of abscission, altered leaf morphology, and parthenocarpic fruit. Similar phenotypes were seen in Arabidopsis overexpressing SlTPR1. SlTPR1 overexpression did not increase ethylene production but caused enhanced accumulation of mRNA from the ethylene responsive gene ChitB and the auxin-responsive gene SlSAUR1-like, and reduced expression of the auxin early responsive gene LeIAA9, which is known to be inhibited by ethylene and to be associated with parthenocarpy. Cuttings from the SlTPR1-overexpressors produced fewer adventitious roots and were less responsive to indole butyric acid. It is suggested that SlTPR1 overexpression enhances a subset of ethylene and auxin responses by interacting with specific ethylene receptors. SlTPR1 shares features with human TTC1, which interacts with heterotrimeric G-proteins and Ras, and competes with Raf-1 for Ras binding. Models for SlTPR1 action are proposed involving modulation of ethylene signalling or receptor levels. PMID:19036844

  18. SlTPR1, a tomato tetratricopeptide repeat protein, interacts with the ethylene receptors NR and LeETR1, modulating ethylene and auxin responses and development.

    PubMed

    Lin, Zhefeng; Arciga-Reyes, Luis; Zhong, Silin; Alexander, Lucy; Hackett, Rachel; Wilson, Ian; Grierson, Don

    2008-01-01

    The gaseous hormone ethylene is perceived by a family of ethylene receptors which interact with the Raf-like kinase CTR1. SlTPR1 encodes a novel TPR (tetratricopeptide repeat) protein from tomato that interacts with the ethylene receptors NR and LeETR1 in yeast two-hybrid and in vitro protein interaction assays. SlTPR1 protein with a GFP fluorescent tag was localized in the plasmalemma and nuclear membrane in Arabidopsis, and SlTPR1-CFP and NR-YFP fusion proteins were co-localized in the plasmalemma and nuclear membrane following co-bombardment of onion cells. Overexpression of SlTPR1 in tomato resulted in ethylene-related pleiotropic effects including reduced stature, delayed and reduced production of inflorescences, abnormal and infertile flowers with degenerate styles and pollen, epinasty, reduced apical dominance, inhibition of abscission, altered leaf morphology, and parthenocarpic fruit. Similar phenotypes were seen in Arabidopsis overexpressing SlTPR1. SlTPR1 overexpression did not increase ethylene production but caused enhanced accumulation of mRNA from the ethylene responsive gene ChitB and the auxin-responsive gene SlSAUR1-like, and reduced expression of the auxin early responsive gene Le